Evidence Report/Technology Assessment 

Number 143 

Management of Small Cell Lung Cancer 

Prepared for: 

Agency for Healthcare Research and Quality 

U.S. Department of Health and Human Services 

540 Gaither Road 

Rockville, MD 20850 

www.ahrq.gov 

Contract No. 290-02-0026 

Prepared by: 

Blue Cross and Blue Shield Association Technology Evaluation Center 

Evidence-Based Practice Center, Chicago, Illinois 

Investigators 

Jerome Seidenfeld, Ph.D. 

David J. Samson 

Claudia Bonnell, R.N., M.L.S. 

Kathleen M. Ziegler, Pharm.D. 

Naomi Aronson, Ph.D. 

AHRQ Publication No. 06-E016 

July 2006
This report is based on research conducted by the Blue Cross and Blue Shield Association 

Technology Evaluation Center Evidence-based Practice Center (EPC) under contract to the 

Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-02-

0026). The findings and conclusions in this document are those of the author(s) who are 

responsible for its content, and do not necessarily represent the views of AHRQ. No statement 

in this report should be construed as an official position of AHRQ or of the U.S. Department of 

Health and Human Services. 

The information in this report is intended to help clinicians, employers, policymakers, and others 

make informed decisions about the provision of health care services. This report is intended as a 

reference and not as a substitute for clinical judgment. 

This report may be used, in whole or in part, as the basis for development of clinical practice 

guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage 

policies. AHRQ or U.S. Department of Health and Human Services endorsement of such 

derivative products may not be stated or implied. 
ii

This document is in the public domain and may be used and reprinted without permission except 

those copyrighted materials noted for which further reproduction is prohibited without the 

specific permission of copyright holders. 

Suggested Citation: 

Seidenfeld J, Samson DJ, Bonnell CJ, Ziegler KM, Aronson N. Management of Small Cell Lung 

Cancer. Evidence Report/Technology Assessment No. 143. (Prepared by Blue Cross and Blue 

Shield Association Technology Evaluation Center Evidence-based Practice Center under 

Contract No. 290-02-0026.) AHRQ Publication No. 06-E016. Rockville, MD: Agency for 

Healthcare Research and Quality. July 2006. 

No investigators have any affiliations or financial involvement (e.g., employment, 

consultancies, honoraria, or stock options, expert testimony, grants, or patients 

received or pending, or royalties) that conflict with material presented in this report. 
iii

Preface 

 The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based 

Practice Centers (EPCs), sponsors the development of evidence reports and technology 

assessments to assist public- and private-sector organizations in their efforts to improve the 

quality of health care in the United States. The reports and assessments provide organizations 

with comprehensive, science-based information on common, costly medical conditions and new 

health care technologies. The EPCs systematically review the relevant scientific literature on 

topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to 

developing their reports and assessments. 

 To bring the broadest range of experts into the development of evidence reports and health 

technology assessments, AHRQ encourages the EPCs to form partnerships and enter into 

collaborations with other medical and research organizations. The EPCs work with these partner 

organizations to ensure that the evidence reports and technology assessments they produce will 

become building blocks for health care quality improvement projects throughout the Nation. The 

reports undergo peer review prior to their release. 

 AHRQ expects that the EPC evidence reports and technology assessments will inform 

individual health plans, providers, and purchasers as well as the health care system as a whole by 

providing important information to help improve health care quality. 

 We welcome comments on this evidence report. They may be sent by mail to the Task Order 

Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, 

Rockville, MD 20850, or by e-mail to epc@ahrq.hhs.gov. 

Carolyn M. Clancy, M.D. 

Director 

Agency for Healthcare Research and Quality 

Jean Slutsky, P.A., M.S.P.H. 

Director, Center for Outcomes and Evidence 

Agency for Healthcare Research and Quality 

William F. Lawrence, M.D., M.S. 

EPC Program Task Order Officer 

Agency for Healthcare Research and Quality 

Beth A. Collins Sharp, Ph.D., R. N. 

Director, EPC Program 

Agency for Healthcare Research and Quality 
iv

Acknowledgments 

The research team would like to acknowledge the efforts of Maxine A.Gere, M.S., for general 

editorial assistance and program support; Carol Gold-Boyd for administrative support; Mark D. 

Grant, M.D., M.P.H., and Thomas A. Ratko, Ph.D., for fact-checking; Tracey Perez, R.N., J.D., 

for program support; and William F. Lawrence, M.D., M.S., of the Agency for Healthcare 

Research and Quality for advice as our Task Order Officer.
v

Structured Abstract 

Objectives: This is a systematic review of evidence on issues in managing small cell lung 

cancer (SCLC). Key questions addressed are: the sequence, timing and dosing characteristics of 

primary thoracic radiotherapy (TRTx) for limited-stage disease; primary TRTx for extensivestage disease; effect of prophylactic cranial irradiation (PCI); positron emission tomography 

(PET) for staging; treatment of mixed histology tumors; surgery; and second- and subsequentline treatment for relapsed/progressive disease. 

Data Sources: MEDLINE®, EMBASE, and the Cochrane Register 

Review Methods: The review methods were defined prospectively in a written protocol. We 

sought randomized controlled trials that compared the interventions of interest. Where 

randomized trials were limited or nonexistent, we sought additional studies. We performed 

meta-analysis of studies that compared early and late TRTx. 

Results: The strongest evidence available for this Report is a patient-level meta-analysis 

showing that PCI improves survival of SCLC patients who achieved complete response 

following primary therapy from 15.3 percent to 20.7 percent (p=0.01). No other question 

yielded evidence so robust. The case for concurrent over sequential radiation delivery rests 

largely on a single multicenter trial. Support for early concurrent therapy comes from one 

multicenter trial, but two other multicenter trials found no advantage. Our meta-analysis did not 

find significant reductions in 2- and 3-year mortality for early TRTx. Favorable results from a 

single-center trial on TRTx for extensive stage disease need replication in a multicenter setting. 

For other questions (i.e., management of mixed histology disease; surgery for early limited 

SCLC), relevant comparative studies were nonexistent. PET may be more sensitive in detecting 

disease outside the brain than conventional staging modalities, but studies were of poor quality 

and reliable estimates of performance are not possible. 

Conclusions: PCI improves survival among those with a complete response to primary therapy. 

A research agenda is needed to optimize the effectiveness of TRTx and its components. PET for 

staging may be useful, but its role awaits clarification by rigorous studies. No relevant evidence 

was available to address management of mixed histology disease or surgery for early limited 

SCLC.

vii

Contents 

 

Executive Summary...............................................................................................................1 

Evidence Report 

Chapter 1. Introduction ........................................................................................................9 

 Objective of Systematic Review......................................................................................9 

 Epidemiology and Public Health Impact of Small Cell Lung Cancer.............................9 

 Current Staging and Treatment Strategies for Small Cell Lung Cancer..........................9 

 Staging and Classification...........................................................................................9 

 Treatment Strategies ...................................................................................................10 

 Key Questions for this Systematic Review......................................................................14 

Chapter 2. Methods...............................................................................................................17 

 Peer Review........ ...........................................................................................................17 

Study Selection Criteria ...................................................................................................17 

 Types of Studies...........................................................................................................17 

 Types of Participants....................................................................................................18 

 Types of Interventions .................................................................................................18 

 Types of Outcomes ......................................................................................................19 

 Search Strategy and Review ............................................................................................20 

 Search Strategy. ...............................................................................................................20 

 Search Screen..................................................................................................................20 

 Data Extraction and Analysis...........................................................................................21

 Data Elements... ..........................................................................................................21 

 Evidence Tables...........................................................................................................23 

 Assessment of Study Quality...........................................................................................23 

 Therapeutic Studies......................................................................................................23 

 Diagnostic Studies .......................................................................................................23 

 Definitions of Ratings Based on Criteria.....................................................................24 

 Meta-Analysis................................................................................................................25 

Chapter 3. Results ..................................................................................................................27 

 Key Question 1.... ...........................................................................................................27 

 Overview...................................................................................................................27 

 Concurrent vs. Sequential ............................................................................................27 

 Alternating vs. Sequential............................................................................................36 

 Alternating vs. Concurrent...........................................................................................38 

 Early Alternating vs. Late Alternating.........................................................................39 

 Conclusions................................................................................................................40 

 Key Question 2.... ...........................................................................................................41 

 Overview...................................................................................................................41 

 Results......................................................................................................................46 

 Conclusions................................................................................................................48 
viii

 Meta-Analysis/Meta-Regression......................................................................................52 

 Overview...................................................................................................................52 

 Conclusions................................................................................................................65 

 Key Question 3.... ...........................................................................................................65 

 Overview...................................................................................................................66 

 Results......................................................................................................................67 

 Conclusions................................................................................................................73 

 Key Question 4.... ...........................................................................................................73 

 Overview...................................................................................................................73 

 Results......................................................................................................................79 

 Conclusions................................................................................................................83 

 Key Question 5..... ..........................................................................................................83 

 Overview...................................................................................................................83 

 Results......................................................................................................................86 

 Conclusions................................................................................................................91 

 Key Question 6.... ...........................................................................................................91 

 Overview...................................................................................................................92 

 Study Populations ........................................................................................................96 

 Diagnostic Accuracy....................................................................................................96 

 Staging Accuracy.........................................................................................................98 

 Changes in Patient Management..................................................................................98 

 Conclusions................................................................................................................100 

 Key Question 7.... ...........................................................................................................101 

 Overview...................................................................................................................101 

 Results......................................................................................................................102 

 Conclusions................................................................................................................103 

 Key Question 8.... ...........................................................................................................103 

 Overview...................................................................................................................103 

 Randomized, Controlled Trials....................................................................................112 

 Nonrandomized Comparisons......................................................................................112 

 Adverse Events.. ..........................................................................................................113 

 Conclusions................................................................................................................113 

 Key Question 9.... ...........................................................................................................114 

 Overview...................................................................................................................114 

 Randomized, Controlled Trials....................................................................................114 

 Overview of Outcomes ................................................................................................123 

 Phase II Trial Evidence................................................................................................129 

 Conclusions................................................................................................................131 

Chapter 4. Conclusions ..........................................................................................................133 

Chapter 5. Discussion/Future Research .................................................................................139 

References and Included Studies ...........................................................................................143 
ix

List of Acronyms/Abbreviations............................................................................................151 

Figures 

Figure 1. Quorum Flow Diagram..........................................................................................21 

Figure 2. Two-Year Mortality Funnel Plot, Early vs. Late Thoracic Radiotherapy for 

 Limited Stage Small-Cell Lung Cancer................................................................53 

Figure 3. Two-Year Mortality Random Effects Forest Plot, Early vs. Late Thoracic 

 Radiotherapy for Limited Stage Small-Cell Lung Cancer, All Trials ...................55 

Figure 4. Two-Year Mortality Random Effects Influence Plot, Early vs. Late Thoracic 

 Radiotherapy for Limited Stage Small-Cell Lung Cancer.....................................56 

Figure 5. Three-Year Mortality Funnel Plot, Early vs. Late Thoracic Radiotherapy for 

 Limited Stage Small-Cell Lung Cancer.................................................................59 

Figure 6. Three-Year Mortality Fixed Effects Forest Plot, Early vs. Late Thoracic 

 Radiotherapy for Limited Stage Small-Cell Lung Cancer....................................61 

Figure 7. Three-Year Mortality Fixed Effects Influence Plot, Early vs. Late Thoracic 

 Radiotherapy for Limited Stage Small-Cell Lung Cancer....................................62 

Summary Tables 

Table 1. Alternatives for combined chemotherapy and radiation to treat Limited 

 SCLC....................................................................................................................13 

Table 2. Overall Summary of Question 1 Trials................................................................28 

Table 3. Sample and Treatments: Alternating, Concurrent, or Sequential 

 Radiotherapy........................................................................................................29 

Table 4. Survival Outcomes: Alternating, Concurrent and Sequential Radiotherapy .......32 

Table 5. Adverse Events: Alternating, Concurrent, or Sequential Radiotherapy ..............33 

Table 6. Adverse Events Reported in Takada and Park Trials ..........................................36 

Table 7. Adverse Events Reported in Gregor and Sun Trial .............................................38 

Table 8. Adverse Events Reported in Lebeau Trial...........................................................39 

Table 9. Adverse Events Reported in Work Trial..............................................................40 

Table 10. Selected study parameters of RCTs comparing times to give concurrent 

 TRTx....................................................................................................................42 

Table 11. Sample and Methods: Early Versus Late Radiotherapy .....................................43 

Table 12. Survival Outcomes: Early Versus Late Radiotherapy .........................................47 

Table 13. Adverse Events: Early Versus Late Concurrent TRTx........................................48 

Table 14. Adverse Events: Early Versus Late Radiotherapy..............................................49 

Table 15. Egger Linear Regression Test for Publication Bias, 2-Year Mortality................53 

Table 16. Individual Trial 2-Year Mortality Relative Risks, Confidence 

 Intervals and Covariate Matrix ............................................................................54 

Table 17. Results from Heterogeneity Tests and Random Effects Meta-Analysis..............54 

Table 18. Results of Subgroup/Sensitivity Analyses, Two-Year Mortality ........................57 

Table 19. Results of Meta-Regression.................................................................................58 

Table 20. Egger Linear Regression Test for Publication Bias, 3Year Mortality.................59 
x

Table 21. Individual Trial 3-Year Mortality Relative Risks, Confidence Intervals 

 and Covariate Matrix ...........................................................................................60 

Table 22. Results from Heterogeneity Tests and Fixed Effects Meta-Analysis..................60 

Table 23. Results of Subgroup/Sensitivity Analyses, Three-Year Mortality ......................63 

Table 24. Results of Meta-Regression.................................................................................63 

Table 25. Summary of Published Meta-Analyses on Early Versus Late Thoracic 

 Radiation Therapy for Limited-Stage Small-Cell Lung Cancer..........................64 

Table 26. Selected Study Characteristics Of Rcts Comparing One Versus Two 

 Fractions Per Day.................................................................................................66 

Table 27. Sample and Methods: Alternative Fractionations Schemes 

 (once versus twice daily) .....................................................................................69 

Table 28. Survival Outcomes: Alternative Fractionations Schemes 

 (once versus twice daily) .....................................................................................70 

Table 29. Adverse Events: Alternative Fractionations Schemes 

 (once versus twice daily) .....................................................................................71 

Table 30. Selected Characteristics of RCTs Comparing Chemotherapy 

 with versus without TRTx ...................................................................................76

Table 31. Sample and Methods: Chemotherapy with versus without 

 Thoracic Radiation Therapy, Extensive Stage Disease (ESD) ............................77 

Table 32. Survival Outcomes: Chemotherapy with versus without 

 Thoracic Radiation Therapy, Extensive Stage Disease (ESD) ............................80 

Table 33. Adverse Events: Chemotherapy with versus without 

 Thoracic Radiation Therapy, Extensive Stage Disease (ESD) ............................81 

Table 34. RCTs of PCI versus no PCI for SCLC in CR......................................................85 

Table 35. Meta-analytic Results for Efficacy Outcomes Reported 

 in the Cochrane Review.......................................................................................86 

Table 36. Cochrane Review Subgroup Analyses for Mortality and 

 Brain Metastasis...................................................................................................88 

Table 37. Adverse Effects Reported from RCTs of PCI versus no PCI..............................89 

Table 38. Sample Selection: Positron Emission Tomography for 

 Staging of Small-Cell Lung Cancer.....................................................................93 

Table 39. Test/Reference Standard Procedure and Interpretation: 

 Positron Emission Tomography for Staging of Small-Cell Lung Cancer ...........94 

Table 40. Diagnostic Accuracy Results: Positron Emission Tomography 

 for Staging of Small-Cell Lung Cancer ...............................................................97 

Table 41. Staging Accuracy Results/Changes in Patient Management: 

 Positron Emission Tomography for Staging of Small-Cell Lung Cancer ...........99 

Table 42. Ratings of Study Quality for Key Question 6......................................................101 

Table 43. Studies Comparing Surgery versus No Surgery for Early 

 Limited Stage SCLC............................................................................................105 

Table 44. Sample and Methods: Surgery versus No Surgery for 

 Very Early Limited Stage Disease.......................................................................106 

Table 45. Eligibility criteria and staging procedures used in studies 

 of surgery for very early limited stage SCLC......................................................108 
xi

Table 46. Survival Outcomes: Surgery versus No Surgery for 

 Very Early Limited Stage Disease.......................................................................109 

Table 47. Adverse Events: Surgery versus No Surgery for Very 

 Early Limited Stage Disease.................................................................................111 

Table 48. RCTs Comparing Alternative Chemotherapy Regimens 

 for Relapsed, Progressive, or Extensive-Stage SCLC ........................................115 

Table 49. Sample and Treatments: Treatment of Recurrent/Progressive Disease...............116 

Table 50. Efficacy Outcomes: Treatment of Recurrent/Progressive Disease......................118 

Table 51. Adverse Events: Treatment of Recurrent/Progressive Disease ...........................120 

Table 52. Multicenter Phase II Trials of Note for Key Question 9.......................................130 

Appendixes 

Appendix A: Exact Search Strings 

Appendix B: Sample Data Abstraction Forms 

Appendix C: Evidence Tables 

Appendix D: List of Excluded Studies 

Appendix E: Technical Expert Panel and Peer Reviewers 

Appendixes and Evidence Tables for this report are provided electronically at 

 http://www.ahrq.gov/downloads/pub/evidence/pdf/lungcansmall/lungcan.pdf
1

Executive Summary 

Introduction 

Small-cell lung cancer (SCLC) accounts for 13–20 percent of the 172,570 new cases and 

163,510 deaths from lung cancer expected in the U.S. in 2005 (American Cancer Society, 2005; 

Murren, Glatstein, and Pass, 2001; Simon and Wagner, 2003; Physicians Data Query 2005; 

Chua, Steer, and Yip, 2004; Ettinger, 2004; Stupp, Monnerat, Turrisi, et al., 2004). Untreated 

SCLC is aggressive, with a median survival of 2 to 4 months after diagnosis (Physicians Data 

Query, 2005). 

The American College of Chest Physicians (ACCP), nominated SCLC as a topic for an 

evidence report to support updating of its 2003 guideline. Consultation with technical experts, 

some nominated by ACCP, identified nine key issues in need of systematic review: 

1. For limited-stage SCLC, what are the relative benefits and harms (survival, toxicity, and 

quality of life) of thoracic radiotherapy (TRTx) combined with chemotherapy either in 

alternating fashion, concurrently or sequentially? 

2. For limited-stage SCLC, do outcomes (survival, toxicity, or quality of life) differ if 

concurrent TRTx is given in early versus late chemotherapy cycles? 

3. For limited-stage SCLC, do outcomes (survival, toxicity, quality of life) of primary 

therapy differ if one varies dose rate, treatment interval, or fractionation scheme for 

delivering TRTx? Comparisons of interest include: 

• accelerated regimens (>10 Gy per week completed over a short interval) versus 

standard duration regimens (<10 Gy per week) versus split courses delivered over the 

standard interval; and 

• single daily fractions versus hyperfractionated (two or more daily fractions or 

concomitant boost). 

4. What are the relative benefits and harms (survival, toxicity, and quality of life) of adding 

TRTx to chemotherapy for primary treatment of extensive-stage SCLC? 

5. What are the benefits and harms (survival, toxicity and quality of life) of prophylactic 

cranial irradiation (PCI)? 

6. Does the addition of positron emission tomography (PET) scanning improve the accuracy 

of staging for patients diagnosed with SCLC, over the use of other techniques, including 

computed tomography (CT) and magnetic resonance imaging (MRI), without PET? 
2

7. What are the outcomes (survival, toxicity and quality of life) of treatments used to 

manage patients with mixed small cell/non-small cell lung cancers? 

8. What is the role of surgery and what is its impact on survival in patients with early stage 

SCLC? How do available studies define early stage SCLC? 

9. What are the outcomes of second- or subsequent-line therapy in patients with relapsed or 

progressive SCLC? Where available data permit, patients with limited- and extensivestage disease will be addressed separately, as will those with refractory disease (relapse 

or progression within 3 months of primary treatment). 

Methods 

 The review methods were defined prospectively in a written protocol. A technical expert 

group provided consultation. The draft report was also reviewed by other experts and 

stakeholders. 

 Primary outcomes include: duration of survival, disease- or progression-free survival; quality 

of life; brain metastasis; and adverse events. Secondary outcomes include: response rates; 

response duration; and recurrence. For key question 6 (PET staging) additional outcomes are 

diagnostic accuracy and changes in patient management. 

 Electronic database searches of MEDLINE (through 12/21/04), EMBASE (through 3/04/05), 

and the Cochrane Controlled Trials Register (through 3/11/05).were conducted. The search was 

not limited to English language, but foreign-language references without abstracts were 

excluded. Relevant conference proceedings were searched electronically. 

 We sought randomized, controlled trials (RCTs) that compared the interventions of interest. 

Where randomized trials were limited or nonexistent, we sought additional studies. For question 

8 (surgery), we also sought nonrandomized comparative trials, prospective or retrospective. For 

question 9 (second- or subsequent line therapy), we also sought phase II multicenter studies 

reporting on at least 25 patients. For question 6 (PET staging), we sought single-arm trials that 

permitted computation of specificity and sensitivity in relation to an appropriate reference 

standard. 

 A single reviewer screened titles and abstracts for full-text retrieval; citations marked as 

uncertain were reviewed by a second reviewer. Review of full-text articles was conducted in the 

same fashion to determine inclusion in the systematic review. One reviewer performed primary 

data abstraction and a second reviewer reviewed the evidence tables for accuracy. All 

disagreements were resolved by consensus. 

 The general approach to assessing quality of evidence from studies of therapeutic 

interventions developed by the U.S. Preventive Services Task Force (Harris, Helfand, Woolf, et 

al., 2001) was applied. For diagnostic studies, we used the Quality Assessment of Diagnostic 

Accuracy Studies (QUADAS) tool. 

 We performed meta-analysis that combined studies included in key questions 1 and 2. The 

metrics were 2-year and 3-year mortality relative risks (RRs). Publication bias was tested using 

Egger’s linear regression (Egger, Davey Smith, Schneider, et al., 1997). A standard test for 

heterogeneity, the Q statistic, was used (Cochran, 1954). If significant, the combined RR point 
3

estimate was computed with a random effects (RE) model (DerSimonian and Laird, 1986). If 

not, a fixed effects (FE) model would be used (Cochran, 1937). Pooled estimates of treatment 

effects were derived using the inverse variance-weighted method (Cochran, 1937). 

Subgroup/sensitivity analyses were performed for earliest initiation of TRTx, hyperfractionation; 

platinum chemotherapy; concurrent TRTx; and study quality. Analyses were performed using 

STATA 9.0 and Microsoft Excel 2002. 

Results 

1. For limited-stage SCLC, what are the relative benefits and harms of TRTx 

combined with chemotherapy either in alternating fashion, concurrently, or 

sequentially? 

 One multicenter trial and one single-center trial (n=307) compared concurrent and sequential 

TRTx. Results are not conclusive but suggest better outcomes for concurrent TRTx. Overall 

survival adjusted for confounders significantly favored concurrent TRTx in the Takada, 

Fukuoka, Kawahara, et al. trial (2002; n=228), although unadjusted results were not significant. 

Additionally, the Park, Kim, Jeong, et al. (1996) trial found significantly longer response 

duration for concurrent TRTx. Of 11 types of adverse events reported, only leukopenia occurred 

significantly more frequently in the concurrent TRTx group in both studies. 

 No conclusions could be drawn on alternating TRTx. No significant differences in overall or 

progression-free survival were found in any of four trials: two (n=458) comparisons to sequential 

TRTx; one (n=156) comparison concurrent TRTx; and one (n=199) comparison of early and late 

alternating TRTx. 

2. For limited-stage SCLC, do outcomes differ if concurrent TRTx is given in early 

versus late chemotherapy cycles? 

The evidence is equivocal, finding no difference or small advantage for early concurrent 

TRTx. One large multicenter trial of good quality significantly favored concurrent therapy given 

in an early cycle (Murray, Coy, Pater, et al., 1993/Coy, Hodson, Murray, et al., 1994/Feld, 

Payne, Hodson, et al., 1988), as did 2 smaller trials. Of the two large multicenter trials that 

found no significant difference in survival, one did not use platinum chemotherapy (Perry, Eaton, 

Propert, et al., 1987/Ahles, Silberfarb, Rundle, et al., 1994/Perry, Herndon, Eaton, et al., 1988) 

and the other is published only in abstract (James, Spiro, O’Donnell, et al., 2003). 

Leukopenia/neutropenia appeared to be more common with early TRTx. 

Meta-analysis was performed in an attempt to obtain clearer results. Studies selected for Key 

Questions 1 and 2 were viewed as comparing early and late TRTx, and were pooled to give a 

more robust analysis. We did not find statistically significant reductions in 2- and 3-year 

mortality for early TRTx over late TRTx. The relative risk (RR) at 2 years was 0.921 (95 

percent CI: 0.844–1.005) and the RR at 3 years was 0.991 (95 percent CI: 0.955–1.029). 
4

3. For limited-stage SCLC, do outcomes (survival, toxicity, quality of life) of primary 

therapy differ if one varies dose rate, treatment interval, or fractionation scheme for 

delivering TRTx? 

Evidence to compare dose rates, treatment intervals, or fractionation schemes is limited. 

Two RCTs compared one versus two fractions a day for previously untreated SCLC. One 

compared an accelerated regimen versus the standard duration, while the other compared a splitcourse regimen versus the standard duration. 

Compared to a single daily fraction, two daily fractions delivered concurrently with platinum 

chemotherapy improved overall survival (23 vs. 19 months, log rank p=0.04) in a large 

multicenter trial of good quality (Turrisi, Kim, Blum, et al., 1999/Yuen, Zou, Turrisi, et al., 

2000; n=417). The second trial is difficult to interpret, since multiple variables were studied 

simultaneously (Schild, Bonner, Shanahan, et al., 2004/Sloan, Bonner, Hillman, et al., 

2002/Bonner, Sloan, Shanahan, et al., 1999; n=161), but there was no difference in survival with 

one versus two fractions per day. 

Esophagitis was more frequent with two fractions daily. 

4. What are the relative benefits and harms (survival, toxicity, and quality of life) of 

adding thoracic radiation therapy to chemotherapy for primary treatment of 

extensive-stage SCLC? 

One single-center RCT (Jeremic, Shibamoto, Nikolic, et al., 1999; n=99) suggests that 

adding concurrent TRTx improves survival of patients with extensive-stage disease that responds 

to an initial three cycles of platinum/etoposide chemotherapy with a complete response (CR) 

outside the thorax and at least a partial response in the thorax. Uncontrolled data from the same 

trial suggest little to no benefit for other patients. Grades 3/4 esophagitis were more common 

with TRTx. 

5. What are the benefits and harms (survival, toxicity and quality of life) of 

prophylactic cranial irradiation? 

 An individual patient data meta-analysis on seven RCTs (N=987) conducted by the Cochrane 

PCI Overview Collaborative Group shows that PCI improves survival of SCLC patients in CR 

after primary therapy. PCI increases 3-year survival from 15.3 percent to 20.7 percent (p=0.01), 

an absolute increase of 5.4 percent. PCI also significantly decreases the risk for brain metastasis 

and increases the likelihood of disease-free survival. The sole trial reported after the metaanalysis generally agrees with these findings. 

 Subgroup analyses showed that PCI significantly decreases brain metastases for SCLC 

patients in CR regardless of age, disease stage or performance status at diagnosis, and whether or 

not TRTx is part of the induction regimen. Survival benefit does not appear to differ among 

subgroups. 

 Additional subgroup analyses suggested that increasing the PCI dose from 8 to 40 Gy and 

starting PCI within the first 6 months after achieving complete response may reduce the 

likelihood of brain metastases. However, these hypotheses, derived from subgroup analyses, 

require formal testing in RCTs. 

 Although data are scant, acute toxicities of PCI seem tolerable at the doses used in these 
5

trials (8–40 Gy in 1.8 to 3 Gy fractions) and neurocognitive deficits no greater than existed prior 

to PCI. 

6. Does the addition of PET scanning improve the accuracy of staging for patients with 

SCLC over the use of other techniques, including CT and MRI, without PET? 

The evidence is limited and of poor quality, thus no conclusions can be drawn. Six studies 

(N=277) suggest that, except for brain metastases, PET added to conventional staging is more 

sensitive in detecting disease. However, there is so much uncertainty about the execution and 

interpretation of the reference standard in all of these studies that confidence is quite low in 

estimates of diagnostic and staging accuracy. The frequency of incorrect changes in stage 

attributable to PET is unknown due to incomplete reporting. 

7. What are the outcomes (survival, toxicity and quality of life) of treatments used to 

manage patients with mixed small cell/non-small cell lung cancers? 

There are few studies of any design that included patients with mixed histology. No 

conclusions can be drawn from the available evidence. 

8. What is the role of surgery and what is its impact on survival in patients with early 

stage SCLC? How do available studies define early stage SCLC? 

We sought studies that compared surgery to no surgery in patients with very early limited 

SCLC, defined as no preoperative evidence of involved nodes (clinically N0). Two randomized 

controlled trials and 8 nonrandomized comparative studies were reviewed. None studied a 

homogeneous group of patients with respect to nodal status; nor were separate outcomes reported 

for a subgroup of patients without evidence of nodal involvement. Thus no conclusion can be 

drawn. 

9. What are the outcomes of second- or subsequent-line therapy in patients with 

relapsed or progressive SCLC? 

Nine RCTs address second- or subsequent-line treatment of SCLC, each of which compared 

different sets of chemotherapy regimens. Two randomized trials directly compared 

chemotherapy with best supportive care for recurrent SCLC. The first studied second-line 

methotrexate plus doxorubicin and found an overall response rate of 23 percent for the 

chemotherapy arm. The second reported that oral topotecan resulted in a statistically significant 

increase in survival (26 weeks vs. 14 weeks) and slower decline in quality of life. High-grade 

neutropenia occurred in one-third of patients. Another trial compared oral versus intravenous 

topotecan; leukopenia and neutropenia were more frequent with the intravenous route, but 

survival and response were no greater. Other RCTs found higher rates of adverse events for one 

treatment over another, but no associated survival advantage that would offset increased high 

grade toxicity. 

Five multicenter phase II trials of note published since 2000 have reported overall response 

rates of 20 percent or more. Only one study, using topotecan plus cisplatin, enrolled more than 

50 patients. Approximately one-fourth of both sensitive and refractory patients responded. 
6

Three-quarters or more of both patient groups had high-grade leukopenia and neutropenia. A 

small study of irinotecan plus cisplatin found very high rates of partial response and low 

hematologic toxicity. The combination of paclitaxel, ifosfamide, and cisplatin achieved a high 

overall response rate and high-grade leukopenia in nearly all patients. One-quarter of those 

given paclitaxel plus carboplatin had a response and about half had high-grade neutropenia. In a 

study of doxorubicin plus carboplatin, nearly half of patients responded; however, 4 out of 5 had 

grade 3 or 4 granulocytopenia. 

Discussion and Future Research 

The strongest evidence available for this report is a patient-level meta-analysis showing that 

PCI improves survival of SCLC patients who achieved CR following primary therapy. No other 

question yielded evidence so robust. Our conclusions typically relied on a single trial showing 

treatment effects that were modest at best, and sometimes equivocal. This was apparent in our 

review of evidence for the sequence, timing, dosing and fractionation of TRTx. For example, the 

case for concurrent over sequential delivery rests largely on a single multicenter trial (Takada, 

Fukuoka, Kawahara, et al., 2002). Support for early concurrent therapy comes from the 

multicenter trial by Murray-Coy-Field (Murray, Coy, Pater, et al., 1993/Coy, Hodson, Murray, et 

al., 1994/Feld, Payne, Hodson, et al., 1988); however, two other multicenter trials, (Perry, Eaton, 

Propert, et al., 1987/Ahles, Silberfarb, Rundle, et al., 1994/Perry, Herndon, Eaton, et al., 1988; 

James, Spiro, O’Donnell, et al., 2003 [abstract]) found no advantage. However, the metaanalysis of 11 studies did not find significant reductions in 2- and 3-year mortality for early 

TRTx. For some questions (i.e., management of mixed histology disease; surgery for early 

limited SCLC) comparative trials were nonexistent. 

 Results reported by Jeremic, Shibamoto, Nikolic, et al., (1999) on TRTx for extensive-stage 

disease, need replication in a multicenter setting. 

 PET may be more sensitive in detecting disease outside the brain than conventional staging 

modalities. Future studies should fully report the frequency of correct and incorrect staging 

changes when PET is added to conventional tests and should link diagnostic performance to 

outcomes such as improvement in survival or reduced morbidity. Studies should be conducted 

according to standards described by the Quality Assessment of Diagnostic Accuracy Studies 

(QUADAS) and reported according to the Standards for Reporting of Diagnostic Accuracy 

(STARD) statement. 

 Complicating the evaluation of SCLC treatment are overall poor outcomes and small effect 

sizes, necessitating large numbers of patients in trials. Furthermore, interventions are 

multimodal with a multiplicity of variables that might contribute to the effectiveness. 

Trials that are poorly designed, conducted, or reported waste limited resources. To advance 

clinical knowledge and practice, the field should adhere to standards of research quality and set 

an agenda for research priorities. Given modest gains in survival, quality of life assessment 

should be integral to clinical trials and should adhere to recommended research methods, 

including handling of missing data. 
7

Conclusions 

PCI improves survival among those with a complete response to primary therapy. A research 

agenda is needed to optimize the effectiveness of TRTx and its components. PET for staging 

may be useful, but its role awaits clarification by rigorous studies. No relevant evidence was 

available to address management of mixed histology disease or surgery for early limited SCLC. 

9 

Chapter 1. Introduction 

This systematic review summarizes and analyzes evidence on selected aspects of managing 

patients diagnosed with small cell lung cancer (SCLC). This section outlines the review’s 

clinical scope, highlights relevant aspects of the disease’s epidemiology and public health 

impact, describes briefly current treatment guidelines and uncertainties, and overviews key 

questions to be addressed. 

Objective of Systematic Review 

The American College of Chest Physicians (ACCP) is preparing to update its 2003 evidencebased guideline on diagnosis and management of lung cancer. To support this effort, the ACCP 

nominated SCLC as a topic for systematic review by one of the Agency for Healthcare Research 

and Quality’s (AHRQ) Evidence-based Practice Centers (EPC). Consultation with technical 

experts, some nominated by ACCP, identified key issues in need of systematic review. 

Epidemiology and Public Health Impact of 

Small Cell Lung Cancer 

Small cell lung cancer (SCLC) accounts for 13–20 percent of the estimated 172,570 new 

cases and 163,510 deaths from lung cancer expected in the U.S. in 2005 (American Cancer 

Society, 2005; Murren, Glatstein, and Pass 2001; Simon and Wagner, 2003; Physicians Data 

Query 2005; Chua, Steer, and Yip, 2004; Ettinger 2004; Stupp, Monnerat, Turrisi, et al., 2004). 

Untreated SCLC has the most aggressive clinical course of any lung tumor, with a median 

survival of only 2 to 4 months after diagnosis (Physicians Data Query, 2005). Since it 

metastasizes rapidly, SCLC is present outside the hemithorax of origin in most patients at 

diagnosis (Physicians Data Query, 2005). 

Current Staging and Treatment Strategies for 

Small Cell Lung Cancer 

Staging and Classification

SCLC is also known as “oat cell” carcinoma or small cell undifferentiated carcinoma 

(American Cancer Society, 2004). SCLC can be subtyped according to cellular classification as 

1) small cell carcinoma; 2) mixed small cell/large cell carcinoma; or 3) combined small cell 
10 

carcinoma (i.e., small cell lung cancer combined with neoplastic squamous and/or glandular 

components) (Physician Data Query, 2005). 

Although the TNM classification scheme used for non-SCLC is applicable to SCLC staging 

(Cameron and Schwartz, 2005), most clinicians use a simplified two-stage scheme developed by 

the Veterans Administration Lung Cancer Study Group (Simon and Wagner, 2003; Physician 

Data Query, 2005). Limited-stage SCLC (approximately 30 percent of patients at diagnosis) 

includes those with tumor confined to the hemithorax of origin, the mediastinum, or the 

supraclavicular lymph nodes (Simon and Wagner, 2003; Physicians Data Query, 2005). In 

extensive-stage SCLC, tumor has spread outside these limits; patients with distant metastases are 

always considered to have extensive disease (Physician Data Query, 2005). At the time of 

diagnosis, 60–65 percent of SCLC patients have extensive disease (Osterlind, 2001). Estimates 

of median survival with current therapies are 16–24 months for those with limited-stage disease, 

and 6–12 months for those with extensive-stage disease (Physician Data Query, 2005). 

Diagnostic procedures commonly used to establish the presence of distant metastases include 

bone marrow aspiration, brain scans using computed tomography (CT) or magnetic resonance 

imaging, chest and abdomen scans using CT, and radionuclide bone scans (Physician Data 

Query, 2005; Murren, Turrisi, and Pass, 2005). Whether positron emission tomography (PET) 

metabolic scanning using 18-fluorodeoxyglucose (18-FDG) provides any additional information 

to current staging techniques is uncertain (Murren, Turrisi, and Pass, 2005; Simon and Wagner, 

2003). 

Treatment Strategies 

Treatments for SCLC are selected by stage and other features of disease extent (Physician 

Data Query, 2005). Few patients with extensive SCLC currently attain long-term survival. 

Their survival at 2 years after diagnosis is approximately 5 percent and at 5 years is less than 1 

percent (Murren, Turrisi, and Pass, 2005). 

Over time, there has been better success in the management of patients with limited disease. 

The proportion of long-term survivors among these patients has doubled from the 1970s to the 

1990s (Janne, Freidlin, Saxman, et al., 2002; Murren, Turrisi, and Pass, 2005). While this may 

be due in part to stage migration, it is probably more associated with the change in practice of 

using platinum-based, rather than cyclophosphamide-based, combination chemotherapy 

regimens (Murren, Turrisi, and Pass, 2005). Attempts to improve on those results, either by 

adding a third drug or by substituting newer drugs have not yielded more long-term survivors 

thus far. It appears that further improvement requires both more and more complete responses to 

primary therapy (i.e., chemotherapy and radiation). Absent that, other interventions seem to 

largely alter the pattern of relapse, but not overall survival. 

Chemotherapy. Chemotherapy is used for most patients, either as adjuvant therapy for the 

few patients eligible for surgery, or as primary therapy for patients with inoperable tumors. 

Preferred regimens have evolved over time (Murren, Turrisi, and Pass, 2005). Current 

guidelines recommend platinum-etoposide combinations in patients with limited-stage disease 

and platinum-based regimens in patients with extensive-stage disease (Simon and Wagner, 2003; 

Osterlind, 2001). According to the 2003 ACCP guidelines, there is no evidence on the benefit of 

maintenance chemotherapy in any patient achieving a partial or complete remission, and 

maintenance therapy is not recommended outside of a clinical trial (Simon and Wagner, 2003). 
11 

Surgery. Surgery is usually limited to patients with smaller tumors (T1 or T2) and no 

evidence of nodal involvement or spread outside the hemithorax of origin (Physician Data 

Query, 2005). Whether surgery added to chemotherapy for patients with limited-stage disease 

improves survival is currently uncertain. 

Thoracic Radiotherapy. Meta-analyses published in the 1990s demonstrated the benefit of 

adding thoracic radiotherapy (TRTx) to chemotherapy in patients with limited-stage disease 

(Warde and Pignon, 1992; Pignon, Arrigada, Ihde, et al., 1992). Addition of TRTx to 

chemotherapy increased 2- to 3-year overall survival by an absolute 5.4 percent over 

chemotherapy alone (Warde and Payne, 1992; Pignon, Arrigada, Ihde, et al., 1992; Carney, 

1999). Addition of TRTx to chemotherapy in patients with limited-stage SCLC is now the 

recommended course of therapy (Simon and Wagner, 2003). However, uncertainties remain 

with respect to optimal timing, sequencing, and radiation regimens (i.e., dosages and 

fractionation schemes) (Turrisi, 1994; Osterlind, 2001). Table 1 summarizes factors that might 

influence how chemotherapy and radiation may interact when used for primary treatment of 

limited stage SCLC. 

Meta-analyses using different study inclusion criteria have addressed the timing of TRTx 

given with chemotherapy for limited-stage SCLC. Cancer Care Ontario (2003) included 5-year 

survival data for 4 studies involving 777 patients, finding no difference between early and late 

TRTx. Huncharek and McGarry compared the impact of early (i.e., given with the first or 

second course of systemic therapy) versus delayed (i.e., with the final courses) TRTx in patents 

with limited disease (Huncharek and McGarry, 2004). The analysis pooled data from 8 

randomized, controlled trials enrolling over 1,500 patients and found that early, concurrent TRTx 

(i.e., administered during the same time period as chemotherapy) improved 1, 2, and 3-year 

overall survival relative to delayed TRTx, and that TRTx with etoposide/cisplatin regimens 

performed better compared with non-etoposide/cisplatin regimens. This meta-analysis was 

flawed by double-counting data from one study (i.e., Goto, Nishiwaki, Takada, et al. 1999 and 

Takada, Fukuoka, Kawahara, et al., 2002). 

A meta-analysis by the Cochrane Collaboration (Pijls-Johannesma, De Ruysscher, Lambin, 

et al. 2004), included 7 studies, 6 of which overlapped with those in the Huncharek and McGarry 

meta-analysis, and found that the 2–3 year survival difference as a function of timing was less 

certain. The Cochrane meta-analysis identified patient selection issues and differences in 

systemic regimens as potential confounders. Fried, Morris, Poole, et al. (2004) included 7 

studies with 1,500 patients and found that 2-year survival was significantly improved by early 

TRTx, but the pooled result was not significant at 3 years. Two-year subgroup analysis showed 

that using hyperfractionation and platinum chemotherapy were associated with significant 

advantages favoring early TRTx, but significant results were not obtained in studies using 

conventional fractionation and non-platinum chemotherapy. 

The role of radiation therapy in extensive disease is less established than in patients with 

limited-stage disease (Murren, Turrisi, and Pass, 2005). Several large studies reported in the 

1980s by the Southwest Oncology Group (SWOG) and that did not randomize patients to TRTx 

versus no TRTx, suggested that, although thoracic radiation reduced initial relapse at the primary 

tumor site, there was no effect on overall survival (Murren, Turrisi, and Pass, 2005; Livingston, 

Mira, Chen, et al., 1984; Livingston, Schulman, Mira, et al., 1986). 
12 

Prophylactic Cranial Irradiation. The frequency of brain metastasis in SCLC patients led 

to the hypothesis that subclinical metastases are commonly present in the brain at diagnosis. 

Thus, clinicians often add prophylactic cranial irradiation (PCI), particularly for patients 

achieving a complete remission (CR) after primary therapy. Without PCI, patients who achieve 

an extracranial CR have a 50–80 percent actuarial risk of developing CNS metastases within 2–3 

years (Simon and Wagner, 2003; Murren, Turrisi, and Pass, 2005; Carney, 1999). In addition, 

among patients who achieve a CR with chemotherapy, approximately 15 percent have brain 

metastases as the initial or only manifestation of recurrence (Carney, 1999). A patient-level 

meta-analysis of almost 1,000 patients in complete remission from 7 randomized, controlled 
13 

Summary Table 1. Alternatives for Combined Chemotherapy and Radiation to Treat Limited SCLC

treatment variable alternatives known or possible 

advantages 

known or possible 

disadvantages 

platinum/etoposide (PE) most effective regimen in 

multiple meta-analyses 

relapse common despite initial 

high response rate 

cyclophosphamide- and/or 

doxorubicin-based (CD) none known response rates, survival inferior to PE 

alternating PE/CD less likely to select PE-resistant 

cells for survival 

uncertain; limits choices for 2ndline therapy? 

chemotherapy 

regimen 

PE + third (newer) drug less likely to select PE-resistant 

cells for survival 

increased toxicity without 

evidence of better survival 

30 to 40 Gy less normal tissue toxicity than 

larger doses local failure rate ~80% 

>40 to 50 Gy decreases local failure rate to 

30–50% increases normal tissue toxicity

cumulative radiation 

dose (once daily 

fractions) 

>50 to 65 Gy may increase tumor kill, 

decrease local failure rate 

further increases normal tissue 

toxicity 

larger volume (includes 

regional lymphatics) may reduce regional failure rate must limit total dose to avoid 

toxicity radiation target 

volume smaller volume (limited to 

involved fields) 

smaller target permits larger 

dose; may decrease failure, yet 

avoid toxicity 

tumor cells beyond target may 

survive, leading to relapse and 

progression 

>2 Gy per fraction increases tumor cell kill per 

fraction 

increases normal tissue acute 

and late toxicities 

fraction size 

<2 Gy per fraction 

permits delivering larger total 

dose in standard time without 

excess toxicity 

reduces tumor cell kill per 

fraction 

once daily more convenient (patients) and 

efficient (facilities) 

permits tumor cell repair 

(normal cells faster) frequency of 

fractions hyperfractionation (>2/day)

permits accelerated 

radiotherapy with equal or less 

toxicity 

less convenient (patients) and 

efficient (facilities) 

standard schedule: 4–6 

weeks (<10 Gy/week) 

less risk for acute and late 

toxicity to normal tissues 

radiation-resistant tumor cell 

clone may emerge duration of radiation 

therapy accelerated schedule: 

<3 weeks (>10 Gy/week) 

more effective for fast-growing 

tumors (e.g., SCLC); also 

permits dose escalation 

may increase risk of acute and 

late toxicities 

sequential 

smaller radiation target if tumor 

shrinks; fewer radiationresistant hypoxic tumor cells 

sacrifices potential drugradiation synergy 

concurrent 

potential for synergy if one 

modality sensitizes cells to 

other’s effects 

may also synergize damage to 

normal cells (esophagus, bone 

marrow) 

sequence of 

chemotherapy and 

radiation therapy 

alternating or split course permits recovery from acute 

toxicity 

permits tumor cells to 

repopulate 

early cycles less survival of chemotherapy 

resistant tumor cells more hematopoietic toxicity radiation timing 

relative to 

chemotherapy 

course late cycles less hematopoietic toxicity chemotherapy-resistant tumor 

cells may emerge 
14 

trials showed the addition of PCI can reduce the risk of CNS metastases by over half and 

significantly improves survival (Auperin, Arriagada, Pignon, et al. 1999; Prophylactic Cranial 

Irradiation Overview Collaborative Group, 2000; Carney, 1999). 

Definitive recommendations regarding optimal timing of PCI and radiation dosage issues 

(e.g., optimizing dose to balance efficacy and toxicity, fractionation) still require additional study 

(Prophylactic Cranial Irradiation Overview Collaborative Group, 2000; Boher and Wenz, 2002). 

According to one of the PCI meta-analyses, “Establishing the optimal dose and timing of 

treatment so as to reduce further the incidence of brain metastases with minimal and acceptable 

toxicity should be the aim of future clinical trials” (Prophylactic Cranial Irradiation Overview 

Collaborative Group, 2000). 

Data on the adverse effects of PCI, both acute (e.g., skin burns, headaches) and latedeveloping (e.g., neurocognitive impairment, overt cerebral necrosis) are also not well 

characterized from analyses of controlled trials (Boher and Wenz, 2002). Although many 

retrospective studies describe an association between PCI and neurotoxicity, evidence from 

prospective, controlled trials does not appear to support that association (Bohrer and Wenz, 

2002). 

Second-Line Therapy. Most patients respond to primary therapy, but relapse after 

remissions of varying duration (Murren, Turrisi, and Pass, 2005). Second-line therapy is offered 

to most patients if the first remission has lasted 3–6 months; relapse after 3 months or more is 

also known as “sensitive relapse” (Murren, Turrisi, and Pass, 2005). Evidence of benefit is 

lacking from second-line therapy for refractory SCLC (i.e., no remission after primary therapy). 

Response to second-line therapy appears to be related to the chemotherapy agents given in both 

the induction and second-line regimens (Murren, Turrisi, and Pass, 2005). It is also unknown 

whether third or subsequent lines of therapy for relapsed or progressive SCLC improve outcomes 

compared with best supportive care. 

Key Questions for this Systematic Review 

As stated previously, consultation with experts has identified critical concerns deserving of 

inquiry to support the ACCP update to guidelines on the diagnosis and management of lung 

cancer. Thus, this systematic review of the literature will address the following questions 

regarding managing patients with small cell lung cancer: 

1. For limited-stage SCLC, what are the relative benefits and harms (survival, toxicity, and 

quality of life) of TRTx combined with chemotherapy either in alternating fashion, 

concurrently or sequentially? 

2. For limited-stage SCLC, do outcomes (survival, toxicity, or quality of life) differ if 

concurrent TRTx is given in early versus late chemotherapy cycles? 

3. For limited-stage SCLC, do outcomes (survival, toxicity, quality of life) of primary 

therapy differ if one varies dose rate, treatment interval, or fractionation scheme for 

delivering TRTx? Comparisons of interest include: 
15 

• accelerated regimens (>10 Gy per week completed over a short interval) versus 

standard duration regimens (<10 Gy per week) versus split courses delivered over the 

standard interval; and 

• single daily fractions versus hyperfractionated (two or more daily fractions or 

concomitant boost). 

4. What are the relative benefits and harms (survival, toxicity, and quality of life) of adding 

TRTx to chemotherapy for primary treatment of extensive-stage SCLC? 

5. What are the benefits and harms (survival, toxicity and quality of life) of prophylactic 

cranial irradiation (PCI)? 

6. Does the addition of PET scanning improve the accuracy of staging for patients 

diagnosed with SCLC, over the use of other techniques, including CT and MRI, without 

PET? 

7. What are the outcomes (survival, toxicity and quality of life) of treatments used to 

manage patients with mixed small cell/non-small cell lung cancers? 

8. What is the role of surgery and what is its impact on survival in patients with early stage 

SCLC? How do available studies define early stage SCLC? 

9. What are the outcomes of second- or subsequent-line therapy in patients with relapsed or 

progressive SCLC? Where available data permit, patients with limited- and extensivestage disease will be addressed separately, as will those with refractory disease (relapse 

or progression within 3 months of primary treatment). 

17 

Chapter 2. Methods 

The objective of this Evidence Report is to systematically review and synthesize available 

evidence on managing patients diagnosed with small cell lung cancer (SCLC). The Key 

Questions addressed here were proposed by the American College of Chest Physicians, the 

partner organization for this evidence report and were refined after consultation with experts. 

Peer Review 

A technical expert group provided consultation for the systematic review. The draft report 

was reviewed by 10 external reviewers, including members of the technical expert group, the 

Task Order Officer, other invited technical experts, and stakeholders (Appendix E).* Revisions 

were made to the draft report based on reviewers’ comments. 

Study Selection Criteria 

Types of Studies 

All questions, except Question 6, addressed therapeutic interventions. We sought 

randomized, controlled trials that compared the interventions of interest. No minimum number 

of patients per study arm was required for randomized, controlled trials. Because there were few 

randomized, controlled trials available to address Questions 8 and 9, we sought additional 

studies. For Question 8 (surgery), we also sought nonrandomized comparative trials, both 

prospective and retrospective in design. For Question 9 (second- or subsequent-line therapy), we 

also sought phase II multicenter trials reporting on at least 25 patients. 

Question 6 (PET for staging) addresses a diagnostic intervention. Although we sought 

randomized, controlled trials comparing the outcomes of SCLC patients staged with and without 

use of PET, no such studies were identified. We then sought prospective, single-arm trials that 

reported on at least 25 patients undergoing imaging to stage SCLC; correlated 18-

fluorodeoxyyglucose (FDG) PET findings with findings from other imaging modalities and an 

appropriate reference standard; and permitted computation of sensitivity and specificity. 

Our search and selection criteria included English-language studies, as well as foreignlanguage studies that had an English-language abstract. 

Studies were excluded if no outcome of interest to this review was reported. Studies were 

also excluded if the patient population of interest was fewer than 80 percent of included patients, 

or, alternatively, results for the patient population of interest were not separately reported. When 

 

*

 Appendixes cited in this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/lungcansmall/lungcan.pdf
18 

multiple reports were available for the same study, it was counted as a single trial and outcome 

data from the report with the longest follow-up were used. 

Types of Participants

• Key Questions 1–3 (First-line chemotherapy with thoracic radiotherapy [TRTx]) — 

 patients with a histopathologically confirmed diagnosis of SCLC staged as limited 

 disease. 

• Key Question 4 (thoracic radiation therapy) — Patients with a histopathologically 

confirmed diagnosis of SCLC staged as extensive disease undergoing first-line therapy. 

• Key Question 5 (prophylactic cranial irradiation) — Patients with a histopathologically 

confirmed diagnosis of SCLC that has completely responded to primary therapy 

(regardless of stage). 

• Key Question 6 (PET staging) — Patients with a histopathologically confirmed diagnosis 

of SCLC. 

• Key Question 7 (management mixed disease) — Patients with a histopathologically 

confirmed diagnosis of mixed small cell/non-small cell lung cancer. 

• Key Question 8 (surgery) — Patients with a histopathologically confirmed diagnosis of 

SCLC staged as limited disease with small tumors and no nodal involvement 

• Key Question 9 (second- or subsequent-line therapy) — Patients with a 

histopathologically confirmed diagnosis of SCLC that either relapsed or progressed after 

a response that lasted at least 3 months following primary therapy for: (a) limited-stage or 

(b) extensive-stage disease; or (c) patients with refractory disease (defined as no response 

or progression within 3 months of primary therapy). 

Types of Interventions

• Key Question 1 — Comparison of chemotherapy combined with sequential TRTx, 

chemotherapy combined with concurrent TRTx and chemotherapy combined with 

alternating TRTx.

• Key Question 2 — Chemotherapy combined with concurrent TRTx initiated early 

cycles (i.e., 1 or 2) versus chemotherapy combined with concurrent TRTx initiated in late 

cycles (i.e., 3 or later). 

• Key Question 3 — Chemotherapy combined with standard-interval TRTx versus 

chemotherapy combined with accelerated TRTx: OR chemotherapy combined with splitcourse TRTx chemotherapy combined with standard-interval TRTx; OR chemotherapy 

combined with single daily fractions of TRTx; OR chemotherapy combined with 

hyperfractionated TRTx.
19 

• Key Question 4 — Chemotherapy combined with TRTx versus chemotherapy alone.

• Key Question 5 — Prophylactic cranial irradiation (PCI) versus no prophylactic 

radiation after primary therapy is completed and response is assessed. 

• Key Question 6 — Positron-emission tomography (PET) vs. no PET, added to other 

staging modalities, including computed tomography (CT) and magnetic resonance 

imaging (MRI). 

• Key Question 7 — Chemotherapy with or without TRTx delivered in any sequence or 

schedule used for limited-stage SCLC 

• Key Question 8 — Surgical excision of SCLC tumors, preceded by neoadjuvant 

chemotherapy or followed by adjuvant chemotherapy, and either with or without TRTx 

and PCI, versus no surgical excision 

• Key Question 9 — Chemotherapy using drugs approved by the U.S. Food and Drug 

Administration for at least one indication to treat a malignant disease (various regimens). 

Types of Outcomes

Primary (health) outcomes of interest include: 

 duration of survival, disease-free survival, and/or progression-free survival 

 quality of life 

 brain metastasis-free survival and subsequent treatment(s) for brain metastasis 

 palliation of measurable symptoms 

 treatment-related adverse events 

 perioperative adverse events 

Secondary (intermediate) outcomes include: 

 objective response rates (complete and partial responses; separately and summed) 

 response durations 

 pathologically complete resection rates 

 recurrence rates 
20 

For key question 6 (PET staging) additional outcomes of interest are: 

• diagnostic accuracy 

• outcomes other than diagnostic accuracy, such as staging accuracy, change in stage and 

impact on management decisions 

Search Strategy and Review 

Search Strategy 

Electronic databases. The following databases were searched for citations. The full search 

strategy is displayed in Appendix A.* The search was not limited to English-language 

references, but foreign-language references without abstracts were disregarded. 

• MEDLINE® (through 12/21/04) 

• EMBASE (through 03/04/05) 

• Cochrane Controlled Trials Register (through 03/11/05) 

Additional Sources of Evidence. The Technical Expert Panel and individuals and 

organizations providing peer review were asked to inform the project team of any studies 

relevant to the key questions that were not included in the draft list of selected studies. 

Search Screen 

Search results were stored in a ProCite® database. Using the study selection criteria for 

screening titles and abstracts, a single reviewer marked each citation as either: (1) eligible for 

review as full-text articles; (2) ineligible for full-text review; or (3) uncertain. Citations marked 

as uncertain were reviewed by a second reviewer and resolved by consensus opinion, with a third 

reviewer to be consulted if necessary. Using the final study selection criteria, review of full-text 

articles was conducted in the same fashion to determine inclusion in the systematic review. A 

total of 630 references were retrieved at a full-text level; 89 were included in this review (Figure 

1). Records of the reason for exclusion for each paper retrieved in full-text, but excluded from 

the review, were kept in the ProCite® database (see Appendix D, Excluded Studies). 

 

*

 Appendixes cited in this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/lungcansmall/lungcan.pdf. 
21 

Figure 1. QUOROM Flow Diagram 

Data Extraction and Analysis 

Data Elements 

The data elements below were abstracted, or recorded as not reported, from therapeutic 

intervention studies. 

• critical features of the study design (for example, patient inclusion/exclusion criteria, 

number of subjects, use of blinding); 

• potential patient characteristic confounders: 

 age 

 gender 

6,346 studies identified 

on literature searches 

5,716 studies 

excluded based on 

titles and abstracts 

630 studies retrieved as 

full-text articles 

541 studies excluded 

after full review 

89 studies met study 

selection criteria 

Q1 

7 

studies 

Q2 

10 

studies 

Q3 

5 

studies 

Q4 

5 

studies 

Q5 

7 

studies 

Q6 

7 

studies 

Q7 

0 

studies 

Q8 

12 

studies 

Q9 

37 

studies 
22 

 race 

 extent of disease and stage 

 performance status 

 comorbidities 

• treatment protocols (for example, treatment intensity, frequency, duration, other prior and 

concurrent treatment factors); 

• patient monitoring procedures (for example, follow-up duration and frequency, outcome 

assessment methods); and 

• the specified key outcomes and data analysis method (when statistical test results were 

lacking for adverse events data, reviewers performed tests with the STATMAN statistical 

program). 

The data elements below were abstracted, or recorded as not reported, from diagnostic 

accuracy studies of imaging modalities used in staging SCLC: 

• patient selection criteria 

• details about the reference standard (validity and degree of detail in description) 

• decision rules for determining which patients received the reference standard 

• whether the index test and reference standard were interpreted blind to each other 

• whether verification bias (index test results influenced decisions to perform reference 

standard) was avoided 

• details about the index test (degree of detail about performing of test, interpretation) 

• study design (prospective, retrospective) 

• reporting of diagnostic accuracy results (completeness, appropriate calculation of 

accuracy measures, use of confidence intervals) 

• outcomes other than diagnostic accuracy, such as staging accuracy, change in stage and 

impact on management decisions 
23 

Evidence Tables 

Templates for evidence tables were created in Microsoft Excel® and Microsoft Word® 

Appendix B).* One reviewer performed primary data abstraction of all data elements into the 

evidence tables, and a second reviewer reviewed the evidence tables for accuracy. 

Disagreements were resolved by discussion, and if necessary, by consultation with a third 

reviewer. When small differences occurred in quantitative estimates of data from published 

figures, the values obtained by the two reviewers were averaged. 

Assessment of Study Quality 

Therapeutic Studies 

The general approach to grading evidence developed by the U.S. Preventive Services Task 

Force (Harris et al. 2001) was applied. Quality of the abstracted studies was assessed by one 

reviewer and fact-checked by a second. Discordant quality assessments were resolved by 

discussion or by consultation with a third reviewer, if necessary. The quality criteria for 

randomized, controlled trials were as follows: 

• Initial assembly of comparable groups: adequate randomization, including concealment 

and whether potential confounders (e.g., baseline characteristics, other concomitant care) 

were distributed equally among groups 

• Maintenance of comparable groups (includes attrition, crossovers, adherence, 

contamination) 

• Important differential loss to follow-up or overall high loss to follow-up 

• Measurements: equal, reliable, and valid (includes masking of outcome assessment) 

• Clear definition of interventions 

• All important outcomes considered 

• Analysis: adjustment for potential confounders, intention-to-treat analysis 

Diagnostic Studies 

The Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool underwent a 

rigorous development process by Whiting, Rutjes, Dinnes, et al. (2004) and includes the 

following items: 

 

*

 Appendixes cited in this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/lungcansmall/lungcan.pdf. 
24 

• Was the spectrum of patients representative of the patients who will receive the test in 

practice? 

• Were selection criteria clearly described? 

• Is the reference standard likely to classify the target condition correctly? 

• Is the period between reference standard and index test short enough to be reasonably 

sure that the target condition did not change between the two tests? 

• Did the whole sample or a random selection of the sample, receive verification using a 

reference standard of diagnosis? 

• Did patients receive the same reference standard regardless of the index test result? 

• Was the reference standard independent of the index test (i.e. the index test did not form 

part of the reference standard)? 

• Was the execution of the index test described in sufficient detail to permit replication of 

the test? 

• Was the execution of the reference standard described in sufficient detail to permit 

replication of the reference standard? 

• Were the index test results interpreted without knowledge of the results of the reference 

standard? 

• Were the reference standard results interpreted without knowledge of the results of the 

index test? 

• Were the same clinical data available when test results were interpreted as would be 

available when the test is used in practice? 

• Were uninterpretable/intermediate test results reported? 

• Were withdrawals from the study explained? 

Definition of Ratings Based on Criteria

The rating of therapeutic intervention studies encompasses the 3 quality categories described 

below. No analogous quality categories have been incorporated into the QUADAS tool for 

assessing diagnostic accuracy studies. Rather, each of the 14 QUADAS items is considered 

individually. 
25 

Good: Meets all criteria: Comparable groups are assembled initially and maintained 

throughout the study (follow-up at least 80 percent); reliable and valid measurement instruments 

are used and applied equally to the groups; interventions are spelled out clearly; all important 

outcomes are considered; and appropriate attention to confounders in analysis. In addition, for 

randomized, controlled trials (RCTs), intention to treat analysis (i.e., all patients randomized 

were analyzed) is used. 

Fair: Studies will be graded “fair” if any or all of the following problems occur, without the 

fatal flaws noted in the “poor” category below: Generally comparable groups are assembled 

initially but some question remains whether some (although not major) differences occurred with 

follow-up; measurement instruments are acceptable (although not the best) and generally applied 

equally; some but not all important outcomes are considered; and some but not all potential 

confounders are accounted for. Intention-to-treat analysis is done for RCTs. 

Poor: Studies will be graded “poor” if any of the following fatal flaws exists: Groups 

assembled initially are not close to being comparable or maintained throughout the study; 

unreliable or invalid measurement instruments are used or not applied at all equally among 

groups (including not masking outcome assessment); and key confounders are given little or no 

attention. For RCTs, intention-to-treat analysis is lacking. 

Meta-Analysis 

Quantitative synthesis of evidence was carried out by combining studies meeting selection 

criteria for key questions 1 and 2. Eleven such randomized controlled trials (RCTs) could be 

viewed as comparing early and late thoracic radiotherapy (TRTx) for limited-stage small cell 

lung cancer (see “Results: Results of Meta-Analysis/Meta-Regression”). This Review defines 

early TRTx as given in cycles 1 or 2 and late as given in cycle 3 or later and at least 3 weeks 

after the start of early TRTx. Of the 11 RCTs, all provide 3-year overall survival data and 9 give 

2-year data. The metrics used in the meta-analysis were 2-year and 3-year mortality relative 

risks (RRs). Estimates of survival were multiplied by sample sizes and rounded to the nearest 

whole number to derive the numbers alive and dead at 2 years and 3 years. While this method 

has been used in 4 previous meta-analyses on the timing of TRTx for limited SCLC, it does not 

take into account censoring and therefore may inflate subject counts. Even if a consensus 

method to incorporate censoring was available, it could not be applied to 6 of 11 studies due to 

insufficient detail in articles. Our method assures easy comparisons with previous meta-analyses 

and inclusion of more studies. 

Meta-analysis was not worth pursuing for other questions in this Review. For key questions 

3, 4, 7, 8, and 9, there was either an inadequate number of studies or excessive heterogeneity of 

treatments for pooled analysis. Question 5 was the subject of a recent patient-level meta-analysis 

(Auperin, Arriagada, Pignon, et al. 1999; Prophylactic Cranial Irradiation Overview 

Collaborative Group, 2000; Carney, 1999) and thus, a meta-analysis was not necessary for this 

Review. Uncertainty about the reference standard used in studies on question 6 was so great that 

a meta-analysis could give unwarranted weight to uniformly poor quality studies. 
26 

The first step in the meta-analysis was to assess whether publication bias was likely. This 

was first done visually with funnel plots, in which the trials are sorted along the vertical axis in 

ascending order of the standard error of the log odds ratio. A formal test for publication was 

performed using Egger’s linear regression (Egger, Davey Smith, Schneider, et al., 1997). Trial 

standardized effect estimates were fit to precision values (the inverse of the standard error), using 

least squares and trial’s inverse variance as weights. Asymmetry suggestive of publication bias 

would be indicated by a regression intercept value that significantly deviates from zero. 

The next step in the meta-analysis is to determine whether significant heterogeneity of 

treatment effects exists. A standard test for heterogeneity is the Q statistic (Cochran, 1954). The 

null hypothesis of homogeneity is rejected below an alpha level of 0.10. If rejected, the 

combined RR point estimate should be computed with a random effects (RE) model 

(DerSimonian and Laird, 1986). Where necessary, the between-study variance component (tau 

squared) was calculated using the algebraic method described by Sutton, Abrams, Jones, et al. 

(2000). If the null hypothesis of homogeneity is not rejected, a fixed effects (FE) model would 

be used (Cochran, 1937). 

Pooled estimates of treatment effects were derived using the inverse variance-weighted 

method (Cochran, 1937). Meta-analysis results are presented graphically in forest plots. 

Subgroup/sensitivity analyses were performed for these variables: whether early TRTx was 

given at the earliest opportunity; whether hyperfractionation was used; whether platinum was 

included in chemotherapy (CTx); whether early TRTx was given concurrent with CTx; and 

whether the trial was rated as being of good quality. Influence analysis was conducted by 

excluding each trial individually to reveal the impact on effect estimates. Results are presented 

graphically. 

Random effects meta-regression, as described by Berkey, Hoaglin, Mosteller, et al. (1995), 

was conducted to explore sources of heterogeneity. All covariates are dichotomous variables, 

the same variables as those in subgroup/sensitivity analyses. Single variables were tested first. 

Multiple variables were included only as an exercise due to concerns of overfitting. Analyses 

were carried out using STATA 9.0 and Microsoft Excel 2002. 
27 

Chapter 3. Results 

Key Question 1 

For limited-stage small cell lung cancer (SCLC), what are the relative benefits and harms 

(survival, toxicity, and quality of life) of thoracic radiotherapy (TRTx) combined with 

chemotherapy, either in alternating fashion, concurrently or sequentially? 

This question concerns how TRTx is given in relation to chemotherapy. Alternating TRTx is 

administered between chemotherapy cycles. Concurrent TRTx is TRTx given at the same time 

as chemotherapy. Sequential TRTx is given after completion of chemotherapy. 

Overview 

As summarized in Summary Table 2, 6 randomized, controlled trials (RCTs) made 

comparisons of alternating, concurrent and sequential TRTx for limited stage SCLC. Two trials 

(n=307) compared concurrent and sequential TRTx (Takada, Fukuoka, Kawahara, et al., 2002; 

Park, Kim, Jeong, et al., 1996). Two trials compared alternating to sequential TRTx (Gregor, 

Drings, Burghouts, et al., 1997; Sun, Zhang, Yin, et al., 1995; n=458). One trial compared 

alternating to concurrent TRTx (Lebeau, Urban, Brechot, et al., 1999, n=156). The Work and 

colleagues trial (Work, Nielsen, Bentzen, et al., 1997/Work, Bentzen, Nielsen, et al., 1996) 

compared early alternating and late alternating TRTx (n=199). Collectively, the 6 trials 

randomized 228 patients to concurrent treatment, 337 patients to alternating treatment, and 385 

patients to sequential treatment. It is worth noting that these studies were generally small in size 

and likely underpowered to find small but clinically significant differences in survival. 

Study populations and treatment protocols are summarized in Summary Table 3. Additional 

details are in Appendix Tables 1A–D, 1H.*

 Information in the tables came exclusively from 

articles except for the Park, Kim, Jeong, et al. (1996) study. Park, Kim, Jeong, et al. (1996) did 

not report survival probabilities at yearly intervals, so an author was contacted directly and 

additional data were sought. The data obtained from the author represented a larger patient 

sample than described in the article. 

Concurrent vs. Sequential 

 Interventions. Two trials compared concurrent and sequential TRTx. Radiation dose in the 

Takada, Fukuoka, Kawahara, et al. (2002) study was 45 Gy, while it varied between 40 and 50 

Gy in the Park, Kim, Jeong, et al. (1996) study. Both studies gave concurrent TRTx in weeks 1-

3. Sequential TRTx occurred in weeks 13-15 in the Takada, Fukuoka, Kawahara, et al. (2002) 

trial and between weeks 19 and 24 in the Park, Kim, Jeong, et al. (1996) study. Takada, 

Fukuoka, Kawahara, et al. (2002) delivered 2 daily fractions of TRTx in both groups, while Park, 

Kim, Jeong, et al. (1996) gave it to the concurrent group. Both studies gave prophylactic cranial 

 

*

 Appendixes cited in this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/lungcansmall/lungcan.pdf
28 

irradiation (PCI). Platinum-based chemotherapy was used by Park, Kim, Jeong, et al. (1996), but 

not by Takada, Fukuoka, Kawahara, et al. (2002). 

Summary Table 2. Overall Summary of Question 1 Trials 

TRTx Timing 

Study 

Treatment 

arm 

Control 

arm 

Treatment 

n 

Control 

n Pt? CTx 

TRTx 

Dose 

(Gy) 

#Fracs

/d 

Tx Control PCI

? 

Quality 

Rating 

Takada, 

Fukuoka, 

Kawahara, 

et al., 2002 

Multicenter 

concurrent sequential 114 114 yes PE 45 

2/d 

wk 1-3 wk 13-

15 

yes Good 

Park, Kim, 

Jeong, et 

al., 1996 

Single 

center 

concurrent sequential 32 47 yes CAVCbPE 40-50 

2/d,1/d 

wk 1-3 wk 19-

24 

yes Poor 

 

Sun, Zhang, 

Yin, et al., 

1995 

Multicenter 

alternating sequential 64 59 no/ 

yes 

COM

E, 

CECAP 

30-60 

1/d 

wk 4-9 wk 13-18 ? Poor 

Gregor, 

Drings, 

Burghouts, 

et al., 1997 

Multicenter 

alternating sequential 170 165 no CAE 50 

1/d 

wk 7,11, 

15,19 

wk 15-

18 

? Good 

 

Lebeau, 

Urban, 

Brechot, et 

al., 1999 

Multicenter 

alternating concurrent 74 82 no CAECVE 55/50 

1/d 

wk 6-7, 

10-11, 

14-16 

wk 5-9 yes Good 

 

Work, 

Nielsen, 

Bentzen, et 

al. 

1997/Work, 

Bentzen, 

Nielsen, et 

al., 1996 

Single 

center 

early 

alternating 

late 

alternating 

99 100 yes CAVPE 40-45 

1/d 

wk 1-2, 

6-7 

wk 18-

19, 23-

24 

yes Fair 

Abbreviations table provided at the end of the Report. 
29 

Summary Table 3. Sample and Treatments: Alternating, Concurrent, or Sequential Radiotherapy Study n Age 

% Female % Performance Status 

CTx Regimen RTx Regimen 

Gregor, Drings, Burghouts, et al., 1997 EORTC LCCG Multiple European institutions, 3/89 -1/95 

Total 335 Seq 165 Alt 170 

md (rng) 61 (33-75) 61 (34-74) 

32.1 34.1 

0 1 2 3 46.1 47.9 4.2 1.8 47.1 44.7 5.9 2.4 ECOG 

CAE same 

Dose Schedule 50 Gy wks 15-18, 20 frac, 1/d, 5/w 50 Gy wks 7, 11, 15, 19; 20 frac, 

Lebeau, Urban, Brechot, et al., 1999 26 French institutions, 5/88 – 5/94 

Total 156 Alt 74 Conc 82 

mn 58 57 

14.9 20.7 

0 1 2-3 NR 50.0 44.6 4.1 1.4 51.2 46.3 2.4 0.0 ECOG 

CAE-CVE same 

Dose Schedule 55 Gy wks 6-7, 10-11, 20 Gy, 8 fr wks 14-15, 15 Gy, 6 frac, 150 Gy wks 5-9, 40 Gy, 16 frac, 7 

Takada, Fukuoka, Kawahara, et al., 2002 15 Japanese institutions, 5/91 - 1/95 

Total 228 Seq 114 Conc 114 

md (rng) 64 (30-74) 65 (39-74) 

18.4 20.2 

0 1 2 28.9 65.8 5.3 21.9 72.8 5.3 ECOG 

PE same 

Dose Schedule 45 Gy wks 13-15, 30 frac, 2/d, 5/w 45 Gy wks 1-3, 30 frac, 2/d, 5/wk 

Sun, Zhang, Yin, et al., 1995 15 Chinese institutions, 1983 -1989 

Total 123 Seq 59 Alt 64 

COME, CE-CAP Same 

Dose Schedule 45-60 Gy Local dis, after 2 CTx cyc, 30-45 Gy MS/SC LNs, 3-4 wks 45-60 Gy Local dis, between 2 CTx c30-45 Gy MS/SC LNs, 3-4 wks 

Abbreviations table provided at the end of the Report.
30 

Summary Table 3. Sample and Treatments: Alternating, Concurrent, or Sequential Radiotherapy (continued) Study n Age 

% Female % Performance Status 

CTx Regimen RTx Regimen 

Work, Nielsen, Bentzen, et al. 1997/Work, 

Bentzen, Nielsen, et al., 1996 single-center study, 3/81-9/89 

Total 199 L Alt 100 E Alt 99 

md (rng) 59 (36-69) 61 (36-70) 

29 45 

100 90-80 70-60 50-40 10.0 70.0 15.0 5.0 13.1 68.7 14.1 4.0 KPS 

CAPE Same 

Dose Schedule 40-45 Gy wks 18-19, 23-24, 1 frac/d 40-45 Gy wks 1-2, 6-7, 1 frac/d 

Park, Kim, Jeong, et al., 1996 Korean Center 5/91 – 5/96 

Total 51 Seq 24 Conc 27 

mn (sd) 60.6 (8.9) 57.5 (8.8) 

20.8 14.8 

0 1 2 25.0 45.8 29.2 14.8 63.0 22.2 

CAVCbPE Same 

Dose Schedule 40-50 Gy wks 19-24, 1 frac/d  45 Gy wks 1-3, 2 frac/d 
31 

 Populations. Groups were well-balanced on age, gender and performance status in the 

Takada, Fukuoka, Kawahara, et al. (2002) study (n=228). The sample of 51 patients in the Park, 

Kim, Jeong, et al. (1996) article was also well-balanced on these characteristics, but the survival 

data represented 79 patients and no comparison of baseline characteristics is available for all. 

 Quality and Reporting. The Takada, Fukuoka, Kawahara, et al. (2002) trial was rated as 

being of good quality. The Park, Kim, Jeong, et al. (1996) study was rated as poor due to 

insufficient information about assembly and maintenance of comparable groups, in addition to 

uncertainty about full accounting of subjects in data analysis. 

 Results. Survival outcomes are shown in Summary Table 4 and adverse events in Summary 

Table 5. More detailed results are in Appendix Tables 1E-1G.* Both studies showed survival 

results favoring concurrent TRTx, but were generally not statistically significant. Unadjusted 

overall survival did not differ significantly between concurrent and sequential TRTx, although p 

values were nearly significant. Overall median survival favored concurrent therapy by 5.1 

months (Park, Kim, Jeong, et al., 1996) and 7.5 months (Takada, Fukuoka, Kawahara, et al., 

2002). A Cox proportional hazards model regression found that treatment was a significant 

predictor of survival, producing a hazard ratio of 0.70 (95 percent confidence interval [CI]: 0.52–

0.94) for concurrent relative to sequential TRTx. Takada, Fukuoka, Kawahara, et al. (2002) also 

reported that median progression-free survival favored the concurrent group by 2 months 

(p=0.084), but Park, Kim, Jeong, et al. (1996) did not report on progression. 

Neither study reported on quality of life, but both reported tumor response data. Both found 

nonsignificantly higher overall response rates (ORRs) in the concurrent group, although the Park, 

Kim, Jeong, et al. (1996) study found a fairly large difference in rates that approached 

significance. In the Takada, Fukuoka, Kawahara, et al., 2002) study, ORRs were 96.5 percent; 

for concurrent and 92.1 percent for sequential (p=0.25). The complete responses (CRs) were 

higher in the concurrent group (39.5 percent) than in the sequential group (27.2 percent, p=0.07). 

In the Park, Kim, Jeong, et al. (1996) trial, the concurrent group achieved an ORR of 88 percent, 

versus 63 percent for sequential (p=0.13). Mean response duration was longer in the sequential 

group than in the concurrent group (395 days vs. 180 days, p=0.03). 

Among 12 categories of adverse events, 5 were reported by both studies (Summary Table 6). 

Significant between-group differences were not found in either trial for anemia, 

thrombocytopenia, infection and fever. Both studies found significantly higher risks of 

leukopenia for those in the concurrent arm. In the Takada, Fukuoka, Kawahara, et al. (2002) 

study, grade 3 or 4 leukopenia was seen in 88.4 percent of concurrent-arm patients and in 53.6 

percent of sequential-arm patients (p=0.001). The risk of higher grade leukopenia among 

concurrent TRTx patients in the Park, Kim, Jeong, et al. (1996) study was 51.8 percent, 

compared with 16.7 percent of sequential TRTx patients (p=0.02). One study reported data on 

each of 7 adverse events, none of which was marked by significant differences between 

concurrent and sequential TRTx: treatment-related mortality, nausea/vomiting, esophagitis, renal 

toxicity; alopecia, arrhythmias, and hepatic toxicity.

 

*

 Appendixes cited in this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/lungcansmall/lungcan.pdf
32 

Summary Table 4. Survival Outcomes: Alternating, Concurrent and Sequential Radiotherapy Study N OS Md (mo)1 yr 2 yr 3 yr 4 yr 5 yr PFS Md (mo) 1 yr 2 yr 3 yr Gregor, Drings, Burghouts, et al., 1997 

Seq 165 Alt 170 Difference: 

 15 64% 23% 15% ~14% ~12%  14 60% 26% 12% ~10% ~4%  -1 -4% 3% -3% -4% -8% (CPHM: RR 0.88, 95% CI 0.68-1.1, p=0.237; p=0.288, logrank) 

 12 50% 22% 17%  10 43% 16% 10%  -2 -7% -6% -7% (Log-rank p=0.07) 

Lebeau, Urban, Brechot, et al., 1999 

Alt 74 Conc 82 Difference 

 14.0 63% 17% 11% 6% 6%  13.5 54% 13% 6% 4% 4%  -0.5 -9% -4% -5% -2% -2% 

(p=0.15, log-rank, 66 Alt deaths, 77 Conc deaths) 

Takada, Fukuoka, Kawahara, et al., 2002 

Seq 114 Conc 114 Difference 

 19.7 ~80% 35.1% 20.2% ~20% 18.3%  27.2 ~80% 54.4% 29.8% ~25% 23.7%  7.5 0% 19.3% 9.6% 5% 5.4% (p=0.097 eligible patients, p=0.086 all randomized, log-rank; CPMH: HR 0.70, 95% CI 0.52-0.94, p=0.02) 

 ~10 ~38% ~19% ~15%  ~12 ~50% ~28% ~25%  2 12% 9% 10% (p=0.084, log-rank)) 

Sun, Zhang, Yin, et al., 1995 

Seq 59 Alt 64 Difference 

 64.0% 13.6% 12.0%  62.5% 28% 16.0%  -1.5% 14.4% 4% 

Work, Nielsen, Bentzen, et al. 1997/Work, 

Bentzen, Nielsen, et al., 1996 

L Alt 100 E Alt 99 Difference 

 12.0 ~49% 18.8% ~12% ~12% 12.0%  10.5 ~43% 20.2% ~13% ~12% 10.8%  -1.5 -6% 1.4% 1% 0% -1.2% (p=0.41, not significant, RR 0.88, 95% CI 0.66-1.08) 

 NR ~15 ~58% 31.7% ~27%  NR ~9 ~42% 27.7% 25%  -18% -4% 0.2% (PWIFR, HR 0.79, 95% CI 0.56-1.12) 

Park, Kim, Jeong, et al., 1996 

Seq 47 Conc 32 Difference 

 16.0 74.4% 27.7% 8.8% 4.4% 2.2% 

 18.4 81.3% 29.0% 13.8% 10.7% 7.4%  2,4 6.9% 1.3% 5.0% 6.3% 5.2% (p=0.11) 

Abbreviations table provided at the end of the Report. 
33 

Summary Table 5. Adverse Events: Alternating, Concurrent, or Sequential Radiotherapy Toxicity Type Study Severity or Grade Group n % Group n % p NTreatment-related mortality 

Lebeau 1999 Deaths from aplasia 

Deaths from pulmonary fibrosis 

Alt 74 2.7 Conc 82 3.7 0.67 Alt 74 1.4 Conc 82 7.3 0.05 

GW

 Takada 2002 Seql 110 3.6 Conc 112 2.7 0.72  Work 1997 L Alt 100 0 E Alt 99 0 1.00 Nausea/Vomiting Gregor 1997 Or vomiting, acute (WHO grade) 

0 1 2 3 4 

NR 

Seql 165 25.5 Alt 169 36.1 0.129  21.8 21.3  37.6 25.4  13.3 15.4  0.6 1.2  1.2 0.6 

LeW

 Takada 2002 Or vomiting (WHO grade > 3) Seql 110 19.1 Conc 112 10.7 0.09 Anorexia Le

TW

Lethargy Le

TW

Neurosensory Work 

1997/1996 

Moderate neurotoxicity (grade < 3) in 11 (of 199); no difference between groups Le

TP

Hearing loss Le

TW

Esophagitis Gregor 1997 Acute (WHO grade) 

0 1 2 3 

Late esophageal stenosis 

(WHO grade) 

0 1 2 3 

NR 

Seql 165 83.0 Alt 169 75.7 0.198  7.9 11.8  6.1 9.5  3.0 3.0 Seql 143 82.5 Alt 135 94.1 0.010  11.2 3.0  2.8 1.5  2.1 0.7  1.4 0.7 

LeW

 Takada 2002 WHO grade > 3 Seql 110 3.6 Conc 112 8.9 0.17 Abbreviations table provided at the end of the Report.
34 

Summary Table 5. Adverse Events: Alternating, Concurrent, or Sequential Radiotherapy (continued) Toxicity Type Study Severity or Grade Group n % Group n % p NBronchopulmonary Gregor 1997 Late Lung fibrosis (RTOG grade) 

0 1 2 3 4 

NR 

Seql 143 19.6 Alt 135 11.1 0.135  19.6 20.0  21.7 27.4  18.2 14.8  18.9 24.4  2.1 2.2 

TW

 Lebeau 1999 Pulmonary fibrosis Alt 74 2.7 Conc 82 8.5 0.17 Pneumonitis Le

TW

Kidney Work 

1997/1996 

 quantified by chromium-edathamil clearance; did not 

differ between groups 

LeT

 Park 1996 ECOG grade 3 

ECOG grade 4 

Seql 24 0 Conc 27 0 1.00  0 0 

Anemia Takada 2002 WHO grade 3 Seql 110 41.8 Conc 112 53.6 0.08 Le

S

 Park 1996 ECOG grade 3 

ECOG grade 4 

Seql 24 0 Conc 27 3.7 1.00  0 0 

Thrombocytopenia Gregor 1997 Acute (WHO grade) 

0 1 2 3 4 

NR 

Seql 165 55.2 Alt 169 24.9 <0.001 13.9 17.2  10.9 23.1  12.7 11.8  6.7 20.7  0.6 2.4 

Le

 Takada 2002 (WHO grade) 

3 4 

> 3 

Seql 110 12.7 Conc 112 29.5 0.11  13.6 7.1  26.4 36.6 

 Work 

1997/1996 

WHO grades 3 & 4 L Alt 100 13 E Alt 99 13 1.00 

 Park 1996 ECOG grade 3 

ECOG grade 4 

Seql 24 0 Conc 27 0 1.00  0 3.7 
35 

Summary Table 5. Adverse Events: Alternating, Concurrent, or Sequential Radiotherapy (continued) Toxicity Type Study Severity or Grade Group n % Group n % p Leukopenia or neutropenia 

Gregor 1997 Acute leukopenia (WHO grade) 

0 1 2 3 4 

NR 

Seql 165 6.7 Alt 169 4.1 <0.001 5.5 1.2  10.9 3.6  34.5 17.8  41.8 71.6  0.6 1.8 

 Lebeau 1999 Neutropenia (grade 3 or 4) Alt 74 60.8 Conc 82 58.5 0.87  Takada 2002 Leukopenia (WHO grade) 

3 4 

3 or 4 

Seql 110 44.5 Conc 112 50.9 0.001  9.1 37.5  53.6 88.4 

 Work 1997/1996 WHO grades 3 & 4 leukopenia 

WHO grade 4 leukopenia 

L Alt 100 39 E Alt 99 67 <0.001 6 23 0.0006

 Park 1996 Leukopenia ECOG grade 3 

ECOG grade 4 

Seql 24 12.5 Conc 27 40.7 0.0176 4.2 11.1 

Infection Takada 2002 WHO grade >3 Seql 110 0.9 Conc 112 5.4 0.12  Work 1997/1996 neutropenic fever in 8 patients; no difference between 

groups 

 Park 1996 ECOG grade 3 

ECOG grade 4 

Seql 24 0 Conc 27 3.7 1.00  0 0 

Other Takada 2002 Alopecia (WHO grade >3) Seql 109 12.7 Conc 109 11.6 0.99  Takada 2002 Fever (WHO grade >3) Seql 110 1.8 Conc 112 1.8 0.99  Takada 2002 Arrhythmias (WHO grade >3) Seql 110 0.0 Conc 112 1.8 0.50  Park 1996 Hepatic ECOG grade 3 

Hepatic ECOG grade 4 

Seql 24 0 Conc 27 0 1.00  0 0 
36 

Summary Table 6. Adverse Events Reported in Takada and Park Trials 

Adverse Event 

Takada Park 

Treatment-related Mortality 

 NR 

Nausea/vomiting 

 NR 

Esophagitis 

 NR 

Anemia 

 

Thrombocytopenia 

 

Leukopenia 

▲ ▲

Kidney 

NR 

Infection 

 

Fever 

 

Alopecia 

 NR 

Arrhythmias 

 NR 

Hepatic 

NR 

▲=significantly more frequent in concurrent than in sequential arm; ▼=significantly less frequent in concurrent than in 

sequential arm; NR=not reported; blank cell=outcome reported, but arms not significantly different 

Summary. These 2 studies suggest better efficacy outcomes for concurrent TRTx than for 

sequential TRTx, with inconsistent statistical significance, along with similar rates of adverse 

events of all types except leukopenia, which was more common for concurrent TRTx. 

Unadjusted analyses of overall survival found nearly significant differences favoring concurrent 

over sequential TRTx in 2 studies. One study using adjustment by Cox regression found a 

significant treatment effect for concurrent TRTx. One study that analyzed progression-free 

survival reported a nearly significant difference in favor of concurrent TRTx. CRs were more 

common with concurrent therapy in both studies, but not significantly so (p values were 0.07 and 

0.13). One study found a significantly longer response duration for concurrent TRTx. Only 1 of 

11 types of adverse events showed significant between-group differences. Leukopenia was more 

common for concurrent TRTx in both studies. 

Alternating vs. Sequential 

 Interventions. Both Sun, Zhang, Yin, et al. (1995) and Gregor, Drings, Burghouts, et al. 

(1997) delivered TRTx in single fractions per day. There was a wide range of total doses in the 

Sun, Zhang, Yin, et al. (1995) study (30–60 Gy), while the Gregor, Drings, Burghouts, et al. 

(1997) study gave 50 Gy to all patients. Alternating TRTx was given between weeks 4 and 9 in 

the Sun, Zhang, Yin, et al. (1995) study, whereas Gregor, Drings, Burghouts, et al. (1997) 

administered it every 4 weeks between 7 and 20 weeks. In the Gregor, Drings, Burghouts, et al. 

(1997) study, 4 weeks of TRTx in the alternating arm was given over a period of 13 weeks 
37 

wherease sequential TRTx was given over 4 consecutive weeks. Sun, Zhang, Yin, et al. (1995) 

provided TRTx over 6 consective weeks in both the alternating and sequential arms. That study 

also used platinum-based chemotherapy in the later period of the trial, but no patients received it 

in the Gregor, Drings, Burghouts, et al. (1997) study. Neither report made clear whether patients 

received PCI. 

 Populations. The Sun, Zhang, Yin, et al. (1995) article did not report any baseline patient 

characteristics; it simply stated that 123 patients had localized disease. Patient groups in the 

Gregor, Drings, Burghouts, et al. (1997) study (n=335) were well-matched on the 3 key 

characteristics: age, gender and performance status. 

 Quality and Reporting. Gregor, Drings, Burghouts, et al. (1997) received a good study 

quality rating. Sun, Zhang, Yin, et al. (1995) was rated as poor because details were lacking for 

all quality domains. 

 Results. Gregor, Drings, Burghouts, et al. (1997) did not find a statistically significant 

difference between groups in adjusted survival. Median survival was 15 months in the 

sequential group and 14 months in the alternating group. The entire survival curve for the 

sequential TRTx group was slightly higher than that of the alternating group. Between 1 and 4 

years, survival probabilities differed by 4 percent or less, while the difference was 8 percent at 5 

years. In the Sun, Zhang, Yin, et al. (1995) study, statistical test results for survival were 

missing. At 1 year, the survival probability was higher in the sequential group by 1.5 percent, 

whereas at 2 an 3 years, it was higher for the alternating group by 14.4 percent and 4 percent. 

Relative risks (RR) for death at 2 years and 3 years were computed for purposes of metaanalysis. At 2 years, the RR of 0.831 significantly favors alternating TRTx (95 percent CI: 

0.692–0.999). The difference is smaller and in the same direction at 3 years, with an RR of 

0.957, but nonsignificant (95 percent CI: 0.831–1.102). The difference in progression-free 

survival favoring sequential TRTx in the Gregor, Drings, Burghouts, et al. (1997) study 

approached statistical significance (p=0.07). Neither study reported on tumor response or quality 

of life. 

Sun, Zhang, Yin, et al. (1995) reported no data on adverse events (Summary Table 7), while 

Gregor, Drings, Burghouts, et al. (1997) gave data on 6 types. There were no between-group 

differences in the incidence of nausea/vomiting, acute esophagitis, or late pulmonary fibrosis. 

Late esophagitis was significantly less frequent in the alternating group, compared to the 

sequential group (p=0.01). Both thrombocytopenia and leukopenia were more common 

(p<0.001) in the alternating group. 
38 

Summary Table 7. Adverse Events Reported in Gregor and Sun Trials 

Adverse Event Gregor Sun 

Nausea/vomiting 

NR 

Acute Esophagitis 

NR 

Late Esophagitis 

▼ NR 

Late Pulmonary Fibrosis 

NR 

Thrombocytopenia 

▲ NR 

Leukopenia 

▲ NR 

▲=significantly more frequent in alternating than in sequential arm; ▼=significantly less frequent in alternating than in 

sequential arm; NR=not reported; blank cell=outcome reported, but arms not significantly different 

 Summary. Results are mixed on the relative impact on outcomes for alternating and 

sequential TRTx. One study reported that the survival curve for sequential TRTx was always 

higher than that for alternating TRTx, but the difference was not significant. The other study 

showed a significant difference in the RR of death at 2 years favoring alternating TRTx. The 

study reporting progression-free survival found a nearly significant advantage for sequential 

TRTx. Late esophagitis was more common for the sequential group, but thrombocytopenia and 

leukopenia were more frequent in the alternating group. These data do not show a clear 

advantage for either sequential or alternating TRTx. 

Alternating vs. Concurrent 

 Interventions. The Lebeau, Urban, Brechot, et al. (1999) study delivered doses of 55 Gy to 

the alternating TRTx group and 50 Gy to the concurrent TRTx group.* Radiation was given in 

once daily fractions to both groups. Concurrent TRTx was offered across 5 weeks from week 5 

through 9, while alternating TRTx occurred across 11 weeks during weeks 6–7, 10–11 and 14–

16. Both groups received PCI. Non-platinum chemotherapy was administered. 

 Populations. The 2 groups of patients in this study (n=156) were well-matched on baseline 

characteristics. 

 Quality and Reporting. This trial received a good study quality rating. 

 

* During final preparation of this report, a second comparison was published of concurrent versus alternating TRTx (Blackstock, 

Bogart, Matthews, et al., 2005). The study compared five weeks of continuous radiation concurrent with chemotherapy cycles 

1-2 (n=56) versus split-course alternating radiation given during weeks without chemotherapy in cycles 1-3 (n=54). Overall 

survival did not differ between the two groups (median, 14 versus 15 months; survival at 2 years, 36% versus 31%; survival at 5

years 18% versus 17%). Since radiation began in week 1 for the continuous arm and in week 2 for the alternating arm, this study 

did not meet inclusion criteria for meta-analysis of early versus late radiation therapy.
39 

 Results. The entire survival curve for alternating TRTx lies slightly above that for 

concurrent TRTx, but the difference overall was not significant. Differences in survival 

probabilities ranged from a high at 1 year of 9 percent to a low of 2 percent at 5 years. 

Progression-free survival and quality of life was not reported. There was no statistically 

significant difference between groups in tumor response rates. 

Four types of adverse events (Summary Table 8) were noted by Lebeau, Urban, Brechot, et 

al. (1999). The only outcome that showed a statistically significant between-group difference 

was deaths from pulmonary fibrosis, which were more common in the concurrent TRTx group 

(p=0.05). 

Summary Table 8. Adverse Events Reported in Lebeau Trial 

Adverse Event Lebeau 

Deaths from aplasia 

Deaths from Pulmonary 

Fibrosis 

▲

Pulmonary Fibrosis 

Neutropenia 

▲=significantly more frequent in concurrent than in alternating arm; ▼=significantly less frequent in concurrent than in 

alternating arm; NR=not reported; blank cell=outcome reported, but arms not significantly different 

Summary. The single study comparing alternating and concurrent TRTx does not suggest a 

meaningful improvement in survival associated with alternating TRTx. Overall survival did not 

differ significantly, with a difference between medians of only 0.5 months favoring alternating 

TRTx. Deaths from pulmonary fibrosis were more frequent in the concurrent TRTx group. 

Early Alternating vs. Late Alternating 

 Interventions. The dose given to both groups in the early phase of the Work and colleagues 

study (Work, Nielsen, Bentzen, et al., 1997/Work, Bentzen, Nielsen, et al., 1996) was 40 Gy; it 

was increased later to 45 Gy. Radiation was delivered as a single daily fraction in both treatment 

arms. TRTx was given during weeks 1–2 and 6–7 in the early-alternating group and in weeks 

18–19 and 23–24 in the late-alternating group. Given the somewhat lower total dose in this 

study compared with other studies addressed above and administration in split-course fashion, 

TRTx was given at a relatively low dose rate. Both groups received PCI. The chemotherapy 

regimen for all patients was platinum-based; however the regimen was given in an unusual 

schedule and the doses of drugs actually delivered is unclear.. 

 Populations. Groups receiving early and late alternating TRTx were well-balanced on 

baseline patient characteristics. 
40 

 Quality and Reporting. This study was rated as fair in quality. The key deficiency was an 

inadequate description of the randomization method. 

 Results. Work and colleagues (Work, Nielsen, Bentzen, et al., 1997/Work, Bentzen, 

Nielsen, et al., 1996) reported that median survival was slightly longer in the late-alternating 

group (1.5 months), while 2- and 3-year survival probabilities were slightly higher in the earlyalternating group. Overall, there was no significant difference in survival between groups. 

There was an 18 percent difference at 1 year in percentage without in-field recurrence (PWIFR) 

favoring late-alternating TRTx, but differences at later times were much smaller and the groups 

did not differ significantly. Tumor response rates did not differ for the 2 patient groups. No 

quality of life data were collected. 

Of the 6 categories of adverse events, only leukopenia showed a difference between groups 

(Summary Table 9). This outcome was significantly more common among those receiving early 

alternating TRTx. 

Summary Table 9. Adverse Events Reported in Work Trial 

Adverse Event Work 

Treatment-related Mortality 

Neurotoxicity 

Kidney 

Thrombocytopenia 

Leukopenia ▲

Infection 

▲=significantly more frequent in early alternating than in late alternating arm; ▼=significantly less frequent in early alternating 

than in late alternating arm; NR=not reported; blank cell=outcome reported, but arms not significantly different 

Summary. The single study comparing early and late alternating is does not support 

conclusions about the relative effectiveness of these approaches to TRTx. There was no 

significant difference between groups on overall survival, percentage without in-field recurrence 

and tumor response. Of 6 types of adverse events reported, groups differed only in the frequency 

of leukopenia, which was significantly higher among those receiving early alternating TRTx. 

Conclusions 

Among 6 studies meeting selection criteria for Key Question 1, two trials (n=307) compared 

concurrent and sequential TRTx. Two trials compared alternating to sequential TRTx (n=458). 
41 

One trial compared alternating to concurrent TRTx (n=156). The final trial compared early 

alternating and late alternating TRTx (n=199). Comparing these trials with others addressing 

TRTx delivery, survival is generally lower is this set relative to studies assessing the effect of 

hyperfractionation. Although an explanation is not readily apparent, possible reasons include 

patient selection, stage drift and the adequacy of chemotherapy. 

Concurrent vs. Sequential. Results are not conclusive but suggest better outcomes for 

concurrent TRTx. Although not statistically significant, unadjusted overall survival and CR rates 

favored concurrent TRTx in both studies. However, adjusted overall survival in the larger study 

was significantly in favor of concurrent TRTx. A smaller study found significantly longer 

response duration for concurrent TRTx in 1 study. Out of 11 types of adverse events, only 

leukopenia occurred significantly more frequently, in the concurrent TRTx group in both studies. 

 Alternating vs. Sequential. Inconsistent findings were observed in the 2 studies and no 

conclusions can be drawn that one is superior to the other. The direction of the advantage on 

overall survival differed in the 2 studies. 

Alternating vs. Concurrent. In the single study comparing alternating and concurrent 

TRTx, there was no statistically significant effect on survival and no conclusions of differential 

efficacy could be drawn. 

Early Alternating vs. Late Alternating. In the single study comparing early versus late 

alternating TRTx, there was no statistically significant difference in survival, thus no conclusions 

of differences in efficacy can be reached. 

Key Question 2 

For limited-stage SCLC, do outcomes (survival, toxicity, or quality of life) differ if 

concurrent TRTx is given in early versus late chemotherapy cycles? 

Overview 

Six randomized, controlled trials (RCTs) compared outcomes of alternate times to administer 

TRTx concurrently in first-line therapy for limited stage SCLC (N=1,177). Summary Table 10 

summarizes selected study variables; further details are in Summary Table 11 and Appendix 

Tables 2A-C, 2H.* Each of the three larger trials randomized from 125 to 166 patients per arm 

(Murray, Coy, Pater, et al., 1993/Coy, Hodson, Murray, et al., 1994/Feld, Payne, Hodson, et al., 

1988 [hereafter referred to as “Murray-Coy-Feld”]; Perry, Eaton, Propert, et al., 1987/Ahles, 

Silberfarb, Rundle, et al., 1994/Perry, Herndon, Eaton, et al., 1988; [hereafter referred to as 

“Perry-Ahles-Perry”]; James, Spiro, O’Donnell, et al., 2003). Together, the three smaller trials 

 

*

 Appendixes cited in this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/lungcansmall/lungcan.pdf.
42 

included less than one-fourth of all patients studied (Jeremic Shibamoto, Acimovic, et al., 1997; 

Qiao, Zhou, Xin, et al., 2004; Skarlos, Samantas, Briassoulis, et al., 2001). 

Summary Table 10. Selected study parameters of RCTs comparing times to give concurrent TRTx 

N TRTx timing 

study early late Pt? chemoTx

regimen

TRTx 

dose (Gy)

# 

frac

s early late 

PCI

? 

# 

centers 

pub 

type 

quality 

rating 

Murray, Coy, 

Pater, et al., 

1993/Coy, 

Hodson, Murray, 

et al., 1994/Feld, 

Payne, Hodson, 

et al., 1988 

155 153 yes CAV/PE 40 1/d wk 4-6 wk 16-18 yes multi full good 

Perry, Eaton, 

Propert, et al., 

1987/Ahles, 

Silberfarb, 

Rundle, et al., 

1994/Perry, 

Herndon, Eaton, 

et al., 1988 

125 145 no CAVE 50 1/d wk 1-5 wk 10-14 yes multi full fair 

Jeremic 

Shibamoto, 

Acimovic, et al., 

1997 

52 51 yes PE/CbE 54 2/d wk 1-4 wk 6-9 yes one full fair 

Qiao, Zhou, Xin, 

et al., 2004 45 45 yes CbE 50 or 60 1/d wk 1-5/6 wk 12-16/17 ? one full fair 

Skarlos, 

Samantas, 

Briassoulis, et 

al., 2001 

42 39 yes CbE 45 2/d wk 1-3 wk 10-12 yes multi full fair 

James, Spiro, 

O’Donnell, et al., 

2003 

159 166 yes CAV/PE 40 1/d wk 4-6 wk 16-18 yes multi abstr not 

rated 

Abbreviations table provided at the end of the Report. 
43 

Summary Table 11. Sample and Methods: Early Versus Late Radiotherapy Study N Age 

% Female % Performance Status 

CTx Regimen RTx Regimen 

Murray, Coy, Pater, et al., 1993/Coy, Hodson, Murray, et al., 1994/Feld, Payne, Hodson, et al., 1988 22 centers 1/85 - 12/88 

Total 308 Early 155 Late 153 

md 61.8 61.6 

40.6 34.6 

0 1 2 3 21.9 65.2 12.3 0.6 22.2 68.0 9.2 0.7 ECOG 

CAV-PE same 

Dose Schedule 40 Gy wks 4-6, 1/d, 5/wk, 15/cou 40 Gy wks 16-18, 1/d, 5/wk, 15/co

Perry, Eaton, Propert, et al., 1987/Ahles, Silberfarb, Rundle, et al., 1994/Perry, Herndon, Eaton, et al., 1988 22 centers 1/81 - 6/84 

Total 270 Early 125 Late 145 

% < 60 48 45 

38 37 

0 1 2/3 38 48 13 42 45 9 CALGB 

CAVE same 

Dose Schedule 50 Gy wks 1-5, 40 Gy+10 Gy boo 50 Gy wks 10-14, 40 Gy+10 Gy b 

Jeremic Shibamoto, Acimovic, et al., 1997 single center 1/88-12/92 

Total 103 Early 52 Late 51 

mn (rng) 57 (40-67) 57 (44-66) 

40.4 39.2 

90, 100 50-80 52 48 47 53 KPS 

PE/Cb-E same 

Dose Schedule 54 Gy wks 1-4, 2/d, 5/wk  54 Gy wks 6-9, 2/d, 5/wk 

Abbreviations table provided at the end of the Report. 
44 

Summary Table 11. Sample and Methods: Early Versus Late Radiotherapy (continued) Study N Age 

% Female % Performance Status 

CTx Regimen RTx Regimen 

Qiao, Zhou, Xin, et al., 2004 single center 3/93-1/98 

Total 90 Early 45 Late 45 

md (rng) 57 (36-58) 56 (38-69) 

24.3 33.3 

all randomized patients had KPS >70 (excluded if <60) Cb-E 

same 

Dose Schedule  50-60 Gy begun 1st CTx cyc, over 6 

 50-60 Gy begun after 4th CTx cyc, ov

Skarlos, Samantas, Briassoulis, et al., 2001 multicenter 12/93 - 11/99 

Total 81 Early 42 Late 39 

md (rng) 61 (40-76) 60 (37-76) 

7 10 

0 1 2 3 26 50 24 41 44 15 ECOG 

Cb-E same 

Dose Schedule 45 Gy wks 1-3, 2/d, 5/wk  45 Gy wks 10-12, 2/d, 5/wk 

James, Spiro, O’Donnell, et al., 2003 (abstract only) multicenter; 1/93 -1/02 

Total 325 Early 159 Late 166 

md (rng) 62 (34-74) 62 (33-74) 

40 43 

0-1 2-3 91 9 89 11 ECOG 

CAV-PE same 

Dose Schedule 40 Gy wks 4-6, 1/d, 5/wk  40 Gy wks 16-18, 1/d, 5/wk 
45

Interventions. Available studies did not uniformly define early and late concurrent therapy, 

with respect to either the chemotherapy cycle or weeks during which they administered TRTx. 

Most trials (4 of 6) began TRTx in chemotherapy cycle 1 (i.e., week 1) for those randomized to 

early concurrent therapy; two waited until cycle 2 (week 4) (Murray-Coy-Feld; James, Spiro, 

O’Donnell, et al., 2003). Those randomized to late concurrent therapy began TRTx in cycle 3 

(week 6) in one trial (Jeremic Shibamoto, Acimovic, et al., 1997), cycle 4 (week 10 or 12) in 

three trials (Perry-Ahles-Perry; Qiao, Zhou, Xin, et al., 2004; Skarlos, Samantas, Briassoulis, et 

al., 2001), and cycle 6 (week 16) in the remaining two trials (Murray-Coy-Feld, James, Spiro, 

O’Donnell, et al., 2003). 

Five of six RCTs used platinum-etoposide chemotherapy regimens, including two of three 

larger trials; Perry-Ahles-Perry was the exception. Total TRTx dose was >40 Gy in each RCT, 

and only two used doses greater than 50 Gy (Jeremic Shibamoto, Acimovic, et al., 1997; Qiao, 

Zhou, Xin, et al., 2004). Three trials gave TRTx over a 3-week period (Murray-Coy-Feld; 

Skarlos, Samantas, Briassoulis, et al., 2001; James, Spiro, O’Donnell, et al., 2003 2003), one 

gave TRTx over four weeks (Jeremic Shibamoto, Acimovic, et al., 1997), and two gave TRTX 

over five or six weeks (Perry-Ahles-Perry; Qiao, Zhou, Xin, et al., 2004). Thus, weekly doses 

were 10 Gy in two trials (Perry-Ahles-Perry; Qiao, Zhou, Xin, et al., 2004), 13.35 Gy in two 

trials (Murray-Coy-Feld; James, Spiro, O’Donnell, et al., 2003), and 15 Gy in two trials (Jeremic 

Shibamoto, Acimovic, et al., 1997; Skarlos, Samantas, Briassoulis, et al., 2001). Four trials 

administered single daily fractions (Murray-Coy-Feld; Perry-Ahles-Perry; Qiao, Zhou, Xin, et 

al., 2004; James, Spiro, O’Donnell, et al., 2003) and two gave two fractions per day (Jeremic 

Shibamoto, Acimovic, et al., 1997; Skarlos, Samantas, Briassoulis, et al., 2001). Five of six 

trials included PCI for each arm; Qiao, Zhou, Xin, et al. (2004) did not report PCI use. 

Study Populations. Most trials studied patients with relatively favorable baseline 

characteristics, and were nearly always well-balanced across arms for consistently-reported 

factors (Summary Table 11). In four of six trials, performance status (PS) was 0-1 at enrollment 

for 75 percent to 91 percent of patients across arms (Murray-Coy-Feld; Perry Ahles-Perry; 

Skarlos, Samantas, Briassoulis, et al., 2001; James, Spiro, O’Donnell, et al., 2003). PS also was 

well balanced across arms in Jeremic Shibamoto, Acimovic, et al. (1997), but many patients (~50 

percent) had Karnofsky scores of 50-80. Qiao, Zhou, Xin, et al. (2004) excluded patients with 

Karnofsky PS <60, but did not report PS distribution by arm. For all six trials, the median or 

mean age ranged from approximately 55 to 62 years, and was balanced across arms. Each trial 

enrolled mostly men (8.6 percent women in one trial, 33 percent to 43 percent across five 

others), and had similar proportions of women in each arm. 

Other prognostic factors and baseline characteristics were reported inconsistently (Appendix 

Table 2B*

). Only three trials reported the proportion with weight loss at entry (Perry-AhlesPerry; Jeremic Shibamoto, Acimovic, et al., 1997; Skarlos, Samantas, Briassoulis, et al., 2001). 

Only three trials reported the proportion with disease outside the lung (Murray-Coy-Feld, Qiao, 

Zhou, Xin, et al., 2004; Skarlos, Samantas, Briassoulis, et al., 2001). Only one trial reported the 

proportion of former smokers (Skarlos, Samantas, Briassoulis, et al., 2001). No trials reported 

racial distributions. 

 

*

 Appendixes cited in this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/lungcansmall/lungcan.pdf.
46

Study Quality and Reporting. The larger studies included one good-quality and one fairquality multicenter trial, each published in full. The third large trial also was multicenter, but 

was reported only in abstract and information to rate quality was lacking. Two of three small 

trials were single-center and one was multicenter; each was of fair quality and published in full. 

Results 

In one large and two smaller trials, results significantly favored the early TRTx arms for 

overall (OS), progression-free (PFS), or local recurrence-free (LRFS) survival (Summary Table 

12). Murray-Coy-Feld (n=308) reported significantly longer median OS (21.2 versus 16.0 

months; p=0.008) and greater 2- and 3-year survival (40 percent versus 33.7 percent and 29.7 

percent versus 21.5 percent, respectively) with early TRTx. Murray-Coy-Feld also reported 

significantly greater PFS with early TRTx (median, 15.4 versus 11.8 months; 26 percent versus 

19 percent at 3 years; p=0.036). Qiao, Zhou, Xin, et al. (2004; n=90) reported longer median OS 

(26 versus 19 months; p<0.05) and greater 3-year survival (33 percent versus 22 percent) with 

early TRTx, but did not report an outcome related to progression or recurrence. Jeremic 

Shibamoto, Acimovic, et al. (1997; n=103) reported significantly greater 2- and 3-year LRFS 

with early TRTx (90 percent versus 69 percent and 73 percent versus 61 percent, respectively; 

p=0.011). While median OS (34 versus 26 months) and 2- and 3-year survival also favored early 

TRTx in the Jeremic Shibamoto, Acimovic, et al. (1997) trial, these results were just barely 

statistically nonsignificant (p=0.052). 

Between-arm differences in response rates were not statistically significant in any trial 

(Appendix Table 2F). 

In two large and one smaller RCTs, OS and time to treatment failure (TTF) did not differ 

significantly between arms randomized to early or late TRTx (Summary Table 12). Perry-AhlesPerry (n=270), the only trial that did not use platinum, reported non-significant differences in OS 

(P=0.144) and TTF (p=0.238). James, Spiro, O’Donnell, et al. (2003; n=325), the sole trial 

published as an abstract, only reported OS and also found no significant difference (p=0.18). 

Skarlos, Samantas, Briassoulis, et al. (2001; n=81) reported nonsignificant differences for 

median OS (p=0.65) and median TTF (p=0.6). 

A small pilot sub-study from one RCT reported the only data comparing quality of life 

outcomes after early versus late TRTx. Ahles et al. (1994) scored responses to measures of 

mood, psychosocial function, and cognitive function for 14-17 patients (of n=121) given early 

TRTx and 10-12 (of n=141) given late TRTx in the Perry-Ahles-Perry trial (Appendix Table 

2F).*

 
47

Summary Table 12. Survival Outcomes: Early Versus Late Radiotherapy Study N 

Overall Survival Med 1 yr 2 yr 3 yr 4 yr 5 yr 

Other Outcomes (progression, failureMed 1 yr 2 yr 3 yr 

Murray, Coy, Pater, et al., 1993/Coy, Hodson, Murray, et al., 1994/Feld, Payne, Hodson, et al., 1988 

Early 155 Late 153 Difference 

21.2 ~77% 40% 29.7% 23.7% 20% 16.0 ~63% 33.7% 21.5% 15.1% 11% 5.2 14% 6.3% 8.2% 8.6% 9% (p=0.008, log-rank; 0.005 Wilcoxon) 

15.4 ~65% ~28% 26% 11.8 ~48% ~24% 19% 3.6 17% 4% 7% (PFS, p=0.036, log-rank; 0.014 Wilcoxo

Perry, Eaton, Propert, et al., 1987/Ahles, Silberfarb, Rundle, et al., 1994/Perry, Herndon, Eaton, et al., 1988 

Early 125 Late 145 Difference 

13.0 ~53% ~24% ~10% 14.5 ~62% ~30% ~20% -1.5 -9% -6% -10% (p=0.144; not significant) 

11.0 ~45% 15% ~8% 11.2 ~50% 25% ~15% -0.2 -5% -10% -7% (TTF, p=0.238; not significant) 

Jeremic Shibamoto, Acimovic, et al., 1997 

Early 52 Late 51 Difference 

34 90% 71% 48% 35% 30% 26 71% 53% 39% 25% 15% 8 19% 18% 9% 10% 15% (p=0.052) 

52 94% 90% 73% 51 74% 69% 61% 1 20% 21% 12% (LRFS, p=0.011) 

Qiao, Zhou, Xin, et al., 2004 

Early 45 Late 45 Difference 

26 78% 33% 27% 19 53% 22% 16% 7 25% 11% 11% (log-rank, p<0.05) 

Skarlos, Samantas, Briassoulis, et al., 2001 

Early 42 Late 39 Difference 

17.5 ~65% 36% 22% 17 ~80% 29% 13% 0.5 -15% 7% 9% (p=0.65, not significant) 

9.5 ~40% ~25% ~20% 10.5 ~35% ~15% ~15% -1.0 5% 10% 5% (TTF, p=0.6, not significant) 

James, Spiro, O’Donnell, et al., 2003 (abstract only) 

Early 159 Late 166 Difference 

13.5 16% 15.1 20% -1.6 -4% (HR = 1.18; 95% CI: 0.93, 1.51; p=0.18) 

Abbreviations table available at the end of the Report. 
48

They compared these with scores for another group randomized to chemotherapy without 

TRTx (not abstracted). Results suggested larger decrements of mood and psychosocial function 

after chemotherapy plus TRTx than after chemotherapy alone. However, they found no 

meaningful differences in magnitude of decrement between early and late TRTx groups. 

Table 13 shows that leukopenia/neutropenia and esophagitis were the only adverse events 

consistently reported by all six trials. Although leukopenia/neutropenia was more common in 

the early arm of five RCTs, only Qiao, Zhou, Xin, et al. (2004; p<0.05) and James, Spiro, 

O’Donnell, et al. (2003; p=0.006) reported that differences were statistically significant 

(Summary Table 14). Of four reporting RCTs, only Murray-Coy-Feld reported significantly 

more anemia in the early treatment arm (49 percent versus 37 percent, p=0.03). Skarlos, 

Samantas, Briassoulis, et al. (2001) reported significantly more grade 3 esophagitis with late than 

with early TRTx. However, the arms did not differ significantly when grades 1-3 were pooled, 

and the other five trials reported no significant differences in grade 3 or 3+4 combined. 

Summary Table 13. Adverse Events, Early versus Late Concurrent TRTx 

Adverse 

Event 

Murray/Coy/ 

Feld 

Perry/Ahles/ 

Perry 

Jeremic 

1997 Qiao 2004 Skarlos 

2001 James 2003 

leukopenia/ 

neutropenia ▲ ▲

anemia ▲ NR NR 

esophagitis ▼ 

▲=significantly more frequent in early than in late arm; ▼=significantly less frequent in early than in late arm; NR=not 

reported; blank cell=outcome reported, but arms not significantly different 

Between-arm differences in treatment-related mortality (3 reporting trials), nausea/ vomiting 

(5 reporting trials), neurosensory effects (3 reporting trials), bronchopulmonary effects or 

pneumonitis (3 reporting trials each), thrombocytopenia (5 reporting trials), and infections (4 

reporting trials) were not statistically significant. 

Conclusions 

Overall, the evidence is equivocal, either finding no difference or a small advantage for early 

TRTx. One larger trial of good quality significantly favored concurrent therapy given in an early 

cycle (Murray-Coy-Feld; median OS 21.2 versus 16.0 months; p=0.008), as did 2 smaller trials. 

Of the two larger trials that that found no significant difference, one did not use platinum 

chemotherapy and the other has not been published in full text. Meta-analysis on the question of 

early versus late TRTx was performed to attempt to obtain clearer results. 

Leukopenia/neutropenia appeared to be more common with early concurrent TRTx, although 

differences were statistically significant in only two of six reporting trials. Other events do not 

appear to be more frequent with either early or late TRTx. However, evidence is limited as 

adverse events were not reported consistently across all trials. 
49

S`1ummary Table 14. Adverse Events: Early Versus Late Radiotherapy Toxicity Type Study Severity or Grade Early n % Late n % p Not ReportTreatment-related mortality 

Murray 1993 Coy 1994 Feld 1988 

 155 1.3 153 1.3 NS Jeremic 199

 Perry 1987 

Ahles 1994 Perry 1998 

 125 4 145 1 NS 

 Skarlos 2001 42 0 39 0 NS Nausea/Vomiting Murray 1993 

Coy 1994 Feld 1988 

required IV fluids 155 11.6 153 15.8 NS Qiao 2004 

 Perry 1987 

Ahles 1994 Perry 1998 

nausea and vomiting, NOS 122 18 140 10 NS 

 Jeremic 1997 nausea and vomiting, grades 3 & 4 52 9.6 51 7.8 NS  Skarlos 2001 grade 3 nausea and vomiting 42 2.5 39 2.5 NS  James 2003 nausea and vomiting, grades 3 & 4 159 2 166 3 NS Anorexia Perry 1987 

Ahles 1994 Perry 1998 

>10% weight loss ? 14 NR NR Murray 1993

Jeremic 1992003 

 Qiao 2004 weight loss (% not specified) 45 20 45 33.3 NS Lethargy Murray 1993

Perry 1987/Jeremic 1992001; Jame

Neurosensory Murray 1993 

Coy 1994 Feld 1988 

severe 

life-threatening 

lethal 

155 0.6 153 3.3 NS for all 0 1.3 3 levels  0.6 0 combined

Jeremic 199

 Perry 1987 

Ahles 1994 Perry 1998 

“neuromuscular effects” 124 17 144 16 NS 

 Skarlos 2001 grade 2 & 3 neurotoxicity 42 0 39 0 NS Hearing loss Murray 1993

Perry 1987/Jeremic 1992001; Jame

Abbreviations table provided at the end of the Report. 
50

Summary Table 14. Adverse Events: Early Versus Late Radiotherapy (continued) Toxicity Type Study Severity or Grade Early n % Late n % p Not ReportEsophagitis Murray 1993 

Coy 1994 Feld 1988 

fluids only 

IV fluids 

149 11.4 133 6.8 NS for  3.4 0.8 both  levels combined

 Perry 1987 

Ahles 1994 Perry 1998 

not specified ? 10 ? 8 

 Jeremic 1997 grades 3 & 4 52 28.9 51 25.5 NS  Qiao 2004 45 42.2 45 28.9 NS  Skarlos 2001 grade 3 42 2.5 39 18 0.026 

 (p=0.82 for overall incidence)

 James 2003 grades 3 & 4 159 7 166 4 NS Bronchopulmonary Perry 1987 

Ahles 1994 Perry 1998 

not specified 122 9 133 6 NS Murray 1993

2004; Jame

 Jeremic 1997 grades 3 & 4 52 1.9 51 0 NS  Skarlos 2001 Grade 3 42 5.0 39 7.5 NS Pneumonitis Murray 1993 

Coy 1994 Feld 1988 

any 

lethal 

149 3.2 133 0.7 NS  0 0 

Jeremic 1992003 

 Perry 1987 

Ahles 1994 Perry 1998 

not specified 122 9 133 4.5 NS 

 Qiao 2004 radio-pneumonia 45 8.9 45 6.7 NS Kidney Murray 1993 

Coy 1994 Feld 1988 

creatinine > 354 μmol/L 155 0 153 0.7 NS Perry 1987/

Jeremic 199

 Skarlos 2001 grade 2 or 3 42 0 39 0 NS Anemia Murray 1993 

Coy 1994 Feld 1988 

Hb <80 g/L 155 49 153 36.8 0.0275 Perry 1987/

Qiao 2004 

 Jeremic 1997 grades 3 & 4 52 13.5 51 7.8 NS  Skarlos 2001 grades 3 & 4 42 19 39 12.5 NS  James, 2003 grades 3 & 4 159 9 166 5 NS Thrombocytopenia Murray 1993 

Coy 1994 Feld 1988 

<25 x 109/L 155 3.9 153 2.6 NS Qiao 2004 

 Perry 1987 

Ahles 1994 Perry 1998 

<25 x 109/L 122 1 140 2 NS 

 Jeremic 1997 grades 3 & 4 52 38.5 51 21.6 NS  Skarlos 2001 grades 3 & 4 42 21.5 39 23 NS  James, 2003 grades 3 & 4 159 9 166 9 NS 
51

Summary Table 14. Adverse Events: Early Versus Late Radiotherapy (continued) Toxicity Type Study Severity or Grade Early n % Late n % p Not RepoLeukopenia or neutropenia 

Murray 1993 Coy 1994 Feld 1988 

neutrophils<0.5 x 109/L 155 70.3 153 61.4 NS 

 Perry 1987 

Ahles 1994 Perry 1998 

WBC<1 x 109/L 117 35 118 25 NS 

 Jeremic 1997 leukopenia, grades 3 & 4 52 32.7 51 41.2 NS  Qiao 2004 grade 2 

grade 3 grade 4 

45 6.7 45 24.4  71.1 57.8 0.02 (for  22.2 17.8 3+4) 

 Skarlos 2001 grades 3 & 4 leukopenia 42 35.5 39 20.5 NS  James, 2003 grades 3-4 leucopenia 159 74 166 55 0.006 Infection Murray 1993 

Coy 1994 Feld 1988 

neutropenic fever 

septic shock 

lethal 

155 4.5 153 3.3 NS  0.6 0.7 (for all 3  0 1.3 combined)

Qiao 2004

 Perry 1987 

Ahles 1994 Perry 1998 

sepsis 125 20 140 15 NS 

 Jeremeic 1997 grades 3 & 4 52 13.5 51 13.7 NS  Skarlos 2001 neutropenic fever 42 5 39 2.5 NS Other Murray 1993 

Coy 1994 Feld 1988 

severe dermatitis 

blisters 

149 2.0 133 1.5 NS (for  4.0 0.7 both  combined)

 Qiao 2004 mild digestive tract reaction 45 73.3 45 55.6 NS 
52

Meta-Analysis/Meta-Regression 

Overview 

All but one of the studies selected for Key Questions 1 and 2 can be viewed as comparing 

early and late TRTx. Key Question 2 is limited to studies in which both early and late TRTx 

were given concurrently with chemotherapy, while Key Question 1 included those with arms 

defined by TRTx given either concurrently, sequentially or in alternating fashion. Only the study 

by Lebeau, Urban, Brechot et al. (1999) is excluded because only 1 week separated the start of 

TRTx in the study’s 2 arms. Four previous meta-analyses have compared the impact of early 

and late TRTx, but none have included all 11 studies reviewed here. Three meta-analyses are 

summarized in Summary Table 25; a meta-analysis by Cancer Care Ontario (2003) is omitted 

because it used much more restrictive study selection criteria, including only 4 studies. The 

meta-analysis of 8 studies by Fried, Morris, Poole, et al. (2004) used the most rigorous methods 

and comprised the largest pool of the previous meta-analyses. The present meta-analysis 

addresses whether the findings of Fried, Morris, Poole, et al. (2004) can be reproduced in light of 

a larger study pool and different meta-analytic techniques. 

Fried, Morris, Poole, et al. (2004) used the Mantel-Haenszel pooling method and found no 

significant heterogeneity at either 2 or 3 years; thus, fixed-effects models were employed. A 

significant increase in 2-year survival was found for early TRTx over late TRTx (RR: 1.17, 95 

percent CI: 1.02–1.35). The effect was not significant at 3 years (RR: 1.13, 95 percent CI: 0.92–

1.39). Subgroups of studies using hyperfractionation and platinum regimens had significant 

increases in 2- and 3-year survival favoring early TRTx, nonsignificant results were found for 

subgroups that did not use hyperfraction and platinum. Random effects meta-regression of risk 

differences (RDs) found that higher RDs were seen at both 2 and 3 years when studies used both 

hyperfractionation and platinum chemotherapy. Thus, larger effects of early over late TRTx 

were associated with combining hyperfractionation and platinum chemotherapy. 

The present meta-analysis differs from that of Fried, Morris, Poole, et al. (2004) in the 

following ways: it included 3 additional studies; it used inverse variance weighting rather than 

the Mantel-Haenszel pooling method; and random effects meta-regression was carried out using 

RRs for this analysis and RDs by Fried, Morris, Poole, et al. (2004). In addition, Fried, Morris, 

Poole, et al. (2004) created 3 subgroups from the combination of hyperfractionation and 

platinum and used indicator variables for them in the meta-regression. This Review kept these 

variables separate. It could be argued that the hetereogeneity of comparisons across studies is 

too great to warrant pooling them. Like previous meta-analyses on this topic, we address this 

concern by using influence analysis, subgroup/sensitivity analysis, and meta-regression to 

investigate whether potential sources of hetereogeneity are associated with different results. 

2-Year Mortality. The funnel plot in Figure 2 shows asymmetry in the lower right portion, 

suggestive of publication bias. The Egger regression test (Summary Table 15) reveals that the 

intercept differs significantly from zero. These results suggest the presence of publication bias. 

Summary Table 16 and Figure 3 show 2-year RRs for each individual trial, along with 95 

percent confidence intervals (CIs). It should be noted that all RRs were computed based on data 

from articles for all studies except Park, Kim, Jeong, et al. (1996). The Park, Kim, Jeong, et al. 

(1996) article did not give survival probabilities at yearly periods so an author was contacted 
53

who provided data for a larger sample than was described in the original articles. The Sun, 

Zhang, Yin, et al. (1995) and Takada, Fukuoka, Kawahara, et al. (2002) trials both obtained 2-

year RRs showing a significant reduction in the risk of mortality for early TRTx. One study 

(Perry, Herndon, Eaton, et al. 1998) found a slight nonsignificant increase in mortality for early 

TRTx and the remaining 6 studies yielded nonsignificant decreases in mortality for early TRTx. 

Summary Table 15. Egger Linear Regression Test for Publication Bias, 2-Year Mortality 

 Coefficient Standard Error L95 U95 t p value 

Intercept -2.444 0.936 -4.658 -0.230 -2.61 0.035 

Figure 2: Two-Year Mortality Funnel Plot, Early vs.Late Thoracic 

Radiotherapy for Limited Stage Small-Cell Lung Cancer

0 .05 .1 .15 .2 .25

Standard error of log RR

.67 .8 1 1.25 1.5

Relative risk - log scale

Funnel plot with pseudo 95% confidence limits
54

Summary Table 16. Individual Trial 2-Year Mortality Relative Risks, Confidence Intervals and Covariate Matrix

Study 

Early 

Deaths 

Early 

n 

Late 

Deaths 

Late 

n RR L95 U95 Earliest Hyper Plat Conc GQ

Murray 93 155 101 153 0.909 0.766 1.079 0 0 1 1 1 

Sun 46 64 51 59 0.831 0.692 0.999 0 0 0 0 0 

Park 23 32 34 47 0.994 0.751 1.314 1 1 1 0 0 

Gregor 126 170 127 165 0.963 0.852 1.088 0 0 0 0 1 

Jeremic 15 52 24 51 0.613 0.366 1.028 1 1 1 1 0 

Work 79 99 81 100 0.985 0.859 1.130 1 0 1 0 0 

Perry 104 125 113 145 1.068 0.950 1.200 1 0 0 1 0 

Skarlos 27 42 28 39 0.895 0.664 1.208 1 1 1 1 0 

Takada 52 114 74 114 0.703 0.552 0.895 1 1 1 0 1 

The Q statistic value obtained here (Summary Table 17) exceeds the threshold for concluding 

that significant heterogeneity of treatment effects exists, therefore a random effects pooled 

estimate was computed (see forest plot in Figure 3). The pooled RR is 0.921 and the 95 percent 

CI overlaps the null value of 1.0 (0.844, 1.005). Figure 4 presents the results of influence 

analysis, in which each individual study is excluded from the random effects pooled estimate. 

This graph can be interpreted by finding the studies that depart to the greatest extent from the 

vertical line for the full pooled estimate RR of 0.92. When the Perry study is excluded, the 

lowest RR estimate, 0.898, is obtained. So Perry exerts the greatest influence of pulling the 

pooled estimate toward the null or an advantage for late TRTx. Exclusion of the Takada, 

Fukuoka, Kawahara, et al. (2002) study results in the highest RR estimate, 0.955. Takada, 

Fukuoka, Kawahara, et al. (2002) is the most influential study in drawing the pooled estimate in 

the direction favoring early TRTx. Exclusion of the Perry study was the only instance in which a 

significant pooled result was obtained. However, as a whole, excluding any individual study has 

little influence on the estimate of the pooled RR. 

Summary Table 17. Results from Heterogeneity Tests and Random Effects Meta-Analysis 

 Study Subject p RE p 

 n n Q value RR L95 U95 Z Value 

2-Year Mortality 9 1726 15.393 0.052 0.921 0.844 1.005 -1.852 0.064 
55

Summary Table 18 gives the results of subgroup/sensitivity analysis. Selection of variables 

defining subgroups was constrained by the relatively small pool of studies. Fine gradations of 

variables dilute the power to detect differences between early and late TRTx. Two concerns 

guide interpretation of subgroup results: the magnitude of differences in RR point estimates for 

different levels of a variable and whether statistical significance is achieved in any subgroup. Q 

statistic values exceeded the threshold for significant heterogeneity in 4 instances: among those 

studies that delivered the early TRTx at the earliest time (beginning in the first week of 

chemotherapy), those that did not use platinum chemotherapy, those that gave TRTx and 

chemotherapy concurrently, and those studies rated as being of good quality. These subgroups 

were pooled using random-effects models, while all other subgroups were pooled with fixedeffects. 

Use of hyperfractionation was the variable with the greatest difference in point estimates of 

RR between subgroups of studies. Inclusion of studies using hyperfractionation produced a 

significant pooled RR of 0.815 (95 percent CI: 0.702–0.946). Studies that used once daily 

fractionation had a pooled RR much closer to the null, 0.972 (95 percent CI: 0.913–1.035). 

There was a moderate difference between point estimates of those studies that did and did not 

use platinum. Studies using platinum in chemotherapy regimens obtained a greater reduction in 

mortality, with a significant RR of 0.905 (95 percent CI: 0.829–0.987). Those not using 

Figure 3: Two-Year Mortality Random Effects Forest Plot, Early vs.Late

Thoracic Radiotherapy for Limited Stage Small-Cell Lung Cancer, All Trials

Favors Early (Relative risk - log scale) Favors Late

.5 .8 1 1.25 2

 Combined

 Takada

 Skarlos

 Perry

 Work

 Jeremic

 Gregor

 Park

 Sun

 Murray
56

platinum yielded an RR close to the null, 0.964 (95 percent CI: 0.848–1.096). The set of studies 

that offered the earliest early TRTx did not result in a statistically significant reduction in 

mortality at 2 years for early TRTx (RR=0.914, 95 percent CI: 0.792–1.054). The point estimate 

for those studies not among the earliest was nearly identical and also nonsignificant (RR=0.918, 

95 percent CI: 0.841–1.001). .Those using concurrent TRTx had a nonsignificant RR of 0.938 

(95 percent CI: 0.799–1.100) and those not using concurrent TRTx had a significant RR of 0.920 

(95 percent CI: 0.854–0.992). There was a considerable difference between studies of good 

quality and lesser quality, but pooled results were nonsignificant for both. Good quality studies 

produced a RR of 0.874 (95 percent CI: 0.744–1.027). Lesser quality studies had a RR of 0.975 

(95 CI: 0.906–1.050). A random effects meta-regression (Table 19) found that no variables was 

a significant predict of differences in treatment effect at 2 years, but hyperfractionation was 

nearly significant (p=0.07). 

Figure 4: Two-Year Mortality Random Effects Influence Plot, Early vs.Late

Thoracic Radiotherapy for Limited Stage Small-Cell Lung Cancer

 0.81 0.84 0.92 1.00 1.03

 Murray

 Sun

 Park

 Gregor

 Jeremic

 Work

 Perry

 Skarlos

 Takada

 Study ommited

 Meta-analysis random-effects estimates (exponential form)
57

Summary Table 18. Results of Subgroup/Sensitivity Analyses, Two-Year Mortality 

 Study Subject p p 

2-Year Mortality n n Q value Model RR L95 U95 Z value 

Earliest-Yes 6 960 12.796 0.025 RE 0.914 0.792 1.054 -1.241 0.215

Earliest-No 3 766 1.720 0.423 FE 0.918 0.841 1.001 -1.929 0.054

 

Hyperfractionation-Yes 4 491 4.921 0.178 FE 0.815 0.702 0.946 -2.691 0.007

Hyperfractionation-No 5 1235 5.893 0.207 FE 0.972 0.913 1.035 -0.890 0.373

 

Platinum-Yes 6 998 8.300 0.140 FE 0.905 0.829 0.987 -2.258 0.024

Platinum-No 3 728 5.212 0.074 RE 0.964 0.848 1.096 -0.563 0.573

 

Concurrent RTx-Yes 4 762 6.285 0.099 RE 0.938 0.799 1.100 -0.790 0.430

Concurrent RTx-No 5 964 7.726 0.102 FE 0.920 0.854 0.992 -2.182 0.029

 

Good Quality-Yes 3 871 5.209 0.074 RE 0.874 0.744 1.027 -1.638 0.101

Good Quality-No 6 855 8.647 0.124 FE 0.975 0.906 1.050 -0.672 0.501
58

Summary Table 19. Results of Meta-Regression 

2 Year Mortality 

 

Model Z p value 

Initial tau 

squared

Model tau 

squared

 

Earliest 0.26 0.797 0.0077 0.0086 

 

Hyperfractionation -1.81 0.070 0.0034 

Platinum -0.98 0.327 0.0070 

Concurrent 0.57 0.571 0.0074 

Good Quality -0.82 0.414 0.0073 

3-Year Mortality. The funnel plot (Figure 5) suggests the presence of publication bias. 

Point estimates appear to be missing in the lower right region of the plot. Linear regression 

(Egger test, Table 20) shows that the intercept differs significantly from zero, confirming that 

publication bias may be present. 

Three-year mortality RRs for individual trials are given in Table 21. Three trials obtained 

RR estimates favoring late TRTx, while the other 8 favor early TRTx. The 95 percent CIs all 

overlap the null value RR of 1.0. 

Table 22 shows that the Q statistic value does not exceed the level for concluding that 

significant heterogeneity of effects is present. Thus, a fixed effects model was used to compute a 

pooled 3-year RR (see forest plot in Figure 6). The obtained estimate was 0.991 (95 percent CI: 

0.955–1.029). Based on these results, it cannot be concluded that use of early TRTx significant 

reduces the risk of mortality at 3 years. 

The influence analysis plot in Figure 7 shows only extremely small changes in the pooled RR 

estimate when individual studies are excluded. When the Perry study is excluded, the lowest 

pooled RR estimate is produced: 0.977. This study has the greatest impact on drawing the 

pooled RR toward the null or effects favoring late TRTx. The largest pooled RR is derived when 

the Murray study is excluded: 1.000. Murray has the strongest influence on pulling the pooled 

RR away from the null, favoring early TRTx. Point estimates changed very little when 

individual studies were excluded. 

Results of subgroup/sensitivity analysis are presented in Summary Table 23. The subset of 

studies using hyperfractionation yielded a significant pooled RR of 0.908 (95 percent CI: 0.828–

0.995). Those that used once daily fractionation had a nonsignificant pooled RR of 1.008 (95 

percent CI: 0.968–1.050). No other subgroup produced a significant result. Studies in which 

platinum was part of chemotherapy regimens had an RR of 0.958 (95 percent CI: 0.910–1.009). 

Non-platinum studies produced an RR of 1.029 (95 percent CI: 0.975–1.085). The group of 

studies in which early TRTx was begun at the earliest time produced a nearly null-value RR 

(0.998, 95 percent CI: 0.953–1.045). Those studies that began early TRTx after the first week of 

chemotherapy produced a similar RR (0.980, 95 percent CI: 0.921–1.042). Studies that offered 

concurrent RTx had a similar pooled RR (0.997, 95 percent CI: 0.947–1.051) compared with 
59

those that did not (RR: 0.985, 95 percent CI: 0.935–1.038). There was a modest difference 

between studies of good quality versus lesser quality. Good quality studies had an RR of 0.948 

(95 percent CI: 0.843–1.064), while fair and poor quality studies had an RR of 1.000 (95 CI: 

0.956, 1.047). Results of random effects meta-regression are shown in Summary Table 24. Use 

of hyperfractionation (p=0.04) was the only significant predictor, while use of platinum (p=0.06) 

was nearly a significant predictor of differences in treatment effects. 

Summary Table 20. Egger Linear Regression Test for Publication Bias, 3Year Mortality 

 Coefficient Standard Error L95 U95 t p value 

Intercept -2.351 0.540 -3.573 -1.130 -4.35 0.002 

Figure 5: Three-Year Mortality Funnel Plot, Early vs. Late 

Thoracic Radiotherapy for Limited Stage Small-Cell Lung Cancer

0 .05 .1 .15 .2

Standard error of log RR

.67 .8 1 1.25 1.5

Relative risk - log scale

Funnel plot with pseudo 95% confidence limits
60

Summary Table 21. Individual Trial 3-Year Mortality Relative Risks, Confidence Intervals and Covariate Matrix 

Study 

Early 

Deaths 

Early 

N 

Late 

Deaths 

Late 

n RR L95 U95 Earliest Hyper Plat Conc GQ

Murray 109 155 120 153 0.897 0.786 1.023 0 0 1 1 1 

Sun 54 64 52 59 0.957 0.831 1.102 0 0 0 0 0 

Park 28 32 43 47 0.956 0.817 1.119 1 1 1 0 0 

Gregor 150 170 140 165 1.040 0.955 1.132 0 0 0 0 1 

Jeremic 27 52 31 51 0.854 0.607 1.203 1 1 1 1 0 

Work 86 99 88 100 0.987 0.888 1.097 1 0 1 0 0 

Perry 115 125 128 145 1.042 0.963 1.128 1 0 0 1 0 

Skarlos 33 42 34 39 0.901 0.739 1.099 1 1 1 1 0 

Takada 80 114 91 114 0.879 0.756 1.023 1 1 1 0 1 

James 134 159 133 166 1.052 0.951 1.164 1 0 1 1 0 

Qiao 30 45 35 45 0.857 0.662 1.111 0 0 1 1 0 

Summary Table 22. Results from Heterogeneity Tests and Fixed Effects Meta-Analysis 

 Study Subject p FE p 

 n n Q value RR L95 U95 Z Value

3-Year Mortality 11 2141 12.019 0.284 0.991 0.955 1.029 -0.457 0.648
61

Figure 6: Three-Year Mortality Fixed Effects Forest Plot, Early vs. Late 

Thoracic Radiotherapy for Limited Stage Small-Cell Lung Cancer, All Trials

Favors Early (Relative risk - log scale) Favors Late

.67 .8 1 1.25 1.5

 Combined

 Qiao

 James

 Takada

 Skarlos

 Perry

 Work

 Jeremic

 Gregor

 Park

 Sun

 Murray
62

Figure 7: Three-Year Mortality Fixed Effects Influence Plot, Early vs. Late 

Thoracic Radiotherapy for Limited Stage Small-Cell Lung Cancer

 0.94 0.96 0.99 1.03 1.04

 Murray

 Sun

 Park

 Gregor

 Jeremic

 Work

 Perry

 Skarlos

 Takada

 James

 Qiao

 Study ommited

 Meta-analysis fixed-effects estimates (exponential form)
63

Summary Table 23. Results of Subgroup/Sensitivity Analyses, Three-Year Mortality 

 Study Subject p p 

3-Year Mortality n n Q value Model RR L95 U95 Z value 

Earliest-Yes 7 1285 7.037 0.317 FE 0.998 0.953 1.045 -0.089 0.929

Earliest-No 4 856 4.770 0.189 FE 0.980 0.921 1.042 -0.644 0.520

 

Hyperfractionation-Yes 4 491 0.722 0.868 FE 0.908 0.828 0.995 -2.061 0.039

Hyperfractionation-No 7 1650 7.095 0.312 FE 1.008 0.968 1.050 0.406 0.685

 

Platinum-Yes 8 1413 7.302 0.398 FE 0.958 0.910 1.009 -1.637 0.102

Platinum-No 3 728 1.167 0.558 FE 1.029 0.975 1.085 1.039 0.299

 

Concurrent RTx-Yes 6 1177 7.872 0.163 FE 0.997 0.947 1.051 -0.098 0.922

Concurrent RTx-No 5 964 4.045 0.400 FE 0.985 0.935 1.038 -0.549 0.583

 

Good Quality-Yes 3 871 5.580 0.061 RE 0.948 0.843 1.064 -0.908 0.364

Good Quality-No 8 1270 5.981 0.542 FE 1.000 0.956 1.047 0.015 0.988

Summary Table 24. Results of Meta-Regression 

3 Year Mortality 

 

Model Z p value 

Initial tau 

squared

Model tau 

squared

 

Earliest 0.40 0.688 0.0008 0.0016 

Hyperfractionation -2.05 0.040 <0.0001 

Platinum -1.88 0.060 <0.0001 

Concurrent 0.12 0.906 0.0016 

Good Quality -0.61 0.540 0.0015 
64

Summary Table 25. Summary of Published Meta-Analyses on Early Versus Late Thoracic Radiation Therapy for Limited-St

Study/ 

MetaAnalysis 

2002 

Takada 

1993 

Murray 

1998 

Perry 

1997 

Jeremic 

2001 

Skarlos 

1997 

Work 

2003 

James 

1997 

Gregor 

1999 

Lebeau 

1999 

Goto 

1995 

Sun 

2004 

Qiao 

1996 

Park Method/ 

Measures 

Handling 

of Heterogeneity Results(

Fried, Morris, 

Poole, et al. 

(2004) 

X X X X X X * X 

Fixed 

effects 

(M-H) 

2 yr OS 3 yr OS 

RR RD 

NNT 

M-H χ2, 

subgroup 

analysis, 

sensitivity 

analysis, 

random 

effects 

metaregression 

All studies: 2 3 yr OS RR M-H χ2 p=.1

Excluding TaSubgroups: Hyperfractio Platinum  Concurrent R M-R: hyperfrsignificant di

PijlsJohannesma

, De 

Ruysscher, 

Lambin, et 

al. (2005) 

X X X X X X X 

Random 

effects 

2-3 yr OS 

5 yr OS 

OR, RR 

χ2, 

subgroup 

analysis, 

random 

effects 

metaregression 

All studies: 25 yr OS OR 

χ2 p=.006, 2

Subgroups: Platinum  RTx < 30 d M-R: signific30 d and sur

Huncharek & 

McGarry 

(2004) 

X X X X X X X X 

Fixed 

effects 

(Peto) 

1 yr OS 2 yr OS 3 yr OS 

Peto OR 

Q, 

sensitivity 

analysis 

All studies: 1 2 yr OS P-O3 yr OS P-OQ, p<.001, 1 Subgroups: -Work, -LebePlatinum-Y Double-counpreliminary r

* James, Spiro, O’Donnell, et al. (2003) study included by Fried, Morris, Poole, et al. (2004) only in informal post-hoc analysis; M-H: Mantel-Haenszel stratifie

regression; N: no; NS: not significant; OR: odds ratio; OS: overall survival; P-OR: Peto odds ratio; Q: heterogeneity statistic; RD: risk difference; RR: risk ratio

Y: yes.
65

Summary. This meta-analysis indicates that the findings of Fried, Morris, Poole, et al. 

(2004) are not reproducible when different pooling methods are used and 3 additional studies are 

included. We found evidence of publication bias at both 2 and 3 years, while Fried, Morris, 

Poole, et al. (2004) found it at neither time. Significant heterogeneity was observed at 2 years 

here but not at 3 years. Thus, we used a random effects model at 2 years and a fixed effects 

model at 3 years, but Fried, Morris, Poole, et al. (2004) did not find significant heterogeneity at 

either period and used only fixed effects models. While Fried, Morris, Poole, et al. (2004) 

reported a significant advantage for early TRTx at 2 years and nonsignificance at 3 years, 

nonsignificant results were obtained here at both periods. 

Subgroups including studies using hyperfractionation or platinum yielded significant 

advantages for early TRTx at 2 years in both Fried, Morris, Poole, et al. (2004) and this metaanalysis. At 3 years, Fried, Morris, Poole, et al. (2004) reported that both subgroups retained 

significance, while here only hyperfractionation was significant. The current meta-regression 

found hyperfractionation to be nearly significant (p=0.07) at 2 years; hyperfractionation was 

significant at 3 years (p=0.04) and platinum was nearly significant at 3 years (p=0.06). Fried, 

Morris, Poole, et al. found that hyperfractionation and platinum predicted heterogeneity in risk 

differences. 

As an exercise, we ran multiple variable meta-regression models, but none were significant at 

either period. In particular, hyperfractionation and platinum were not significant independent 

predictors here in multiple variable models. In contrast, Fried, Morris, Poole, et al. (2004) found 

larger effects when the variables were combined. Any meta-gresssion with multiple variables 

models is limited by the risk of overfitting when the pool of studies is small. 

Conclusions 

All but one of the studies selected for Key Questions 1 and 2 can be viewed as comparing 

early and late TRTx. Therefore, these studies were pooled to give a more robust analysis of 

early versus late TRTx. Overall, we did not find significant reductions in 2- and 3-year mortality 

for early TRTx over late TRTx. The RR at 2 years was 0.921 (95 percent CI: 0.844–1.005) and 

the RR at 3 years was 0.991 (0.955, 1.029). Although the overall analysis was nonsignificant, 

sensitivity analysis suggests that if there is an advantage favoring early TRTx it would seem to 

depend on use of hyperfractionation and possibly use of platinum chemotherapy. 

Key Question 3 

For limited-stage SCLC, do outcomes (survival, toxicity, quality of life) of primary therapy 

differ if one varies dose rate, treatment interval, or fractionation scheme for delivering TRTx? 

Comparisons of interest include: 

• accelerated regimens (>10 Gy per week completed over a short interval) versus standard 

duration regimens (<10 Gy per week) versus split courses delivered over the standard 

interval; and 
66

• single daily fractions versus hyperfractionated (two or more daily fractions or 

concomitant boost). 

Overview 

Two randomized controlled trials (RCTs) compared one versus two fractions per day for 

previously-untreated limited stage SCLC (Turrisi, Kim, Blum, et al., 1999/Yuen, Zou, Turrisi, et 

al., 2000 [hereafter referred to as “Turrisi/Yuen”]; Schild, Bonner, Shanahan, et al., 2004/Sloan, 

Bonner, Hillman, et al., 2002/Bonner, Sloan, Shanahan, et al., 1999 [hereafter referred to as 

“Schild/Sloan/Bonner”]; N=678). No other randomized trials directly compared dose rates, 

treatment intervals or fractionation schemes. Summary Table 26 summarizes selected 

characteristics; further details are in Appendix Tables 3A-C, 3H.* 

Summary Table 26 Selected study characteristics of RCTs comparing one versus two fractions per day 

N TRTx dose, 

Gy # fractions x size; TRTx duration study 

2/d 1/d 

chemoT

x 

regimen 2/d 1/d 2/day 1/day 

TRTx 

started PCI? 

Turrisi, Kim, Blum, 

et al., 1999/Yuen, 

Zou, Turrisi, et al., 

2000 

211 206 PE 45 45 30 x 1.5 Gy; 3 

wks 

25 x 1.8 Gy; 5 

wks week 1 yes 

Schild, Bonner, 

Shanahan, et al., 

2004/Sloan, 

Bonner, Hillman, et 

al., 2002/Bonner, 

Sloan, Shanahan, 

et al., 1999 

130 131 PE 48 50.4 32 x 1.5 Gy; 6 

wks* 28 x 1.8 Gy; 6 

wks 

week 

13 yes 

* Split course: 16 fractions over 1.5 weeks, 2.5 weeks rest, then final 16 fractions over 1.5 weeks 

Abbreviations table provided at the end of the Report. 

Interventions. While total radiation doses were similar (45–50 Gy), and each trial compared 

one versus two fractions per day, they differed with respect to TRTx timing relative to 

chemotherapy cycles and other regimen features. The Turrisi/Yuen trial began TRTx in week 

one of cycle one, used the same total dose (45 Gy) in each arm, and gave radiation continuously 

(5 days/week for 3 or 5 weeks) in each arm. Thus, patients randomized to two fractions per day 

received 3 Gy daily and 15 Gy weekly, while those randomized to one fraction per day received 

1.8 Gy daily and 9 Gy weekly. 

The Schild/Sloan/Bonner trial administered three chemotherapy cycles, then restaged and 

randomized patients and began TRTx at week 13. Patients whose tumor had progressed during 

the initial three cycles were excluded if a single radiation field no longer encompassed the full 

extent of disease. Those randomized to two fractions per day received two split courses, each 24 

Gy over 1.5 weeks, separated by 2.5 weeks’ rest. Those randomized to one fraction per day 

received 50.4 Gy over 6 weeks, as 5 days/week of continuous TRTx. Thus, patients in the twoper-day arm received 3 Gy each treatment day, and 16 Gy/week in each of two 1.5 week courses. 

Those in the one-per-day arm received 1.8 Gy daily and 9 Gy weekly for 5 weeks and 3 days. 

 

* Appendixes cited in this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/lungcansmall/lungcan.pdf.
67

Both RCTs used cisplatin-etoposide chemotherapy (Summary Table 26). However, cisplatin 

dose in the Turrisi/Yuen trial was 60 mg/m2

 each 21-day cycle, but was 30 mg/m2 each 28 day 

cycle in the Schild/Sloan/ Bonner trial (Appendix Table 3C).*

Study Populations. Each trial’s study population had relatively good prognosis, and was 

well-balanced across arms for consistently reported baseline characteristics (Summary Table 27, 

Appendix Table 3B).*

 More than 90 percent of patients had good performance status (PS) of 0-1 

at enrollment. Median or mean age ranged from 61 to 63 years across arms. Each trial enrolled 

mostly men (41 percent to 43 percent women across arms). Each reported the proportion of 

patients with weight loss at entry, and few (1–5 percent) had lost more than 10 percent. 

The two trials did not consistently report other prognostic factors or baseline characteristics 

(Appendix Table 3B).* One trial reported both the proportion with disease outside the lung and 

the patients’ racial distribution (Turrisi/Yuen). The other trial stratified patients by response to 

initial chemotherapy (Schild/ Sloan/Bonner). Neither trial reported the proportion of former or 

current smokers. 

Study Quality and Reporting. Both trials were multicenter studies, published in full, and 

rated as good quality. 

Results 

The Turrisi/Yuen trial, using immediate concurrent TRTx, found that overall survival (OS) 

significantly favored the 2/day arm (Summary Table 28). The trial (n=211 2/day arm, 206 1/day 

arm) reported significantly longer median OS (23 versus 19 months; HR=1.2, 95 percent CI: 

1.0–1.6; p=0.04) and greater 2- and 5-year survival (47 percent versus 41 percent, and 26 percent 

versus 16 percent, respectively) with two fractions per day (Turrisi/Yuen). However, the 

difference in failure-free survival at 2 years (29 percent versus 24 percent) was not statistically 

significant (p=0.10). Between-arm differences in response rates also were not statistically 

significant (Appendix Table 3F).*

Using late TRTx and split course therapy in the 2/day arm, Schild/Sloan/Bonner reported no 

significant difference between arms in overall (p=0.68) or progression-free (p=0.68) survival. 

Since this trial stratified patients by responses to three cycles of chemotherapy given before 

randomization, excluded any whose disease progressed substantially, and used an extended splitcourse rather than accelerated schedule in the 2/day arm, response rates could not be compared 

across arms or trials in a meaningful way. 

Neither trial reported quality of life outcomes (Appendix Table 3F).*

The trials differed with respect to the frequency and/or between-arm comparisons of some 

adverse events, but were similar for others (Summary Table 29). Schild/Sloan/Bonner reported 3 

percent treatment-related deaths in the 2/day arm and none in the 1/day arm (p=0.04), while 

Turrisi/Yuen reported similar rates in each arm (2–3 percent). Turrisi/Yuen reported no 

significant differences between arms in the proportion of patients experiencing one or more 

grade 3 (25 percent versus 23 percent), or grade 4 (62 percent versus 63 percent) toxicities. In 

contrast, Schild/Sloan/ Bonner reported significantly more patients in the 2/day arm than the 

 

* Appendixes cited in this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/lungcansmall/lungcan.pdf.
68

1/day arm with a non-hematologic toxicity of grade >3 (54.6 percent versus 38.9 percent, 

p=0.01) or grade 5 (3 percent versus zero, p=0.04). 
69

Summary Table 27. Sample and Methods: Alternative Fractionations Schemes (once versus twice daily) Study N Age 

% Female % Performance Status 

CTx Regimen RTx Regimen 

Turrisi, Kim, Blum, et al., 1999/Yuen, Zou, Turrisi, et al., 2000 multicenter trial 5/89-7/92 

Total 417 1 F/d 206 2 F/d 211 

md (rng) 63 (34-80) 61 (30-82) 

41 42 

0 1 2 3 43 51 5 39 55 5 

PE (4 x 21 day cycles; 1 or 2 during, 2 or 3 after TRTx) 

Dose Schedule 1 F/d: 45 Gy 1.8 Gy/frac, 5 d/wk, 5 wks, 

 wk of CTx 2 F/d 45 Gy 1.5 Gy/frac, 5 d/wk, 3 wks,  wk of CTx 

Schild, Bonner, Shanahan, et al., 2004/Sloan, Bonner, Hillman, et al., 2002/Bonner, Sloan, Shanahan, et al., 1999 multicenter trial 9/90 -11/96 

Total 261 1 F/d 131 2 F/d 130 

mn (rng) 61.8 (38-81) 62.1 (37-79) 

42.0 43.1 

0-1 2 97.7 5.3 93.1 6.9 

PE (6 x 28 day cycles; 3 before, 2 during, 1 after TRTx) 

Dose Schedule 1 F/d: 50.4 Gy 28 x 1.8 Gy fracs, 38 d, 1st 

 AP-PA fields, last 10.8 Gy  fields excluding spine, wks 2 F/d 48 Gy 32 x 1.5 Gy fracs; >4 hours 

 course (16 fracs in 1.5 wee rest; then 16 fracs in 1.5 w

Abbreviations table provided at the end of the Report. 
70

Summary Table28. Survival Outcomes: Alternative Fractionations Schemes (once versus twice daily) Study N 

Overall Survival 

Med 1 yr 2 yr 3 yr 4 yr 5 yr 

Failure- or Progression-Free S

Med 1 yr 2 yr 3 yr 

Turrisi, Kim, Blum, et al., 1999/Yuen, Zou, Turrisi, et al., 2000 

1 F/d 206 2 F/d 211 Difference 

19 ~75% 41% ~32% ~29% 16% 23 ~70% 47% ~28% ~20% 26% 4 ~5% 6% ~4% ~9% 10% (log-rank p=0.04; HR 1.2, 95% CI: 1.0, 1.6) 

FFS: 24%  29%  5%  (p=0.10) 

Schild, Bonner, Shanahan, et al., 2004/Sloan, Bonner, Hillman, et al., 2002/Bonner, Sloan, Shanahan, et al., 1999 multicenter trial 9/90 -11/96 

1 F/d 131 2 F/d 130 Difference 

20.6 ~74% 44% ~33% ~23% 20.4% 20.6 ~74% 44% ~31% ~26% 22% 0 0% 0% -2% 3% 1.6% (p=0.68, log-rank) 

PFS: ~14 ~57% 31.3% ~25%  ~14 ~58% 30.8% ~27%  0 1% -0.5% 2% (p=0.68, log-rank) 

Abbreviations table provided at the end of the Report. 
71

Summary Table 29. Adverse Events: Alternative Fractionations Schemes (once versus twice daily) Toxicity Type Study Severity or Grade 1 F/d n % 2 F/d n % p Not ReportTreatment-related mortality 

Turrisi 1999 Yuen 2000 

 203 2 206 3 NS 

 Bonner 1999 

Sloan 2002 Schild 2004 

 131 0 130 4 0.04 

Nausea/Vomiting Turrisi 1999 

Yuen 2000 

grade 3 vomiting grade 4 vomiting 

203 8 206 8  2 1 NS (3+4)

 Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 nausea 

> grade 3 vomiting 

132 16.7 130 16.9 NS  12.1 14.6 NS 

Anorexia Turrisi 1999 

Yuen 2000 

grade 3 weight loss grade 4 weight loss 

203 3 206 2  0 0 NS (3+4)

 Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 132 3.0 130 2.3 NS 

Lethargy Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 132 3.0 130 7.7 NS Turrisi 1999

Neurosensory Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 132 7.6 130 11.5 NS Turrisi 1999

Hearing loss Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 132 1.5 130 3.8 NS Turrisi 1999

Esophagitis Turrisi 1999 

Yuen 2000 

grade 3 grade 4 

203 11 206 27 <0.001  5 5 

 Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 132 5.3 130 12.3 0.05 (per

 investigators; 0.074 by corrected χ2)

Bronchopulmonary Turrisi 1999 

Yuen 2000 

grade 3 

grade 4 & 5 

203 3 206 4  1 2 NS (3-5) 

 Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 132 4.5 130 6.2 NS 

Pneumonitis Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 132 4.5 130 6.2 NS Turrisi 1999

Kidney Turrisi 1999

1999/Sloan 

Anemia Turrisi 1999 

Yuen 2000 

grade 3 grade 4 

203 23 206 23  3 5 NS (3+4)

 Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 132 3.0 130 2.3 NS 
72

Summary Table29. Adverse Events: Alternative Fractionations Schemes (once versus twice daily) (cont’d) Toxicity Type Study Severity or Grade 1 F/d n % 2 F/d n % p Not RepoThrombocytopenia Turrisi 1999 

Yuen 2000 

grade 3 grade 4 

203 16 206 13  8 8 NS (3+4)

 Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 

grade 4 

128 60.9 127 45.7 0.0145  24.2 20.5 NS 

Leukopenia or neutropenia 

Turrisi 1999 Yuen 2000 

grade 3 grade 4 

203 41 206 38 NS (3+4) 39 44 NS 

 Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 

grade 4 

128 88.3 127 89.8 NS  37.5 36.2 NS 

Hemoglobin Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 128 5.3 127 3.8 NS Turrisi 199

Infection Turrisi 1999 

Yuen 2000 

grade 3 

grades 4 & 5 

203 6 206 6  2 3 NS (3-5) 

 Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 132 2.3 130 3.8 NS 

Other Turrisi 1999 

Yuen 2000 

one or more grade 3, no grade 4 one or more grade 4, no grade 5 

203 23 206 25 NS  63 62 NS 

 Bonner 1999 

Sloan 2002 Schild 2004 

any hematologic, > grade 3 

any hematologic,, > grade 4 

any nonhematologic, > grade 3 

any nonhematologic, > grade 4 

any nonhematologic, grade 5 

any toxicity, > grade 3 

any toxicity, > grade 4 

any toxicity, grade 5 

131 90.1 130 89.2 NS  43.5 42.3 NS  38.9 54.6 0.01  9.2 13.8 NS  0.0 3.1 0.04  91.6 92.3 NS  46.6 46.9 NS  0.0 3.1 0.04 
73

With respect to hematologic toxicities, Schild/ Sloan/Bonner reported substantially more 

grade >3 thrombocytopenia (46 percent and 61 percent for 2/day and 1/day, respectively) than 

did Turrisi/Yuen (21 percent and 24 percent for 2/day and 1/day, respectively). The difference 

significantly favored the 2/day arm in Schild/Sloan/Bonner. However, grade 4 

thrombocytopenia did not differ significantly between arms in either trial. Neither trial reported 

a significant difference between arms in incidence of grade >3 anemia, but it was substantially 

more common with early TRTx and larger cisplatin doses (Turrisi/Yuen; 26 percent and 28 

percent) than with late TRTx and smaller cisplatin doses (Schild/Sloan/Bonner; 3 percent and 2.3 

percent). Grade >3 leukopenia/ neutropenia was common in both trials, and did not differ across 

arms in either (>80 percent in each). 

With respect to non-hematologic toxicities, esophagitis was more common with twice daily 

than with once daily TRTx in each trial. Esophagitis also appeared more common in the 

Turrisi/Yuen trial, which used an accelerated schedule in the hyperfractionated arm, than in the 

other study, which used a split-course schedule. Both trials reported no significant differences 

between arms in incidence of vomiting, anorexia, bronchopulmonary effects, and infections. 

Grade >3 vomiting was not uncommon (9–15 percent). The other grade >3 adverse events 

reported by both trials each occurred in <10 percent of patients. Only Schild/Sloan/Bonner 

reported on lethargy, neurosensory effects, hearing loss, and pneumonitis. Between-arm 

differences were not statistically significant for any of these adverse events. 

Conclusions 

Evidence to compare dose rates, treatment intervals, or fractionation schemes is limited. One 

RCT suggests that starting TRTx with the first cycle of cisplatin-etoposide chemotherapy and 

giving it in two daily fractions over 3 weeks increases overall survival when compared with the 

same dose begun at the same time but given in one daily fraction over 5 weeks. Evidence from a 

second trial is difficult to interpret, since multiple variables were studied simultaneously. 

However, it found no difference in overall survival between treatment arms managed with one 

versus two fractions per day. Neither trial reported data on quality of life. Esophagitis was the 

only adverse event reported more frequently with two fractions per day than with one fraction 

per day in both trials. 

Key Question 4 

What are the relative benefits and harms (survival, toxicity, and quality of life) of adding 

TRTx to chemotherapy for primary treatment of extensive-stage SCLC? 

Overview 

Five small RCTs compared outcomes of chemotherapy with versus without TRTx for 

previously-untreated extensive stage SCLC (N=238; 110–135 randomized to +TRTx, 103–128 to 

-TRTx). Summary Table 30 summarizes selected characteristics of these trials; more complete 
74

details are in Summary Table 31 and Appendix Tables 4A-C, 4H.* The Jeremic, Shibamoto, 

Nikolic, et al. (1999) trial randomized 109 patients; other trials were smaller, ranging from 18 to 

54 patients. 

Interventions. Of the five available trials, only Jeremic, Shibamoto, Nikolic, et al. (1999) 

tested effects of TRTx in the context of current treatment strategies (regimens, doses, and 

schedules). Although both Jeremic, Shibamoto, Nikolic, et al. (1999) and Lebeau, Chastang, 

Brechot, et al. (1993) used platinum-etoposide chemotherapy regimens, only Jeremic, 

Shibamoto, Nikolic, et al. (1999) administered chemotherapy and radiation concurrently. 

Lebeau, Chastang, Brechot, et al. (1993) gave radiation therapy after all chemotherapy was 

completed (sequential administration), while the other three trials alternated chemotherapy and 

radiation and did not use platinum-based chemotherapy. Also noteworthy are the wide range of 

radiation doses used by Lebeau, Chastang, Brechot, et al. (1993), and the low dose and unusual 

schedule of TRTx used by Brincker, Hindberg, Hansen, et al. (1987). 

Another study design feature, unique to Jeremic, Shibamoto, Nikolic, et al. (1999) (Appendix 

Table 4A),*

 permits outcomes of randomized (chemotherapy-responsive) patients to be 

compared with those of nonrandomized patients who responded less completely outside the 

chest. All patients registered for this trial received 3 cycles of cisplatin/etoposide (PE) before 

randomization. To be eligible for the RCT, patients had to achieve a complete response (CR) 

outside the thorax and respond at least partially (PR) in the thorax after three PE cycles. Those 

who achieved only a PR outside the thorax, and those with less than PR in either site, were not 

randomized, but were treated with chemotherapy plus TRTx and followed. 

Study Populations. Only Jeremic, Shibamoto, Nikolic, et al. (1999) limited enrollment to 

extensive-stage disease (ESD) patients. The others included both stages (Appendix Table 4A),*

but reported at least one outcome separately by arm for those with ESD. Rosenthal, Tattersall, 

Fox, et al. (1991) did not report the number of ESD patients per treatment arm. 

Data on baseline characteristics showed that ESD patients enrolled in each arm of Jeremic, 

Shibamoto, Nikolic, et al. (1999) and Nou, Brodin, and Bergh (1998) were similar (Summary 

Table 31, Appendix Table 4B).* The other RCTs pooled baseline characteristics for extensiveand limited-stage patients (Lebeau, Chastang, Brechot, et al., 1993; Brincker, Hindberg, Hansen, 

et al., 1987) or for all participants (Rosenthal, Tattersall, Fox, et al., 1991), thus similarity of 

ESD patients was uncertain. 

Most patients in Jeremic, Shibamoto, Nikolic, et al. (1999) had good performance at 

enrollment (67 percent with Karnofsky scores 90-100, excluded if <60), while Nou, Brodin, and 

Bergh (1998) included many with poorer performance (median Karnofsky score 60, range 30–

90). Median age ranged from 59 to 65 years across study arms. Both trials enrolled mostly men 

(25 percent to 41 percent women across arms). Just over half of patients in each trial had >2 

metastatic sites (50 percent to 58 percent across arms; Appendix Table 4B).†

 Less than half of 

patients in Jeremic, Shibamoto, Nikolic, et al. (1999) had lost >5 percent of body weight at 

enrollment, but Nou, Brodin, and Bergh (1998) did not report this potential marker of poor 

prognosis. Neither trial reported distributions by race. 

 

*

 Appendixes cited in this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/lungcansmall/lungcan.pdf. †

 Appendixes cited in this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/lungcansmall/lungcan.pdf.
75

Study Quality and Reporting. All five trials were published in full, but only two were 

multicenter studies (Lebeau, Chastang, Brechot, et al., 1993; Rosenthal, Tattersall, Fox, et al., 

1991) and only Nou, Brodin, and Bergh (1998) was a good-quality trial. Jeremic, Shibamoto, 

Nikolic, et al. (1999) was of fair quality since it did not report on methods used for randomizing 

patients. The other three were of poor quality to evaluate the role of TRTx for ESD patients 

(Appendix Table 4H).* Data were unavailable for each of the poor quality trials to evaluate the 

comparability of randomized ESD patients; two had excessive loss to follow-up (Rosenthal, 

Tattersall, Fox, et al. 1991; Brincker, Hindberg, Hansen, et al., 1987), and each failed to analyze 

and report all important outcomes separately for ESD patients. 
76

Summary Table 30. Selected Characteristics of RCTs Comparing Chemotherapy with versus without TRTx 

N study +TRTx -TRTx Pt? chemoTx regimen TRTx timing* TRTx dose TRTx schedule; fractionation PC

Jeremic, Shibamoto, Nikolic, et al., 1999 55 54 yes PE/CbE concurrent 54 Gy wks 10-13; 36 x 1.5Gy, 2/d yeNou, Brodin, and Bergh, 1988 28 26 no CAVML alternating 40 Gy wks 10-13; 20 x 2 Gy, 1/d no Lebeau, Chastang, Brechot, et al., 1993 10 8 yes LCAE/PEVe sequential 32-65 Gy wks 36-39; 2 Gy fracs, 1/d somRosenthal, Tattersall, Fox, et al., 1991 27 total; N/arm NR no M-CAV alternating 40 Gy wks 10-?; 20 x 2 Gy, ?/d ? Brincker, Hindberg, Hansen, et al., 1987 16 14 no CAV/LME alternating 12 Gy days 60 and 100; 6 Gy each ? 

* Timing relative to chemotherapy administration Abbreviations table provided at the end of the Report. 
77

Summary Table 31. Sample and Methods: Chemotherapy with versus without Thoracic Radiation Therapy, Extensive Stage DisStudy N Age 

% Female % Performance Status 

CTx Regimen RTx Regimen 

Jeremic, Shibamoto, Nikolic, et al., 19991 single center: 01/88 – 06/93 

Total 109 +TRTx 55 -TRTx 54 nonrandomized CR/PR: 34 PR/PR: 28 SD/PD 35 

md (rng) 59 (38-70 59 (39-71) 

40 41 

100 90 80 70 31 36 18 15 24 43 18 15 KPS 

PE/Cb-E Dose Schedule 

54 Gy 24 x 1.5 Gy fracs; 2 frac then 12 x 1.5 Gy fracs, 2 

Nou, Brodin, and Bergh, 19882 single center 01/80 - 12/83 (ESD only) 

Total 54 +TRTx 28 -TRTx 26 

md (rng) 65 (55-78) 60 (41-81) 

25 31 

med (rng) 60 (30-90) 60 (30-90) KPS 

cytoxan, vincristine, doxorubicin, methotrexate, lomustine 

Dose Schedule 40 Gy 1 frac/d, 2 Gy each, 5 d/

Lebeau, Chastang, Brechot, et al., 19933 27 centers 10/85 - 04/88 

Total 18 +TRTx 10 -TRTx 8 

> 60 

48 38.5 

4 8 

90-100 70-80 60 63 22 15 46 50 4 KPS 

CCNU, cytoxan, doxorubicin, etoposide, cisplatin, vindesine 

Dose Schedule mn 46.5 Gy begun 4 wks after last (rng: 32- schedules: 32 Gy in 9 65 Gy) to 65 Gy in 33 frac ove 

Rosenthal, Tattersall, Fox, et al., 19913 3 centers 01/77 - 07/79 

Total 27 +TRTx ? -TRTx ? 

md (rng) 60 (26-77) 

24 

0 1 2 ? 1 88 3 8 

cytoxan, vincristine, doxorubicin; + methotrexate (IV or intrathecal) 

Dose Schedule 40 Gy 20 fracs between CTx c 

Abbreviations table provided at the end of the Report. 
78

Summary Table 31. Sample and Methods: Chemotherapy with versus without Thoracic Radiation Therapy, Extensive Stage DisStudy N Age 

% Female % Performance Status 

CTx Regimen RTx Regimen 

Brincker, Hindberg, Hansen, et al., 19873 single center 03/81 - 01/84 

Total 30 +TRTx 16 -TRTx 14 

md (rng) 60 (42-69) 63 (46-69) 

27 27 

0 1 2 3 34 51 15 24 57 19 

cytoxan, vincristine, doxorubicin, methotrexate, lomustine, etoposide 

Dose Schedule 12 Gy 2 fracs, 6 Gy each, day  hemi-body and day 100  body 

1 enrollment limited to ESD patients; 2 enrolled ESD & LSD patients, and reported characteristics of each separately; 3 enrolled ESD & LSD patients, but only reported characteristics for the two groups pooled 
79

Results 

Jeremic, Shibamoto, Nikolic, et al. (1999) reported that adding concurrent TRTx to platinumbased chemotherapy for good-performance patients selected by their response to an initial 3 

cycles of platinum-etoposide (PE) significantly improved overall survival (median OS, 17 versus 

11 months; 2- and 3-year OS, 38 percent versus 28 percent and 22 percent versus 13 percent 

respectively; p=0.041) and relapse-free survival (median RFS, 13 versus 9 months; 2- and 3-year 

RFS, 35 percent versus 22 percent and 20 percent versus 9 percent, respectively; p=0.045) 

(Summary Table 32). Jeremic, Shibamoto, Nikolic, et al. (1999) also reported that adding TRTx 

to chemotherapy for these selected patients significantly increased CR rates in the thorax at week 

21 (96 percent versus 66 percent; p=0.00005) (Appendix Table 4F). However, the improvement 

in duration of CRs in the thorax did not achieve statistical significance (mean, 22+26 versus 

14+16 months; p=0.055). 

Only 3% of non-randomized patients who achieved PR outside the thorax and CR in the 

thorax after three cycles of PE survived at 3 years, despite TRTx and additional chemotherapy 

(Summary Table 32). Furthermore, no patients who achieved only PR at each site survived at 

three years. However, data are unavailable to compare these outcomes with similar patients 

managed without TRTx. 

No other trial reported a statistically significant effect of TRTx on survival of ESD patients 

(Summary Table 32). This includes Lebeau, Chastang, Brechot, et al. (1993), which only 

randomized patients in CR after eight cycles of chemotherapy (Appendix Tables 4A, 4F)*

 and 

used a chemotherapy regimen with cisplatin (Summary Table 31). Whether the absence of a 

significant effect reflects the small size and inadequate statistical power of these trials, or is 

attributable to their use of chemotherapy regimens, timing and sequencing of TRTx, or radiation 

doses and schedules that differed from those used in Jeremic, Shibamoto, Nikolic, et al. (1999) is 

uncertain, since available data are insufficient. 

None of the trials reported data on quality of life (Appendix Table 4F).* Jeremic, Shibamoto, 

Nikolic, et al. (1999) reported significantly more grade 3 and 4 esophagitis (27 percent versus 

zero, p=0.0002), but significantly less grade 3 and 4 nausea and vomiting (9 percent versus 34 

percent, p=0.0038) and renal toxicity (zero versus 22 percent, p=0.001) in the arm given TRTx 

(Summary Table 33). No other statistically significant differences between arms were reported 

for adverse events. 

 

* Appendixes cited in this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/lungcansmall/lungcan.pdf.
80

Summary Table 32. Survival Outcomes: Chemotherapy with versus without Thoracic Radiation Therapy, Extensive Stage DiseStudy N OS Med 1 yr 2 yr 3 yr 4 yr 5 yr RFS Med 1 yr 2 yr 3 yr Jeremic,19991 +TRTx 55 

-TRTx 54 Difference CR/PR: 34 PR/PR: 28 SD/PD 35 

17 65% 38% 22% 13% 9.1% 11 46% 28% 13% 5.6% 3.7% 6 19% 10% 9% 7.4% 5.4% (p=0.041 by log-rank test) unrandomized groups by post-3rd cycle response (thorax/ 

elsewhere): 8 35% 8.8% 2.9% 0% 0% 6 21% 3.6% 0% 0% 0% 3 0% 0% 0% 0% 0% 

13 56% 35% 20% 9 41% 22% 9.3% 4 15% 13% 10.7% 6 26% 5.9% 0% 5 18% 0% 0% NR 0% 0% 0% 

Nou 19882 +TRTx 28 

-TRTx 26 Difference 

9.2 32% 0% 0% 0% 7.6 26% 0% 0% 0% 1.6 6% 0% 0% 0% (chi-square 0.045, 0.8<p<0.9, by life-table analysis) 

Lebeau 19933 +TRTx 10 

-TRTx 8 Difference 

~6.3 ~10% ~10% 0% 0% 0% ~7.0 ~25% ~12% ~12% 0% 0% -0.7 -15% -2% -12% 0% 0% (p = 0.43 by log-rank test) 

Rosenthal 19913 Total 27 

+TRTx ? -TRTx ? Difference 

5 (95% CI: 2-8) 7 (95% CI: 3-10) -2 (p=0.796) 

Brincker 19873 +TRTx 16 

-TRTx 14 Difference 

7 ~25% 0% 0% 0% 0% 10 ~30% 0% 0% 0% 0% -3 -5% 0% 0% 0% 0% (p = 0.44) 

7 ~23 0% 0% 8.5 ~26 0% 0% -1.5 -3% 0% 0% (p = 0.45) 

1 enrollment limited to ESD patients; 2 enrolled ESD & LSD patients, and reported characteristics of each separately; 3 enrolled ESD & LSD patients, but only reported characteristics for the two groups pooled 
81

Summary Table 33. Adverse Events: Chemotherapy with versus without Thoracic Radiation Therapy, Extensive Stage Disease Toxicity Type Study Severity or Grade 

+TRTx -TRTx n % n % p Not Repo

Treatment-related mortality 

Nou 1988 28 4 26 4 NS Jeremic 1

1991; Brin

Nausea/Vomiting Jeremic 1999 acute grades 3/4 nausea and vomiting 55 9 54 34 0.0038 Nou 1988

1991 

 Brincker 1987 “no significant differences between the two 

treatment groups” 

Anorexia Jeremic 1

Rosentha

Lethargy Jeremic 1

Rosentha

Neurosensory Brincker 1987 “no significant differences between the two 

treatment groups” 

Jeremic 1Rosentha

Hearing loss Jeremic 1

Rosentha

Esophagitis Jeremic 1999 acute grades 3/4 esophageal 55 27 54 0 0.0002 Nou 1988

1991; Brin

Bronchopulmonary Jeremic 1999 acute grade 3 (no grade 4, either arm) 55 5 54 0 0.082 Nou 1988

1991; Brin

Pneumonitis Brincker 1987 no cases observed Jeremic 1

Rosentha

Kidney Jeremic 1999 acute grades 3 or 4 55 0 54 22 0.001 Nou 1988

1991; Brin

Anemia Jeremic 1999 acute grades 3 or 4 55 11 54 20 0.39 Lebeau 19 Nou 1988 hemoglobin nadir Similar medians and ranges between groups  Brincker 1987 hemoglobin <6 mmol/L 41 ~50 37 ~27 

(LSD+ESD) (LSD+ESD) 

Thrombocytopenia Jeremic 1999 acute grades 3/4 55 27 54 42 0.23 Lebeau 19 Nou 1988 thrombocyte count nadir (109/L) Similar medians between groups  Brincker 1987 platelets <75x103/μl 41 ~65 37 ~10 

(LSD+ESD) (LSD+ESD) 
82

Summary Table 33. Adverse Events, Chemotherapy with versus without Thoracic Radiation Therapy, Extensive Stage Disease Toxicity Type Study Severity or Grade 

+TRTx -TRTx n % n % p Not Repo

Leukopenia or neutropenia 

Jeremic 1999 acute grade 3/4 leukopenia 55 44 54 61 0.18 Lebeau 19

 Nou 1988 leukocyte count nadir (109/L) Similar medians and ranges between groups  Brincker 1987 leukocytes < 2.5x103/μl 41 ~37 37 ~18 

(LSD+ESD) (LSD+ESD) 

Infection Jeremic 1999 acute grades 3-5 55 23 54 33 0.64 Lebeau 19 Nou 1988 septicemia Similar medians and ranges between groups  Brincker 1987 febrile episodes No significant differences between arms Other Jeremic 1999 combined late grades 3/4 toxicities 55 5 54 0 0.082 Lebeau 19 Nou 1988 “other serious side effects” 28 29 26 8 NS  Brincker 1987 tolerated 75-100% of CTx doses in cycles 

after hemibody RTx completed 

28 25 32 91 (LSD+ESD) (LSD+ESD) 
83

Conclusions 

Evidence from one small single-center randomized trial suggests adding concurrent TRTx to 

chemotherapy may improve survival of ESD patients who respond to an initial three cycles of PE 

chemotherapy with a CR outside the thorax and at least a PR in the thorax. Uncontrolled data 

from the same trial suggest that there is little to no benefit from adding TRTx to chemotherapy 

for ESD patients who achieve no better than a PR outside the thorax after three cycles of PE. 

With the regimens used in Jeremic, Shibamoto, Nikolic, et al. (1999), concurrent TRTx 

apparently increases grades 3 and 4 esophagitis. 

No other trials were able to reproduce the results reported by Jeremic, Shibamoto, Nikolic, et 

al. (1999). Limitations of these trials include small sample sizes lack of a platinum-containing 

drug in their chemotherapy regimens, and use of nonconcurrent TRTx. 

Key Question 5 

What are the benefits and harms (survival, toxicity and quality of life) of prophylactic cranial 

irradiation (PCI) for patients with SCLC in complete remission (CR) after primary therapy? 

Overview 

 The literature search identified seven RCTs comparing primary therapy for SCLC with 

versus without PCI (Summary Table 34). One of these was excluded because randomization and 

PCI preceded completion of primary therapy and evaluation of response (n=51; Niiranen, Holsti, 

and Salmo, 1989). Thus, each arm included some patients with less than CR. A second was 

excluded because it also randomized patients to PCI or no PCI before response was known, and 

because an initial randomization assigned half the patients to radiotherapy without chemotherapy 

(n=104 in 4 groups; Seydel, Creech, Pagano, et al., 1985). The remaining five trials 

onlyrandomized patients who achieved CR after primary chemotherapy with or without TRTx 

(pooled N=922; Arriagada, Le Chevalier, Borie, et al., 1995/Arriagada, Le Chevalier, Riviere, et 

al., 2002; Laplanche, Monnet, Santos-Miranda, et al., 1998; Gregor, Cull, Stephens, et al., 1997; 

Ohonoshi, Ueoka, Kawahara, et al., 1993; Cao, Huang, and Tu, 2000). 

 Four of these five studies were included in a Cochrane review and meta-analysis that 

collected updated individual patient data from each RCT (Prophylactic Cranial Irradiation 

Overview Collaborative Group 2000; Auperin, Arriagada, Pignon, et al., 1999). Cao, Huang, 

and Tu (2000; n=51) was the exception. The Cochrane review also included one study published 

before 1985 (Aroney, Aisner, Wesley, et al., 1983; n=29) and two unpublished trials (Wagner, 

Kim, Turrisi, et al., 1996; Danish/NCI trial; pooled N=87) that were not identified by our 

literature search. Additionally, the Cochrane review collected data on randomized patients 

excluded from investigators’ published analyses, permitting intent-to-treat analysis of results for 

987 patients in CR from seven RCTs (526 randomized to PCI, 461 to no PCI). Finally, the 

Cochrane review collected individual patient data on duration of follow-up and on covariates at 

randomization including age, gender, extent of disease, performance status, induction regimen 

(chemotherapy with versus without TRTx), and time since initial therapy, to permit analyses that 

tested whether these covariates influenced the magnitude of benefit from PCI. The Cochrane 
84

review excluded Niiranen, Holsti, and Salmo (1989) and Seydel, Creech, Pagano, et al. (1985) 

(as does this review), plus eight other RCTs published before 1985, for similar reasons (some 

randomized patients not in CR; pooled N=929). 

Since individual patient data submitted for the Cochrane review included longer follow up 

and permitted analyses not possible with abstracted data from a literature-based systematic 

review, and since only one eligible study was published subsequently (Cao, Huang, and Tu, 

2000; N=51), the Results section below summarizes and highlights the principal findings of the 

Cochrane review, and also summarizes results of the Cao, Huang, and Tu (2000) study. 
85

Summary Table 34. RCTs of PCI versus no PCI for SCLC in CR 

N Randomized PCI Regimen Study + PCI no PCI all in CR? Pt? chemoTx regimen TRTx dose fractions duration p

Arriagada, Le Chevalier, Borie, et al., 1995 

149 151 yes some various; # type NR 91%-93% each arm; reg. NR 24 Gy 8 x 3 Gy 12 days (4 d/wk) 

Laplanche, Monnet, SantosMiranda, et al., 1998 

100 111 yes ?? various; # type NR not reported 24-30 Gy <3 Gy each <3 weeks 

Gregor, Cull, Stephens, et al., 1997 

194 120 yes some various; # NR 84% each arm; reg. NR 8-40 Gy 2 Gy each 1-3+ weeks 

Ohonoshi, Ueoka, Kawahara, et al., 1993 

23 23 yes no same for all all LS; 20 x 2 Gy/d 40 Gy 20 x 2 Gy 4 weeks 

Aroney, Aisner, Wesley, et al., 1983 

15 14 yes no same for all not reported 30 Gy 10 x 3 Gy 2 weeks 

Wagner, Kim, Turrisi, et al., 1996 17 15 yes NR not reported 57%; reg. NR 24 Gy 8 x 3 Gy not reported Danish/NCI 28 27 yes NR not reported 42%; reg. NR 24 Gy 8 x 3 Gy not reported Cao, Huang, and Tu, 2000 26 25 yes some two; # NR all; 40-64 Gy 1.8-2 Gy/d 25-30 Gy 1.8-2 Gy ea. 2-3 weeks Seydel, Creech, Pagano, et al., 1985 

52 51 ?? no one; half only all; 45 Gy 1.8-2 Gy/d 30 Gy 10 x 3 Gy 2 weeks 

Niiranen, Holsti, and Salmo, 1989 25 26 no no two; half each all; 25 x 2.2 Gy/d 40 Gy 20 x 2 Gy 4 weeks 
86

Results 

Cochrane Review and Meta-Analysis. 

 Study Characteristics. At the time of analysis, median follow-up for the control and PCI 

groups was 5.3 and 5.9 years, respectively; 846 of 987 randomized patients had died (PCI 

Overview Collaborative Group 2000; Auperin, Arriagada, Pignon, et al., 1999). Of seven 

included trials, three enrolled 84 percent of patients (Arriagada, Le Chevalier, Borie, et al., 

1995/Arriagada, Le Chevalier, Riviere, et al., 2002; Laplanche, Monnet, Santos-Miranda, et al., 

1998; Gregor, Cull, Stephens, et al., 1997) while the other four contributed 29 to 55 each 

(Aroney, Aisner, Wesley, et al., 1983; Wagner, Kim, Turrisi, et al., 1996; Ohonoshi, Ueoka, 

Kawahara, et al., 1993; Danish/NCI trial). The control (N=461) and PCI (n=526) groups were 

well balanced for gender (76–77 percent male), age (median 59 years, ranges 26–80 and 21–79), 

performance status (66–67 percent PS 0, 30–32 percent PS 1) and other covariates. Reviewers 

judged each trial to be methodologically sound, including adequate randomization and allocation 

concealment. 

For most patients in these trials, the specific chemotherapy regimens used to induce CR were 

not reported but it is likely platinum-based regimens were used only for a minority. The large 

trials did not mandate a uniform chemotherapy regimen (Arriagada, Le Chevalier, Borie, et al., 

1995/Arriagada, Le Chevalier, Riviere, et al., 2002; Laplanche, Monnet, Santos-Miranda, et al., 

1998; Gregor, Cull, Stephens, et al., 1997). Only Gregor, Cull, Stephens, et al. (1997) reported 

the variety of regimens used, but since they did not report the proportion given each regimen, an 

unknown number of patients received cisplatin or carboplatin. Of the four smaller trials, Aroney, 

Aisner, Wesley, et al. (1983) and Ohonoshi, Ueoka, Kawahara, et al. (1993) each used a uniform 

regimen, but neither included a platinum drug. While Cochrane reviewers collected individual 

patient data on whether they received TRTx, information was unavailable (either in the review or 

in the original publications) on doses, fractionation schemes, or timing relative to chemotherapy. 

Summary Table 35 summarizes the review’s pooled estimates of efficacy outcomes. 

Summary Table 35. Meta-analytic Results for Efficacy Outcomes Reported in the Cochrane Review 

N evaluated 95% CI event-free at 3 yrs (by KM) Outcome +PCI -PCI 

Hazard 

Ratio lower upper p +PCI -PCI differenc

e 

mortality 526 461 0.84 0.73 0.97 0.01 20.7% 15.3% 5.4% 

disease-free survival 526 461 0.75 0.65 0.86 <0.00003 

brain metastasis 524 457 0.46 0.38 0.57 <0.00001 33.3% 58.6% 25.3% 

non-brain metastasis 325 332 0.89 0.69 1.15 0.4 

loco-regional recurrence 323 334 0.97 0.75 1.26 0.8 

 Mortality and Survival. Although six of seven included trials observed proportionally more 

deaths in the control arms, the hazard ratio (HR) for mortality did not significantly favor the PCI 

arm in any single trial. However, meta-analysis showed that PCI significantly decreased the 

likelihood of death (HR=0.84; 95 percent CI: 0.73–0.97; p = 0.01). Cox modeling to adjust for 

extent of disease, gender and age did not appreciably change the relative likelihood (HR=0.83; 
87

p=0.009). The HR remained constant despite further adjustment for performance status, 

induction regimen (with versus without TRTx), and time from induction to randomization. 

Kaplan-Meier actuarial analysis estimated an absolute increase of 5.4 percent in the proportion of 

patients alive at 3 years (from 15.3 percent without PCI to 20.7 percent with PCI). The survival 

benefit persisted beyond 3 years, and there was no evidence of statistical heterogeneity among 

the seven included trials. 

 Other Efficacy Endpoints. The HR for brain metastasis significantly favored the PCI arm in 

five of seven trials; the Danish/NCI and Laplanche, Monnet, Santos-Miranda, et al. (1998) trials 

were the exceptions. Meta-analysis showed reduced likelihood of brain metastasis among those 

randomized to PCI (HR = 0.46; 95 percent CI: 0.38–0.57; p <0.001). Kaplan-Meier analysis 

estimated an absolute decrease of 25.3% in the cumulative rate of brain metastasis at 3 years 

(from 58.6 percent without PCI to 33.3 percent with PCI). 

Additional analyses demonstrated that PCI increased the likelihood of disease-free survival 

(HR=0.75; 95 percent CI: 0.65–0.86; p < 0.001), but did not reduce extra-cerebral metastases 

(HR=0.89; 95% CI: 0.69–1.15; p=0.4) or locoregional recurrence (HR=0.97; 95% CI: 0.75–1.26; 

p=0.8). However, data on non-brain metastases and locoregional recurrence were available for 

only 67% of randomized patients. 

 PCI Dose-Response. Trials (and subgroups from different centers in Gregor, Cull, Stephens, 

et al., 1997) were divided by total radiation dose used for PCI: 8 Gy delivered in one fraction, 

24–25 Gy delivered in 8–12 fractions, 30 Gy delivered in 10 fractions, and 36 or 40 Gy delivered 

in 18 or 20 fractions. Summary Table 36 summarizes results of this and other subgroup 

analyses. 

 Evidence was lacking for a trend towards smaller HR (greater impact on survival) with larger 

PCI dose (p = 0.89), but few patients were treated at the lowest and highest doses. In contrast, 

the HR to develop brain metastasis decreased significantly as PCI dose increased (p = 0.02), 

suggesting larger doses had a greater magnitude of beneficial effect. 
88

Summary Table 36. Cochrane Review Subgroup Analyses for Mortality and Brain Metastasis

mortality brain metastasis 

covariate subgroups N evaluated 95% CI N evaluated 95% CI 

+PCI -PCI 

hazard

ratio lower upper p +PCI -PCI

hazard 

ratio lower upper p 

8 Gy 26 16 0.69 0.35 1.37 0.3 26 16 0.76 0.28 2.10 0.6 

24-25 Gy 330 340 0.88 0.75 1.04 0.12 329 338 0.52 0.41 0.67 <0.00001

30 Gy 119 82 0.81 0.59 1.12 0.2 118 80 0.34 0.19 0.59 0.0002 

PCI dose 

36-40 Gy 51 59 0.81 0.54 1.20 0.3 51 59 0.27 0.14 0.51 0.00001

<54 yrs 147 158 0.84 0.65 1.08 0.18 147 157 0.55 0.39 0.77 0.0005 

age 55-64 yrs 250 185 0.90 0.73 1.11 0.3 248 184 0.49 0.35 0.68 <0.00002

>65 yrs 129 118 0.79 0.60 1.03 0.09 129 116 0.37 0.24 0.59 <0.0001

limited 464 383 0.85 0.73 0.99 0.04 462 382 0.48 0.38 0.61 <0.00001

disease stage extensive 62 78 0.77 0.54 1.11 0.16 62 75 0.38 0.23 0.64 0.0002 

performance 0 212 215 0.85 0.69 1.05 0.13 211 214 0.47 0.35 0.63 <0.00001

status 1-3 103 111 0.78 0.58 1.04 0.09 103 110 0.50 0.32 0.78 0.003 

induction +TRTx 314 248 0.86 0.71 1.03 0.10 314 248 0.43 0.33 0.57 <0.00001

therapy -TRTx 94 86 0.88 0.64 1.21 0.4 92 82 0.40 0.23 0.67 0.0005 

male 403 352 0.77 0.66 0.90 0.0009 401 348 0.47 0.37 0.60 <0.00001

gender female 123 109 1.05 0.78 1.42 0.7 123 109 0.50 0.32 0.78 0.002 

<4 mos. 84 77 0.92 0.66 1.29 0.6 83 75 0.27 0.16 0.46 <0.00001

4-6 mos. 127 152 0.79 0.61 1.02 0.07 126 150 0.50 0.35 0.72 0.0002 

time from 

induction to 

randomization >6 mos. 102 91 1.01 0.74 1.38 0.9 102 91 0.69 0.44 1.08 0.1 

Subgroup Analyses. Patient subgroups were evaluated for differences in magnitude of 

benefit from PCI. Subgroups were defined by individual patient data on age (<54 versus 55-64 

versus >65 years), gender, disease stage at diagnosis (limited versus extensive), performance 

status (0 versus 1-3), induction regimen (with versus without TRTx), and time from beginning 

induction to randomization (<4 versus 4-6 versus >6 months). Only two subgroup comparisons 

suggested significant differences in benefit from PCI for overall survival or brain metastasis. 

Results for males (n =755) showed statistically significant decreases in mortality (HR=0.77; 

95 percent CI: 0.66–0.90; p = 0.0009) and brain metastasis (HR=0.47; 95 percent CI: 0.37–0.60; 

p<0.0001) among those randomized to PCI. However, results for females (n=232) showed no 

significant effect of PCI on survival (HR=1.05; 95 percent CI: 0.78–1.42; p=0.7) despite a 

significant effect on brain metastasis (HR=0.50; 95 percent CI: 0.32–0.78; p=0.0002). A 

statistical test for interaction of gender with treatment effect on survival was of borderline 

significance (p=0.07). 

PCI delayed by <4 months from start of induction therapy (HR=0.27; 95 percent CI: 0.16–

0.46; p<0.0001) or by 4 to 6 months (HR=0.50; 95 percent CI: 0.35–0.72; p=0.0002) 

significantly reduced the likelihood of brain metastasis. In contrast, PCI delayed >6 months 

(HR=0.69; 95 percent CI: 0.44–1.08; p=0.10) did not significantly decrease the likelihood of 

brain metastasis. Note that each fully published trial with some patients given PCI later than 6 
89

months after induction (3 of 4 trials, with 95 percent of 193 patients in this subgroup) specified 

that patients were randomized to PCI or no PCI within 14 days of achieving CR. This trend 

(smaller effect on likelihood of brain metastasis as delay lengthened) was statistically significant 

(p=0.01). However, the relationship between time from induction therapy to PCI and hazard 

ratio for death did not show a similar statistically significant trend. 

 Adverse Events. The Cochrane review did not abstract and report data on adverse events. Of 

five fully-published studies, only Arriagada et al. (1995) reported acute events during PCI; these 

included fever or asthenia (24 percent), headache (24 percent), vomiting (10 percent), skin 

erythema (9 percent), and altered mood (6 percent). Adverse event data were unavailable from 

the two unpublished trials (Wagner, Kim, Turrisi, et al., 1996; Danish/NCI trial). 

Two trials prospectively studied neuropsychological or cognitive sequelae of PCI in patients 

who survived >6 months from treatment (Arriagada, Le Chevalier, Borie, et al. 1995; Gregor, 

Cull, Stephens, et al., 1997; Table 37). The Gregor, Cull, Stephens, et al. (1997) trial also 

reported data on symptoms that affect quality of life (QoL). Each compared measurements at 

baseline with measurements at times after PCI. Information was unavailable on ages and other 

baseline characteristics of those tested for late neuropsychological or cognitive effects. 

Additionally, available evidence did not permit testing of the hypothesis that the likelihood of 

neuropsychological deficits may increase with increasing PCI dose. 

In Arriagada, Le Chevalier, Borie, et al. (1995), neuropsychological assessments (made by a 

neurologist at baseline and late after PCI) included evaluation of higher brain function, mood, 

sensation, walking, cerebellar function, tendon reflexes, and sensibility. Additionally, blinded 

assessors reviewed pre- and post-PCI brain computed tomography (CT) scans for evidence of 

structural abnormalities (e.g., cortical atrophy or ventricular dilatation). 

Summary Table 37. Adverse Effects Reported from RCTs of PCI versus no PCI 

Study 

acute 

toxicities 

reported

? 

most 

common 

events 

type of 

assessme

nt 

N 

randomized 

N evaluated 

at 

baseline 

# w no 

or only 

mild 

baseline 

deficits 

#, time of 

reassessments 

principal 

findings 

Arriagada, 

Le 

Chevalier, 

Borie, et 

al., 1995 

yes 

fever 

24% 

headache 

24% 

vomiting 

10% 

neuropsychological; 

brain CT 

total: 

300 

+PCI: 

149 

-PCI: 

151 

229 

114 

115 

94 

44 

50 

33 of 58 @ 18 mos. 

23 of 35 @ 30 mos. 

groups did not differ 

in # of new changes 

or abnormalities 

cognitive 

total: 

314 

+PCI: 

194 

-PCI: 

120 

125 

76 

49 

diff. tests:

44-58 

29-37 

59 of 106 @ 6 mos. 

32 of 54 @ 1 yr 

9 of 20 @ 2 yr 

groups did not differ 

in # of new deficits 

Gregor, 

Cull, 

Stephens, 

et al., 1997 

no 

symptoms 

affecting 

QoL 

total: 

314 

+PCI: 

194 

-PCI: 

120 

not 

reported

diff tests:

11-21 

7-14 

re-assessed @ 6 

mos., 1 & 2 yr; #’s 

not reported; 

larger proportion of 

−PCI than of +PCI 

showed 

deterioration 
90

Of 300 randomized patients, baseline assessments were available for only 229 (115 controls 

and 114 randomized to PCI). Only 50 control patients (43 percent) and 44 randomized to PCI 

(39 percent) were free of neuropsychological abnormalities at baseline assessment. Investigators 

re-assessed 33 of 58 patients alive at 18 months and 23 of 35 alive at 30 months. They reported 

no statistically significant differences between treatment groups with respect to appearance of 

further neuropsychological changes or CT scan abnormalities over two years from PCI. 

However, only 11 percent or less of all randomized patients contributed to these observations, 

and the report did not explain why some patients alive at 18 and 30 months were not re-assessed. 

Gregor, Cull, Stephens, et al. (1997) assessed cognitive function at baseline, 6 months, and 1 

and 2 years with a battery of optional measures including the National Adult Reading Test, 

Paced Auditory Serial Addition Task, Rey-Osterrieth Complex Figure Test, and Auditory Verbal 

Learning Test. Of 314 randomized patients, at least one test result was submitted for N=136 (52 

controls, 84 PCI). Of these, baseline data were available for N=125, 6-month data for N=59 (of 

106 assessable), one-year data for N=32 (of 54 assessable), and two-year data for N=9 (of 20 

assessable). Each test showed evidence of new impairments at 6 months and 1 year in some 

patients free of impairments at baseline. However, investigators reported no evidence of 

sustained deterioration with time, and no notable differences between the PCI and control groups 

with respect to new cognitive deficits. 

Gregor, Cull, Stephens, et al. (1997) also measured symptoms that affect QoL at the same 

intervals used for cognitive function, with the Rotterdam Symptom Checklist and the Hospital 

Anxiety and Depression Scale. Symptoms that showed the greatest deterioration from baseline 

to 6 months included tiredness, lack of energy, irritability, decreased sexual interest, shortness of 

breath, and cough. For each symptom, of those who reported themselves with no or mild 

symptoms at baseline, a larger proportion of controls than of those given PCI reported moderate 

or severe symptoms at 6 months. Based on these data, investigators concluded deterioration was 

worse in controls than in the PCI group. 

Ohonoshi, Ueoka, Kawahara, et al. (1993) did not formally assess neuropsychological 

function or measure cognitive function or quality life. However, they reported that one of seven 

patients who survived more than two years after PCI developed symptoms of late central nervous 

system toxicity. These included memory impairment and gait ataxia at 30 months, with CT scan 

evidence of cortical atrophy. Ohonoshi, Ueoka, Kawahara, et al. (1993) did not report on late 

toxicity in the 4 control patients alive at 2 years. 

 Subsequent Study. Cao, Huang, and Tu (2000) reported the only eligible RCT of PCI 

versus no PCI omitted from the Cochrane review and meta-analysis (N = 47; 24 to PCI, 23 to 

control). Study arms were well-balanced and most patients had relatively favorable baseline 

characteristics: mean age, 55-56 (range 39–65), Karnofsky score >70, two females in each arm, 

all patients initially diagnosed with limited stage disease and in CR after chemotherapy plus 

TRTx. Chemotherapy regimens were either cyclophosphamide/doxorubicin/vincristine or 

etoposide plus carboplatin or cisplatin, with most patients also given lomustine. All patients 

received 40-66 Gy TRTx in 1.8-2 Gy fractions, given sequentially for most (17 controls, 18 PCI) 

and in alternating fashion for the rest (6 from each group). PCI began 11 to 58 days after 

achieving CR (mean, 33 days) at a mean dosage of 28.8 Gy (range, 25.2 to 30.6 Gy) in single 

daily fractions of 1.8 to 2 Gy, 5 days/week. 

Cao, Huang, and Tu (2000) reported fewer cranial metastases at 3 years after irradiation in 

the arm given PCI (3.8 percent versus 28 percent, p<0.05). However, differences in survival at 
91

one (85 percent versus 72 percent), two (73 percent versus 40 percent) or three (42 percent 

versus 32 percent) years were not statistically significant (median, 20 versus 8.3 months; log 

rank p>0.05). Acute reactions to PCI included mild nausea and dizziness, but frequencies were 

not reported. Late effects in 11 patients who survived >3 years included two with memory 

deficits and three with dizziness and lack of strength. Brain CT scans on 7 of the 11 survivors 

showed no structural abnormalities. 

Conclusions 

Evidence from an individual patient data Cochrane review and meta-analysis on seven RCTs 

(N=987) conducted by the PCI Overview Collaborative Group shows that PCI modestly but 

significantly improves survival of SCLC patients in CR after primary therapy. PCI increases the 

proportion alive at 3 years from 15.3 percent of controls to 20.7 percent of those randomized to 

PCI, an absolute increase of 5.4 percent. PCI also significantly decreases the risk for brain 

metastasis and increases the likelihood of disease-free survival. The sole trial reported after the 

meta-analysis confirms effects of PCI on brain metastasis, and generally agrees with the modest 

effect on overall survival. 

Subgroup analyses using individual patient data showed that PCI significantly decreases 

brain metastases for SCLC patients in CR regardless of age, disease stage or performance status 

at diagnosis, and whether or not TRTx is part of the induction regimen. Although effects of PCI 

on survival lacks statistical significance for nearly all these subgroups, it does not appear that any 

subgroup benefits more or less than others with respect to each of these covariates. 

Additional subgroup analyses suggested that increasing the PCI dose from 8 to 40 Gy and 

starting PCI within the first 6 months after achieving CR may decrease the likelihood of brain 

metastasis. Patient gender also may interact with effects of PCI on survival. However, these 

hypotheses, derived from subgroup analyses, require formal testing in randomized, controlled 

trials. 

Data on acute toxicities of PCI are scant, but those available suggest they are tolerable at the 

doses used in these trials (8–40 Gy in 1.8 to 3 Gy fractions). Evidence from two trials suggests 

neuropsychological and cognitive deficits and structural abnormalities on brain CT scans are 

relatively common among SCLC patients in CR after primary therapy. However, available 

evidence did not show greater deterioration of existing deficits or more frequent appearance of 

new abnormalities among the minority randomized to PCI who survive 1–2 years or more, than 

among the fewer controls with equivalent survival duration. 

Key Question 6 

Does the addition of positron emission tomography (PET) scanning improve the accuracy of 

staging for patients diagnosed with SCLC, over the use of other techniques, including CT and 

MRI, without PET? 
92

Overview 

Evidence of the effect of PET on health outcomes, such as overall survival or avoidance of 

unnecessary procedures, is of greatest interest to this review. RCTs were sought that compared 

outcomes of staging tests that included PET versus the same tests without PET in patients who 

had a confirmed diagnosis of SCLC. No such studies were found. 

Single-arm studies with the following characteristics were sought: prospective design; 

reported on at least 20 patients undergoing imaging to stage SCLC; correlated 18-

fluorodeoxyglucose (FDG) PET findings with findings from other imaging modalities and an 

appropriate reference standard; applied the reference standard to patients with and without 

metastasis to a given anatomic site (to permit computation of sensitivity and specificity); and 

reported at least one outcome of interest. Outcomes included: diagnostic and staging accuracy; 

patient management decisions, which may be altered by imaging results, duration of survival; 

disease-free survival and/or progression-free survival; quality of life; palliation of measurable 

symptoms; treatment-related adverse effects; objective response rates; and response durations. 

Studies were excluded if they did not report data needed to calculate diagnostic accuracy; or if 

they did not report separate diagnostic accuracy results for SCLC and NSCLC patients. Since 

the question posed here concerned the incremental value of PET relative to staging tests, the 

comparison of greatest interest is between results of conventional staging tests alone and 

conventional staging tests plus PET. 

Due to the limited evidence available, the study selection criteria on prospective design and 

on appropriate reference standard were relaxed. Six studies reporting on a total of 277 patients 

(range: 20–120) are included in this review. Data from these studies primarily concerned 

diagnostic and staging accuracy. Characteristics of these studies are summarized in Summary 

Table 38 (sample selection) and Summary Table 39 (tests and reference standards). Four of the 

six studies were clearly prospective in design (Bradley, Dehdashti, Mintun et al., 2004; Brink, 

Schumacher, Mix et al., 2004; Kamel, Zwahlen, Wyss, et al., 2003; Shen, Shiau, Wang, et al., 

2002), while 1 study produced a mix of data collected prospectively and retrospectively (Blum, 

MacManus, Rischin, et al., 2004) and 1 study was of uncertain design (Schumacher, Brink, Mix, 

et al., 2001). Three studies enrolled consecutive series of patients (Blum, MacManus, Rischin, et 

al., 2004; Brink, Schumacher, Mix et al., 2004; Kamel, Zwahlen, Wyss, et al., 2003). Three of 

the 6 studies provide staging accuracy data based on comparisons of conventional staging tests 

alone and conventional staging plus PET (Blum, MacManus, Rischin, et al., 2004; Bradley, 

Dehdashti, Mintun et al., 2004; Kamel, Zwahlen, Wyss, et al., 2003). Three studies compared 

staging results of conventional tests alone and PET alone (Brink, Schumacher, Mix et al., 2004; 

Shen, Shiau, Wang, et al., 2002; Schumacher, Brink, Mix, et al., 2001). 

Study quality was assessed as described in the Methods chapter, using the QUADAS tool 

(Whiting, Rutjes, Dinnes, et al., 2004). A major weakness of the included evidence is the 

uniformly poor quality of information reported about the reference standard. None of the 6 

studies adequately described the execution of the reference standard and whether the reference 

standard correctly classifies the target condition. Without these details, the definition of a 

positive reference standard result is unclear. Thus the poor quality of information reported on 

reference standards undermines confidence in the estimates of sensitivity, specificity and staging 

accuracy that can be drawn from this literature. 
93

Summary Table 38. Sample Selection: Positron Emission Tomography for Staging of Small-Cell Lung Cancer Study Design Patient Selection n Age (yr) Gender (%) 

 Stage Limited Ex % 

Blum, MacManus, Rischin, et al., 2004 

partially prospective, partially retrospective 

proven SCLC underwent PET; consecutive patients; newly diagnosedinitial staging in 15, restaging in 21; PET based on review of all clinical data and was performed to guide clinical management; 

36 med 64 M 66 

F 33 

 

Bradley, Dehdashti, Mintun et al., 2004 

prospective newly diagnosed confirmed limited 

stage SCLC, completed standard staging procedures 

24 mn 60 

rng 33-90 

M 44 F 56 

 87.5 

Brink, Schumacher, Mix et al., 2004 

prospective consecutive patients with histologically 

confirmed SCLC examined with FDGPET during primary staging 

120 mn 60.8 

sd 8.9 

M 75 F 25 

 37 

Kamel, Zwahlen, Wyss, et al., 2003 

prospective consecutive patients with SCLC 

referred for whole-body FDG-PET; initial staging in 24 patients and restaging after therapy in 20 patients (both in 2) 

42 mn 62 

rng 45-83 

M 64 F 36 

 62.5 

Shen, Shiau, Wang, et al., 2002 

retrospective histologically confirmed SCLC; KPS >

60%; total serum bilirubin < 2.0 mg/dL; 

serum creatinine < 2.5 mg/dL; fasting 

blood sugar < 150 mg/dL 

25 mn 56 

sd 7 rng 45-68 

M 72 F 28 

 40 

Schumacher, Brink, Mix, et al., 2001 

unclear histologically proven SCLC, primary 

staging in 24, therapy follow-up in 4, both in 2; therapy was surgery, RTx and CTx (ACO, EPI-CO, VIP-E, VIC-E); all treatment stopped >1 mo before 

PET 

30 mn 57 

sd 13 rng 34-78 

M 77 F 23 

 30 

Abbreviations table provided at the end of the Report. 
94

Summary Table39. Test/Reference Standard Procedure and Interpretation: Positron Emission Tomography for Staging of Small-CStudy PET 

Conventional Staging Tests Reference Standard 

PET: Ref Stand Blind? 

Blum, MacManus, Rischin, et al., 2004 

> 4 hr fast; + attenuation 

correction, qualitative interpretation, access to results of the previous imaging and clinical information 

initial staging - high-quality CT of chest, upper abdomen, brain, usually bone scan; restaging after initial treatment - CT, bone scan, X-ray; 

if discordant results, TP = site biopsy+; or site + only on PET with other progression < 6 mos of PET, no treatment; TN = site biopsy-; or conventional equivocal/negative site with no progression for > 6 mos, no treatment 

Unclea

Bradley, Dehdashti, Mintun et al., 2004 

4-hr fast, 10-15 mCi FDG, 50 min delay + attenuation 

correction, visual interpretation; 

2 experienced nuclear physicians; first, independent, blinded to conventional, then observers reread with conventional, final consensus of blinded readings; also semiquantitative maximum standardized uptake value 

history, physical exam, chest X-ray, chest CT, upper abdominal CT, bone scan, contrast-enhanced CT/MRI of brain; all conventional staging procedures completed < 4 wk of PET 

protocol-defined approaches for further evaluation or biopsy: PET+ intrapulmonary parenchymal metastases outside RTx portal, do biopsy; thin-cut CT- or US-guided FNA where feasible; liver PET+, do biopsy/FNA cytology; adrenal PET+, do biopsy; bone PET+, evaluate by appropriate imaging studies (X-ray, CT, MRI, repeat bone scan) or biopsy or bone scan/MRI if multiple bone metastases suspected 

Unclea

Brink, Schumacher, Mix et al., 2004 

12 hr fast, 5 MBq/kg FDG, 90 

min delay; data corrected for dead time, decay, photon attenuation; whole-body PET performed after CT (mean 12 d, range 1-26 d), hard copy and computer workstation, 2 independent investigators blinded to other data; hot spot evaluation, consensus 

conventional staging by 

history, physical exam, bronchoscopy, thoracic/abdominal contrastenhanced CT, cranial CT/MRI in 91, bone biopsy in 84 (refused in 36) 

histology in ~20%; available data; followup, committee of physicians (2 clinicians, 2 nuclear specialists) achieved reference standard diagnosis by consensus; when histologic results were unavailable, consensus based on sum of available data, including follow-up, non-validated results excluded from data analysis 

Yes 

Kamel, Zwahlen, Wyss, et al., 2003 

> 4 hr fast, 300-400 MBq FDG; 

40-50 min delay; segmented or PET/CT fusion attenuation correction, pre-PET staging and post-PET staging were always performed independently; clinical information available, including CT 

history, physical exam, 

blood tests, bronchoscopy, contrast-enhanced CT of chest, upper abdomen, bone scan, CT/MRI of brain in 9 

when possible, biopsies or other imaging studies were performed to resolve discrepancies between modalities 

Unclea

Abbreviations table provided at the end of the Report.
95

Summary Table39. Test/Reference Standard Procedure and Interpretation: Positron Emission Tomography for Staging of Smal(continued) Study PET 

Conventional Staging Tests Reference Standard 

PET: Ref Stand Blind? 

Shen, Shiau, Wang, et al., 2002 

6 hr fast; 10 mCi (370 MBq) FDG; 

40-50 min delay, agreement of at least 2 of 3 experienced nuclear medicine specialists blind to clinical stage 

within 2 wk of PET: history, 

physical exam, blood chemistry, chest X-ray +

chest CT/MRI, brain CT/MRI, abdominal CT/MRI + hepatic US, 

pelvic CT/MRI, bone scan, bone marrow biopsy 

final stage was verified by pathologic findings from thoracotomyy/mediastinoscopy. other imaging results, follow-up > 1 yr 

Unclear 

Schumacher, Brink, Mix, et al., 2001 

12 hr fast; 5 MBq FDG/kg; 90 min 

delay attenuation correction ,hard copy and computer workstation; visual interpretation, 2 experienced independent blinded investigators; consensus; standardized uptake value > 4 

within 2 wk before or after 

PET: CT/MRI of brain, thorax, abdomen carried out according to standard protocols, thin-section or contrast enhancement used if needed 

if discrepancies between PET and other staging procedures found, selective additional examinations performed or existing images reevaluated; in some cases, clinical 

follow-up proved/disproved inconsistent findings; confirmation necessary within 4 wk 

Unclear 
96

Study Populations 

The proportion of patients enrolled who had limited stage disease ranged from 30 percent to 

87.5 percent in 5 studies; it could not be determined in the study by Blum, MacManus, Rischin, 

et al. (2004). Three studies (Blum, MacManus, Rischin, et al., 2004; Kamel, Zwahlen, Wyss, et 

al., 2003; Schumacher, Brink, Mix, et al., 2001) included samples mixed with those undergoing 

initial staging and other being restaged. In only one study was it clear that selection of patients 

was not based on referral for PET scanning (Bradley, Dehdashti, Mintun et al., 2004). 

Diagnostic Accuracy 

Three studies (Blum, MacManus, Rischin, et al., 2004; Brink, Schumacher, Mix et al., 2004; 

Shen, Shiau, Wang, et al., 2002; total N=181) reported diagnostic accuracy data (Summary Table 

40). Results are presented below according to stage or site of disease. 

Any Disease. The study by Blum, MacManus, Rischin, et al. (2004) was the only one that 

reported diagnostic accuracy with reference to any disease. These investigators only included 

data on sensitivity in 36 patients, which they estimated at 100 percent for PET. This study does 

not address whether there was additional value to adding PET to staging, information about 

extent of disease was not reported. 

Lymph Nodes. Using the patient (n=118) as the unit of analysis, Brink, Schumacher, Mix et 

al. (2004) found that PET had a sensitivity of 100 percent for detecting lymph node metastasis, 

compared with 69.8 percent for conventional staging. PET specificity was 98.5 percent, while it 

was 93.8 percent for conventional staging. The study by Shen, Shiau, Wang, et al. (2002) also 

used a patient-based analysis, but grouped lymph nodes into regions. Few patients provided data 

on negative nodes, so specificity was not reported. Shen, Shiau, Wang, et al. (2002) did not 

provide separate sensitivity data for PET and conventional imaging. PET was found to be 100 

percent sensitive in each of 3 lymph regions: in 9 patients with mediastinal or hilar lymph 

metastases; in 7 patients with ipsilateral supraclavicular lymph metastases; and in 5 patients with 

contralateral supraclavicular lymph metastases. There were 2 PET false positives in 

mediastinal/hilar lymph nodes. 

Other Regional Sites. Shen, Shiau, Wang, et al. (2002) reported that sensitivity for 

ipsilateral lung foci was 100 percent in 2 patients. 
97

Summary Table 40. Diagnostic Accuracy Results: Positron Emission Tomography for Staging of Small-Cell Lung Cancer Study Test Focus n TP FN FP TN Prev Sens 

Sens 95% CIL 

Sens 95% CIU Spec 

Spec 95% CIL 

Spec 95% CIU PPV 

Blum, MacManus, Rischin, et al., 2004 

PET any disease 36 36 0 100% 90.3% 100% 

Bradley, Dehdashti, Mintun et al., 2004 

PET Any disease 24 24 0 1 0 100% 85.5% 100% 

PET LNs 118 53 0 1 64 44.9% 100% 93.3% 100% 98.5% 91.7% 100% 98Conv 118 37 16 4 61 44.9% 69.8% 55.7% 81.7% 93.8% 85.0% 98.3% 90PET dist, non-brain 70 45 1 2 22 65.7% 97.8% 88.5% 99.9% 91.7% 73.0% 99.0% 95Conv 70 38 8 5 19 65.7% 82.6% 68.6% 92.2% 79.2% 57.8% 92.9% 88PET brain 91 6 7 2 76 14.3% 46.2% 19.2% 74.9% 97.4% 91.0% 99.7% 75

Brink, Schumacher, Mix et al., 2004 

Conv 91 13 0 0 78 14.3% 100% 75.3% 100% 100% 95.4% 100% 10

Kamel, Zwahlen, Wyss, et al., 2003 

PET regl mets 18 20 0 2 0 100% 83.2% 100%  MD/HL LNs 9 9 0 2 0 100% 66.4% 100%  ips SC LNs 7 7 0 0 0 100% 59.0% 100%  ips lung 2 2 0 0 0 100% 15.8% 100%  distant 24 23 1 1 0 95.8% 78.9% 100%  contr SC LNs 5 5 0 0 0 100% 47.8% 100%  contr lung 3 3 0 1 0 100% 29.2% 100%  liver 3 3 0 0 0 100% 29.2% 100%  bone/marrow 6 6 0 0 0 100% 54.1% 100%  brain 2 1 1 0 0 50.0% 1.3% 99%  adrenal 2 2 0 0 0 100% 15.8% 100% 

Shen, Shiau, Wang, et al., 2002 

other extrathoracic 3 3 0 0 0 

100%

29.2% 100%

Schumacher, Brink, Mix, et al., 2001 Abbreviations table available at the end of the Report. 
98

Distant Sites, Non-Brain. Among 70 patients, Brink, Schumacher, Mix et al. (2004) found 

that PET’s sensitivity for distant non-brain sites was 97.8 percent, compared with 82.6 percent 

for conventional staging. Specificity was 91.7 percent for PET and 79.2 percent for conventional 

staging. In the Shen, Shiau, Wang, et al. (2002) study, PET had 100 percent sensitivity in 19 

patients. Sites in this study included contralateral lung (1 false positive), liver, bone/marrow, 

adrenal and other extrathoracic. 

Brain Metastases. In the Brink, Schumacher, Mix et al. (2004) study, PET’s sensitivity was 

46.2 percent, compared with 100 percent for conventional staging, among 13 patients. 

Specificities were 97.4 percent for PET and 100 percent for conventional staging. Shen, Shiau, 

Wang, et al. (2002) included 2 patients with brain metastases and PET detected 1 (50 percent 

sensitivity). 

Staging Accuracy 

All 6 studies reported on instances in which PET correctly upstaged disease among those 

undergoing initial staging (Table 41). The proportions were: 3 of 15 (20 percent) in Blum, 

MacManus, Rischin, et al. (2004); 1 of 24 (4.2 percent) in Bradley, Dehdashti, Mintun et al. 

(2004); 10 of 120 (8.3 percent) in Brink, Schumacher, Mix et al. (2004); 3 of 24 (12.5 percent) in 

Kamel, Zwahlen, Wyss, et al. (2003); 1 of 25 (4 percent) in Shen, Shiau, Wang, et al. (2002); and 

5 of 30 (19.2 percent) in Schumacher, Brink, Mix, et al. (2001). Three studies mentioned 

examples of PET correctly downstaging disease. Brink, Schumacher, Mix et al. (2004) found 3 

cases in 24 (12.5 percent), Kamel, Zwahlen, Wyss, et al. (2003) observed 1 in 24 (4.2 percent) 

and Shen, Shiau, Wang, et al. (2002) saw 1 in 25 (4 percent). Among patients being restaged, 

Schumacher, Brink, Mix, et al. (2001) reported that PET correctly upstaged disease in 1 of 6 

patients (16.7 percent). 

In two studies, PET was found to correctly rule in disease at various sites. In the Bradley, 

Dehdashti, Mintun et al. (2004) study the site was lung in 1 patient (4.2 percent) and regional 

lymph nodes in 6 (25 percent). In the Kamel, Zwahlen, Wyss, et al. (2003) study, the sites were: 

visceral/soft tissue in 1 patient undergoing initial staging (4.2 percent); lung in 1 restaged patient 

(5 percent); and breast/axilla in 1 restaged patient. PET was shown to correctly rule out disease 

in selected sites in the Kamel, Zwahlen, Wyss, et al. (2003)study, including: adrenal gland in 1 

patient who was initially staged (4.2 percent); bone in 1 who was restaged (5 percent); and 

lymph node in 2 restaged patients (10 percent). 

Only Kamel, Zwahlen, Wyss, et al. (2003) and Shen, Shiau, Wang, et al. (2002) reported the 

frequency of incorrect staging by PET; it is unclear from the other studies how often restaging by 

PET was incorrect. Both Kamel, Zwahlen, Wyss, et al. (2003) and Shen, Shiau, Wang, et al. 

(2002) found no cases incorrectly upstaged or downstaged by PET at initial staging, but Kamel, 

Zwahlen, Wyss, et al. (2003)reported 1 case being restaged that was incorrectly upstaged. 

Changes in Patient Management 

Four studies reported on instances in which patient management was changed based on PET 

results. The total proportions were: 41.7 percent in Blum, MacManus, Rischin, et al. (2004); 

58.3 percent in Brink, Schumacher, Mix et al. (2004); 29.2 percent in Bradley, Dehdashti, 

Mintun, et al. (2004) and 28.6 percent in Kamel, Zwahlen, Wyss, et al. (2003). Specific changes 
99

Summary Table41. Staging Accuracy Results/Changes in Patient Management: Positron Emission Tomography for Staging of SStudy Test Use 

PET Correctly Changed Stage  # % 

PET Ruled-in (R/I) or Ruled-out (R/O) Metastases  Site # % 

PET Missed Metastases Site # % 

PET Changed Patient Ma # % Changes 

Blum, MacManus, Rischin, et al., 2004 

PET staging up 3 20 4 26.7 forgone RT

 1 6.7 ED, receiv CTx/RTx  2 13.3 RTx target  3 12 PCI omitte 3 12 PCI select 2 8 forgone CT NED 

Bradley, Dehdashti, Mintun et al., 2004 

PET staging up 1 4.2 R/I lung 1 4.2 

R/I regl LNs 6 25 

 7 29.2 RTx target 

Brink, Schumacher, Mix et al., 2004 

PET staging up 10 8.3 

down 3 2.5 

brain 1 0.8 10 8.3 forgone RT

 3 2.5 selected C 1 0.8 missed bra affected tr

Kamel, Zwahlen, Wyss, et al., 2003 

PET staging 

restaging 

up 3 12.5 down 1 4.2 

R/I visceral/ 

soft tissue 1 4.2 

R/O adrenal 1 4.2 R/I lung 1 5 R/I breast/ 

axilla 1 5 

R/O LN 2 10 R/O bone 1 5 

brain 2 8.3 LN 1 5 

 12 29  9 37 forgone RT altered rad selected s 3 15 CTx reinst CTx disco

Shen, Shiau, Wang, et al., 2002 

PET staging up 1 4 

down 1 4 

Schumacher, Brink, Mix, et al., 2001 

PET staging 

restaging 

up 5 19.2 up 1 16.7 
100

included the following: forgoing of RTx for extensive disease; palliative CTx/RTx selected for 

extensive disease; change in RTx target volume; PCI selected; PCI omitted; forgoing of CTx for 

no evidence of disease; CTx/RTx selected for limited disease; surgery selected; CTx reinstituted; 

and CTx discontinued. 

Study Quality. The quality assessment tool used for Key Question 6 includes 14 items, 8 of 

which focus on the reference standard (Appendix Table 4G).* A reference standard is the basis 

for estimating sensitivity and specificity. As noted, the quality of information about the 

reference standard was uniformly poor, undermining confidence in estimates of sensitivity and 

specificity. The ratings of study quality can be seen in Summary Table 42. 

Given 14 items in the instrument and 6 studies, there were 84 data points, among which 51 

percent were rated as unclear, underlining the prevalence of poor reporting in these articles. 

In only 1 study (Bradley, Dehdashti, Mintun et al., 2004) was it clear if the sample was 

representative of population of interest. Conventional staging suggested that patients in the 

Bradley, Dehdashti, Mintun et al. (2004) study had limited disease, so PET was used to 

determine if any patients were understaged. In all of the other 5 studies, it is unclear why 

patients were referred for PET and no study clearly stated that an intact group of patients newly 

diagnosed with SCLC were enrolled. Selection criteria were clear only in the Bradley, 

Dehdashti, Mintun et al. (2004) study. For all other studies, criteria were unclear. Articles by 

Brink, Schumacher, Mix et al. (2004) and Shen, Shiau, Wang, et al. (2002) suggest that PET 

results influenced performance of the reference standard. In the other 4 studies, it is unclear if 

PET results influenced performance of the reference standard. The Bradley, Dehdashti, Mintun 

et al. (2004) study did not incorporate PET into the reference standard, while in all other studies, 

it was unclear whether PET and the reference standard were independent. Only the Bradley, 

Dehdashti, Mintun et al. (2004) study stated that PET was interpreted blind to the reference 

standard; all others were unclear. 

Conclusions 

Six studies reporting on a total of 277 patients (range 20-120) provided data on the diagnostic 

accuracy of PET in SCLC. The evidence suggests that, except for detection of brain metastases, 

the PET added to conventional staging is more sensitive in detecting disease than conventional 

staging alone. Upstaging was reported in 4–20 percent of patients and downstaging in 4–13 

percent of patients. Three studies reported very high occurrence of patient management changes 

that were attributed to PET (29–58 percent). 

However, the quality of these studies is consistently poor and insufficient detail in reporting 

was the norm. There is such a high degree of uncertainty about the execution and interpretation 

of the reference standard in all of these studies that confidence is quite low in estimates of 

diagnostic and staging accuracy. Although these studies report that PET has correctly upstaged 

or downstaged the extent of disease, the frequency of incorrect changes in stage attributable to 

PET is unknown due to incomplete reporting. It is not possible to determine the frequency with 

which management changes, based on PET results, were actually beneficial or harmful. 

Thus it is not possible from the limited and poor quality evidence that is available to 

determine whether the use of PET adds value relative to conventional staging tests for SCLC. 

 

* Appendixes cited in this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/lungcansmall/lungcan.pdf.
101

Summary Table 42. Ratings of Study Quality for Key Question 6 

Item Blum Bradley Brink Kamel Shen Schumacher 

Representative sample? ? + ? ? ? ? 

Clear patient selection criteria? ? + ? ? ? ? 

Correct reference standard classification of 

target? ? ? ? ? ? ? 

Short period between test and reference 

standard? ? ? ? ? ? ? 

Random/whole sample received reference 

standard? + + + + + + 

Received reference standard regardless of 

test results? ? ? - ? - - 

Reference standard independent of test? ? + + ? ? ? 

Test execution sufficiently described? + + + + - + 

Reference standard execution sufficiently 

described? - - - - - - 

Test interpreted blind to reference standard? ? ? + ? ? ? 

Reference standard interpreted blind to test? ? ? ? ? ? ? 

Clinical data available? + +/- - + - - 

Uninterpretable/indeterminate results? - - - - - + 

Withdrawals explained? + + + + + + 

Key Question 7 

What are the outcomes (survival, toxicity and quality of life) of treatments used to manage 

patients with mixed small cell/non-small cell lung cancers? 

Overview 

Two types of studies were sought: RCTs that compared alternative chemotherapy regimens 

for mixed small cell/non-small cell cancers; and phase II prospective trials reporting on at least 

25 patients treated with a single regimen that reported at least one health outcome of interest. 

Health outcomes included: duration of survival; disease-free survival and/or progression-free 
102

survival; quality of life; treatment-related adverse effects; objective tumor response rates; and 

response durations. 

Results 

No studies meet selection criteria for this question. Very few references from the literature 

search represented studies of any kind that included patients with mixed histology. Several 

studies are described below, along with reasons for exclusion. 

• The single-arm study by Ruffini, Rena, Oliaro, et al. (2002) was excluded because it 

could not be confirmed as a prospective phase II multicenter trial. It was clearly 

conducted as a single-center case series of patients with mixed histologic pattern who 

underwent surgery. The article does not mention that it was prospective and is likely to 

be retrospective. Between 1993 and 1999, 1158 patients underwent surgery for lung 

tumors. Among these were 59 patients with a mixed histologic pattern, separated into 3 

main subgroups: 1) adenosquamous carcinoma, n=33, 2) combined neuroendocrine + 

non-neuroendocrine carcinoma (NNEC), n=21, and 3) biphasic tumors, n=5. The second 

subgroup included 14 patients with SCLC: 10 who had SCLC + squamous cell carcinoma 

and 4 who had SCLC + adenocarcinoma. The article provides survival data for 19 of the 

patients in the second subgroup. 

• SmytheEstrera, Swisher, et al. (2001) was excluded because it was not prospective or 

multicenter and it did not enroll the minimum of 25 patients. These authors reported a 

single-center retrospective study of 11 patients who underwent surgery for NSCLC after 

treatment for SCLC. The study period spanned 1978 to 1998. Survival results for the 

mixed histology patients were compared with 3 control groups: 1) 23 patients with stage I 

NSCLC undergoing any resection; 2) 46 patients with stage I NSCLC undergoing wedge 

resection; and 3) 17 patients undergoing wedge resection who had NSCLC and a prior 

malignancy. 

• A subset of patients with mixed histology from an RCT is discussed by Aisner, 

Finkelstein, Ettinger, et al. (1990). This study is excluded because outcomes are not 

presented according to treatment group. Patients with extensive stage SCLC received 

one of 2 induction chemotherapy regimens and complete responders were further 

randomized to maintenance chemotherapy or observation after whole brain irradiation. A 

pathologist reviewed the tumor specimens according to a revised classification scheme 

that includes a variant-morphology category characterized as the small-cell/large-cell 

(SC/LC) subtype. An initial review of 577 patients identified 24 with the SC/LC subtype. 

Subsequent review with a second pathologist confirmed only 11 patients in this category. 

Of these 11 patients, 3 achieved a complete response and 4 achieved a partial response. 

• The paper by Johnson, Ihde, Bunn, et al. (1985) is excluded because it presents outcome 

data for only a single patient with mixed histology. This article summarized data from a 

series of intramural NCI clinical trials that included 252 patients with newly diagnosed 

SCLC. Of these, 19 patients were of SC/LC subtype. The article focuses on 19 patients 
103

who achieved long-term survival (>30 months). Only 1 SC/LC patient was a member of 

this group. 

Conclusions 

No studies meet selection criteria for this question. Very few references from the literature 

search represented studies of any kind that included patients with mixed histology. No 

conclusions can be drawn on outcomes of treatment for patients with mixed small cell/non-small 

cell lung cancers. 

Key Question 8 

What is the role of surgery and what is its impact on survival in patients with very early stage 

SCLC? How do available studies define very early stage SCLC? 

Overview 

Very early limited SCLC is defined as no preoperative evidence of involved nodes (clinically 

N0). In a retrospective analysis of 264 limited stage SCLC patients treated with chemotherapy 

and radiation from 1976 through 1985, Shepherd, Ginsberg, Haddad et al. (1993) found 

significantly (p=0.02) better survival for patients clinically staged with negative mediastinal 

nodes, compared to those with positive mediastinal nodes and also to those with pneumonic 

consolidation, pleural effusion, atelectasis, or supraclavicular adenopathy. About half the 

patients classified node negative underwent mediastinoscopy and half were staged by thoracic 

CT or X-ray only. Unfortunately, retrospective analyses of resected SCLC patients show that 

clinical (preoperative) staging frequently underestimates pathologic stage (Shepherd, Ginsberg, 

Patterson et al. 1989; Shepherd, Ginsberg, Feld et al. 1991; Inoue, Miyoshi, Yasumitsu et al. 

2000) and inadequately separates limited stage patients by prognosis (Waddell and Shepherd, 

2004). Moreover, detection of involved nodes depends on the methods used for staging. 

For this question, randomized, controlled trials that compared surgery to no surgery in 

patients with very early limited SCLC were sought. Two randomized, controlled trials were 

identified (Lad, Piantadosi, Thomas, et al., 1994; Liao, Zhao, Zhou, et al., 1995), but each had 

serious limitations for purposes of this review (Summary Table 43). First, neither used platinum 

based chemotherapy, and thus had limited relevance to contemporary treatment settings. 

Second, neither RCT studied a homogeneous group with respect to nodal status at randomization 

(Summary Table 44). The larger RCT (Lad, Piantadosi, Thomas, et al., 1994; N=146) included 

patients with involved mediastinal nodes, and it is uncertain whether Liao, Zhao, Zhou, et al. 

(1995; N=40) excluded such patients. Neither study reported outcomes separately for a 

subgroup without nodal involvement. Since relevant RCT data were lacking, we also sought data 

from non-randomized comparative studies, both prospective and retrospective (see Summary 

Table 43 and Appendix Tables 8A-D).*

 Eight studies were identified: 

 

*

 Appendixes cited in this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/lungcansmall/lungcan.pdf.
104

• one case-control study (Badzio, Kurowski, Karnicka-Mlodkowska, et al., 2004/Badzio, 

Jassem, Kurowski, et al., 2005); 

• a prospective study of surgery with a comparison group of surgical candidates who did 

not undergo thoracotomy (Shepherd, Ginsberg, Patterson, et al. 1989); 

• four retrospective analyses (Namikawa, Den, Kimura, et al., 1994; Hara, Ohta, Ichinose, 

et al., 1991/Hara, Ichinose, Kuda et al., 1991; Friess, McCracken, Troxell, et al., 1985; 

Osterlind, Hansen, Hansen, et al., 1985); and 

• two registry analyses (Rostad, Naalsund, Jacobsen, et al., 2004; George, Fitzgerald, 

Brown, et al., 1986). 

These studies had similar limitations with respect to treatment regimens and included patients 

(Summary Tables 43 and 45). Three studies used platinum-based regimens (Badzio, Kurowski, 

Karnicka-Mlodkowska, et al., 2004/Badzio, Jassem, Kurowski, et al., 2005; Shepherd, Ginsberg, 

Patterson, et al. 1989; Hara, Ohta, Ichinose, et al., 1991/Hara, Ichinose, Kuda et al., 1991), but 

not for all included patients. Only the Rostad, Naalsund, Jacobsen, et al. (2004) registry analysis 

restricted their study population to patients with very early limited stage disease (N0 patients 

clinically staged Ia or Ib). 
105

Summary Table 43. Studies Comparing Surgery versus No Surgery for Early Limited Stage SCLC 

N evaluated resections study Study +surg -surg 

Pt? ChemoTx

regimen TRTx? PCI? types1 timing2 

response 

status3 type 

# 

centers

quality

rating

Lad, 

Piantadosi, 

Thomas, et 

al., 1994 

70 76 no CAV all all 54 c, 4 

p, 12 T after 40% CR 60% PR RCT multi fair 

Liao, Zhao, 

Zhou, et al., 

1995 

20 20 no IMAV -surg 

only NR NR mid 70-80% CR RCT one poor 

Badzio, 

Kurowski, 

KarnickaMlodkowska, 

et al., 

2004/Badzio, 

Jassem, 

Kurowski, et 

al., 2005 

67 67 some4 various 58% of 

-surg 

34% 

of 

+surg

30 P 

37 L before not relevant 

casecontrol one poor 

Shepherd, 

Ginsberg, 

Patterson et 

al. 1989 

38 19 ~5% various all all 

8 P, 25 

L 

5 T 

after 45% CR 

50% PR 

nonrandom. multi fair 

Namikawa, 

Den, Kimura, 

et al., 1994 

58 43 NR NR NR NR NR NR ? retrospect. one poor 

Hara, Ohta, 

Ichinose, et 

al., 

1991/Hara, 

Ichinose, 

Kuda et al., 

1991 

36 45 ~33% various all NR 

4 P, 27 

L 

5 B 

19 

before 

17 after

24% CR 

59% CR 

retrospect. one poor 

Friess, 

McCracken, 

Troxell, et 

al., 1985 

15 246 no COMF 

or CAV all all 3 P 12L before not relevant 

retrospect. multi fair 

Osterlind, 

Hansen, 

Hansen, et 

al., 1985 

33 46 no CCM+V+

A+E 

33% 

each 7-12%

11c, 

13p 

9<p 

before not 

relevant 

retrospect. two fair 

Rostad, 

Naalsund, 

Jacobsen, et 

al., 2004 

29 96 NR NR NR NR 3P, 15L 

3B, 5<p before not relevant registry multi poor 

George, 

Fitzgerald, 

Brown, et al., 

1986 

13 88 no various NR NR NR before not 

relevant registry multi poor 

1

 resection types: c=complete; p=partial; <p=less than a partial resection; T=thoracotomy only (open and close); 

P=pneumonectomy; L=lobectomy; B=bilobectomy; 2 resection timing: after = after all chemotherapy cycles; before = before any 

chemotherapy; mid = between cycles; 3

 at the time of randomization or resection; 4 proportion treated with platinum not reported. 
106

Summary Table44. Sample and Methods: Surgery versus No Surgery for Very Early Limited Stage Disease 

Study N Age 

% Female % Performance Status 

+Surg: Type of Resections CTX Regimen RTx Regim

Lad et al. 1994 RCT multi-center late 1983 - 10/1989 

Total 146 +surg 70 -surg 76 

md (rng) 59 (35-72); arms pooled, but “well matched” 

35 arms pooled but “well matched”

82% with KPS >90 

arms pooled but “well matched” 

54 complete  4 partial 12 open & close 

CAV same 

Dose 50 Gy  

Liao et al. 1995 single center RCT (Shanghai) 1/90-12/91 

Total 40 +surg 20 -surg 20 

mn (rng) 50 (33-74) 54 (31-66) 

10 10 

 NOT REPORTED 

not reported 

same for all: ifosfamide, Mesna, doxorubicin, vincristine 

Dose only for -suschedule n

Badzio et al. 2004, 2005; pair-matched case/control one center 1984-96 

Total 134 +surg 67 -surg 67 in CR 23 

mn (rng) 57 (29-70) 54 (36-71)  (p=0.03) 

15 22 (p=0.27) 

0 1 2 3 60 36 4 58 33 9 WHO 

30 pneumonectomy; 37 lobectomy 

CAV, CDE, PE or MCCC/CAV/ VI CCMV or ACOM 

Dose 30-50 1Gy 2  

Shepherd et al. 1989; adjuv. surgery post chemoTx; nonrandomized multi-center 

Total 57 +surg 38 -surg 19 

md (rng) 60 (39-77) 59 (44-75) 

32 47 

 NOT REPORTED 

8 pneumonectomy; 25 lobectomy; 5 thoracotomy only CAV+etoposide or PE 

Dose 25-35 Gy same 

Namikawa et al. 1994 retrospective series; single center 1960-86 

Total 101 +surg 58 -surg 43 

NOT REPORTED 

NOT REPORTED NOT REPORTED 

NOT REPORTED 

NOT REPORTED 

Dose  NO

Hara et al. 1991 retrospective series; single center 1972-89 

Total 81 +surg 36 -surg 45 

mn (rng) 64 (44-76) 63 (45-83) 

17 16 

0 1 2 3 50 44 6 18 78 4 ECOG 

4 pneumonectomy; 27 lobectomy; 5 bilobectomy various regimens same 

Dose 30-70 Gy (mn 46 Gy) 

Friess et al. 1985 retrospective analysis of SWOG 7628 patients; 1977-9 

Total 261 +surg 15 -surg 246 

NOT REPORTED 

NOT REPORTED NOT REPORTED 

3 pneumonectomy; 12 lobectomy 4 different regimens 

Dose 2 x 30 Gy + 

15 Gy boost 
107

Summary Table44. Sample and Methods: Surgery versus No Surgery for Very Early Limited Stage Disease (continued) 

Study N Age 

% Female % Performance Status 

+Surg: Type of Resections CTX Regimen RTx Regim

Osterlind et al. 1985; retrospective analysis of patients from 6 trials, 2 Danish institutions, 3/73-9/81 

Total 79 +surg 33 -surg 46 

mn (sd) 55 (+8) 

60 (+6) 

18 28 

AJC1 0-1 2 3-4

 83 17 0  91 6 3 

11 complete, 13 partial, 9 <partial resections 

CCM + vincristine + (doxorubicin + etoposide) Dose 

33% of eacdose, schereported   

Rostad et al. 2004 registry analysis all cases in Norway, 1993-9 

Total 125 +surg 29 -surg 96 

“no age difference” between groups 

NOT REPORTED NOT REPORTED 

3 pneumonectomy; 15 lobectomy; 3 bilobectomy; 5 minor resection 

NOT REPORTED 

Dose no details p 

George et al. 1986 registry analysis all cases in Rochester, NY 1975-81 

Total 101 +surg 13 -surg 88 

14% 31-5029% 51-6038% 61-7019% >71 

(groups pooled) 

35 (groups pooled) NOT REPORTED 

NOT REPORTED 

CCM, CMVP, CC, or CAV same 

Dose no details p 

1 American Joint Committee for Cancer Staging, 1979 

Abbreviations table provided at the end of this Report. 
108

Summary Table 45. Eligibility criteria and staging procedures used in studies of surgery for very early limited stage SCLC 

eligibility criteria for inclusion by clinical staging evaluation staging procedu

Study

diagnosis 

before 

thoracotomy?

solitary 

nodules? 

peripheral 

T2 tumors 

T3 tumors 

involved 

mediastinal 

nodes 

involved 

supraclavicular nodes 

involved 

hilar nodes 

pleural 

effusion 

pericardial 

effusion 

superior s

vena cava yndrome 

disease 

stage II 

disease 

stage III 

chest 

imaging 

abdominal 

imaging 

brain 

imaging 

bone 

imaging 

Lad et al., 1994 yes no yes yes yes ? ? ? no no yes yes ? 

yes; 

method 

unknown

CT 

yes; 

method 

unknow

Liao et al., 1995 yes no yes yes ? ? ? ? ? ? yes yes CT CT & US CT RNS Badzio et al., 2004 no ? yes no yes no ? no ? ? yes yes CT CT or US CT RNS Shepherd et al., 1989 

yes no yes yes if N0 yes ? ? ? ? ? yes yes some CT RNS CT or RNS RNS 

Namikawa et al., 1994 

most ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? 

Hara et al., 1991 yes ? yes ? yes ? ? ? ? ? yes yes CT CT or RNS CT or RNS CT or RNS Friess et al., 1985 yes ? ? ? yes yes ? ? ? ? ? ? X ray RNS RNS RNS Osterlind et al., 1985 

yes ? ? ? no no no ? ? ? no no ? ? ? ? 

Rostad et al., 2004 ? ? yes no no no no ? ? ? no no CT for some ? ? ? George et al., 1986 ? ? yes yes yes yes yes no ? ? yes yes CT for some CT, US or RNS in 75% CT or RNS in 77% ? yes=eligible for inclusion, or procedure was used for staging ; no=not eligible for inclusion or not used or evaluated for staging ; ?= cannot be determine

published report; Abbreviations table provided at the end of this Report. 
109

Summary Table 46. Survival Outcomes: Surgery versus No Surgery for Very Early Limited Stage Disease Study N OS Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr (%) TTP Med (mos) 1 yr 2 yr 3 yr Lad et al., 1994 multi-center RCT 

+surg 70 -surg 76 Difference 

 15.4 ~60 20 ~20 ~20 ~20 18.6 ~65 20 ~20 ~20 ~20 -3.2 -5 0 log rank p=0.78 

 NOT REPORTED 

Liao et al., 1995 single-center RCT (Shanghai) 1/90-12/91 

+surg 20 -surg 20 Difference 

 79 52 24  63 18 18  16 34 6 (log rank p=0.12; t-test at 2 yr, p<0.05) 

 NOT REPORTED 

Badzio et al., 2004, 2005 single center case-control 

+surg 67 -surg 67 (in CR 23) Difference 

 22.3 70 43 ~35 ~30 27  11.2 45 17 ~12 ~4 4 (22) (36) (26)  11.1 25 26 ~23 ~26 23p < 0.001; HR = 0.42; 95% CI: 0.28, 0.61 

 20.9  (time to relapse or progress 7  13.9 p < 0.001 

Shepherd et al., 1989 non-randomized multi-center 

+surg 38 -surg 19 Difference 

 22.8 ~63 ~47 ~36 ~36 36  11.8 ~48 ~10 ~10 ~10  10 ~15 ~37 ~26 ~26 p = 0.049 

 NOT REPORTED 

Namikawa et al., 1994 single center case series 

resected 43 explored1 15 

-surg 43 Difference 

 8.1  5.1  5.2  2.9 (statistical test result not reported) 

 NOT REPORTED 

Hara et al., 1991 single center case series 

+surg 36 -surg2: CR 19 

PR 20 

Difference 

 33 38  24.5 21  12.5 0  8.5 (+surg – CR)  20.5 (+surg – PR) (statistical test result not reported) 

 NOT REPORTED 

1 patients found intra-operatively to have unresectable disease 2 results for unresected patients reported separately for complete (CR) and partial (PR) responders to chemotherapy + TRTx 
110

Summary Table 46. Survival Outcomes: Surgery versus No Surgery for Very Early Limited Stage Disease (continued) Study N OS Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr (%) TTP Med (mos) 1 yr 2 yr 3 yr Friess et al., 1985 4-arm RCT subgroup analysis 

+surg 15 -surg 246  333 

Difference 

 25 44  10.5 (p=0.0037) 13.7 (p<0.05)  10 (range, 1-46+; p=0.03)  15 30.3 

 NOT REPORTED 

Osterlind et al., 1985; retrospective analysis, patients from 6 trials, 2 Danish institutions, 3/73-9/81 

+surg 33 -surg 46 Difference 

 ~37 ~16 ~14 ~14 ~50 ~16 ~10 ~8 ~(-13) 0 ~4 ~6  (p=0.35 by life table analysis) 

DFS: 15% at 1.5 yr, 12% at 2 yr  15% at 1.5 yr, 13% at 2 yr  none 

Rostad et al., 2004 registry analysis 

+surg 29 -surg 96 Difference 

 44.9  (95% CI: 23.9, 65.9) 11.3  (95% CI: 4.2, 18.4) 33.6 

 NOT REPORTED 

George et al., 1986 registry analysis 

+surg 13 -surg (all) 88  CTx 43  RTx 20  both 25 

Difference 

 30.8 ~70 ~56 ~46 ~40 ~40  12.4  11.9 ~43 ~15 ~10 ~4 0  13.4 ~58 ~20 ~20 ~20 18  14.1  18.4 [+surg – (all -surg)]; (p=0.009 versus all –surg) 

 NOT REPORTED 

3 subgroup of unresected patients selected for “similar initial presentation” as those resected 
111

Summary Table 47. Adverse Events: Surgery versus No Surgery for Very Early Limited Stage Disease Toxicity Type Study Severity or Grade Early n % Late n % p Not RepoTreatment-related Lad 1994 70 2.9 76 NR Badzio 20 or operative Liao 1995 20 0 20 0 1985; Ostmortality Shepherd1 1989 38 0 19 NR1 Hara 1991 36 0 45 NR  George 1986 13 0 88 121 2 of 72 patients (3%) died after the first course of chemotherapy. 2 given chemotherapy plus TRTx 

Only Shepherd, Ginsberg, Patterson, et al. (1989) reported post-operative complications other than mortality. Among 38 resected patients, they observ

1 severe bronchospasm (2.6%) 1 prolonged atelectasis (2.6%) 1 pulmonary edema (2.6%) 2 transient arrhythmias (5.3%) 1 assisted ventilation for 6 weeks (2.6%) 
112

Randomized, Controlled Trials 

Interventions. Although two RCTs compared outcomes for limited stage SCLC patients 

managed with versus without surgery, neither trial fully adhered to a contemporary management 

strategy (Lad, Piantadosi, Thomas, et al., 1994; Liao, Zhao, Zhou, et al., 1995; see Table 43, 

Table 44, Appendix Tables 8A-D). Only the Lad, Piantadosi, Thomas, et al., (1994) trial used 

TRTx (and PCI) for all patients, while the Liao, Zhao, Zhou, et al. (1995) trial only gave TRTx 

to those randomized to no surgery. Patients in the Lad, Piantadosi, Thomas, et al. (1994) trial 

received TRTx sequentially after completing chemotherapy (and post-operative recovery if 

randomized to surgery). The Liao, Zhao, Zhou, et al. (1995) trial scheduled operations (and 

TRTx for the other arm) after chemotherapy cycles 2 or 3 (of up to 7). Each treatment regimen 

lacked platinum. 

Study Populations. Published information suggests that neither RCT studied a 

homogeneous group of patients with respect to nodal status at randomization (Table 44). Lad, 

Piantadosi, Thomas, et al. (1994) randomized limited stage patients in CR or PR after five cycles 

of induction (neoadjuvant) chemotherapy. They did not report nodal status by clinical staging 

after chemotherapy for either arm. However, of 70 patients randomized to surgery, 15 were 

clinically N0 at registration (before induction), and 16 were pathologically N0 after resection. 

Ninety to 95 percent of those Liao, Zhao, Zhou, et al. (1995) randomized were in stage III. They 

reported 70–80 percent in CR, but it is uncertain when in the course of therapy these remissions 

were achieved. Liao, Zhao, Zhou, et al. (1995) also did not report nodal status before 

chemotherapy or after cycles 2-3, when surgery or radiation therapy took place. 

Neither trial required mediastinoscopy or other invasive staging. Noninvasive staging was 

inadequately described in both RCTs. 

Results. By log rank analysis, neither RCT found a statistically significant difference 

between Kaplan-Meier survival curves for those managed with versus without surgery (Lad, 

Piantadosi, Thomas, et al., 1994, p=0.78; Liao, Zhao, Zhou, et al., 1995, p=0.12; see Table 46, 

Appendix Table 8E). However, Liao, Zhao, Zhou, et al. (1995) reported a significant difference 

in percent survival at two years that favored the arm randomized to surgery (52 percent versus 18 

percent; p<0.05 by t-test). Neither RCT reported time to relapse or progression, disease-free 

survival, or quality of life outcomes. 

Nonrandomized Comparisons 

Interventions. Only three of the eight studies reported that all patients received TRTx 

(Shepherd, Ginsberg, Patterson, et al., 1989; Hara, Ohta, Ichinose, et al., 1991/Hara, Ichinose, 

Kuda et al., 1991; Friess, McCracken, Troxell, et al., 1985), and only two used PCI (Shepherd, 

Ginsberg, Patterson, et al. 1989; Friess, McCracken, Troxell, et al., 1985). Only the Shepherd, 

Ginsberg, Patterson, et al. (1989) study resected patients after chemotherapy was completed. 

Three studies used platinum-based regimens (Badzio, Kurowski, Karnicka-Mlodkowska, et al., 

2004/Badzio, Jassem, Kurowski, et al., 2005; Shepherd, Ginsberg, Patterson, et al., 1989; Hara, 

Ohta, Ichinose, et al., 1991/Hara, Ichinose, Kuda et al., 1991), but not for all included patients. 
113

Study Populations. Inclusion and exclusion criteria (Summary Table 43, Appendix Table 

8A)*

 showed that only the Rostad, Naalsund, Jacobsen, et al. (2004) registry analysis restricted 

their study population to patients with very early limited stage disease (N0 patients clinically 

staged Ia or Ib). However, Rostad, Naalsund, Jacobsen, et al. (2004) did not report TRTx or PCI 

use, and excluded 18 patients who received adjuvant chemotherapy after surgery from their 

analysis. Thus, none of the eight non-randomized comparisons addressed the population of 

interest given contemporary treatment with versus without surgery. 

Results. Four of eight nonrandomized studies reported significantly longer survival for the 

group given surgery than for the comparison group managed without surgery (Badzio, Kurowski, 

Karnicka-Mlodkowska, et al., 2004/Badzio, Jassem, Kurowski, et al., 2005; Shepherd, Ginsberg, 

Patterson, et al., 1989; Friess, McCracken, Troxell, et al., 1985; George, Fitzgerald, Brown, et 

al., 1986; see Summary Table 8B, Appendix Table 8E). The Badzio case-control study (Badzio, 

Kurowski, Karnicka-Mlodkowska, et al., 2004/Badzio, Jassem, Kurowski, et al., 2005) also 

reported a statistically significant increase in time to relapse or progression for those given 

surgery. No non-randomized comparison evaluated quality of life outcomes. 

One cannot exclude the influence of patient selection and other biases in the survival results 

from non-randomized studies. Most did not report adequate details to evaluate the similarity of 

study groups with respect to baseline characteristics and prognostic factors (Table 44, Appendix 

Tables 8b and 8H). Information also was inadequate to determine whether patients in each group 

were managed similarly with respect to chemotherapy and radiation therapy regimens (Table 44, 

Appendix Table 8C). 

Adverse Events 

Perioperative mortality was 2.9 percent in the Lad, Piantadosi, Thomas, et al. (1994) RCT 

(Table 47, Appendix Table 8G).* It was zero in the Liao, Zhao, Zhou, et al. (1995) RCT and in 

three reporting non-randomized comparisons. Only two of these five studies reported treatmentrelated mortality in the comparison groups managed without surgery (Liao, Zhao, Zhou, et al., 

1995; George, Fitzgerald, Brown, et al., 1986). Only the Shepherd, Ginsberg, Patterson, et al. 

(1989) study reported other adverse events, but did not report their rates in the comparison 

group. 

Conclusions 

For this question, we sought randomized and nonrandomized studies that compared surgery 

to no surgery in patients with very early limited SCLC, defined as no preoperative evidence of 

involved nodes (clinically N0). Two randomized controlled trials and 8 nonrandomized 

comparative studies were included in the review, but none provided evidence that directly 

address the question. 

None of these comparisons studied a homogeneous group of patients with respect to nodal 

status; nor were separate outcomes reported for the subgroup of patients without nodal 

involvement. Moreover, the treatment regimens used had limited relevance to contemporary 

 

* Appendixes cited in this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/lungcansmall/lungcan.pdf.
114

treatment settings; for example, 5 studies did not use platinum based chemotherapy for any 

patients, and the remaining 3 used platinum based therapy only for some patients. Thus no 

conclusion can be drawn on the outcomes of management of very early limited SCLC with 

versus without surgery. 

Key Question 9 

What are the outcomes of second- or subsequent-line therapy in patients with relapsed or 

progressive SCLC? Where available data permit, patients with limited- and extensive-stage 

disease will be addressed separately, as will those with refractory disease (relapse or progression 

within 3 months of primary treatment). 

Overview 

Two types of studies were sought: randomized, controlled trials (RCTs) that compared 

alternative chemotherapy regimens for relapsed, progressive, or extensive-stage SCLC; and 

phase II multicenter, prospective trials reporting on at least 25 patients treated with a single 

regimen that reported at least one health outcome of interest. Health outcomes included: 

duration of survival; disease-free survival and/or progression-free survival; quality of life; 

treatment-related adverse effects; objective tumor response rates; and response durations. 

The primary focus here is on RCTs (Summary Tables 48–51; Appendix Tables 9A–9G).*

 

The main purpose of single-arm phase II trials is to assess responsiveness to a chemotherapy 

regimen and select treatments for further testing in RCTs. Phase II trials in Appendix Tables 

9H-9M*

 are presented mainly to illustrate the regimens that have been tried on relapsed or 

progressive SCLC. The lack of comparisons between regimens within such trials limits their 

usefulness to this Review. Several recent studies that reported encouraging response data will be 

noted. 

Randomized, Controlled Trials 

Among 9 RCTs meeting selection criteria, sample sizes ranged from 32 to 610 and they 

collectively included 1,415 patients. As shown in Table 48, each of the 9 trials compared 

different sets of chemotherapy regimens. Seven trials compared 2 regimens and the Wolff, 

Birch, Sarma, et al. (1986) trial compared 3. Six studies specifically noted that second-line 

regimens were compared (von Pawel, Gatzemeier, Pujol, et al., 2001,; von Pawel, Schiller, 

Shepherd, et al., 1999; Postmus, Smit, Kirkpatrick, et al., 1993; Trillet-Lenoir, Lasset, Arpin, et 

al., 1992; O’Bryan, Crowley, Kim, et al., 1990; Spiro, Souhami, Geddes, et al. 1989). The study 

by Sculier, Lafitte, Lecomte, et al. (2002) stated that patients had previously undergone 

chemotherapy that did not include cisplatin and etoposide, but did not specify the distribution of 

number of previous regimens. It was also unspecified by O’Brien, Ciuleanu, Tsekov, et al. 

 

* Appendixes cited in this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/lungcansmall/lungcan.pdf.
115

(2005). Wolff, Birch, Sarma, et al. (1986) described this distribution: 80 percent had previously 

had 1 chemotherapy regimen, 14 percent had 2; and 6 percent had 3. 

Data on age, gender and performance status were reported by all studies except von Pawel, 

Schiller, Shepherd, et al. (1999), which only give performance status. O’Brien, Ciuleanu, 

Tsekov, et al. (2005) did not provide separate gender distributions for the two groups. The study 

by Spiro, Souhami, Geddes, et al. (1989) was a 2-stage randomized trial. In the first stage, 

patients were randomized to either 4 or 8 cycles of primary chemotherapy consisting of 

cyclophosphamide, vincristine and etoposide. The second stage randomized patients at relapse 

to either methotrexate plus doxorubicin or supportive care. Two pairs of first stage groups were 

compared at the second stage and shown to be similar on age, gender, performance status and 

stage. Where information was available, groups appeared comparable on these characteristics.

Summary Table 48. RCTs Comparing Alternative Chemotherapy Regimens for Relapsed, Progressive, or 

Extensive-Stage SCLC 

N 

Grp1 

N 

Grp2 

N 

Grp3 

Regime

n 1 

Regime

n 2 

Regime

n 3 

Previous 

Regimens 

pub 

type 

quality 

rating 

O’Brien, Ciuleanu, 

Tsekov, et al., 

2005 

70 71 po T BSC Abstr ? 

Sculier, Lafitte, 

Lecomte, et al., 

2002 

31 34 PE CbPE No PE; EVI, 

VAC, RTx, 

Surgery 

Full Fair 

von Pawel, 

Gatzemeier, Pujol, 

et al., 2001 

52 54 po T iv T Full Fair 

von Pawel, 

Schiller, 

Shepherd, et al., 

1999 

107 104 iv T CAV Platinum, 

CAV, 

PE+CAV, 

RTx, 

Immunotherapy, 

Surgery 

Full Fair 

Postmus, Smit, 

Kirkpatrick, et al., 

1993 

43 25 VIMP CDE Full Fair 

Trillet-Lenoir, 

Lasset, Arpin, et 

al., 1992 

15 17 Low PE High PE Full Poor 

O’Bryan, Crowley, 

Kim, et al., 1990 

45 58 BTOC PE CAV, E, 

other 

Full Poor 

Spiro, Souhami, 

Geddes, et al., 

1989 

294 290 MA BSC CV Full Poor 

Wolff, Birch, 

Sarma, et al., 

1986 

26 27 26 E100 E200 E300 1-3 CTx 

regimens, 

RTx, 

Surgery 

Full Poor 

Abbreviations table provided at the end of the Report. 
116 

Summary Table 49. Sample and Treatments: Treatment of Recurrent/Progressive Disease Study Inclusion Chemotherapy Agents Age (yr) Gender (%) 

Performan

O’Brien, Ciuleanu, Tsekov, et al., 2005 

relapsed SCLC ineligible for further IV CTx 

po T topotecan BSC best supportive  care 

 po T BSC

mn md 60 59 rng sd 

 All

M 73 F 27 

PS po 

0/1 73 

Sculier, Lafitte, Lecomte, et al., 2002 

proven SCLC prior CTx did not include PE 

PE cisplatin  etoposide CbPE carboplatin  cisplatin  etoposide 

 PE CbPE

mn md 58 59 rng 41-73 39-70 sd 

 PE CbPEM 84 76 F 16 24 

KPS PE 60-70 45 80-100 55 

von Pawel, Gatzemeier, Pujol, et al., 2001 

limited or extensive SCLC recurrence > 3 

mo after CR/PR to 1st-line CTx 

po T topotecan iv T topotecan 

 po T iv T

mn 59.9 58.2 md rng 38-79 35-74 sd 

 po T iv T

M 75.0 79.6 F 25.0 20.4 

PS po 0 191 652 15

von Pawel, Schiller, Shepherd, et al., 1999 

progressive, limited or extensive SCLC PD > 60 d after 1stline CTx 

iv T topotecan CAV cytoxan  doxorubin  vincristine 

 ECOG iv 

0 161 592 23

Postmus, Smit, Kirkpatrick, et al., 1993 

proven SCLC PD < 3 mo of last 

CTx 1st-line CTx: IMP, VP or CDE; PD after IMP/VP has 2nd-line 

CDE; PD after CDE had VIMP 

VIMP vincristine  ifosfamide  mesna  carboplatin CDE cytoxan  doxorubicin  etoposide 

 IMP VP CDE

mn md 57 58 55 rng 38- 39- 43-  69 73 67 sd 

 MP VP CDEM 71 86 88 F 29 14 12 

ECOG IM0 24 1 43 2 24 3 10 

Trillet-Lenoir, Lasset, Arpin, et al., 1992 

relapsed SCLC after 1st-line CTx PE1 cisplatin 20 etoposide 60 

PE2 cisplatin 40  etoposide 100 

 PE1 PE2

mn 56.73 52.47 md rng sd 8.7 5.95 

 PE1 PE2

M 100 88 F 0 12 

KPS PEmn 79sd 13

O’Bryan, Crowley, Kim, et al., 1990 

failed or relapsed SCLC after 1st-line 

CTx 

BTOC vincristine  thiotepa  cytoxan  carmustine PE cisplatin  etoposide 

 BTOC PEmn md 58 61 rng 41-75 38-76 sd 

 BTOC PEM 80 64 F 20 36 

KPS BT0-1 53 2-3 47 

Abbreviations table provided at the end of the Report.
117 

Summary Table 49. Sample and Treatments: Treatment of Recurrent/Progressive Disease (continued) Study Inclusion Chemotherapy Agents Age (yr) Gender (%) 

Performan

Spiro, Souhami, Geddes, et al., 1989 

histologically, cytologically proven SCLC; < 75; 

MA methotrexate  doxorubicin BSC best supportive  care 

Wolff, Birch, Sarma, et al., 1986 

recurrent SCLC, prior CTx did not include E 

E100 etoposide 100 E200 etoposide 200 E300 etoposide 300 

 100 200 300< 50 19 11 15 50-60 38 56 46 > 60 42 33 31 

 100 200 300

M 58 93 81 F 42 7 19 

KPS 100 60 0 70 46 80 27 90 19 100 8 
118 

Summary Table 50. Efficacy Outcomes: Treatment of Recurrent/Progressive Disease 

Study 

Overall Survival (%)  N Med 1 yr Test 

 Tumor Response (%) 

N CR PR SD PD NE Test 

O’Brien, Ciuleanu, Tsekov, et al., 2005 

 N Med 1 yr po T 71 26 wks 49 (6 mo) BSC 70 14 wks 26 HR=0.64 (95% CI: 0.45, 0.90, p=0.0104) 

po T 71 7 44 BSC 70 

Sculier, Lafitte, Lecomte, et al., 2002 

PE 31 18.9 wks 18 Log-rank, CbPE 34 33.0 wks 19 p=0.11 

PE 31 0 29 CbPE 34 9 38 

von Pawel, Gatzemeier, Pujol, et al., 2001 

po T 52 32.3 wks ~25 adjusted iv T 54 25.1 wks ~8 RR=0.90  (95% CI  0.55, 1.47) 

po T 52 1.9 21.2 19.2 30.8 26.9 Differeniv T 54 3.7 11.1 29.6 42.6 13.0 8.3% (9 -6.6%, 2

von Pawel, Schiller, Shepherd, et al., 1999 

iv T 107 25.0 wks 14.2 Log-rank, CAV 104 24.7 wks 14.4 p=0.772,  Adjusted  RR=1.17  (p=0.322) 

iv T 107 0.0 24.3 19.6 45.8 10.3 DifferenCAV 104 1.0 17.3 11.5 52.9 17.3 P=0.285  

Postmus, Smit, Kirkpatrick, et al., 1993 

VIMP 43 19 wks CDE 25 22 wks 

VIMP 25 4 56 8 24 8 CDE 43 14 37 19 23 7 

TrilletLenoir, Lasset, Arpin, et al., 1992 

PE1 15 13 wks PE2 17 16.5 wks 

PE1 15 6.6 20 13.3 60 PE2 17 11.8 23.5 11.8 52.9 

O’Bryan, Crowley, Kim, et al., 1990 

BTOC 45 13 wks RR 1.3 PE 58 16 wks (95%CI  0.9, 2.0) BTOCgood 11 10 wks RR 3.3 PEgood 16 35 wks (95%CI  0.2, 9.1) BTOCpoor 34 14 wks RR1.1 PEpoor 68 12 wks (95%CI  0.7, 1.8) 

BTOC 45 0 13 PE 58 2 10 (p=0.91BTOCgood 11 27 PEgood 16 27 BTOCpoor 34 9 PEpoor 68 9 
119 

Summary Table 50. Efficacy Outcomes: Treatment of Recurrent/Progressive Disease (continued) Study 

Overall Survival (%)  N Med 1 yr Test 

 Tumor Response (%) 

N CR PR SD PD NE Test 

Spiro, Souhami, Geddes, et al., 1989 

MA MA 170 4 19 45 32 1 

Wolff, Birch, Sarma, et al., 1986 

E100 26 12.6 wks ~4 Log-rank, E200 27 20.0 wks ~12 GehanE300 26 22.5 wks ~24 Wilcoxon  (p=NS) 

E100 26 4 E200 27 7 E300 26 4 
120 

Summary Table 51. Adverse Events: Treatment of Recurrent/Progressive Disease Toxicity Type Study Description Group n Gr 3 % Gr 4 % Treatment-related mortality O’Bryan 1990 Drug-related deaths BTOC 45 4 0.28 

PE 84 1 

Alopecia Sculier 2002 PE 28 21 (3/4) 0.15 

CbPE 31 39 

 von Pawel 2001 po T 52 1.9 0.0 0.06 

iv T 54 13.0 0.0 

 von Pawel 1999 iv T 107 0.0 (3/4) 1.0 

CAV 104 0.0 

Fatigue von Pawel 2001 po T 52 5.8 0.0 0.36 

iv T 54 1.9 0.0 

 von Pawel 1999 iv T 107 4.7 (3/4) 0.28 

CAV 104 8.7 

Diarrhea von Pawel 2001 po T 52 7.7 0.0 0.054 

iv T 54 0.0 0.0 

 von Pawel 1999 iv T 107 0.9 (3/4) 1.0 

CAV 104 0.0 

Nausea O’Brien 2005 po T 71 1 1.0 

BSC 70 0 

 von Pawel 1999 iv T 107 39.3 (3/4) 0.89 

CAV 104 40.4 

Vomiting O’Brien 2005 po T 71 3 0.50 

BSC 70 0 

 Sculier 2002 Nausea/vomiting PE 30 7 (3/4) 0.23 

 32 0 

 von Pawel 2001 po T 52 11.5 0.0 0.16 

iv T 54 3.7 0.0 

 von Pawel 1999 iv T 107 2.9 (3/4) 1.0 

CAV 104 1.9 

 Wolf 1986 Nausea/vomiting/bloody diarrhea/ 

stomatitis 

E100 26 5 0 0.44 E200 27 4 0 E300 26 10 0 

Anorexia von Pawel 1999 iv T 107 0.9 (3/4) 1.0 

CAV 104 0.0 

Diarrhea O’Brien 2005 po T 71 6 0.12 

BSC 70 0 

Lethargy O’Brien 2005 Fatigue po T 71 4 1.0 

BSC 70 4 

Neurosensory O’Brien 2005 Pain po T 71 3 0.44 

BSC 70 6 

Neuromotor Hearing loss Esophagitis 18 Comparison of grade 3 and above versus others Fisher’s exact test. 
121 

Summary Table 51. Adverse Events: Treatment of Recurrent/Progressive Disease (continued) Toxicity Type Study Description Group n Gr 3 % Bronchopulmonary O’Brien 2005 Dyspnea po T 71 3 

BSC 70 9 

 von Pawel 2001 Dyspnea 

Pulmonary embolism 

po T 52 9.6 iv T 54 9.3 po T 52 1.9 iv T 54 0 

Pneumonitis von Pawel 2001 Pneumonia po T 52 5.8 

iv T 54 0.0 

Hepatic Kidney Hemorrhage Anemia O’Brien 2005 po T 71 25 (3 von Pawel 2001 po T 52 27.5 

iv T 54 26.4 

 von Pawel 1999 iv T 104 39.4 

CAV 101 17.8 

Thrombocytopenia O’Brien 2005 po T 71  Sculier 2002 PE 30 17 (

CbPE 32 38 

 von Pawel 2001 po T 52 25.5 

iv T 54 24.5 

 von Pawel 1999 iv T 104 28.8 

CAV 101 9.9 

 Postmus 1993 VIMP 25 8 

CDE 43 6 

 Trillet-Lenoir 1992 PE1 15 0 

PE2 17 18 

 Wolff 1986 Neutropenia E100 26 0 

E200 27 0 E300 26 24 

Leukopenia or neutropenia O’Brien 2005 Neutropenia po T 71  Sculier 2002 Leukopenia PE 30 60 (

CbPE 32 56 

 von Pawel 2001 Leukopenia 

Neutropenia 

po T 52 27.5 iv T 54 45.3 po T 52 21.6 iv T 54 25.9 

19 Comparison of grade 3 and above versus others Fisher's exact test. 
122 

Summary Table 51. Adverse Events: Treatment of Recurrent/Progressive Disease (continued) Toxicity Type Study Description Group n Gr 3 % Leukopenia or neutropenia von Pawel 1999 Leukopenia 

Neutropenia 

iv T 104 54.8 CAV 101 37.6 iv T 104 18.3 CAV 99 15.2 

 Postmus 1993 Leukopenia VIMP 25 26 

CDE 43 38 

 Trillet-Lenoir 1992 Leukopenia PE1 15 33 

PE2 17 12 

 Wolff 1986 E100 26 5 

E200 27 25 E300 26 0 

Infection O’Brien 2005 Febrile neutropenia 

Neutropenic infections 

Sepsis 

po T 71 po T 71 po T 71 

 Sculier 2002 PE 30 3 (3/

CbPE 33 3 

 von Pawel 2001 Fever po T 52 3.8 

iv T 54 1.9 

Other 
123 

Study Quality. Of the nine RCTs meeting selection criteria, four were rated as being of fair 

quality (Sculier, Lafitte, Lecomte, et al., 2002; von Pawel, Gatzemeier, Pujol, et al., 2001; von 

Pawel, Schiller, Shepherd, et al., 1999; Postmus, Smit, Kirkpatrick, et al., 1993, 4 were rated as 

poor (Trillet-Lenoir, Lasset, Arpin, et al., 1992; O’Bryan, Crowley, Kim, et al., 1990; Spiro, 

Souhami, Geddes et al. 1989; Wolff, Birch, Sarma, et al. 1986), and one could not be rated 

because it has only been reported as a conference abstract (O’Brien, Ciuleanu, Tsekov, et al., 

2005). The fair trials had moderate flaws mainly in the initial assembly of comparable groups: 

either the randomization method was inadequately described or insufficient information was 

available about group baseline characteristics. The 4 poor trials had multiple problems, but 3 

failed to define interventions clearly enough. Specifically, the number of intended cycles of 

chemotherapy was unspecified in these articles. 

Overview of Outcomes 

Overall Survival. Eight of nine trials reported data on overall survival, but only the study by 

O’Brien, Ciuleanu, Tsekov, et al. (2005) found a statistically significant difference between 

groups, in this case favoring oral topotecan over best supportive care. 

Time to Progression. Neither of the two studies reporting on time to progression (von 

Pawel, Gatzemeier, Pujol, et al., 2001; von Pawel, Schiller, Shepherd, et al., 1999) found 

statistically significant differences between groups. 

Quality of Life. The two studies by von Pawel et al. both reported data from a symptom 

scale that includes 9 domains. Only the earlier study, comparing intravenous topotecan and 

CAV, mentioned statistically significant differences between treatment groups. 

Adverse Events. Specific risks of adverse events varied as expected given that these studies 

used a variety of treatments. Higher risks of grade 3 and 4 toxicity may be acceptable if a 

treatment yields a substantial survival advantage. O’Brien, Ciuleanu, Tsekov, et al. (2005) found 

significantly greater survival for oral topotecan over best supportive care, while toxicities were 

low. The 2001 trial by von Pawel, Gatzemeier, Pujol, et al. found no difference in survival 

between oral and intravenous topotecan, but the intravenous route was associated with higher 

rates of leukopenia and neutropenia. The 1999 study by von Pawel, Schiller, Shepherd, et al. 

reported no survival difference between intravenous topotecan and CAV, but the topotecan 

group had higher risks of anemia and thrombocytopenia. Trillet-Lenoir, Lasset, Arpin, et al. 

(1992) observed similar survival for low and high dose PE, but the high dose group experienced 

more leukopenia. The small study conducted by Wolf did not find significant differences in 

survival for 3 doses of etoposide, but there was a trend toward better survival with higher dose, 

as well as more thrombocytopenia and neutropenia.

Tumor Response. Excluding the O’Brien, Ciuleanu, Tsekov, et al. (2005) and Spiro, 

Souhami, Geddes, et al. (1989) studies that did not actively treat the control group, none of the 

other 7 studies found significant differences in tumor response or duration between treatment 

groups. 
124 

O’Brien, Ciuleanu, Tsekov, et al. (2005). Oral Topotecan (po T) vs. Best Supportive Care 

(BSC). 

Study Quality. Since there is insufficient information about this study’s methods, study 

quality could not be rated. 

Overall Survival. This study, available only as a conference abstract, randomized 71 patients 

to oral topotecan and 70 patients to best supportive care. There was a 36 percent reduction in the 

risk of death for those receiving topotecan (hazard ratio=0.64, 95 percent CI: 0.45–0.90, 

p=0.0104). Median survival was longer for the topotecan patients (26 weeks vs. 14 wks) and 6-

month survival was increased (49 percent vs. 26 percent). 

Time to Progression. No data. 

Quality of Life. This study administered the EQ-5D health-related quality of life 

questionnaire and found a significantly faster rate of deterioration in the BSC group. 

Adverse Events. No significant differences were found in the incidence of these adverse 

events: vomiting, diarrhea, fatigue, pain and dyspnea. No hematologic toxicity was noted in the 

abstract for the BSC group, but in the topotecan group 7 percent had grade 3 or 4 anemia, 7 

percent had grade 4 thrombocytopenia and 33 percent had grade 4 neutropenia. In the topotecan 

group, the risk of febrile neutropenia was 3 percent, while 1 percent had neutropenic infections 

and 4 percent developed sepsis. 

Tumor Response. The abstract noted that the response rate for topotecan was 7 percent, but 

it was unclear what proportions had complete or partial responses. A further 44 percent 

experienced a stable disease after topotecan. 

Summary. Compared with best supportive care, oral topotecan significantly improves 

survival in patients with relapsed SCLC. The decline in quality of life is faster in patients 

receiving best supportive care. Neutropenia is the most common major adverse event. Careful 

assessment of the methodologic quality of this study awaits full publication beyond a conference 

abstract. 

Sculier, Lafitte, Lecomte, et al. (2002). Cisplatin/Etoposide (PE) vs. 

Carboplatin/Cisplatin/Etoposide (CbPE). 

Study Quality. This study was rated as fair, its main shortcoming concerned its lack of detail 

about the randomization method and lack of blinded interpretation of tumor response, which was 

the primary outcome. 

Overall Survival. This trial reported on 31 patients who received cisplatin and etoposide and 

34 patients who received that regimen plus carboplatin. These investigators found a median 

survival advantage of 14.1 weeks for the CbPE group relative to the PE group, although the 

difference was not statistically significant (p=0.11). 

Time to Progression. No data. 
125 

Quality of Life. No data. 

Adverse Events. Although nearly twice as CbPE patients as PE patients had grade 3 or 4 

alopecia (39 percent vs. 20 percent), the difference was not statistically significant. The authors 

reported that 19 percent of patients receiving PE experienced grade 3 or 4 thrombocytopenia, 

compared with 12 percent receiving CbPE, a nonsignificant difference. Grade 3 or 4 leukopenia 

occurred in 60 percent given PE and 56 percent given CbPE (p=0.97). The same percentage of 

patients (3 percent) in both groups developed infections. 

Tumor Response. Thie trial found an ORR of 47 percent for CbPE and an ORR of 29 

percent for PE. Median response duration was 33.9 weeks for CbPE and 22.6 weeks for PE. No 

statistical test results for these outcomes were provided. 

Summary. The data from this trial suggested slightly improved survival and tumor response 

in adding carboplatin to the combination of cisplatin and etoposide. This small underpowered 

study did not find significant differences between groups on any outcome. It is important to 

remember that this trial enrolled only patients who did not have previous therapy with platinum 

and etoposide. 

von Pawel, Gatzemeier, Pujol, et al. (2001). Oral Topotecan (po T) vs. Intravenous 

Topotecan (iv T). 

Study Quality. This trial was rated as fair; the principal problem was lack of detail about the 

randomization method. 

Overall Survival. These authors randomized 52 patients to oral topotecan and 54 patients to 

intravenous topotecan. They reported that median survival using oral topotecan was 32.3 weeks, 

compared with 25.1 weeks for intravenous topotecan. The difference was not statistically 

significant. 

Time to Progression. These authors found that median time to disease progression was 

similar in the oral (14.9 weeks) and intravenous (13.1 weeks) topotecan groups. The difference 

was not statistically significant. 

Quality of Life. This article stated that both oral and intravenous topotecan were associated 

with symptom improvement, but specific results of statistical tests were not given. 

Adverse Events. Significant differences were not observed between groups on the following 

grade 3 and grade 4 outcomes: alopecia, vomiting, dyspnea, pulmonary embolism, pneumonia, 

anemia, thrombocytopenia and fever. Grade 3 diarrhea was significantly more common in the 

group receiving oral topotecan (7.7 percent vs. 0 percent). Grade 3 leukopenia was significantly 

more frequent in the intravenous group (45.3 percent vs. 27.5 percent). Grade 4 neutropenia 

occurred significantly more often among intravenous topotecan patients (67.3 percent vs. 35.3 

percent). 

Tumor Response. The ORR for oral topotecan was 23.1 percent and the proportion for 

intravenous topotecan was 14.8 percent. The difference was not statistically significant. 
126 

Summary. This study observed no significant difference in survival between those give oral 

or intravenous topotecan. The difference in overall response was not significant, but favored the 

oral route. Some hematologic toxicities were more common for intravenous, but most other 

adverse events occurred at similar rates. 

 von Pawel, Schiller, Shepherd, et al. (1999). Intravenous Topotecan (iv T) vs. 

Cyclophosphamide/Doxorubin/Vincristine (CAV). 

Study Quality. This study was rated as fair. While the randomization method was 

sufficiently described and seemed adequate, age and gender distributions were not specified, co 

it could not be established if groups were comparable on these characteristics at baseline. 

Overall Survival. The total assigned to intravenous topotecan was 107, while 104 received 

CAV. Median survival was nearly identical for intravenous topotecan (25 weeks) and CAV 

(24.7 weeks). The analysis that adjusted for covariates was not statistically significant. 

Time to Progression. Median progression-free survival differed by only 1 week between the 

iv T and CAV groups in this trial. 

Quality of Life. The percentage of patients improved on symptoms was greater for 

intravenous topotecan than CAV for all domains except hemoptysis, which showed a 

nonsignificant difference of 6.6 percent. Five domains significantly favored intravenous 

topotecan: dyspnea, anorexia, hoarseness, fatigue and impaired activities of daily living. 

Adverse Events. Significant differences were not found between groups for these grade 3 or 

4 outcomes: fatigue, nausea, vomiting and anorexia. The group receiving intravenous topotecan 

had a risk of grade 3 or 4 anemia that was twice that of the CAV group: 42.3 percent versus 19.8 

percent (p<0.001). The rates of both grade 3 and grade 4 thrombocytopenia were significantly 

higher for the intravenous topotecan group, compared with the CAV group (grade 3: 28.8 percent 

vs. 9.9 percent; grade 4: 28.89 percent vs. 5 percent). Risks of grade 3 or 4 leukopenia were 

similar for intravenous topotecan (76.5 percent) and CAV (81.2 percent), as were grade 3 or 4 

neutropenia (78.5 percent) and CAV (76.9 percent). 

Tumor Response. Intravenous topotecan had an ORR of 24.3 percent, while CAV had an 

ORR of 18.3 percent, a difference that was not statistically significant. 

Summary. Intravenous topotecan and CAV produced similar overall and progression-free 

survival. Five symptom domains showed significantly greater improvement in the intravenous 

topotecan group. Anemia and thrombocytopenia was more common among those receiving 

intravenous topotecan. 

Postmus, Smit, Kirkpatrick, et al. (1993). Vincristine/Ifosfamide/Mesna/Carboplatin 

(VIMP) vs. Cyclophosphamide/Doxorubicin/Etoposide (CDE). 

Study Quality. This study was rated as fair, due to missing information about the method of 

randomization. 
127 

Overall Survival. This study did not include the results of a statistical test on survival 

duration, but median survival differed between groups by only 3 weeks and given the small 

sample (n=68; 43 had VIMP and 25 had CDE), this is probably not statistically significant. 

Time to Progression. No data. 

Quality of Life. No data. 

Adverse Events. In this study, there was a significantly higher incidence of grade 3 or 4 

thrombocytopenia in the VIMP group (53 percent) compared with the CDE group (9 percent). 

Incidence of grade 3 or 4 leukopenia was similar for VIMP (66 percent) and CDE (63 percent). 

Tumor Response. This study did not mention statistical test results. The ORR for the VIMP 

group was 60 percent and the figure for the CDE group was 51 percent. 

Summary. The VIMP and CDE groups did not differ significantly on survival or tumor 

response. The only outcome that differed was the incidence of grade 3 or 4 thrombocytopenia, 

which was significantly more frequent in the VIMP group. 

Trillet-Lenoir, Lasset, Arpin, et al. (1992). Cisplatin 20/Etoposide 60 (PE1) vs. Cisplatin 

40/Etoposide 100 (PE2). 

Study Quality. This study was rated as poor because the randomization method was not 

sufficiently described, no primary outcome was identified, interventions were incompletely 

described and it was unclear if outcome measurement was valid, reliable and equal. 

Overall Survival. This study found that the high-dose PE2 group (n=15) had a longer 

median survival than the low-dose group (n=17) by 3.5 weeks. There was no mention of 

statistical test results on survival, but this trial was very small and the difference is unlikely to be 

statistically significant. 

Time to Progression. No data. 

Quality of Life. No data. 

Adverse Events. This study showed that high-dose PE was associated with a significantly 

higher risk of grade 3 or 4 thrombocytopenia than low-dose PE (42 percent vs. 7 percent). Grade 

4 leukopenia was much more frequent (76 percent vs. 13 percent) in the high-dose PE group. 

Tumor Response. The high-dose PE group had an ORR of 26.6 percent while the low-dose 

group achieved an ORR of 35.3 percent. No statistical test findings were noted by the authors, 

but the small sample size of 32 patients would require a large difference to achieve statistical 

significance. 

Summary. Survival and tumor response were roughly similar in the low-dose and high-dose 

PE groups, while there were higher rates of thrombocytopenia and leukopenia in the high-dose 

group. 
128 

 O’Bryan, Crowley, Kim, et al. (1990). 

Vincristine/Thiotepa/Cyclophosphamide/Carmustine (BTOC) vs. Cisplatin/Etoposide (PE). 

Study Quality. This study’s quality was rated as poor owing to lack of information about the 

randomization technique, lack of blinding for the primary outcome (tumor response), and lack of 

details about treatment. 

Overall Survival. There were 45 patients in the BTOC group and 58 in the PE group. The 

authors presented 3 sets of results: all patients; good prognosis patients; and poor prognosis 

patients. None of the analyses demonstrated a statistically significant difference between BTOC 

and PE. Median survival nonsignificantly favored PE among all patients and good prognosis 

patients. The difference was large for good prognosis patients (25 weeks), but only 27 patients 

were in this subset. The relation between treatments was reversed for bad prognosis patients: 

median survival was better by 2 weeks for BTOC over PE. 

Time to Progression. No data. 

Quality of Life. No data. 

Adverse Events. The trial reported that 4 percent of patients in the BTOC group experienced 

drug-related death, compared with 1 percent for PE, a difference that was not statistically 

significant. 

Tumor Response. The trial found no statistically significant difference between the ORR for 

BTOC (13 percent) and PE (12 percent). Identical ORRs were obtained for treatment groups 

with both good and poor prognoses. 

Summary. This trial found no significant differences between BTOC and PE in survival, 

tumor response or drug-related death. 

Spiro, Souhami, Geddes, et al. (1989). Methotrexate/Doxorubicin vs. Supportive Care 

Study Quality. Quality was rated as poor due to lack of details about the randomization 

technique and a high loss of patients in the second stage of the study (42 percent). 

Overall Survival. This outcome was not reported on the basis of the second randomization 

(to second-line chemotherapy or supportive care), rather it was based on the first randomization 

to either 4 or 8 cycles of primary chemotherapy. Therefore, it is unclear how patients given 

chemotherapy or supportive care upon relapse compare in terms of survival. 

Time to Progression. As above, this outcome was not presented based on treatment 

approach given at relapse. 

Quality of Life. This outcome was not reported. 

Adverse Events. Toxicity data were not provided for second-line chemotherapy. 
129 

Tumor Response. Of the 294 patients randomized to receive chemotherapy at relapse, 170 

received it and were assessed for response. Complete response was achieved in 4 percent and 

partial response was observed in 19 percent. 

Summary. Results were presented from this study mainly based on randomization for firstline chemotherapy. An overall response rate of 23 percent to second-line chemotherapy was 

observed, but other data are lacking on outcomes after randomization at relapse, comparing 

chemotherapy and supportive care. 

Wolff, Birch, Sarma, et al. (1986). Etoposide 100 (E100) vs. Etoposide 200 (E200) vs. 

Etoposide 300 (E300). 

Study Quality. The Wolff, Birch, Sarma, et al. (1986) trial received a poor quality rating due 

to uncertainty on the comparability of groups at baseline, lack of blinded assessment of tumor 

response, the primary outcome, lack of detail about treatments and inappropriate analysis of 

results. 

Overall Survival. There were 26, 27 and 26 patients in the groups receiving 100 mg, 200 mg 

and 300 mg of etoposide, respectively. No statistically significant differences were found 

between etoposide dose groups. The 200 mg and 300 mg groups were similar in median survival 

(20 weeks and 22.5 weeks, respectively), while the median for 100 mg group was 12.6 weeks. 

Time to Progression. No data. 

Quality of Life. No data. 

Adverse Events. There was a significant dose gradient for higher grade thrombocytopenia in 

3 groups given single agent etoposide therapy: 5 percent for 100 mg; 79 percent for 200 mg; and 

86 percent for 300 mg. The trial found that grade 3 or 4 neutropenia was much more likely in 

the etoposide 300 mg group (57 percent), compared with those receiving 100 mg (15 percent) or 

200 mg (13 percent). 

Tumor Response. Only PRs were achieved in each of the 3 etoposide groups: 4 percent for 

100 mg; 7 percent for 200 mg; and 4 percent for 300 mg. 

Summary. Significant differences in survival and tumor response were not observed 

between 3 different doses of single-agent etoposide. Thrombocytopenia and leukopenia were 

more common for higher dose etoposide 

Phase II Trial Evidence 

Among multicenter phase II trials published since 2000 (Summary Table 52; see Appendix 

Tables 9H–9M),20 5 deserve brief mention due to encouraging response data. While overall 

response rates of 20 percent or higher were reported by these trials, high rates of hematologic 

 

20 Appendixes cited in this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/lungcansmall/lungcan.pdf. 
130 

toxicity were observed. Each used a different treatment regimen. The largest study was 

Ardizzoni, Manegold, Debruyne, et al. (2003, n=116); all others enrolled fewer than 50 patients. 

Ando, Kobayashi, Yoshimura, et al. (2004) reported data for 25 patients who were given 

irinotecan plus cisplatin for refractory or relapsed SCLC after first-line etoposide therapy. 

Partial responses were observed in 81 percent of 16 relapsed patients and 78 percent of 9 

refractory patients. Grade 3 thrombocytopenia was seen in 12 percent and 24 percent had grade 

3 or 4 neutropenia. 

Summary Table 52. Multicenter Phase II Trials of Note for Key Question 9 

Study Patient Selection N Regimen Previous Treatment (%) 

Ando, Kobayashi, 

Yoshimura, et al., 

2004 

refractory (off CTx < 2 

mo) or relapsed (off CTx 

> 2 mo) after initial 

etoposide regimen 

25 irinotecan+cisplatin PE 16 

CbP 84 

TRTx 20 

Surgery 4 

Ardizzoni, 

Manegold, 

Debruyne, et al., 

2003 

relapsed after 1st-line CTX 

(except camptothecin 

analogues; cisplatin 

allowable if responsive, 

CTx > 6 mo before 

116 topotecan+cisplatin Sen Ref 

TRTx 69 31 

med # 

CTX 3 3 

Cisplatin 22 5 

Carbopl 24 36 

Etopos 90 83 

Kosmas, Tsavaris , 

Malamos, et al. et al. 

,2001 

relapsed after CbE CTx +

TRTx; not curable by 

other 2nd-line CTx or RTx 

33 paclitaxel+ifosfamide+cis

platin 

CTx 100 

TRTx 42 

Kakolyris, 

Mavroudis, 

Tsavaris, et al., 2001 

refractory; had failed 1 

prior 1st-line CTx 

32 paclitaxel+carboplatin EP 84 

CAB 16 

RTx 47 

Surgery 6 

Sonpavde, Ansari, 

Walker, et al., 2000 

recurrent; 1 prior 

combination CTx regimen 

46 doxorubicin+paclitaxel Platinum-E 

+ VIP 100 

RTx 59 

Ardizzoni, Manegold, Debruyne, et al. (2003) collected outcomes for 110 patients who 

received topotecan plus cisplatin for either sensitive (n=68) or refractory (n=42) SCLC. Among 

sensitive patients, a CR was seen in 1.5 percent and PR in 27.9 percent. The incidence of grade 

3 or 4 leukopenia was 80.9 percent and neutropenia occurred in 76.5 percent. At least 1 episode 

of febrile neutropenia happened in 19 percent. There was a PR rate of 23.8 percent in refractory 

patients. Grade 3 or 4 leukopenia was observed in 75.6 percent and the risk of neutropenia was 

the same. At least 1 instance of febrile neutropenia occurred in 15 percent. 

Kosmas, Tsavaris, Malamos, et al. (2001) enrolled 33 patients who relapsed after initial 

treatment with carboplatin plus etoposide. Second-line therapy was paclitaxel, ifosfamide and 

cisplatin. The CR rate was 24.2 percent and the PR rate was 48.5 percent. Grade 3 anemia was 

seen in 18 percent. Grade 3 thrombocytopenia affected 36 percent. Grade 3 or 4 leukopenia 

occurred in 73 percent, the rate of neutropenia was 91 percent. Grade 3 febrile neutropenia was 

found in 18 percent. 
131 

Kakolyris, Mavroudis, Tsavaris, et al. (2001) gave data for 29 patients who were refractory 

after first-line chemotherapy and then were offered paclitaxel plus carboplatin. CR was achieved 

in 3 percent and PR in 22 percent. Grade 3 or 4 neutropenia was observed in 48 percent. 

Sonpavde, Ansari, Walker, et al. (2000) recruited 46 patients who recurred after first-line 

therapy and were given doxorubicin plus carboplatin. CRs were measured in 7 percent and PRs 

in 35 percent. Grade 3 or 4 granulocytopenia occurred in 80 percent. 

Conclusions 

Nine randomized trials have made 9 different comparisons for second- or subsequent-line 

treatment of SCLC. Two randomized trials have directly compared chemotherapy with best 

supportive care for recurrent SCLC. The first studied second-line methotrexate plus doxorubicin 

and found an overall response rate of 23 percent for the chemotherapy arm. The second reported 

that oral topotecan resulted in a modest but significant improvement in survival, slower decline 

in quality of life and high grade neutropenia in one third. In another trial, oral topotecan had 

nonsignificantly higher median survival and overall response rate than intravenous topotecan, 

which had higher risks of leukopenia and neutropenia. A study that addressed the addition of 

carboplatin to cisplatin and etoposide is of limited use given that it in enrolled only those who 

did not receive first-line cisplatin and etoposide, which is the current standard regimen. One 

small study comparing 3 doses of monotherapy etoposide did not find significant survival 

differences, but a trend favored the highest dose, along with increased thrombocytopenia and 

neutropenia. Other studies found higher rates of adverse events for one treatment over another, 

but no associated survival advantage that would offset increased high grade toxicity. One 

example is a comparison of oral and intravenous topotecan which reported that the intravenous 

route was associated with higher rates of leukopenia and neutropenia. A study comparing 

intravenous topotecan and CAV showed that the topotecan group had higher risks of anemia and 

thrombocytopenia. High dose PE had more leukopenia than low dose PE. 

Five multicenter phase II trials of note published since 2000 have reported overall response 

rates of 20 percent or more. Only one study, using topotecan plus cisplatin, enrolled more than 

50 patients. Approximately one-fourth of both sensitive and refractory patients responded. 

Three-quarters or more of both patient groups had high grade leukopenia and neutropenia. A 

small study of irinotecan plus cisplatin found very high rates of partial response and low 

hematologic toxicity. The combination of paclitaxel, ifosfamide and cisplatin achieved a high 

ORR and high grade leukopenia in nearly all patients. One quarter of those given paclitaxel plus 

carboplatin had a response and about half had high grade neutropenia. In a study of doxorubicin 

plus carboplatin, nearly half responded, but 4 out of 5 had grade 3 or 4 granulocytopenia. 

Whether these regimens should be used in practice awaits randomized trials. 

133 

Chapter 4. Conclusions 

1. For limited-stage SCLC, what are the relative benefits and 

harms of TRTx combined with chemotherapy either in 

alternating fashion, concurrently, or sequentially?

One multicenter trial and one single-center trial (n=307) compared concurrent and sequential 

TRTx. Results are not conclusive but suggest better outcomes for concurrent TRTx. Overall 

survival adjusted for confounders significantly favored concurrent TRTx in the Takada, 

Fukuoka, Kawahara, et al. trial (2002; n=228), although unadjusted results were not significant. 

Additionally, the Park, Kim, Jeong, et al. (1996) trial found significantly longer response 

duration for concurrent TRTx. Of 11 types of adverse events reported, only leukopenia occurred 

significantly more frequently in the concurrent TRTx group in both studies. 

No conclusions could be drawn on the relative benefits and harms of TRTx combined with 

chemotherapy in alternating fashion. No significant differences in survival or progression-free 

survival were found in any of four trials. Two trials (n=458) compared alternating to sequential 

TRTx; one trial (n=156) compared alternating to concurrent TRTx; and one trial (n=199) 

compared early alternating and late alternating TRTx. 

2. For limited-stage SCLC, do outcomes differ if concurrent 

TRTx is given in early versus late chemotherapy cycles? 

Overall, the evidence is equivocal, either finding no difference or a small advantage for early 

TRTx. One multi-center trial of good quality significantly favored concurrent therapy given in 

an early cycle (Murray, Coy, Pater, et al., 1993/Coy, Hodson, Murray, et al., 1994/Feld, Payne, 

Hodson, et al., 1988), as did 2 smaller trials. Of the two larger multi-center trials that that found 

no significant difference in survival, one did not use platinum chemotherapy (Perry, Eaton, 

Propert, et al., 1987/Ahles, Silberfarb, Rundle, et al., 1994/Perry, Herndon, Eaton, et al., 1988) 

and the other has not been published in full-text (James, Spiro, O’Donnell, et al., 2003). 

Leukopenia/neutropenia appeared to be more common with early concurrent TRTx, although 

differences were statistically significant in only two of six reporting trials. Other events do not 

appear to be more frequent with either early or late TRTx. However, evidence is limited as 

adverse events were not reported consistently across all trials 

Meta-analysis was performed on survival outcome of early versus late TRTx in an attempt to 

obtain clearer results. For purposes of the meta-analysis, the studies selected for Key Questions 

1 and 2 were viewed as comparing early and late TRTx. Therefore, these studies were pooled to 

give a more robust analysis of early versus late TRTx. Overall, we did not find significant 

reductions in 2- and 3-year mortality for early TRTx over late TRTx. The RR at 2 years was 

0.921 (95 percent CI: 0.844–1.005) and the RR at 3 years was 0.991 (0.955–1.029). Although 

the overall analysis was not significant, sensitivity analysis suggests that if there is an advantage 
134 

favoring early TRTx it would accompany use of hyperfractionation and possibly use of platinum 

chemotherapy. 

3. For limited-stage SCLC, do outcomes (survival, toxicity, 

quality of life) of primary therapy differ if one varies 

dose rate, treatment interval, or fractionation scheme for 

delivering radiotherapy? Comparisons of interest 

include: 

• accelerated regimens (>10 Gy per week completed over a short interval) versus 

standard duration regimens (<10 Gy per week) versus split courses delivered over 

the standard interval; and 

• single daily fractions versus hyperfractionated (two or more daily fractions or 

concomitant boost). 

Evidence to compare dose rates, treatment intervals, or fractionation schemes is limited. 

Two RCTs compared one versus two fractions a day for previously untreated SCLC. One 

compared an accelerated regimen versus the standard duration, while the other compared a splitcourse regimen versus the standard duration. 

Compared to a single daily fraction, two daily fractions delivered concurrently with platinum 

chemotherapy improved overall survival in a large multicenter trial of good quality (Turrisi, 

Kim, Blum, et al., 1999/Yuen, Zou, Turrisi, et al., 2000; N=417). More specifically, this trial 

showed that starting TRTx with the first cycle of cisplatin-etoposide chemotherapy and giving it 

in two daily fractions over 3 weeks increased overall survival (23 vs. 19 months, log rank 

p=0.04) when compared with the same dose begun at the same time but given in one daily 

fraction over 5 weeks. 

Evidence from the second trial is difficult to interpret, since multiple variables were studied 

simultaneously (Schild, Bonner, Shanahan, et al., 2004/Sloan, Bonner, Hillman, et al., 

2002/Bonner, Sloan, Shanahan, et al., 1999; N=161). However, it found no difference in overall 

survival between treatment arms managed with one versus two fractions per day. 

Neither trial reported data on quality of life. Esophagitis was the only adverse event reported 

more frequently with two fractions per day than with one fraction per day in both trials. 

4. What are the relative benefits and harms (survival, 

toxicity, and quality of life) of adding thoracic radiation 

therapy to chemotherapy for primary treatment of extensivestage SCLC? 

Evidence from one single-center RCT (Jeremic, Shibamoto, Nikolic, et al., 1999; N= 99) 

suggests that adding concurrent TRTx improves survival of patients with extensive-stage disease 
135 

that responds to an initial three cycles of platinum/etoposide chemotherapy with a complete 

response outside the thorax and at least a partial response in the thorax. Uncontrolled data from 

the same trial suggest little to no benefit for patients who achieve no better than a partial 

response outside the thorax. With the regimens used in this trial, concurrent TRTx apparently 

increases grades 3 and 4 esophagitis. 

No other trials have reproduced the results reported by Jeremic, Shibamoto, Nikolic, et al. 

(1999). Four earlier trials (N=129) are limited by small sample sizes and non- platinum 

chemotherapy regimens; none used concurrent TRTx. 

5. What are the benefits and harms (survival, toxicity and 

quality of life) of prophylactic cranial irradiation? 

Evidence from an individual patient data Cochrane review and meta-analysis on seven RCTs 

(N=987) conducted by the PCI Overview Collaborative Group shows that PCI modestly 

improves survival of SCLC patients in CR after primary therapy. PCI increases the proportion 

alive at 3 years from 15.3 percent to 20.7 percent (P=0.01), an absolute increase of 5.4 percent. 

PCI also significantly decreases the risk for brain metastasis and increases the likelihood of 

disease-free survival. The sole trial reported after the meta-analysis confirms effects of PCI on 

brain metastasis, and generally agrees with the modest effect on overall survival. 

Subgroup analyses using individual patient data showed that PCI significantly decreases 

brain metastases for SCLC patients in CR regardless of age, disease stage or performance status 

at diagnosis, and whether or not TRTx is part of the induction regimen. Although PCI does not 

have significant effect on survival for most of these subgroups, it does not appear that any of 

these subgroups benefits more or less than others. 

Additional subgroup analyses suggested that increasing the PCI dose from 8 to 40 Gy and 

starting PCI within the first 6 months after achieving CR may decrease the likelihood of brain 

metastasis. Patient gender also may interact with effects of PCI on survival. However, these 

hypotheses, derived from subgroup analyses, require formal testing in RCTs. 

Data on acute toxicities of PCI are scant, but those available suggest they are tolerable at the 

doses used in these trials (8–40 Gy in 1.8 to 3 Gy fractions). Evidence from two trials suggests 

neuropsychological and cognitive deficits and structural abnormalities on brain CT scans are 

relatively common among SCLC patients in CR after primary therapy but before PCI. Available 

evidence on patients who survived 1–2 years, while limited, did not show greater deterioration of 

existing deficits or more frequent appearance of new abnormalities with PCI than among 

controls. 

6. Does the addition of PET scanning improve the accuracy 

of staging for patients with SCLC over the use of other 

techniques, including CT and MRI, without PET? 

It is not possible from the limited and poor quality evidence that is available to determine 

whether the use of PET adds value relative to conventional staging tests for SCLC. 
136 

Six studies reporting on a total of 277 patients (range 20–120) provided data on the 

diagnostic accuracy of PET in SCLC. The evidence suggests that, except for detection of brain 

metastases, PET added to conventional staging is more sensitive in detecting disease than 

conventional staging alone. Upstaging was reported in 4–20 percent of patients and downstaging 

in 4–13 percent of patients. Three studies reported very high occurrence of patient management 

changes that were attributed to PET (29–58 percent). 

However, the quality of these studies is consistently poor and insufficient detail in reporting 

was the norm. There is such a high degree of uncertainty about the execution and interpretation 

of the reference standard in all of these studies that confidence is quite low in estimates of 

diagnostic and staging accuracy. Although these studies report that PET has correctly upstaged 

or downstaged the extent of disease, the frequency of incorrect changes in stage attributable to 

PET is unknown due to incomplete reporting. It is not possible to determine the frequency with 

which management changes based on PET results were actually beneficial or harmful. 

7. What are the outcomes (survival, toxicity and quality of 

life) of treatments used to manage patients with mixed small 

cell/non-small cell lung cancers? 

No studies meet selection criteria for this question. Very few references from the literature 

search represented studies of any kind that included patients with mixed histology. No 

conclusions can be drawn on outcomes of treatment for patients with mixed small cell/non-small 

cell lung cancers. 

8. What is the role of surgery and what is its impact on 

survival in patients with early stage SCLC? How do available 

studies define early stage SCLC? 

For this question, we sought randomized and nonrandomized studies that compared surgery 

to no surgery in patients with very early limited SCLC, defined as no preoperative evidence of 

involved nodes (clinically N0). Two randomized controlled trials and 8 nonrandomized 

comparative studies were included in the review, but none provided evidence that directly 

addresses the question. 

None of these comparisons studied a homogeneous group of patients with respect to nodal 

status; nor were separate outcomes reported for a subgroup of patients without evidence of nodal 

involvement by current staging methods. Moreover, the treatment regimens used had limited 

relevance to contemporary treatment settings; for example, 5 studies did not use platinum-based 

chemotherapy for any patients, and the remaining 3 used platinum based therapy only for some 

patients. Thus no conclusion can be drawn on the outcomes of management of very early limited 

SCLC with versus without surgery. 
137 

9. What are the outcomes of second- or subsequent-line 

therapy in patients with relapsed or progressive SCLC? 

Where available data permit, patients with limited- and 

extensive-stage disease will be addressed separately, as will 

those with refractory disease. 

Nine RCTs address second- or subsequent-line treatment of SCLC, each of which compared 

different sets of chemotherapy regimens. Two randomized trials directly compared 

chemotherapy with best supportive care for recurrent SCLC. The first studied second-line 

methotrexate plus doxorubicin and found an overall response rate of 23 percent for the 

chemotherapy arm. The second reported that oral topotecan resulted in a statistically significant 

increase in survival (26 weeks vs. 14 weeks) and slower decline in quality of life. High grade 

neutropenia occurred in one third of patients. Another trial compared oral versus intravenous 

topotecan; leukopenia and neutropenia were more frequent with the intravenous route, but 

survival and response were no greater. 

A study that addressed the addition of carboplatin to cisplatin and etoposide is of limited use 

given that it enrolled only those who did not receive first-line cisplatin and etoposide, which is 

the current standard regimen. One small study comparing 3 doses of monotherapy etoposide did 

not find significant survival differences, but a trend favored the highest dose, along with 

increased thrombocytopenia and neutropenia. Other studies found higher rates of adverse events 

for one treatment over another, but no associated survival advantage that would offset increased 

high grade toxicity. A study comparing intravenous topotecan and CAV chemotherapy showed 

that the topotecan group had higher risks of anemia and thrombocytopenia. High-dose 

platinum/etoposide had more leukopenia than low-dose platinum/etoposide. 

Five multicenter phase II trials of note published since 2000 have reported overall response 

rates of 20% or more. Only one study, using topotecan plus cisplatin, enrolled more than 50 

patients. Approximately one fourth of both sensitive and refractory patients responded. Threequarters or more of both patient groups had high grade leukopenia and neutropenia. A small 

study of irinotecan plus cisplatin found very high rates of partial response and low hematologic 

toxicity. The combination of paclitaxel, ifosfamide and cisplatin achieved a high ORR and high 

grade leukopenia in nearly all patients. One-quarter of those given paclitaxel plus carboplatin 

had a response and about half had high grade neutropenia. In a study of doxorubicin plus 

carboplatin, nearly half of patients responded; however, 4 out of 5 had grade 3 or 4 

granulocytopenia. The clinical applicability of these regimens awaits the results of randomized 

trials. 

139 

Chapter 5. Discussion and Future Research 

The majority of evidence reviewed for this report addresses treatments added to primary 

chemotherapy for small cell lung cancer (SCLC). The main objective is to improve survival by 

increasing the rate and durability of complete response (CR) resulting from primary treatment; 

and, for those who do not achieve CR, to delay progression. Questions focus on whether 

outcomes can be optimized by manipulating variables of adjunctive treatments and their 

combination. 

The strongest evidence available for this report shows that prophylactic cranial irradiation 

(PCI) improves survival of SCLC patients who achieved CR following primary therapy. 

Although the benefit is modest, an absolute increase of 5.4 percent in 3-year survival, the 

evidence is robust and convincing. For this knowledge, clinicians and their patients are the 

beneficiaries of the PCI Overview Cochrane Collaborative Group, which conducted an 

individual patient-level meta-analysis, a laborious undertaking. Thus seven discrete randomized, 

controlled trials were transformed into a rich source of data on almost one-thousand patients, 

adequate to support clinically relevant subgroup analyses. The results are encouraging in that it 

appears that all subgroups of eligible patients can potentially benefit from PCI, regardless of age, 

disease stage, performance status at diagnosis, and whether or not thoracic radiotherapy (TRTx) 

is part of the induction regimen. Two trials comparing alternative doses and schedules for PCI 

are in progress, one in the U.S. (RTOG-0212) and one in Europe (FRE-IGR-PCI-99). Targeted 

accrual for the two trials together is over 900 patients. These trials will provide additional data 

on neurotoxicity and quality of life. 

Patient level meta-analysis was not available for any other key question considered in this 

evidence report. No other question yielded a body of evidence so robust. Where we attempted 

to draw conclusions, we typically relied on a single trial showing treatment effects that were 

modest at best, and sometimes equivocal. This was apparent in our review of evidence for the 

sequence, timing, dosing and fractionation of TRTx. For some questions (i.e., management of 

mixed-histology disease; surgery for early limited SCLC) comparative trials were nonexistent. 

Perhaps the most vexing questions are those regarding the delivery of TRTx. Strategies for 

sequencing, timing, dosing, and fractionation are not well supported by a strong evidence base; 

each rests largely on a single study that shows significant findings. The case for concurrent over 

sequential delivery rests largely on a single multi-center trial (Takada 2002) supplemented by a 

smaller study judged to be of poor quality (Park 1996). We found the results to be suggestive, 

but not conclusive, of better outcomes for concurrent over sequential TRTx. No studies show an 

advantage for alternating TRTx, but none show it to be inferior. Support for early concurrent 

therapy comes largely from the results of the multicenter trial by Murray-Coy-Feld (Murray, 

Coy, Pater, et al., 1993/Coy, Hodson, Murray, et al., 1994/Feld, Payne, Hodson, et al., 1988); but 

two other multicenter trials, one using non-platinum chemotherapy (Perry, Eaton, Propert, et al., 

1987/Ahles, Silberfarb, Rundle, et al., 1994/Perry, Herndon, Eaton, et al., 1988) and the other not 

yet published in full text (James, Spiro, O’Donnell, et al., 2003), found no advantage. We 

conducted a meta-analysis of 11 studies, which did not find significant reductions in 2- and 3-

year mortality for early TRTx over late TRTx. 

Compared to a single daily fraction, two fractions per day of accelerated TRTx delivered 

concurrently with platinum chemotherapy improved overall survival in a large multicenter trial 

of good quality (Turrisi, Kim, Blum, et al., 1999/Yuen, Zou, Turrisi, et al., 2000). In contrast to 
140 

a subsequent study comparing single to twice-daily fractionation (Schild, Bonner, Shanahan, et 

al., 2004/Sloan, Bonner, Hillman, et al., 2002/Bonner, Sloan, Shanahan, et al., 1999), which is 

difficult to interpret because multiple variables were studied simultaneously, the Turrisi study 

compared only the variable of fractionation. An approach to comparing early- versus lateconcurrent TRTx, would be to reproduce this twice daily fractionation regimen varying only the 

element of timing. In concept, late-concurrent TRTx could be advantageous if better tolerated, 

thus permitting more patients to complete their full course and intensity of chemotherapy. In 

contrast, our meta-analytic sensitivity analysis suggests that an advantage for early TRTx 

depends on use of hyperfractionation, a finding that is hypothesis-generating only. 

With respect to treatment for extensive-stage disease, results reported by Jeremic, Shibamoto, 

Nikolic et al. (1999) on the addition of TRTx to chemotherapy need replication in a multicenter 

setting. This applies both to the evidence suggesting benefit from TRTx for those with complete 

disappearance of extrathoracic lesions after three cycles of platinum/etoposide, and to the 

uncontrolled evidence suggesting little or no benefit if extra-thoracic lesions only partially 

respond. 

Use of positron emission tomography (PET) as an adjunct to conventional tests is relevant to 

initial staging and restaging after treatment. Because PET may be more sensitive in detecting 

disease outside the brain than conventional staging modalities, and has been suggested to 

correctly upstage or downstage disease, it should be investigated in better quality studies to 

confirm these results and determine if it improves clinical management of SCLC. Currently 

available studies are limited primarily by inadequate quality, especially failure to define an 

adequate reference standard. An informative design would compare the frequency of correct 

upstaging, correct downstaging, incorrect overstaging and incorrect understaging for PET plus 

conventional staging tests in relation to conventional staging tests alone. The use of PET/CT is 

becoming more common and should be addressed in future studies. Future studies should be 

conducted according to standards described by the Quality Assessment of Diagnostic Accuracy 

Studies (QUADAS) and reported according to the Standards for Reporting of Diagnostic 

Accuracy (STARD) statement. 

Authors of a systematic review will rarely be proven wrong in calling for more rigorous 

evidence from well-conducted, randomized, controlled trials. However, it is also fair to 

acknowledge that some diseases and treatments pose greater difficulties in conducting trials to 

evaluate the effectiveness of interventions. A central challenge in evaluating treatments for 

SCLC is that overall disease outcome is poor and, at this time, the potential for an intervention to 

change the course of disease is limited. Because treatment effect sizes are small, large numbers 

of patients are needed in trials to test effectiveness. Complicating this is the multimodal nature 

of interventions and, as exemplified by TRTx, the multiplicity of variables that might contribute 

to the effectiveness of a single component of a multimodal intervention. And for some 

populations of interest (i.e., mixed histology disease; early limited disease), the number of 

affected individuals is small, making prospective study difficult. 

The very circumstances that comprise the challenges to research in SCLC highlight the 

necessity of setting a systematic and rigorous research agenda to accumulate findings that can 

improve clinical care and outcomes. To this end, we make the following recommendations for 

future research. 

• In assessing strategies for the delivery of multimodality interventions, such as TRTx, 

design trials to clearly test a single variable (e.g., early concurrent vs. late concurrent). 

Multi-arm trials could permit testing of more than one variable simultaneously. Given 
141 

the potential complexity of variables and combinations, there should be a consensus on 

the priority of strategies and elements to be tested. 

• Trials that are poorly designed, conducted, or reported waste limited resources. To 

advance clinical knowledge and practice, the field should adhere to standards of research 

quality, as well as setting an agenda for research priorities. 

• Quality of life assessment should be an integral to clinical trials. Given modest gains in 

survival, it is important to assess the quality of the survival. Quality of life research 

poses intrinsic difficulties, including missing data as disease progresses. Studies should 

adhere to recommended methods for quality of life research and handling of missing data. 

• Future trials should use consensus definitions for patient enrollment criteria, subgroup 

characteristics and trial endpoints. Adverse events data should be consistently reported 

and collected. The use of consistent definitions and end-points can produce a more robust 

body of cumulative evidence improving the ability to compare results among trials and 

increasing the potential for combined analyses. 

Finally, clinicians and investigators would be well-served by improved indexing and search 

terms so that electronic literature databases would better distinguish records on SCLC from those 

on non-small cell lung cancer. 

143 

References and Included Studies 

Agelaki S, Syrigos K, Christophylakis C, et al. A 

multicenter phase II study of the combination of 

irinotecan and gemcitabine in previously treated 

patients with small-cell lung cancer. Oncology 2004; 

66(3):192-6. 

Ahles TA, Silberfarb PM, Rundle AC, et al. Quality of 

life in patients with limited small-cell carcinoma of the 

lung receiving chemotherapy with or without radiation 

therapy, for cancer and leukemia group B. Psychother 

Psychosom 1994; 62(3-4):193-9. 

Aisner SC, Finkelstein DM, Ettinger DS, et al. The 

clinical significance of variant-morphology small-cell 

carcinoma of the lung. J Clin Oncol 1990; 8(3):402-8. 

Albain KS, Crowley JJ, Hutchins L, et al. Predictors 

of survival following relapse or progression of small 

cell lung cancer. Southwest Oncology Group Study 

8605 report and analysis of recurrent disease data 

base. Cancer 1993; 72(4):1184-91. 

Alderson P, Green S, Higgins JPT, eds. Cochrane 

Reviewers’ Handbook 4.2.2 [updated March 2004]. 

Available online at 

http://www.cochrane.org/resources/handbook/hbook.h

tm (accessed November 19, 2004). 

American Cancer Society. Cancer Facts and Figures 

2005. Atlanta, GA: American Cancer Society, 2005. 

Available online at 

http://www.cancer.org/docroot/STT/stt_0.asp. 5 Last 

accessed June 15, 2005. 

American Cancer Society. Detailed guide: lung cancer 

-- What is lung cancer? American Cancer Society, 

2004. Available online at 

http://www.cancer.org/docroot/CRI/content/CRI_2_4_

1X_What_is_lung_cancer_26.asp. Last accessed June 

15, 2005. 

Ando M, Kobayashi K, Yoshimura A, et al. Weekly 

administration of irinotecan (CPT-11) plus cisplatin 

for refractory or relapsed small cell lung cancer. Lung 

Cancer 2004; 44(1):121-7. 

Ardizzoni A, Hansen H, Dombernowsky P, et al. 

Topotecan, a new active drug in the second-line 

treatment of small-cell lung cancer: a phase II study in 

patients with refractory and sensitive disease. The 

European Organization for Research and Treatment of 

Cancer Early Clinical Studies Group and New Drug 

Development Office, and the Lung Cancer 

Cooperative Group. J Clin Oncol 1997; 15(5):2090-6. 

Ardizzoni A, Manegold C, Debruyne C, et al. 

European organization for research and treatment of 

cancer (EORTC) 08957 phase II study of topotecan in 

combination with cisplatin as second-line treatment of 

refractory and sensitive small cell lung cancer. Clin 

Cancer Res 2003; 9(1):143-50. 

Aroney RS, Aisner J, Wesley MN, et al. Value of 

prophylactic cranial irradiation given at complete 

remission in small cell lung carcinoma. Cancer Treat 

Rep 1983;67:675-82. 

Arriagada R, Le Chevalier T, Borie F, et al. 

Prophylactic cranial irradiation for patients with smallcell lung cancer in complete remission. J Natl Cancer 

Inst 1995; 87(3):183-90. 

Arriagada R, Le Chevalier T, Riviere A, et al. Patterns 

of failure after prophylactic cranial irradiation in 

small-cell lung cancer: analysis of 505 randomized 

patients. Ann Oncol 2002; 13(5):748-54. 

Auperin A, Arriagada R, Pignon JP, et al. for the 

Prophylactic Cranial Irradiation Overview 

Collaborative Group. Prophylactic cranial irradiation 

for patients with small-cell lung cancer in complete 

remission. N Engl J Med 1999;341:476-84. 

Badzio A, Jassem J, Kurowski K, et al.The impact of 

primary pulmonary resection on local control and 

survival in limited disease (LD) small cell lung cancer 

(SCLC) patients (pts): a retrospective comparative 

study. Lung Cancer 2005; 49(suppl2):S316. Abstract 

P-750. 

Badzio A, Kurowski K, Karnicka-Mlodkowska H, et 

al. A retrospective comparative study of surgery 

followed by chemotherapy vs. non-surgical 

management in limited-disease small cell lung cancer. 

Eur J Cardiothorac Surg 2004; 26(1):183-8. 

Berkey CS, Hoaglin DC, Mosteller F, et al. A randomeffects regression model for meta-analysis. Stat Med 

1995; 14:395–411. 

Blackstock AW, Bogart JA, Matthews C, et al. Splitcourse versus continuous thoracic radiation therapy for 

limited-stage small-cell lung cancer: final report of a 

randomized phase III trial. Clin Lung Cancer 2005; 

6(5):287-92. 

Blum R, MacManus MP, Rischin D, et al. Impact of 

positron emission tomography on the management of 

patients with small-cell lung cancer: preliminary 

experience. Am J Clin Oncol 2004; 27(2):164-71. 

Bohrer M, Wenz F. Prophylactic cranial irradiation in 

limited-disease small-cell lung cancer - why, when, 

how much? Onkologie. 2002 Feb;25(1):66-8. 
144 

Bonner JA, Sloan JA, Shanahan TG, et al. Phase III 

comparison of twice-daily split-course irradiation 

versus once-daily irradiation for patients with limited 

stage small-cell lung carcinoma. J Clin Oncol 1999; 

17(9):2681-91. 

Bradley JD, Dehdashti F, Mintun MA, et al. Positron 

emission tomography in limited-stage small-cell lung 

cancer: a prospective study. J Clin Oncol 2004; 

22(16):3248-54. 

Brincker H, Hindberg J, Hansen PV. Cyclic 

alternating polychemotherapy with or without upper 

and lower half-body irradiation in small cell anaplastic 

lung cancer. A randomized study. Eur J Cancer Clin 

Oncol 1987; 23(2):205-11. 

Brink I, Schumacher T, Mix M, et al. Impact of 

(18F)FDG-PET on the primary staging of small-cell 

lung cancer. Eur J Nucl Med Mol Imaging 2004; 

31(12):1614-20. 

Cameron RB, Schwartz D. Current concepts in the 

staging of lung cancer. PPO Updates, 2005; 19(1):1-

16. 

Cancer Care Ontario. The role of thoracic 

radiotherapy as an adjunct to standard chemotherapy 

in limited-stage small cell lung cancer: update. 2003 

Jan. Available online at 

http://www.cancercare.on.ca/pdf/full7_13_3.pdf. Last 

accessed December 2005. 

Cao K, Huang H, Tu M. [Clinical study of 

prophylactic cranial irradiation for small-cell lung 

cancer]. Zhonghua Zhong Liu Za Zhi 2000; 22(4):336-

8. 

Carney DN. Prophylactic cranial irradiation and 

small-cell lung cancer. N Engl J Med, 1999; 

341(7):524-6. 

Chin R Jr, McCain TW, Miller AA, et al. Whole body 

FDG-PET for the evaluation and staging of small cell 

lung cancer: a preliminary study. Lung Cancer 2002; 

37(1):1-6. 

Chua YJ, Steer C, Yip D. Recent advances in 

management of small-cell lung cancer. Cancer Treat 

Rev 2004; 30(6):521-43. 

Cochran WG. The combination of estimates from 

different experiments. Biometrics 1954; 10:101-129. 

Cochran WG. Problems arising in the analysis of a 

series of similar experiments. J R Stat Soc 1937; Suppl 

4(1):102-118. 

Coy P, Hodson DI, Murray N, et al. Patterns of failure 

following loco-regional radiotherapy in the treatment 

of limited stage small cell lung cancer. Int J Radiat 

Oncol Biol Phys 1994; 28(2):355-62. 

DerSimonian R, Laird N. Meta-analysis in clinical 

trials. Control Clin Trials 1986; 7:177-188. 

Egger M, Davey Smith G, Schneider M, et al. Bias in 

meta-analysis detected by a simple, graphical test. 

BMJ 1997; 315(7109):629-34. 

Einhorn LH, Loehrer PJ. Hoosier Oncology Group 

studies in extensive and recurrent small cell lung 

cancer. Semin Oncol 1995; 22(1 Suppl 2):28-31. 

Einhorn LH, Pennington K, McClean J. Phase II trial 

of daily oral VP-16 in refractory small cell lung 

cancer: a Hoosier Oncology Group study. Semin 

Oncol 1990; 17(1 Suppl 2):32-5. 

Ettinger DS. Overview and state of the art in the 

management of lung cancer. Oncology (Huntingt), 

2004; 18(7 Suppl 4):3-9. 

Faylona EA, Loehrer PJ, Ansari R, et al. Phase II 

study of daily oral etoposide plus ifosfamide plus 

cisplatin for previously treated recurrent small-cell 

lung cancer: a Hoosier Oncology Group Trial. J Clin 

Oncol 1995; 13(5):1209-14. 

Feld R, Payne D, Hodson I, et al. Complications of 

treatment of small cell carcinoma of the lung. 

Experience from a recent Canadian trial. Antibiot 

Chemother 1988; 41:204-9. 

Fried DB, Morris DE, Poole C, et al. Systematic 

review evaluating the timing of thoracic radiation 

therapy in combined modality therapy for limitedstage small-cell lung cancer. J Clin Oncol 2004; 

22(23):4837-45. 

Friess GG, McCracken JD, Troxell ML, et al. Effect 

of initial resection of small-cell carcinoma of the lung: 

a review of Southwest Oncology Group Study 7628. J 

Clin Oncol 1985; 3(7):964-8. 

George TK, Fitzgerald D, Brown BS, et al. Long-term 

survival in limited-stage small cell lung carcinoma. 

Experience in Rochester, New York from 1975 to 

1981. Cancer 1986; 58(6):1193-8. 

Girling DJ, Stott H, Stephens RJ, Fox W. Fifteen-year 

follow-up of all patients in a study of post-operative 

chemotherapy for bronchial carcinoma. Br J Cancer 

1985; 52(6):867-73. 

Goto K, Nishiwaki Y, Takada M, et al. Final results 

of a phase III study of concurrent versus sequential 

thoracic radiotherapy in combination with cisplatin 

and etoposide for limited-stage small cell lung cancer: 

the Japanese Clinical Oncology Group Study. Proc 

Am Soc Clin Oncol 1999; 18:468a. 
145 

Graziano SL, Lee K, Propert KJ, et al. Phase II trial of 

etoposide and cisplatin for refractory small cell lung 

cancer: a Cancer and Leukemia Group B Study. Med 

Pediatr Oncol 1990; 18(1):22-6. 

Gregor A, Cull A, Stephens RJ, et al. Prophylactic 

cranial irradiation is indicated following complete 

response to induction therapy in small cell lung 

cancer: results of a multicentre randomised trial. 

United Kingdom Coordinating Committee for Cancer 

Research (UKCCCR) and the European Organization 

for Research and Treatment of Cancer (EORTC). Eur 

J Cancer 1997b; 33(11):1752-8. 

Gregor A, Drings P, Burghouts J, et al. Randomized 

trial of alternating versus sequential 

radiotherapy/chemotherapy in limited-disease patients 

with small-cell lung cancer: a European Organization 

for Research and Treatment of Cancer Lung Cancer 

Cooperative Group Study. J Clin Oncol 1997a; 

15(8):2840-9. 

Gridelli C, De Marinis F, Rossi A, et al. A phase II 

study of VM-26 plus lonidamine in pretreated small 

cell lung cancer. Anticancer Res 1997; 17(2B):1277-9. 

Groen HJ, Fokkema E, Biesma B, et al. Paclitaxel and 

carboplatin in the treatment of small-cell lung cancer 

patients resistant to cyclophosphamide, doxorubicin, 

and etoposide: a non-cross-resistant schedule. J Clin 

Oncol 1999; 17(3):927-32. 

Hainsworth JD, Burris HA 3rd, Erland JB, et al. 

Combination chemotherapy with gemcitabine and 

vinorelbine in the treatment of patients with relapsed 

or refractory small cell lung cancer: a phase II trial of 

the Minnie Pearl Cancer Research Network. Cancer 

Invest 2003; 21(2):193-9. 

Hara N, Ichinose Y, Kuda T, et al. Long-term 

survivors in resected and nonresected small cell lung 

cancer. Oncology. 1991a; 48(6):441-7. 

Hara N, Ohta M, Ichinose Y, et al. Influence of 

surgical resection before and after chemotherapy on 

survival in small cell lung cancer. J Surg Oncol 1991b; 

47(1):53-61. 

Harris RP, Helfand M, Woolf SH, et al. (Methods 

Work Group, Third US Preventive Services Task 

Force.) Current methods of the US Preventive 

Services Task Force: a review of the process. Am J 

Prev Med 2001 Apr; 20(3 Suppl):21-35. 

Hauber HP, Bohuslavizki KH, Lund CH, et al. 

Positron emission tomography in the staging of smallcell lung cancer: a preliminary study. Chest 2001; 

119(3):950-4. 

Hoang T, Kim K, Jaslowski A, et al. Phase II study of 

second-line gemcitabine in sensitive or refractory 

small cell lung cancer. Lung Cancer 2003; 42(1):97-

102. 

Huang Q, Muzitansky A, Mark EJ. Pulmonary 

neuroendocrine carcinomas. A review of 234 cases 

and a statistical analysis of 50 cases treated at one 

institution using a simple clinicopathologic 

classification. Arch Pathol Lab Med. 2002 

May;126(5):545-53. 

Huncharek M, McGarry R. A meta-analysis of the 

timing of chest irradiation in the combined modality 

treatment of limited-stage small cell lung cancer. 

Oncologist, 2004; 9(6):665-72. 

Inoue M, Miyoshi S, Yasumitsu T, et al. Surgical 

results for small cell lung cancer based on the new 

TNM staging system. Thoracic Surgery Study Group 

of Osaka University, Osaka, Japan. Ann Thorac Surg 

2000; 70(5):1615-9. 

Issell BF, Einhorn LH, Comis RL, et al. Multicenter 

phase II trial of etoposide in refractory small cell lung 

cancer. Cancer Treat Rep 1985; 69(1):127-8. 

Iyoda A, Hiroshima K, Baba M, et al. Pulmonary 

large cell carcinomas with neuroendocrine features are 

high-grade neuroendocrine tumors. Ann Thorac Surg 

2002; 73:1049-1054. 

James LE, Spiro S, O’Donnell KM, et al. A 

randomised study of timing of thoracic irradiation in 

small cell lung cancer (SCLC) - study 8. Lung 

Cancer 2003; 41(Suppl 2):S23. Abstract. 

Japan Cooperative Oncology Group on Lung Cancer. 

Phase II study of carboplatin in patients with 

nonresected lung cancer. Cancer Chemother 

Pharmacol 1990; 26(2):101-4. 

Janne PA, Freidlin B, Saxman S, et al. Twenty-five 

years of clinical research for patients with limitedstage small cell lung carcinoma in North America. 

Cancer 2002; 95(7):1528-38. 

Jassem J, Karnicka-Mlodkowska H, van Pottelsberghe 

C, et al. Phase II study of vinorelbine (Navelbine) in 

previously treated small cell lung cancer patients. 

EORTC Lung Cancer Cooperative Group. Eur J 

Cancer 1993; 29A(12):1720-2. 

Jeremic B, Shibamoto Y, Acimovic L, et al. Initial 

versus delayed accelerated hyperfractionated radiation 

therapy and concurrent chemotherapy in limited smallcell lung cancer: a randomized study. J Clin Oncol 

1997; 15(3):893-900. 

Jeremic B, Shibamoto Y, Nikolic N, et al. Role of 

radiation therapy in the combined-modality treatment 

of patients with extensive disease small-cell lung 

cancer: A randomized study. J Clin Oncol 1999; 

17(7):2092-9. 
146 

Johnson BE, Ihde DC, Bunn PA, et al. Patients with 

small-cell lung cancer treated with combination 

chemotherapy with or without irradiation. Data on 

potential cures, chronic toxicities, and late relapses 

after a five- to eleven-year follow-up. Ann Intern Med 

1985; 103(3):430-8. 

Kakolyris S, Mavroudis D, Tsavaris N, et al. 

Paclitaxel in combination with carboplatin as salvage 

treatment in refractory small-cell lung cancer (SCLC): 

a multicenter phase II study. Ann Oncol 2001; 

12(2):193-7. 

Kamel EM, Zwahlen D, Wyss MT, et al. Whole-body 

(18)F-FDG PET improves the management of patients 

with small cell lung cancer. J Nucl Med 2003; 

44(12):1911-7. 

Karrer K, Denck H, Drings P, Orel J, Bruno MF. 

Combination of surgery and chemotherapy for smallcell bronchial carcinoma. Drugs Exp Clin Res 1986; 

12(1-3):191-200. 

Karrer K, Denck H, Karnicka-Mlodkowska H, et al. 

Surgery for cure followed by combined modality 

treatment for small cell bronchial carcinoma. ISC 

Lung Cancer Study Group. Int J Clin Pharmacol Res 

1988; 8(6):415-21. 

Karrer K, Denck H, Karnicka-Mlodkowska H, et al. 

The importance of surgery as the first step in 

multimodality treatment of small cell bronchial 

carcinoma. The ISC Lung Cancer Study Group. Int J 

Clin Pharmacol Res 1990; 10(5):257-63. 

Karrer K, Denck H, Karnicka-Mlodkowska H, et al. 

The role of ifosfamide and cyclophosphamide in the 

multi-modality treatment after surgery for cure for 

small-cell bronchial carcinomas (SCLC). Med Oncol 

Tumor Pharmacother 1989; 6(2):143-9. 

Karrer K, Shields TW, Denck H, Hrabar B, VogtMoykopf I, Salzer GM. The importance of surgical 

and multimodality treatment for small cell bronchial 

carcinoma. J Thorac Cardiovasc Surg 1989; 

97(2):168-76. 

Karrer K, Ulsperger E. Surgery for cure followed by 

chemotherapy in small cell carcinoma of the lung. For 

the ISC-Lung Cancer Study Group. Acta Oncol 1995; 

34(7):899-906. 

Karrer K. Surgery in SCLC as first step of 

multimodality treatment. Anticancer Res 1994; 

14(1B):327-31. 

Kosmas C, Tsavaris NB, Malamos NA, et al. Phase II 

study of paclitaxel, ifosfamide, and cisplatin as 

second-line treatment in relapsed small-cell lung 

cancer. J Clin Oncol 2001; 19(1):119-26. 

Lad T, Piantadosi S, Thomas P, et al. A prospective 

randomized trial to determine the benefit of surgical 

resection of residual disease following response of 

small cell lung cancer to combination chemotherapy. 

Chest 1994; 106(6 Suppl):320S-3S. 

Laplanche A, Monnet I, Santos-Miranda JA, et al. 

Controlled clinical trial of prophylactic cranial 

irradiation for patients with small-cell lung cancer in 

complete remission. Lung Cancer 1998; 21(3):193-

201. 

Laplanche A, Monnet I, Santos-Miranda JA, et al. 

Controlled clinical trial of prophylactic cranial 

irradiation for patients with small-cell lung cancer in 

complete remission. Lung Cancer 1998; 21(3):193-

201. 

Lebeau B, Chastang C, Brechot JM, et al. A 

randomized trial of delayed thoracic radiotherapy in 

complete responder patients with small-cell lung 

cancer. Petites Cellules Group. Chest 1993; 

104(3):726-33. 

Lebeau B, Urban T, Brechot JM, et al. A randomized 

clinical trial comparing concurrent and alternating 

thoracic irradiation for patients with limited small cell 

lung carcinoma. "Petites Cellules" Group. Cancer 

1999; 86(8):1480-7. 

Liao M, Zhao J, Zhou Y. [Multimodality therapy of 

late stage lung cancer]. Zhonghua Zhong Liu Za Zhi 

1995; 17(5):384-6. 

Livingston RB, Mira JG, Chen TT, et al. Combined 

modality treatment of extensive small cell lung cancer: 

a Southwest Oncology Group study. J Clin Oncol 

1984 Jun; 2(6):585-90. 

Livingston RB, Schulman S, Mira JG, et al. Combined 

alkylators and multiple-site irradiation for extensive 

small cell lung cancer: a Southwest Oncology Group 

Study. Cancer Treat Rep 1986 Dec; 70(12):1395-401. 

Masters GA, Declerck L, Blanke C, et al. Phase II trial 

of gemcitabine in refractory or relapsed small-cell 

lung cancer: Eastern Cooperative Oncology Group 

Trial 1597. J Clin Oncol 2003; 21(8):1550-5. 

Murray N, Coy P, Pater JL, et al. Importance of timing 

for thoracic irradiation in the combined modality 

treatment of limited-stage small-cell lung cancer. The 

National Cancer Institute of Canada Clinical Trials 

Group. J Clin Oncol 1993; 11(2):336-44. 

Murren J, Glatstein E, Pass HI. Small cell lung 

cancer. In: DeVita VT, Jr, Hellman S, Rosenberg SA, 

editors. Cancer: principles and practice of oncology. 

6th edition. Philadelphia: Lippincott, Williams & 

Wilkins; 2001. p. 983-1018. 
147 

Murren JR, Turrisi AT, Pass HI. Small cell lung 

cancer. In: DeVita VT, Jr, Hellman S, Rosenberg SA, 

editors. Cancer: principles and practice of oncology. 

7th edition. Philadelphia: Lippincott, Williams & 

Wilkins; 2005. p. 810-843. 

Namikawa S, Den T, Kimura M, et al. The role of 

surgical resection and the effects of neo-adjuvant 

therapy in the management of small cell lung cancer. 

Surg Today 1994; 24(4):342-6. 

Niiranen A, Holsti P, Salmo M. Treatment of small 

cell lung cancer. Two-drug versus four-drug 

chemotherapy and loco-regional irradiation with or 

without prophylactic cranial irradiation. Acta Oncol 

1989; 28(4):501-5. 

Nou E, Brodin O, Bergh J. A randomized study of 

radiation treatment in small cell bronchial carcinoma 

treated with two types of four-drug chemotherapy 

regimens. Cancer 1988; 62(6):1079-90. 

O'Brien M, Ciuleanu T, Tsekov H, et al. Survival 

benefit of oral topotecan plus supportive care versus 

supportive care alone in relapsed, resistant SCLC. 

Lung Cancer 2005; 49(suppl 2):S54. Abstract O-157. 

O'Bryan RM, Crowley JJ, Kim PN, et al. Comparison 

of etoposide and cisplatin with bis-chloroethylnitrosourea, thiotepa, vincristine, and 

cyclophosphamide for salvage treatment in small cell 

lung cancer. A Southwest Oncology Group Study. 

Cancer 1990; 65(4):856-60. 

Ohnoshi T, Hiraki S, Ueda N, et al. Long-term results 

of combination chemotherapy with or without 

irradiation in small cell lung cancer: a 5- to 11-year 

follow-up. Intern Med 1993; 32(3):215-20. 

Ohonoshi T, Ueoka H, Kawahara S, et al. 

Comparative study of prophylactic cranial irradiation 

in patients with small cell lung cancer achieving a 

complete response: a long-term follow-up result. Lung 

Cancer 1993; 10(1-2):47-54. 

Osterlind K. Chemotherapy in small cell lung cancer. 

Eur Respir J 2001 Dec; 18(6):1026-43. 

Osterlind K, Hansen M, Hansen HH, et al. Treatment 

policy of surgery in small cell carcinoma of the lung: 

retrospective analysis of a series of 874 consecutive 

patients. Thorax 1985; 40(4):272-7. 

Park SK, Kim GH, Jeong SS, et al. The effects 

according to the timing of thoracic radiotherapy in 

limited stage small cell lung cancer. Tuberc Respir Dis 

1996; 43:903-15. 

Perry MC, Eaton WL, Propert KJ, et al. Chemotherapy 

with or without radiation therapy in limited small-cell 

carcinoma of the lung. N Engl J Med 1987; 

316(15):912-8. 

Perry MC, Herndon JE 3rd, Eaton WL, et al. Thoracic 

radiation therapy added to chemotherapy for small-cell 

lung cancer: an update of Cancer and Leukemia Group 

B Study 8083. J Clin Oncol 1998; 16(7):2466-7. 

Physicians Data Query (PDQ). Small cell lung cancer 

treatment (health professional version). U.S. National 

Cancer Institute, National Institutes of Health; last 

modified 05/17/2005; accessed on 6/15/2005. 

Available online at: 

http://cancernet.nci.nih.gov/cancertopics/pdq/treatmen

t/small-cell-lung/healthprofessional

Pignon JP, Arriagada R, Ihde DC, et al. A metaanalysis of thoracic radiotherapy for small-cell lung 

cancer. N Engl J Med. 1992 Dec 3;327(23):1618-24. 

Pijls-Johannesma MCG, De Ruysscher D, Lambin P, 

et al. Early versus late chest radiotherapy for limited 

stage small cell lung cancer. The Cochrane Database 

of Systematic Reviews 2004, Issue 4. Art. No.: 

CD004700. DOI: 10.1002/14651858.CD004700.pub2. 

Pirogov AI, Polotskii BE, Al-Ansari N, et al. [Clinical 

evaluation of the small-cell and poorly differentiated 

forms of squamous-cell and glandular lung cancers]. 

Vopr Onkol 1989; 35(2):154-8. 

Postmus PE, Smit EF, Kirkpatrick A, et al. Testing the 

possible non-cross resistance of two equipotent 

combination chemotherapy regimens against smallcell lung cancer: a phase II study of the EORTC Lung 

Cancer Cooperative Group. Eur J Cancer 1993; 

29A(2):204-7. 

Prophylactic Cranial Irradiation Overview 

Collaborative Group. Cranial irradiation for 

preventing brain metastases of small cell lung cancer 

in patients in complete remission. Cochrane Database 

Syst Rev. 2000;(4):CD002805. 

Qiao TK, Zhou DA, Xin L, et al. [Concurrent 

radiotherapy combined with carboplatin and etoposide 

in limited stage small cell lung cancer]. Zhonghua Jie 

He He Hu Xi Za Zhi 2004; 27(4):237-9. 

Ronze S, Noel G, Mazeron JJ. [A randomized clinical 

trial comparing concurrent and alternating thoracic 

irradiation for patients with limited small cell lung 

carcinoma]. Cancer Radiother 2000; 4(4):325-6. 

Rosenthal MA, Tattersall MHN, Fox RM, et al. 

Adjuvant thoracic radiotherapy in small cell lung 

cancer: Ten-year follow-up of a randomized study. 

Lung Cancer 1991; 7(4):235-41. 

Rostad H, Naalsund A, Jacobsen R, et al. Small cell 

lung cancer in Norway: should more patients have 

been offered surgical therapy? Eur J Cardiothorac 

Surg 2004 Oct; 26(4):782-6. 
148 

Ruffini E, Rena O, Oliaro A, et al. Lung tumors with 

mixed histologic pattern. Clinico-pathologic 

characteristics and prognostic significance. Eur J 

Cardiothorac Surg 2002; 22(5):701-7. 

Schamanek A, Karrer K. Importance of surgery in the 

multimodality treatment for small cell lung cancer 

(SCLC). Radiol Oncol 1994; 28:351-8. 

Schild SE, Bonner JA, Shanahan TG, et al. Long-term 

results of a phase III trial comparing once-daily 

radiotherapy with twice-daily radiotherapy in limitedstage small-cell lung cancer. Int J Radiat Oncol Biol 

Phys 2004; 59(4):943-51. 

Schumacher T, Brink I, Mix M, et al. FDG-PET 

imaging for the staging and follow-up of small cell 

lung cancer. Eur J Nucl Med 2001; 28(4):483-8. 

Sculier JP, Lafitte JJ, Lecomte J, et al. A phase II 

randomised trial comparing the cisplatin-etoposide 

combination chemotherapy with or without 

carboplatin as second-line therapy for small-cell lung 

cancer. Ann Oncol 2002; 13(9):1454-9. 

Sculier JP, Thiriaux J, Bureau G, et al. A phase II 

study testing weekly platinum derivative combination 

chemotherapy as second-line treatment in patients 

with advanced small cell lung cancer. Int J Oncol 

1995; 6(2):425-9. 

Sessa C, Wanders J, Roelvink M, et al. Second-line 

treatment of small-cell lung cancer with the 

camptothecin-derivative GI147211: a study of the 

EORTC Early Clinical Studies Group (ECSG). Ann 

Oncol 2000; 11(2):207-10. 

Seydel HG, Creech R, Pagano M, et al. Prophylactic 

versus no brain irradiation in regional small cell lung 

carcinoma. Am J Clin Oncol 1985; 8(3):218-23. 

Shen YY, Shiau YC, Wang JJ, et al. Whole-body 18F2-deoxyglucose positron emission tomography in 

primary staging small cell lung cancer. Anticancer Res 

2002; 22(2B):1257-64. 

Shepherd FA, Ginsberg RJ, Feld R, et al. Surgical 

treatment for limited small-cell lung cancer. The 

University of Toronto Lung Oncology Group 

experience. J Thorac Cardiovasc Surg 1991; 

101(3):385-93. 

Shepherd FA, Ginsberg RJ, Haddad R, et al. 

Importance of clinical staging in limited small-cell 

lung cancer: a valuable system to separate prognostic 

subgroups. The University of Toronto Lung Oncology 

Group. J Clin Oncol 1993; 11(8):1592-7. 

Shepherd FA, Ginsberg RJ, Patterson GA, et al. A 

prospective study of adjuvant surgical resection after 

chemotherapy for limited small cell lung cancer. A 

University of Toronto Lung Oncology Group study. J 

Thorac Cardiovasc Surg 1989; 97(2):177-86. 

Simon GR, Wagner H for the American College of 

Chest Physicians. Small cell lung cancer. Chest 

2003; 123(1 Suppl):259S-271S. 

Skarlos DV, Samantas E, Briassoulis E, et al. 

Randomized comparison of early versus late 

hyperfractionated thoracic irradiation concurrently 

with chemotherapy in limited disease small-cell lung 

cancer: a randomized phase II study of the Hellenic 

Cooperative Oncology Group (HeCOG). Ann Oncol 

2001; 12(9):1231-8. 

Sloan JA, Bonner JA, Hillman SL, et al. A qualityadjusted reanalysis of a Phase III trial comparing 

once-daily thoracic radiation vs. twice-daily thoracic 

radiation in patients with limited-stage small-cell lung 

cancer(1). Int J Radiat Oncol Biol Phys 2002; 

52(2):371-81. 

Smyth JF, Smith IE, Sessa C, et al. Activity of 

docetaxel (Taxotere) in small cell lung cancer. The 

Early Clinical Trials Group of the EORTC. Eur J 

Cancer 1994; 30A(8):1058-60. 

Smythe WR, Estrera AL, Swisher SG, et al. Surgical 

resection of non-small cell carcinoma after treatment 

for small cell carcinoma. Ann Thorac Surg 2001; 

71(3):962-6. 

Sonpavde G, Ansari R, Walker P, et al. Phase II study 

of doxorubicin and paclitaxel as second-line 

chemotherapy of small-cell lung cancer: a Hoosier 

Oncology Group Trial. Am J Clin Oncol 2000; 

23(1):68-70. 

Spiro SG, Souhami RL, Geddes DM, et al. Duration 

of chemotherapy in small cell lung cancer: a Cancer 

Research Campaign trial. Br J Cancer 1989 Apr; 

59(4):578-83. 

Stupp R, Monnerat C, Turrisi AT 3rd, et al. Small cell 

lung cancer: state of the art and future perspectives. 

Lung Cancer 2004; 45(1):105-17. 

Sun Y, Zhang XR, Yin WB, et al. Prospective 

multimodality treatment of SCLC--experience during 

the past 18 years. Gan To Kagaku Ryoho 1995; 22 

Suppl 3:222-5. 

Sutton AJ, Abrams KR, Jones DR, et al. Methods for 

meta-analysis in medical research. John Wiley & 

Sons; West Sussex, England, 2000. p. 73-86. 

Takada M, Fukuoka M, Kawahara M, et al. Phase III 

study of concurrent versus sequential thoracic 

radiotherapy in combination with cisplatin and 

etoposide for limited-stage small-cell lung cancer: 

results of the Japan Clinical Oncology Group Study 

9104. J Clin Oncol 2002; 20(14):3054-60. 
149 

The Prophylactic Cranial Irradiation Overview 

Collaborative Group. Cranial irradiation for 

preventing brain metastases of small cell lung cancer 

in patients in complete remission. The Cochrane 

Database of Systematic Reviews 2000, Issue 4. Art. 

No.: CD002805. DOI: 10.1002/14651858.CD002805. 

Theuer W, Selawry O, Karrer K. The impact of 

surgery on the multidisciplinary treatment of 

bronchogenic small cell carcinoma (updated review 

including ongoing studies). Med Oncol Tumor 

Pharmacother 1992; 9(3):119-37. 

Trillet-Lenoir V, Lasset C, Arpin D, et al. 

[Comparison of 2 cisplatin and etoposide dosages in 

relapsing small cell lung cancer]. Bull Cancer 1992; 

79(12):1173-81. 

Turrisi AT 3rd. Platinum combined with radiation 

therapy in small cell lung cancer: focusing like a laser 

beam on crucial issues. Semin Oncol 1994 Jun;21(3 

Suppl 6):36-42. 

Turrisi AT 3rd, Glover DJ. Thoracic radiotherapy 

variables: influence on local control in small cell lung 

cancer limited disease. Int J Radiat Oncol Biol Phys 

1990; 19(6):1473-9. 

Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily 

compared with once-daily thoracic radiotherapy in 

limited small-cell lung cancer treated concurrently 

with cisplatin and etoposide. N Engl J Med 1999; 

340(4):265-71. 

van der Lee I, Smit EF, van Putten JW, et al. Singleagent gemcitabine in patients with resistant small-cell 

lung cancer. Ann Oncol 2001; 12(4):557-61. 

von Pawel J, Gatzemeier U, Pujol JL, et al. Phase ii 

comparator study of oral versus intravenous topotecan 

in patients with chemosensitive small-cell lung cancer. 

J Clin Oncol 2001; 19(6):1743-9. 

von Pawel J, Schiller JH, Shepherd FA, et al. 

Topotecan versus cyclophosphamide, doxorubicin, 

and vincristine for the treatment of recurrent small-cell 

lung cancer. J Clin Oncol 1999; 17(2):658-67. 

Waddell TK, Shepherd FA. Should aggressive surgery 

ever be part of the management of small cell lung 

cancer? Thorac Surg Clin 2004; 14(2):271-81. 

Wagner H, Kim K, Turrisi A, et al., for the Eastern 

Cooperative Oncology Group, Radiation Therapy 

Oncology Group. A randomized phase III study of 

prophylactic cranial irradiation versus observation in 

patients with small cell lung cancer achieving a 

complete response: Final report of an incomplete trial. 

Proceedings of the American Society of Clinical 

Oncology. 1996;15:376. 

Warde P, Payne D. Does thoracic irradiation improve 

survival and local control in limited-stage small-cell 

carcinoma of the lung? A meta-analysis. J Clin Oncol 

1992 Jun;10(6):890-5. 

Whiting P, Rutjes AWS, Dinnes J, et al. Development 

and validation of methods for assessing the quality of 

diagnostic accuracy studies. Health Technol Assess 

2004; 8(25):1-234. 

Wolff SN, Birch R, Sarma P, et al. Randomized doseresponse evaluation of etoposide in small cell 

carcinoma of the lung: a Southeastern Cancer Study 

Group Trial. Cancer Treat Rep 1986; 70(5):583-7. 

Work E, Bentzen SM, Nielsen OS, et al.. Prophylactic 

cranial irradiation in limited stage small cell lung 

cancer: survival benefit in patients with favourable 

characteristics. Eur J Cancer 1996; 32A(5):772-8. 

Work E, Nielsen OS, Bentzen SM, et al. Randomized 

study of initial versus late chest irradiation combined 

with chemotherapy in limited-stage small-cell lung 

cancer. Aarhus Lung Cancer Group. J Clin Oncol 

1997; 15(9):3030-7. 

Yoshikawa K, Tsubota N, Kodama K, et al.. 

Prospective study of extended segmentectomy for 

small lung tumors: the final report. Ann Thorac Surg 

2002; 73(4):1055-8. 

Yuen AR, Zou G, Turrisi AT, et al. Similar outcome 

of elderly patients in intergroup trial 0096: Cisplatin, 

etoposide, and thoracic radiotherapy administered 

once or twice daily in limited stage small cell lung 

carcinoma. Cancer 2000; 89(9):1953-60. 

151 

List of Acronyms/Abbreviations 

- without 

# number 

# number 

∆ change 

? unknown, unclear 

+ with 

<p less than a partial resection 

1° primary 

18-FDG 18-fluorodeoxyglucose 

95% CIL lower limit 95% confidence interval 

95% CIU upper limit 95% confidence interval 

A Asian 

A doxorubicin (Adriamycin®) 

abstr abstract 

ACCP American College of Chest Physicians 

AHRQ Agency for Healthcare Research and Quality 

ALT alanine transaminase 

Alt alternating 

AP anterioposterior 

ASCO American Society of Clinical Oncology 

AST aspartate transaminases 

ASTRO American Society for Therapeutic Radiology and 

Oncology 

B bilobectomy 

B Black 

BSC best supportive care 

c complete 

C cyclophosphamide 

CALGB Cancer and Leukemia Group B 

Cb carboplatin 

CCNU lomustine 

CD cyclophosphamide- and/or doxorubicin-based 

chemotherapy 

chemoTx chemotherapy 

CI confidence interval 

CNS central nervous system 

Conc concurrent 

cont’d continued 

contr contralateral 

Conv conventional 

CPHM Cox proportional hazard model 

CR complete response 

CT computed tomography 

Ctrl control 

CTx chemotherapy 

d day 

DA diagnostic accuracy 

dist distant 

Dx diagnosis 

E Alt early alternating 

E etoposide 

E etoposide 

ea each 

ECOG Eastern Cooperative Oncology Group 

endosc endoscopic 

EORTC LCCG European Organization for the Research and 
152 

Treatment of Cancer Lung Cancer Cooperative 

Group 

EPC Evidence-based Practice Center 

EQ-5D EuroQOL 5-dimension health-related quality of life 

instrument 

ES extensive stage 

ESD extensive-stage disease 

F female 

F fractions 

F/d fractions per day 

F/U follow-up 

FDA Food and Drug Administration 

FE fixed effects 

FEV1 forced expiratory volume in 1 second 

FN false negative 

FNA fine-needle aspiration 

FP false positive 

Frac(s) fraction(s) 

FWHM full width, half maximum 

GQ good quality 

Gy Gray 

H Hispanic 

HL hilar 

HR hazard ratio 

hr hour 

Hyper hyperfractionated 

ips ipsilateral 

IV intravenous 

K-M Kaplan-Meier 

KPS Karnofsky Performance Status 

L Alt late alternating 

L lobectomy 

L lomustine 

L95 upper limit 95% confidence interval 

LCSG Lung Cancer Study Group 

LDH lactic dehydrogenase 

LINAC linear accelerator 

LN lymph node 

LRFS local recurrence-free survival 

LRFS local recurrence-free survival 

LS limited stage 

LSD limited-stage disease 

M male 

M methotrexate 

MBq megabecquerel 

mCi milliCurie 

md median 

MD mediastinal 

mets metastases 

MeV megaelectron volt 

mg milligram 

M-H Mantel-Haenszel 

MI myocardial infarction 

mn mean 

mo(s). month(s) 

MR meta regression 

MRI magnetic resonance imaging 

MS mediastinal 

N no 

n number 

N pooled number 

NCI National Cancer Institute 
153 

NE not evaluable 

NED no evidence of disease 

neg negative 

NNEC non-neuroendocrine carcinoma 

NNT number needed to treat 

nonrandom. nonrandomized 

NOS not otherwise specified 

NR not reported 

NS nonsignificant 

NSCLC non-small-cell lung cancer 

O other 

OR odds ratio 

ORR overall response rate 

OS overall survival 

P cisplatin 

p partial 

P pneumonectomy 

PA posterioanterior 

PCI prophylactic cranial radiation 

PD progressive disease 

PE platinum/etoposide chemotherapy 

PET positron emission tomography 

PFS progression-free survival 

PI primary investigator 

po oral 

P-OR Peto odds ratio 

pos positive 

PR partial response 

PS performance status 

Pt platinum 

pub publication 

PWIFR percent/proportion with in-field recurrence 

Q heterogeneity statistic 

QoL quality of life 

QUADAS Quality Assessment of Diagnostic Accuracy Studies 

R/I ruled in 

R/O ruled out 

radiol radiologic 

RadioTx radiotherapy 

RCT randomized, controlled trial 

RD risk difference 

RE random effects 

reg regimen 

regl regional 

retrospect retrospective 

RFS recurrence-free survival 

rng range 

RNS radionuclide scan 

ROC receiver operating characteristic 

RR relative risk 

RR risk ratio 

SC supraclavicular 

SC/LC small-cell/large-cell subtype 

SCLC small cell lung cancer 

SD stable disease 

SE standard error 

Sens sensitivity 

Seq sequential 

Spec specificity 

STARD Standards for Reporting of Diagnostic Accuracy 

sup-clav supraclavicular 

supraclav supraclavicular 
154 

surg surgery 

SWOG Southwest Oncology Group 

T thoracotomy only (open and close) 

TN true negative 

TNM Tumor, Node, Metastasis (staging system) 

TP true positive 

TRTx thoracic radiotherapy 

TTF time to failure 

Tx treatment; therapy 

U.S. United States 

U95 upper limit 95% confidence interval 

ULN upper limit of normal 

US ultrasound 

V vincristine 

VC vital capacity 

Ve vindesine 

W White 

WBC white blood cell 

WHO World Health Organization 

wk(s) week(s) 

Wt weight 

XRT radiotherapy 

Y yes 

yr year 

Abbreviations of Combination Chemotherapy Regimens 

ACO doxorubicin, cyclophosphamide, and vincristine 

ACOM doxorubicin, lomustine, methotrexate, vincristine 

BTOC vincristine, thiotepa, cyclophosphamide, carmustine 

CAE cyclophosphamide, doxorubicin, etoposide 

CAV cyclophosphamide, doxorubicin, vincristine 

CbE carboplatin, etoposide 

CbPE carboplatin, cisplatin, etoposide 

CC cyclophosphamide, lomustine 

CCM cyclophosphamide, lomustine, methotrexate 

CCMV cyclophosphamide, lomustine, methotrexate, vincristine 

CDE cyclophosphamide, doxorubicin, etoposide 

CE-CAP cyclophosphamide, doxorubicin, cisplatin 

COME cyclophosphamide, vincristine, methotrexate, etoposide 

COMF cyclophosphamide, vincristine, methotrexate, fluorouracil 

CVMP cyclophosphamide, vincristine, methotrexate, cisplatin 

EP etoposide, platinum compound 

LCAE lomustine, cyclophosphamide, doxorubicin, etoposide 

M-CAV methotrexate, cyclophosphamide, doxorubicin, vincristine 

MCCC/VI methotrexate, cyclophosphamide, lomustine, ifosfamide, etoposide 

PE cisplatin, etoposide 

PEVe platinum, epirubicin, etoposide 

PMP cisplatin, methotrexate, procarbazine 

VCMV vincristine, cyclophosphamide, mitomycin, chromomycin 

VIC-E/VICE vincristine, ifosfamide, carboplatin, etoposide 

VIMP vincristine, ifosfamide, mesna, carboplatin 

VIP-E etoposide, ifosfamide, cisplatin, and epirubicin 
A-1

Appendix A. Exact Search Strings 

MEDLINE search (performed through 12/21/04) 

EMBASE search (performed through 03/04/05) 

Cochrane Controlled Clinical Trials Register (performed through 03/11/05) 

Database Search Strategies: Key Questions 1–5, 7–9 

• (lung neoplasms [mh] AND (“small cell” [tw] OR “small-cell” [tw])) OR 

• carcinoma, small cell [mh] OR 

• ((“small cell” [tw] OR “small-cell” [tw]) AND (lung [tw] OR pulmonary [tw] OR 

bronchial [tw] OR bronchogenic [tw])) 

Results of this search will be limited to citations also identified by the Cochrane Handbook 

search strategy for controlled trials (Alderson et al. 2004): 

• randomized controlled trial [pt] OR 

• controlled clinical trial [pt] OR 

• randomized controlled trials [mh] OR 

• random allocation [mh] OR 

• double-blind method [mh] OR 

• single-blind method [mh] OR 

• clinical trial [pt] OR 

• clinical trials [mh] OR 

• "clinical trial" [tw] OR 

• ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR 

blind* [tw])) OR 

• placebos [mh] OR 

• placebo* [tw] OR 

• random* [tw] OR 

• research design [mh:noexp] OR 

• comparative study [mh] OR 

• evaluation studies [mh] OR 

• follow-up studies [mh] OR 

• prospective studies [mh] OR 

• control* [tw] OR 

• prospectiv* [tw] OR 

• volunteer* [tw]) 

For Key Question 6 (PET Imaging), the following search terms were used: 

(carcinoma, small cell [mh] OR ((“small cell” [tw] OR “small-cell” [tw]) AND (lung [tw] OR 

pulmonary [tw] OR bronchial [tw] OR bronchogenic [tw]))) AND (positron* [tw] OR pet [tw] 

OR “PET-CT” OR “PET/CT” OR FDG*) 
B-1

Appendix B. Sample Data Abstraction Forms Question # Table A: Sample Selection Study Inclusion Exclusion n, Randomized n, Withdrawn 

nP

 Total Grp1 Grp2 Total Grp1 Grp2 T Total Grp1 Grp2 Total Grp1 Grp2 T Total Grp1 Grp2 Total Grp1 Grp2 T Total Grp1 Grp2 Total Grp1 Grp2 T Total Grp1 Grp2 Total Grp1 Grp2 T Total Grp1 Grp2 Total Grp1 Grp2 T
B-2

Question # Table B: Patient Characteristics Study Age Gender (%) Race (%) Performance Status 

Comorbidities or PrognFactors 

 Grp1 Grp2

mn md rng sd 

 Grp1 Grp2M F 

 Grp1 Grp2

B W H A O 

ECOG Grp1 Grp20 1 2 3 

 Grp1 G

 Grp1 Grp2

mn md rng sd 

 Grp1 Grp2M F 

 Grp1 Grp2

B W H A O 

ECOG Grp1 Grp20 1 2 3 

 Grp1 G

 Grp1 Grp2

mn md rng sd 

 Grp1 Grp2M F 

 Grp1 Grp2

B W H A O 

ECOG Grp1 Grp20 1 2 3 

 Grp1 G

 Grp1 Grp2

mn md rng sd 

 Grp1 Grp2M F 

 Grp1 Grp2

B W H A O 

ECOG Grp1 Grp20 1 2 3 

 Grp1 G

 Grp1 Grp2

mn md rng sd 

 Grp1 Grp2M F 

 Grp1 Grp2

B W H A O 

ECOG Grp1 Grp20 1 2 3 

 Grp1 G

 Grp1 Grp2

mn md rng sd 

 Grp1 Grp2M F 

 Grp1 Grp2

B W H A O 

ECOG Grp1 Grp20 1 2 3 

 Grp1 G
B-3

Question # Table C: Treatments Study Chemotherapy regimen, per protocol Group 1 XRT Group 2 XRT  Agent Dose Schedule Dose Schedule Dose Schedule Agent Dose Schedule Dose Schedule Dose Schedule Agent Dose Schedule Dose Schedule Dose Schedule Agent Dose Schedule Dose Schedule Dose Schedule Agent Dose Schedule Dose Schedule Dose Schedule Agent Dose Schedule Dose Schedule Dose Schedule
B-4

Question # Table D: Outcome Assessment Study 

Primary Outcomes 

Secondary Outcomes Response Criteria Observer F/U 

 To

mn md rng sd 

 To

mn md rng sd 

 To

mn md rng sd 

 To

mn md rng sd 

 To

mn md rng sd 

 To

mn md rng sd 
B-5

Question # Table E: Survival Outcomes Study Overall Survival Progression-Free Survival  N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr 

Grp1 Grp2 Statistical Test Results 

 N Med (mos) 1 yr 2 yr 3 yGrp1 Grp2 Statistical Test Results 

 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr 

Grp1 Grp2 Statistical Test Results 

 N Med (mos) 1 yr 2 yr 3 yGrp1 Grp2 Statistical Test Results 

 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr 

Grp1 Grp2 Statistical Test Results 

 N Med (mos) 1 yr 2 yr 3 yGrp1 Grp2 Statistical Test Results 

 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr 

Grp1 Grp2 Statistical Test Results 

 N Med (mos) 1 yr 2 yr 3 yGrp1 Grp2 Statistical Test Results 

 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr 

Grp1 Grp2 Statistical Test Results 

 N Med (mos) 1 yr 2 yr 3 yGrp1 Grp2 Statistical Test Results 

 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr 

Grp1 Grp2 Statistical Test Results 

 N Med (mos) 1 yr 2 yr 3 yGrp1 Grp2 Statistical Test Results 
B-6

Question # Table F: Tumor Response and Quality of Life Study Tumor Response Quality of Life 

 N CR PR SD PD NE Grp1 Grp2 Statistical Test Results 

 Grp1 Grp2 GrpScale Domain F/U n n mn

 N CR PR SD PD NE Grp1 Grp2 Statistical Test Results 

 Grp1 Grp2 GrpScale Domain F/U n n mn

 N CR PR SD PD NE Grp1 Grp2 Statistical Test Results 

 Grp1 Grp2 GrpScale Domain F/U n n mn

 N CR PR SD PD NE Grp1 Grp2 Statistical Test Results 

 Grp1 Grp2 GrpScale Domain F/U n n mn

 N CR PR SD PD NE Grp1 Grp2 Statistical Test Results 

 Grp1 Grp2 GrpScale Domain F/U n n mn

 N CR PR SD PD NE Grp1 Grp2 Statistical Test Results 

 Grp1 Grp2 GrpScale Domain F/U n n mn
B-7

Question # Table G: Adverse Events Toxicity Type Study Severity or Grade Results Treatment-related mortality F/U (yr) Grp1 n % Grp2 n % p Nausea F/U (yr) Grp1 n % Grp2 n % p Vomiting F/U (yr) Grp1 n % Grp2 n % p Anorexia F/U (yr) Grp1 n % Grp2 n % p Lethargy F/U (yr) Grp1 n % Grp2 n % p Neurosensory F/U (yr) Grp1 n % Grp2 n % p Hearing loss F/U (yr) Grp1 n % Grp2 n % p Esophagitis F/U (yr) Grp1 n % Grp2 n % p Bronchopulmonary F/U (yr) Grp1 n % Grp2 n % p Pneumonitis F/U (yr) Grp1 n % Grp2 n % p Kidney F/U (yr) Grp1 n % Grp2 n % p Anemia F/U (yr) Grp1 n % Grp2 n % p Thrombocytopenia F/U (yr) Grp1 n % Grp2 n % p Leukopenia or neutropenia F/U (yr) Grp1 n % Grp2 n % p Infection F/U (yr) Grp1 n % Grp2 n % p Other F/U (yr) Grp1 n % Grp2 n % p 
B-8

Question # 

Table H: Study Quality Ratings 

Study 

Initial Assembly of 

Comparable Groups

Low Loss to 

Followup, 

Maintenance of 

Comparable 

Groups 

Measurements 

Reliable, Valid, 

Equal* 

Interventions 

Comparable/ 

Clearly Defined 

Appropriate 

Analysis of 

Results 

Overall 

Rating 

 
B-9

Question 6: Positron Emission Tomography for Staging of Small-Cell Lung Cancer Table 6A: Sample Selection Study Design Inclusion Exclusion n, Enrolled 

n, WiExclu

Question 6: Positron Emission Tomography for Staging of Small-Cell Lung Cancer Table 6B: Patient Characteristics Study Age (yr) Gender (%) 

 Stage Limited Extensive  % % Race 

Performance Status (%) 

 med M 

F 

 med M 

F 

 med M 

F 

 med M 

F 

 med M 

F 

 med M 

F 

Question 6: Positron Emission Tomography for Staging of Small-Cell Lung Cancer Table 6C: Test Procedure and Interpretation Study PET Procedure PET Interpretation 

Conventional StagProcedure 
B-10

Question 6: Positron Emission Tomography for Staging of Small-Cell Lung Cancer Table 6D: Reference Standard Procedure and Interpretation, Management Decisions Study 

Decision Rules for Receiving Reference Standard 

Reference Standard Procedure Reference Standard Interpretation Manageme

Question 6: Positron Emission Tomography for Staging of Small-Cell Lung Cancer Table 6E: Diagnostic Accuracy Results Study Test Focus n TP FN FP TN Prev Sens 

Sens 95% CIL 

Sens 95% CIU Spec 

Spec 95% CIL 

Spec 95% CIU PPV 

Question 6: Positron Emission Tomography for Staging of Small-Cell Lung Cancer Table 6F: Staging Accuracy Results Study Test Use 

Correctly Upstaged  # % 

Incorrectly Upstaged  # % 

Correctly Downstaged  # % 

Incorrectly Downstaged  # % 

Identified Unsuspected Metastases Site # % 

Ruled Out Suspected Metastases Site # % 
B-11

Question 6: Positron Emission Tomography for Staging of Small-Cell Lung Cancer Table 6G: Patient Management and Other Results Study Test Use 

PET Changed Patient Management  # % Changes Other Findings 

Question 6: Positron Emission Tomography for Staging of Small-Cell Lung Cancer Table 4G: Study Quality Ratings Study 

Representative sample? 

Clear Selection Criteria? 

Reference standard correctly classifies target condition? 

Period between test, reference standard short enough? 

Whole sample or selection received reference standar

Study 

Patients received reference standard regardless of test results? 

Reference standard independent of test? 

Test execution sufficiently described? 

Reference standard execution sufficiently described? 

Study 

Test results interpreted blind to reference standard? 

Reference standard results interpreted blind to test? 

Clinical practice data available for test interpretation? 

Uninterpretable/ indeterminate results reported? 

Wex
B-12
Appendix C 

Evidence Tables 
C-1 

Question 1. Alternating, Concurrent and Sequential Radiotherapy Table 1A: Sample Selection Study Inclusion Exclusion n, Randomized n, Withdrawn 

nP

Gregor 1997 EORTC LCCG Multiple European institutions, accrual 3/89 through 1/95 

Previously untreated, confirmed SCLC, age < 75, ECOG PS 0-3, limited disease with adequate hematologic and biochemical function 

Serious preexisting disease, T1N0M0 disease suitable for resection, bulky mediastinal disease (> 50% of max transverse diameter of thorax on PA X-ray before CTx), pleural effusion obscuring extent of pretreatment disease 

Total Seq Alt 349 174 175 

Total Seq Alt 14 9 5 (ineligible; 3 incorrect histology, 8 extensive disease, 3 preexisting thrombocytopenia) 

T3

Lebeau 1999 26 French institutions, accrual 5/88 through 5/94 

Confirmed SCLC; limited stage; no previous RTx,, CTx or surgery; ECOG PS 0-3, no history pf previous neoplasm in last 5 yrs 

Age > 70; renal, hepatic, respiratory failure, serious cardiac disease 

Total Alt Conc 164 

Total Alt Conc 8 (ineligible: 5 extensive disease, 2 NSCLC, 1 inadequate pulmonary function tests) 

T1

Takada 2002 15 Japanese institutions, accrual 5/91 through 1/95 

Confirmed SCLS, limited state, measurable/assessable disease, age < 75, ECOG PS < 2, adequate organ function, 

leukocytes > 4K/mm3, 

hemoglobin > 11 g/dL, platelets > 100K/mm3, serum 

creatinine < 1.5 mg/dL, serum AST/ALT < 2xULN, serum bilirubin < 2.0 mg/dL, 24 hr creatinine clearance > 60 mL/min/m2, arterial oxygen > 70 mmHg. 

Malignant pleural effusions or stage I by TNM, symptomatic cardiac disease, history of MI in previous 3 mo 

Total Seq Conc 231 117 114 

Total Seq Conc 3 3 0 (ineligible: 2 extensive disease, 1 malignant lymphoma) 

T2

Sun 1995 15 Chinese institutions, accrual 1983 through 1989 

Localized disease Not specified Total Seq Alt Total Seq Conc T

1
C-2 

Question 1. Alternating, Concurrent and Sequential Radiotherapy Table 1A: Sample Selection (continued) Study Inclusion Exclusion n, Randomized n, Withdrawn 

nP

Work 1997 Work 1996 single-center study accrual 3/81-9/89 

confirmed SCLC; age<70 yr; 

limited stage (unilateral disease w/wo mediastinal involvement, + ipsilateral supraclavicular nodes, or invasion of trachea or contralateral main bronchus); no prior chemoTx, radioTx; or surgery for 1o tumor; KPS 

>40% 

age>70y; extensive stage disease (disease outside one lung, mediastinum and ipselateral supraclav. nodes, or pleural effusion); prior malignancy 

Total L Alt E Alt 199 100 99 

Total L Alt E Alt 0 0 0 

T1

Park 1996 Accrual 5/91 – 5/96 Korean Center 

Diagnosed with limited stage SCLC; age < 80 yrs; ECOG PS < 2; normal liver, 

hematologic and adrenal function; FEV1 > 1 L; VC > 45% 

 Total Seq Conc 

79 47 32 

Total Seq Conc T

7
C-3 

Question 1. Alternating, Concurrent and Sequential Radiotherapy Table 1B: Patient Characteristics Study Age Gender (%) Race (%) Performance Status 

Comorbidities or PrognFactors 

Gregor 1997 Seq Alt

mn md 61 61 rng 33-75 34-74 sd 

 Seq Alt

M 67.9 65.9 F 32.1 34.1

 Seq AltB W H A O 

ECOG Seq Alt

0 46.1 47.1 1 47.9 44.7 2 4.2 5.9 3 1.8 2.4 

 Seq AWt ↓ < 10% 76.4 7Wt ↓ > 10% 9.7 1NR 13.9 1

Lebeau 1999 Alt Conc

mn 58 57 md rng sd 

 Alt Conc

M 85.1 79.3 F 14.9 20.7 

 Alt ConcB W H A O 

ECOG Alt Conc0 50.0 51.2 1 44.6 46.3 2-3 4.1 2.4 NR 1.4 0.0 

 Alt CMn vital cap 86% 8Supraclav LN 12.2% 8

Takada 2002 Seq Conc

mn md 64 65 rng 30-74 39-74 sd 

 Seq Conc

M 81.6 79.8 F 18.4 20.2 

 Seq ConcB W H A O 

ECOG Seq Conc0 28.9 21.9 1 65.8 72.8 2 5.3 5.3 

 Seq CWt ↓ < 10% 89.5 9Wt ↓ > 10% 7.0 5NR 3.5 3Stage II 8.8 6Stage IIIA 50.0 5Stage IIIB 41.2 3

Sun 1995 All Seq Alt

mn md rng 29-71 sd 

 All Seq Alt

M 72.4 F 27.6 

 Seq Alt

B W H A O 

ECOG Seq Alt

0 1 2 3 

 Seq A

Work 1997 Work 1996 

 L Alt E Alt

mn md 59 61 rng 36-69 36-70 sd 

 L Alt E Alt

M 71 55 F 29 45 

 L Alt E Alt

B W not H reported A O 

KPS L Alt E Alt100 10.1 13.1 90-80 70.0 68.7 70-60 15.0 14.1 50-40 5.0 4.0 

 L Alt E 

 none  reported 

Park 1996 Seq Conc

mn 60.6 57.4 md rng sd 8.9 8.8 

 Seq Conc

M 79.2 85.2 F 20.8 14.8 

 Seq ConcB W H A O 

ECOG Seq Conc0 25.0 14.8 1 45.8 63.0 2 29.2 22.2 

 Seq CSmoking pack- 31 3yrs (mn+sd) +20.6 +
C-4 

Question 1. Alternating, Concurrent and Sequential Radiotherapy Table 1C: Treatments Study Chemotherapy regimen, per protocol Control XRT Treatment XRT Gregor 1997 Sequential: 

Agent Dose Schedule

cytoxan 1 g/m2 d 1, wks 1,4,7,10,13 

doxorubicin 45 mg/ m2 d 1, wks 1,4,7,10,13 

etoposide 100 mg/ m2 d 1,3,5, wks 1,4,7,10,13 

Alternating: same agents, doses, days, wks 1,5,9,13,17,19 

Sequential Dose Schedule

50 Gy 20 fractions, 1 fraction/d, 5  d/wk, wks 15-18, 1st 15  fractions wider field, last 5  fractions narrower field, > 4  MeV 

Alternating Dose Schedule

50 Gy 20 fractions, 1 fract d/wk, wks 7, 11, 15 1st 15 fractions wid field, last 5 fraction narrower field, > 4 

Lebeau 1999 Agent Dose Schedule

cytoxan 1 g/m2 d 1, wks 1,5,9,13,17,22 

doxorubicin 45 mg/ m2 d 1, wks 1,13,17,22 

vindesine 3 mg/ m2 d 1, wks 5,9, etoposide 150 mg/ m2 d 1,2, wks 1,5,9,13,17,22

Alternating Dose Schedule

55 Gy 1st and 2nd courses: 20 Gy 

 in 8 fractions over 12 d,  wks 6-7, 10-11, 3rd

 course: 15 Gy in 6 fractions  over 10 d, wks 14-15, > 8  MeV linac 

Concurrent Dose Schedule

50 Gy 40 Gy 16 fractions  d, then 10 Gy in 4  fractions over 7 d, w 9, > 8 MeV linac 

Takada 2002 Agent Dose Schedule

Sequential cisplatin 80 mg/ m2 d 1, wks 1,4,7,10 

etoposide 100 mg/ m2 d 1,2,3, wks 1,4,7,10 

Concurrent cisplatin 80 mg/ m2 d 1, wks 1,5,9,13 

etoposide 100 mg/ m2 d 1,2,3, wks 1,5,9,13 

Sequential Dose Schedule

45 Gy 30 fractions, 2 fractions/d,  5d/wk, wks 13-15 

Concurrent Dose Schedule

45 Gy 30 fractions, 2 frac 5d/wk, wks 1-3 

Sun 1995 Agent Dose Schedule

1983-1988 ea 3 wks, 2-3 cycles cytoxan 600 mg/m2 d 1,8 

vincristine 1 mg/m2 d 1,8 

methotrexate 20 mg d 2,5,8,11 etoposide 100 mg d 1-5 1989 ea 2-3 wks, 2-3 cycles carboplatin 300 mg/m2 d 1 

etoposide 100 mg/ m2 d 1-5 

cytoxan 600 mg/m2 d 1,8 

doxorubicin 40 mg/ m2 d 1, cisplatin 50 mg d 3-5 

Sequential Dose Schedule

Local disease 45- 6 wks, after 2 cycles of CTx60Gy Mediastinum/supraclavicular nodes 30- 3-4 wks 45 Gy 

Alternating Dose Schedule

Local disease 45- 6 wks, between 2 c60Gy of CTx Mediastinum/supraclavicula30- 3-4 wks 45 Gy 
C-5 

Question 1. Alternating, Concurrent and Sequential Radiotherapy Table 1C: Treatments (continued) Study Chemotherapy regimen, per protocol Control XRT Treatment XRT Work 1997 Work 1996 

Agent Dose Schedule

cisplatin 60 mg/m2 d1; cycles 2, 4, 9 (early) 

or cycles 1, 2, 8 (late) 

etoposide 120 mg/m2 d4,6,8; cycles 2, 4, 9 

(early) or cycles 1, 2, 8 (late) 

cytoxan 1 g/m2 d1; cycles 5-8, 10, 11 

(early) or 3-6, 10,11 (late) 

doxorubicin 45 mg/m2 d1; same as cytoxan 

vincristine 1.4 mg/m2 d1; same as cytoxan 

Later Alternating Dose Schedule

40 Gy wk 18-19 & 23-24 (cycles n=41; 7&9); split-course; 1 45 Gy frac/d, 5 d/wk; 11 n=59 frac/course; 20 or 22.5  Gy/course; 8-16 MV  photons; chemoTx (dose given between courses;  change, 10/84) 

Early Alternating Dose Schedule

40 Gy wk 1-2 & 6-7 (cyclen=45; split-course; 1 frac/45 Gy wk; 11 frac/course; n=54 22.5 Gy/course; 8- photons; chemoTx  (dose between cou change, 10/84) 

Park 1996 Agent Dose Schedule

cytoxan 1 g/m2 every 21 d, cycles 1, 3, 5

doxorubicin 40 mg/m2 every 21 d, cycles 1, 3, 5

vincristine 1 mg/m2 every 21 d, cycles 1, 3, 5

etoposide 500 ml every 21 d, cycles 2, 4, 6cisplatin 60 mg/m2 every 21 d, cycles 2, 4, 6

carboplatin 324 mg/m2 every 21 d, cycles 2, 4, 6

Sequential Dose Schedule

40-50 Gy wk 19-24, 1 frac/d, 1.8-2  Gy/frac 

Concurrent Dose Schedule

45 Gy wk 1-3, 2 frac/d, 3 1.5 Gy/frac 
C-6 

Question 1. Alternating, Concurrent and Sequential Radiotherapy Table 1D: Outcome Assessment Study 

Primary Outcomes 

Secondary Outcomes Response Criteria Observer F/U 

Gregor 1997 Overall survival Time to progression, 

toxicity, first site of failure 

 Not specified Not 

specified 

 To

mn md 43 rng sd 

Lebeau 1999 Overall survival Tumor response, 

toxicity, toxicityrelated mortality 

CR= no clinical, radiol, endosc evidence of tumor, 

>1 mo 

PR= ↓ by >50%, all measureable lesions, >1 mo 

SD= ↓ by < 50%, measurable lesions PD= ↑ by >25%, cross sectional area, >1 lesion, or 

any new lesion irrespective of response elsewhere 

NE= did not receive > 2 courses CTx or refused 

RTx 

Not blinded To

mn md 66 rng > sd 

Takada 2002 Overall survival Tumor response, 

progression-free survival, toxicity 

WHO criteria Not 

specified 

 To

mn md rng sd 

Sun 1995 Not specified Not Specified Not specified Not 

specified 

 To

mn md rng sd 

Work 1997 Work 1996 

overall survival no formal power calculation 

in-field recurrence rate; CNS recurrence rate; response rates; adverse events 

WHO criteria unspecified;

blinding not mentioned 

 To

mn plamd diarng dusd 

Park 1996 Not specified Tumor response, 

survival, local control, adverse events 

CR= no signs of tumor, > 4 wks PR= ↓ by >50%, any accountable lesion, no new 

symptoms, > 4 wks 

SD= ↓ by < 50%, any accountable lesion, > 4 wksPD= ↑ by >25%, any accountable lesion, > 4 wks

Not specified 

 To

mn md rng sd 
C-7 

Question 1. Alternating, Concurrent and Sequential Radiotherapy Table 1E: Survival Outcomes Study Overall Survival Progression-Free Survival Gregor 1997 N Md (mos) 1 yr 2 yr 3 yr 4 yr 5 yr 

Seq 165 15 64% 23% 15% ~14% ~12% Alt 170 14 60% 26% 12% ~10% ~4% (CPHM: RR 0.88, 95% CI 0.68, 1.1, p=0.237; p=0.288, log-rank) 

 N Md (mos) 1 yr 2 yr 3 ySeq 165 12 ~50% ~22% ~17Alt 170 10 ~43% ~16% ~10(Log-rank p=0.07) 

Lebeau 1999 N Md (mos) 1 yr 2 yr 3 yr 4 yr 5 yr 

Alt 74 14.0 63% 17% 11% 6% 6% Conc 82 13.5 54% 13% 6% 4% 4% (p=0.15, log-rank, 66 Alt deaths, 77 Conc deaths) 

 N Md (mos) 1 yr 2 yr 3 yAlt Conc 

Takada 2002 N Md (mos) 1 yr 2 yr 3 yr 4 yr 5 yr 

Seq 114 19.7 ~80% 35.1% 20.2% ~20% 18.3% Conc 114 27.2 ~80% 54.4% 29.8% ~25% 23.7% (p=0.097 eligible patients, p=0.086 all randomized, log-rank; CPMH: HR 0.70, 95% CI 0.52, 0.94, p=0.02) 

 N Md (mos) 1 yr 2 yr 3 ySeq 114 ~10 ~38% ~19% ~15Conc 114 ~12 ~50% ~28% ~25(p=0.084, log-rank)) 

Sun 1995 N Md (mos) 1 yr 2 yr 3 yr 4 yr 5 yr 

Seq 59 64.0% 13.6% 12.0% Alt 64 62.5% 28% 16.0% 

 N Md (mos) 1 yr 2 yr 3 ySeq Alt 

Work 1997 Work 1996 

 N Md (mos) 1 yr 2 yr 3 yr 4 yr 5 yr

L Alt 100 12.0 ~55% 18.8% ~12% ~12% 12.0% E Alt 99 10.5 ~43% 20.2% ~13% ~12% 10.8%  (p=0.41, not significant) 

PWIFR: N Md (mos) 1 yr 2 yr 3 yr 

L Alt 100 ~15 ~58% 31.7% ~27% E Alt 99 ~9 ~40% 27.7% ~25% 

Park 1996 N Mn (mos) 1 yr 2 yr 3 yr 4 yr 5 yr 

Seq 47 16.0 74.4% 27.7% 8.8% 4.4% 2.2% Conc 32 18.4 81.3% 29.0% 13.8% 10.7% 7.4% (p=0.11) 

 N Md (mos) 1 yr 2 yr 3 ySeq Conc 
C-8 

Question 1. Alternating, Concurrent and Sequential Radiotherapy Table 1F: Tumor Response and Quality of Life 

Study Tumor Response Quality of Life 

Gregor 1997 N CR PR SD PD NE 

Seq Alt 

 Seq Conc Seq Scale Domain F/U n n mn

 NOT MEASURED 

Lebeau 1999 N CR PR SD PD NE 

Alt 74 49% 46% 4% 1% Conc 82 53% 37% 7% 3% (p=0.26) 

 Seq Conc Seq Scale Domain F/U n n mn

 NOT MEASURED 

Takada 2002 N CR PR SD PD NE 

Seq 114 27.2% 64.9% 2.6% 3.5% 1.8% Conc 114 39.5% 57.0% 0.9% 0.9% 1.8% 

(CR p=0.07, ORR p=0.25) 

 Seq Conc Seq Scale Domain F/U n n mn

 NOT MEASURED 

Sun 1995 N CR PR SD PD NE 

Seq Conc 

 Seq Conc Seq Scale Domain F/U n n mn

 NOT MEASURED 

Work 1997 Work 1996 

 N CR PR SD PD NE Seq 100 61.2% 23.5% 10.2% 5.1% Conc 99 59% 30% 5% 6% (NS) 

Scale Domain F/U Early n Late n Ear NOT MEASURED 

Park 1996 N CR PR SD PD NE 

Seq 24 13% 50% 29% 4% 4% Conc 27 30% 48% 4% 11% 7% (response, p=0.13, response duration, mn+sd, Conc 395 d 

+61.1, Seq 180 d +43.9, p=0.03) 

 Seq Conc Seq Scale Domain F/U n n mn

 NOT MEASURED 
C-9 

Question 1. Alternating, Concurrent and Sequential Radiotherapy Table 1G: Adverse Events Toxicity Type Study Severity or Grade Group n % Group n % p NTreatment-related mortality 

Lebeau 1999 Deaths from aplasia 

Deaths from pulmonary fibrosis 

Alt 74 2.7 Conc 82 3.7 0.67 Alt 74 1.4 Conc 82 7.3 0.05 

GW

 Takada 2002 Seql 110 3.6 Conc 112 2.7 0.72  Work 1997 L Alt 100 0 E Alt 99 0 1.00 Nausea/Vomiting Gregor 1997 Nausea or vomiting, acute (WHO grade) 

0 1 2 3 4 

NR 

Seql 165 25.5 Alt 169 36.1 0.129  21.8 21.3

 37.6 25.4 13.3 15.4 0.6 1.2

 1.2 0.6

LeW

 Takada 2002 Nausea or vomiting (WHO grade > 3) Seql 110 19.1 Conc 112 10.7 0.09 Anorexia Le

TW

Lethargy Le

TW

Neurosensory Work 1997; 

1996 

Moderate neurotoxicity (grade < 3) in 11 (of 199); no difference between groups Le

TP

Hearing loss Le

TW

Esophagitis Gregor 1997 Acute (WHO grade) 

0 1 2 3 

Late esophageal stenosis 

(WHO grade) 

0 1 2 3 

NR 

Seql 165 83.0 Alt 169 75.7 0.198

 7.9 11.8  6.1 9.5  3.0 3.0

Seql 143 82.5 Alt 135 94.1 0.010 

 11.2 3.0  2.8 1.5  2.1 0.7  1.4 0.7 

LeW

 Takada 2002 WHO grade > 3 Seql 110 3.6 Conc 112 8.9 0.17 
C-10 

Question 1. Alternating, Concurrent and Sequential Radiotherapy Table 1G: Adverse Events (continued) Toxicity Type Study Severity or Grade Group n % Group n % p NBronchopulmonary Gregor 1997 Late Lung fibrosis (RTOG grade) 

0 1 2 3 4 

NR 

Seql 143 19.6 Alt 135 11.1 0.135

 19.6 20.0  21.7 27.4  18.2 14.8  18.9 24.4  2.1 2.2

TW

 Lebeau 1999 Pulmonary fibrosis Alt 74 2.7 Conc 82 8.5 0.17 Pneumonitis Le

TW

Kidney Work 1997; 

1996 

 quantified by chromium-edathamil clearance; did not 

differ between groups 

LeT

 Park 1996 ECOG grade 3 

ECOG grade 4 

Seql 24 0 Conc 27 0 1.00  0 0 

Anemia Takada 2002 WHO grade 3 Seql 110 41.8 Conc 112 53.6 0.08 Le

S

 Park 1996 ECOG grade 3 

ECOG grade 4 

Seql 24 0 Conc 27 3.7 1.00  0 0 

Thrombocytopenia Gregor 1997 Acute (WHO grade) 

0 1 2 3 4 

NR 

Seql 165 55.2 Alt 169 24.9 <0.001

 13.9 17.2  10.9 23.1  12.7 11.8  6.7 20.7  0.6 2.4 

Le

 Takada 2002 (WHO grade) 

3 4 

> 3 

Seql 110 12.7 Conc 112 29.5 0.11  13.6 7.1  26.4 36.6 

 Work 1997; 

1996 

WHO grades 3 & 4 L Alt 100 13 E Alt 99 13 1.00 

 Park 1996 ECOG grade 3 

ECOG grade 4 

Seql 24 0 Conc 27 0 1.00  0 3.7 
C-11 

Question 1. Alternating, Concurrent and Sequential Radiotherapy Table 1G: Adverse Events (continued) Toxicity Type Study Severity or Grade Group n % Group n % p NLeukopenia or neutropenia 

Gregor 1997 Acute Leukopenia (WHO grade) 

0 1 2 3 4 

NR 

Seql 165 6.7 Alt 169 4.1 <0.001

 5.5 1.2  10.9 3.6  34.5 17.8  41.8 71.6  0.6 1.8

S

 Lebeau 1999 Neutropenia (grade 3 or 4) Alt 74 60.8 Conc 82 58.5 0.87  Takada 2002 Leukopenia (WHO grade) 

3 4 

3 or 4 

Seql 110 44.5 Conc 112 50.9 0.001  9.1 37.5  53.6 88.4 

 Work 1997; 

1996 

WHO grades 3 & 4 leukopenia 

WHO grade 4 leukopenia 

L Alt 100 39 E Alt 99 67 <0.001 6 23 0.0006

 Park 1996 Leukopenia ECOG grade 3 

ECOG grade 4 

Seql 24 12.5 Conc 27 40.7 0.0176 4.2 11.1 

Infection Takada 2002 WHO grade > 3 Seql 110 0.9 Conc 112 5.4 0.12 Le

S

 Work 1997; 

1996 

 neutropenic fever in 8 patients; no difference between 

groups 

 Park 1996 ECOG grade 3 

ECOG grade 4 

Seql 24 0 Conc 27 3.7 1.00  0 0 

Other Takada 2002 Alopecia (WHO grade > 3) Seql 109 12.7 Conc 109 11.6 0.99  Takada 2002 Fever (WHO grade > 3) Seql 110 1.8 Conc 112 1.8 0.99  Takada 2002 Arrhythmias (WHO grade > 3) Seql 110 0.0 Conc 112 1.8 0.50  Park 1996 Hepatic ECOG grade 3 

Hepatic ECOG grade 4 

Seql 24 0 Conc 27 0 1.00  0 0 
C-12 

Question 1. Alternating, Concurrent and Sequential Radiotherapy Table 1H: Study Quality Ratings Study 

Initial Assembly of Comparable Groups 

Low Loss to Followup, Maintenance of Comparable Groups 

Measurements Reliable, Valid, Equal* 

Interventions Comparable/ Clearly Defined 

Appropriate Analysis of Results 

Overall Rating 

Gregor 1997 Yes Yes Yes Yes Yes Good Lebeau 1999 Yes Yes Yes Yes Yes Good Takada 2002 Yes Yes Yes Yes Yes Good Sun 1995 ? ? ? ? ? Poor Work 1997 Work 1996 

Partial 

(arms balanced but 

“Randomization... 

based on a table of random numbers.”) 

yes yes yes yes Fair 

Park 1996 ? ? Yes Yes ? Poor 
C-13

Question 2. Early versus Late Radiotherapy Table 2A: Sample Selection Study Inclusion Exclusion n, Randomized 

n, Withdrawn or Excluded 

nP

Murray 1993 Coy 1994 Feld 1988 22 centers accrual 1/85 through 12/88 

confirmed SCLC; limited stage (unilateral disease w/wo vena cava syndrome, mediastinal involvement, or + ipsilateral supraclavicular nodes); no prior chemoTx or radioTx; ECOG PS 0-3; adequate renal, hepatic, hematologic function; vital capacity >45%; 

FEV1>40% 

age>80y; extensive stage disease (disease outside one lung, mediastinum and supraclav. nodes, or pleural effusion); tumor size > prespecified limit of TRTx field size; serious cardiac disease; prior malignancy <5 years ago 

Total Early Late 332 168 164 

Total Early Late 24 (7%) 13 11 exclusions: extensive stage 5 not SCLC 10 poor lung func 3 tumor>RTx field 4 non-assessable 2 lesion 

T3

Perry 1987 Ahles 1994 Perry 1998 22 centers accrual 1/81 through 6/84 

confirmed SCLC; limited stage (unilateral disease w/wo vena cava syndrome, mediastinal involvement, or + supraclavicular nodes); no prior chemoTx or radioTx; CALGB PS 0-3 

MI within prior 6 mos; extensive stage disease (disease outside one lung, mediastinum and supraclav. nodes, or pleural effusion) 

Total Early Late 426 3-arm study; data on regimen III (no TRTx) not abstracted 

Total Early Late 27 (6%) exclusions: extensive stage 7 not SCLC 5 contraindications 3 wrong Tx: 1 withdrew consent 11 

T2(1

Jeremic 1997 single center accrual 1/88-12/92; closed early since PI moved 

confirmed SCLC; limited stage (unilateral disease w/wo vena cava syndrome, mediastinal involvement, or + ipsilateral supraclavicular nodes); no prior therapy; KPS >50%; 

adequate hematologic, renal, hepatic function 

age>70y; extensive stage 

disease (disease outside one lung, mediastinum and supraclav. nodes, or pleural effusion); serious cardiac or renal disease; prior malignancy <5 years ago 

Total Early Late 107 54 53 

Total Early Late 4 (4%) 2 2 exclusions: extensive stage 3 concurrent 1 bladder cancer 

T1

Qiao 2004 single center accrual 3/93-1/98 

limited stage SCLC (unilateral disease), previously untreated, could bear comprehensive treatment, KPS >60, age <70, normal liver and kidney function 

metastasis beyond homolateral hilus, mediastinum, and supraclavicular lymph nodes 

Total Early Late 90 45 45 

Total Early Late T

9

Skarlos 2001 multicenter accrual 12/93 to 11/99 

confirmed SCLC; limited stage (unilateral disease w/wo vena cava syndrome, mediastinal involvement, or + ipsilateral supraclavicular nodes); no prior chemoTx or radioTx; ECOG PS 0-2; adequate renal, hepatic, hematologic function 

extensive stage disease (disease outside one lung, mediastinum and ipsilateral supraclav. nodes, or pleural effusion); prior malignancy 

Total Early Late 86 

Total Early Late 5 (6%) exclusions: pleural effusion 4 adrenal mets 1 

T8
C-14

Question 2. Early versus Late Radiotherapy Table 2A: Sample Selection (continued) Study Inclusion Exclusion n, Randomized 

n, Withdrawn or Excluded 

nP

James 2003 (abstract only) multicenter; accrual 1/1993 through 1/2002 

limited stage disease (definition not reported) 

extensive stage disease (definition not reported) 

Total Early Late 325 159 166 

Total Early Late 0 0 0 

T3
C-15

Question 2. Early versus Late Radiotherapy Table 2B: Patient Characteristics Study Age (yr) Gender (%) Race 

Performance Status 

(%) 

Comorbidities or Prog

Factors (%) 

Murray 1993 Coy 1994 Feld 1988 

 Early Late

mn md 61.8 y 61.6 y rng sd 

 Early Late

M 59.4 65.4 F 40.6 34.6 

 Early LateB W not H reported A O 

ECOG Early Late0 21.9 22.2 1 65.2 68.0 2 12.3 9.2 3 0.6 0.7 

 Early Lelevated LDH 25.1% 2LDH unknown 16.2% 1disease extent: lung only 38.7% 3+ mediastinum 53.5% 5+ supraclavic- 7.8% ular nodes 

Perry 1987 Ahles 1994 Perry 1998 

 Early Late

<50 14% 12% 50-9 32% 33% 60-9 41% 43% 70-9 13% 12% 

 Early Late

M 62 63 F 38 37 

 Early LateB W not H reported A O 

CALGB Early Late0 38 42 1 48 45 2 or 3 13 9 

 Early Lweight loss >10% at 14 1entry 

Jeremic 1997 Early Late

mn 57 57 md 59 59 rng 40-67 44-66 sd 

 Early Late

M 59.6 60.8 F 40.4 39.2 

 Early LateB W not H reported A O 

KPS Early Late90, 100 52 47 50-80 48 53 

 Early Lweight loss >5% at 52 5entry 

Qiao 2004 Early Late

mn md 57 56 rng 36-68 38-69 sd 

 Early Late

M 75.6 66.7 F 24.4 33.3 

 Early LateB W not H reported A O 

 Early LateKPS >70 for all; 

excluded if KPS <60 

 Early L

lung only 28.9 2hilum /MS LN 60 6SC LN 11.1 1

Skarlos 2001 Early Late

mn md 61 60 rng 40-76 37-76 sd 

 Early Late

M 93 90 F 7 10 

 Early LateB W not H reported A O 

ECOG Early Late0 26 41 1 50 44 2 24 15 

 Early Lsmokers 100 9extra-lung disease: mediastinum 67 6ips. sup-clav. 17 weight loss 21 1>5% in past 6 mos 

James 2003 (abstract only) 

 Early Late

mn md 62 62 rng 34-74 33-74 sd 

 Early Late

M 60 57 F 40 43 

 Early LateB W not H reported A O 

ECOG Early Late0-1 91 89 2-3 9 11

 Early L none  reported 
C-16

Question 2. Early versus Late Radiotherapy Table 2C: Treatments Study Chemotherapy regimen, per protocol Early TRTx Late TRTx Murray 1993 Coy 1994 Feld 1988 

Agent Dose Schedule

cytoxan 1 g/m2 d 1, wk 1, 8, 14 (early) 

 wk 1, 7, 13 (late) doxorubicin 50 mg/m2 d 1, as for cytoxan 

vincristine 2 mg d 1, as for cytoxan etoposide 100 mg/m2 d 1-3 wk 4, 11, 17 (early) wk 4, 10, 16 (late) cisplatin 25 mg/m2 d 1-3, as for etoposide 

Dose Schedule

40 Gy wks 4-6: 15 fracs, 2.67 Gy  each, 1 frac/d, 5 d/wk; 60Co 

 or linac photons (4-25  MeV); 1 wk rest post TRTx  before chemoTx cycles 3-6

Dose Schedule

40 Gy wks 16-18: 15 fracs Gy each; 1 frac/d, 5 

60Co or linac photo

 25 MeV) 

Perry 1987 Ahles 1994 Perry 1998 

Agent Dose Schedule

vincristine 1.4 mg/m2 d1; q21d 

cytoxan 1 g/m2 d1; q21d 

etoposide 80 mg/m2 d1,2,3; q21d (to cycle 7) 

doxorubicin 50 mg/m2 d1; (replaced etoposide (chemoTx for for odd cycles #7-17, to 18 months) total dose of 350 mg/m2) 

Dose Schedule

50 Gy wks 1-5: 40 Gy, then 10  Gy boost; source, # and  size of fractions not  specified  (likely 2 Gy/d, 5 d/wk) 

Dose Schedule

50 Gy wks 10-14: 40 Gy 10 Gy boost; sou and size of fractio specified  (likely 2 Gy/d, 5 d/

Jeremic 1997 Agent Dose Schedule

carboplatin 30 mg every RTx day etoposide 30 mg every RTx day cisplatin 30 mg/m2 d 1-3; wk 6,9,12,15 (early) 

 wk 1,4,11,14 (late) etoposide 120 mg/m2 as for cisplatin 

Dose Schedule

54 Gy wks 1-4; 1.5 Gy fracs 2x/d  4.5-6 hr apart, 5x/wk; 36  fracs on 18 d over 3.6 wk;  concurrent chemoTx given  during interval between  fracs 

Dose Schedule 

54 Gy wks 6-9; 1.5 Gy fr 4.5-6 hr apart, 5x/ fracs on 18 d over  concurrent chemo during interval bet fracs 

Qiao 2004 Agent Dose Schedule

carboplatin 100 mg d 1-5, wks 1,4,7,10,13,16etoposide 100 mg d 1-5, wks 1,4,7,10,13,16

Dose Schedule50 or started in first CTx cycle; 60 Gy given over 6 wks; 2 Gy  fracs, 1x/d, 5d/wk, 40 Gy  to front and back, 20 Gy  from oblique angles/avoid- ing spinal cord; total 50  Gy if no LN metastasis 

Dose Schedule

60 Gy started after 4th CT

 same treatement p radiation areas and  dosages as early g

Skarlos 2001 Agent Dose Schedule

carboplatin AUC of 6 d1, each of six 21-d  cycles etoposide 100 mg/m2 d 1-3, each of six 21-d 

 cycles 

Dose Schedule

45 Gy wks 1-3; 1.5 Gy fracs 2 

frac/d, 5 d/wk 

Dose Schedule

45 Gy wks 10-12; 1.5 Gy 

frac/d, 5 d/wk 

James 2003 (abstract only) 

Agent Dose Schedule

cytoxan 1 g/m2 d 1, wks 1, 7, 13 

doxorubicin 50 mg/m2 d 1, wks 1, 7, 13 

vincristine 2 mg d 1, wks 1, 7, 13 etoposide 100 mg/m2 ds 1-3, wks 4, 10, 16 cisplatin 25 mg/m2 ds 1-3, wks 4, 10, 16 

Dose Schedule

40 Gy wks 4-6: 15 fracs, 2.67 Gy  each, 1 frac/d, 5 d/wk;  source not specified 

Dose Schedule

40 Gy wks 16-18: 15 fracs Gy each; 1 frac/d, 5  source not specifie
C-17

Question 2. Early versus Late Radiotherapy Table 2D: Outcome Assessment Study 

Primary Outcomes 

Secondary Outcomes Response Criteria Observer F/U 

Murray 1993 Coy 1994 Feld 1988 

overall survival 80% power to detect increase in 2-year survival from 20% to 35% at 2-sided p<0.05 

progression-free survival; response rates; time to local recurrence; time to brain relapse; first relapse pattern (local versus distant versus both); adverse events

CR= no clinical, radiol evidence of tumor, >1 mo PR= ↓ by >50%, all measureable lesions, >1 mo SD= ↓ in lesion size by <50% or ↑ by <25%, >1 mo

PD= ↑ by >25%, cross sectional area, >1 lesion, or 

any new lesion 

unspecified; blinding not mentioned 

 To

mn md <5 rng 2.7sd 

Perry 1987 Ahles 1994 Perry 1998 

not specified; no power calculation 

overall, disease-free and failure-free survival; time to failure in chest; response rates; adverse events 

CR= no clinical, radiol evidence of tumor, >1 mo PR= ↓ by >50%, all measureable lesions, >1 mo SD= ↓ in lesion size by <50% >1 mo 

PD= any objective ↑ in lesion size 

unspecified; blinding not mentioned 

 To

 10 mn md rng sd 

Jeremic 1997 survival at 2 yr 

planned 80% power to detect 20% ∆ in 2 

yr survival at p<0.05, assuming 25% baseline survival, but closed early 

local recurrence-free and distant mets-free survival; response rates; adverse events

CR= disappearance of all measurable/assessable 

disease & no new lesions, ≥4 wk 

PR= ↓ by >50%, Σall lesions[products of crosssectional diameters], no new lesions, ≥4 wk 

SD= ↓ by <50% or ↑ by <25% in above sum PD= ↑ by ≥25% in above sum 

unspecified; blinding not mentioned 

 Tomn nomd rng sd 

Qiao 2004 not specified; no 

power calculation 

overall survival; response rates at 4 months; adverse events; cause of death 

CR= no clinical, radiol evidence of tumor, >4 wk 

PR= >50% ↓, Σall lesions[products, 2 greatest perpendicular diams.], no new lesions, ≥4 wk 

SD= did not meet criteria for CR, PR or PD PD= ↑ by ≥25% in above sum, without prior CR, 

PR or SD (WHO criteria)

unspecified; blinding not mentioned 

 To

 5 ymn md rng sd 

Skarlos 2001 overall response rate 

(ORR = CR + PR) n=84 had 80% power to detect 25% ↑ in ORR at 5% level, if ORR=70% for late TRTx 

overall survival; time to progression; adverse events 

CR= no clinical, radiol evidence of tumor, >4 wk 

PR= >50% ↓, Σall lesions[products, 2 greatest perpendicular diams.], no new lesions, ≥4 wk 

SD= did not meet criteria for CR, PR or PD PD= ↑ by ≥25% in above sum, without prior CR, 

PR or SD (WHO criteria)

unspecified; blinding not mentioned 

 To

mn 35 md rng sd 

James 2003 (abstract only) 

overall survival (no power calculation) 

adverse event; overall response rate (CR+PR) 

CR= not provided PR= not provided SD= not provided PD= not provided 

unspecified;blinding not mentioned 

 Tomn md rng sd 
C-18

Question 2. Early versus Late Radiotherapy Table 2E: Survival Outcomes Study Overall Survival 

Progression-Free Survival (PFS), Time to Failure (TTFRecurrence-Free Survival (LRFS), or Proportion WithField Recurrence (PWIFR) 

Murray 1993 Coy 1994 Feld 1988 

 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr

Early 155 21.2 ~77% 40% 29.7% 23.7% 20%Late 153 16.0 ~63% 33.7% 21.5% 15.1% 11% (p=0.008, log-rank; 0.005 Wilcoxon) 

PFS: N Med (mos) 1 yr 2 yr 3 yr 4 yr 

Early 155 15.4 ~64% ~28% 26% ~23% Late 153 11.8 ~48% ~24% 19% ~17  (p=0.036, log-rank; 0.014 Wilcoxon) 

Perry 1987 Ahles 1994 Perry 1998 

 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr

Early 125 13.0 ~53% ~24% ~10% Late 145 14.5 ~62% ~30% ~20%  (p=0.144; not significant) 

TTF: N Med (mos) 1 yr 2 yr 3 yr 4 yr 

Early 125 11.0 ~48% 15% ~9% ~7% Late 145 11.2 ~52% 21% ~14% ~12%  (p=0.238; not significant) 

Jeremic 1997 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr

Early 52 34 90% 71% 48% 35% 30%Late 51 26 71% 53% 39% 25% 15% (p=0.052) 

LRFS: N Med (mos) 1 yr 2 yr 3 yr 4 yr 

Early 52 94% 90% 73% 63% Late 51 74% 69% 61% 46%  (p=0.011) 

Qiao 2004 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr

Early 45 26 78% 33% 27%Late 45 19 53% 22% 16%(log-rank, p<0.05) 

 N Med (mos) 1 yr 2 yr 3 yr 4 yr 

Early Late 

Skarlos 2001 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr

Early 42 17.5 ~65% 36% 22% Late 39 17 ~80% 29% 13%  (p=0.65, not significant) 

TTF: N Med (mos) 1 yr 2 yr 3 yr 4 yr 

Early 42 9.5 ~40% ~25% ~20% Late 39 10.5 ~35% ~15% ~15%  (p=0.6, not significant) 

James 2003 (abstract only) 

 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr

Early 159 13.5 16% Late 166 15.1 20%  (HR = 1.18; 95% CI: 0.93, 1.51; p=0.18) 

 N Med (mos) 1 yr 2 yr 3 yr 4 yr 

Early Late NOT REPORTED 
C-19

Question 2. Early versus Late Radiotherapy Table 2F: Tumor Response and Quality of Life 

Study Tumor Response Quality of Life 

Murray 1993 Coy 1994 Feld 1988 

 N CR PR SD PD NE

Early 155 63.9% 20.6% 5.2% 9.7% 0.6% Late 153 55.6% 25.5% 2.0% 15.0% 1.9%  (not significantly different; p= 0.14) 

Scale Domain F/U Early n Late n Ear NOT MEASURED 

Perry 1987 Ahles 1994 Perry 1998 

 N CR PR SD PD NE

Early 121 49% 30% 14% 2% 4% Late 141 58% 25% 9% 3% 5%  (not significantly different; p=0.13) 

Scale Domain F/U Early n Late n EarProfile of total score pre-Tx 16 12 20.Mood States post RTx 35.Handicap total score pre-Tx 14 10 4Rating Scale post RTx 6Trails B time to pre Tx 17 11 18Test complete post RTx 19

Jeremic 1997 wk 15: N CR PR SD PD NE

Early 52 96% 2% 2% Late 51 82% 2% 10% 6% (dead) (p=0.023) 

Scale Domain F/U Early n Late n Ear NOT MEASURED 

Qiao 2004 N CR PR SD PD NE

Early 45 67% 31% 2% Late 45 47% 44% 9% (p>0.05) 

Scale Domain F/U Early n Late n Ear NOT MEASURED 

Skarlos 2001 N CR PR SD PD NE

Early 42 40.5% 35.5% 14% 5% 5% Late 39 56.5% 36.0% 5% 2.5% 0  (ORR: 76% early, 92.5% late; p=0.07) 

Scale Domain F/U Early n Late n Ear NOT MEASURED 

James 2003 (abstract only) 

 N CR PR SD PD NE

Early 159 ORR=79% Late 166 ORR=78% 

Scale Domain F/U Early n Late n Ear NOT MEASURED 

ORR = overall response rate (CR + PR) 
C-20

Question 2. Early versus Late Radiotherapy Table 2G: Adverse Events 

Toxicity Type Study Severity or Grade Results 

Treatment-related mortality Murray 1993 

Coy 1994 Feld 1988 

not applicable 

F/U (yr) Early n % Late n % 2.7-5+ 155 1.3 153 1.3 

 Perry 1987 

Ahles 1994 Perry 1998 

not applicable 

F/U (yr) Early n % Late n % 1.44 125 4 145 1 

 Jeremic 

1997 not applicable 

F/U (yr) Early n % Late n %  NOT REPORTED 

 Qiao 2004 

not applicable 

F/U (yr) Early n % Late n % 

 Skarlos 

2001 not applicable 

F/U (yr) Early n % Late n % 2.9 (med) 42 0 39 0 

 James 2003 

(abstract only) 

not applicable 

F/U (yr) Early n % Late n %  NOT REPORTED 

Nausea Murray 1993 

Coy 1994 Feld 1988 

 F/U (yr) Early n % Late n % 

 Perry 1987 

Ahles 1994 Perry 1998 

 F/U (yr) Early n % Late n % 

 Jeremic 

1997 

 F/U (yr) Early n % Late n % 

 Qiao 2004 F/U (yr) Early n % Late n %  Skarlos 

2001 

 F/U (yr) Early n % Late n % 

 James 2003 

(abstract only) 

 F/U (yr) Early n % Late n % 
C-21

Question 2. Early versus Late Radiotherapy Table 2G: Adverse Events (continued) Toxicity Type Study Severity or Grade Results Vomiting Murray 1993 

Coy 1994 Feld 1988 

required IV fluids 

F/U (yr) Early n % Late n % 2.7 – 5+ 155 11.6 153 15.8  (p not significant) 

 Perry 1987 

Ahles 1994 Perry 1998 

nausea and vomiting, NOS 

F/U (yr) Early n % Late n % 1.44 122 18 140 10 

 Jeremic 

1997 acute nausea and vomiting 

grades 3 & 4 

F/U (yr) Early n % Late n % not reported 52 9.6 51 7.8 

 Qiao 2004 F/U (yr) Early n % Late n %  Skarlos 

2001 grade 3 nausea and vomiting 

F/U (yr) Early n % Late n % 2.9 (med) 42 2.5 39 2.5 

 James 2003 

(abstract only) 

nausea and vomiting 

grades 3 & 4 

F/U (yr) Early n % Late n % ??? 159 2 166 3 

Anorexia Murray 1993 

Coy 1994 Feld 1988 

 F/U (yr) Early n % Late n % 

 Perry 1987 

Ahles 1994 Perry 1998 

>10% weight loss 

F/U (yr) Early n % Late n % 1.44 ??? 14 not reported 

 Jeremic 

1997 

 F/U (yr) Early n % Late n % 

 Qiao 2004 weight loss 

(% not specified) 

F/U (yr) Early n % Late n % ??? 45 20 45 33.3 

 Skarlos 

2001 

 F/U (yr) Early n % Late n % 

 James 2003 

(abstract only) 

 F/U (yr) Early n % Late n % 
C-22

Question 2. Early versus Late Radiotherapy Table 2G: Adverse Events (continued) Toxicity Type Study Severity or Grade Results Lethargy Murray 1993 

Coy 1994 Feld 1988 

 F/U (yr) Early n % Late n % 

 Perry 1987 

Ahles 1994 Perry 1998 

 F/U (yr) Early n % Late n % 

 Jeremic 

1997 

 F/U (yr) Early n % Late n % 

 Qiao 2004 F/U (yr) Early n % Late n %  Skarlos 

2001 

 F/U (yr) Early n % Late n % 

 James 2003 

(abstract only) 

 F/U (yr) Early n % Late n % 

Neurosensory Murray 1993 

Coy 1994 Feld 1988 

severe 

life-threatening 

lethal 

F/U (yr) Early n % Late n %  155 0.6 153 3.3 2.7-5+ 0 1.3  0.6 0 

 Perry 1987 

Ahles 1994 Perry 1998 

“neuromuscular effects” 

F/U (yr) Early n % Late n % 1.44 124 17 144 16 

 Jeremic 

1997 

 F/U (yr) Early n % Late n % 

 Qiao 2004 F/U (yr) Early n % Late n %  Skarlos 

2001 grade 2 & 3 neurotoxicity 

F/U (yr) Early n % Late n % 2.9 (med) 42 0 39 0 

 James 2003 

(abstract only) 

 F/U (yr) Early n % Late n % 
C-23

Question 2. Early versus Late Radiotherapy Table 2G: Adverse Events (continued) Toxicity Type Study Severity or Grade Results Hearing loss Murray 1993 

Coy 1994 Feld 1988 

 F/U (yr) Early n % Late n % 

 Perry 1987 

Ahles 1994 Perry 1998 

 F/U (yr) Early n % Late n % 

 Jeremic 

1997 

 F/U (yr) Early n % Late n % 

 Qiao 2004 F/U (yr) Early n % Late n %  Skarlos 

2001 

 F/U (yr) Early n % Late n % 

 James 2003 

(abstract only) 

 F/U (yr) Early n % Late n % 

Esophagitis Murray 1993 

Coy 1994 Feld 1988 

fluids only 

IV fluids 

F/U (yr) Early n % Late n % 2.7-5+ 149 11.4 133 6.8  3.4 0.8 

 Perry 1987 

Ahles 1994 Perry 1998 

not specified 

F/U (yr) Early n % Late n % 1.44 ??? 10 ??? 8 

 Jeremic 

1997 acute, grades 3 & 4 

F/U (yr) Early n % Late n % not reported 52 28.9 51 25.5 

 Qiao 2004 

radio-esophagitis 

F/U (yr) Early n % Late n %  45 42.2 45 28.9 (p>0.05) 

 Skarlos 

2001 grade 2 

grade 3 

F/U (yr) Early n % Late n % 2.9 (med) 42 16.5% 39 2.5%  2.5% 18%  (p=0.82 for any grade, 0.03 for grade 3) 

 James 2003 

(abstract only) 

grades 3 & 4 

F/U (yr) Early n % Late n % ??? 159 7 166 4 
C-24

Question 2. Early versus Late Radiotherapy Table 2G: Adverse Events (continued) Toxicity Type Study Severity or Grade Results Bronchopulmonary Murray 1993 

Coy 1994 Feld 1988 

 F/U (yr) Early n % Late n % 

 Perry 1987 

Ahles 1994 Perry 1998 

not specified 

F/U (yr) Early n % Late n % 1.44 122 9 133 6 

 Jeremic 

1997 acute, grades 3 & 4 

F/U (yr) Early n % Late n % not reported 52 1.9 51 0 

 Qiao 2004 F/U (yr) Early n % Late n %  Skarlos 

2001 grade 3 

F/U (yr) Early n % Late n % 2.9 (med) 42 5.0% 39 7.5%  p = 0.69 

 James 2003 

(abstract only) 

 F/U (yr) Early n % Late n % 

Pneumonitis Murray 1993 

Coy 1994 Feld 1988 

any 

lethal 

F/U (yr) Early n % Late n % 2.7-5+ 149 3.2 133 0.7  0 0 

 Perry 1987 

Ahles 1994 Perry 1998 

not specified 

F/U (yr) Early n % Late n % 1.44 122 9 133 4.5 

 Jeremic 

1997 

 F/U (yr) Early n % Late n % 

 Qiao 2004 

radio-pneumonia 

F/U (yr) Early n % Late n %  45 8.9 45 6.7 

 Skarlos 

2001 

 F/U (yr) Early n % Late n % 

 James 2003 

(abstract only) 

 F/U (yr) Early n % Late n % 
C-25

Question 2. Early versus Late Radiotherapy Table 2G: Adverse Events (continued) Toxicity Type Study Severity or Grade Results Kidney Murray 1993 

Coy 1994 Feld 1988 

creatinine > 354 μmol/L 

F/U (yr) Early n % Late n % 2.7-5+ 155 0 153 0.7  (p not significant) 

 Perry 1987 

Ahles 1994 Perry 1998 

 F/U (yr) Early n % Late n % 

 Jeremic 

1997 

 F/U (yr) Early n % Late n % 

 Qiao 2004 F/U (yr) Early n % Late n %  Skarlos 

2001 grade 2 or 3 

F/U (yr) Early n % Late n % 2.9 (med) 42 0 39 0 

 James 2003 

(abstract only) 

 F/U (yr) Early n % Late n % 

Anemia Murray 1993 

Coy 1994 Feld 1988 

Hb <80 g/L 

F/U (yr) Early n % Late n % 2.7-5+ 155 49 153 36.8  (p = 0.03) 

 Perry 1987 

Ahles 1994 Perry 1998 

 F/U (yr) Early n % Late n % 

 Jeremic 

1997 acute, grades 3 & 4 

F/U (yr) Early n % Late n % not reported 52 13.5 51 7.8 

 Qiao 2004 F/U (yr) Early n % Late n %  Skarlos 

2001 grades 3 & 4 

F/U (yr) Early n % Late n % 2.9 (med) 42 19 39 12.8 

 James 2003 

(abstract only) 

grades 3 & 4 

F/U (yr) Early n % Late n % not reported 159 9 166 5 
C-26

Question 2. Early versus Late Radiotherapy Table 2G: Adverse Events (continued) Toxicity Type Study Severity or Grade Results Thrombocytopenia Murray 1993 

Coy 1994 Feld 1988 

<25 x 109/L F/U (yr) Early n % Late n % 2.7-5+ 155 3.9 153 2.6 

 (p not significant) 

 Perry 1987 

Ahles 1994 Perry 1998 

<25 x 109/L F/U (yr) Early n % Late n % 1.44 122 1 140 2 

 Jeremic 

1997 acute, grades 3 & 4 

F/U (yr) Early n % Late n % not reported 52 38.5 51 21.6 

 Qiao 2004 F/U (yr) Early n % Late n %  Skarlos 

2001 grades 3 & 4 

F/U (yr) Early n % Late n % 2.9 (med) 42 21.4% 39 23.1% 

 James 2003 

(abstract only) 

grades 3 & 4 

F/U (yr) Early n % Late n % not reported 159 9 166 9 

Leukopenia or neutropenia Murray 1993 

Coy 1994 Feld 1988 

neutrophils<0.5 x 109/L F/U (yr) Early n % Late n % 2.7-5+ 155 70.3 153 61.4 

 (p not significant) 

 Perry 1987 

Ahles 1994 Perry 1998 

WBC<1 x 109/L F/U (yr) Early n % Late n % 1.44 117 35 118 25 

 Jeremic 

1997 acute leukopenia, grades 3 & 4 

F/U (yr) Early n % Late n % not reported 52 32.7 51 41.2 

 Qiao 2004 leukocyte decline 

grade 2 grade 3 grade 4 

F/U (yr) Early n % Late n % NR 45 6.7 45 24.4  71.1 57.8  22.2 17.8 (grade 3 & 4, p<0.05) 

 Skarlos 

2001 grades 3 & 4 leukopenia 

F/U (yr) Early n % Late n % 2.9 (med) 42 35.7 39 20.5 

 James 2003 

(abstract only) 

grades 3-4 leucopenia 

F/U (yr) Early n % Late n % not reported 159 74 166 55  (p=0.006) 
C-27

Question 2. Early versus Late Radiotherapy Table 2G: Adverse Events (continued) Toxicity Type Study Severity or Grade Results Infection Murray 1993 

Coy 1994 Feld 1988 

neutropenic fever 

septic shock 

lethal 

F/U (yr) Early n % Late n %  155 4.5 153 3.3 2.7-5+ 0.6 0.7  0 1.3 

 Perry 1987 

Ahles 1994 Perry 1998 

sepsis 

fatal sepsis 

F/U (yr) Early n % Late n % 1.44 125 20 140 15  3 1 

 Jeremeic 

1997 acute grades 3 & 4 

F/U (yr) Early n % Late n % not reported 52 13.5 51 13.7 

 Qiao 2004 F/U (yr) Early n % Late n %  Skarlos 

2001 neutropenic fever 

F/U (yr) Early n % Late n % 2.9 (med) 42 5 39 2.5 

 James 2003 

(abstract only) 

 F/U (yr) Early n % Late n % 

Other Murray 1993 

Coy 1994 Feld 1988 

severe dermatitis 

blisters 

F/U (yr) Early n % Late n % 2.7-5+ 149 2.0 133 1.5  4.0 0.7 

 Perry 1987 

Ahles 1994 Perry 1998 

 F/U (yr) Early n % Late n % 

 Jeremic 

1997 

 F/U (yr) Early n % Late n % 

 Qiao 2004 

mild digestive tract reaction 

F/U (yr) Early n % Late n %  45 73.3 45 55.6 

 Skarlos 

2001 

 F/U (yr) Early n % Late n % 

 James 2003 

(abstract only) 

 F/U (yr) Early n % Late n % 
C-28 

Question 2. Early versus Late Radiotherapy Table 2H: Study Quality Ratings Study 

Initial Assembly of Comparable Groups 

Low Loss to Followup, Maintenance of Comparable Groups 

Measurements Reliable, Valid, Equal* 

Interventions Comparable/ Clearly Defined 

Appropriate Analysis of Results 

Overall Rating 

Murray 1993 Coy 1994 Feld 1988 

partial 

(arms balanced but 

randomization method 

not described) 

yes yes yes yes fair 

Perry 1987 Ahles 1994 Perry 1998 

partial 

(arms balanced but 

randomization method 

not described) 

yes yes yes yes fair 

Jeremic 1997 

partial 

(arms balanced but 

randomization method 

not described) 

yes yes yes yes fair 

Qiao 2004 

partial 

(arms balanced but 

randomization method 

not described) 

yes yes yes yes fair 

Skarlos 2001 

yes yes 

partial 

(overall response 

rate was primary 

outcome) 

yes yes fair 

James 2003 (abstract only) partial (arms balanced but 

randomization method 

not described) 

yes 

? 

(no mention of 

intent to treat or # 

included in 

analyses) 

yes yes 

not rated 

since 

abstract 

only 

* Those who rated response or progression were not described as blinded or masked to patients’ allocated treatment in any of these repo
C-29 

Question 3. Alternative Fractionation Schemes (once versus twice daily) Table 3A: Sample Selection Study Inclusion Exclusion n, Randomized n, Withdrawn Turrisi 1999 Yuen 2000 multicenter trial ECOG/Intergroup #0096 accrual 5/89-7/92 

confirmed SCLC confined to one hemithorax, the ipselateral supraclavicular fossa, or both; no previous cancer; adequate organ function (WBC≥4x103/ 

mm3; platelets≥1x105/ mm3; 

serum creatinine<130μmol/L; serum aspartate and alanine aminotransferase levels <2 x upper limit of normal range; serum bilirubin < 8.6 μmol/L; FEV1 ≥ 1.0 L) 

bilateral disease, pleural effusion, contralateral hilar or supraclavicular adenopathy; ECOG PS ≥3; symptomatic cardiac disease or MI within past 6 mos; prior chemotherapy or radiotherapy for any malignancy 

Total 1 F/d 2 F/d

417 206 211 

Total 1 F/d 2 F/d36 21 15 reasons: withdrew from Tx 7 no preTx tumor size 8 extensive disease 6 NSCLC 6 incomplete staging 5 ↑ serum AST 1 incorrect Dx 1 ECOG PS ≥3 1 

Schild 2004 Sloan 2002 Bonner 1999 NCCT 89-20-52 Multiple US institutions, accrual 9/90 through 11/96 

Confirmed limited disease SCLC, WBC > 3,500/μL, platelets > 100K/ μL, hemoglobin > 9.5 g/dL, serum creatinine < 2 F/dULN, normal total bilirubin, AST/ALT < 3xULN, FEV-1 > 1 L, ECOG PS < 2, met predefined 

restaging criteria after 3 cycles prerandomization EP CTx: thoracic disease still within RTx ports, ECOG PS < 2, 

WBC > 3,500/μL, platelets > 100K/ μL, serum creatinine < 2 F/dULN, FEV-1 > 1 L, other chemistry values < 3xULN, no distant mets other than brain 

MI < 3 months, uncontrolled CHF, uncontrolled arrhythmia, more than minimal pleural effusion, recent malignancy, prior therapy for this malignancy, weight loss > 10% < 3 mo, pregnant, lactating 

Total 1 F/d 2 F/d 262 132 130 

Total 1 F/d 2 F/d 1 1 0 (1 ineligible) 
C-30 

Question 3. Alternative Fractionation Schemes (once versus twice daily) Table 3B: Patient Characteristics Study Age (yr) Gender (%) Race (%) 

Performance Status 

(%) 

Comorbidities or PrognFactors (%) 

Turrisi 1999 Yuen 2000 

 1 F/d 2 F/dmn md 63 61 rng 34-80 30-82 sd >65 40% 31%  (p=0.07) 

 1 F/d 2 F/d

M 59 58 F 41 42 

 1 F/d 2 F/dB 7 8 W 90 89 O 3 3 

ECOG: 1 F/d 2 F/d0 43 39 1 51 55 2 5 5 

 1 F/d 2 

5-10% ↓ weight 15% 1>10% ↓ weight 5% ipsilateral lung 49% 5mediastinum 59% 6ips SC nodes 3% variant morphol 2% 

Schild 2004 Sloan 2002 Bonner 1999 

 1 F/d 2 F/dmn 61.8 62.1 md 63.0 62.5 rng 38-81 37-79 sd 

 1 F/d 2 F/d

M 58.0 56.9 F 42.0 43.1 

 1 F/d 2 F/dB W H A O 

ECOG 1 F/d 2 F/d0-1 97.7 93.1 2 5.3 6.9 

 1 F/d 2 

Measurable 38.9% 3Assessable 61.1% 6Wt ↓ < 5% 87.8% 8

Wt ↓ 5-10% 11.5% 1Wt ↓ > 10% 0.8% 0CTx, > SD 93.1% 9CTx, SD 5.3% 4CTx, LPD 0.8% 0CTx, BrM 0.8% 0
C-31 

Question 3. Alternative Fractionation Schemes (once versus twice daily) Table 3C: Treatments Study Chemotherapy regimen, per protocol One Daily Fraction of TRTx Two Daily Fractions of TTurrisi 1999 Yuen 2000 

Agent Dose Schedule

cisplatin 60 mg/m2 d1, 3-wk cycles x 4 

etoposide 120 mg/m2 d1-3, 3-wk cycles x 4 

Dose Schedule

45 Gy 1.8 Gy fracs, 5 d/wk for 5 wk; 

started in 1st wk of chemoTx; 

linac photons only 

Dose Schedule

45 Gy 1.5 Gy fracs, 2/

d/wk for 3 wk; sin 1st wk of chem

linac photons on

Schild 2004 Sloan 2002 Bonner 1999 

Agent Dose Schedule

Prerandomization cisplatin 30 mg/m2 d 1-3, wks 1, 5, 9 

etoposide 130 mg/m2 d 1-3, wks 1, 5, 9  (4-wk cycles) Postrandomization cisplatin 30 mg/m2 d 1-3, wks 13, 17, 21 etoposide 100 mg/m2 d 1-3, wks 13, 17, 21 

Dose Schedule

50.4 Gy 28 x 1.8 Gy frac, 38 d, 1st 39.6 

 Gy in AP-PA fields, last 10.8 Gy  in oblique fields excluding  spine, 4-10 MeV, wks 13-17 

Dose Schedule

48 Gy 32 x 1.5 Gy frac

 apart; split cours week 13: 16 frac 1.5 wks, 2.5 wk  more fracs over 
C-32 

Question 3. Alternative Fractionation Schemes (once versus twice daily) Table 3D: Outcome Assessment Study 

Primary Outcomes 

Secondary Outcomes Response Criteria Observer F/U 

Turrisi 1999 Yuen 2000 

survival at 2 years 82% power to detect absolute ∆ of 15% 

(25% 1/d; 40% 2/d) at 0.05 level (2 sided) 

median overall survival; time to treatment failure; local failure rates; response rates; adverse events 

CR= no clinical evidence of disease PR= ≥50%↓ in l x w product of any measurable 

tumor for at least 4 weeks 

SD= not reported PD= ≥10%↓ in body weight, ≥25%↑ in diameter 

of any tumor ≥2 cm diameter, ≥50%↑ in 

diameter of any tumor <2 cm diameter, or any new tumor 

not specifiedblinding not mentioned 

 To

mn md ~8 rng ~5sd 

Schild 2004 Sloan 2002 Bonner 1999 

Overall survival Local progression, 

distant progression, progression-free survival, toxicity 

CR= total disappearance of tumor PR= ↓ by >50% in greatest perpendicular 

diameters, all measureable lesions, >1 mo 

SD= ↓ by < 50%, measurable lesions, ↑ by < 25%, 

no new lesions 

PD= ↑ by >25%, any 1 lesion, new lesion, ↓ in PS 

by > 2 levels 

Not specified 

 To

mn md 7.4 rng 4.6sd 
C-33 

Question 3. Alternative Fractionation Schemes (once versus twice daily) Table 3E: Survival Outcomes Study Overall Survival (%) Progression-Free or Failure-Free Survival (PFTurrisi 1999 Yuen 2000 

 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr

1 F/d 206 19 ~75 41% ~32 ~29 16% 2 F/d 211 23 ~70 47% ~28 ~20 26%  (log-rank p=0.04; HR 1.2, 95% CI: 1.0, 1.6) 

FFS: N Med (mos) 1 yr 2 yr 3 yr 

1 F/d 206 24% 2 F/d 211 29%  (p=0.10) 

Schild 2004 Sloan 2002 Bonner 1999 

 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr 1 F/d 131 20.6 ~74% 44% ~33% ~23% 20.4% 2 F/d 130 20.6 ~74% 44% ~31% ~26% 22% (p=0.68, log-rank) 

 N Med (mos) 1 yr 2 yr 3 y1 F/d 131 ~14 ~57% 31.3% ~252 F/d 130 ~14 ~58% 30.8% ~27(p=0.68, log-rank) 
C-34 

Question 3. Alternative Fractionation Schemes (once versus twice daily) Table 3F: Tumor Response and Quality of Life 

Study Tumor Response (%) Quality of Life 

Turrisi 1999 Yuen 2000 

 N CR PR SD PD NE

1/d 185 49 38 4 8 2 2/d 196 56 31 4 6 4  (P=0.23; no significant difference) 

Scale Domain F/U 1/d n 2/d n 1/d 

 NOT MEASURED 

Bonner 1999 Sloan 2002 Schild 2004 

 N CR PR SD PD NE

1/d 132 55 2/d 130 69 

Scale Domain F/U 1/d n 2/d n 1/d 

 NOT MEASURED 
C-35 

Question 3. Alternative Fractionation Schemes (once versus twice daily) Table 3G: Adverse Events 

Toxicity Type Study Severity or Grade Results 

Treatment-related mortality Turrisi 1999 

Yuen 2000 not applicable 

F/U (yr) 1/d n % 2/d n %

med ~8 203 2 206 3 

 Bonner 1999 

Sloan 2002 Schild 2004 

not applicable 

F/U (yr) 1/d n % 2/d n %

med 7.4 131 0 130 3 

Nausea Turrisi 1999 

Yuen 2000 

F/U (yr) 1/d n % 2/d n %

 Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 

F/U (yr) 1 F/d n % 2 F/d n %  132 16.7 130 16.9 

Vomiting Turrisi 1999 

Yuen 2000 grade 3 

grade 4 

F/U (yr) 1/d n % 2/d n %

med ~8 203 8 206 8  2 1 

 Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 

F/U (yr) 1 F/d n % 2 F/d n %  132 12.1 130 14.6 

Anorexia Turrisi 1999 

Yuen 2000 grade 3 weight loss (grade 4=0, both arms) F/U (yr) 1/d n % 2/d n % med ~8 203 3 206 2 

 Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 

F/U (yr) 1 F/d n % 2 F/d n %  132 3.0 130 2.3 

Lethargy Turrisi 1999 

Yuen 2000 

F/U (yr) 1/d n % 2/d n %

 Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 

F/U (yr) 1 F/d n % 2 F/d n %  132 3.0 130 7.7 p=0.09 

Neurosensory Turrisi 1999 

Yuen 2000 

F/U (yr) 1/d n % 2/d n %

 Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 

F/U (yr) 1 F/d n % 2 F/d n %  132 7.6 130 11.5 
C-36 

Question 3. Alternative Fractionation Schemes (once versus twice daily) Table 3G: Adverse Events (continued) 

Toxicity Type Study Severity or Grade Results 

Hearing loss Turrisi 1999 

Yuen 2000 

F/U (yr) 1/d n % 2/d n %

 Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 

F/U (yr) 1 F/d n % 2 F/d n %  132 1.5 130 3.8 

Esophagitis Turrisi 1999 

Yuen 2000 grade 3 

grade 4 

F/U (yr) 1/d n % 2/d n %

med ~ 8 203 11 206 27  5 5  (p<0.001) 

 Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 

F/U (yr) 1 F/d n % 2 F/d n %  132 5.3 130 12.3 p=0.05 

Bronchopulmonary Turrisi 1999 

Yuen 2000 grade 3 

grades 4 & 5 

F/U (yr) 1/d n % 2/d n %

med 8 yr 203 3 206 4  1 2 

 Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 

F/U (yr) 1 F/d n % 2 F/d n %  132 4.5 130 6.2 

Pneumonitis Turrisi 1999 

Yuen 2000 

F/U (yr) 1/d n % 2/d n %

 Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 

F/U (yr) 1 F/d n % 2 F/d n %  132 4.5 130 6.2 

Kidney Turrisi 1999 

Yuen 2000 

F/U (yr) 1/d n % 2/d n %

 Bonner 1999 

Sloan 2002 Schild 2004 

F/U (yr) 1/d n % 2/d n %

Anemia Turrisi 1999 

Yuen 2000 grade 3 

grade 4 

F/U (yr) 1/d n % 2/d n %

med ~8 203 23 206 23  3 5 

 Bonner 1999 

Sloan 2002 Schild 2004 > grade 3 

F/U (yr) 1/d n % 2/d n %

 132 3.0 130 2.3 
C-37 

Question 3. Alternative Fractionation Schemes (once versus twice daily) Table 3G: Adverse Events (continued) 

Toxicity Type Study Severity or Grade Results 

Thrombocytopenia Turrisi 1999 

Yuen 2000 grade 3 

grade 4 

F/U (yr) 1/d n % 2/d n %

med ~8 203 16 206 13  8 8 

 Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 

grade 4 

F/U (yr) 1 F/d n % 2 F/d n %  128 60.9 127 45.7  24.2 20.5 

Leukopenia or neutropenia Turrisi 1999 

Yuen 2000 grade 3 leukopenia 

grade 4 leukopenia 

F/U (yr) 1/d n % 2/d n %

med ~8 203 41 206 38  39 44 

 Bonner 1999 

Sloan 2002 Schild 2004 

leukopenia 

> grade 3 

grade 4 

F/U (yr) 1 F/d n % 2 F/d n %  128 88.3 127 89.8  37.5 36.2 

Hemoglobin Turrisi 1999 

Yuen 2000 

F/U (yr) 1/d n % 2/d n %

 Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 

grade 4 

F/U (yr) 1 F/d n % 2 F/d n %  128 5.3 127 3.8  0.0 0.0 

Infection Turrisi 1999 

Yuen 2000 grade 3 

grades 4 & 5 

F/U (yr) 1/d n % 2/d n %

med ~8 203 6 206 6  2 3 

 Bonner 1999 

Sloan 2002 Schild 2004 

> grade 3 

F/U (yr) 1 F/d n % 2 F/d n %  132 2.3 130 3.8 
C-38 

Question 3. Alternative Fractionation Schemes (once versus twice daily) Table 3G: Adverse Events 

Toxicity Type Study Severity or Grade Results 

Other Turrisi 1999 

Yuen 2000 one or more grade 3, no grade 4

one or more grade 4, no grade 5

F/U (yr) 1/d n % 2/d n %

med ~8 203 23 206 25  63 62 

Any hematologic 

> grade 3 > grade 4 

F/U (yr) 1 F/d n % 2 F/d n %  131 90.1 130 89.2 p=0.82  43.5 42.3 p=0.84 

Any nonhematologic 

> grade 3 

> grade 4 

grade 5 

F/U (yr) 1 F/d n % 2 F/d n %  131 38.9 130 54.6 p=0.01  9.2 13.8 p=0.24  0.0 3.1 p=0.04 

Bonner 1999 Sloan 2002 Schild 2004 

Any toxicity 

> grade 3 

> grade 4 

grade 5 

F/U (yr) 1 F/d n % 2 F/d n %  131 91.6 130 92.3 p=0.83  46.6 46.9 p=0.95  0.0 3.1 p=0.04 
C-39

Question 3. Alternative Fractionation Schemes Table 3H: Study Quality Ratings Study 

Initial Assembly of Comparable Groups 

Low Loss to Followup, Maintenance of Comparable Groups 

Measurements Reliable, Valid, Equal* 

Interventions Comparable/ Clearly Defined 

Appropriate Analysis of Results 

Overall Rating 

Turrisi 1999 Yuen 2000 Yes Yes Yes Yes Yes Good Bonner 1999 Sloan 2002 Schild 2004 

Yes Yes Yes Yes Yes Good 

* Those who rated response or progression were not described as blinded or masked to patients’ allocated treatment in any of these repo
C-40

Question 4. Chemotherapy with versus without Thoracic Radiation Therapy, Extensive-Stage Disease (ESD) Table 4A: Sample Selection Study Inclusion Exclusion n, Randomized 

n, Withdrawn or Excluded 

nP

Jeremic 1999 single center: Kragujevac Univ. Hospital, Yugoslavia accrual Jan. 1988 through June 1993 

confirmed SCLC; extensive stage (disease outside one hemithorax, mediastinum and supraclav. nodes; tumor of >size than tolerable RTx field; or w cytology+ pleural effusion); no prior chemoTx or radioTx; KPS ≥70; adequate renal, hepatic, hematologic function; CR outside thorax and CR or PR in thorax after 3 cycles of PE chemoTx 

age>70y; limited stage disease (unilateral disease, w/wo mediastinal involvement, + ipsilateral supraclavicular nodes or cytologyneg pleural effusion); recent or concurrent severe uncontrolled cardiovascular or pulmonary disease; CNS mets or substantially impaired mental status; prior cancer except non-melanoma skin 

Total +TRTx -TRTx 109 55 54 unrandomized groups by post-3rd cycle response (thorax/ elsewhere): CR/PR: 34 PR/PR: 28 SD or PD: 35 

Total +TRTx -TRTx 0 0 0  0  0  0 

T1ubreCPS

Nou 1988 Univ. Hospital, Uppsala accrual 01/80 through 12/83 

confirmed SCLC; any age, PS, or expected survival; LSD if one hemithorax ± ipselateral supraclavicular nodes; all others, ESD 

surgically resected for uncertain tumor type subsequently found to be SCLC; 

Total +TRTx -TRTx 54 28 26 (also randomized n=56 with LSD) 

Total +TRTx -TRTx 0 0 0 

T5

Lebeau 1993 27 centers in France accrual 10/85 through 04/88 

confirmed SCLC; any age, gender, performance status, or disease extent; CR after 5 wks ±heparin then 8 cycles of sequential or alternating chemoTx regimens; some outcomes reported separately by treatment arm for ESD 

renal failure; previous chemotherapy or radiation therapy; curative thoracic surgery; “patients who could not be followed up closely” 

Total +TRTx -TRTx 18 10 8 (also randomized 35 pts w LSD; n=422 for two previous randomizations) 

Total +TRTx -TRTx 0 0 0 

T1

Rosenthal 1991 3 centers in Australia accrual 01/77 through 07/79 

confirmed SCLC; evaluable or measurable disease (LSD or ESD); previously untreated; serum creatinine and liver function tests ≤1.5 X ULNR; response (CR or PR) after 3 cycles of chemotherapy 

prior chemo- or radiation therapy; cerebral metastasis; advanced age (not defined) and senility; severe co-existent disease (not defined); non-response after 3 cycles of chemotherapy 

Total +TRTx -TRTx 27 ? ? treated n=139 (91, LSD; 48, ESD); randomized responders (66, LSD; 27, ESD) to ±TRTx 

Total +TRTx -TRTx 0 ? ? 

T2

Brincker 1987 Odense Univ. Hospital, Denmark accrual 03/81 through 01/84 

confirmed SCLC; <70 years of age; WHO PS 0-2; no clinical signs of CNS metastasis; with or without prior thoracotomy or radical resection ESD defined as metastasis to soft tissue, vicera, or bone or malignant pleural effusion 

age ≥ 70 years; WHO PS >2; clinical signs of CNS metastasis 

Total +TRTx -TRTx 43 25 18 

Total +TRTx -TRTx 13 9 4 (patients dead before day 100 not evaluable; didn’t receive full RTx therapy) 

T3
C-41 

Question 4. Chemotherapy with versus without Thoracic Radiation Therapy, Extensive-Stage Disease Table 4B: Patient Characteristics Study Age (yr) Gender (%) Race 

Performance Status 

(%) 

Comorbidities or Pro

Factors (%) 

Jeremic 1999 +TRTx -TRTx

mn md 59 59 rng 38-70 39-71 sd  md rngCR/PR: 58 41-70 PR/PR: 60 44-69 SD or PD: 59 41-69 

 +TRTx -TRTx

M 60 59 F 40 41  M F

CR/PR: 62 38 PR/PR: 61 39 SD or 60 40 PD 

 +TRTx -TRTx

B W not H reported A O 

KPS +TRTx -TRTx

100 31 24 

90 36 43 80 18 18 70 15 15  70/80 90/100

CR/PR 35 65 PR/PR 32 68 

SD or PD 31 69 

 +TRTx 

weight loss 45.5 ≥5% # metastatic sites: 1 41.8 2 49.1 ≥3 9.1 

Nou 1988 +TRTx -TRTx

mn md 65 60 rng 55-78 41-81 sd 

 +TRTx -TRTx

M 75 69 F 25 31 

 +TRTx -TRTx

B W not H reported A O 

KPS +TRTx -TRTx

med 60 60 range 30-90 30-90 

 +TRTx cerebral mets 7 2 metastatic 36 sites ≥3 metastatic 14 sites 

Lebeau 1993 (only reported characteristics of combined LSD & ESD patients) 

 +TRTx -TRTx% <50 22 23 50-9 30 38.5 60-9 33 23 70-81 15 15.5 

 +TRTx -TRTx

M 96 92 F 4 8 

 +TRTx -TRTx

B W not H reported A O 

KPS +TRTx -TRTx

90-100 63 46 70-80 22 50 60 15 4 

 +TRTx + heparin 45 - heparin 30 not randomized 25 seq. chemoTx 67 alt. chemoTx 33 

Rosenthal 1991 (only reported characteristics of all enrolled patients, LSD + ESD, w/wo TRTx) 

 +TRTx -TRTxmn md 60 rng 26-77 sd 

 +TRTx -TRTx

M 76 F 24 

 +TRTx -TRTx

B W not H reported A O 

ECOG +TRTx -TRTx

0 1 1 88 2 3 unknown 8 

 +TRTx 

Brincker 1987 (only reported characteristics of evaluable combined LSD & ESD patients) 

 +TRTx -TRTxmn md 60 63 rng 42-69 46-69 sd 

 +TRTx -TRTx

M 73 73 F 27 27 

 +TRTx -TRTx

B W not H reported A O 

WHO +TRTx -TRTx

0 34 24 1 51 57 2 15 19 

 +TRTx 
C-42 

Question 4. Chemotherapy with versus without Thoracic Radiation Therapy, Extensive-Stage Disease Table 4C: Treatments Study Chemotherapy regimen, per protocol with Thoracic Radiotherapy PJeremic 1999 Agent Dose Schedule

cisplatin 80 mg/m2 day 1, wks 1, 4, 7, 16 & 19 (+TRTx); 

also wks 10 & 13, -TRTx and nonrandomized CR/PR and PR/PR groups 

etoposide 80 mg/m2 days 1-3, wks 1, 4, 7, 16 & 19 

(+TRTx); also wks 10 & 13, -TRTx and non-randomized groups 

carboplatin 50 mg each day of TRTx, between fracs etoposide 50 mg each day of TRTX, between fracs 

Dose Schedule

54 Gy 24 fracs, 1.5 Gy ea, twice daily over 2.5 wks, 

then 12 fracs, 1.5Gy ea, twice daily on 6 days; wks 10-13; 4.5 to 6 hr between fracs; 6-10 MV linac photons 

non-randomized CR/PR and PR/PR groups received same concurrent TRTx and carboplatin/etoposide chemotherapy, wks 16-19 

25 215noPreby 

Nou 1988 Agent Dose Schedule (all cycles, 3 weeks) 

Cytoxan 250 mg/m2 days 1, 2 and 3, A cycles 

vincristine 2 mg day 1, A cycles and B cycles doxorubicin 50 mg/m2 day 1, A cycles methotrexate 100 mg/m2 day 1, A and B cycles (leucovorin 

on day 2) 

lomustine 40 mg/m2 day 1, every other B cycle Cytoxan 750 mg/m2 day 1, all B cycles 

Dose Schedule

40 Gy 1 frac/day, 2 Gy each, 5 days/wk, over 4 

weeks; beginning after 3 cycles of regimen A; -TRTx arm give 4th cycle of A regimen at 

same time; then both arms give 4 cycles each, B regimen, then A, then B, then A, then B; 8- or 16 mV linac photons 

no

Lebeau 1993 Agent Dose Schedule

CCNU 80 mg day 1, X8 4-wk cycles (sequential) 

cycles 1, 3, 5, 7 (alternating) 

Cytoxan 1 gm/m2 day 1, X8 4-wk cycles (sequential) 

cycles 1, 3, 5, 7 (alternating) 

doxorubicin 45 mg/m2 day 1, X8 4-wk cycles (sequential) 

cycles 1, 3, 5, 7 (alternating) 

etoposide 225 mg/m2 day 1, X8 4-wk cycles (sequential) 

cycles 2, 4, 6, 8 (alternating) 

cisplatin 80 mg/m2 day 1 q4 wk, altern. cycles 2, 4, 6, 8 

vindesine 3 mg/m2 day 1 q4 wk, altern. cycles 2, 4, 6, 8 

Dose Schedule

varied started 4 wks after final chemotherapy cycle; 

dosage ranged from 32 Gy in 9 fracs over 11 or 18 days to 65 Gy in 33 fracs over 64 days; mean 46.5 Gy-equivalents (corresponds to 5 fracs/wk, 2 Gy each) per patient; range 41-65 Gy-equivalents; all used megavoltage X-rays, ≥4 MeV 

“...ceotst+TTLSinsc

Rosenthal 1991 Agent Dose Schedule

vincristine 1 mg/m2 day 1, q3wk, for 10 cycles 

Cytoxan 750 mg/m2 day 1, q3wk, for 10 cycles 

doxorubicin 50 mg/m2 day 1, q3wk, for 10 cycles methotrexate 12 mg intrathecal, with each chemo cycle or 1 g/m2 IV, with folinic acid, cycles 1-3 

 only (initial randomization) 

Dose Schedule

40 Gy 20 fracs, given between chemotherapy 

cycles 3 and 4 in +TRTx arm; other details not provided 

no

Brincker 1987 Agent Dose Schedule

vincristine 2 mg day 1, odd cycles, 4 wk each doxorubicin 50 mg/m2 day 1, odd cycles, 4 wk each 

Cytoxan 600 mg/m2 day 1, odd cycles, 4 wk each lomustine 60 mg/m2 day 1, even cycles, 4 wk each methotrexate 20 mg/m2 days 1&3, even cycles, 4 wk eachetoposide 100 mg/m2 days 1-4, even cycles, 4 wk each 

Dose Schedule

12 Gy 600 cGy hemi-body irradiation as single 

fraction, to upper body on day 60 in place of chemoTx cycle 3, and to lower body on day 100 in place of cycle 4; 8 MeV linac photons

(alternating chemoTx cycles continued to death or progression for up to 18 months in both arms) 

no
C-43 

Question 4. Chemotherapy with versus without Thoracic Radiation Therapy, Extensive-Stage Disease Table 4D: Outcome Assessment Study 

Primary Outcomes 

Secondary Outcomes Response Criteria Observer F/U 

Jeremic 1999 CR rate 

80% power to detect ↑ in CR rate from 25% to 50% at 1-sided 0.05 level 

overall, local recurrence-free, distant metastasis-free, and relapse-free survival; objective response rates; adverse events

CR= disappearance of all measurable/assessable 

disease & no new lesions, ≥4 wk 

PR= ↓ by >50%, Σall lesions[products of crosssectional diameters], no new lesions, ≥4 wk SD= ↓ by <50% or ↑ by <25% in above sum PD= ↑ by ≥25% in above sum 

 unspecified(blinding not mentioned) 

 To

mn md burng pasd tim

Nou 1988 survival duration response rates and 

durations; first sites of recurrence or progression; adverse events; autopsy findings 

CR= complete disappearance of all recognizable 

lesions 

PR= ↓ by >50% in longest X perpendicular 

diameter, Σ over all measurable lesions 

anything less than PR defined as “no response” 

 unspecified(blinding not mentioned) 

 To

mn md “mrng of sd (a

Lebeau 1993 survival from TRTx 

randomization (the only outcome reported by treatment arm separately for ESD patients) 

time and site of first recurrence; duration of disease-free and treatment-free survival; adverse events 

CR= disappearance of all measurable and 

evaluable lesions 

PR= ↓ by >50% in longest and perpendicular 

diameter for all measurable lesions 

anything less than PR defined as “no response” 

 unspecified(blinding not mentioned) 

 To

mn md “...rng leasd 

Rosenthal 1991 median survival 

(the only outcome reported by treatment arm separately for ESD patients) 

response rates; relapse rates; sites of failure; “non-tumor related” deaths (all pooled for LSD + ESD patients) 

CR= not provided PR= not provided SD= not provided PD= not provided 

 unspecified(blinding not mentioned) 

 To

mn md “terng sd 

Brincker 1987 not specified response rates; 

overall survival; time to progression 

CR= total disappearance for ≥90 days of all 

disease manifestations 

PR= ↓ by >50% for ≥90 dys in product of longest 

perpendicular diameters of indicator lesion 

NC= response for <90 days or ↓ by <50% PD= ≥25% ↑ in size, measured as for PR (resected patients: CR if no new lesions by day 90)

“all case reviewed independently by two observers” (blinding not mentioned) 

 To

“Follow-uonly 3 patime of aand 47.7 randomiz
C-44 

Question 4. Chemotherapy with versus without Thoracic Radiation Therapy, Extensive-Stage Disease Table 4E: Survival Outcomes Study Overall Survival Relapse-Free Survival (RFS) or Time to ProgresJeremic 1999 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr

+TRTx 55 17 65 38 22 13 9.1 -TRTx 54 11 46 28 13 5.6 3.7  (p=0.041 by log-rank test) unrandomized groups by post-3rd cycle response (thorax/ elsewhere): 

CR/PR 34 8 35 8.8 2.9 0 0 PR/PR 28 6 21 3.6 0 0 0 SD or PD 35 3 0 0 0 0 0 

RFS N Med (mos) 1 yr 2 yr 3 y

+TRTx 55 13 56 35 20 -TRTx 54 9 41 22 9. (p=0.045 by log-rank test) unrandomized groups by post-3rd cycle response (

CR/PR 34 6 26 5.9 0 PR/PR 28 5 18 0 0 SD or PD 35 NR 0 0 0 

Nou 1988 N Med (mos) 1 yr 2 yr 3 yr 4 yr

+TRTx 28 9.2 (range, 3.8-19.3) ~32 0 0 0 -TRTx 26 7.6 (range, 2.2-22.7) ~26 0 0 0  (chi-square 0.045, 0.8<p<0.9, by life-table analysis) 

 N Med (mos) 1 yr 2 yr 3 y

+TRTx -TRTx not reported for ESD patients 

Lebeau 1993 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr

+TRTx 10 ~6.3 ~10 ~10 0 0 0 -TRTx 8 ~7.0 ~25 ~12 ~12 0 0  (p = 0.43 by log-rank test) 

 N Med (mos) 1 yr 2 yr 3 y

+TRTx -TRTx not reported separately for ESD 

Rosenthal 1991 

 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr

+TRTx ? 5 (95% CI: 2-8) -TRTx ? 7 (95% CI: 3-10)  (p=0.796) 

 N Med (mos) 1 yr 2 yr 3 y

+TRTx -TRTx not reported separately for ESD 

Brincker 1987 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr

+TRTx 16 7 ~25 0 0 0 0 -TRTx 14 10 ~30 0 0 0 0  (p = 0.44) 

TTP N Med (mos) 1 yr 2 yr 3 y

+TRTx 16 7 ~23 0 0 -TRTx 14 8.5 ~26 0 0  (p = 0.45) 
C-45 

Question 4. Chemotherapy with versus without Thoracic Radiation Therapy, Extensive-Stage Disease Table 4F: Tumor Response and Quality of Life 

Study Tumor Response (%) Quality of Life 

Jeremic 1999 N CR PR SD PD NE

+TRTx 55 96 (mean duration: 22 ± 26 mos) -TRTx 53 66 (mean duration: 14 ± 16 mos) (local CR rates at wk 21, p = 0.00005; duration, p = 0.055) 

Scale Domain F/U +TRT n -TRT n +TR NOT MEASURED 

Nou 1988 N CR med duration PR med duration NR

+TRTx 28 11 12.4 mo 75 1.4 mo 14 -TRTx 26 8 12.5 mo 62 1.3 mo 31 

Scale Domain F/U +TRT n -TRT n +TR

 NOT MEASURED 

Lebeau 1993 N CR PR SD PD NE

+TRTx 10 100 (only randomized patients in CR -TRTx 8 100 after 8 cycles of chemotherapy) 

Scale Domain F/U +TRT n -TRT n +TR NOT MEASURED 

Rosenthal 1991 

 N CR PR SD PD NE

+TRTx -TRTx not reported separately for ESD patients 

Scale Domain F/U +TRT n -TRT n +TR NOT MEASURED 

Brincker 1987 N CR PR NC PD NE

+TRTx 16 12 44 25 19 0 -TRTx 14 7 50 29 14 0 

Scale Domain F/U +TRT n -TRT n +TR NOT MEASURED 
C-46 

Question 4. Chemotherapy with versus without Thoracic Radiation Therapy, Extensive-Stage Disease Table 4G: Adverse Events 

Toxicity Type Study Severity or Grade Results 

Treatment-related mortality Jeremic 

1999 not applicable 

F/U (yr) +TRTx n % -TRTx n %  not reported 

 Nou 1988 

not applicable 

F/U (yr) +TRTx n % -TRTx n % all until 28 4 26 4 death (p NS) 

 Lebeau 

1993 not applicable 

F/U (yr) +TRTx n % -TRTx n % 

 Rosenthal 

1991 not applicable 

F/U (yr) +TRTx n % -TRTx n % 

 Brincker 

1987 not applicable 

F/U (yr) +TRTx n % -TRTx n % 

Nausea Jeremic 

1999 

 F/U (yr) +TRTx n % -TRTx n % 

 Nou 1988 F/U (yr) +TRTx n % -TRTx n %  Lebeau 

1993 

 F/U (yr) +TRTx n % -TRTx n % 

 Rosenthal 

1991 

 F/U (yr) +TRTx n % -TRTx n % 

 Brincker 

1987 

“no significant differences 

between the two treatment 

groups” 

F/U (yr) +TRTx n % -TRTx n % 

Vomiting Jeremic 

1999 acute grades 3/4 nausea and 

vomiting 

F/U (yr) +TRTx n % -TRTx n % not 55 9 54 34 reported (p = 0.0038) 

 Nou 1988 F/U (yr) +TRTx n % -TRTx n %  Lebeau 

1993 

 F/U (yr) +TRTx n % -TRTx n % 

 Rosenthal 

1991 

 F/U (yr) +TRTx n % -TRTx n % 

 Brincker 

1987 

 F/U (yr) +TRTx n % -TRTx n % 
C-47 

Question 4. Chemotherapy with versus without Thoracic Radiation Therapy, Extensive-Stage Disease Table 4G: Adverse Events (continued) Toxicity Type Study Severity or Grade Results Anorexia Jeremic 

1999 

 F/U (yr) +TRTx n % -TRTx n % 

 Nou 1988 F/U (yr) +TRTx n % -TRTx n %  Lebeau 

1993 

 F/U (yr) +TRTx n % -TRTx n % 

 Rosenthal 

1991 

 F/U (yr) +TRTx n % -TRTx n % 

 Brincker 

1987 

 F/U (yr) +TRTx n % -TRTx n % 

Lethargy Jeremic 

1999 

 F/U (yr) +TRTx n % -TRTx n % 

 Nou 1988 F/U (yr) +TRTx n % -TRTx n %  Lebeau 

1993 

 F/U (yr) +TRTx n % -TRTx n % 

 Rosenthal 

1991 

 F/U (yr) +TRTx n % -TRTx n % 

 Brincker 

1987 

 F/U (yr) +TRTx n % -TRTx n % 

Neurosensory Jeremic 

1999 

 F/U (yr) +TRTx n % -TRTx n % 

 Nou 1988 F/U (yr) +TRTx n % -TRTx n %  Lebeau 

1993 

 F/U (yr) +TRTx n % -TRTx n % 

 Rosenthal 

1991 

 F/U (yr) +TRTx n % -TRTx n % 

 Brincker 

1987 

“no significant differences 

between the two treatment 

groups” 

F/U (yr) +TRTx n % -TRTx n % 
C-48 

Question 4. Chemotherapy with versus without Thoracic Radiation Therapy, Extensive-Stage Disease Table 4G: Adverse Events (continued) Toxicity Type Study Severity or Grade Results Hearing loss Jeremic 

1999 

 F/U (yr) +TRTx n % -TRTx n % 

 Nou 1988 F/U (yr) +TRTx n % -TRTx n %  Lebeau 

1993 

 F/U (yr) +TRTx n % -TRTx n % 

 Rosenthal 

1991 

 F/U (yr) +TRTx n % -TRTx n % 

 Brincker 

1987 

 F/U (yr) +TRTx n % -TRTx n % 

Esophagitis Jeremic 

1999 acute grades 3/4 esophageal 

F/U (yr) +TRTx n % -TRTx n % not 55 27 54 0 reported (p=0.0002) 

 Nou 1988 F/U (yr) +TRTx n % -TRTx n %  Lebeau 

1993 

10 cases of dysphagia reported (LSD+ESD patients), but not attributed to esophagitis 

F/U (yr) +TRTx n % -TRTx n % 

 Rosenthal 

1991 

 F/U (yr) +TRTx n % -TRTx n % 

 Brincker 

1987 

no significant difference between groups in stomatitis, not attributed to esophagitis 

F/U (yr) +TRTx n % -TRTx n % 

Bronchopulmonary Jeremic 

1999 acute grade 3 

(no grade 4, either arm) 

F/U (yr) +TRTx n % -TRTx n % not 55 5 54 0 reported (p=0.082) 

 Nou 1988 F/U (yr) +TRTx n % -TRTx n %  Lebeau 

1993 

 F/U (yr) +TRTx n % -TRTx n % 

 Rosenthal 

1991 

 F/U (yr) +TRTx n % -TRTx n % 

 Brincker 

1987 

 F/U (yr) +TRTx n % -TRTx n % 
C-49 

Question 4. Chemotherapy with versus without Thoracic Radiation Therapy, Extensive-Stage Disease Table 4G: Adverse Events (continued) Toxicity Type Study Severity or Grade Results Pneumonitis Jeremic 

1999 

 F/U (yr) +TRTx n % -TRTx n % 

 Nou 1988 F/U (yr) +TRTx n % -TRTx n %  Lebeau 

1993 

3 cases radiation pneumonitis reported (one symptomatic), but not separated by SD versus ESD 

F/U (yr) +TRTx n % -TRTx n % 

 Rosenthal 

1991 

 F/U (yr) +TRTx n % -TRTx n % 

 Brincker 

1987 no cases observed 

F/U (yr) +TRTx n % -TRTx n % 

Kidney Jeremic 

1999 acute grades 3 or 4 

F/U (yr) +TRTx n % -TRTx n % not 55 0 54 22 reported (p = 0.001) 

 Nou 1988 F/U (yr) +TRTx n % -TRTx n %  Lebeau 

1993 

 F/U (yr) +TRTx n % -TRTx n % 

 Rosenthal 

1991 

 F/U (yr) +TRTx n % -TRTx n % 

 Brincker 

1987 

 F/U (yr) +TRTx n % -TRTx n % 

Anemia Jeremic 

1999 acute grades 3 or 4 

F/U (yr) +TRTx n % -TRTx n % not 55 11 54 20 reported (p = 0.39) 

 Nou 1988 

hemoglobin nadir (median, range)

F/U (yr) +TRTx n med (rng) -TRTx n med (rng)

until 28 84 g/L 26 84 g/L death (62-120) (51-117) 

 Lebeau 

1993 

 F/U (yr) +TRTx n % -TRTx n % 

 Rosenthal 

1991 

 F/U (yr) +TRTx n % -TRTx n % 

 Brincker 

1987 hemoglobin <6 mmol/l 

F/U (yr) +TRTx n % -TRTx n % until 41 ~50 37 ~27 death (LSD+ESD) (LSD+ESD) 
C-50 

Question 4. Chemotherapy with versus without Thoracic Radiation Therapy, Extensive-Stage Disease Table 4G: Adverse Events (continued) Toxicity Type Study Severity or Grade Results Thrombocytopenia Jeremic 

1999 acute grades 3/4 

F/U (yr) +TRTx n % -TRTx n % not 55 27 54 42 reported (p = 0.23) 

 Nou 1988 thrombocyte count nadir (109/L) 

(median, range) 

F/U (yr) +TRTx n med (rng) -TRTx n med (rng)

until 28 25 26 27 death (<10-140) (<10-219)

 Lebeau 

1993 

 F/U (yr) +TRTx n % -TRTx n % 

 Rosenthal 

1991 

 F/U (yr) +TRTx n % -TRTx n % 

 Brincker 

1987 platelets <75x103/μl 

F/U (yr) +TRTx n % -TRTx n % until 41 ~63 37 ~10 death (LSD+ESD) (LSD+ESD) 

Leukopenia or neutropenia Jeremic 

1999 acute grade 3/4 leukopenia 

F/U (yr) +TRTx n % -TRTx n % not 55 44 54 61 reported (p = 0.18) 

 Nou 1988 leukocyte count nadir (109/L) 

(median, range) 

F/U (yr) +TRTx n med (rng) -TRTx n med (rng)

until 28 0.5 26 0.5 death (<0.1-2.7) (<0.1-3.3) 

 Lebeau 

1993 

 F/U (yr) +TRTx n % -TRTx n % 

 Rosenthal 

1991 

F/U (yr) +TRTx n % -TRTx n % 

 Brincker 

1987 leukocytes < 2.5x103/μl 

F/U (yr) +TRTx n % -TRTx n % until 41 ~37 37 ~18 death (LSD+ESD) (LSD+ESD) 
C-51 

Question 4. Chemotherapy with versus without Thoracic Radiation Therapy, Extensive-Stage Disease Table 4G: Adverse Events (continued) Toxicity Type Study Severity or Grade Results Infection Jeremic 

1999 acute grades 3-5 

F/U (yr) +TRTx n % -TRTx n % not 55 23 54 33 reported (p=0.64) 

 Nou 1988 septicemia number 

(median, range) 

F/U (yr) +TRTx n med (rng) -TRTx n med (rng)

until 28 2 26 1 death (0-4) (0-4) 

 Lebeau 

1993 

 F/U (yr) +TRTx n % -TRTx n % 

 Rosenthal 

1991 

 F/U (yr) +TRTx n % -TRTx n % 

 Brincker 

1987 febrile episodes: no significant differences between arms F/U (yr) +TRTx n % -TRTx n % 

Other Jeremic 

1999 combined late grades 3/4 

toxicities 

F/U (yr) +TRTx n % -TRTx n % not 55 5 54 0 reported (p = 0.082) 

 Nou 1988 

“other serious side effects” 

F/U (yr) +TRTx n % -TRTx n % until 28 29 26 8 death (p NS) 

 Lebeau 

1993 

 F/U (yr) +TRTx n % -TRTx n % 

 Rosenthal 

1991 

 F/U (yr) +TRTx n % -TRTx n % 

 Brincker 

1987 

tolerated 75-100% of chemoTx doses in cycles after hemibody radiation completed 

F/U (yr) +TRTx n % -TRTx n % until prog. 28 25 32 91 or death (LSD+ESD) (LSD+ESD) 
C-52 

Question 4. Chemotherapy with versus without Thoracic Radiation Therapy, Extensive-Stage Disease Table 4H: Study Quality Ratings Study 

Initial Assembly of Comparable Groups 

Low Loss to Followup, Maintenance of Comparable Groups 

Measurements Reliable, Valid, Equal* 

Interventions Comparable/ Clearly Defined 

Appropriate Analysis of Results 

Overall Rating 

Jeremic 1999 partial 

(arms balanced but 

randomization method 

not described) 

yes yes yes yes fair 

Nou 1988 partial 

(arms balanced but 

randomization method 

not described) 

yes yes yes yes fair 

Lebeau 1993 partial 

(arms balanced for 

LSD+ESD patients, 

but data unavailable 

to compare ESD only 

groups) 

yes yes 

partial 

(varied TRTx 

regimens; lack of 

details on PCI 

regimen and 

patient selection 

partial 

(only reported 

overall survival 

separately for 

ESD patients)

poor 

(to address 

Q4) 

Rosenthal 1991 uncertain 

(baseline data not 

reported separately 

for treatment groups) 

uncertain 

(conflicting 

information on 

randomization to 

±TRTx) 

yes yes 

partial 

(only reported 

overall survival 

separately for 

ESD patients)

poor 

(to address 

Q4) 

Brincker 1987 

yes 

no 

(excluded 13/43, 

died before day 

100) 

yes yes 

partial 

(toxicities not 

reported 

separately for 

ESD group) 

poor 

* Those who rated response or progression were not described as blinded or masked to patients’ allocated treatment in any of these repo
C-53

Question 6: Positron Emission Tomography for Staging of Small-Cell Lung Cancer Table 6A: Sample Selection Study Design Inclusion Exclusion n, Enrolled 

n, WiExclu

Blum 2004 partially 

prospective, partially retrospective 

histologically/cytologically proven SCLC underwent PET imaging at this institution; consecutive patients; newly diagnosed in 15 who also underwent routine initial staging, restaging in 21; in all cases, PET scan 

based on review of all clinical data and was performed to guide clinical management; clinical information for 19 obtained from prospective PET SCLC database; clinical information for remaining patients was derived retrospectively 

 36 

Bradley 2004 prospective newly diagnosed confirmed limited stage SCLC, 

completed standard staging procedures, bilateral hilar involvement defined as limited stage, ipsilateral supraclavicular adenopathy eligible 

evidence of disease beyond one hemithorax and mediastinum; diabetes-related fasting hyperglycemia 

25 1 

(refusPET) 

Brink 2004 prospective consecutive patients with histologically confirmed 

SCLC examined with FDG-PET during primary staging 

 120 6 (8 s

(discrcould clarifipatieatten

Kamel 2003 prospective consecutive patients with SCLC referred at this 

institution for whole-body FDG-PET 2/99-1/03; PET and conventional modalities used for initial staging in 24 patients and restaging after therapy in 20 patients (both in 2) 

diabetes mellitus 45 3 

(inco

Shen 2002 retrospective histologically confirmed SCLC; KPS > 60%; total 

serum bilirubin < 2.0 mg/dL; serum creatinine < 2.5 

mg/dL; fasting blood sugar < 150 mg/dL 

prior CTx or RTx 25 

Schumacher 2001 

unclear histologically proven SCLC, primary staging in 24, 

therapy follow-up in 4, both in 2; therapy was surgery, RTx and CTx (ACO, EPI-CO, VIP-E, VIC-E); all treatment stopped >1 mo before PET 

 30 

(36 scans, 77 sites) 

 
C-54

Question 6: Positron Emission Tomography for Staging of Small-Cell Lung Cancer Table 6B: Patient Characteristics Study Age (yr) Gender (%) 

 Stage Limited Extensive  % % Race 

Performance Status (%) 

Blum 2004 med 64 M 66 

F 33 

 78 22 NR NR 

Bradley 2004 mn 60 

rng 33-90 

M 44 F 56 

 87.5 12.5 NR NR 

Brink 2004 mn 60.8 

sd 8.9 

M 75 F 25 

 37 63 NR NR 

Kamel 2003 mn 62 

rng 45-83 

M 64 F 36 

 62.5 37.5 NR NR 

Pandit 2003 mn 63.8 

sd 9.6 

M 41 F 59 

 43 57 NR NR 

Shen 2002 mn 56.4 

sd 7.2 rng 45-68 

M 72 F 28 

 40 60 NR NR 

Schumacher 2001 

mn 57 sd 13 rng 34-78 

M 77 F 23 

 30 70 NR NR 
C-55

Question 6: Positron Emission Tomography for Staging of Small-Cell Lung Cancer Table 6C: Test Procedure and Interpretation Study PET Procedure PET Interpretation 

Conventional StagProcedure 

Blum 2004 > 4 hr fast; scanner – GE Quest 300-H; images 

with and without transmission attenuation correction; whole-body scans of neck, thorax, abdomen; images processed using iterative 

reconstruction of raw and attenuation-corrected data 

physician reporting the PET scans had access to the results of the previous imaging and clinical information; PET scans were interpreted qualitatively; sites of increased uptake coded as uninvolved when due to intercurrent pathology or radiation pneumonitis; PET was not reinterpreted based on subsequent clinical course; PET of brain not performed 

initial staging - highquality CT of chest, abdomen, brain, usubone scan; restagininitial treatment - CTbone scan, X-ray; technically inadequaoutside imaging sturepeated internally 

Bradley 2004 4-hr fast, blood glucose determination (< 150 

mg/dL), patient supine, 10-15 mCi FDG, series of overlapping 2 min transmission and 5 min emission scans at each bed position, 50 min after IV injection, from upper/mid neck to upper thigh, CTI/Siemans ECAT HR+ scanner, emission images reconstructed with orderedsubset estimation-maximization iterative algorithm with segmented attenuation correction, transmission images and non-attenuationcorrected images reconstructed by filtered back projection with a mathematical attenuation correction 

FDG-PET images interpreted prospectively by subjective visual assessment (with ROC grading scheme) for presence of abnormal FDG accumulation, 2 experienced nuclear physicians first independently interpreted PET blinded to results of conventional imaging studies, then observers reread PET images in combination with conventional imaging studies, final PET interpretation based on consensus of 2 observers for blinded readings; also performed semiquantitative evaluation of average maximum standardized uptake value for primary tumor and up to 5 mediastinal metastatic disease sites 

history, physical exachest X-ray, chest Cupper abdominal CTbone scan, contrastenhanced CT/MRI obrain; all conventionstaging procedures completed < 4 wk o

Brink 2004 12 hr fast, IV injection 5 MBq/kg FDG; elevated 

fasting plasma glucose (> 6.0 mmol/L) normalized with fast-acting insulin; whole-body scan 90 min after injection; scanner –CTI ECAT EXACT 922 tomograph with 16.2 cm field of view; spatial resolution 7.0 mm FWHM; brain scan 60 min after injection; transmission scan for attenuation correction 2m, emission scan 8 min at each bed position; data corrected for dead time, decay, photon attenuation, images reconstructed by iterative algorithm using ordered set expectation-maximisation and segmented attenuation correction. 

images viewed on hard copy and computer 

workstation, read independently by 2 investigators blinded to other data; any hot spots interpreted as either benign or malignant (focal increased tracer uptake exceeding normal regional accumulation and lesion located at typical metastatic site); images then compared, consensus reached by discussion 

whole-body PET 

performed after CT 12 d, range 1-26 d); conventional staging history, physical exabronchoscopy, thoracic/abdominal contrast-enhanced Ccranial CT/MRI in 9bone biopsy in 84 (refused in 36) 
C-56

Question 6: Positron Emission Tomography for Staging of Small-Cell Lung Cancer Table 6C: Test Procedure and Interpretation (continued) Study PET Procedure PET Interpretation 

Conventional Stag

Procedure 

Kamel 2003 > 4 hr fast, IV injection of 300-400 MBq FDG, 

40-50 rest for organ uptake, , urinary voiding before scan, 2-min transmission scans, static whole-body scan covered patient from pelvic floor to head, 2 scanners (Advance NXi PET scanner, DISCOVERY LS combined PET/CT inline device); emission scans with 4-min acquisition time at each of 6-7 bed positions; image datasets reconstructed iteratively with 

segmented attenuation correction in 26 patients; PET/CT device image datasets reconstructed iteratively using CT data for attenuation correction in 16 patients 

pre-PET staging and post-PET staging were 

always performed independently; PET interpreted with all available clinical information, including CT 

history, physical exa

blood tests, bronchoscopy, contenhanced CT of cheupper abdomen, boscan, CT/MRI of bra

Shen 2002 6 hr fast; fasting sugar levels obtained for all; 10 

mCi (370 MBq) FDG IV injection; scan after 40-50 min; scanner – Siemens-CTI EXACT HR+ or GE advance PET system; 7-8 bed positions; transmission 3 min; emission 7 min; whole-body scan 

agreement of at least 2 of 3 experienced nuclear 

medicine specialists blind to clinical stage 

within 2 wk of PET: 

history, physical exablood chemistry, chray + chest CT/MRI

CT/MRI, abdominal CT/MRI + hepatic U

pelvic CT/MRI, bone scan, bone marrow biopsy 

Schumacher 2001 

12 hr fast; IV injection 5 MBq FDG/kg; scans started after 90 min; scanner – Siemens ECAT EXACT 921/31 tomograph; 31 planes with 10.6 cm field of view; spatial resolution 6.0 mm FWHM; transmission scan 3 min; emission scan 9 min for each of 7-9 bed positions; from subinguingal region to skull base; images produced based on ordered subset expectation maximization iterative reconstruction algorithm including segmented attenuation correction; separate brain scans in 14 

2 experienced blinded independent 

investigators; soft tissue/bone lesions defined as focally increased tracer uptake exceeding normal limits of regional FDG uptake in the area, if lesion located in typical metastatic site, or if standardized uptake value > 4; images reviewed on hard copy and computer workstation; if observers disagreed, consensus reached, used for analysis of results 

within 2 wk before o

PET: CT/MRI of brathorax, abdomen caout according to staprotocols, thin-secticontrast enhancemeused if needed 
C-57

Question 6: Positron Emission Tomography for Staging of Small-Cell Lung Cancer Table 6D: Reference Standard Procedure and Interpretation, Management Decisions Study 

Decision Rules for Receiving Reference Standard 

Reference Standard Procedure Reference Standard Interpretation Manageme

Blum 2004 NR NR in case of discordance, TP defined as 1) 

site with biopsy+; or 2) site detected only by PET with tumor progression on structural imaging within 6 mo of PET without treatment; TN defined as 1) site with negative adequate biopsy; or 2) equivocal/negative site on conventional assessment with no progression for > 6 

mo without treatment 

when availused to asFDG-avid lvolume) 

Bradley 2004 protocol-defined approaches for 

further evaluation or biopsy: PET+ intrapulmonary parenchymal metastases outside RTx portal, do biopsy; thin-cut CT- or US-guided FNA where feasible; liver PET+, do biopsy/FNA cytology; adrenal PET+, do biopsy; bone PET+, evaluate by appropriate imaging studies (X-ray, CT, MRI, repeat bone scan) or biopsy or bone scan/MRI if multiple bone metastases suspected 

NR NR left to the d

physician, potential exby biopsy w

Brink 2004 if discrepancies appeared between 

conventional staging and PET, selective additional examinations after review by 1-3 physicians; when discordant LN results between staging examinations did not influence disease stage, no validation sought 

histology in ~20%; available data; follow-up 

committee of physicians (2 clinicians, 2 nuclear specialists) achieved reference standard diagnosis by consensus; when histologic results were unavailable, consensus based on sum of available data, including follow-up, non-validated results excluded from data analysis 

NR 

Kamel 2003 when possible, biopsies or other 

imaging studies were performed to resolve discrepancies between modalities; 

NR NR it was cons

use clear bfindings for decisions, previously stage disearadiation oPET and pand changwere deter
C-58

Question 6: Positron Emission Tomography for Staging of Small-Cell Lung Cancer Table 6D: Reference Standard Procedure and Interpretation, Management Decisions (continued) Study 

Decision Rules for Receiving Reference Standard 

Reference Standard Procedure Reference Standard Interpretation Manageme

Shen 2002 if final PET interpretation 

suggested previously unsuspected lesion, physical exam, biopsy, CT and/or additional nuclear imaging performed 

final stage was verified by pathologic findings from thoracotomyy/mediastinoscopy. other imaging results, follow-up > 1 yr 

NR NR 

Schumacher 2001 

PET findings were compared with the sum of the findings of other staging procedures 

if discrepancies between PET and other staging procedures found, selective additional examinations performed or existing images re-evaluated; in some cases, clinical follow-up proved/disproved inconsistent findings; confirmation necessary within 4 wk 

NR NR 
C-59

Question 6: Positron Emission Tomography for Staging of Small-Cell Lung Cancer Table 6E: Diagnostic Accuracy Results Study Test Focus n TP FN FP TN Prev Sens 

Sens 95% CIL 

Sens 95% CIU Spec 

Spec 95% CIL 

Spec 95% CIU PPV 

Blum 2004 PET any disease 36 36 0 100% 90.3% 100% Bradley 2004 PET any disease 24 24 0 1 0 100% 85.8% 100% Brink 2004 PET LNs 118 53 0 1 64 44.9% 100% 93.3% 100% 98.5% 91.7% 100% 98.1

Conv 118 37 16 4 61 44.9% 69.8% 55.7% 81.7% 93.8% 85.0% 98.3% 90.2PET dist, non-brain 70 45 1 2 22 65.7% 97.8% 88.5% 99.9% 91.7% 73.0% 99.0% 95.7Conv 70 38 8 5 19 65.7% 82.6% 68.6% 92.2% 79.2% 57.8% 92.9% 88.4PET brain 91 6 7 2 76 14.3% 46.2% 19.2% 74.9% 97.4% 91.0% 99.7% 75.0Conv 91 13 0 0 78 14.3% 100% 75.3% 100% 100% 95.4% 100% 100

Kamel 2003 Shen 2002 PET regl mets 18 20 0 2 0 100% 83.2% 100% MD/HL LNs 9 9 0 2 0 100% 66.4% 100% ips SC LNs 7 7 0 0 0 100% 59.0% 100% ips lung 2 2 0 0 0 100% 15.8% 100% distant 24 23 1 1 0 95.8% 78.9% 100% contr SC LNs 5 5 0 0 0 100% 47.8% 100% contr lung 3 3 0 1 0 100% 29.2% 100% liver 3 3 0 0 0 100% 29.2% 100% bone/marrow 6 6 0 0 0 100% 54.1% 100% brain 2 1 1 0 0 50.0% 1.3% 99% adrenal 2 2 0 0 0 100% 15.8% 100% other extrathorac 3 3 0 0 0 100% 29.2% 100%Schumacher 2001 
C-60

Question 6: Positron Emission Tomography for Staging of Small-Cell Lung Cancer Table 6F: Staging Accuracy Results Study Test Use 

Correctly Upstaged  # % 

Incorrectly Upstaged  # % 

Correctly Downstaged  # % 

Incorrectly Downstaged  # % 

Identified Unsuspected Metastases Site # % 

Ruled Out Suspected Metastases Site # % 

Blum 2004 PET staging 3 20 Bradley 2004 PET staging 1 4.2 1 4.2 lung 1 4.2 

regl LNs 6 25 

Brink 2004 PET staging 10 8.3 3 2.5 Kamel 2003 PET staging 

restaging 

 3 12.5  1 5 

 0 0  1 5 

 1 4.2  2 10 

 0 0  0 0 

visceral/ soft tissue 1 4.2 lung 1 5 breast/ axilla 1 5 

adrenal 1 4LN 2 1bone 1 5 

Shen 2002 PET staging 1 4 0 0 1 4 0 0 Schumacher 2001 

PET staging 

restaging 

 5 19.2  1 16.7 
C-61

Question 6: Positron Emission Tomography for Staging of Small-Cell Lung Cancer Table 6G: Patient Management and Other Results Study Test Use 

PET Changed Patient Management  # % Changes Other Findings 

Blum 2004 PET staging 

restaging 

 4 26.7 forgone RTx for ED  1 6.7 ED, received palliative CTx/RTx  2 13.3 RTx target volume changed  3 12 PCI omitted  3 12 PCI selected  2 8 forgone CTx, observation for NED 

in 11 of 14 discordant disease sites (79%accurate; 9 of 25 follow-up patients achiemo median time to progression, compare

Bradley 2004 PET Staging 7 29.2 RTx target volume changed PET correctly identified tumor in each prim

that was suspected on CT; unblinded PET blinded; PET found no brain metastases (blinded interobserver agreement 83%; unagreement 96% 

Brink 2004 PET 10 8.3 forgone RTx for ED 

 3 2.5 selected CTx/RTx  1 0.8 missed brain metastasis, affected  treatment 

complete agreement between PET and o75 patients; differences occurred in 45 pacorrect in 47/65, PET incorrect in 10/65, uinterobserver agreement kappa 0.94 

Kamel 2003 PET either 

staging restaging 

 12 29  9 37 forgone RTx for ED (3)  altered radiation field (5)  selected surgery (1)  3 15 CTx reinstituted (1)  CTx discontinued (2) 

incongruence between PET and anatomic mismatch did not change final staging de

Shen 2002 41 of 42 (97.6%) metastases were identif

PET FPs and 1 FN 

Schumacher 2001 

 PET and other staging tests agreed in 23 

LD, 12 for ED, 5 for NED); disagreed in 1PET FPs (1 brain) 
C-62

Question 6: Positron Emission Tomography for Staging of Small-Cell Lung Cancer Table 6G: Study Quality Ratings Study 

Representative sample? 

Clear Selection Criteria? 

Reference standard correctly classifies target condition? 

Period between test, reference standard short enough? 

Whole sample or selection received reference standar

Blum 2004 Unclear Unclear Unclear Unclear Yes Bradley 2004 Yes Yes Unclear Unclear Yes Brink 2004 Unclear Unclear Unclear Unclear Yes Kamel 2003 Unclear Unclear Unclear Unclear Yes Shen 2002 Unclear Unclaar Unclear Unclear Yes Schumacher 2001 Unclear Unclear Unclear Unclear Yes Study 

Patients received reference standard regardless of test results? 

Reference standard independent of test? 

Test execution sufficiently described? 

Reference standard execution sufficiently described? 

Blum 2004 Unclear Unclear Yes No Bradley 2004 Unclear Yes Yes No Brink 2004 No Yes Yes No Kamel 2003 Unclear Unclear Yes No Shen 2002 No Unclear No No Schumacher 2001 No Unclear Yes No Study 

Test results interpreted blind to reference standard? 

Reference standard results interpreted blind to test? 

Clinical practice data available for test interpretation? 

Uninterpretable/ indeterminate results reported? 

Wex

Blum 2004 Unclear Unclear Yes No Bradley 2004 Unclear Unclear Yes/No No Brink 2004 Yes Unclear No No Kamel 2003 Unclear Unclear Yes No Shen 2002 Unclear Unclear No No Schumacher 2001 Unclear Unclear No Yes 
C-63 

Question 8. Surgery versus No Surgery for Limited-Stage Disease Table 8A: Sample Selection Study Inclusion Exclusion n, Randomized n, Withdrawn Lad et al. 1994 multicenter European/American trial (LCSG/ECOG/ EORTC) accrual 1983-89 

confirmed diagnosis of pure SCLC histology; limited stage disease (one hemithorax with negative supraclavicular nodes and no pleural effusion); “fit for thoracotomy”; CR or PR after 5 cycles of CAV; resectable disease; normal brain CT scan 

“true T1NOM0 small cell lesions: peripheral nodules”; supraclavicular nodal mets.; pleural, pericardial effusion; super. vena cava syndrome; esophageal invasion; <PR after 5 cycles of CAV; unresectable disease; unfit for thoracotomy 

Total +Surg -Surg

146 70 76[71 responders refused randomization post CAV] 

Total +Surg -Surg

0 0 0

Liao et al. 1995 one center RCT (Shanghai) accrual 1/90-12/91 

stage II or III lung cancer (40 SCLC and 40 NSCLC, randomized separately, and outcomes reported separately); no other inclusion criteria reported 

none reported Total +Surg -Surg

40 20 20 

Total +Surg -Surg

0 0 0 

Badzio et al. 2004; 2005 retrospective “pairmatched casecontrol” study single institution (Poland) accrual 1984-96 

surgery if thoracotomy needed 

to establish diagnosis; stages I-IIIA; included if pre-op data sufficient for clinical staging; controls: suitable for surgery 

(one involved hemithorax, neg. ipsilateral supraclavicular nodes); 

surgical patients: inadequate 

data for accurate clinical staging; controls: pleural effusion; 

“low performance status”; pair matched for: PS, clinical T and N stages, sex 

Total +Surg -Surg

76 176 

7 +Surg w inadequate pre-op. data for clinical staging 2 +Surg not matched to –Surg controls 

Total +Surg -Surg

 9 109 109 -Surg patients not matched to +Surg 

Shepherd et al. 1989 prospective multicenter study (Toronto); adjuvant surgery post chemo Tx; compared operated with not operated patients 

confirmed SCLC by histology or cytology; central lesions; surgical candidates (defined as N1 or early N2 disease; or T3 N0) 

peripheral nodule; extensive disease; medically unfit for surgery 

Total +Surg -Surg

72 38 34 

Total +Surg -Surg

15 15 ineligible for surgery post chemoTx for: poor response, 9 became unfit, 3 died in month1, 2 lost to follow-up, 1 

Namikawa et al. 1994 retrospective analysis of one-center (Japan) series; treated 1960-86 

all non-metastatic SCLC treated over study period 

stage IV disease Total +Surg -Surg

101 58 43 resected 43 explored 15 

Total +Surg -Surg

 0 0 0 

Hara et al. 1991a, 1991b; retrospecttive analysis of onecenter (Japan) series; 1972-89 

stages I, II or IIIA histologically or cytologically proven localized SCLC; selected for surgery if technically resectable 

stage > IIIA; non-resectable for: tumor extension into adjacent structures, medical contra-indications, refusal 

Total +Surg -Surg

 81 36 45 

Total +Surg -Surg

0 0 0 
C-64 

Question 8. Surgery versus No Surgery for Limited-Stage Disease Table 8A: Sample Selection (continued) Study Inclusion Exclusion n, Randomized n, Withdrawn Friess et al. 1985 retrospective analysis of patients enrolled in SWOG 7628 trial, 1977-9 

limited disease (1 hemithorax and ipselateral supraclavicular nodes); compared survival of those who underwent surgery before randomization to those not resected 

extensive stage disease Total +Surg -Surg

262 16 246 

Total +Surg -Surg

1 1 0 one surgical patient had carcinoid, not SCLC 

Osterlind et al. 1985; retrospective analysis of patients from 6 trials at 2 Danish institutions, 3/73-9/81 

histologically confirmed SCLC; no prior therapy but resection; no distant metastasis; operable based on bronchoscopy, mediastinoscopy and lung function tests 

no pre-operative diagnosis (i.e., undergoing diagnostic thoracotomy); distant metastasis; mediastinoscopy not done 

Total +Surg -Surg

79 33 46 

Total +Surg -Surg

0 0 0 

Rostad et al. 2004 retrospective analysis, Cancer Registry of Norway; all cases 1993-9 

all technically operable (T1 or T2, N0, M0) limited stage (Ia or Ib) SCLC cases in Norway 

extensive disease; technically inoperable; medical contra-indication to surgery 

Total +Surg -Surg

 38 96 

Total +Surg -Surg

 18  (given adjuv.  chemoTx) 

George et al. 1986 population-based registry analysis; all SCLC cases in Rochester, NY; 1975-81 

limited disease (one hemithorax with or without ipsilateral hilar, supraclavicular or mediastinal lymph node involvement 

extensive disease; pleural effusion; inadequate data in chart for staging or evaluation 

Total +Surg -Surg

151 

Total +Surg -Surg

52 (17, improper entry; 3, 2nd malignancy; 13, 

dead week 1; 1, refused Tx; 12, pathol. unavail.; 4, mixed histol.; 2, NSCLC 
C-65 

Question 8. Surgery versus No Surgery for Limited-Stage Disease Table 8B: Patient Characteristics Study Age (yr) Gender (%) Race (%) 

Performance Status 

(%) 

Comorbidities or Factors (%) 

Lad et al. 1994 multicenter European/American trial (LCSG/ECOG/ EORTC) accrual 1983-89 

 +Surg -Surgmn md 59 rng 35-72 sd “groups evenly  matched” 

 +Surg -SurgM 65 F 35 “groups evenly matched” 

 +Surg -SurgB W 92 O “groups evenly matched” 

KPS +Surg -Surg

>9 82 

 ”groups equally  balanced” 

 +S

<10% weight 

loss >5 cm2 resid tumor “g b

Liao et al. 1995 one center RCT (Shanghai) accrual 1/90-12/91 

 +Surg -Surgmn 50 54.4 md rng 33-74 31-66 sd 

 +Surg -SurgM 90 90 F 10 10 

 +Surg -SurgB not W reported O 

 +Surg -Surg

 NOT  REPORTED

 +Sclinical stage: II 1III 9

Badzio et al. 2004; 2005 retrospective “pairmatched casecontrol” study 

 +Surg -Surgmn 57 54 md rng 29-70 36-71 sd  p=0.03 

 +Surg -SurgM 85 78 F 15 22  p=0.27 

 +Surg -SurgB not W reported O 

WHO +Surg -Surg

0 60 58 1 36 33 2 4 9  p=0.57 

 +Su% T1/T2 14/8%N0/N1/N2 37/33clinical stage: % 1/2/3 39/32/mean tumor size ((range) 26 (1-9

Shepherd et al. 1989; prospective multi-center study (Toronto); adjuvant surgery post chemo Tx; compared those given vs. not given surgery 

 +Surg -Surgmn md 60 59 rng 39-77 44-75 sd 

 +Surg -SurgM 68 53 F 32 47 

 +Surg -SurgB not W reported O 

 +Surg -Surg

 NOT  REPORTED 

 +S(%) stage I 2stage II 3stage III 3

Namikawa et al. 1994 retrospective analysis of onecenter (Japan) series; treated 1960-86 

 +Surg -Surgmn md NOT rng REPORTED sd 

 +Surg -SurgM NOT F REPORTED “proportion of women higher” in -Surg group 

 +Surg -SurgB not W reported O 

 +Surg -Surg

 NOT  REPORTED 

 +Smean time from “oinitiation of treatmresected: explored: 

Hara et al. 1991a, 1991b retrospective analysis of onecenter (Japan) series; treated 1972-89 

 +Surg -Surgmn 64 63 md rng 44-76 45-83 sd 

 +Surg -SurgM 83 84 F 17 16 

 +Surg -SurgB not W reported O 

ECOG +Surg -Surg

0 50 18 1 44 78 2 6 4 

clinical stage +SI II IIIA 
C-66 

Question 8. Surgery versus No Surgery for Limited-Stage Disease Table 8B: Patient Characteristics (continued) Study Age (yr) Gender (%) Race (%) 

Performance Status 

(%) 

Comorbidities or Factors (%) 

Friess et al. 1985; retrospective analysis of patients enrolled in SWOG 7628 trial, 1977-9 

 +Surg -Surgmn md NOT rng REPORTED sd 

 +Surg -SurgM NOT F REPORTED 

 +Surg -SurgB not W reported O 

 +Surg -Surg NOT  REPORTED 

age, sex, and initisurgical subset wdifferent” from the group 

Osterlind et al. 1985; retrospective analysis of patients from 6 trials at 2 Danish institutions, 3/73-9/81 

 +Surg -Surgmn 55 60 md rng sd 8 6 

 +Surg -SurgM 82 72 F 18 28 

 +Surg -SurgB not W reported O 

AJC1 +Surg -Surg0-1 83 91 2 17 6 3-4 0 3 

 +S

symptom duration(med, rng): 2 (bone marrow or livinvolvement: 9 LDH>ULN2: 50 

AST>ULN2: 20 

Rostad et al. 2004 retrospective analysis, Cancer Registry of Norway; all cases 1993-9 

 +Surg -Surgmn md “no age differrng ence” between sd groups 

 +Surg -SurgM NOT F REPORTED 

 +Surg -SurgB not W reported O 

 +Surg -Surg NOT  REPORTED

 +S

George et al. 1986; population-based registry analysis; all SCLC cases in Rochester, NY; 1975-81 

 all 101

31-40 2% 41-50 12% 51-60 29% 61-70 38% 71-80 14% >80 5% 

 all 101M 65% F 35% 

 +Surg -Surg

B W not O reported 

 +Surg -Surg not  reported 

22% enrolled on aprotocol 

1 American Joint Committee for Cancer Staging, 1979 
C-67 

Question 8. Surgery versus No Surgery for Limited-Stage Disease Table 8C: Treatments Study Chemotherapy regimen, per protocol Surgical Procedures (+Surgery arm) TRTx (if included) Lad et al. 1994 multicenter European/American trial; accrual 1983-89 

Agent Dose Schedule

Cytoxan 1 g/m2 day 1, q3wk, X5 

doxorubicin 50 mg/m2 day 1, q3wk, X5 

vincristine 1.4 mg/m2 day 1, q3wk, X5 

thoracotomy and attempted resection: 54 complete, 4 partial resections; 12 unresectable (open & close) 

Dose Schedule

50 Gy 25 fractions, aft

surgery for + ar

Liao et al. 1995 one center RCT (Shanghai) accrual 1/90-12/91 

Agent Dose Schedule

ifosfamide 1.2 g/m2 days 1-5 

MESNA 400 mg days 1-5 doxorubicin 50 mg/m2 day 1 

vincristine 1 mg/m2 day 1 

(2-3 cycles initially, then surg or RTx, then 4 additional cycles; duration of cycles not reported) 

procedures not described; surgery done after chemotherapy cycle 2 for most, cycle 3 for a few (#’s not reported); up to 4 more chemotherapy cycles postoperatively 

Dose Schedule

TRTx used only in -surg aafter 1st 2-3 cycles; dose 

schedule not reported; up more chemotherapy cycleTRTx 

Badzio et al. 2004; 2005 retrospective “pair-matched case-control” study 

surgical patients given one of four regimens postop: CAV, 4-8 cycles; CDE, 4-6 cycles; PE, 4-6 cycles; or MCCC/CAV/VI; control patients given CCMV or ACOM doses and schedules not reported 

pneumonectomy, n=30; lobectomy, n=37 Dose Schedule

30, 40 n=39 from -surg or 50 only; in 10, 20 oGy fractions, respec

Shepherd et al. 1989; prospective multi-center study (Toronto); adjuvant surgery post chemo Tx; compared those given vs. not given surgery 

various regimens for variable number of cycles, including: CAV, 1-6 cycles, n=29 resected, 33 of 34 not resected; CAV+etoposide, 5 cycles, n=1 resected; PE, 3-6 cycles, n=2 resected, 1 of 34 not resected 

(chemotherapy regimens reported only for all 34 non-resected patients, eligible or ineligible) 

of 38 patients who underwent thoracotomy, 8 required pneumonectomy, 25 had lobectomy, 5 not resected at thoracotomy (4 had unresectable disease; 1 had no identifiable residual tumor to resect); all had radical mediastinal lymph node dissection no thoracotomy for any –Surg patients 

post-operative radiotheratumor bed and mediastinutotal dose ranged from 25 10 fracs. to 35 Gy in 20 fr-Surg patients “received tsame radiotherapy at comof chemotherapy” 

Namikawa et al. 1994 retrospective single-center (Japan) series; treated 1960-86 

 NOT REPORTED NOT REPORTED NOT REPORTE

Hara et al. 1991a 1991b retrospective analysis of onecenter (Japan) series; treated 1972-89 

various regimens for both +surg and –surg groups; 

VCMC 13 25 CAV 3 9 PE 4 3 CAV + PMP 4 1 CAV + CVMP 2 0 CAV + PE 8 5 others 2 2 (doses and schedules reported but not abstracted)

n=19, surgery→ adjuvant chemotherapyN=17, neoadj. chemoTx→surgery; complete pneumonectomy, 4 lobectomy, 27 bilobectomy 5 surgery “complete” 31 surgery “incomplete” 5 

Dose Schedule

46 Gy 1.4-2.0 Gy daily (avg) 36 fractions 30-70 Gy (range) 
C-68 

Question 8. Surgery versus No Surgery for Limited-Stage Disease Table 8C: Treatments (continued) Study Chemotherapy regimen, per protocol Surgical Procedures (+Surgery arm) TRTx (if included) Friess et al. 1985 retrospective analysis of patients enrolled in SWOG 7628 trial, 1977-9 

all patients randomized to one of 4 treatment arms that ”...included chemotherapy followed by radiation therapy to the primary site and whole brain prophylaxis.” Surgical subset evenly and randomly distributed to 4 treatment arms (5, 3, 3, and 4) 

12 lobectomy  3 pneumonectomy 

2 courses 30 Gy with 15 Goptional boost 

Osterlind et al. 1985; retrospective analysis of patients from 6 trials; 2 Danish institutions, 3/73-9/81 

various regimens for both +surg and –surg groups; 

CCM 10 10 CCMV 19 17 CCMV+doxorubicin+ 4 19 etoposide (doses and schedules not reported) 

11 (33%), complete resection 13 (39%), partial resection  9 (27%), neither pneumonectomy nor  lobectomy (<partial resection)

+surg: n=11 (33%) -surg: n=15 (33%) no details re dose or sche

Rostad et al. 2004 retrospective analysis, Cancer Registry of Norway; all cases 1993-9 

NOT REPORTED (for technically operable but not resected group; “The majority treated with combined chemotherapy or concurrent chemoradiotherapy” using doxorubicin, cyclophosphamide, vincristine, or cisplatin based regimens) 

 lobectomy: 15 stage Ia, 5 stage Ib bilobectomy: 3 stage Ia, 1 stage Ib pneumonect.: 3 stage Ia, 4 stage Ib minor resect.: 5 stage Ia, 1 stage Ib 1 unknown, for stage or surgery 

 NO DETAILS  REPORTED 

George et al. 1986; populationbased registry analysis; all SCLC cases in Rochester, NY; 1975-81 

CTx or CTx+RTx patients given CCM, CMVP, CC, or CAV doses and schedules not specified 

not specified; of total n=13, 10 given adjuvant chemotherapy and 2 given adjuvant radiation therapy 

 NO DETAILS  REPORTED 
C-69 

Question 8. Surgery versus No Surgery for Limited-Stage Disease Table 8D: Outcome Assessment Study 

Primary Outcomes 

Secondary Outcomes Response Criteria Observer F/U 

Lad 1994 multicenter European/American trial; accrual 1983-89 

mortality (90% probability to detect HR = 2 at 2-sided p=0.05, assuming median OS = 30 mos in superior arm) 

surgical success rate; sites of treatment failure; survival by TNM stage; 

CR= no evidence of SCLC by pathology PR= NOT REPORTED SD= PD= 

NOT 

SPECIFIED

 Tomn md rng sd 

Liao et al. 1995 one center RCT (Shanghai) accrual 1/90-12/91 

overall survival; power analysis not reported 

complete responses; rates of local relapse, distant metastasis 

CR= PR= “WHO tumor treatment remission rate SD= standards” (not described or referenced) PD= 

NOT 

SPECIFIED

 Tomn md rng sd 

Badzio et al. 2004; 2005 retrospective “pair-matched case-control” study 

overall survival from time of diagnosis 

time to local relapse or progression; 

CR= PR= NOT REPORTED SD= PD= 

NOT 

SPECIFIED

 Tomn md 72 rng sd 

Shepherd et al. 1989; prospective multi-center study (Toronto); adjuvant surgery post chemo Tx; compared those given vs. not given surgery 

overall survival from start of pre-op chemoTx to date of death or last followup 

responses to pre-op chemoTx; survival by clinical and pathologic (-Surg only) stage; sites of relapse 

CR= PR= NOT REPORTED SD= PD= 

NOT 

SPECIFIED

 Tomn md rng busd fo ye

Namikawa et al. 1994 retrospective analysis of onecenter (Japan) series; treated 1960-86 

overall survival none CR= 

PR= NOT REPORTED SD= PD= 

 To

mn md rng sd 

Hara et al. 1991a 1991b; retrospective analysis of one-center (Japan) series; treated 1972-89 

overall survival response rates (preoperative chemoTx 

and –Surg groups); sites of relapse; operative mortality 

CR= no clinical evidence of disease PR= >50%↓, sum of shortest+longest dimensions 

of all measurable lesions for >4 wks 

SD= no objective progression or regression PD= definite progression of disease 

NOT 

SPECIFIED

 To

mn md rng sd 
C-70 

Question 8. Surgery versus No Surgery for Limited-Stage Disease Table 8D: Outcome Assessment (continued) Study 

Primary Outcomes 

Secondary Outcomes Response Criteria Observer F/U 

Friess et al. 1985 retrospective analysis of patients enrolled in SWOG 7628 trial, 1977-9 

overall survival none NOT APPLICABLE 

NOT 

APPLICABLE 

 Tomn md rng sd 

Osterlind et al. 1985; retrospective analysis of patients from 6 trials; 2 Danish institutions, 3/73-9/81 

overall survival disease-free survival; 

relapse rate 

CR= PR= NOT REPORTED SD= PD= NOT SPECIFIED

 Tomn md rng 3-sd 

Rostad et al. 2004 retrospective analysis, Cancer Registry of Norway; all cases 1993-9 

overall survival none CR= 

PR= NOT REPORTED SD= PD= 

NOT 

RELEVANT

 Tomn md rng sd 

George et al. 1986; populationbased registry analysis; all SCLC cases in Rochester, NY; 1975-81 

overall survival from time of diagnosis 

response rates (nonsurgical patients) CR= PR= Used “...standard ECOG criteria determined 

SD= by the treating physician at the time” PD= 

NOT 

SPECIFIED

 Tomn 48 md rng sd 
C-71 

Question 8. Surgery versus No Surgery for Limited-Stage Disease Table 8E: Survival Outcomes Study Overall Survival (%) Time to Relapse or Progression (TTR/P) Lad 1994 multicenter European/American trial; accrual 1983-89 

 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr

+surg 70 15.4 ~60 20 ~20 ~20 ~20 -surg 76 18.6 ~65 20 ~20 ~20 ~20  (log rank p=0.78) 

 N Med (mos) 1 yr 2 yr 3 yr 

+surg -surg NOT REPORTED 

Liao et al. 1995 one center RCT (Shanghai) accrual 1/90-12/91 

 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr

+surg 20 79 52 24 -surg 20 63 18 18  (log rank p=0.12; t-test for OS at 2 yr, p<0.05) 

 N Med (mos) 1 yr 2 yr 3 yr 

+surg -surg NOT REPORTED 

Badzio et al. 2004, 2005; retrospective matched pair case-control 

 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr

+surg 67 22.3 70 43 ~35 ~30 27 -surg 67 11.2 45 17 ~12 ~4 4 in CR 23 22 36 26  (p < 0.001; HR = 0.42; 95% CI: 0.28, 0.61) 

 N Med (mos) 1 yr 2 yr 3 yr 

+surg 67 20.9 -surg 67 7  (p < 0.001) 

Shepherd et al. 1989; prospective multi-center study (Toronto); adjuvant surgery post chemo Tx; compared those given vs. not given surgery 

 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr

+surg 38 22.8 ~63% ~47% ~36% ~36% 36% -surg 19 11.8 ~48% ~10% ~10% ~10%  (p=0.049) 

 N Med (mos) 1 yr 2 yr 3 yr 

+surg -surg NOT REPORTED 

Namikawa et al. 1994 retrospective analysis of onecenter (Japan) series; treated 1960-86 

 N Mn (mos) 1 yr 2 yr 3 yr 4 yr 5 yr

+surg resect. 43 8.1 eplor. 15 5.1  (statistical test result not stated) -surg 43 5.2 

 N Med (mos) 1 yr 2 yr 3 yr 

+surg -surg NOT REPORTED 

Hara et al. 1991a 1991b retrospective analysis of one-center (Japan) series; treated 1972-89 

 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr

+surg 36 33 56 38 -surg: CR 19 24.5 ~32 21 PR 20 12.5 0 SD/PD 6 6.5 0 

 N Med (mos) 1 yr 2 yr 3 yr 

+surg -surg NOT REPORTED 
C-72 

Question 8. Surgery versus No Surgery for Limited-Stage Disease Table 8E: Survival Outcomes (continued) Study Overall Survival (%) Time to Relapse or Progression (TTR/P) Friess et al. 1985 retrospective analysis of patients enrolled in SWOG 7628 trial, 1977-9 

 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr

+surg 15 25 44 -surg 246 10.5 13.7  (p=0.0037) (p<0.05) -surg, selected for “similar initial presentation” as +surg:  33 10 (range, 1-46+; p=0.03) 

 N Med (mos) 1 yr 2 yr 3 yr 

+surg -surg NOT REPORTED 

Osterlind et al. 1985; retrospective analysis of patients from 6 trials; 2 Danish institutions, 3/73-9/81 

 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr

+surg 33 ~37 ~16 ~14 ~14 -surg 46 ~50 ~16 ~10 ~8 (p=0.35 by life table analysis) 

DFS N Med (mos) 1.5 yr 2 yr 3 yr 

+surg 33 15 12 -surg 46 15 13 

Rostad et al. 2004 retrospective analysis, Cancer Registry of Norway; all cases 1993-9 

 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr

+surg 29 44.9  95% CI: 23.9, 65.9-surg 96 11.3  95% CI: 4.2, 18.4

 N Med (mos) 1 yr 2 yr 3 yr 

+surg -surg NOT REPORTED 

George et al. 1986; populationbased registry analysis; all SCLC cases in Rochester, NY; 1975-81 

 N Med (mos) 1 yr 2 yr 3 yr 4 yr 5 yr

+surg 13 30.8 ~70 ~56 ~46 ~40 ~40 -surg 88 12.4 CTx 43 11.9 ~43 ~15 ~10 ~4 0 RTX 20 13.4 ~58 ~20 ~20 ~20 ~18 both 25 14.1  (p=0.009 versus –surg) 

 N Med (mos) 1 yr 2 yr 3 yr 

+surg -surg NOT REPORTED 
C-73 

Question 8. Surgery versus No Surgery for Limited-Stage Disease Table 8F: Tumor Response and Quality of Life 

Study Tumor Response (%) Quality of Life 

Lad 1994 multicenter RCT; accrual 1983-89 

 N CR PR SD PD NE

+surg 70 19 -surg 76 NOT REPORTED 

Scale Domain F/U +surg n -surg n +su

 NOT MEASURED 

Liao et al. 1995 one center RCT (Shanghai) 1/90-12/91 

 N CR PR SD PD NE

+surg 20 70 -surg 20 80 

Scale Domain F/U +surg n -surg n +su

 NOT MEASURED 

Badzio et al. 2004, 2005; retrospecttive “matched pair case-control” study 

 N CR PR SD PD NE

+surg -surg NOT REPORTED 

Scale Domain F/U +surg n -surg n +su

 NOT MEASURED 

Shepherd et al. 1989; prospective multicenter trial (Toronto); adjuvant surgery post chemoTx; compared those given vs. not given surgery 

 N CR PR SD NC/PD ED*

+surg 38 45 50 --- 5 0 -surg 34 29 32 --- 32 6 all 72 38 42 --- 18 3 *ED = early death 

Scale Domain F/U +surg n -surg n +su

 NOT MEASURED 

Namikawa et al. 1994 retrospective analysis, onecenter (Japan) series; treated 1960-86 

 N CR PR SD PD NE

+surg -surg NOT REPORTED 

Scale Domain F/U +surg n -surg n +su

 NOT MEASURED 

Hara et al. 1991a 1991b; retrospective analysis of one-center (Japan) series; treated 1972-89 

 N CR PR SD PD NE

+surg NOT APPLICABLE -surg 45 42.5 44 13.5 

Scale Domain F/U +surg n -surg n +su

 NOT MEASURED 
C-74 

Question 8. Surgery versus No Surgery for Limited-Stage Disease Table 8F: Tumor Response and Quality of Life (continued) Study Tumor Response (%) Quality of Life Friess et al. 1985; retrospective analysis of patients enrolled in SWOG 7628 trial, 1977-9 

 N CR PR SD PD NE

+surg -surg NOT REPORTED 

Scale Domain F/U +surg n -surg n +su NOT MEASURED 

Osterlind et al. 1985; retrospective analysis of patients from 6 trials; 2 Danish institutions, 3/73-9/81 

 N CR PR SD PD NE

+surg -surg NOT REPORTED 

Scale Domain F/U +surg n -surg n +su NOT MEASURED 

Rostad et al. 2004 retrospective analysis, Cancer Registry of Norway; all cases 1993-9 

 N CR PR SD PD NE

+surg -surg NOT REPORTED 

Scale Domain F/U +surg n -surg n +su NOT MEASURED 

George et al. 1986; populationbased registry analysis; all SCLC cases, Rochester, NY; 1975-81 

 N CR PR SD/NR PD NE

+surg 13 92 0 0 8 0 -surg 88 32 CTx 43 12 25 16 47 0 RTx 20 55 10 15 20 0 both 25 48 40 4 8 0 

Scale Domain F/U +surg n -surg n +su NOT MEASURED 
C-75 

Question 8. Surgery versus No Surgery for Limited-Stage Disease 

Table 8G: Adverse Events 

Toxicity Type Study Severity or Grade Results 

Treatment-related (operative) 

mortality 

Lad et al. 

1994 not 

applicable 

F/U (yr) +surg n % -surg n %

not 70 2.9 76 not 

reported reported

 Liao et al. 

1994 not 

applicable 

F/U (yr) +surg n % -surg n %

not 20 0 20 0 

reported 

 Badzio et al. 

2004, 2005 not 

applicable 

F/U (yr) +surg n % -surg n %

 NOT REPORTED 

 Shepherd et 

al. 1989 not 

applicable 

F/U (yr) +surg n % -surg n %

 >1 38 0 eligible 19 

 [2 of 72 (3%) died after 1st course of chemoTx] 

 Namikawa et 

al. 1994 not 

applicable 

F/U (yr) +surg n % -surg n %

 NOT REPORTED 

 Hara et al. 

1991a, 1991b not 

applicable 

F/U (yr) +surg n % -surg n %

not 36 0 45 not 

reported reported

 Friess et al. 

1985 not 

applicable 

F/U (yr) +surg n % -surg n %

 NOT REPORTED 

 Osterlind et 

al. 1985 not 

applicable 

F/U (yr) +surg n % -surg n %

3-9+ NOT REPORTED 

 Rostad et al. 

2004 not 

applicable 

F/U (yr) +surg n % -surg n %

 NOT REPORTED 

 George et al. 

1986 not 

applicable 

F/U (yr) +surg n % -surg n %

3.7 (mn) 13 0 88 1 

 (given CTx+RTx)

Shepherd et al. (1989) is the only study that reported postoperative complications other than mortality. Among 38 resected, they observed: 

1 severe bronchospasm (2.6%) 

1 prolonged atelectasis (2.6%) 

1 pulmonary edema (2.6%) 

2 transient arrhythmias (5.3%) 

1 assisted ventilation for 6 weeks (2.6%) 
C-76 

Question 8. Surgery versus No Surgery for Limited-Stage Disease Table 8H: Study Quality Ratings Study 

Initial Assembly of Comparable Groups 

Low Loss to Followup, Maintenance of Comparable Groups 

Measurements Reliable, Valid, Equal 

Interventions Comparable/ Clearly Defined 

Appropriate Analysis of Results 

Overall Rating 

Lad et al. 1994 multicenter RCT European/American 

uncertain 

(report states groups “evenly matched” but baseline data pooled across arms) 

yes 

(all randomized patients included in analysis) 

yes yes 

uncertain 

peri-operative 

mortality only 

reported 

adverse event

fair 

Liao et al. 1995 one center RCT (Shanghai) 

uncertain 

insufficient data on baseline characteristics (no data on performance status) 

no 

15-20% per arm lost to follow-up 

yes 

uncertain 

extent of surgery, TRTx regimen not reported 

uncertain operative 

complications 

not reported 

poor 

Badzio et al. 2004 retrospective “pairmatched case-control” one-center study 

uncertain 

not randomized; “pairmatched case-control” study; groups differed significantly in age 

yes 

(all matched pairs 

followed and 

analyzed) 

yes 

uncertain 

regimens, doses 

varied and not 

specified 

no 

no data on 

adverse 

events 

poor 

Shepherd et al. 1989; prospective multi-ctr study (Toronto); adjuvant surgery post chemo Tx; compared those given vs. not given surgery 

uncertain 

not randomized; 

more females, stage 

III patients in -Surg 

group; more males, 

stage II patients in 

+Surg group 

yes 

all followed and 

analyzed 

yes 

uncertain 

regimens, doses 

varied and 

inadequately 

specified 

yes 

most complete 

reporting on 

operative 

complications

fair 

Namikawa et al. 1994 retrospective analysis, one-center series 

no 

not randomized; inadequate data 

comparing base-line 

characteristics 

yes 

all followed and 

analyzed 

yes 

uncertain 

regimens, doses 

varied and not 

specified 

no 

statistical test 

results not 

reported, no 

data on 

adverse 

events 

poor 

Hara et al. 1991 retrospective analysis of one-center (Japan) series; treated 1960-86 

no 

not randomized; large 

differences between 

groups for stage, PS 

yes 

all followed and 

analyzed 

yes 

uncertain 

regimens, doses, 

varied (although 

well reported) 

yes poor 

Friess et al. 1985 retrospective analysis of patients enrolled in SWOG 7628 trial, 1977-9 

uncertain 

(report states groups “evenly matched” but baseline data not reported) 

yes 

all followed and 

analyzed 

yes yes 

uncertain 

surgical group 

denominator 

unavailable for 

mortality 

fair 
C-77 

Question 8. Surgery versus No Surgery for Limited-Stage Disease Table 8H: Study Quality Ratings (continued) Study 

Initial Assembly of Comparable Groups 

Low Loss to Followup, Maintenance of Comparable Groups 

Measurements Reliable, Valid, Equal 

Interventions Comparable/ Clearly Defined 

Appropriate Analysis of Results 

Overall Rating 

Osterlind et al. 1985; retrospective analysis of patients from 6 trials; 2 Danish institutions, 3/73-9/81 

yes 

while not randomized, 

groups appear similar 

yes 

all followed and 

analyzed 

yes 

partial 

chemoTx, TRTx 

and PCI doses 

and schedules 

not reported 

partial 

only reported 

OS and DFS 

fair 

Rostad et al. 2004 population-based registry analysis 

no 

not randomized; no 

data comparing baseline characteristics 

yes 

all in database 

followed and 

analyzed 

yes 

uncertain 

regimens, doses 

varied and not 

specified 

no 

no data on 

adverse 

events 

poor 

George et al. 1986 population-based registry analysis 

no 

not randomized; no 

data comparing baseline characteristics 

yes 

all in database 

followed and 

analyzed 

yes 

uncertain 

regimens, doses 

varied and not 

specified 

no 

no data on 

adverse 

events 

poor 
C-79

Question 9. Treatment of Recurrent/Progressive Disease Table 9A: Sample Selection, Randomized Trials Study Inclusion Exclusion 

n, Randomized 

n, Withdrawn or Excluded 

O’Brien 2005 relapsed SCLC ineligible for further IV 

CTx; PS 0-2 

 141 

Sculier 2002 1/94 – 4/01 European Lung Cancer Working Party 

Proven SCLC; prior CTx did not include platinum or etoposide; evaluable/ measureable lesion; KPS > 60; adequate 

hematologic, hepatic, renal function; 

Active or non-cured malignancy; age > 75; active infectious disease, psychological disorders, MI < 3 mo, CHF/arrhythmia, 

72 7 

von Pawel 2001 31 centers in Europe, South Africa and Australia 

Limited or extensive SCLC had recurred >

3 mo after CR/PR to 1st-line CTx; 

enrollment stratified by stage, response duration, presence liver metastases; > 2 

cm measurable disease; LE > 2 mo; 

adequate bone marrow, hepatic, renal function; > 4 wks since surgery, 24 hrs 

since RTx; 

Previous/current malignancies; brain metastases allowable if signs/symptoms attributable to them or on corticosteroids; severe or uncontrolled medical problems 

106 

von Pawel 1999 International multicenter trial 

Documented progressive, limited or extensive SCLC; PD > 60 d after 1st-line 

CTx; > 1 bidimensionally measurable 

lesion; ECOG PS 0-2; adequate bone marrow, hepatic, renal function; > 4 wks 

since surgery, 24 hrs since RTx; 

Previous/current malignancies; brain metastases if symptomatic or on corticosteroids; pre-existing cardiac disease (CHF/arrhythmias/MI < 3 mo); CAV contraindicated; exceeded lifetime doses of doxorubicin or epirubicin; prior topotecan; > 1 prior CTx regimen 

211 

Postmus 1993 6/86 – 5/90 Multiple European centers 

Proven SCLC; age < 75; ECOG PS 0-3; 

adequate hematoogic, hepatic, renal function; documented progression < 3 mo 

of last CTx; previously treated with combination CTx on EORTC 08862 protocol; 

CNS metastases 68 

Trillet-Lenoir 1992 8/87 – 4/91 8 centers in France 

Documented relapsing SCLC to 1st-line 

CTx; adequate hematologic, hepatic function 

Age > 65; KPS < 60%; severe renal, cardiac disease 

37 5 

O’Bryan 1990 SWOG 

SCLC; failed or relapsed after 1st-line 

CTx; measurable tumor; recovered from prior therapy; KPS 3 or better; LE > 6 wks; 

good risk = tolerated prior CTx, no prior RTx, age < 65 

Prior treatment with this study’s combination of drugs (but use of cisplatin or vincristine allowable); 

103 (+26 nonrandomized patients) 

 
C-79

Question 9. Treatment of Recurrent/Progressive Disease Table 9A: Sample Selection, Randomized Trials (continued) Study Inclusion Exclusion 

n, Randomized 

n, Withdrawn or Excluded 

Spiro 1989 02/82 – 09/85 Multiple centers in the United Kingdom 

2-stage randomized trial: stage 1 – 1st-line 

chemotherapy (4 or 8 cycles of CVE), stage 2 – 2nd-line chemotherapy/ 

supportive care; histologically, cytologically proven SCLC; < 75; 

Vascular, renal, neurological disease which would preclude chemotherapy 

610 440 

Wolff 1986 US center 

Proven SCLC; prior CTx not including etoposide; recurrent and measurable disease; age < 65; LE > 2 mo; KPS > 

60%; normal peripheral blood cell counts; 

Evidence of serious organ dysfunction not attributable to tumor 

79 2 
C-80

Question 9. Treatment of Recurrent/Progressive Disease Table 9B: Patient Characteristics, Randomized Trials Study Age (yr) Gender (%) 

Previous Treatment Regimens (%) 

Performance Status 

(%) 

Comorbid

F

O’Brien 2005 po T BSC

mn md 60 59 rng sd 

 All

M 73 F 27 

 PS po T BSC

0/1 73 67 

 

ED med TTP 

Sculier 2002 PE CbPE

mn md 58 59 rng 41-73 39-70 sd 

 PE CbPE

M 84 76 F 16 24 

 PE CbPE

EVI 84 79 VAC, other 16 21 RTx 6 18 Surgery 3 0 

KPS PE CbPE

60-70 45 32 80-100 55 68 

 

> 5% ↓ wt OR 1st CT

von Pawel 2001 

 po T iv T

mn 59.9 58.2 md rng 38-79 35-74 sd 

 po T iv T

M 75.0 79.6 F 25.0 20.4 

 PS po T iv T

0 19.2 33.3 1 65.4 38.9 2 15.4 27.8 

 

limited extensive liver mets 

von Pawel 1999 

 iv T CAV

Platinum 51.4 44.2 CAV 18.7 15.4 PE+CAV 12.1 16.3 RTx 61.7 55.8 Immunotherapy 0.0 1.9 Surgery 14.0 27.9 

ECOG iv T CAV0 16.8 19.2 1 59.8 61.5 2 23.4 19.2 

 

Prior brain Med TTP-Liver mets Brain mets Limited Extensive 

Postmus 1993 IMP VP CDE

avg 57 58 55 rng 38- 39- 43-  69 73 67 sd 

 MP VP CDEM 71 86 88 F 29 14 12 

 IMP VP CDE

1 1st-line cycle 0 9 0 

2 cycles 14 32 8 3 cycles 10 14 0 4 cycles 5 14 16 5 cycles 71 32 52 > 5 cycles 0 0 24 

ECOG IMP VP CDE

0 24 18 20 1 43 45 40 2 24 32 20 3 10 5 20 

1st-2nd-line 0-4 wks 5-8 9-13 Stage

Limited Extensive 

Trillet-Lenoir 1992 

 PE1 PE2mn 56.73 52.47 md rng sd 8.7 5.95 

 PE1 PE2

M 100 88 F 0 12 

 KPS PE1 PE2

mn 79.17 74.71 sd 13.82 10.06 

 

mn LDH sd, LDH 1st-line OR

O’Bryan 1990 BTOC PE

mn md 58 61 rng 41-75 38-76 sd 

 BTOC PE

M 80 64 F 20 36 

 BTOC PE

CAV 49 52 Etoposide 24 19 Other 27 29 

KPS BTOC PE0-1 53 39 2-3 47 61 

 

Limited Extensive Good risk Poor risk 
C-81

Question 9. Treatment of Recurrent/Progressive Disease Table 9B: Patient Characteristics, Randomized Trials (continued) Study Age (yr) Gender (%) 

Previous Treatment Regimens (%) 

Performance Status 

(%) 

Comorbid

F

Spiro 1989 MA PE

mn md rng sd 

 MA BSC

M F 

 MA BSC MA BSC 

Wolff 1986 100 200 300

< 50 19 11 15 50-60 38 56 46 > 60 42 33 31 

 100 200 300M 58 93 81 F 42 7 19 

 100 200 300

1 CTx reg 88 78 73 2 CTx regs 12 19 12 3 CTx regs 0 4 15 RTx 54 52 73 Surgery 23 22 38 

KPS 100 200 300

60 0 15 0 70 46 33 46 80 27 41 31 90 19 7 12 100 8 4 12 

Site 

Contra lunLiver Brain Marrow Bone Subcut Med LNs SC LNs 
C-82

Question 9. Treatment of Recurrent/Progressive Disease Table 9C: Treatments, Randomized Trials Study Treatment Regimen Outcomes Response Criteria ObserO’Brien 2005 Group Agent Dose Schedule

po T topotecan 2.3 mg/ m2 d1-5, q 21 d 

BSC best supportive  care 

Overall survival (1O), symptom control, tumor response, adverse events 

WHO criteria 

Sculier 2002 Group Agent Dose Schedule

PE cisplatin 20 mg/m2 d1-3, q 21 d, > 3 cycles 

 etoposide 100 mg/m2 d1-3, q 21 d, > 3 cycles CbPE carboplatin 200 mg/m2 d1, q 21 d, > 3 cycles 

 cisplatin 20 mg/m2 d2-3, q 21 d, > 3 cycles 

 etoposide 100 mg/m2 d1-3, q 21 d, > 3 cycles 

Tumor response (1O), response duration, survival, adverse outcomes 

CR= all clinically detectable disease 

gone, > 4 wks 

PR= ↓ by >50%, all measureable 

lesions, > 4 wks 

SD= ↓ in lesion size by <50% or ↑

by <25%, no PD > 3 mo 

PD= ↑ by >25%, cross sectional 

area, >1 lesion/new lesion 

 

von Pawel 2001 Group Agent Dose Schedule

po T topotecan 2.3 mg/m2 po, d1-5, q 21 d, > 4 

 cycles iv T topotecan 1.5 mg/m2 iv, d1-5, q 21 d, > 4 

 cycles 

Tumor response (1O), time to 

progression, survival, symptoms, adverse events 

WHO criteria Blinde

Von Pawel 1999 Group Agent Dose Schedule

iv T topotecan 1.5 mg/m2 iv, d1-5, q 21 d, 1- 

 15 cycles CAV cytoxan 1 g/m2 d1, q 21 d, 1-7 cycles 

 doxorubin 45 mg/m2 d1, q 21 d, 1-7 cycles 

 vincristine 2 mg d1, q 21 d, 1-7 cycles 

Tumor response (1O), time to 

progression, survival, symptoms, adverse events 

WHO criteria Blinde
C-83

Question 9. Treatment of Recurrent/Progressive Disease Table 9C: Treatments, Randomized Trials (continued) Study Treatment Regimen Outcomes Response Criteria ObserPostmus 1993 Group Agent Dose Schedule

IMP ifosfamide 5 g/ m2 d1, q 28 d, max 5 cycles 

 mesna 4.35 g/ m2 d1, q 28 d, max 5 cycles 

 carboplatin 400 mg/ m2 d1, q 28 d, max 5 cycles 

VP vincristine 2 mg d1, 8, q 28 d, max 5  cycles  carboplatin 400 mg/ m2 d1, q 28 d, max 5 cycles CDE cytoxan 1 g/ m2 d1, q 28 d, max 5 cycles 

 doxorubicin 45 mg/ m2 d1, q 28 d, max 5 cycles 

 etoposide 100 mg/ m2 d1, 3, 5, q 28 d, max 5 

 cycles IMP, VP, CDE were 1st-line regimens, progression on 

IMP/VP treated with 2nd-line CDE, progression on CDE 

treated with 2nd-line VIMP 

Tumor response (1O), survival, adverse events 

WHO criteria 

Trillet-Lenoir 1992 

Group Agent Dose Schedule

PE1 cisplatin 20 mg/m2 d1-5, q 28 d 

 etoposide 60 mg/m2 d1-5, q 28 d PE2 cisplatin 40 mg/m2 d1-5, q 28 d  etoposide 100 mg/m2 d1-5, q 28 d 

Tumor response (1O), 

survival, adverse events 

 

O’Bryan 1990 Group Agent Dose Schedule

BTOC vincristine 2 mg d1, 21, 42  thiotepa 20 mg/m2 d1, 21, 42 

 cytoxan .375/.5 g/ m2 d1, 21, 42 

 carmustine 100 mg/m2 d1, 21, 42 

PE cisplatin 50 mg/m2 d2 

 75 mg/m2 d2  etoposide 100 mg/m2 d1, 3, 4 

 125 mg/m2 d1, 3, 4 

Tumor response (1O), 

survival, adverse events 

CR= all clinically detectable disease 

gone, > 4 wks 

PR= ↓ by >50%, all measureable 

lesions, > 4 wks 

 

Spiro 1989 Group Agent Dose Schedule

MA methotrexate 50 mg/ m2 q 21 d, < 9 cycles 

 doxorubicin 50 mg/ m2 q 21 d, < 9 cycles BSC best supportive  care 

Survival (1O), 

progresssion-free survival, tumor ressponse 

CR= all clinically detectable disease 

gone, 

PR= ↓ by >50%, all measureable 

lesions, > 3 wks 

SD= ↓ in lesion size by <50% 

 
C-84

Question 9. Treatment of Recurrent/Progressive Disease Table 9C: Treatments, Randomized Trials (continued) Study Treatment Regimen Outcomes Response Criteria ObserWolff 1986 Group Agent Dose Schedule

E100 etoposide 100 mg/m2 d1-3 

E200 etoposide 200 mg/m2 d1-3 E300 etoposide 300 mg/m2 d1-3 

Tumor response (1O), 

survival, adverse events 

SECSG criteria 
C-85

Question 9. Treatment of Recurrent/Progressive Disease Table 9D Survival Outcomes Study Overall Survival (%) Progression-Free Survival (%) O’Brien 2005 N Med 1 yr 2 yr 3 yr 4 yr 5 yr 

po T 71 26 wks 49 (6 mo) BSC 70 14 wks 26 HR=0.64 (95% CI: 0.45, 0.90, p=0.0104) 

 N Med 1 yr 2 yr 3 po T 71 84 d BSC 70 90 d 

Sculier 2002 N Med 1 yr 2 yr 3 yr 4 yr 5 yr 

PE 31 18.9 wks 18 CbPE 34 33.0 wks 19 Log-rank, p=0.11 

 N Med 1 yr 2 yr 

von Pawel 2001 

 N Med 1 yr 2 yr 3 yr 4 yr 5 yr po T 52 32.3 wks ~25 iv T 54 25.1 wks ~8 adjusted RR=0.90 (95% CI 0.55, 1.47, NS) 

 N Med 1 yr 2 yr po T 52 14.9 wks ~5 iv T 54 13.1 wks adjusted RR=0.98 (95% CI 0.63, 1.54, NS) 

von Pawel 1999 

 N Med 1 yr 2 yr 3 yr 4 yr 5 yr iv T 107 25.0 wks 14.2 CAV 104 24.7 wks 14.4 Log-rank, p=0.772, adjusted RR=1.17 (p=0.322) 

 N Med 1 yr 2 yr iv T 107 13.3 wks CAV 104 12.3 wks p=0.552 

Postmus 1993 N Med 1 yr 2 yr 3 yr 4 yr 5 yr 

VIMP 43 19 wks CDE 25 22 wks 

 N Med 1 yr 2 yr 

Trillet-Lenoir 1992 

 N Med 1 yr 2 yr 3 yr 4 yr 5 yr PE1 15 13 wks PE2 17 16.5 wks 

 N Med 1 yr 2 yr 

O’Bryan 1990 N Med 1 yr 2 yr 3 yr 4 yr 5 yr 

BTOC 45 13 wks PE 58 16 wks (RR 1.3, 95%CI 0.9, 2.0) BTOCgood 11 10 wks PEgood 16 35 wks (RR 3.3, 95%CI 1.2, 9.1) BTOCpoor 34 14 wks PEpoor 68 12 wks (RR1.1, 95%CI 0.7, 1.8) 

 N Med 1 yr 2 yr 

Spiro 1989 N Med 1 yr 2 yr 3 yr 4 yr 5 yr 

MA BSC 

 N Med 1 yr 2 yr 

Wolff 1986 N Med 1 yr 2 yr 3 yr 4 yr 5 yr 

E100 26 12.6 wks ~4 E200 27 20.0 wks ~12 E300 26 22.5 wks ~24 Log-rank, Gehan-Wilcoxon, p=NS) 

 N Med 1 yr 2 yr 
C-86

Question 9. Treatment of Recurrent/Progressive Disease Table 9E: Tumor Response and Quality of Life, Randomized Trials 

Study Tumor Response (%) Quality of Life 

O’Brien 2005 N CR PR SD PD NE 

po T 71 7 44 BSC 70 

 Scale Domain F/U 

 QoL EQ-5D: significantly faster deterio

Sculier 2002 N CR PR SD PD NE 

PE 31 0 29 CbPE 34 9 38 Median response duration: PE 5.2 mo, CbPE 7.8 mo 

 Scale Domain F/U 

von Pawel 2001 

 N CR PR SD PD NE po T 52 1.9 21.2 19.2 30.8 26.9 iv T 54 3.7 11.1 29.6 42.6 13.0 Difference in ORR = 8.3% (95% CI -6.6%, 23.1%, NS) Median response duration: po T 18.1 wks, iv T 13.9 wks 

 po Topotecan Scale Domain F/U n % improvSymptoms chest pain post-CTx 19 42.1  dyspnea 29 13.8  cough 31 16.1  hemoptysis 3 33.3  anorexia 27 18.5  insomnia 25 32.0  hoarseness 14 35.7  fatigue 33 21.2  impaired ADLs 31 25.8 

von Pawel 1999 

 N CR PR SD PD NE iv T 107 0.0 24.3 19.6 45.8 10.3 CAV 104 1.0 17.3 11.5 52.9 17.3 Difference in ORR, p=0.285 Median response duration iv T 14.4, CAV 15.3 (p=0.300) 

 iv Topotecan Scale Domain F/U n % improvSymptoms chest pain post-CTx 44 25.0  dyspnea* 68 27.9 *p<0.05 cough 69 24.6  hemoptysis 15 26.7  anorexia* 56 32.1  insomnia 57 33.3  hoarseness* 40 32.5  fatigue* 70 22.9  impaired ADLs* 67 26.9 

Postmus 1993 N CR PR SD PD NE 

VIMP 25 4 56 8 24 8 CDE 43 14 37 19 23 7 Median response duration VIMP 16 wks (4-30), CDE 19 wks (12-34) 

 Scale Domain F/U 

Trillet-Lenoir 1992 

 N CR PR SD PD NE PE1 15 6.6 20 13.3 60 PE2 17 11.8 23.5 11.8 52.9 

 Scale Domain F/U 

O’Bryan 1990 N CR PR SD PD NE 

BTOC 45 0 13 PE 58 2 10 (p=0.91) BTOCgood 11 27 PEgood 16 27 BTOCpoor 34 9 PEpoor 68 9 

 Scale Domain F/U 
C-87

Question 9. Treatment of Recurrent/Progressive Disease Table 9E: Tumor Response and Quality of Life, Randomized Trials 

Study Tumor Response (%) Quality of Life 

Spiro 1989 N CR PR SD PD NE 

MA 170 4 19 45 32 1 

 Scale Domain F/U 

Wolff 1986 N CR PR SD PD NE 

E100 26 4 E200 27 7 E300 26 4 

 Scale Domain F/U 
C-88

Question 9. Treatment of Recurrent/Progressive Disease Table 9F: Adverse Events, Randomized Trials 

Toxicity Type Study Description Group n Gr 3 % 

Treatment-related mortality O’Bryan 1990 Drug-related deaths BTOC 45 4 

PE 84 1 

Alopecia Sculier 2002 PE 28 21 (3

CbPE 31 39 

 von Pawel 2001 po T 52 1.9 

iv T 54 13.0 

 von Pawel 1999 iv T 107 0.0 (

CAV 104 0.0 

Fatigue von Pawel 2001 po T 52 5.8 

iv T 54 1.9 

 von Pawel 1999 iv T 107 4.7 (

CAV 104 8.7 

Diarrhea von Pawel 2001 po T 52 7.7 

iv T 54 0.0 

 von Pawel 1999 iv T 107 0.9 (

CAV 104 0.0 

Nausea O’Brien 2005 po T 71 1 

BSC 70 0 

 von Pawel 1999 iv T 107 39.3 

CAV 104 40.4 

Vomiting O’Brien 2005 po T 71 3 

BSC 70 0 

 Sculier 2002 Nausea/vomiting PE 30 7 (3

 32 0 

 von Pawel 2001 po T 52 11.5 

iv T 54 3.7 

 von Pawel 1999 iv T 107 2.9 (

CAV 104 1.9 

 Wolf 1986 Nausea/vomiting/bloody diarrhea/ 

stomatitis 

E100 26 5 E200 27 4 E300 26 10 

Anorexia von Pawel 1999 iv T 107 0.9 

CAV 104 0.0 

Diarrhea O’Brien 2005 po T 71 6 

BSC 70 0 

Lethargy O’Brien 2005 Fatigue po T 71 4 

BSC 70 4 

Neurosensory O’Brien 2005 Pain po T 71 3 

BSC 70 6 

Neuromotor Hearing loss 1 Comparison of grade 3 and above versus others Fisher’s exact test. 
C-89

Question 9. Treatment of Recurrent/Progressive Disease Table 9F: Adverse Events, Randomized Trials (continued) Toxicity Type Study Description Group n Gr 3 % Esophagitis Bronchopulmonary O’Brien 2005 Dyspnea po T 71 3 

BSC 70 9 

 von Pawel 2001 Dyspnea 

Pulmonary embolism 

po T 52 9.6 iv T 54 9.3 po T 52 1.9 iv T 54 0 

Pneumonitis von Pawel 2001 Pneumonia po T 52 5.8 

iv T 54 0.0 

Hepatic Kidney Hemorrhage Anemia O’Brien 2005 po T 71 25 (3 von Pawel 2001 po T 52 27.5 

iv T 54 26.4 

 von Pawel 1999 iv T 104 39.4 

CAV 101 17.8 

Thrombocytopenia O’Brien 2005 po T 71  Sculier 2002 PE 30 17 (

CbPE 32 38 

 von Pawel 2001 po T 52 25.5 

iv T 54 24.5 

 von Pawel 1999 iv T 104 28.8 

CAV 101 9.9 

 Postmus 1993 VIMP 25 8 

CDE 43 6 

 Trillet-Lenoir 1992 PE1 15 0 

PE2 17 18 

 Wolff 1986 Neutropenia E100 26 0 

E200 27 0 E300 26 24 

Leukopenia or neutropenia O’Brien 2005 Neutropenia po T 71  Sculier 2002 Leukopenia PE 30 60 (

CbPE 32 56 

 von Pawel 2001 Leukopenia 

Neutropenia 

po T 52 27.5 iv T 54 45.3 po T 52 21.6 iv T 54 25.9 

2 Comparison of grade 3 and above versus others Fisher's exact test. 
C-90

Question 9. Treatment of Recurrent/Progressive Disease Table 9F: Adverse Events, Randomized Trials (continued) Toxicity Type Study Description Group n Gr 3 % Leukopenia or neutropenia von Pawel 1999 Leukopenia 

Neutropenia 

iv T 104 54.8 CAV 101 37.6 iv T 104 18.3 CAV 99 15.2 

 Postmus 1993 Leukopenia VIMP 25 26 

CDE 43 38 

 Trillet-Lenoir 1992 Leukopenia PE1 15 33 

PE2 17 12 

 Wolff 1986 E100 26 5 

E200 27 25 E300 26 0 

Infection O’Brien 2005 Febrile neutropenia 

Neutropenic infections 

Sepsis 

po T 71 po T 71 po T 71 

 Sculier 2002 PE 30 3 (3/

CbPE 33 3 

 von Pawel 2001 Fever po T 52 3.8 

iv T 54 1.9 

Other 
C-91 

Question 9. Treatment of Recurrent/Progressive Disease Table 9G: Study Quality Ratings, Randomized Trials Study 

Initial Assembly of Comparable Groups 

Low Loss to Followup, Maintenance of Comparable Groups 

Measurements Reliable, Valid, Equal 

Interventions Comparable/ Clearly Defined 

Appropriate Analysis of Results 

Overall Rating 

O’Brien 2005 ? 

Available 

only in 

abstract 

Sculier 2002 Partial 

(arms balanced but randomization method not described) 

Yes 

Partial 

(overall response 

rate was primary 

outcome) 

Yes Yes Fair 

von Pawel 2001 Partial 

(arms balanced but randomization method not described) 

Yes Yes Yes Yes Fair 

von Pawel 1999 Partial 

(randomization method adequate, but age and gender distributions not specified) 

Yes Yes Yes Yes Fair 

Postmus 1993 Partial 

(arms balanced but randomization method not described) 

Yes 

Partial 

(overall response 

rate was primary 

outcome) 

Yes Yes Fair 

Trillet-Lenoir 1992 Partial 

(arms balanced but randomization method not described) 

Yes ? No Yes Poor 

O’Bryan 1990 Partial 

(arms balanced but randomization method not described) 

Yes 

Partial 

(overall response 

rate was primary 

outcome) 

No Yes Poor 

Spiro 1989 Partial 

(arms balanced but randomization method not described) 

? Yes Yes No Poor 

Wolff 1986 

No Yes 

Partial 

(overall response 

rate was primary 

outcome) 

No No Poor 
C-92 

Question 9. Treatment of Recurrent/Relapsed Disease Table 9H: Sample Selection, Phase II StudiesStudy Inclusion Exclusion 

n, Enrolled 

n, W

Ando 2004 2/98 – 5/01 Multiple centers in Japan 

Diagnosis of SCLC; refractory (off CTx < 2 mo, n=16) or relapsed (off CTx > 2 mo, n=9) after initial etoposide regimen; measurable disease; ECOG PS >2; adequate bone marrow, hepatic, rental 

function; age 15-75 

brain metastases; severe medical problems that would interfere with compliance 

25 

Agelaki 2004 11/99 – 09/02 Multiple centers in Greece 

Confirmed SCLC, refractory or relapsing, bidimensionally measurable disease, limited or extensive and had relapsed after > 1 

CTx regimen, WHO PS 0-2, LE > 3 mo, > 4 wks since CTX, RTx to 

< 25 % of marrow-containing bones > 4 wks after; adequate 

hematologic, renal, hepatic function; brain metastases allowed if previous RTx with clinical, radiologic improvement; age 18-75 

Infections, malnutrition, concurrent active malignancy 

31 5 

Goto 2004 10/98-03/01 Multiple centers in Japan 

Histologically/cytologically confirmed SCLC; responded to 1st-line 

therapy, relapsed > 8 wks; age < 75; ECOG PS 0-2; measurable 

disease; adequate hematologic, hepatic, renal function 

Massive pleural effusion; prior RTx to area larger than 1/3 bone marrow volume; active infection; contraindications to use or irinotecan 

40 

Ardizzoni 2003 1/97 – 4/99 Multiple European centers 

Confirmed SCLC, relapsed, > bidimensionally measurable lesion 

outside areas of prior RTx, WHO PS 0-2; PD after 1st-line CTX 

(except camptothecin analogues; cisplatin allowable if responsive, CTx > 6 mo before;1st-line CTx regimen given twice allowable; all 

CTx/Rtx stopped > 4wks with recovery from side effects; 

asymptomatic brain metastases allowable; brain RTx allowable after current treatment; symptomatic brain metastases allowable if prior treatment adequate; adequate hematologic, renal, hepatic function; 

age 18-75; 

Pre-existing uncontrolled cardiac disease; documented MI < 3 mo; > grade 2 sensory/motor 

neuropathy; active infection; past or current history of neoplasms 

116 6 

ine

Hainsworth 2003 3/98 – 2/99 6 US centers 

Proven SCLC; PD after 1 CTx regimen; < 2 course prior RTx; < 25% 

of marrow-bearing bone in RTx fields; brain metastases allowable if minimal neurologic impairment with whole brain RTx; ECOG PS 0-2; adequate hematologic, hepatic, renal function 

 30 

Hoang et al. 2003 4/98 – 10/01 Wiconsin Oncology Group 

Previously treated SCLC patients; sensitive (recurrence > 3 mo after 1st-line CTx) or refractory (PD or recurrence < 3 mo); limited or 

extensive; measurable/evaluable; 1 prior CTx regimen; ECOG PS 0-2; LE > 3 mo; age > 18; adequate hematologic, hepatic, renal function; > 4 wks since CTx/surgery; > 24 hr since RTx; clinically 

stable brain metastase allowable 

 27 3 

Masters 2003 12/97 – 9/98 Multiple US centers 

Proven SCLC; sensitive (relapse > 90 d after CTx) or refractory 

(relapse < 90 d after CTx); limited or extensive; PD after initial CTx; prior RTx allowable, measurable disease outside field or clear PD within field; ECOG PS 0-2; adequate renal, hepatic, bone marrow function 

Ongoing toxicity > grade 1; prior gemcitabine treatment 

46 4 

2 2 pr
C-93 

Question 9. Treatment of Recurrent/Relapsed Disease Table 9H: Sample Selection, Phase II Studies (continued) Study Inclusion Exclusion 

n, Enrolled 

n, W

Kosmas 2001 Multiple centers in Greece 

Confirmed SCLC; relapsed after CbE CTx + TRTx; not curable by 

other 2nd-line CTx or RTx; WHO PS 0-2; LE > 3 mo; adequate 

hematopoietic, hepatic, renal function 

previous CTx; active CAD; unstable diabetes mellitus; NCI > grade 2 peripheral neuropathy; 

prior RTx to > 30% of bone marrow 

33 

Kakolyris 2001 11/97 – 8/99 Multiple centers in Greece 

Confirmed SCLC; refractory; had failed 1 prior 1st-line CTx; WHO PS 

0-2; LE > 3 mo; adequate hematologic, hepatic, renal function; brain 

metastases allowable if RTx given, lesions stable, clinically improved; Age < 75 

Other medical problems severe enough to affect compliance; >

20% ↓ body weight; active infection; massive liver metastases; second primary tumor 

32 3 

NE 

van der Lee 2001 2/97 – 11/98 Multiple centers in the Netherlands 

Proven SCLC; relapsed < 3 mo of last CTx; limited or extensive; 

prior RTx allowable if not all measurable lesions in field; age > 18; 

ECOG PS 0-3; adequate hematologic, hepatic, renal function 

Uncontrolled infection; prior gemcitabine; symptomatic brain metastases; other malignancy < 3 yr before 

41 3 

NE 

Sessa 2000 3/95 – 8/97 16 European centers 

Confirmed SCLC; progressive recurrent after 1st-line CTx; > 1 

bidimensionally measurable lesion; WHO PS 0-2; 1 prior CTx regimen that did not include camptothecin analogues; adequate hematologic, hepatic and renal function 

Signs of brain or leptomeningeal disease; history CHF; active heart disease requiring antiarrhythmics 

67 5 

NE 

Sonpavde 2000 8/96 – 1/98 Hoosier Oncology Group 

Recurrent, measurable SCLC; KPS > 50%; adequate hematologic, hepatic, cardiac, renal function; 1 prior combination CTx regimen 

 46 

Groen 1999 2/96 – 9/97 3 centers in the Netherlands 

Proven SCLC; relapsed < 3 mo after last CTx; age 18-75; ECOG PS 0-3; bidimensionally measurable disease; adequate hematologic, hepatic, renal function; concurrent RTx allowable if not all measurable sites in field 

Significant cardiac disease; uncontrolled infection; concurrent CTx 

35 1 

NE 

Ardizzoni 1997 7/92 – 9/94 22 European centers 

Confirmed SCLC; PD after 1 1st-line CTx that did not include a 

camptothecin analog; > 1 bidimensionally measurable lesion outside 

RTx field; age < 75; WHO PS 0-2; LE > 3 mo; > 3 wks since 

systemic treatment, recovered from side effects; brain mets with neurologic symptoms allowable if controlled by RTx/steroids; adequate hematologic, hepatic, renal function 

 101 8 
C-94 

Question 9. Treatment of Recurrent/Relapsed Disease Table 9H: Sample Selection, Phase II Studies (continued) Study Inclusion Exclusion 

n, Enrolled 

n, W

Gridelli 1997 Multiple centers in Italy 8/94-2/96 

Proven pretreated SCLC; ECOG PS 0-2; age < 75; normal platelet, 

renal, hepatic function; 

Significant heart disease 30 

Einhorn 1995 2/90 – 8/93 Hoosier Oncology Group 

Refractory SCLC; no previous ifosfamide 46 5 

Faylona 1995 2/90 – 8/93 Hoosier Oncology Group 

Previously treated progressive or recurrent SCLC; KPS > 50; 

adequate bone marrow, renal function; 1 prior CTx regimen 

Prior ifosfamide or etoposide; history of CHF; patients who progressed within 4 wks on EP 

46 4 

Sculier 1995 9/91 – 12/93 12 European centers 

Proven SCLC; prior non-platinum CTx and failed 1st-line; had 

evaluable/measurable lesion; KPS > 60; age < 75 

Other prior malignancy; active infectious disease, CNS disease, psychiatric disorders, recent MI, > WHO grade II peripheral polyneuropathy; CTx/ RTx < 4 wks before 

41 

Smyth 1994 Multiple European centers 

Verified SCLC; evidence of PD; locally advanced or metastatic extensive disease; > 1 lesion measurable bidimensionally; WHO PS 

0-2; age 18-75; adequate hematologic, hepatic, renal function; no more than 1 prior CTx regimen; if prior RTx, assessed site outside field 

No more than one prior CTx 34 6 

Albain 1993 SWOG-8605 Multiple US centers 

Diagnosis of SCLC; measurable or evaluable disease; progressed during initial therapy or relapsed after an interval of response; limited or extensive; > 3 wks since prior CTx; must have failed > 1 

CTx regimen; after interim analysis prior CTx limited to regimen with cyclophosphamide or EP; limited stage patients must have failed RTx with measurable/evaluable disease outside field; brain metastases allowable if patients could receive brain RTx; initial SWOG PS 0-4, then limited to 0-2 

 69 2 

Jassem 1993 6/90 – 5/91 8 European centers 

Confirmed SCLC; progressive recurrent not amenable for curative surgery/RTx; response to 1st-line CTx; > 3 mo since prior CTx; 

measurable/evaluable disease outside irradiated area; brain/leptomeningeal disease allowable if controlled by RTx 

Previous/current other malignancies; poor medical risks because of non-malignant systemic disease, active uncontrolled infection, peripheral neuropathy 

26 1 
C-95 

Question 9. Treatment of Recurrent/Relapsed Disease Table 9H: Sample Selection, Phase II Studies (continued) Study Inclusion Exclusion 

n, Enrolled 

n, W

Einhorn 1990 5/88 – 9/88 Hoosier Oncology Group 

Consecutive patients diagnosed with SCLC; measurable/evaluable progressive disease; > 1 prior combination CTx regimen; KPS > 50; 

adequate hematologic, hepatic, renal function; CTx finished > 3 wks 

 26 

Graziano 1990 6/83-5/84 Multiple US centers 

Documented measurable SCLC, failed to respond to or relapsed after initial response to 1 prior CTx regimen; prior mono etoposide or cisplatin allowable; CALGB PS 0-2; > 4 wks since surgery, RTx, CTx; adequate hematologic, hepatic, renal function 

previous/concomitant malignancy; serious medical/ psychiatric illness 

43 8 

JCOGLC 1990 1/86 – 1/88 Multiple centers in Japan 

Proven SCLC/NSCLC; nonresected; evaluable/measurable; LE ≥ 3 

mo; adequate hematologic, hepatic, renal function; age > 15; > 4 

wks since any prior CTx/RTx; 1st-line and 2nd+-line 

 31 

Sculier 1990 Multiple European centers 

Failed (relapse/no response) to a 1st-line treatment with etoposide+vindesine+cisplatin; evaluable/measurable disease;KPS 

> 50; adequate hematologic, hepatic, renal function; < 75 

history of prior malignancy; active infectious disease; recent myocardial infarction; congestive heart failure; cardiac arrhythmia 

49 4 

Issell 1985 Multiple US centers 

Refractory SCLC; failure to responde to previous combination CTx with > 3 Rx; measurable disease 

Prior etoposide; evidence of liver or renal failure 

116 21 
C-96 

Question 9. Treatment of Recurrent/Relapsed Disease Table 9I: Patient Characteristics, Phase II Studies Study Age 

Gender (%) Stage (%) 

Time Since Last CTx (%) 

Initial Reponse (%) 

Previous Treatment Regimens (%) Race (%) 

Performance Status (%) 

Ando. 2004 

mn 65.3 md rng sd 9.7 

M 96 F 4 

LD 36 ED 64 

< 2 mo 64 > 2 mo 36 

CR 0 PR 60 SD 32 PD 8 NE 

PE 16 CbP 84 TRTx 20 Surgery 4 

 ECOG

0-1 88 2 12 

Agelaki 2004 

mn md 60 rng 38-78 sd 

M 94 F 6 

LD 6 ED 94 

 #1 CTx 48 

#2 CTx 39 #3 CTx 10 PE 100 Topotecan 48 CVE 3 Docataxel/ Gemcitibine 6 

 

Goto 2004 mn 

md 40 rng 41-74 sd 

M 72.5 F 27.5 

LD 12.5 ED 87.5 

 PE 28 

CbE 28 PE-VAE 15 PI 5 Other CTx 10 TRTx 20 

 ECOG

0 22.5 1 75 2 2.5 

Ardizzoni 2003 

Sensitive md 60 rng (38-73) Refractory md 55 rng (35-75) 

Sensitive M 79 F 21 Refractory M 17 F 83 

Sensitive LD 27 ED 74 Refractory LD 33 ED 67 

Sensitive md 165 d Refractory md 30 d 

 Sen Ref 

TRTx 69 31 med#CTx 3 3 Cisplatin 22 5 Carbopl 24 36 Etopos 90 83 

 WHO Sen Ref 

0 18 12 1 71 64 2 12 24 

Hainsworth 2003 

mn md 62 rng 34-78 sd 

M 57 F 43 

 CR 23 

PR 57 SD 20 PD NE 

Plat/E 57 Plat/E/pacl 40 Plat/E/pacl/ topotecan 3 

 

Hoang 2003 

mn md 61 rng 45-74 sd 

M 63 F 37 

LD 11 ED 89 

 CTx 100 

RTx 56 

 ECOG

0-1 93 2 7 

Masters 2003 

mn 60.6 md 60.1 rng 41-83 sd 

M 59.5 F 40.5 

 CR 33 

PR 38 SD 14 PD 14 NE 

TRTx 57 Mono CTx 7 Comb 86 Both 7 Surgery 19 

B 5 W 95 H A O 

ECOG

0 24 1 55 2 21 
C-97 

Question 9. Treatment of Recurrent/Relapsed Disease Table 9I: Patient Characteristics, Phase II Studies (continued) Study Age 

Gender (%) Stage (%) 

Time Since Last CTx (%) 

Initial Reponse (%) 

Previous Treatment Regimens (%) Race (%) 

Performance Status (%) 

Kosmas 2001 

mn 62 md rng 55-70 sd 

M 91 F 9 

LD 45 ED 55 

< 3 mo 61 > 3 mo 39 

CR 18 PR 58 SD 12 PD 12 NE 

CTx 100 TRTx 42 

 WHO

md 1 rng 0-2 

Kakolyris 2001 

mn md 60.5 rng 38-77 sd 

M 84 F 16 

LD 0 ED 100 

 EP 84 

CAB 16 RTx 47 Surgery 6 

 WHO

0 28 1 63 2 9 

van der Lee 2001 

< 60 58 > 60 42 

M 76 F 24 

LD 34 ED 66 

 #1 CTx 24 

#2 CTx 47 #3 CTx 29 1st CDE 89 

1st ECE 3 1st oral E 8 

Sessa 2000 

Sensitive md 60 rng 39-76 Refractory md 61 rng 36-79 

Sensitive M 65 F 35 Refractory M 69 F 31 

 Sensitive 

md 7.9 mo rng 3.2-19.6 Refractory md 2.1 rng 0.2-7.5 

 CTx + RTx 44 WHO Sen Ref 

0 19 28 1 62 55 2 19 17 

Sonpavde 2000 

mn md 63 rng 43-77 sd 

M 54 F 46 

LD 63 ED 37 

< 3 mo 30 > 3 mo 70 

CR 39 PR 46 SD 2 PD 13 NE 

Platinum-E + VIP 100 

RTx 59 

 KPS

med 80 rng 50-90 
C-98 

Question 9. Treatment of Recurrent/Relapsed Disease Table 9I: Patient Characteristics, Phase II Studies (continued) Study Age 

Gender (%) Stage (%) 

Time Since Last CTx (%) 

Initial Reponse (%) 

Previous Treatment Regimens (%) Race (%) 

Performance Status (%) 

Groen 1999 

mn md 59 rng 40-73 sd 

M 69 F 31 

LD 44 ED 56 

med 6 wks  0-11 

CR 15 PR 65 SD 18 PD 3 NE 

#1 CTx 53 #2 CTx 44 #3 CTx 3 CTx 100 RTx 21 1st CDE 97 

 ECOG

0 21 1 56 2 18 3 6 

Ardizzoni 1997 

mn md 58 rng sd 

M 69 F 31 

LD 62 ED 38 

< 6 mo 82 > 6 mo 18 

 < 3 CTx Rx 58 

> 3 CTx Rx 42 RTx 37 ImmunoTx 6 Surgery 12 

 WHO

0 25 1 57 2 18 

Gridelli 1997 

mn md 61 rng 44-74 sd 

M 93 F 7 

LD 10 ED 90 

 Prior etopos 73 ECOG

0 7 1 47 2 47 

Einhorn 1995 

mn md 61 rng 45-76 sd 

M 78 F 22 

LD 22 ED 78 

< 6 mo 44 > 6 mo 56 

 Cisplatin 85 

RTx 49 

 KKPS

80-100 63 70 29 50-60 7 

Faylona 1995 

mn md 60 rng 45-76 sd 

M 79 F 22 

LD 21 ED 79 

< 6 mo 43 > 6 mo 57 

 Cisplatin 86 

RTx 50 

Sculier 1995 

mn md 59 rng 40-74 sd 

M 90 F 10 

LD 25 ED 75 

 CR 3 

PR 78 SD PD 20 NE 

IVE 85 IVA 10 EVI 5 

 KPS

med 80 rng 60-100 

Smyth 1994 

mn md 61 rng 36-72 sd 

M 82 F 18 

 CTx 79 

RTx 24 Surgery 24 

 WHO

0 24 1 65 2 12 

Albain 1993 

mn md 59 rng 30-76 sd 

M 79 F 21 

LD 9 ED 91 

 1 CTx reg 88 

> 2 CTx reg 12 

2-4 CTx Rx 46 > 4 CTX Rx 54 RTx 50 

 SWOG

0-1 54 2-4 46 
C-99 

Question 9. Treatment of Recurrent/Relapsed Disease Table 9I: Patient Characteristics, Phase II Studies (continued) Study Age 

Gender (%) Stage (%) 

Time Since Last CTx (%) 

Initial Reponse (%) 

Previous Treatment Regimens (%) Race (%) 

Performance Status (%) 

Jassem 1993 

mn md 59 rng 41-73 sd 

M 76 F 24 

 CR 44 

PR 56 SD PD NE 

RTx 60 WHO

med 1 rng 0-2 

Einhorn 1990 

 M 58 

F 42 

LD 50 ED 50 

 EP 96 

CAV 54 

 KPS

med 70 rng 50-100 

Graziano 1990 

mn md 60 rng 35-69 sd 

M 66 F 34 

 md 2 mo 

rng 1-27 

 md# CTx Rx 4 

rng 2-7 md# CTx reg 2 rng 1-10 RTX 74% 

 CALGB

0 11 1 46 2 40 

JCOGLC 1990 Sculier 1990 

mn md 59 rng 36-74 sd 

M 93 F 7 

LD 33 ED 67 

 CR/ 

PR 47 

PEV 36 EV 64 

 KPS

md 70 rng 50-90 

Issell 1985 mn 

md 60 rng 27-85 sd 

M 74 F 26 

LD 17 ED 83 

 ADR –CCNU 61 

CCNU –ADR 21 ADR+CCNU 18 

 ECOG

0-1 49 2-4 51 
C-100 

Question 9. Treatment of Recurrent/Relapsed Disease Table 9J: Treatments, Phase II Studies Study Treatment Regimen Outcomes Response Criteria ObserAndo. 2004 Agent Dose Schedule

Irinotecan 60 mg/m2 d1, 8, 15, q 4 wks, > 2 

 cycles if no PD Cisplatin 30 mg/m2 d1, 8, 15, q 4 wks, > 2  cycles if no PD 

Tumor response, survival, adverse events 

WHO criteria 

Agelaki 2004 Agent Dose Schedule

Gemcitabine 1g/ m2 d1, 8, q 21 d to progress-

 ion/max cycles Irinotecan 300 mg/ m2 d8, q 21 d to progress- ion/max cycles 

Tumor response, survival, adverse events 

WHO criteria 

Goto 2004 Agent Dose Schedule

Cisplatin 25 mg/m2 d1, q 7 d, 9 cycles 

Etoposide 60 mg/m2 d1-3, q 21 d, 5 cycles Irinotecan 90 mg/m2 d1, q 14 d, 4 cylces 

Tumor response, survival, progression-free survival, adverse events 

WHO criteria 

Ardizzoni 2003 Agent Dose Schedule

Topotecan .75 mg/ m2 d1-5, q 21 d, max 6 

 cycles Cisplatin 60 mg/m2 d1, q 21 d, max 6 cycles 

Tumor response, adverse events, overall survival, time to progression 

WHO criteria 

Hainsworth 2003 Agent Dose Schedule

Vinorelbine 20 mg/m2 d1, 8, 15, q 28 d, max 6 

 cycles Gemcitabine 1 g/m2 d1, 8, 15, q 28 d, max 6 

 cycles 

Tumor response, response duration, survival, adverse events 

CR= all clinically detectable disease 

gone, > 4 wks 

PR= ↓ by >50%, all measureable 

lesions, > 4 wks 

SD= ↓ in lesion size by <50% or ↑

by <25%, no PD > 3 mo 

PD= ↑ by >25%, cross sectional 

area, >1 lesion, or any new 

lesion 

Hoang 2003 Agent Dose Schedule

Gemcitabine 1.25 g/m2 d1, 8, q 21 d Tumor response, time to progression, 

survival, adverse events 

ECOG criteria 

Masters 2003 Agent Dose Schedule

Gemcitabine 1 g/m2 d1, 8, 15, q 28 d Tumor response, duration of 

remission, survival, adverse events 

Standard criteria 
C-101 

Question 9. Treatment of Recurrent/Relapsed Disease Table 9J: Treatments, Phase II Studies (continued) Study Treatment Regimen Outcomes Response Criteria ObserKosmas 2001 Agent Dose Schedule

Paclitaxel 175 mg/m2 d1, planned 6 cycles 

Ifosfamide 5 g/m2 d1-2, planned 6 cycles 

Cisplatin 100 mg/m2 d1-2, planned 6 cycles 

Tumor response, time to progression, survival, adverse events 

CR= no clinical, radiol evidence of 

tumor, > 4 wks 

PR= ↓ by >50%, all measureable 

lesions, > 4 wks 

SD= ↓ in lesion size by <50% or ↑

by ≤25% 

PD= ↑ by >25%, cross sectional 

area, >1 lesion, or any new 

lesion 

Kakolyris 2001 Agent Dose Schedule

Paclitaxel 200 mg/m2 d1, q 4 wks, to 6 cycles 

 or response + 3 cycles Carboplatin AUC=6 d2, q 4 wks, to 6 cycles  or response + 3 cycles 

Tumor response, time to progression, survival, adverse events 

WHO criteria 

van der Lee 2001 Agent Dose Schedule

Gemcitabine 1 g/m2 d1, 8, 15, q 28 d, max 5 

 Cycles 

Tumor response, survival, adverse events 

WHO criteria 

Sessa 2000 Agent Dose Schedule

GI147211 1.2 mg/m2 d1-5, q 21 d, > 2 cycles 

(camptothecinderivative) 

Tumor response, response duration, adverse events 

WHO criteria 

Sonpavde 2000 Agent Dose Schedule

Doxorubicin 40 mg/m2 q 21 d 

Paclitaxel 175 mg/m2 q 21 d 

Tumor response, survival, time to progression, adverse events 

Groen 1999 Agent Dose Schedule

Paclitaxel 175 mg/m2 q 21 d, max 5 cycles 

Carboplatin AUC=7 q 21 d, max 5 cycles 

Tumor response, response duration, time to progression, survival, adverse events 

CR= complete resolution of all signs 

of known disease, > 4 wks 

PR= ↓ by >50%, all measureable 

lesions, > 4 wks 

SD= ↓ in lesion size by <50% or ↑

by <25% 

PD= ↑ by >25%, cross sectional 

area, >1 lesion, or any new 

lesion 

Ardizzoni 1997 Agent Dose Schedule

Topotecan 1.5 mg/ m2 d1-5, q 21 d, max 6 

 mo after max response 

Tumor response, time to progression, survival, adverse events 
C-102 

Question 9. Treatment of Recurrent/Relapsed Disease Table 9J: Treatments, Phase II Studies (continued) Study Treatment Regimen Outcomes Response Criteria ObserGridelli 1997 Agent Dose Schedule

VM-26 100 mg/m2 d1-3, q 21 d, max 6 

 cycles Lonidamine 600 mg po, d1-5, q 21 d, max 6  Cycles 

Tumor response, progression-free survival, survival, adverse events 

WHO criteria 

Einhorn 1995 Agent Dose Schedule

Ifosfamide 1.2 g/m2 d1-4, q 28 d, max 4 

 cycles Etoposide 37.5 mg/m2 d1-4, q 28 d, max 4  cycles Cisplatin 20 mg/m2 d1-4, q 28 d, max 4  cycles 

Tumor response, adverse events 

Faylona 1995 Agent Dose Schedule

Ifosfamide 1.2 g/m2 d1-4, q 28 d, max 4 

 cycles Etoposide 37.5 mg/m2 po, d1-21/d1-14, q 28 d,  max 4 cycles Cisplatin 20 mg/m2 d1-4, q 28 d, max 4  cycles 

Tumor response, progression-free survival, survival, adverse events 

CR= all clinically detectable disease 

gone, > 4 wks 

PR= ↓ by >50%, all measureable 

lesions, > 4 wks 

SD= ↓ in lesion size by <50% or ↑

by <25%, no PD > 3 mo 

PD= ↑ by >25%, cross sectional 

area, >1 lesion, or any new 

lesion 

Sculier 1995 Agent Dose Schedule

Carboplatin 100 mg/m2 d1, q 7 d, max 24 cycles 

Cisplatin 25 mg/m2 d1, q 7 d, max 24 cycles 

Tumor response, survival, adverse events 

 CR= all clinically detectable 

disease gone, > 4 wks 

PR= ↓ by >50%, all measureable 

lesions, > 4 wks 

SD= ↓ in lesion size by <50% or ↑

by <25%, no PD > 3 mo 

PD= ↑ by >25%, cross sectional 

area, >1 lesion, or any new 

lesion 

Smyth 1994 Agent Dose Schedule

Docataxel 100 mg/m2 d1, q 21 d, max 7 cycles Tumor response, respons duration, 

adverse events 

WHO criteria 

Albain 1993 Agent Dose Schedule

Cytoxan 500 mg/ m2 d1, q 21 d, max 4 cycles 

Cytarabine 250 mg/m2 d1, q 21 d, max 4 cycles Vincristine 2 mg d14, q 21 d, max 4  cycles 

Tumor response, survival, adverse events 

SWOG criteria 

Jassem 1993 Agent Dose Schedule

Vinorelbine 30 mg/m2 d1, q 7 d, max 13 cycles Tumor response, adverse events WHO criteria 
C-103 

Question 9. Treatment of Recurrent/Relapsed Disease Table 9J: Treatments, Phase II Studies (continued) Study Treatment Regimen Outcomes Response Criteria ObserEinhorn 1990 Agent Dose Schedule

Etoposide 50 mg/m2 po, daily Tumor response, response duration, 

survival, adverse events 

CR= no clinical, radiol evidence of 

tumor, >1 mo 

PR= ↓ by >50%, all measureable 

lesions, >1 mo 

SD= ↓ in lesion size by <50% or ↑

by <25% 

PD= ↑ by >25%, cross sectional 

area, >1 lesion, or any new 

lesion 

Graziano 1990 Agent Dose Schedule

Etoposide 80 mg/m2 d1-5, q 21 d, > 2 cycles 

Cisplatin 20 mg/m2 d1-5, q 21 d, > 2 cycles 

Tumor response, survival, adverse events 

 CR= no clinical, radiol evidence of 

tumor, > 4 wks 

PR= ↓ by >50%, all measureable 

lesions, > 4 wks 

SD= ↓ in lesion size by <50% or ↑

by <25% 

PD= ↑ by >25%, cross sectional 

area, >1 lesion, or any new 

lesion 

JCOGLC 1990 Agent Dose Schedule

Carboplatin 300 mg/m2 d1, q 28 d Tumor response CR= no clinical, radiol evidence of tumor, >1 mo 

PR= ↓ by >50%, all measureable 

lesions, >1 mo 

SD= ↓ in lesion size by <50% or ↑

by <25% 

PD= ↑ by >25%, cross sectional 

area, >1 lesion, or any new 

lesion 

Sculier 1990 Agent Dose Schedule

Cytoxan 1 g/m2 d1, q 21-28 d, 10 cycles 

Vincristine 1.4 mg/m2 d1, q 21-28 d, 10 cycles 

Doxorubicin 45 mg/m2 d1, q 21-28 d, 10 cycles 

Tumor response CR= no clinical, radiol evidence of 

tumor, > 4 wks 

PR= ↓ by >50%, all measureable 

lesions, > 4 wks 

SD= ↓ in lesion size by <50% or ↑

by <25% 

PD= ↑ by >25%, cross sectional 

area, >1 lesion, or any new 

lesion 

Issell 1985 Agent Dose Schedule

Etoposide 80 mg/m2 d1-5, q 21-28 d 

 160 mg/m2 po, d2-5, q 21-28 d (last  16 patients) 

Tumor response, adverse events 
C-104 

Question 9. Treatment of Recurrent/Relapsed Disease Table 9K Survival Outcomes, Phase II Studies Study Overall Survival (%) Progression-Free Survival (%) Ando 2004 N Med 1 yr 2 yr 3 yr 4 yr 5 yr 

 25 7.9 mo 44 20 

 N Med 1 yr 2 yr 

Agelaki 2004 N Med 1 yr 2 yr 3 yr 4 yr 5 yr 

Total 31 6 mo 17 Refractory 15 5.37 mo Relapsed 16 5.97 mo 

 N Med 1 yr 2 yr 

Goto 2004 N Med 1 yr 2 yr 3 yr 4 yr 5 yr 

 40 11.8 49 ~15 ~5 

 N Med 1 yr 2 yr  40 5.0 ~10 ~3 

Ardizzoni 2003 N Med 1 yr 2 yr 3 yr 4 yr 5 yr 

Sensitive 68 6.4 mo 19.7 Refractory 42 6.1 mo 15.2 

TTP N Med 1 yr 2 yr Sensitive 68 4.7 mo Refractory 42 3.0 mo 

Hainsworth 2003 

 N Med 1 yr 2 yr 3 yr 4 yr 5 yr  30 5 mo ~15 

 N Med 1 yr 2 yr 

Hoang 2003 N Med 1 yr 2 yr 3 yr 4 yr 5 yr 

Sensitive 15 8.8 mo 33.3 Refractory 12 4.2 16.7 Total 27 6.4 25.4 

 N Med 1 yr 2 yr Sensitive 15 6 mo Refractory 12 5.6 Total 27 6 

Masters 2003 N Med 1 yr 2 yr 3 yr 4 yr 5 yr 

Relapsed 24 7.3 Refractory 18 6.9 Total 42 7.1 ~28 

 N Med 1 yr 2 yr 

Kosmas 2001 N Med 1 yr 2 yr 3 yr 4 yr 5 yr 

 33 28 wks 12 

TTP N Med 1 yr 2 yr  33 20 wks 

Kakolyris 2001 N Med 1 yr 2 yr 3 yr 4 yr 5 yr 

 32 7 mo 15 

TTP N Med 1 yr 2 yr  32 5.5 mo 

van der Lee 2001 

 N Med 6 mo 2 yr 3 yr 4 yr 5 yr  41 17 wks 30 

 N Med 1 yr 2 yr 

Sonpavde 2000 

 N Med 1 yr 2 yr 3 yr 4 yr 5 yr  46 25 wks 

TTP N Med 1 yr 2 yr  46 14 wks 

Groen 2000 N Med 1 yr 2 yr 3 yr 4 yr 5 yr 

 34 31 wks 9 

TTP N Med 1 yr 2 yr  34 21 wks 

Ardizzoni 1997 N Med 1 yr 2 yr 3 yr 4 yr 5 yr 

Sensitive 46 6.9 mo ~28 Refractory 47 4.7 mo ~9 

TTP N Med 1 yr 2 yr Overall 93 2.8 mo 

Gridelli 1997 N Med 1 yr 2 yr 3 yr 4 yr 5 yr 

 30 4 mo 10% 

PFS N Med 1 yr 2 yr  30 2 mo 

Einhorn 1995 N Med 1 yr 2 yr 3 yr 4 yr 5 yr 

 41 29 wks 

 N Med 1 yr 2 yr 

Faylona 1995 N Med 1 yr 2 yr 3 yr 4 yr 5 yr 

 42 29 wks ~22 

 N Med 1 yr 2 yr  42 20 wks ~5 

Sculier 1995 N Med 1 yr 2 yr 3 yr 4 yr 5 yr 

 40 16.6 wks ~10 

 N Med 1 yr 2 yr 

Albain 1993 N Med 6 mo 2 yr 3 yr 4 yr 5 yr 

 67 2.5 mo 16 

 N Med 1 yr 2 yr 
C-105 

Question 9. Treatment of Recurrent/Relapsed Disease Table 9K Survival Outcomes, Phase II Studies (continued) Study Overall Survival (%) Progression-Free Survival (%) Einhorn 1990 N Med 1 yr 2 yr 3 yr 4 yr 5 yr 

 26 18 wks 

 N Med 1 yr 2 yr 

Graziano 1990 N Med 1 yr 2 yr 3 yr 4 yr 5 yr 

 35 6.0 mo 14 

 N Med 1 yr 2 yr 

Sculier 1990 N Med 1 yr 2 yr 3 yr 4 yr 5 yr N Med 1 yr 2 yr Issell 1985 N Med 1 yr 2 yr 3 yr 4 yr 5 yr 

 95 12 wks 

 N Med 1 yr 2 yr 
C-106 

Question 9. Treatment of Recurrent/Relapsed Disease Table 9L Tumor Response and Quality of Life, Phase II Studies Study Tumor Response (%) Quality of Life Ando 2004 N CR PR SD PD NE 

Refractory 16 0 81 13 6 Relapsed 9 0 78 22 0 Total 25 80 16 4 

 Scale Domain F/U 

Agelaki 2004 N CR PR SD PD NE 

Total 31 0 10 22 68 Refractory 15 13 Relapsed 15 6 

 Scale Domain F/U 

Goto 2004 N CR PR SD PD NE 

 40 13 65 10 10 3 

 Scale Domain F/U 

ArdizzonI 2003 N CR PR SD PD NE 

Sensitive 68 1.5 27.9 36.8 5.9 14.7 Refractory 42 0 23.8 26.2 38.1 9.5 

 Scale Domain F/U n 

Hainsworth 2003 

 N CR PR SD PD NE  28 0 10 36 54 

 Scale Domain F/U n 

Hoang 2003 N CR PR SD PD NE 

 27 0 0 11 78 

 Scale Domain F/U n 

Masters 2003 N CR PR SD PD NE 

Relapsed 24 0 16.7 0 75.0 8.3 Refractory 18 0 5.6 5.6 88.9 0 Total 42 0 11.9 2.4 81.0 4.8 

 Scale Domain F/U n 

Kosmas 2001 N CR PR SD PD NE 

 33 24.2 48.5 15 12 

 Scale Domain F/U n 

Kakolyris 2001 N CR PR SD PD NE 

 32 3 22 22 53 median response duration 3 mo (1-9) 

 Scale Domain F/U n 

van der Lee 2001 

 N CR PR SD PD NE  38 0 13 21 66 

 Scale Domain F/U n 

Sessa 2000 N CR PR SD PD NE 

 66 0 16.6 32 median response duration 160 d (129-189) PR median response duration 146.5 d (77-321) SD 

 Scale Domain F/U n 

Sonpavde 2000 

 N CR PR SD PD NE  46 7 35 13 

 Scale Domain F/U n 

Groen 1999 N CR PR SD PD NE 

 34 6 68 24 3 

 Scale Domain F/U n 

Ardizzoni 1997 N CR PR SD PD NE 

Sensitive 46 13 24 31 29 2 Refractory 47 2 4 40 43 0 Total 93 8 14 36 36 1 Median response duration 7.6 mo (5.1-12.2) 

 Scale Domain F/U n 

Gridelli 1997 N CR PR SD PD NE 

 30 3.3 10 10 70 

 Scale Domain F/U n 
C-107 

Question 9. Treatment of Recurrent/Relapsed Disease Table 9L Tumor Response and Quality of Life, Phase II Studies (continued) Study Tumor Response (%) Quality of Life Einhorn 1995 N CR PR SD PD NE 

 41 15 39 

 Scale Domain F/U n 

Faylona 1995 N CR PR SD PD NE 

 42 14 40 

 Scale Domain F/U n 

Sculier 1995 N CR PR SD PD NE 

 38 13 21 55 

 Scale Domain F/U n 

Smyth 1994 N CR PR SD PD NE 

 34 0 21 21 35 18 median response duration 4.7 mo (3.5-12.6) 

 Scale Domain F/U n 

Albain 1993 N CR PR SD PD NE 

 67 0 4 15 

 Scale Domain F/U n 

Jassem 1993 N CR PR SD PD NE 

 25 0 16 28 48 

 Scale Domain F/U n 

Einhorn 1990 N CR PR SD PD NE 

 26 4 19 23 median response duration 9 wks (6-20) 

 Scale Domain F/U n 

Graziano 1990 N CR PR SD PD NE 

 35 3 17 43 17 

 Scale Domain F/U n 

JCOGLC 1990 N CR PR SD PD NE 

 31 38.7 

 Scale Domain F/U n 

Sculier 1990 N CR PR SD PD NE 

 45 0 13 31 56 

 Scale Domain F/U n 

Issell 1985 N CR PR SD PD NE 

 95 1 11 

 Scale Domain F/U n 
C-108 

Question 9. Treatment of Recurrent/Relapsed Disease Table 9M: Adverse Events, Phase II Studies 

Toxicity Type Study Group/Description n Gr 3 % Gr 4 % 

Treatment-related mortality Agelaki 2004 31 0  Ardizzoni 2003 Sensitive, early death, toxicity 

Refractory, early death, toxicity 

68 7.4 42 0 

 Hainsworth 2003 30 0  Groen 1999 35 0  Gridelli 1997 30 0  Faylona 1995 42 14  Albain 1993 67 6  Sculier 1990 45 2  Issell 1985 95 1 Alopecia Ando 2004 25 0  Goto 2004 40 0  Ardizzoni 2003 Sensitive 

Refractory 

68 19 0 42 10 0 

 Hainsworth 2003 30 0 (3/4)  Masters, 2003 44 0 0  Kosmas 2001 33 100 0  Sessa 2000 241 cycles 0 0  Ardizzoni 1997 403 cycles 0.7 0  Gridelli 1997 30 10 0  Smyth 1994 27 0 0  Jassem 1993 25 28 4 Fatigue Agelaki 2004 31 13  Hainsworth 2003 30 17 (3/4)  Masters, 2003 44 2 0  Kosmas 2001 33 0 0  Kakolyris 2001 32 19 0  Groen 1999 35 0 0  Ardizzoni 1997 Fatigue/malaise 403 cycles 2.7 0.7  Smyth 1994 Asthenia/malaise/fatigue 22 27 5 Diarrhea Ando 2004 25 8 0  Agelakii 2004 31 10(3/4)  Goto 2004 40 8  Ardizzoni 2003 Sensitive 

Refractory 

68 1 1 42 2 0 

 Kosmas 2001 33 0 0  Kakolyris 2001 32 0 0  Sonpavde 2000 46 2  Groen 1999 35 0 3  Ardizzoni 1997 403 cycles 0.2 0  Faylona 1995 42 2  Smyth 1994 14 7 0 
C-109 

Question 9. Treatment of Recurrent/Relapsed Disease Table 9M: Adverse Events, Phase II Studies (continued) 

Toxicity Type Study Group/Description n Gr 3 % Gr 4 % 

Nausea Ardizzoni 2003 Sensitive 

Refractory 

68 3 0 42 2 0 

 Masters, 2003 44 2 0  van der Lee 2001 38 0 0  Sessa 2000 241 cycles 2.4 0.4  Groen 1999 35 0 0  Ardizzoni 1997 403 cycles 0.7 0  Smyth 1994 16 13 0  Jassem 1993 25 0 0 Vomiting Ando 2004 Nausea and vomiting 25 0 0  Goto 2004 Nausea and vomiting 40 8  Ardizzoni 2003 Sensitive 

Refractory 

68 0 0 32 10 0 

 Hainsworth 2003 Nausea and vomiting 30 3 (3/4)  Masters, 2003 44 0 2  Kosmas 2001 Nausea and vomiting 33 18 0  Kakolyris 2001 Nausea and vomiting 32 0 0  Sessa 2000 241 cycles 1.2 0  Groen 1999 35 0 0  Ardizzoni 1997 403 cycles 0.2 0  Gridelli 1997 Nausea and vomiting 30 0 0  Faylona 1995 Nausea and vomiting 42 2  Sculier 1995 Nausea and vomiting 38 3 3  Smyth 1994 11 0 0  Jassem 1993 Nausea and vomiting 25 0 0 Anorexia Ardizzoni 2003 Sensitive 

Refractory 

68 4 1 32 2 0 

 Masters, 2003 44 2 0 Lethargy Ardizzoni 2003 Sensitive 

Refractory 

68 15 0 32 7 0 

Neurosensory Ardizzoni 2003 Sensitive 

Refractory 

68 1 0 32 0 0 

 Masters 2003 44 0 0  Kakolyris 2001 Neurotoxicity 32 0 0  Sonpavde 2000 Neurotoxicity 46 11  Groen 1999 Paresthesia 35 3 0  Faylona 1995 Neurologic 42 12  Sculier 1995 Neurological 35 3 0  Smyth 1994 14 7 7  Jassem 1993 Neurotoxicity 25 4 0 Neuromotor Ardizzoni 2003 Sensitive 

Refractory 

68 1 0 32 0 2 

 Masters 2003 44 14 0 
C-110 

Question 9. Treatment of Recurrent/Relapsed Disease Table 9M: Adverse Events, Phase II Studies (continued) 

Toxicity Type Study Group/Description n Gr 3 % Gr 4 % 

Hearing loss Esophagitis Faylona 1995 42 2 2 Bronchopulmonary Ando 2004 25 0  Ardizzoni 2003 Shortness of breath, sensitive 

Refractory 

68 10 0 42 7 2 

 Masters, 2003 44 9 0  Kosmas 2001 33 0 0  van der Lee 2001 Dyspnea 38 0 0  Faylona 1995 42 2 Pneumonitis Hoang 2003 27 4 (5) Hepatic Ando 2004 25 0 0  Goto 2004 40 3  Groen 1999 AST/ALT elevation 35 0 0  Ardizzoni 1997 403 cycles 1.0 0  Gridelli 1997 30 6.6 0 Kidney Ando 2004 25 0 0  Goto 2004 40 0  Kosmas 2001 33 0 0  Einhorn 1995 41 2 2  Faylona 1995 42 2 2  Sculier 1995 35 0 0 Hemorrhage Ardizzoni 2003 Sensitive 

Refractory 

68 21 (1-3) 42 26 (1-3) 

 Masters, 2003 44 9 0  Sculier 1995 35 0 0 Anemia Ando 2004 25 4 0  Goto 2004 40 45  Hainsworth 2003 30 0 6  Masters, 2003 44 5 2  Kosmas 2001 33 18 0  Kakolyris 2001 32 0 3  van der Lee 2001 38 0 0  Sessa 2000 241 cycles 3 0.4  Groen 1999 132 cycles 17 0  Ardizzoni 1997 403 cycles 8.9 2.9  Gridelli 1997 30 0 0  Faylona 1995 42 29 2  Smyth 1994 22 5 0  Jassem 1993 25 4 0 
C-111 

Question 9. Treatment of Recurrent/Relapsed Disease Table 9M: Adverse Events, Phase II Studies (continued) 

Toxicity Type Study Group/Description n Gr 3 % Gr 4 % 

Thrombocytopenia Ando 2004 25 12 0  Goto 2004 40 33  Hainsworth 2003 30 37 3  Hoang 2003 27 30 0  Masters, 2003 44 18 9  Kosmas 2001 33 36 9  Kakolyris 2001 32 9 0  van der Lee 2001 38 29 0  Sessa 2000 241 cycles 15 7  Groen 1999 132 cycles 21 10  Ardizzoni 1997 403 cycles 17.6 11.9  Gridelli 1997 30 0 6.6  Einhorn 1995 41 48  Faylona 1995 42 24 48  Sculier 1995 38 31 13  Smyth 1994 5 0 0  Jassem 1993 25 0 0 Leukopenia or neutropenia Ando 2004 Neutropenia 25 12 12  Agelaki 2004 Neutropenia 

Febrile neutropenia 

31 29 (3 or 4) 6 

 Goto 2004 Leukopenia 

Neutropenia 

40 55  73 

 Ardizzoni 2003 Sensitive, Leukopenia 

Neutropenia, 

> 1 episode febrile neutropenia 

Refractory, Leukopenia 

Neutropenia 

> 1 episode febrile neutropenia 

68 33.8 47.1  14.7 61.8  19 42 43.9 31.7  26.8 48.8  15 

 Hainsworth 2003 Leukopenia 

Granulocytopenia 

30 20 6 30 33 10 

 Hoang 2003 Neutropenia 

Febrile Neutropenia 

27 15 15 27 4 0 

 Masters, 2003 Leukopenia 

Granulocytopenia 

44 16 2 44 20 7 

 Kosmas 2001 Leukopenia 

Neutropenia 

Febrile neurtropenia 

33 27 46 33 18 73 33 18 

 Kakolyris 2001 Neutropenia 32 22 16  van der Lee 2001 Leukopenia 38 18 0  Sessa 2000 Neutropenia 241 cycles 16.5 9  Sonpavde 2000 Granulocytopenia 46 17 63  Groen 1999 Leukopenia 132 cycles 27 6 
C-112 

Question 9. Treatment of Recurrent/Relapsed Disease Table 9M: Adverse Events, Phase II Studies (continued) 

Toxicity Type Study Group/Description n Gr 3 % Gr 4 % 

Leukopenia or neutropenia Ardizzoni 1997 Leukopenia 

Neutropenia 

403 cycles 58.5 9.9  28.0 46.9 

 Gridelli 1997 Leukopenia 30 13.3 13.3  Einhorn 1995 Granulocytopenia 41 71  Faylona 1995 Granulocytopenia 42 33 71  Sculier 1995 Leukopenia 38 8 5  Smyth 1994 Leukopenia 

Neutropenia 

32 41 28 31 23 71 

 Jassem 1993 Leukopenia 

Neutropenia 

25 28 4 25 16 16 

 Sculier 1990 Leukopenia 45 27 3 Infection Goto 2004 40 3  Goto 2004 Fever 40 0  Masters, 2003 Fever 44 0 0  van der Lee 2001 Fever 38 0 0  Sessa 2000 241 cycles 1.2 0.4  Ardizzoni 1997 403 cycles 1.0 0.5  Faylona 1995 42 29 10(5) Sculier 1995 35 0 0  Smyth 1994 13 15 15  Jassem 1993 25 0 0 Other Goto 2004 Hyponatremia 40 5  Goto 2004 Mucositis 40 0  Goto 2004 Arrhythmia 40 5  Goto 2004 Eruption 40 3  Goto 2004 Allergy 40 0 
C-113 

Acronyms/Abbreviations Used in Tables 

- without 

# number 

# number 

∆ change 

? unknown, unclear 

+ with 

<p less than a partial resection 

1° primary 

18-FDG 18-fluorodeoxyglucose 

95% CIL lower limit 95% confidence interval 

95% CIU upper limit 95% confidence interval 

A Asian 

A doxorubicin (Adriamycin®) 

abstr abstract 

ACCP American College of Chest Physicians 

AHRQ Agency for Healthcare Research and Quality 

ALT alanine transaminase 

Alt alternating 

AP anterioposterior 

ASCO American Society of Clinical Oncology 

AST aspartate transaminases 

ASTRO American Society for Therapeutic Radiology and 

Oncology 

B bilobectomy 

B Black 

BSC best supportive care 

c complete 

C cyclophosphamide 

CALGB Cancer and Leukemia Group B 

Cb carboplatin 

CCNU lomustine 

CD cyclophosphamide- and/or doxorubicin-based 

chemotherapy 

chemoTx chemotherapy 

CI confidence interval 

CNS central nervous system 

Conc concurrent 

cont’d continued 

contr contralateral 

Conv conventional 

CPHM Cox proportional hazard model 

CR complete response 

CT computed tomography 

Ctrl control 

CTx chemotherapy 

d day 

DA diagnostic accuracy 

dist distant 

Dx diagnosis 

E Alt early alternating 

E etoposide 

E etoposide 

ea each 

ECOG Eastern Cooperative Oncology Group 

endosc endoscopic 

EORTC LCCG European Organization for the Research and 
C-114 

Treatment of Cancer Lung Cancer Cooperative 

Group 

EPC Evidence-based Practice Center 

EQ-5D EuroQOL 5-dimension health-related quality of life 

instrument 

ES extensive stage 

ESD extensive-stage disease 

F female 

F fractions 

F/d fractions per day 

F/U follow-up 

FDA Food and Drug Administration 

FE fixed effects 

FEV1 forced expiratory volume in 1 second 

FN false negative 

FNA fine-needle aspiration 

FP false positive 

Frac(s) fraction(s) 

FWHM full width, half maximum 

GQ good quality 

Gy Gray 

H Hispanic 

HL hilar 

HR hazard ratio 

hr hour 

Hyper hyperfractionated 

ips ipsilateral 

IV intravenous 

K-M Kaplan-Meier 

KPS Karnofsky Performance Status 

L Alt late alternating 

L lobectomy 

L lomustine 

L95 upper limit 95% confidence interval 

LCSG Lung Cancer Study Group 

LDH lactic dehydrogenase 

LINAC linear accelerator 

LN lymph node 

LRFS local recurrence-free survival 

LRFS local recurrence-free survival 

LS limited stage 

LSD limited-stage disease 

M male 

M methotrexate 

MBq megabecquerel 

mCi milliCurie 

md median 

MD mediastinal 

mets metastases 

MeV megaelectron volt 

mg milligram 

M-H Mantel-Haenszel 

MI myocardial infarction 

mn mean 

mo(s). month(s) 

MR meta regression 

MRI magnetic resonance imaging 

MS mediastinal 

N no 
C-115 

n number 

N pooled number 

NCI National Cancer Institute 

NE not evaluable 

NED no evidence of disease 

neg negative 

NNEC non-neuroendocrine carcinoma 

NNT number needed to treat 

nonrandom. nonrandomized 

NOS not otherwise specified 

NR not reported 

NS nonsignificant 

NSCLC non-small-cell lung cancer 

O other 

OR odds ratio 

ORR overall response rate 

OS overall survival 

P cisplatin 

p partial 

P pneumonectomy 

PA posterioanterior 

PCI prophylactic cranial radiation 

PD progressive disease 

PE platinum/etoposide chemotherapy 

PET positron emission tomography 

PFS progression-free survival 

PI primary investigator 

po oral 

P-OR Peto odds ratio 

pos positive 

PR partial response 

PS performance status 

Pt platinum 

pub publication 

PWIFR percent/proportion with in-field recurrence 

Q heterogeneity statistic 

QoL quality of life 

QUADAS Quality Assessment of Diagnostic Accuracy Studies 

R/I ruled in 

R/O ruled out 

radiol radiologic 

RadioTx radiotherapy 

RCT randomized, controlled trial 

RD risk difference 

RE random effects 

reg regimen 

regl regional 

retrospect retrospective 

RFS recurrence-free survival 

rng range 

RNS radionuclide scan 

ROC receiver operating characteristic 

RR relative risk 

RR risk ratio 

SC supraclavicular 

SC/LC small-cell/large-cell subtype 

SCLC small cell lung cancer 

SD stable disease 

SE standard error 
C-116 

Sens sensitivity 

Seq sequential 

Spec specificity 

STARD Standards for Reporting of Diagnostic Accuracy 

sup-clav supraclavicular 

supraclav supraclavicular 

surg surgery 

SWOG Southwest Oncology Group 

T thoracotomy only (open and close) 

TN true negative 

TNM Tumor, Node, Metastasis (staging system) 

TP true positive 

TRTx thoracic radiotherapy 

TTF time to failure 

Tx treatment; therapy 

U.S. United States 

U95 upper limit 95% confidence interval 

ULN upper limit of normal 

US ultrasound 

V vincristine 

VC vital capacity 

Ve vindesine 

W White 

WBC white blood cell 

WHO World Health Organization 

wk(s) week(s) 

Wt weight 

XRT radiotherapy 

Y yes 

yr year 
C-117 

Abbreviations of Combination Chemotherapy Regimens 

ACO doxorubicin, cyclophosphamide, and vincristine 

ACOM doxorubicin, lomustine, methotrexate, vincristine 

BTOC vincristine, thiotepa, cyclophosphamide, carmustine 

CAE cyclophosphamide, doxorubicin, etoposide 

CAV cyclophosphamide, doxorubicin, vincristine 

CbE carboplatin, etoposide 

CbPE carboplatin, cisplatin, etoposide 

CC cyclophosphamide, lomustine 

CCM cyclophosphamide, lomustine, methotrexate 

CCMV cyclophosphamide, lomustine, methotrexate, vincristine 

CDE cyclophosphamide, doxorubicin, etoposide 

CE-CAP cyclophosphamide, doxorubicin, cisplatin 

COME cyclophosphamide, vincristine, methotrexate, etoposide 

COMF cyclophosphamide, vincristine, methotrexate, fluorouracil 

CVMP cyclophosphamide, vincristine, methotrexate, cisplatin 

EP etoposide, platinum compound 

iv T intravenous topotecan 

LCAE lomustine, cyclophosphamide, doxorubicin, etoposide 

M-CAV methotrexate, cyclophosphamide, doxorubicin, vincristine 

MCCC/VI methotrexate, cyclophosphamide, lomustine, ifosfamide, etoposide 

PE cisplatin, etoposide 

PEVe platinum, epirubicin, etoposide 

PMP cisplatin, methotrexate, procarbazine 

po T oral topotecan 

VCMV vincristine, cyclophosphamide, mitomycin, chromomycin 

VIC-E/VICE vincristine, ifosfamide, carboplatin, etoposide 

VIMP vincristine, ifosfamide, mesna, carboplatin 

VIP-E etoposide, ifosfamide, cisplatin, and epirubicin 
C-118 

References Cited in Appendix Tables 

Ahles TA, Silberfarb PM, Rundle AC, et al. Quality of life in patients with limited small-cell 

carcinoma of the lung receiving chemotherapy with or without radiation therapy, for cancer and 

leukemia group B. Psychother Psychosom 1994; 62(3-4):193-9. 

Albain KS, Crowley JJ, Hutchins L, et al. Predictors of survival following relapse or progression 

of small cell lung cancer. Southwest Oncology Group Study 8605 report and analysis of 

recurrent disease data base. Cancer 1993; 72(4):1184-91. 

Ando M, Kobayashi K, Yoshimura A, et al. Weekly administration of irinotecan (CPT-11) plus 

cisplatin for refractory or relapsed small cell lung cancer. Lung Cancer 2004; 44(1):121-7. 

Ardizzoni A, Hansen H, Dombernowsky P, et al. Topotecan, a new active drug in the second-line 

treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive 

disease. The European Organization for Research and Treatment of Cancer Early Clinical 

Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. J 

Clin Oncol 1997; 15(5):2090-6. 

Ardizzoni A, Manegold C, Debruyne C, et al. European organization for research and treatment 

of cancer (EORTC) 08957 phase II study of topotecan in combination with cisplatin as secondline treatment of refractory and sensitive small cell lung cancer. Clin Cancer Res 2003; 9(1):143-

50. 

Badzio A, Jassem J, Kurowski K, et al.The impact of primary pulmonary resection on local 

control and survival in limited disease (LD) small cell lung cancer (SCLC) patients (pts): a 

retrospective comparative study. Lung Cancer 2005; 49(suppl2):S316. Abstract P-750. 

Badzio A, Kurowski K, Karnicka-Mlodkowska H, et al. A retrospective comparative study of 

surgery followed by chemotherapy vs. non-surgical management in limited-disease small cell 

lung cancer. Eur J Cardiothorac Surg 2004; 26(1):183-8. 

Blum R, MacManus MP, Rischin D, et al. Impact of positron emission tomography on the 

management of patients with small-cell lung cancer: preliminary experience. Am J Clin Oncol 

2004; 27(2):164-71. 

Bonner JA, Sloan JA, Shanahan TG, et al. Phase III comparison of twice-daily split-course 

irradiation versus once-daily irradiation for patients with limited stage small-cell lung carcinoma. 

J Clin Oncol 1999; 17(9):2681-91. 

Bradley JD, Dehdashti F, Mintun MA, et al. Positron emission tomography in limited-stage 

small-cell lung cancer: a prospective study. J Clin Oncol 2004; 22(16):3248-54. 

Brincker H, Hindberg J, Hansen PV. Cyclic alternating polychemotherapy with or without upper 

and lower half-body irradiation in small cell anaplastic lung cancer. A randomized study. Eur J 

Cancer Clin Oncol 1987; 23(2):205-11. 
C-119 

Brink I, Schumacher T, Mix M, et al. Impact of (18F)FDG-PET on the primary staging of smallcell lung cancer. Eur J Nucl Med Mol Imaging 2004; 31(12):1614-20. 

Coy P, Hodson DI, Murray N, et al. Patterns of failure following loco-regional radiotherapy in 

the treatment of limited stage small cell lung cancer. Int J Radiat Oncol Biol Phys 1994; 

28(2):355-62. 

Einhorn LH, Loehrer PJ. Hoosier Oncology Group studies in extensive and recurrent small cell 

lung cancer. Semin Oncol 1995; 22(1 Suppl 2):28-31. 

Einhorn LH, Pennington K, McClean J. Phase II trial of daily oral VP-16 in refractory small cell 

lung cancer: a Hoosier Oncology Group study. Semin Oncol 1990; 17(1 Suppl 2):32-5. 

Faylona EA, Loehrer PJ, Ansari R, Sandler AB, Gonin R, Einhorn LH. Phase II study of daily 

oral etoposide plus ifosfamide plus cisplatin for previously treated recurrent small-cell lung 

cancer: a Hoosier Oncology Group Trial. J Clin Oncol 1995; 13(5):1209-14. 

Feld R, Payne D, Hodson I, et al. Complications of treatment of small cell carcinoma of the lung. 

Experience from a recent Canadian trial. Antibiot Chemother 1988; 41:204-9. 

Friess GG, McCracken JD, Troxell ML, Pazdur R, Coltman CA Jr, Eyre HJ. Effect of initial 

resection of small-cell carcinoma of the lung: a review of Southwest Oncology Group Study 

7628. J Clin Oncol 1985; 3(7):964-8. 

George TK, Fitzgerald D, Brown BS, et al. Long-term survival in limited-stage small cell lung 

carcinoma. Experience in Rochester, New York from 1975 to 1981. Cancer 1986; 58(6):1193-8. 

Graziano SL, Lee K, Propert KJ et al. Phase II trial of etoposide and cisplatin for refractory small 

cell lung cancer: a Cancer and Leukemia Group B Study. Med Pediatr Oncol 1990; 18(1):22-6. 

Gregor A, Drings P, Burghouts J, et al. Randomized trial of alternating versus sequential 

radiotherapy/chemotherapy in limited-disease patients with small-cell lung cancer: a European 

Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group Study. J 

Clin Oncol 1997a; 15(8):2840-9. 

Gridelli C, De Marinis F, Rossi A, et al. A phase II study of VM-26 plus lonidamine in 

pretreated small cell lung cancer. Anticancer Res 1997; 17(2B):1277-9. 

Groen HJ, Fokkema E, Biesma B et al. Paclitaxel and carboplatin in the treatment of small-cell 

lung cancer patients resistant to cyclophosphamide, doxorubicin, and etoposide: a non-crossresistant schedule. J Clin Oncol 1999; 17(3):927-32. 

Hainsworth JD, Burris HA 3rd, Erland JB et al. Combination chemotherapy with gemcitabine 

and vinorelbine in the treatment of patients with relapsed or refractory small cell lung cancer: a 

phase II trial of the Minnie Pearl Cancer Research Network. Cancer Invest 2003; 21(2):193-9. 
C-120 

Hara N, Ichinose Y, Kuda T, et al. Long-term survivors in resected and nonresected small cell 

lung cancer. Oncology 1991; 48(6):441-7. 

Hara N, Ohta M, Ichinose Y, et al. Influence of surgical resection before and after chemotherapy 

on survival in small cell lung cancer. J Surg Oncol 1991; 47(1):53-61. 

Hoang T, Kim K, Jaslowski A et al. Phase II study of second-line gemcitabine in sensitive or 

refractory small cell lung cancer. Lung Cancer 2003; 42(1):97-102. 

Issell BF, Einhorn LH, Comis RL et al. Multicenter Phase II trial of etoposide in refractory small 

cell lung cancer. Cancer Treat Rep 1985; 69(1):127-8. 

James LE, Spiro S, O’Donnell KM, et al. A randomised study of timing of thoracic irradiation in 

small cell lung cancer (SCLC) - study 8. Lung Cancer 2003; 41(Suppl 2):S23. Abstract. 

Japan Cooperative Oncology Group on Lung Cancer. Phase II study of carboplatin in patients 

with nonresected lung cancer. Cancer Chemother Pharmacol 1990; 26(2):101-4. 

Jassem J, Karnicka-Mlodkowska H, van Pottelsberghe C, et al. Phase II study of vinorelbine 

(Navelbine) in previously treated small cell lung cancer patients. EORTC Lung Cancer 

Cooperative Group. Eur J Cancer 1993; 29A(12):1720-2. 

Jeremic B, Shibamoto Y, Acimovic L, et al. Initial versus delayed accelerated hyperfractionated 

radiation therapy and concurrent chemotherapy in limited small-cell lung cancer: a randomized 

study. J Clin Oncol 1997; 15(3):893-900. 

Jeremic B, Shibamoto Y, Nikolic N, et al. Role of radiation therapy in the combined-modality 

treatment of patients with extensive disease small-cell lung cancer: A randomized study. J Clin 

Oncol 1999; 17(7):2092-9. 

Kakolyris S, Mavroudis D, Tsavaris N et al. Paclitaxel in combination with carboplatin as 

salvage treatment in refractory small-cell lung cancer (SCLC): a multicenter phase II study. Ann 

Oncol 2001; 12(2):193-7. 

Kamel EM, Zwahlen D, Wyss MT, et al. Whole-body (18)F-FDG PET improves the 

management of patients with small cell lung cancer. J Nucl Med 2003; 44(12):1911-7. 

Kosmas C, Tsavaris NB, Malamos NA, et al. Phase II study of paclitaxel, ifosfamide, and 

cisplatin as second-line treatment in relapsed small-cell lung cancer. J Clin Oncol 2001; 

19(1):119-26. 

Lad T, Piantadosi S, Thomas P, et al. A prospective randomized trial to determine the benefit of 

surgical resection of residual disease following response of small cell lung cancer to combination 

chemotherapy. Chest 1994; 106(6 Suppl):320S-3S. 
C-121 

Lebeau B, Chastang C, Brechot JM, et al. A randomized trial of delayed thoracic radiotherapy in 

complete responder patients with small-cell lung cancer. Petites Cellules Group. Chest 1993; 

104(3):726-33. 

Lebeau B, Urban T, Brechot JM, et al. A randomized clinical trial comparing concurrent and 

alternating thoracic irradiation for patients with limited small cell lung carcinoma. "Petites 

Cellules" Group. Cancer 1999; 86(8):1480-7. 

Liao M, Zhao J, Zhou Y. [Multimodality therapy of late stage lung cancer]. Zhonghua Zhong Liu 

Za Zhi 1995; 17(5):384-6. 

Masters GA, Declerck L, Blanke C et al. Phase II trial of gemcitabine in refractory or relapsed 

small-cell lung cancer: Eastern Cooperative Oncology Group Trial 1597. J Clin Oncol 2003; 

21(8):1550-5. 

Murray N, Coy P, Pater JL, et al. Importance of timing for thoracic irradiation in the combined 

modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of 

Canada Clinical Trials Group. J Clin Oncol 1993; 11(2):336-44. 

Namikawa S, Den T, Kimura M, et al. The role of surgical resection and the effects of neoadjuvant therapy in the management of small cell lung cancer. Surg Today 1994; 24(4):342-6. 

Nou E, Brodin O, Bergh J. A randomized study of radiation treatment in small cell bronchial 

carcinoma treated with two types of four-drug chemotherapy regimens. Cancer 1988; 

62(6):1079-90. 

O'Brien M, Ciuleanu T, Tsekov H, et al. Survival benefit of oral topotecan plus supportive care 

versus supportive care alone in relapsed, resistant SCLC. Lung Cancer. 2005;49(suppl2):S54. 

Abstract O-157. 

O'Bryan RM, Crowley JJ, Kim PN, et al. Comparison of etoposide and cisplatin with bis-chloroethylnitrosourea, thiotepa, vincristine, and cyclophosphamide for salvage treatment in small cell 

lung cancer. A Southwest Oncology Group Study. Cancer 1990; 65(4 ):856-60. 

Osterlind K, Hansen M, Hansen HH, et al. Treatment policy of surgery in small cell carcinoma 

of the lung: retrospective analysis of a series of 874 consecutive patients. Thorax 1985; 

40(4):272-7. 

Park SK, Kim GH, Jeong SS, et al. The effects according to the timing of thoracic radiotherapy 

in limited stage small cell lung cancer. Tuberc Respir Dis 1996; 43:903-15. 

Perry MC, Eaton WL, Propert KJ, et al. Chemotherapy with or without radiation therapy in 

limited small-cell carcinoma of the lung. N Engl J Med 1987; 316(15):912-8. 
C-122 

Perry MC, Herndon JE 3rd, Eaton WL, et al. Thoracic radiation therapy added to chemotherapy 

for small-cell lung cancer: an update of Cancer and Leukemia Group B Study 8083. J Clin Oncol 

1998; 16(7):2466-7. 

Postmus PE, Smit EF, Kirkpatrick A, et al. Testing the possible non-cross resistance of two 

equipotent combination chemotherapy regimens against small-cell lung cancer: a phase II study 

of the EORTC Lung Cancer Cooperative Group. Eur J Cancer 1993; 29A(2):204-7. 

Qiao TK, Zhou DA, Xin L, et al. [Concurrent radiotherapy combined with carboplatin and 

etoposide in limited stage small cell lung cancer]. Zhonghua Jie He He Hu Xi Za Zhi 2004; 

27(4):237-9. 

Rosenthal MA, Tattersall MHN, Fox RM, et al. Adjuvant thoracic radiotherapy in small cell lung 

cancer: Ten-year follow-up of a randomized study. Lung Cancer 1991; 7(4):235-41. 

Rostad H, Naalsund A, Jacobsen R, et al. Small cell lung cancer in Norway: should more 

patients have been offered surgical therapy? Eur J Cardiothorac Surg 2004 Oct; 26(4):782-6. 

Schild SE, Bonner JA, Shanahan TG, et al. Long-term results of a phase III trial comparing 

once-daily radiotherapy with twice-daily radiotherapy in limited-stage small-cell lung cancer. Int 

J Radiat Oncol Biol Phys 2004; 59(4):943-51. 

Schumacher T, Brink I, Mix M, et al. FDG-PET imaging for the staging and follow-up of small 

cell lung cancer. Eur J Nucl Med 2001; 28(4):483-8. 

Sculier JP, Lafitte JJ, Lecomte J, et al. A phase II randomised trial comparing the cisplatinetoposide combination chemotherapy with or without carboplatin as second-line therapy for 

small-cell lung cancer. Ann Oncol 2002; 13(9):1454-9. 

Sculier JP, Thiriaux J, Bureau G, et al. A phase II study testing weekly platinum derivative 

combination chemotherapy as second-line treatment in patients with advanced small cell lung 

cancer. Int J Oncol 1995; 6(2):425-9. 

Sessa C, Wanders J, Roelvink M, et al. Second-line treatment of small-cell lung cancer with the 

camptothecin-derivative GI147211: a study of the EORTC Early Clinical Studies Group 

(ECSG). Ann Oncol 2000; 11(2):207-10. 

Shen YY, Shiau YC, Wang JJ, et al. Whole-body 18F-2-deoxyglucose positron emission 

tomography in primary staging small cell lung cancer. Anticancer Res 2002; 22(2B):1257-64. 

Shepherd FA, Ginsberg RJ, Patterson GA, Evans WK, Feld R. A prospective study of adjuvant 

surgical resection after chemotherapy for limited small cell lung cancer. A University of Toronto 

Lung Oncology Group study. J Thorac Cardiovasc Surg 1989; 97(2):177-86. 

Skarlos DV, Samantas E, Briassoulis E, et al. Randomized comparison of early versus late 

hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease small-
C-123 

cell lung cancer: a randomized phase II study of the Hellenic Cooperative Oncology Group 

(HeCOG). Ann Oncol 2001; 12(9):1231-8. 

Sloan JA, Bonner JA, Hillman SL, et al. A quality-adjusted reanalysis of a Phase III trial 

comparing once-daily thoracic radiation vs. twice-daily thoracic radiation in patients with 

limited-stage small-cell lung cancer(1). Int J Radiat Oncol Biol Phys 2002; 52(2):371-81. 

Smyth JF, Smith IE, Sessa C, et al. Activity of docetaxel (Taxotere) in small cell lung cancer. 

The Early Clinical Trials Group of the EORTC. Eur J Cancer 1994; 30A(8):1058-60. 

Sonpavde G, Ansari R, Walker P, et al. Phase II study of doxorubicin and paclitaxel as secondline chemotherapy of small-cell lung cancer: a Hoosier Oncology Group Trial. Am J Clin Oncol 

2000; 23(1):68-70. 

Spiro SG, Souhami RL, Geddes DM, et al. Duration of chemotherapy in small cell lung cancer: 

a Cancer Research Campaign trial. Br J Cancer 1989 Apr; 59(4):578-83. 

Sun Y, Zhang XR, Yin WB, et al. Prospective multimodality treatment of SCLC--experience 

during the past 18 years. Gan To Kagaku Ryoho 1995; 22 Suppl 3:222-5. 

Takada M, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential 

thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell 

lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 2002; 

20(14):3054-60. 

Trillet-Lenoir V, Lasset C, Arpin D, et al. [Comparison of 2 cisplatin and etoposide dosages in 

relapsing small cell lung cancer]. Bull Cancer 1992; 79(12):1173-81. 

Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic 

radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. 

N Engl J Med 1999; 340(4):265-71. 

van der Lee I, Smit EF, van Putten JW et al. Single-agent gemcitabine in patients with resistant 

small-cell lung cancer. Ann Oncol 2001; 12(4):557-61. 

von Pawel J, Gatzemeier U, Pujol JL, et al. Phase ii comparator study of oral versus intravenous 

topotecan in patients with chemosensitive small-cell lung cancer. J Clin Oncol 2001; 19(6):1743-

9. 

von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, doxorubicin, 

and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 1999; 

17(2):658-67. 

Wolff SN, Birch R, Sarma P, et al. Randomized dose-response evaluation of etoposide in small 

cell carcinoma of the lung: a Southeastern Cancer Study Group Trial. Cancer Treat Rep 1986; 

70(5):583-7. 
C-124 

Work E, Bentzen SM, Nielsen OS, et al. Prophylactic cranial irradiation in limited stage small 

cell lung cancer: survival benefit in patients with favourable characteristics. Eur J Cancer 1996; 

32A(5):772-8. 

Work E, Nielsen OS, Bentzen SM, et al. Randomized study of initial versus late chest irradiation 

combined with chemotherapy in limited-stage small-cell lung cancer. Aarhus Lung Cancer 

Group. J Clin Oncol 1997; 15(9):3030-7. 

Yuen AR, Zou G, Turrisi AT, et al. Similar outcome of elderly patients in intergroup trial 0096: 

Cisplatin, etoposide, and thoracic radiotherapy administered once or twice daily in limited stage 

small cell lung carcinoma. Cancer 2000; 89(9):1953-60. 
D-1

Appendix D. Listing of Excluded Studies 

Exclusion Codes 

UNR study unrelated to treatment/staging of SCLC (citation review) 

FNA foreign language, no abstract 

INV investigational therapy 

NPD no primary data 

NRA narrative review article 

NRD non-relevant disease 

NSP not correct study population 

NRQ non-relevant study question 

NSD not correct study design 

SCS single center phase II single arm study 

FEW too few subjects 

<50 for single-arm studies, XRT, PCI (Qs 1-4) 

<25 for diagnostic accuracy studies (Q5); single-arm studies, mixed SCLC/NSCLC, surgery, 

2nd+-line therapy (Qs 6-8) 

(no lower limit for RCTs) 

Controlled trial of twelve versus six courses of 

chemotherapy in the treatment of small-cell lung 

cancer. Report to the Medical Research Council by 

its Lung Cancer Working Party. Br J Cancer. 1989 

Apr;59(4):584-90. 

Notes: NRQ 

Randomised trial of four-drug vs less intensive twodrug chemotherapy in the palliative treatment of 

patients with small-cell lung cancer (SCLC) and poor 

prognosis. Medical Research Council Lung Cancer 

Working Party. Br J Cancer 1996; 73(3):406-13. 

Notes: NRQ 

Survival, adverse reactions and quality of life during 

combination chemotherapy compared with selective 

palliative treatment for small-cell lung cancer. Report 

to the Medical Research Council by its Lung Cancer 

Working Party. Respir Med 1989; 83(1):51-8. 

Notes: NRQ 

Abner A. Prophylactic cranial irradiation in the 

treatment of small-cell carcinoma of the lung. Chest 

1993; 103(4 Suppl):445S-8S. 

Notes: NRA 

Abratt RP. Commentary on “Novel doublets in 

extensive-stage small cell lung cancer: A randomised 

phase II study of topotecan plus cisplatin or 

paclitaxel (CALGB 9430).” Clin Lung Cancer 3: 

211-212 

Notes: NPD NRQ 

Agelaki S, Veslemes M, Syrigos K, et al. A 

multicenter phase II study of the combination of 

gemcitabine and docetaxel in previously treated 

patients with small cell lung cancer. Lung Cancer 

2004; 43(3):329-33. 

Notes: FEW 

Agra Y, Pelayo M, Sacristan M, et al. Chemotherapy 

versus best supportive care for extensive small cell 

lung cancer. Cochrane Database Syst Rev 2003; 

(4):CD001990. 

Notes: NRQ 

Aisner SC, Finkelstein DM, Ettinger DS, et al. The 

clinical significance of variant-morphology small-cell 

carcinoma of the lung. J Clin Oncol 1990; 8(3):402-

8. 

Notes: NRQ; may inform Q7 
D-2

Akbiyik N, Alexander LL. Cure rates in small cell 

and non-small cell carcinoma of the lung utilizing 

high-dose radiotherapy and chemotherapy. J Natl 

Med Assoc 1986; 78(3):219-23. 

Notes: NSD 

Albain KS, Crowley JJ, LeBlanc M, Livingston RB. 

Determinants of improved outcome in small-cell lung 

cancer: an analysis of the 2,580-patient Southwest 

Oncology Group data base. J Clin Oncol 1990; 

8(9):1563-74. 

Notes: NRQ 

Ali MA, Kraut MJ, Valdivieso M, et al. Phase II 

study of hyperfractionated radiotherapy and 

concurrent weekly alternating chemotherapy in 

limited-stage small cell lung cancer. Lung Cancer 

1998; 22(1):39-44. 

Notes: FEW, NSD 

Ardizzoni A, Antonelli G, Ricci S, et al. 

Ambamustine in the second-line treatment of patients 

with small-cell lung cancer: a phase II Fonicap study. 

Am J Clin Oncol 2000; 23(1):22-5. 

Notes: INV 

Ardizzoni A, Tjan-Heijnen VC, Postmus PE, et al. 

Standard versus intensified chemotherapy with 

granulocyte colony-stimulating factor support in 

small-cell lung cancer: a prospective European 

Organization for Research and Treatment of CancerLung Cancer Group Phase III Trial-08923. J Clin 

Oncol 2002; 20(19):3947-55. 

Notes: NRQ 

Ariyoshi Y, Fukuoka M, Furuse K, et al. Concurrent 

cisplatin-etoposide chemotherapy plus thoracic 

radiotherapy for limited-stage small cell lung cancer. 

Japanese Lung Cancer Chemotherapy Group in 

Japanese Clinical Oncology Group. Jpn J Clin Oncol 

1994; 24(5):275-81. 

Notes: NSD 

Armstrong JG. Long-term outcome of small cell lung 

cancer. Cancer Treat Rev 1990; 17(1):1-13. 

Notes: NRA 

Armstrong JG, Rosenstein MM, Kris MG, et al. 

Twice daily thoracic irradiation for limited small cell 

lung cancer. Int J Radiat Oncol Biol Phys 1991; 

21(5):1269-74. 

Notes: NSD 

Armstrong JG, Rosenstein MM, Scher HI, et al. 

Limited small cell lung cancer: prognostic 

significance of a complete response to the induction 

phase of chemotherapy followed by thoracic 

irradiation. Radiology 1991; 178(3):875-8. 

Notes: NRQ 

Arriagada R. Re: Prophylactic cranial irradiation for 

patients with small-cell lung cancer. J Natl Cancer 

Inst 1995; 87(10):766; author reply 767. 

Notes: NPD 

Arriagada R, Le Chevalier T. Local control and lethal 

toxicity in limited small cell lung cancer. Int J Radiat 

Oncol Biol Phys 1990; 19(5):1333. 

Notes: NPD 

Arriagada R, Le Chevalier T, Baldeyrou P, et al. 

Alternating radiotherapy and chemotherapy 

schedules in small cell lung cancer, limited disease. 

Int J Radiat Oncol Biol Phys 1985; 11(8):1461-7. 

Notes: NSD 

Arriagada R, Le Chevalier T, Pignon JP, et al. Initial 

chemotherapeutic doses and survival in patients with 

limited small-cell lung cancer. N Engl J Med 1993; 

329(25):1848-52. 

Notes: NRQ 

Arriagada R, le Chevalier T, Ruffie P, et al. 

Alternating radiotherapy and chemotherapy in 173 

consecutive patients with limited small cell lung 

carcinoma. GROP and the French Cancer Center's 

Lung Group. Int J Radiat Oncol Biol Phys 1990; 

19(5):1135-8. 

Notes: NSD 

Arriagada R, Le Chevalier T, Ruffie P, et al. 

Alternating radiotherapy and chemotherapy in limited 

small cell lung cancer: the IGR protocols. French 

FNCLCC Lung Cancer Study Group. Lung Cancer 

1994; 10 Suppl 1:S289-98. 

Notes: NRQ 

Arriagada R, Pignon JP, Ihde DC, et al. Effect of 

thoracic radiotherapy on mortality in limited small 

cell lung cancer. A meta-analysis of 13 randomized 

trials among 2,140 patients. Anticancer Res 1994; 

14(1B):333-5. 

Notes: NPD 

Arriagada R, Pignon JP, Le Chevalier T. Initial 

chemotherapeutic doses and long-term survival in 

limited small-cell lung cancer. N Engl J Med 2001; 

345(17):1281-2. 

Notes: NRQ 
D-3

Artel-Cortes A, Gomez-Codina J, Gonzalez-Larriba 

JL, et al. Prospective randomized phase III trial of 

etoposide/cisplatin versus high-dose 

epirubicin/cisplatin in small-cell lung cancer. Clin 

Lung Cancer 2004 Nov;6(3):175-83. 

Notes: NRQ 

Asamoto H, Kawahara M, Iwami F, et al. Cisplatin 

plus oral etoposide in the treatment of patients with 

advanced small cell lung cancer. Japan Clinical 

Oncology Group. Jpn J Clin Oncol 1998; 28(12):745-

8. 

Notes: NSD 

Auchter RM. Early versus late irradiation in smallcell lung cancer (3) (multiple letters). J Clin Oncol 

1998; 16(3):1235-7. 

Notes: NPD; but maybe cite in write-up for Q1 

Auperin A, Arriagada R, Pignon JP, et al. 

Prophylactic cranial irradiation for patients with 

small-cell lung cancer in complete remission. 

Prophylactic Cranial Irradiation Overview 

Collaborative Group. N Engl J Med 1999; 

341(7):476-84. 

Notes: NPD 

Baker RR, Ettinger DS, Ruckdeschel JD, et al. The 

role of surgery in the management of selected 

patients with small-cell carcinoma of the lung. J Clin 

Oncol 1987; 5(5):697-702. 

Notes: FEW 

Ball DL, Bishop JF. Failure of a short course of 

prophylactic cranial irradiation to reduce the 

incidence of cerebral relapse in small cell lung 

cancer. Australas Radiol 1987; 31(4):361-4. 

Notes: NSD 

Bamberga M, Michetti G, Bamberga P, et al. 

Cyclophosphamide, epirubicin, etoposide, cis 

platinum (CEVP) in combination with radiotherapy: 

evaluation of a protocol adopted for 6 years in 148 

cases of small cell lung cancer. Tumori 1992; 

78(5):333-7. 

Notes: SCS NSD (retrospective) 

Beith JM, Clarke SJ, Woods RL, et al. Long-term 

follow-up of a randomised trial of combined 

chemoradiotherapy induction treatment, with and 

without maintenance chemotherapy in patients with 

small cell carcinoma of the lung. Eur J Cancer 1996; 

32A(3):438-43. 

Notes: NRQ 

Belani CP, Bonomi P, Dobbs TW, et al. Docetaxel 

and cisplatin in patients with advanced non small-cell 

lung cancer (NSCLC): a multicenter phase II trial. 

Clin Lung Cancer 1999; 1(2):144-50. 

Notes: NSP 

Berberich W, Schnabel K, Scharding B, et al. 

[Hyperfractionated irradiation of bronchial cancer. 

Results of a pilot study]. Strahlenther Onkol 1987; 

163(2):74-8. 

Notes: NSD 

Berghmans T, Paesmans M, Lafitte JJ, Mascaux C, 

Meert AP, Sculier JP. Role of granulocyte and 

granulocyte-macrophage colony-stimulating factors 

in the treatment of small-cell lung cancer: a 

systematic review of the literature with 

methodological assessment and meta-analysis. Lung 

Cancer 2002; 37(2):115-23. 

Notes: NRQ 

Bergman B, Aaronson NK. Quality-of-life and costeffectiveness assessment in lung cancer. Curr Opin 

Oncol 1995; 7(2):138-43. 

Notes: NRA 

Bergman B, Sullivan M, Sorenson S. Quality of life 

during chemotherapy for small cell lung cancer. II. A 

longitudinal study of the EORTC Core Quality of 

Life Questionnaire and comparison with the Sickness 

Impact Profile. Acta Oncol 1992; 31(1):19-28. 

Notes: NRQ 

Birch R, Omura GA, Greco FA, Perez CA. Patterns 

of failure in combined chemotherapy and 

radiotherapy for limited small cell lung cancer: 

Southeastern Cancer Study Group experience. NCI 

Monogr 1988; (6):265-70. 

Notes: NRQ 

Birch R, Weaver CH, Hainsworth JD, Bobo C, Greco 

FA. A randomized study of etoposide and carboplatin 

with or without paclitaxel in the treatment of small 

cell lung cancer. Semin Oncol 1997; 24(4 Suppl 

12):S12-135-S12-137. 

Notes: NRQ 

Bishop JF. Scheduling of chemotherapy and 

radiotherapy in locally advanced non-small cell lung 

cancer. Lung Cancer 1995; 12 Suppl 2:S53-61. 

Notes: NRA 
D-4

Bleehen NM, Girling DJ, Gregor A, et al. Can longterm survival be improved in patients with small-cell 

lung cancer (SCLC) and good performance status? 

Medical Research Council Lung Cancer Working 

Party. Br J Cancer 1994; 70(1):142-4. 

Notes: FEW 

Bleyer WA. Hobson's choice in the CNS 

radioprophylaxis of small cell lung cancer. Int J 

Radiat Oncol Biol Phys 1988; 15(3):783-5. 

Notes: NPD 

Bonnefoi H, Zulian GB, Mirimanoff RO, Mermillod 

B, Alberto P. Priming low-dose chest radiotherapy 

followed by chemotherapy for limited small-cell lung 

cancer. Ann Oncol 1994; 5(8):771-2. 

Notes: NSD 

Bonomi P. New approaches to symptom 

improvements in lung cancer patients. Lung Cancer 

2003; 41 Suppl 4:S32-6. 

Notes: NRA 

Bowen EF, Anderson JR, Roddie ME. Improving 

surgical resection rates in lung cancer without a two 

stop service. Thorax 2003 Apr;58(4):368. 

Notes: NSP 

Bremnes RM, Sundstrom S, Aasebo U, et al. The 

value of prognostic factors in small cell lung cancer: 

results from a randomised multicenter study with 

minimum 5 year follow-up. Lung Cancer 2003; 

39(3):303-13. 

Notes: NRQ 

Bremnes RM, Sundstrom S, Vilsvik J, et al. 

Multicenter phase II trial of paclitaxel, cisplatin, and 

etoposide with concurrent radiation for limited-stage 

small-cell lung cancer. J Clin Oncol 2001; 

19(15):3532-8. 

Notes: NSD 

Brewster AE, Hopwood P, Stout R, et al. Single 

fraction prophylactic cranial irradiation for small cell 

carcinoma of the lung. Radiother Oncol 1995; 

34(2):132-6. 

Notes: NSD 

Brock MV, Hooker CM, Syphard JE, et al. Surgical 

resection of limited disease small cell lung cancer in 

the new era of platinum chemotherapy: Its time has 

come. J Thorac Cardiovasc Surg 2005 Jan;129(1):64-

72. 

Notes: SCS 

Brodin O, Rikner G, Steinholtz L, Nou E. Local 

failure in patients treated with radiotherapy and 

multidrug chemotherapy for small cell lung cancer. 

Acta Oncol 1990; 29(6):739-46. 

Notes: NSD 

Brown PD, Bonner JA, Foote RL, et al. Long-term 

results of a phase I/II study of high-dose thoracic 

radiotherapy with concomitant cisplatin and 

etoposide in limited stage small-cell lung cancer. Am 

J Clin Oncol 2001; 24(6):556-61. 

Notes: NSD 

Buck AK, Halter G, Schirrmeister H, et al. Imaging 

proliferation in lung tumors with PET: 18F-FLT 

versus 18F-FDG. J Nucl Med 2003; 44 (9):1426-31. 

Notes: NSD 

Buck AK, Hetzel M, Schirrmeister H, et al. Clinical 

relevance of imaging proliferative activity in lung 

nodules. Eur J Nucl Med Mol Imaging 2004. 

Notes: NRQ; excluded 

Bulzebruck H, Holle R, Havemann K, et al. [Analysis 

of the effect of selection in a therapy study]. 

Onkologie 1986; 9(5):274-80. 

Notes: NRQ 

Bunn P, Arriagada R, Choi N, et al. Combined 

modality therapy in small cell lung cancer. Lung 

Cancer 1994; 10 Suppl 1:S25-8. 

Notes: NPD; but maybe cite in write-up 

Bunn PA Jr, Kelly K. New treatment agents for 

advanced small cell and non-small cell lung cancer. 

Semin Oncol 1995; 22(3 Suppl 6):53-63. 

Notes: NRA 

Bunn PA Jr, Kelly K. Prophylactic cranial irradiation 

for patients with small-cell lung cancer. J Natl Cancer 

Inst 1995; 87(3):161-2. 

Notes: NPD 

Bunn PA Jr, Shepherd FA, Sandler A, et al. Ongoing 

and future trials of biologic therapies in lung cancer. 

Lung Cancer 2003; 41 Suppl 1:S175-86. 

Notes: NRA 

Burgers JA, Arance A, Ashcroft L, et al. Identical 

chemotherapy schedules given on and off trial 

protocol in small cell lung cancer: response and 

survival results. Br J Cancer 2002; 87(5):562-6. 

Notes: NRQ 
D-5

Bychko MB, Ol'khovskaia IG. [The results of the 

conservative treatment of patients with small-cell 

lung cancer]. Vopr Onkol 1989; 35 (2):180-4. 

Notes: SCS 

Bynhardt R, Komaki R, Ettinger D, et al. Radiation 

Therapy Oncology Group. Research Plan 2002-2006. 

Lung Cancer Committee. Int J Radiat Oncol Biol 

Phys 2001; 51(3 Suppl 2):44-52. 

Notes: NPD 

Byrne MJ, van Hazel G, Trotter J, et al. Maintenance 

chemotherapy in limited small cell lung cancer: a 

randomised controlled clinical trial. Br J Cancer 

1989; 60(3):413-8. 

Notes: NRQ 

Campling B. Topotecan in small cell lung cancer: 

first or second line? Cancer Biol Ther 2004; 3(1):94-

5. 

Notes: NPD; exclude, but cite in write-up 

Canetta R, Bragman K, Smaldone L, et al. 

Carboplatin: current status and future prospects. 

Cancer Treat Rev 1988; 15 Suppl B:17-32. 

Notes: NRA 

Carlson RW, Sikic BI, Gandara DR, et al. Late 

consolidative radiation therapy in the treatment of 

limited-stage small cell lung cancer. Cancer 1991; 

68(5):948-58. 

Notes: NRQ 

Carney DN. Carboplatin/etoposide combination 

chemotherapy in the treatment of poor prognosis 

patients with small cell lung cancer. Lung Cancer 

1995; 12 Suppl 3:S77-83. 

Notes: NRQ 

Carney DN. Lung cancer--time to move on from 

chemotherapy. N Engl J Med 2002; 346(2):126-8. 

Notes: NPD 

Chanarin N. Chemotherapy plus surgery versus 

surgery alone in non-small-cell lung cancer. N Engl J 

Med 1994; 330(24):1756; author reply 1757. 

Notes: NRD NSP 

Chatani M, Matayoshi Y, Masaki N, et al. [Radiation 

therapy for brain metastases from lung carcinoma: 

the second prospective randomized trial]. Nippon 

Igaku Hoshasen Gakkai Zasshi 1994; 54(14):1380-7. 

Notes: NRQ 

Chatani M, Teshima T, Hata K, et al. Whole brain 

irradiation for metastases from lung carcinoma. A 

clinical investigation. Acta Radiol Oncol 1985; 

24(4):311-4. 

Notes: NRQ 

Chen TT, Chute JP, Feigal E, et al. A model to select 

chemotherapy regimens for phase III trials for 

extensive-stage small-cell lung cancer. J Natl Cancer 

Inst 2000; 92(19):1601-7. 

Notes: NRQ NPD 

Cheran SK, Herndon JE 2nd, Patz EF Jr. Comparison 

of whole-body FDG-PET to bone scan for detection 

of bone metastases in patients with a new diagnosis 

of lung cancer. Lung Cancer 2004; 44(3):317-25. 

Notes: NSD NSP 

Cheson BD. Clinical trials referral resource. NCINavy: small cell lung cancer. Oncology (Huntingt) 

1990; 4(9):129-30. 

Notes: NRQ 

Cheson BD. Clinical trials referral resource. Smallcell lung cancer. Oncology (Huntingt) 1990; 4(1):43-

56. 

Notes: NPD 

Cheson BD, Feigal EG, Phillips PH. Clinical trials 

referral resource. Extensive-stage small-cell lung 

cancer. Oncology (Huntingt) 1993; 7(11):60, 63-4. 

Notes: NPD 

Cheson BD, Feigal EG, Phillips PH. Clinical trials 

referral resource. Small-cell lung cancer. Oncology 

(Huntingt) 1993; 7(10):43-7. 

Notes: NPD 

Chin R Jr, McCain TW, Miller AA, et al. Whole 

body FDG-PET for the evaluation and staging of 

small cell lung cancer: a preliminary study. Lung 

Cancer 2002; 37(1):1-6. 

Notes: FEW 

Chiuten DF, Carr DT, Dhingra HM, et al. 

Combination chemotherapy with vindesine and 

cisplatin for refractory small cell bronchogenic 

carcinoma. Cancer Treat Rep 1986; 70(6):795-6. 

Notes: FEW 

Choi NC, Carey RW, Kaufman SD, Grillo HC, 

Younger J, Wilkins EW Jr. Small cell carcinoma of 

the lung. A progress report of 15 years' experience. 

Cancer 1987; 59(1):6-14. 

Notes: SCS 
D-6

Choi NC, Propert K, Carey R, et al. Accelerated 

radiotherapy followed by chemotherapy for locally 

recurrent small-cell carcinoma of the lung. A phase II 

study of Cancer and Leukemia Group B. Int J Radiat 

Oncol Biol Phys 1987; 13(2):263-6. 

Notes: FEW 

Clark PI, Slevin ML, Joel SP, et al. A randomized 

trial of two etoposide schedules in small-cell lung 

cancer: the influence of pharmacokinetics on efficacy 

and toxicity. J Clin Oncol 1994; 12(7):1427-35. 

Notes: NRQ 

Clerici M. Second line treatment (2 LT) in small cell 

lung cancer (SC). Anticancer Res 1994; 14(1B):337-

9. 

Notes: NRA 

Cocquyt V, De Neve W, Van Belle SJ. 

Chemotherapy plus surgery versus surgery alone in 

non-small-cell lung cancer. N Engl J Med 1994; 

330(24):1756; author reply 1757. 

Notes: NRD NSP 

Coleman RE. Value of FDG-PET scanning in 

management of lung cancer. Lancet 2002; 

359(9315):1361-2. 

Notes: NPD 

Collins C, Higano CS, Livingston RB, et al. 

Cyclophosphamide, vincristine, cisplatin, VP-16 and 

radiation therapy in extensive small-cell lung cancer. 

A Southwest Oncology Group Study. Cancer 

Chemother Pharmacol 1989; 24(2):128-32. 

Notes: NRQ 

Coy P, Hodson I, Payne DG , et al. The effect of dose 

of thoracic irradiation on recurrence in patients with 

limited stage small cell lung cancer. Initial results of 

a Canadian Multicenter Randomized Trial. Int J 

Radiat Oncol Biol Phys 1988; 14(2):219-26. 

Notes: NSD 

Crawford J, Kreisman H, Garewal H, et al. The 

impact of Filgrastim schedule variation on 

hematopoietic recovery post-chemotherapy. Ann 

Oncol 1997; 8(11):1117-24. 

Notes: NRQ 

Cull A, Gregor A, Hopwood P, et al. Neurological 

and cognitive impairment in long-term survivors of 

small cell lung cancer. Eur J Cancer 1994; 

30A(8):1067-74. 

Notes: NSD 

Dales RE, Stark RM, Raman S. Computed 

tomography to stage lung cancer. Approaching a 

controversy using meta-analysis. Am Rev Respir Dis 

1990; 141( 5 Pt 1):1096-101. 

Notes: NPD; no separate data for SCLC; systematic 

review and meta-analysis of CT for staging 

Davies AM, Evans WK, Mackay JA, Shepherd FA. 

Treatment of recurrent small cell lung cancer. 

Hematol Oncol Clin North Am 2004; 18(2):387-416. 

Notes: NPD; exclude but cite in write-up 

Davis S, Crino L, Tonato M, Darwish S, Pelicci PG, 

Grignani F. A prospective analysis of chemotherapy 

following surgical resection of clinical stage I-II 

small-cell lung cancer. Am J Clin Oncol 1993; 

16(2):93-5. 

Notes: SCS 

De Marinis F, Migliorino MR, Paoluzzi L, et al. 

Phase I/II trial of gemcitabine plus cisplatin and 

etoposide in patients with small-cell lung cancer. 

Lung Cancer 2003; 39(3):331-8. 

Notes: NRQ 

De MF, Nelli F, Lombardo M, et al. A multicenter, 

randomized, phase II study of cisplatin, etoposide, 

and gemcitabine or cisplatin plus gemcitabine as 

first-line treatment in patients with poor-prognosis 

small cell lung carcinoma. Cancer 2005; 103(4):772-

9. 

Notes: NRQ 

Dearing MP, Steinberg SM, Phelps R, et al. Outcome 

of patients with small-cell lung cancer: effect of 

changes in staging procedures and imaging 

technology on prognostic factors over 14 years. J 

Clin Oncol 1990; 8(6):1042-9. 

Notes: NRQ 

Debevec M, Orel J. Treatment of small cell lung 

cancer by surgery, chemotherapy, and irradiation. 

Lung Cancer ( LUNG CANCER ) 1991. 

Notes: SCS 

Del Valle ML, Rubiales AS, Garavis M, Rey P, 

Lopez-Lara F. Radioterapia en el carcinoma 

microcítico de pulmón: ¿cuanto antes mejor? 

Oncologia 2000; 23(3):29-37. 

Notes: NPD 

Delbaldo C, Le Pechoux C, Le Chevalier T. 

Combined modality treatment of lung cancer 

(NSCLC and SCLC). Cancer Chemother Biol 

Response Modif 2002; 20:677-95. 

Notes: NRA; exclude, maybe cite in write-up 
D-7

Dodwell D, Gildersleve JQ. Adjuvant thoracic 

radiation in small cell lung cancer. Clin Oncol (R 

Coll Radiol) 1993; 5(6):384-5. 

Notes: NRA 

Dowlati A, Crosby L, Remick SC, et al. Paclitaxel 

added to the cisplatin/etoposide regimen in extensivestage small cell lung cancer -- the use of complete 

response rate as the primary endpoint in phase II 

trials. Lung Cancer 2001; 32(2):155-62. 

Notes: NRQ 

Doyle JJ, Dezii CM, Sadana A. A 

pharmacoeconomic evaluation of cisplatin in 

combination with either etoposide or etoposide 

phosphate in small cell lung cancer. Semin Oncol 

1996; 23(6 Suppl 13):51-60. 

Notes: NRQ 

Eagan RT, Frytak S, Lee RE, Therneau TM, 

Richardson RL, Creagan ET. No routine role for 

vincristine, adriamycin, and cyclophosphamide 

(VAC) or thoracic radiation therapy in extensive 

stage small cell lung cancer. Am J Clin Oncol 1987; 

10(2):141-5. 

Notes: NRQ 

Eberhardt K, Hartmann W, Habermalz H, et al. ACE 

vs alternating PVB/ACE: Results of a controlled 

randomised therapy study in small-cell bronchial 

carcinoma in Bremen hospitals. Pneumologie 1991; 

45(4):173-4. 

Notes: NRQ, exclude 

Eberhardt W, Stamatis G, Stuschke M, et al. 

Prognostically orientated multimodality treatment 

including surgery for selected patients of small-cell 

lung cancer patients stages IB to IIIB: long-term 

results of a phase II trial. Br J Cancer 1999; 

81(7):1206-12. 

Notes: SCS 

Ebi N, Kubota K, Nishiwaki Y, et al. Second-line 

chemotherapy for relapsed small cell lung cancer. Jpn 

J Clin Oncol 1997; 27(3):166-9. 

Notes: SCS 

Eckardt JR. Feasibility of oral topotecan in 

previously untreated patients with small-cell lung 

cancer ineligible for standard therapy. Oncology 

2001; 61 Suppl 1:42-6. 

Notes: NRQ 

Edelman MJ, Chansky K, Gaspar LE, et al. Phase II 

trial of cisplatin/etoposide and concurrent 

radiotherapy followed by paclitaxel/carboplatin 

consolidation for limited small-cell lung cancer: 

Southwest Oncology Group 9713. J Clin Oncol 2004; 

22(1):127-32. 

Notes: NSD, NRQ 

Eckardt JR. Second-line treatment of small-cell lung 

cancer. The case for systemic chemotherapy. 

Oncology (Huntingt) 2003; 17(2):181-8, 191; 

discussion 191-2, passim. 

Notes: NRA 

Elias AD. Dose-intensive therapy for small cell lung 

cancer. Chest 1995; 107(6 Suppl):261S-6S. 

Notes: NRA 

Elias AD, Skarin AT, Richardson P, et al. Doseintensive therapy for extensive-stage small cell lung 

cancer and extrapulmonary small cell carcinoma: 

long-term outcome. Biol Blood Marrow Transplant 

2002; 8(6):326-33. 

Notes: NRQ 

Erkisi M, Unsal M, Tunali C, et al. A randomized 

study comparing cyclophosphamide, doxorubicin, 

vincristine (CAV) with cyclophosphamide, 

etoposide, vincristine, methotrexate (CEVM) in 

patients with small cell lung cancer. J Chemother 

1993; 5 (1):56-9. 

Notes: NRQ 

Erridge SC, Murray N. Thoracic radiotherapy for 

limited-stage small cell lung cancer: issues of timing, 

volumes, dose, and fractionation. Semin Oncol 2003; 

30(1):26-37. 

Notes: NRA 

Ettinger DS. Ifosfamide in the treatment of small cell 

lung cancer. Semin Oncol 1996; 23(3 Suppl 6):2-6. 

Notes: NRA, NRQ 

Ettinger DS. New drugs for treating small cell lung 

cancer. Lung Cancer 1995; 12(Suppl 3):S53-61. 

Notes: NRA 

Ettinger DS. The place of ifosfamide in 

chemotherapy of small cell lung cancer: the Eastern 

Cooperative Oncology Group experience and a 

selected literature update. Semin Oncol 1995; 22(1 

Suppl 2):23-7. 

Notes: NRQ 
D-8

Ettinger DS, Finkelstein DM, Abeloff MD, et al. 

Phase II study of n-methylformamide (NSC 3051) 

and spirogermanium (NSC 192965) in the treatment 

of advanced small cell lung cancer. Invest New 

Drugs 1990; 8(2):183-5. 

Notes: INV 

Ettinger DS, Finkelstein DM, Ritch PS, et al. Study 

of either ifosfamide or teniposide compared to a 

standard chemotherapy for extensive disease small 

cell lung cancer: an Eastern Cooperative Oncology 

Group randomized study (E1588). Lung Cancer 

2002; 37(3):311-8. 

Notes: NRQ 

Evans WK, Radwi A, Tomiak E, et al. Oral etoposide 

and carboplatin. Effective therapy for elderly patients 

with small cell lung cancer. Am J Clin Oncol 1995; 

18(2):149-55. 

Notes: NRQ 

Falk SJ, Maughan TS, Laurence VM, et al. Phase II 

study of carboplatin and adriamycin as second line 

chemotherapy in small cell lung cancer. Clin Oncol 

(R Coll Radiol) 1993; 5(2):85-8. 

Notes: SCS 

Fayers P. Quality-of-life assessment in small cell 

lung cancer. Pharmacoeconomics 1992; 2(3):181-8. 

Notes: NRA; but maybe cite in write-up 

Feld R, Clamon GH, Blum R, et al. Short course 

prophylactic cranial irradiation for small cell lung 

cancer. Am J Clin Oncol 1985; 8(5):371-6. 

Notes: NSD 

Feld R, Evans WK, Coy P, et al. Canadian 

multicenter randomized trial comparing sequential 

and alternating administration of two non-crossresistant chemotherapy combinations in patients with 

limited small-cell carcinoma of the lung. J Clin Oncol 

1987; 5(9):1401-9. 

Notes: NRQ 

Felip E, Rosell R, Domine M, et al. Sequential dosedense paclitaxel followed by topotecan in untreated 

extensive-stage small-cell lung cancer: a Spanish 

Lung Cancer Group phase II study. Ann Oncol 2003; 

14(10):1549-54. 

Notes: NRQ 

Ferry DR, Cullen MH. Chemotherapy in advanced 

small lung cell cancer. BMJ 1994; 308(6933):920. 

Notes: NSP NRD 

Fetscher S, Brugger W, Engelhardt R, et al. Standardand high-dose etoposide, ifosfamide, carboplatin, and 

epirubicin in 100 patients with small-cell lung cancer: 

a mature follow-up report. Ann Oncol 1999; 

10(5):561-7. 

Notes: NRQ 

Fiedler R, Neef H, Hennig H, Rosendahl W, 

Lautenschlager C. [Quality of life after 

pneumonectomy for bronchial carcinoma]. Zentralbl 

Chir 1997; 122( 5):327-31. 

Notes: SCS 

Filipazzi V, Piazza E, Cattaneo MT, et al. Ifosfamide, 

carboplatin and etoposide (ICE) in the treatment of 

small cell lung cancer: A cooperative multicentre 

study. Eur J Oncol 2004; 9(2):107-10. 

Notes: NRQ NSD 

Finley RS. Lung cancer: detection, prevention, and 

therapeutics. Am Pharm 1989; NS29(11):39-46. 

Notes: NPD 

Foley JF, Peterson WC, Mailliard JA. Treatment of 

small cell carcinoma of the lung. Nebr Med J 1989; 

74(11):330-2. 

Notes: SCS 

Fried DB, Morris DE, Poole C, et al. Systematic 

review evaluating the timing of thoracic radiation 

therapy in combined modality therapy for limitedstage small-cell lung cancer. J Clin Oncol 2004; 

22(23):4785-93. 

Notes: NPD 

Frytak S, Shaw EG, Jett JR, et al. Infusion cisplatin 

chemotherapy and hyperfractionated thoracic 

radiotherapy for small-cell lung cancer. Am J Clin 

Oncol 1996; 19(2):193-8. 

Notes: NSD 

Fu Q, Gai X, Ji Z. [Clinical analysis of surgical 

treatment for 86 patients with localized small-cell 

lung cancer]. Zhonghua Zhong Liu Za Zhi 1996; 

18(5):382-4. 

Notes: NSD 

Fukuchi K, Yamaguchi M, Hayashida K, Ishida Y. 

Discrepancy between Tc-99m HMDP bone scan and 

F-18 FDG positron emission tomographic images in a 

patient with small cell lung cancer. Clin Nucl Med 

2003; 28(3):232-3. 

Notes: FEW 
D-9

Fukuoka M, Masuda N, Matsui K, et al. Combination 

chemotherapy with or without radiation therapy in 

small cell lung cancer. An analysis of a 5-year 

follow-up. Cancer 1990; 65(8):1678-84. 

Notes: SCS NSD (retrospective) 

Fukuoka M, Masuda N, Negoro S, et al. CODE 

chemotherapy with and without granulocyte colonystimulating factor in small-cell lung cancer. Br J 

Cancer 1997; 75(2):306-9. 

Notes: NRQ 

Furuse K, Fukuoka M, Nishiwaki Y, et al. Phase III 

study of intensive weekly chemotherapy with 

recombinant human granulocyte colony-stimulating 

factor versus standard chemotherapy in extensivedisease small-cell lung cancer. The Japan Clinical 

Oncology Group. J Clin Oncol 1998; 16(6):2126-32. 

Notes: NRQ 

Furuse K, Kawahara M, Arai R, et al. [Combined 

radiotherapy and chemotherapy modalities in the 

treatment of lung cancer]. Gan To Kagaku Ryoho 

1988; 15(4 Pt 2-3):1628-33. 

Notes: NRQ 

Gaspar LE, Rogers LR. Prophylactic cranial 

irradiation for small-cell lung cancer: to do or not to 

do? Support Oncol 2004; 2:7-9. 

Notes: NPD 

Gatzemeier U, Achterrath W, Heckmayr M, et al. 

[Chemotherapy of small cell bronchial cancer with a 

combination of carboplatin, vincristine and 

etoposide]. Pneumologie 1990; 44 Suppl 1:584-5. 

Notes: NRQ 

Gatzemeier U, Kleisbauer JP, Drings P, et al. 

Lenograstim as support for ACE chemotherapy of 

small-cell lung cancer: a phase III, multicenter, 

randomized study. Am J Clin Oncol 2000; 23(4):393-

400. 

Notes: NRQ 

Gatzemeier U, Radenbach D. Chemotherapy (CAV) 

and surgical resection as combined modality in the 

therapy of small-cell lung cancer. Panminerva Med 

1986; 28(2):63-6. 

Notes: SCS 

Gatzemeier U, von Pawel J, Laumen R, et al. 

Carboplatin/etoposide/vincristine therapy in small 

cell lung cancer. Oncology 1992; 49 Suppl 1:25-33. 

Notes: NSD 

Geara FB, Komaki R, Tucker SL, Travis EL, Cox JD. 

Factors influencing the development of lung fibrosis 

after chemoradiation for small cell carcinoma of the 

lung: evidence for inherent interindividual variation. 

Int J Radiat Oncol Biol Phys 1998; 41(2):279-86. 

Notes: NRQ 

Geddes DM, Dones L, Hill E, et al. Quality of life 

during chemotherapy for small cell lung cancer: 

assessment and use of a daily diary card in a 

randomized trial. Eur J Cancer 1990; 26(4):484-92. 

Notes: NRQ 

Gennatas CS, Balafouta MJ, Panayotopoulos PP, et 

al. A pilot study of an alternating chemotherapy 

regime and sequential radiation therapy in limited 

stage small cell carcinoma of the lung. Eur J Cancer 

1993; 29A(12):1792-3. 

Notes: NSD 

Georgiadis MS, Steinberg SM, Hankins LA, Ihde 

DC, Johnson BE. Obesity and therapy-related 

toxicity in patients treated for small-cell lung cancer. 

J Natl Cancer Inst 1995; 87(5):361-6. 

Notes: NSD 

Giaccone G. Identification of new drugs in pretreated 

patients with small cell lung cancer. Eur J Cancer 

Clin Oncol 1989; 25(3):411-3. 

Notes: NPD 

Giaccone G. Second line chemotherapy in small cell 

lung cancer. Lung Cancer 1989; 207-13. 

Notes: NPD 

Ginsberg RJ. Small cell lung cancer: how should we 

treat it? What is it? Ann Thorac Surg 2000 Nov; 

70(5):1453-4. 

Notes: NPD 

Girling DJ, Stott H, Stephens RJ, et al. Fifteen-year 

follow-up of all patients in a study of post-operative 

chemotherapy for bronchial carcinoma. Br J Cancer 

1985; 52(6):867-73. 

Notes: NRQ 

Glatstein E, Ihde D, Bunn P, et al. Radiotherapy in 

management of limited small cell lung carcinoma: a 

randomized prospective study. Cancer Treat Symp 

1985; 2:97-100. 

Notes: NRQ, exclude 
D-10

Glisson B, Lee JS, Palmer J, et al. Cisplatin, 

ifosfamide, and prolonged oral etoposide in the 

treatment of patients with extensive small cell lung 

carcinoma. Cancer 1998; 82(2):301-8. 

Notes: NRQ, NSD 

Glisson B, Scott C, Komaki R, et al. Cisplatin, 

ifosfamide, oral etoposide, and concurrent 

accelerated hyperfractionated thoracic radiation for 

patients with limited small-cell lung carcinoma: 

results of radiation therapy oncology group trial 93-

12. J Clin Oncol 2000; 18(16):2990-5. 

Notes: NSD 

Glisson BS. Recurrent small cell lung cancer: update. 

Semin Oncol 2003; 30(1):72-8. 

Notes: NPD 

Glisson BS, Kurie JM, Perez-Soler R, et al. Cisplatin, 

etoposide, and paclitaxel in the treatment of patients 

with extensive small-cell lung carcinoma. J Clin 

Oncol 1999; 17(8):2309-15. 

Notes: NRQ 

Gogas H, Lofts FJ, Evans TR, et al. Outpatient 

treatment with epirubicin and oral etoposide in 

patients with small-cell lung cancer. Br J Cancer 

1997; 76(5):639-42. 

Notes: NRQ 

Goodman GE, Crowley JJ, Blasko JC, et al. 

Treatment of limited small-cell lung cancer with 

etoposide and cisplatin alternating with vincristine, 

doxorubicin, and cyclophosphamide versus 

concurrent etoposide, vincristine, doxorubicin, and 

cyclophosphamide and chest radiotherapy: a 

Southwest Oncology Group Study. J Clin Oncol 

1990; 8(1):39-47. 

Notes: NSD 

Gower NH, Rudd RM, Ruiz de Elvira MC, et al. 

Assessment of 'quality of life' using a daily diary card 

in a randomised trial of chemotherapy in small-cell 

lung cancer. Ann Oncol 1995; 6(6):575-80. 

Notes: NRQ 

Grant SC, Kris MG. Phase II trials in small-cell lung 

cancer: shouldn't we be doing better? J Natl Cancer 

Inst 1992; 84(14):1058-9. 

Notes: NPD 

Greco FA, Hainsworth JD. Clinical studies with 

etoposide phosphate. Semin Oncol 1996; 23(6 Suppl 

13):45-50. 

Notes: NRQ 

Greco FA, Hainsworth JD. Emerging role of 

topotecan in first-line therapy of small-cell lung 

cancer. Clin Lung Cancer 2003; 4(5):279-87. 

Notes: NRA 

Greco FA, Hainsworth JD. Paclitaxel, carboplatin, 

and oral etoposide in the treatment of small cell lung 

cancer. Semin Oncol 1996; 23(6 Suppl 16):7-10. 

Notes: NSD 

Gregor A. Combined modality treatment in small 

cell lung cancer (SCLC). Eur J Cancer 1995; 

31A(5):816-8. 

Notes: NPD 

Gregor A. Cranial irradiation in small cell lung 

cancer. Br J Cancer 1991; 63(1):13-4. 

Notes: NPD 

Gregor A. Factors influencing use of alternating 

chemotherapy and radiation schedules in small cell 

lung cancer. Lung Cancer 1994; 10 Suppl 1:S299-

305. 

Notes: NPD NRA 

Gregor A, Drings P, Rinaldi M, et al. Acute toxicity 

of alternating schedule of chemotherapy and 

irradiation in limited small-cell lung cancer in a pilot 

study (08877) of the EORTC Lung Cancer 

Cooperative Group. Ann Oncol 1995; 6(4):403-5. 

Notes: NPD 

Gridelli C, Curcio C, Iaffaioli RV, et al. Carboplatin 

+ epirubicin +VP-16 + lenograstim followed by 

radiotherapy + carboplatin as radiosensitizer in 

limited small cell lung cancer. A multicenter phase II 

study. Anticancer Res 2001; 21(6A):4179-83. 

Notes: NRQ 

Gridelli C, D'Aprile M, Curcio C, et al. Carboplatin 

plus epirubicin plus VP-16, concurrent 'split course' 

radiotherapy and adjuvant surgery for limited small 

cell lung cancer. Gruppo Oncologico Centro-SudIsole (GOCSI). Lung Cancer 1994; 11(1-2):83-91. 

Notes: NSD 

Gridelli C, Manzione L, Perrone F, et al. Carboplatin 

plus paclitaxel in extensive small cell lung cancer: a 

multicentre phase 2 study. Br J Cancer 2001; 

84(1):38-41. 

Notes: NRQ 
D-11

Gridelli C, Perrone F, D'Aprile M, et al. Phase II 

study of intensive CEV (carboplatin, epirubicin and 

VP-16) plus G-CSF (granulocyte-colony stimulating 

factor) in extensive small cell lung cancer. Eur J 

Cancer 1995; 31A(13-14):2424-6. 

Notes: NRQ 

Gridelli C, Perrone F, Ianniello GP, et al. Carboplatin 

plus vinorelbine, a new well-tolerated and active 

regimen for the treatment of extensive-stage smallcell lung cancer: a phase II study. Gruppo 

Oncologico Centro-Sud-Isole. J Clin Oncol 1998; 

16(4):1414-9. 

Notes: NRQ 

Gridelli C, Rossi A, Barletta E, et al. Carboplatin plus 

vinorelbine plus G-CSF in elderly patients with 

extensive-stage small-cell lung cancer: a poorly 

tolerated regimen. Results of a multicentre phase II 

study. Lung Cancer 2002; 36(3):327-32. 

Notes: NRQ, NSD 

Grozea PN, Crowley JJ, Canfield VA, et al. 

Teniposide (VM-26) as a single drug treatment for 

patients with extensive small cell lung carcinoma: a 

Phase II study of the Southwest Oncology Group. 

Cancer 1997; 80(6):1029-33. 

Notes: NRQ 

Gupta NC, Graeber GM, Bishop HA. Comparative 

efficacy of positron emission tomography with 

fluorodeoxyglucose in evaluation of small (<1 cm), 

intermediate (1 to 3cm), and large (>3 cm) lymph 

node lesions. Chest 2000 Mar; 117(3):773-8. 

Notes: NSP exclude 

Hainsworth JD, Gray JR, Stroup SL, et al. Paclitaxel, 

carboplatin, and extended-schedule etoposide in the 

treatment of small-cell lung cancer: comparison of 

sequential phase II trials using different doseintensities. J Clin Oncol 1997; 15(12):3464-70. 

Notes: NRQ 

Hainsworth JD, Hopkins LG, Thomas M, et al. 

Paclitaxel, carboplatin, and extended-schedule oral 

etoposide for small-cell lung cancer. Oncology 

(Huntingt) 1998; 12(1 Suppl 2):31-5. 

Notes: NSD 

Hainsworth JD, Morrissey LH, Scullin DC Jr, et al. 

Paclitaxel, carboplatin, and topotecan in the treatment 

of patients with small cell lung cancer: a phase II trial 

of the Minnie Pearl Cancer Research Network. 

Cancer 2002; 94(9):2426-33. 

Notes: NRQ, NSD 

Hainsworth JD, Stroup SL, Greco FA. Paclitaxel, 

carboplatin, and extended schedule etoposide in the 

treatment of small cell lung carcinoma. Cancer 1996; 

77(12):2458-63. 

Notes: NRQ, NSD 

Halme M, Hallman M, Ruotsalainen T, et al. Tumour 

response and radiation-induced lung injury in patients 

with recurrent small cell lung cancer treated with 

radiotherapy and concomitant interferon-alpha. Lung 

Cancer 1999; 23(1):39-52. 

Notes: FEW 

Hand S, Baker J, Smith AP, Macbeth FR. Outpatient 

intensive chemotherapy for small cell lung cancer: 

five years experience of modified 'ICE' ifosfamide 

carboplatin and etoposide. Clin Oncol (R Coll 

Radiol) 2002; 14(5):367-71. 

Notes: NSD 

Hanna N, Ansari R, Fisher W, et al. Etoposide, 

ifosfamide and cisplatin (VIP) plus concurrent 

radiation therapy for previously untreated limited 

small cell lung cancer (SCLC): a Hoosier Oncology 

Group (HOG) phase II study. Lung Cancer 2002; 

35(3):293-7. 

Notes: NSD 

Hanna NH, Sandier AB, Loehrer PJ Sr, et al. 

Maintenance daily oral etoposide versus no further 

therapy following induction chemotherapy with 

etoposide plus ifosfamide plus cisplatin in extensive 

small-cell lung cancer: a Hoosier Oncology Group 

randomized study. Ann Oncol 2002; 13(1):95-102. 

Notes: NRQ 

Hara N, Ohta M, Ichinose Y, et al. Multimodality 

therapy for small cell carcinoma of the lung--the role 

of surgical treatment. Jpn J Surg 1989; 19(6):699-

707. 

Notes: SCS 

Hardy J, Smith I, Cherryman G, et al. The value of 

computed tomographic (CT) scan surveillance in the 

detection and management of brain metastases in 

patients with small cell lung cancer. Br J Cancer 

1990; 62(4):684-6. 

Notes: NRQ 

Harrigan P. Lung cancer tackled at Tokyo 

conference. Lancet 2000; 356(9236):1173. 

Notes: NPD 
D-12

Hauber HP, Bohuslavizki KH, Lund CH, et al. 

Positron emission tomography in the staging of 

small-cell lung cancer: a preliminary study. Chest 

2001; 119(3):950-4. 

Notes: FEW 

Havemann K, Wolf M, Drings P, et al. Experience of 

a German multicenter study group with ifosfamide in 

small cell lung cancer. Semin Oncol 1989; 16(1 

Suppl 3):9-18. 

Notes: NRQ 

Hazuka MB, Turrisi AT 3rd. The evolving role of 

radiation therapy in the treatment of locally advanced 

lung cancer. Semin Oncol 1993; 20(2):173-84. 

Notes: NRA 

Healey EA, Abner A. Thoracic and cranial 

radiotherapy for limited-stage small cell lung cancer. 

Chest 1995; 107(6 Suppl):249S-54S. 

Notes: NRA 

Heckmayr M, Gatzemeier U, Hossfeld DK, et al. 

[Cisplatin-Vepeside versus Endoxan-Vepeside in the 

treatment of small cell bronchial cancer. A 

randomized study]. Pneumologie 1990; 44 Suppl 

1:256-7. 

Notes: NRQ 

Herskovic A, Orton C, Seyedsadr M, et al. Initial 

experience with a practical hyperfractionated 

accelerated radiotherapy regimen. Int J Radiat Oncol 

Biol Phys 1991; 21(5):1275-81. 

Notes: NSD 

Herskovic A, Scott C, Demas W, et al. Accelerated 

hyperfractionation for bronchogenic cancer: 

Radiation Therapy Oncology Group 9205. Am J Clin 

Oncol 2000; 23(2):207-12. 

Notes: NRD 

Hirsch FR, Osterlind K, Jeppesen N, et al. 

Superiority of high-dose platinum (cisplatin and 

carboplatin) compared to carboplatin alone in 

combination chemotherapy for small-cell lung 

carcinoma: a prospective randomised trial of 280 

consecutive patients. Ann Oncol 2001; 12(5):647-53. 

Notes: NRQ 

Hobdy EM, Kraut E, Masters G, et al. A phase II 

study of topotecan and cyclophosphamide with GCSF in patients with advanced small cell lung cancer. 

Cancer Biol Ther 2004; 3(1):89-93. 

Notes: NRQ, NSP 

Hollaus PH, Wilfing G, Wurnig PN, et al. Risk 

factors for the development of postoperative 

complications after bronchial sleeve resection for 

malignancy: a univariate and multivariate analysis. 

Ann Thorac Surg 2003; 75(3):966-72. 

Notes: NSP 

Hollen PJ, Gralla RJ, Kris MG, Potanovich LM. 

Quality of life assessment in individuals with lung 

cancer: testing the Lung Cancer Symptom Scale 

(LCSS). Eur J Cancer 1993; 29A Suppl 1:S51-8. 

Notes: NRQ 

Hopwood P, Stephens RJ. Symptoms at presentation 

for treatment in patients with lung cancer: 

implications for the evaluation of palliative treatment. 

The Medical Research Council (MRC) Lung Cancer 

Working Party. Br J Cancer 1995; 71(3):633-6. 

Notes: NRQ 

Hopwood P, Stephens RJ, Machin D. Approaches to 

the analysis of quality of life data: experiences gained 

from a medical research council lung cancer working 

party palliative chemotherapy trial. Qual Life Res 

1994; 3(5):339-52. 

Notes: NRQ 

Huang Q, Muzitansky A, Mark EJ. Pulmonary 

neuroendocrine carcinomas: A review of 234 cases 

and a statistical analysis of 50 cases treated at one 

institution using a simple clinicopathologic 

classification. Arch Pathol Lab Med. 2002 

May;126(5):545-53. 

Notes: NRQ NPD; 

Hugli A, Moro D, Mermillod B, et al. Phase II trial of 

up-front accelerated thoracic radiotherapy combined 

with chemotherapy and optional up-front 

prophylactic cranial irradiation in limited small-cell 

lung cancer. Groupe d'Oncologie Thoracique des 

Regions Alpines. J Clin Oncol 2000; 18(8):1662-7. 

Notes: NSD 

Huisman C, Postmus PE, Giaccone G, et al. Secondline chemotherapy and its evaluation in small cell 

lung cancer. Cancer Treat Rev 1999; 25(4):199-206. 

Notes: NRA 

Huncharek M, McGarry R. A meta-analysis of the 

timing of chest irradiation in the combined modality 

treatment of limited-stage small cell lung cancer. 

Oncologist 2004; 9(6):665-72. 

Notes: NPD; 
D-13

Huttner J, Wiener N, Quadt C, et al. A randomized 

clinical trial comparing systemic radiotherapy versus 

chemotherapy versus local radiotherapy in small cell 

lung cancer. Eur J Cancer Clin Oncol 1989; 

25(6):933-7. 

Notes: NRQ 

Ichiki M, Gohara R, Rikimaru T, et al. Combination 

chemotherapy with irinotecan and ifosfamide as 

second-line treatment of refractory or sensitive 

relapsed small cell lung cancer: a phase II study. 

Chemotherapy 2003; 49(4):200-5. 

Notes: SCS 

Ichinose Y, Hara N, Ohta M, et al. Comparison 

between resected and irradiated small cell lung 

cancer in patients in stages I through IIIa. Ann 

Thorac Surg 1992; 53(1):95-100. 

Notes: SCS NSD (retrospective) 

Ihde DC. Small cell lung cancer. State-of-the-art 

therapy 1994. Chest 1995; 107(6 Suppl):243S-8S. 

Notes: NRA 

Iyoda A, Hiroshima K, Baba M, et al. Pulmonary 

large cell carcinomas with neuroendocrine features 

are high-grade neuroendocrine tumors.Ann Thorac 

Surg. 2002 Apr;73(4):1049-54. 

Notes: NRQ; 

Iyoda A, Hiroshima K, Toyozaki T, et al. Adjuvant 

chemotherapy for large cell carcinoma with 

neuroendocrine features. Cancer. 2001 Sep 

1;92(5):1108-12. 

Notes: NRQ 

Jackson DV Jr. Changing trends in small cell lung 

cancer. NC Med J 1986; 47(6):297-300. 

Notes: NRA 

James LE, Gower NH, Rudd RM, et al. A 

randomised trial of low-dose/high-frequency 

chemotherapy as palliative treatment of poorprognosis small-cell lung cancer: a Cancer research 

Campaign trial. Br J Cancer 1996; 73(12):1563-8. 

Notes: NRQ 

Janne PA, Freidlin B, Saxman S, et al. Twenty-five 

years of clinical research for patients with limitedstage small cell lung carcinoma in North America. 

Cancer 2002; 95(7):1528-38. 

Notes: NPD 

Jassem J, Karnicka-Mlodkowska H, Drozd-Lula M, 

et al. [Long-term survival of patients with small cell 

lung cancer]. Pneumonol Pol 1989; 57(10-12):496-

503. 

Notes: NRA 

Jelinek JS, Redmond J 3rd, Perry JJ, et al. Small cell 

lung cancer: staging with MR imaging. Radiology 

1990; 177(3):837-42. 

Notes: NRQ 

Jeremic B, Shibamoto Y, Acimovic L, et al. 

Carboplatin, etoposide, and accelerated 

hyperfractionated radiotherapy for elderly patients 

with limited small cell lung carcinoma: a phase II 

study. Cancer 1998; 82(5):836-41. 

Notes: NSD 

Jett JR, Everson L, Therneau TM, et al. Treatment of 

limited-stage small-cell lung cancer with 

cyclophosphamide, doxorubicin, and vincristine with 

or without etoposide: a randomized trial of the North 

Central Cancer Treatment Group. J Clin Oncol 1990; 

8(1):33-8. 

Notes: NSD 

Jett JR, Hatfield AK, Hillman S, et al. Alternating 

chemotherapy with etoposide plus cisplatin and 

topotecan plus paclitaxel in patients with untreated, 

extensive-stage small cell lung carcinoma: a phase II 

trial of the North Central Cancer Treatment Group. 

Cancer 2003; 97(10):2498-503. 

Notes: NRQ 

Jett JR, Maksymiuk AW, Su JQ, et al. Phase III trial 

of recombinant interferon gamma in complete 

responders with small-cell lung cancer. J Clin Oncol 

1994; 12(11):2321-6. 

Notes: NRQ 

Joel S, O'Byrne K, Penson R, et al. A randomised, 

concentration-controlled, comparison of standard (5-

day) vs. prolonged (15-day) infusions of etoposide 

phosphate in small-cell lung cancer. Ann Oncol 

1998; 9(11):1205-11. 

Notes: NRQ 

Johnson BE. Concurrent approaches to combined 

chemotherapy and chest radiotherapy for the 

treatment of patients with limited stage small cell 

lung cancer. Lung Cancer 1994; 10 Suppl 1:S281-7. 

Notes: NRA NPD 
D-14

Johnson BE. Is more better? Chemotherapy for 

patients with extensive-stage small-cell lung cancer. J 

Natl Cancer Inst. 2001 Feb 21;93(4):254-5. 

Notes: NSP 

Johnson BE, Becker B, Goff WB 2nd, et al. 

Neurologic, neuropsychologic, and computed cranial 

tomography scan abnormalities in 2- to 10-year 

survivors of small-cell lung cancer. J Clin Oncol 

1985; 3(12):1659-67. 

Notes: FEW 

Johnson BE, Bridges JD, Sobczeck M, et al. Patients 

with limited-stage small-cell lung cancer treated with 

concurrent twice-daily chest radiotherapy and 

etoposide/cisplatin followed by cyclophosphamide, 

doxorubicin, and vincristine. J Clin Oncol 1996; 

14(3):806-13. 

Notes: NSD 

Johnson BE, Fischer T, Fischer B, et al. Phase II 

study of imatinib in patients with small cell lung 

cancer. Clin Cancer Res 2003; 9(16 Pt 1):5880-7. 

Notes: FEW 

Johnson BE, Glatstein E, Ihde DC. The National 

Cancer Institute experience with early and late effects 

of combined modality therapy in small cell lung 

cancer. Antibiot Chemother 1988; 41:210-2. 

Notes: NSD 

Johnson BE, Grayson J, Makuch RW, et al. Ten-year 

survival of patients with small-cell lung cancer 

treated with combination chemotherapy with or 

without irradiation. J Clin Oncol 1990; 8(3):396-401. 

Notes: NRQ NSD (retrospective) 

Johnson BE, Ihde DC, Bunn PA, et al. Patients with 

small-cell lung cancer treated with combination 

chemotherapy with or without irradiation. Data on 

potential cures, chronic toxicities, and late relapses 

after a five- to eleven-year follow-up. Ann Intern 

Med 1985; 103(3):430-8. 

Notes: NRQ 

Johnson BE, Kelley MJ. Autocrine growth factors 

and neuroendocrine markers in the development of 

small-cell lung cancer. Oncology (Huntingt) 1998; 

12(1 Suppl 2):11-4. 

Notes: INV 

Johnson BE, Patronas N, Hayes W, et al. Neurologic, 

computed cranial tomographic, and magnetic 

resonance imaging abnormalities in patients with 

small-cell lung cancer: further follow-up of 6- to 13-

year survivors. J Clin Oncol 1990; 8(1):48-56. 

Notes: NSD 

Johnson DH, Bass D, Einhorn LH, et al. Combination 

chemotherapy with or without thoracic radiotherapy 

in limited-stage small-cell lung cancer: a randomized 

trial of the Southeastern Cancer Study Group. J Clin 

Oncol 1993; 11(7):1223-9. 

Notes: NRQ 

Johnson DH, Turrisi AT, Chang AY, et al. 

Alternating chemotherapy and twice-daily thoracic 

radiotherapy in limited-stage small-cell lung cancer: 

a pilot study of the Eastern Cooperative Oncology 

Group. J Clin Oncol 1993; 11(5):879-84. 

Notes: NSD 

Johnson E, Lake D, Herndon JE 2nd, Box JW, Lynch 

TJ, Green MR. Phase II trial of vinorelbine plus 

doxorubicin in relapsed small-cell lung cancer: 

CALGB 9332. Am J Clin Oncol 2004; 27(1):19-23. 

Notes: FEW 

Johnson JR, Morgan DA, Holland IM. Prophylactic 

cranial irradiation for small-cell lung cancer: longterm results. Clin Oncol (R Coll Radiol) 1989; 

1(1):24-7. 

Notes: NSD 

Johnson PW, Muers MF, Peake MD, et al. A 

randomized trial of amifostine as a cytoprotective 

agent in patients receiving chemotherapy for small 

cell lung cancer. Br J Cancer 2001; 84(1):19-24. 

Notes: NRQ 

Joss RA, Alberto P, Bleher EA, et al. Combinedmodality treatment of small-cell lung cancer: 

randomized comparison of three induction 

chemotherapies followed by maintenance 

chemotherapy with or without radiotherapy to the 

chest. Swiss Group for Clinical Cancer Research 

(SAKK). Ann Oncol 1994; 5(10):921-8. 

Notes: NRQ 
D-15

Joss RA, Alberto P, Hurny C, et al. Quality versus 

quantity of life in the treatment of patients with 

advanced small-cell lung cancer? A randomized 

phase III comparison of weekly carboplatin and 

teniposide versus cisplatin, adriamycin, etoposide 

alternating with cyclophosphamide, methotrexate, 

vincristine and lomustine. Swiss Group for Clinical 

Cancer Research (SAKK). Ann Oncol 1995; 6(1):41-

8. 

Notes: NRQ 

Joss RA, Bacchi M, Hurny C, et al. Early versus late 

alternating chemotherapy in small-cell lung cancer. 

Swiss Group for Clinical Cancer Research (SAKK). 

Ann Oncol 1995; 6(2):157-66. 

Notes: NRQ 

Kaba SE, Kyritsis AP, Hess K, et al. TPDC-FuHu 

chemotherapy for the treatment of recurrent 

metastatic brain tumors. J Clin Oncol 1997; 

15(3):1063-70. 

Notes: FEW 

Kalemkerian GP, Jiroutek M, Ettinger DS, Dorighi 

JA, Johnson DH, Mabry M. A phase II study of alltrans-retinoic acid plus cisplatin and etoposide in 

patients with extensive stage small cell lung 

carcinoma: an Eastern Cooperative Oncology Group 

Study. Cancer 1998; 83(6):1102-8. 

Notes: NRQ, NSD 

Kanard A, Frytak S, Jatoi A. Cognitive dysfunction 

in patients with small-cell lung cancer: Incidence, 

causes, and suggestions on management. J Support 

Oncol 2004 Mar-Apr;2(2):127-32; discussion 133-5, 

138-40. 

Notes: NRA; 

Karrer K. Surgery in SCLC as first step of 

multimodality treatment. Anticancer Res 1994; 

14(1B):327-31. 

Notes: NRQ 

Karrer K, Denck H. Multimodality treatment with 

surgery in small-cell lung cancer. Int J Clin 

Pharmacol Res 1987; 7(4):313-28. 

Notes: NRA 

Karrer K, Denck H, Drings P, Orel J, Bruno MF. 

Combination of surgery and chemotherapy for smallcell bronchial carcinoma. Drugs Exp Clin Res 1986; 

12(1-3):191-200. 

Notes: NRQ 

Karrer K, Denck H, Karnicka-Mlodkowska H, et al. 

Surgery for cure followed by combined modality 

treatment for small cell bronchial carcinoma. ISC 

Lung Cancer Study Group. Int J Clin Pharmacol Res 

1988; 8(6):415-21. 

Notes: NRQ 

Karrer K, Denck H, Karnicka-Mlodkowska H, et al. 

The role of ifosfamide and cyclophosphamide in the 

multi-modality treatment after surgery for cure for 

small-cell bronchial carcinomas (SCLC). Med Oncol 

Tumor Pharmacother 1989; 6(2):143-9. 

Notes: NRQ 

Karrer K, Denck H, Karnicka-Mlodkowska H, et al. 

The importance of surgery as the first step in 

multimodality treatment of small cell bronchial 

carcinoma. The ISC Lung Cancer Study Group. Int J 

Clin Pharmacol Res 1990; 10(5):257-63. 

Notes: NRQ 

Karrer K, Shields TW, Denck H, et al. The 

importance of surgical and multimodality treatment 

for small cell bronchial carcinoma. J Thorac 

Cardiovasc Surg 1989; 97(2):168-76. 

Notes: NRQ 

Karrer K, Ulsperger E. Surgery for cure followed by 

chemotherapy in small cell carcinoma of the lung. 

For the ISC-Lung Cancer Study Group. Acta Oncol 

1995; 34(7):899-906. 

Notes: NRQ 

Katakami N, Takada M, Negoro S, et al. Dose 

escalation study of carboplatin with fixed-dose 

etoposide plus granulocyte-colony stimulating factor 

in patients with small cell lung carcinoma. A study of 

the Lung Cancer Study Group of West Japan. Cancer 

1996; 77(1):63-70. 

Notes: NSD, NRQ 

Kawahara M. [Phase III studies of combined 

chemotherapy and radiation in locally advanced nonsmall-cell lung cancer and limited small-cell lung 

cancer]. Gan To Kagaku Ryoho 1995; 22(3):335-40. 

Notes: NRA 

Kelly K, Lovato L, Bunn PA Jr, et al. Cisplatin, 

etoposide, and paclitaxel with granulocyte colonystimulating factor in untreated patients with 

extensive-stage small cell lung cancer: a phase II trial 

of the Southwest Oncology Group. Clin Cancer Res 

2001; 7(8):2325-9. 

Notes: NRQ 
D-16

Khuri FR, Fossella FV, Lee JS, et al. Phase II trial of 

recombinant IFN-alpha2a with etoposide/cisplatin 

induction and interferon/megestrol acetate 

maintenance in extensive small cell lung cancer. J 

Interferon Cytokine Res 1998; 18(4):241-5. 

Notes: NRQ 

Kies MS, Mira JG, Crowley JJ, et al. Multimodal 

therapy for limited small-cell lung cancer: a 

randomized study of induction combination 

chemotherapy with or without thoracic radiation in 

complete responders; and with wide-field versus 

reduced-field radiation in partial responders: a 

Southwest Oncology Group Study. J Clin Oncol 

1987; 5(4):592-600. 

Notes: NRQ 

Kirschling RJ, Grill JP, Marks RS, et al. Paclitaxel 

and G-CSF in previously untreated patients with 

extensive stage small-cell lung cancer: a phase II 

study of the North Central Cancer Treatment Group. 

Am J Clin Oncol 1999; 22(5):517-22. 

Notes: NRQ 

Kitase M, Hara M, Katoh K, et al. FDG-PET in 

patient with clinical T1N0 lung cancer; 

Determination of nodal status. Jpn J Clin Radiol 

2000; 45(1):209-14. 

Notes: FEW 

Klasa RJ, Murray N, Coldman AJ. Dose-intensity 

meta-analysis of chemotherapy regimens in smallcell carcinoma of the lung. J Clin Oncol 1991; 

9(3):499-508. 

Notes: NRQ 

Kobayashi A, Ohno S, Yamasawa H. A clinical 

assessment of radiation pneumonitis in cases with 

lung cancer receiving chemoradiotherapy. Jpn J 

Chest Dis 2002; 61(8):734-42. 

Notes: NSD, NSP 

Kobayashi K, Hino M, Kurane S, et al. [A 

comparative randomized phase II study of CDDP, 

CDDP-carboquone (CQ) and CDDP-etoposide as 

second-line chemotherapy in small cell lung cancer 

(SCLC)]. Gan To Kagaku Ryoho 1989; 16(2):207-

12. 

Notes: INV 

Komaki R, Byhardt RW, Anderson T, et al. What is 

the lowest effective biologic dose for prophylactic 

cranial irradiation? Am J Clin Oncol 1985; 8(6):523-

7. 

Notes: NSD 

Komaki R, Meyers CA, Shin DM, et al. Evaluation of 

cognitive function in patients with limited small cell 

lung cancer prior to and shortly following 

prophylactic cranial irradiation. Int J Radiat Oncol 

Biol Phys 1995; 33(1):179-82. 

Notes: NSD 

Komaki R, Shin DM, Glisson BS, et al. 

Interdigitating versus concurrent chemotherapy and 

radiotherapy for limited small cell lung cancer. Int J 

Radiat Oncol Biol Phys 1995; 31(4 ):807-11. 

Notes: NSD 

Korn EL, Simon R, Friedman MA, et al. Phase II 

trials of small-cell lung cancer. J Clin Oncol 1992; 

10(8):1369-70. 

Notes: NPD 

Kotalik J, Yu E, Markman BR, et al. Practice 

guideline on prophylactic cranial irradiation in smallcell lung cancer. Int J Radiat Oncol Biol Phys 2001; 

50(2):309-16. 

Notes: NPD; 

Kraft A, Arnold H, Zwingers T, et al. Role of 

thoracic radiotherapy combined with chemotherapy 

in limited stage small cell lung cancer (SCLC). A 

randomized multicenter phase III trial. Onkologie 

1990; 13(4):253-8. 

Notes: NRQ 

Kris MG. Lung cancer cure, care, and cost: let the 

data be your guide. J Clin Oncol 1997; 15(9):3027-9. 

Notes: NPD; but maybe cite in write-up 

Kristjansen PE. Should current management of small 

cell lung cancer include prophylactic cranial 

irradiation? Lung Cancer 1994; 10 Suppl 1:S319-29. 

Notes: NPD; but maybe cite in write-up 

Kristjansen PE, Hansen HH. Prophylactic cranial 

irradiation in small cell lung cancer--an update. Lung 

Cancer 1995; 12 Suppl 3:S23-40. 

Notes: NRA 

Kristjansen PE, Kristensen CA. The role of 

prophylactic cranial irradiation in the management of 

small cell lung cancer. Cancer Treat Rev 1993; 

19(1):3-16. 

Notes: NRA 
D-17

Kristjansen PE, Soelberg Sorensen P, Skov Hansen 

M, Hansen HH. Prospective evaluation of the effect 

on initial brain metastases from small cell lung 

cancer of platinum-etoposide based induction 

chemotherapy followed by an alternating multidrug 

regimen. Ann Oncol 1993; 4(7):579-83. 

Notes: NRQ 

Krug LM, Miller VA. Introduction: Small cell lung 

cancer - A frustrating disease. Semin Oncol 

2003;30:1–2. 

Notes: NPD 

Kudoh S, Fujiwara Y, Takada Y, et al. Phase II study 

of irinotecan combined with cisplatin in patients with 

previously untreated small-cell lung cancer. West 

Japan Lung Cancer Group. J Clin Oncol 1998; 

16(3):1068-74. 

Notes: NSD 

Kudoh S, Sawa T, Kurihara N, et al. Phase II study of 

recombinant human interleukin 3 administration 

following carboplatin and etoposide chemotherapy in 

small-cell lung cancer patients. SDZ ILE 964 (IL-3) 

Study. Cancer Chemother Pharmacol 1996; 38 

Suppl:S89-95. 

Notes: NRQ 

Kumagai M, Kutsuzawa T, Fuyuno G, Kondo T, 

Shioya S, Ohta Y. Comparison of 

carboplatin/etoposide/vincristine with 

cisplatin/etoposide as combination chemotherapy for 

small cell lung cancer. Tokai J Exp Clin Med 1995; 

20(4-6):209-14. 

Notes: NRQ 

Kwiatkowski DJ, Propert KJ, Carey RW, et al. A 

phase II trial of cyclophosphamide, etoposide, and 

cisplatin with combined chest and brain radiotherapy 

in limited small-cell lung cancer: a Cancer and 

Leukemia Group B Study. J Clin Oncol 1987; 

5(12):1874-9. 

Notes: NSD 

Lacroix H, Sculier JP. [Chemotherapy in non-small 

cell bronchial carcinoma. 12 years' experience in an 

international cooperative group: EORTC Lung 

Cancer Working Party]. Bull Cancer 1990; 

77(10):997-1005. 

Notes: NSP NRD (NSCLC) 

Langer CJ. Cognitive dysfunction in small-cell lung 

cancer: Myth or reality? J Support Oncol 2004; 

2(2):138-40. 

Notes: NPD 

Lassen U. FDG-PET imaging in small cell lung 

cancer: any value? Lung Cancer 2002; 37(1):7. 

Notes: NPD; exclude, but maybe cite in write-up 

Lassen U, Kristjansen PE, Osterlind K, et al. 

Superiority of cisplatin or carboplatin in combination 

with teniposide and vincristine in the induction 

chemotherapy of small-cell lung cancer. A 

randomized trial with 5 years follow up. Ann Oncol 

1996; 7(4):365-71. 

Notes: NRQ 

Lassen U, Osterlind K, Hansen M, et al. Long-term 

survival in small-cell lung cancer: posttreatment 

characteristics in patients surviving 5 to 18+ years--

an analysis of 1,714 consecutive patients. J Clin 

Oncol 1995; 13(5):1215-20. 

Notes: NRQ 

Laukkanen E, Klonoff H, Allan B, et al. The role of 

prophylactic brain irradiation in limited stage small 

cell lung cancer: clinical, neuropsychologic, and CT 

sequelae. Int J Radiat Oncol Biol Phys 1988; 

14(6):1109-17. 

Notes: NSD 

Laurie SA, Logan D, Markman BR, et al. Practice 

guideline for the role of combination chemotherapy 

in the initial management of limited-stage small-cell 

lung cancer. Lung Cancer 2004; 43(2):223-40. 

Notes: NPD 

Le Cesne A, Le Chevalier T, Arriagada R. Dealing 

with initial chemotherapy doses: a new basis for 

treatment optimisation in limited small-cell lung 

cancer. Ann Oncol 1995; 6 Suppl 3:S53-6. 

Notes: NRA 

Le Chevalier T, Arriagada R. Small cell lung cancer 

and prophylactic cranial irradiation (PCI): perhaps 

the question is not who needs PCI but who wants 

PCI? Eur J Cancer 1997; 33(11):1717-9. 

Notes: NPD 

Le Chevalier T, Arriagada R, Baldeyrou P, et al. 

[Alternating chemotherapy and radiotherapy in the 

induction treatment of small cell bronchial carcinoma 

(forms limited to the thorax)]. Presse Med 1985; 

14(21):1181-8. 

Notes: NRQ 

Le Chevalier T, Arriagada R, Tubiana M. Combined 

chemotherapy and radiotherapy in small-cell lung 

cancer. Cancer Treat Res 1991; 58:139-53. 

Notes: NRA 
D-18

Le CT, Le CA, Arriagada R. Dealing with initial 

chemotherapy doses: A new basis for treatment 

optimization in limited small-cell lung cancer. Bull 

Cancer 1995 82:24S-8S. 

Notes: NRA exclude, 

Le Pechoux C, Arriagada R. Prophylactic cranial 

irradiation in small cell lung cancer. Hematol Oncol 

Clin North Am 2004; 18(2):355-72. 

Notes: NPD; exclude but cite in write-up 

Lebeau B. [Global approach to the treatment of small 

cell bronchial cancers]. Bull Cancer 1987; 74(5):555-

8. 

Notes: NRQ 

Lebeau B, Chastang C, Brechot JM, et al. 

Subcutaneous heparin treatment increases survival in 

small cell lung cancer. "Petites Cellules" Group. 

Cancer 1994; 74(1):38-45. 

Notes: NRQ 

Lebeau B, Chastang C, Schuller MP, et al. 

[Chemotherapy of small cell bronchial cancers. 

Prognostic importance of complete response (1,280 

patients). Groupe Petites Cellules]. Presse Med 1995; 

24(4):217-21. 

Notes: NRQ 

Lee JS, Umsawasdi T, Barkley HT Jr, et al. Timing 

of elective brain irradiation: a critical factor for brain 

metastasis-free survival in small cell lung cancer. Int 

J Radiat Oncol Biol Phys 1987; 13(5):697-704. 

Notes: NSD 

Lee SH, Ahn YC, Kim HJ, et al. Early concurrent 

chemoradiotherapy with prolonged oral etoposide 

and cisplatin for limited-stage small-cell lung cancer. 

Jpn J Clin Oncol 2003; 33(12):620-5. 

Notes: NRQ 

Leo F, Pastorino U. Surgery in small-cell lung 

carcinoma. Where is the rationale? Semin Surg Oncol 

2003; 21(3):176-81. 

Notes: NRA 

Levitan N, Dowlati A, Shina D, et al. Multiinstitutional phase I/II trial of paclitaxel, cisplatin, 

and etoposide with concurrent radiation for limitedstage small-cell lung carcinoma. J Clin Oncol 2000; 

18(5):1102-9. 

Notes: NSD 

Lewinski T, Zulawski M, Meder J, et al. [Elective 

(prophylactic) brain irradiation in small cell lung 

cancer patients treated with chemotherapy combined 

with surgery]. Nowotwory 1990; 40(4):254-9. 

Notes: NSD 

Lexer G, Weitensfelder W, Haiderer O, et al. [Longterm survival following pneumonectomy, 

chemotherapy and radiotherapy in central small cell 

bronchial cancer]. Prax Klin Pneumol 1988 

Jul;42(7):588-9. 

Notes: FEW 

Liengswangwong V, Bonner JA, Shaw EG, et al. 

Limited-stage small-cell lung cancer: patterns of 

intrathoracic recurrence and the implications for 

thoracic radiotherapy. J Clin Oncol 1994; 12(3):496-

502. 

Notes: SCS NSD (retrospective) 

Liengswangwong V, Bonner JA, Shaw EG, et al. 

Prophylactic cranial irradiation in limited-stage small 

cell lung cancer. Cancer 1995; 75(6):1302-9. 

Notes: NSD 

Liu X, Li X, Pang Y, et al. The results of treatment in 

100 patients with limited-stage small cell lung 

cancer. Cancer 1993; 71(2):326-31. 

Notes: NSD 

Livingston RB. Concurrent is the key: combined 

modality small-cell lung cancer. J Clin Oncol 1998; 

16(4):1631. 

Notes: NPD; exclude, but maybe cite in write-up 

Livingston RB, Schulman S, Mira JG, et al. 

Combined alkylators and multiple-site irradiation for 

extensive small cell lung cancer: a Southwest 

Oncology Group Study. Cancer Treat Rep 1986; 

70(12):1395-401. 

Notes: NSD 

Loehrer PJ Sr. Palliative therapy: extensive small cell 

lung cancer. Semin Oncol 1995; 22(2 Suppl 3):40-4. 

Notes: NRA 

Loehrer PJ Sr, Ansari R, Gonin R, et al. Cisplatin 

plus etoposide with and without ifosfamide in 

extensive small-cell lung cancer: a Hoosier Oncology 

Group study. J Clin Oncol 1995; 13(10):2594-9. 

Notes: NRQ 
D-19

Lokich JJ. Teniposide (VM-26) as a single drug 

treatment for patients with extensive small cell lung 

carcinoma: a Phase II study of the Southwest 

Oncology Group. Cancer 1998; 82(5):993. 

Notes: NPD 

Lorigan P, Lee SM, Betticher D, et al. Chemotherapy 

with vincristine/ifosfamide/carboplatin/etoposide in 

small cell lung cancer. Semin Oncol 1995; 22(3 

Suppl 7):32-41. 

Notes: NRA 

Luce S, Paesmans M, Berghmans T, et al. [Critical 

review of the randomized trials assessing the role of 

adjuvant thoracic irradiation and chemotherapy in the 

treatment of limited-stage small cell lung cancer]. 

Rev Mal Respir 1998 Oct; 15(5):633-41. 

Notes: NPD; meta-analysis of TRTX versus no TRTx 

Macchiarini P, Hardin M, Basolo F, et al. Surgery 

plus adjuvant chemotherapy for T1-3N0M0 smallcell lung cancer. Rationale for current approach. Am 

J Clin Oncol 1991; 14(3):218-24. 

Notes: SCS 

Mackay HJ, O'Brien M, Hill S, et al. A phase II study 

of carboplatin and vinorelbine in patients with poor 

prognosis small cell lung cancer. Clin Oncol (R Coll 

Radiol) 2003; 15(4):181-5. 

Notes: NRQ 

Maddison P, Newsom-Davis J, Mills KR, et al. 

 Favourable prognosis in Lambert-Eaton myasthenic 

syndrome and small-cell lung carcinoma. Lancet. 

1999 Jan 9;353(9147):117-8. 

Notes: NRQ 

Mah K, Keane TJ, Van Dyk J, et al. Quantitative 

effect of combined chemotherapy and fractionated 

radiotherapy on the incidence of radiation-induced 

lung damage: a prospective clinical study. Int J 

Radiat Oncol Biol Phys 1994; 28(3):563-74. 

Notes: FEW 

Maksymiuk AW, Jett JR, Earle JD, et al. Sequencing 

and schedule effects of cisplatin plus etoposide in 

small-cell lung cancer: results of a North Central 

Cancer Treatment Group randomized clinical trial. J 

Clin Oncol 1994; 12(1):70-6. 

Notes: NRQ 

Manegold C, Drings P. [Drug therapy in bronchial 

carcinoma]. Schweiz Med Wochenschr 1995; 

125(29):1396-405. 

Notes: NPD 

Manzoor A, Kharadi MY, Mushtaq A. Role of 

prophylactic cranial irradiation in small cell lung 

cancer. JK Pract 2002; 9(2):96-100. 

Notes: NRA 

Maranzano E, Crino L, Piro F, et al. Long-term 

results of induction chemotherapy followed by 

concurrent chemotherapy and thoracic irradiation in 

limited small cell lung cancer. Lung Cancer 2002; 

37(1):79-85. 

Notes: NSD 

Mascaux C, Paesmans M, Berghmans T, et al. A 

systematic review of the role of etoposide and 

cisplatin in the chemotherapy of small cell lung 

cancer with methodology assessment and metaanalysis. Lung Cancer 2000; 30(1 ):23-36. 

Notes: NPD; exclude, but maybe cite in write-up 

Masuda N, Fukuoka M, Furuse K. CODE 

chemotherapy with or without recombinant human 

granulocyte colony-stimulating factor in extensivestage small cell lung cancer. Oncology 1992; 49 

Suppl 1:19-24. 

Notes: NSD 

Mattson K, Niiranen A, Ruotsalainen T, et al. 

Interferon maintenance therapy for small cell lung 

cancer: improvement in long-term survival. J 

Interferon Cytokine Res 1997; 17(2):103-5. 

Notes: NRQ 

Mavroudis D, Papadakis E, Veslemes M, et al. A 

multicenter randomized clinical trial comparing 

paclitaxel-cisplatin-etoposide versus cisplatinetoposide as first-line treatment in patients with 

small-cell lung cancer. Ann Oncol 2001; 12(4):463-

70. 

Notes: NRQ 

Mavroudis D, Pavlakou G, Blazoyiannakis G, et al. 

Sequential administration of cisplatin-etoposide 

followed by topotecan in patients with extensive 

stage small cell lung cancer. A multicenter phase II 

study. Lung Cancer 2003; 39(1):71-6. 

Notes: NRQ 

Mavroudis D, Veslemes M, Kouroussis CH, et al. 

Cisplatin-etoposide alternating with topotecan in 

patients with extensive stage small cell lung cancer 

(SCLC). A multicenter phase II study. Lung Cancer 

2002; 38(1):59-63. 

Notes: NRQ 
D-20

McClay EF, Bogart J, Herndon JE, et al. A phase III 

trial evaluating the combination of cisplatin, 

etoposide, and radiation therapy with or without 

tamoxifen in patients with limited-stage small cell 

lung cancer: Cancer and leukemia group B study 

(9235). Am J Clin Oncol Cancer Clin Trials 2005; 

28(1):81-90. 

Notes: NRQ 

McCracken JD, Janaki LM, Crowley JJ, et al. 

Concurrent chemotherapy/radiotherapy for limited 

small-cell lung carcinoma: a Southwest Oncology 

Group Study. J Clin Oncol 1990; 8(5):892-8. 

Notes: NSD 

Meert AP, Paesmans M, Berghmans T, et al. 

Prophylactic cranial irradiation in small cell lung 

cancer: a systematic review of the literature with 

meta-analysis. BMC Cancer 2001; 1(1):5. 

Notes: NPD (SR-MA) 

Mennecier B, Jacoulet P, Dubiez A, et al. Concurrent 

cisplatin/etoposide chemotherapy plus twice daily 

thoracic radiotherapy in limited stage small cell lung 

cancer: a phase II study. Lung Cancer 2000; 

27(3):137-43. 

Notes: NSD 

Messori A, Trippoli S, Tendi E. G-CSF for the 

prophylaxis of neutropenic fever in patients with 

small cell lung cancer receiving myelosuppressive 

antineoplastic chemotherapy: meta-analysis and 

pharmacoeconomic evaluation. J Clin Pharm Ther 

1996; 21(2):57-63. 

Notes: NRQ 

Meyers CA, Byrne KS, Komaki R. Cognitive deficits 

in patients with small cell lung cancer before and 

after chemotherapy. Lung Cancer 1995; 12(3):231-5. 

Notes: NSD 

Micke P, Faldum A, Metz T, et al. Staging small cell 

lung cancer: Veterans Administration Lung Study 

Group versus International Association for the Study 

of Lung Cancer--what limits limited disease? Lung 

Cancer 2002; 37(3):271-6. 

Notes: NRQ 

Miller KL, Marks LB. Long-term changes in 

pulmonary function tests after definitive irradiation 

for lung cancer. Int J Radiat Oncol Biol Phys 2004; 

58:1008-9. 

Notes: NPD NSP 

Mikhina ZP, Bychkov MB, Motorina LI. [The 

effectiveness of 2 systems of chemoradiation 

treatment in inoperable small-cell lung cancer]. Vopr 

Onkol 1989; 35(2):174-80. 

Notes: NSD 

Minami H, Saka H, Sakai S, Yamamoto M, 

Shimokata K. A phase II study of carboplatin and 

prolonged administration of oral etoposide in patients 

with small-cell lung cancer. Acta Oncol 1997; 

36(7):765-9. 

Notes: NRQ 

Mira JG, Chen TT, Livingston RB, Wilson HE. 

Outcome of prophylactic and therapeutic cranial 

irradiation in disseminated small cell lung carcinoma: 

a Southwest Oncology Group Study. Int J Radiat 

Oncol Biol Phys 1988; 14(5):861-5. 

Notes: NSD 

Mitchell EP, Perry MC, Luikart SD, et al. A phase 

I/II trial of etoposide and cisplatin in extensive small 

cell lung cancer: a cancer and leukemia group B 

study. Lung Cancer 1996; 15(2):215-23. 

Notes: NSD, NRQ 

Mizutani Y, Nishio M, Myojin M, et al. [Importance 

of timing for radiation therapy in limited-stage small 

cell lung cancer]. Nippon Igaku Hoshasen Gakkai 

Zasshi 1996; 56(11):726-30. 

Notes: NSD 

Mok TS, Wong H, Zee B, et al. A Phase I-II study of 

sequential administration of topotecan and oral 

etoposide (toposiomerase I and II inhibitors) in the 

treatment of patients with small cell lung carcinoma. 

Cancer 2002; 95(7):1511-9. 

Notes: NRQ, NSD 

Montazeri A, Gillis CR, McEwen J. Quality of life in 

patients with lung cancer: a review of literature from 

1970 to 1995. Chest 1998; 113(2):467-81. 

Notes: NPD; exclude, but maybe cite in write-up 

Moore TD, Korn EL. Phase II trial design 

considerations for small-cell lung cancer. J Natl 

Cancer Inst 1992; 84(3):150-4. 

Notes: NPD 

Mornex F, Trillet V, Chauvin F, et al. 

Hyperfractionated radiotherapy alternating with 

multidrug chemotherapy in the treatment of limited 

small cell lung cancer (SCLC). Groupe Lyonnais 

d'Oncologie Thoracique. Int J Radiat Oncol Biol 

Phys 1990; 19(1):23-30. 

Notes: NSD 
D-21

Movsas B, Moughan J, Komaki R, et al. 

Radiotherapy patterns of care study in lung 

carcinoma. J Clin Oncol 2003; 21(24):4553-9. 

Notes: NRQ 

Muller LC, Salzer GM, Huber H, et al. Multimodal 

therapy of small cell lung cancer in TNM stages I 

through IIIa. Ann Thorac Surg 1992; 54(3):493-7. 

Notes: SCS PII 

Murray N. Timing of thoracic irradiation for limited 

small-cell lung cancer. J Clin Oncol 1998; 

16(4):1633-5. 

Notes: NPD; exclude, but maybe cite in write-up 

Murray N, Livingston RB, Shepherd FA, et al. 

Randomized study of CODE versus alternating 

CAV/EP for extensive-stage small-cell lung cancer: 

an Intergroup Study of the National Cancer Institute 

of Canada Clinical Trials Group and the Southwest 

Oncology Group. J Clin Oncol 1999; 17(8):2300-8. 

Notes: NRQ 

Murray N, Shah A, Osoba D, et al. Intensive weekly 

chemotherapy for the treatment of extensive-stage 

small-cell lung cancer. J Clin Oncol 1991; 9(9):1632-

8. 

Notes: NRQ 

Naka N, Kawahara M, Okishio K, et al. Phase II 

study of weekly irinotecan and carboplatin for 

refractory or relapsed small-cell lung cancer. Lung 

Cancer 2002; 37(3):319-23. 

Notes: SCS 

Nakanishi Y, Kawarada Y, Hirose N, et al. Phase II 

trial of combination chemotherapy with cisplatin, 

carboplatin and etoposide in stage IIIB and IV smallcell lung cancer. Fukuoka Lung Cancer Study Group. 

Cancer Chemother Pharmacol 1998; 41(6):453-6. 

Notes: NRQ 

Nam YJ, Choi CW, Shin SW, et al. Combination 

chemotherapy with cyclophosphamide, vincristine, 

cisplatin and etoposide (COPE) combined with 

radiotherapy for small cell lung cancer. Korean J 

Intern Med 1995; 10(1):32-7. 

Notes: NRQ 

Naughton MJ, Herndon IJE, Shumaker SA, et al. The 

health-related quality of life and survival of smallcell lung cancer patients: Results of a companion 

study to CALGB 9033. Qual Life Res 2002; 

11(3):235-48. 

Notes: NRQ 

Negoro S, Masuda N, Furuse K, Saijo N, Fukuoka M. 

Dose-intensive chemotherapy in extensive-stage 

small-cell lung cancer. Cancer Chemother Pharmacol 

1997; 40 Suppl:S70-3. 

Notes: NRQ 

Neill HB, Miller AA, Clamon GH, Perry MC, 

Crawford J, Green MR. A phase II study evaluating 

the efficacy of carboplatin, etoposide, and paclitaxel 

with granulocyte colony-stimulating factor in patients 

with stage IIIB and IV non-small cell lung cancer and 

extensive small cell lung cancer. Semin Oncol 1997; 

24(4 Suppl 12):S12-130-S12-134. 

Notes: NRQ 

Neubauer M, Schwartz J, Caracandas J, et al. Results 

of a phase II study of weekly paclitaxel plus 

carboplatin in patients with extensive small-cell lung 

cancer with Eastern Cooperative Oncology Group 

Performance Status of 2, or age > or = 70 years. J 

Clin Oncol 2004; 22(10):1872-7. 

Notes: NSP NRQ 

Nichols CR. The role of ifosfamide in germ cell 

tumors and small cell lung cancer. Semin Oncol 

1995; 22(3 Suppl 7):13-7. 

Notes: NRA 

Nicolucci A, Grilli R, Alexanian AA, et al. Quality, 

evolution, and clinical implications of randomized, 

controlled trials on the treatment of lung cancer. A 

lost opportunity for meta-analysis. JAMA 1989; 

262(15):2101-7. 

Notes: NRQ, systematic review of quality of RCTs 

Niiranen A, Holsti P, Salmo M. Treatment of small 

cell lung cancer. Two-drug versus four-drug 

chemotherapy and loco-regional irradiation with or 

without prophylactic cranial irradiation. Acta Oncol 

1989; 28(4):501-5. 

Notes: NRQ 

Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan 

plus cisplatin compared with etoposide plus cisplatin 

for extensive small-cell lung cancer. N Engl J Med 

2002; 346(2):85-91. 

Notes: NRQ 

Noel G, Deutch E, Feuvret L, Mazeron JJ. 

[Prophylactic cranial irradiation is indicated 

following complete response to induction therapy in 

small cell lung cancer: results of a multicentre 

randomized trial.]. Cancer Radiother 1998; 2(3):313-

4. 

Notes: NPD 
D-22

Noell KT, Deland MM, Harwood AR. Re: 

Prophylactic cranial irradiation for patients with 

small-cell lung cancer. J Natl Cancer Inst 1995; 

87(10):766-7. 

Notes: NPD 

Nomori H, Watanabe K, Ohtsuka T, et al.The size of 

metastatic foci and lymph nodes yielding falsenegative and false-positive lymph node staging with 

positron emission tomography in patients with lung 

cancer. J Thorac Cardiovasc Surg 2004; 127(4):1087-

92. 

Notes: NSP; exclude 

Oelmann E, Thomas M, Serve H, et al. Early tandem 

high-dose ifosfamide, carboplatin, etoposide therapy 

with stem cell rescue for small-cell lung cancer: brief 

report on the results of a phase-I/II trial. Oncology 

2002; 63(3):248-53. 

Notes: NRQ, FEW 

Ohnoshi T, Hiraki S, Fujii M, et al. Mortality and 

morbidity in two-year disease-free survivors of small 

cell lung cancer after treatment with combination 

chemotherapy with or without irradiation. Acta Med 

Okayama 1993; 47(3):209-14. 

Notes: SCS 

Ohnoshi T, Ueoka H, Numata T, et al. [Progress and 

obstacles in chemotherapy and combined modality 

treatment of small cell lung cancer]. Nihon Kyobu 

Shikkan Gakkai Zasshi 1990; 28(2):190-6. 

Notes: NRQ 

Okamoto H, Watanabe K, Nishiwaki Y, et al. Phase 

II study of area under the plasma-concentrationversus-time curve-based carboplatin plus standarddose intravenous etoposide in elderly patients with 

small-cell lung cancer. J Clin Oncol 1999; 

17(11):3540-5. 

Notes: NRQ 

Okawara G, Gagliardi A, Evans WK, et al. The role 

of thoracic radiotherapy as an adjunct to standard 

chemotherapy in limited-stage small-cell lung cancer. 

Curr Oncol 2000; 7(3):162-72. 

Notes: NPD 

Oldham RK, Greco FH, Einhorn L, et al. Preliminary 

results of a randomized trial to evaluate the role of 

radiotherapy in the combined modality therapy of 

limited stage small cell lung cancer. Proc Am Assoc 

Cancer Res 1981; 22:C-674. 

Notes: NRQ, exclude 

Oshita F, Kurata T, Kasai T, et al. Prospective 

evaluation of the feasibility of cisplatin-based 

chemotherapy for elderly lung cancer patients with 

normal organ functions. Jpn J Cancer Res 1995; 

86(12):1198-202. 

Notes: NRQ 

Oshita F, Yamada K, Nomura I, et al. Randomized 

study of dose or schedule modification of granulocyte 

colony-stimulating factor in platinum-based 

chemotherapy for elderly patients with lung cancer. 

Oncol Rep 2001; 8(4):861-6. 

Notes: NRQ 

Osoba D. Intensive chemotherapy for extensive-stage 

small-cell lung cancer (SCLC). Cancer Invest 1992; 

10(2):185-6. 

Notes: NRQ NPD 

Osterlind K, Andersen PK. Prognostic factors in 

small cell lung cancer: multivariate model based on 

778 patients treated with chemotherapy with or 

without irradiation. Cancer Res 1986; 46(8):4189-94. 

Notes: NRQ 

Osterlind K, Hansen HH. Ways to a better treatment 

of small cell lung cancer--a commentary. Ann Oncol 

1992; 3(1):9-10. 

Notes: NPD 

Osterlind K, Hansen HH, Dombernowsky P, et al. 

Determinants of complete remission induction and 

maintenance in chemotherapy with or without 

irradiation of small cell lung cancer. Cancer Res 

1987; 47(10):2733-6. 

Notes: NRQ 

Osterlind K, Hansen HH, Hansen M, et al. Long-term 

disease-free survival in small-cell carcinoma of the 

lung: a study of clinical determinants. J Clin Oncol 

1986; 4(9):1307-13. 

Notes: NRQ 

Paccagnella A, Oniga F, Favaretto A, et al. Elderly 

patients with small cell lung cancer. Tumori 2002; 

88(suppl 1):S145-7. 

Notes: NPD; 

Pandit N, Gonen M, Krug L, Larson SM. The 

prognostic value of [18F]FDG-PET imaging in small 

cell lung cancer. Eur J Nucl Med Mol Imaging 2003; 

30(1):78-84. 

Notes: NSD 
D-23

Payne DG, Murray N, Warde P. [Small cell lung 

carcinoma: role of thoracic irradiation and its timing 

in relation to chemotherapy]. Bull Cancer 1994; 

81(2):119-28. 

Notes: NPD 

Pedersen AG, Kristjansen PE, Hansen HH. 

Prophylactic cranial irradiation and small cell lung 

cancer. Cancer Treat Rev 1988; 15(2):85-103. 

Notes: NRA 

Peng WX, Sano T, Oyama T, et al. Large cell 

neuroendocrine carcinoma of the lung: A comparison 

with large cell carcinoma with neuroendocrine 

morphology and small cell carcinoma. Lung Cancer 

2005 Feb; 47(2):225-33. 

Notes: NRQ 

Perez CA, Bauer M, Edelstein S, et al. Impact of 

tumor control on survival in carcinoma of the lung 

treated with irradiation. Int J Radiat Oncol Biol Phys 

1986; 12(4):539-47. 

Notes: NRD NSP (NSCLC) 

Perez CA, Pajak TF, Rubin P, et al. Long-term 

observations of the patterns of failure in patients with 

unresectable non-oat cell carcinoma of the lung 

treated with definitive radiotherapy. Report by the 

Radiation Therapy Oncology Group. Cancer 1987; 

59(11):1874-81. 

Notes: NSP 

Pignon JP, Arriagada R. Role of thoracic 

radiotherapy in limited-stage small-cell lung cancer: 

quantitative review based on the literature versus 

meta-analysis based on individual data. J Clin Oncol 

1992; 10(11):1819-20. 

Notes: NPD; but maybe cite in write-up 

Pignon JP, Arriagada R, Ihde DC, et al. A metaanalysis of thoracic radiotherapy for small-cell lung 

cancer. N Engl J Med 1992; 327(23):1618-24. 

Notes: NRQ; 

Pignon JP, Tarayre M, Auquier A, et al. Triangular 

test and randomized trials: practical problems in a 

small cell lung cancer trial. Stat Med 1994; 13(13-

14):1415-21. 

Notes: NRQ 

Pirogov AI, Polotskii BE, Al-Ansari N, et al. 

[Clinical evaluation of the small-cell and poorly 

differentiated forms of squamous-cell and glandular 

lung cancers]. Vopr Onkol 1989; 35(2):154-8. 

Notes: NRQ 

Porter D, Boddy A, Thomas H, et al. Etoposide 

phosphate infusion with therapeutic drug monitoring 

in combination with carboplatin dosed by area under 

the curve: a cancer research campaign phase I/II 

committee study. Semin Oncol 1996; 23(6 Suppl 

13):34-44. 

Notes: NRQ 

Postmus PE, Kirkpatrick A, Dalesio O, et al. Two 

carboplatin-containing regimens for small cell lung 

cancer: preliminary results of a randomized phase II 

trial. Cancer Treat Rev 1988; 15 Suppl B:41-4. 

Notes: NRQ 

Postmus PE, Scagliotti G, Groen HJ, et al. Standard 

versus alternating non-cross-resistant chemotherapy 

in extensive small cell lung cancer: an EORTC Phase 

III trial. Eur J Cancer 1996; 32A(9):1498-503. 

Notes: NRQ 

Postmus PE, Smit EF, Berendsen HH, et al. Secondline carboplatin-based chemotherapy for small cell 

lung cancer: the Groningen experience. Semin Oncol 

1992; 19(1 Suppl 2):17-23. 

Notes: FEW SCS 

Postmus PE, Smit EF, Haaxma-Reiche H, et al. 

Teniposide for brain metastases of small-cell lung 

cancer: a phase II study. European Organization for 

Research and Treatment of Cancer Lung Cancer 

Cooperative Group. J Clin Oncol 1995; 13(3):660-5. 

Notes: NRQ 

Pottgen C, Eberhardt W, Stuschke M. Prophylactic 

cranial irradiation in lung cancer. Curr Treat Options 

Oncol 2004; 5(1):43-50. 

Notes: NRA, NPD 

Prendiville J, Lorigan P, Hicks F, et al. Therapy for 

small cell lung cancer using carboplatin, ifosfamide, 

etoposide (without dose reduction), mid-cycle 

vincristine with thoracic and cranial irradiation. Eur J 

Cancer 1994; 30A(14):2085-90. 

Notes: NSD 

Prior C, Oroszy S, Oberaigner W, et al. Adjunctive 

interferon-alpha-2c in stage IIIB/IV small-cell lung 

cancer: a phase III trial. Eur Respir J 1997; 

10(2):392-6. 

Notes: NRQ 
D-24

Proudhom MA, Noel G, Mazeron JJ. [Twice-daily 

compared with once-daily thoracic radiotherapy in 

limited small-cell lung cancer treated concurrently 

with cisplatin and etoposide. Phase III comparison of 

twice-daily split course irradiation versus once-daily 

irradiation for patients with limited stage small-cell 

lung carcinoma]. Cancer Radiother 2000; 4(4):319-

20. 

Notes: NPD 

Pujol JL, Carestia L, Daures JP. Is there a case for 

cisplatin in the treatment of small-cell lung cancer? A 

meta-analysis of randomized trials of a cisplatincontaining regimen versus a regimen without this 

alkylating agent. Br J Cancer 2000; 83(1):8-15. 

Notes: NRQ 

Pujol JL, Daures JP, Riviere A, et al. Etoposide plus 

cisplatin with or without the combination of 4'-

epidoxorubicin plus cyclophosphamide in treatment 

of extensive small-cell lung cancer: a French 

Federation of Cancer Institutes multicenter phase III 

randomized study. J Natl Cancer Inst 2001; 

93(4):300-8. 

Notes: NRQ 

Pujol JL, Douillard JY, Riviere A, et al. Doseintensity of a four-drug chemotherapy regimen with 

or without recombinant human granulocytemacrophage colony-stimulating factor in extensivestage small-cell lung cancer: a multicenter 

randomized phase III study. J Clin Oncol 1997; 

15(5):2082-9. 

Notes: NRQ 

Punt CJ, de Jonge MJ, Monfardini S, et al. RFS2000 

(9-nitrocamptothecin) in advanced small cell lung 

cancer, a phase II study of the EORTC New Drug 

Development Group. Eur J Cancer 2004; 40(9):1332-

4. 

Notes: INV 

Purohit A, Charloux A, Jung GM, et al. Early 

alternating chemotherapy and radiotherapy schedule 

in limited disease stage small cell lung cancer. Eur J 

Cancer 1995; 31A(9):1434-6. 

Notes: NSD 

Quoix E, Breton JL, Daniel C, et al. Etoposide 

phosphate with carboplatin in the treatment of elderly 

patients with small-cell lung cancer: a phase II study. 

Ann Oncol 2001; 12(7):957-62. 

Notes: NRQ 

Quoix E, Fraser R, Wolkove N, et al. Small cell lung 

cancer presenting as a solitary pulmonary nodule. 

Cancer 1990; 66(3):577-82. 

Notes: NRQ 

Raez L, Samuels M, Lilenbaum R. Combined 

modality therapy for limited-disease Small Cell Lung 

Cancer. Curr Treat Options Oncol 2005 Jan;6(1):69-

74. 

Notes: NRA 

Ramalingam S, Belani CP, Day R, et al. Phase II 

study of topotecan and paclitaxel for patients with 

previously untreated extensive stage small-cell lung 

cancer. Ann Oncol 2004; 15(2):247-51. 

Notes: NRQ 

Reck M, Jagos U, Grunwald F, et al. Long-term 

survival in SCLC after treatment with paclitaxel, 

carboplatin and etoposide--a phase II study. Lung 

Cancer 2003; 39(1):63-9. 

Notes: NRQ 

Reck M, von Pawel J, Macha HN, et al. Randomized 

phase III trial of paclitaxel, etoposide, and 

carboplatin versus carboplatin, etoposide, and 

vincristine in patients with small-cell lung cancer. J 

Natl Cancer Inst 2003; 95(15):1118-27. 

Notes: NRQ 

Repetto L, Biganzoli L, Koehne CH, et al. EORTC 

Cancer in the Elderly Task Force guidelines for the 

use of colony-stimulating factors in elderly patients 

with cancer. Eur J Cancer 2003; 39(16):2264-72. 

Notes: NRQ 

Reynolds T. Model aims to reduce discrepancy 

between phase II, phase III trials. J Natl Cancer Inst 

2000; 92(19):1554-5, 1556. 

Notes: NPD 

Richardson G. Sequential staging systems for smallcell lung cancer. Arch Intern Med 1994; 154(6):699. 

Notes: NPD 

Riedel RF, Crawford J. Small-cell lung cancer: a 

review of clinical trials. Semin Thorac Cardiovasc 

Surg 2003; 15(4):448-56. 

Notes: NRA 

Ronze S, Noel G, Mazeron JJ. [A randomized clinical 

trial comparing concurrent and alternating thoracic 

irradiation for patients with limited small cell lung 

carcinoma]. Cancer Radiother 2000; 4(4):325-6. 

Notes: NPD; summary of included trial 
D-25

Rosenstein M, Armstrong J, Kris M, et al. A 

reappraisal of the role of prophylactic cranial 

irradiation in limited small cell lung cancer. Int J 

Radiat Oncol Biol Phys 1992; 24(1 ):43-8. 

Notes: SCS, NSD 

Roszkowski K, Janic G, Jassem J, et al. [Evaluation 

of the second line of treatment of patients with small 

cell carcinoma of the lung]. Pneumonol Pol 1989; 

57(4):240-8. 

Notes: FL-PII 

Rowell NP, Gleeson FV. Steroids, radiotherapy, 

chemotherapy and stents for superior vena caval 

obstruction in carcinoma of the bronchus. Cochrane 

Database Syst Rev 2001; (4):CD001316. 

Notes: NRQ 

Rowland KM Jr, Loprinzi CL, Shaw EG, et al. 

Randomized double-blind placebo-controlled trial of 

cisplatin and etoposide plus megestrol 

acetate/placebo in extensive-stage small-cell lung 

cancer: a North Central Cancer Treatment Group 

study. J Clin Oncol 1996; 14(1):135-41. 

Notes: NRQ 

Ruffini E, Rena O, Oliaro A, et al. Lung tumors with 

mixed histologic pattern. Clinico-pathologic 

characteristics and prognostic significance. Eur J 

Cardiothorac Surg 2002 Nov;22(5):701-7. 

Notes: NSP; but maybe cite in write-up for Q7 

Ruotsalainen TM, Halme M, Tamminen K, et al. 

Concomitant chemotherapy and IFN-alpha for small 

cell lung cancer: a randomized multicenter phase III 

study. J Interferon Cytokine Res 1999; 19(3):253-9. 

Notes: NRQ 

Rushing DA. Phase I/II study of weekly irinotecan 

and paclitaxel in patients with SCLC . Oncology 

(Huntingt) 2000; 14(7 Suppl 5):63-6. 

Notes: NSD, FEW 

Salazar OM. Combined modality treatment of small 

cell lung cancer. Chest 1989; 96(1 Suppl):74S-8S. 

Notes: NPD 

Salzer GM, Muller LC, Huber H. Further evidence of 

the benefits of surgery in the combined management 

of small cell lung cancer. Thorac Cardiovasc Surg 

1988; 36(3):161. 

Notes: SCS NSD (retrospective) 

Salzer GM, Prauer H, Muller L, et al. [Long-term 

results of multimodality therapy of small cell 

bronchial cancer including surgery]. Langenbecks 

Arch Chir Suppl Kongressbd 1991; 544-8. 

Notes: NRQ FEW 

Samantas E, Kalofonos H, Linardou H, et al. Phase II 

study of pegylated liposomal doxorubicin: inactive in 

recurrent small-cell lung cancer. A Hellenic 

Cooperative Oncology Group Study. Ann Oncol 

2000; 11(11):1395-7. 

Notes: FEW 

Samantas E, Skarlos DV, Pectasides D, et al. 

Combination chemotherapy with low doses of 

weekly Carboplatin and oral Etoposide in poor risk 

small cell lung cancer. Lung Cancer 1999; 23(2):159-

68. 

Notes: NRQ 

Sandler AB. Chemotherapy for small cell lung 

cancer. Semin Oncol 2003; 30(1):9-25. 

Notes: NRA 

Santoro A, Parra HS, Bidoli P, et al. A summary of 

the Milan experience with multimodality therapies in 

patients with small cell lung cancer: attempts to 

improve long-term outcome. Semin Oncol 1995; 22(1 

Suppl 2):9-14. 

Notes: SCS 

Sauer R, Andreas P. [The role of radio-oncology in 

the treatment of bronchial cancer]. Helv Chir Acta 

1990; 56(5):749-62. 

Notes: NRA 

Sause WT. What have we accomplished in the 

management of patients with small cell anaplastic 

carcinoma of the lung? Int J Radiat Oncol Biol Phys 

1995; 31(4):1019-20. 

Notes: NPD 

Sause WT. Combination chemotherapy and radiation 

therapy in lung cancer. Semin Oncol 1994; 21(3 

Suppl 6):72-8. 

Notes: NRQ 

Sazon DA, Santiago SM, Soo Hoo GW, et al. 

Fluorodeoxyglucose-positron emission tomography 

in the detection and staging of lung cancer. Am J 

Respir Crit Care Med 1996; 153(1):417-21. 

Notes: NSP 
D-26

Schaefer PL, Marks RS, Mahoney MR, et al. 

Randomized phase II study of daily versus 

continuous-infusion schedules of topotecan in the 

treatment of extensive-stage small cell lung cancers. 

Am J Clin Oncol 2003; 26(3):236-40. 

Notes: NRQ 

Schamanek A KK. Importance of surgery in the 

multimodality treatment for small cell lung cancer 

(SCLC). Radiol Oncol 1994; 28:351-8. 

Notes: NRQ 

Schedel H, Rohloff R, Huber RM, Duft S, Kantlehner 

R. [Endoluminal irradiation of tracheobronchial 

tumors using a high dose rate iridium-192 

afterloading device]. Strahlenther Onkol 1988; 

164(4):202-7. 

Notes: NRQ FEW 

Schiller JH, Adak S, Cella D, et al. Topotecan versus 

observation after cisplatin plus etoposide in 

extensive-stage small-cell lung cancer: E7593--a 

phase III trial of the Eastern Cooperative Oncology 

Group. J Clin Oncol 2001; 19(8):2114-22. 

Notes: NRQ 

Schiller JH, Kim K, Hutson P, et al. Phase II study of 

topotecan in patients with extensive-stage small-cell 

carcinoma of the lung: an Eastern Cooperative 

Oncology Group Trial. J Clin Oncol 1996; 

14(8):2345-52. 

Notes: NRQ, NSD 

Schirrmeister H, Glatting G, Hetzel J, et al. 

Prospective evaluation of the clinical value of planar 

bone scans, SPECT, and (18)F-labeled NaF PET in 

newly diagnosed lung cancer. J Nucl Med 2001; 

42(12):1800-4. 

Notes: NRQ 

Schmid RA, Hautmann H, Poellinger B, et al. 

Staging of recurrent and advanced lung cancer with 

18F-FDG PET in a coincidence technique (hybrid 

PET). Nucl Med Commun 2003; 24(1 ):37-45. 

Notes: FEW 

Schnabel K. [Prophylactic cranial irradiation in 

small-cell bronchial carcinomas with complete tumor 

remission]. Strahlenther Onkol 1995; 171(6):363-4. 

Notes: NPD 

Schutte J, Niederle N, Alberti W, et al. Sequentially 

alternating chemotherapy of small-cell lung cancer 

with etoposide/cisplatinum and adriamycin (4'-epiadriamycin)/cyclophosphamide/vincristine +/- 

mediastinal irradiation. Prax Klin Pneumol 1985; 

39(suppl 1):837-8. 

Notes: NRQ 

Schutte J, Niederle N, Eberhardt W, et al. [Sequential 

induction chemotherapy and radiation treatment of 

inoperable small cell bronchial cancer. Results of a 

prospective randomized study]. Klin Wochenschr 

1989; 67(23):1182-93. 

Notes: NRA 

Sculier JP, Feld R, Evans WK, et al. Neurologic 

disorders in patients with small cell lung cancer. 

Cancer 1987; 60(9):2275-83. 

Notes: NRQ 

Sculier JP, Paesmans M, Bureau G, et al. 

Randomized trial comparing induction chemotherapy 

versus induction chemotherapy followed by 

maintenance chemotherapy in small-cell lung cancer. 

European Lung Cancer Working Party. J Clin Oncol 

1996; 14(8):2337-44. 

Notes: NRQ 

Sculier JP, Paesmans M, Lecomte J, et al. A threearm phase III randomised trial assessing, in patients 

with extensive-disease small-cell lung cancer, 

accelerated chemotherapy with support of 

haematological growth factor or oral antibiotics. Br J 

Cancer 2001; 85(10):1444-51. 

Notes: NRQ 

Sekine I, Nishiwaki Y, Noda K, et al. Randomized 

phase II study of cisplatin, irinotecan and etoposide 

combinations administered weekly or every 4 weeks 

for extensive small-cell lung cancer (JCOG9902-DI). 

Ann Oncol 2003; 14(5):709-14. 

Notes: NRQ 

Serke M, Riedel U, Schonfeld N, et al. [Combined 

alternating radiochemotherapy in stage III (TNM) 

(limited disease) small cell bronchial carcinoma: a 

phase II study with carboplatin/etoposide/vincristine 

and alternating radiotherapy]. Pneumologie 1999; 

53(10):485-92. 

Notes: NSD 
D-27

Sessa C, Wanders J, Roelvink M, et al. Second-line 

treatment of small-cell lung cancer with the 

camptothecin-derivative GI147211: a study of the 

EORTC Early Clinical Studies Group (ECSG). Ann 

Oncol 2000; 11(2):207-10. 

Notes: INV 

Seydel HG, Creech R, Pagano M, et al. Prophylactic 

versus no brain irradiation in regional small cell lung 

carcinoma. Am J Clin Oncol 1985; 8(3):218-23. 

Notes: NRQ 

Shah R, Sabanathan S, Richardson J et al. Results of 

surgical treatment of stage I and II lung cancer. J 

Cardiovasc Surg (Torino) 1996; 37(2):169-72. 

Notes: NSD, FEW 

Shaw EG, Frytak S, Eagan RT, et al. Etoposidecisplatin and thoracic radiation therapy salvage of 

incomplete responders to a noncisplatin induction 

regimen for limited and extensive small-cell 

carcinoma of the lung. Am J Clin Oncol 1996; 

19(2):154-8. 

Notes: SCS 

Shaw EG, Su JQ, Eagan RT et al. Prophylactic 

cranial irradiation in complete responders with smallcell lung cancer: analysis of the Mayo Clinic and 

North Central Cancer Treatment Group data bases. J 

Clin Oncol 1994; 12(11):2327-32. 

Notes: NSD 

Shepherd FA, Giaccone G, Seymour L, et al. 

Prospective, randomized, double-blind, placebocontrolled trial of marimastat after response to firstline chemotherapy in patients with small-cell lung 

cancer: a trial of the National Cancer Institute of 

Canada-Clinical Trials Group and the European 

Organization for Research and Treatment of Cancer. 

J Clin Oncol 2002; 20(22):4434-9. 

Notes: INV, NRQ 

Shepherd FA, Ginsberg R, Patterson GA, et al. Is 

there ever a role for salvage operations in limited 

small-cell lung cancer? J Thorac Cardiovasc Surg 

1991; 101(2):196-200. 

Notes: SCS 

Shepherd FA, Ginsberg RJ, Feld R, Evans WK, 

Johansen E. Surgical treatment for limited small-cell 

lung cancer. The University of Toronto Lung 

Oncology Group experience. J Thorac Cardiovasc 

Surg 1991; 101(3):385-93. 

Notes: SCS 

Simon M, Argiris A, Murren JR. Progress in the 

therapy of small cell lung cancer. Crit Rev Oncol 

Hematol 2004; 49(2):119-33. 

Notes: NRA, NPD 

Skarlos DV, Dimopoulos AM, Kosmidis P, et al. 

Docetaxel and gemcitabine combination, as first-line 

treatment, in patients with extensive disease smallcell lung cancer. A phase II study of the Hellenic 

Cooperative Oncology Group. Lung Cancer 2003; 

41(1):107-11. 

Notes: NRQ 

Skarlos DV, Samantas E, Kosmidis P, et al. 

Randomized comparison of etoposide-cisplatin vs. 

etoposide-carboplatin and irradiation in small-cell 

lung cancer. A Hellenic Co-operative Oncology 

Group study. Ann Oncol 1994; 5(7):601-7. 

Notes: NRQ 

Slodkowska J, Radomski P, Remiszewski P, et al. 

Histologic subtypes of small cell lung carcinoma in 

postreatment autopsy specimens. Electron J Pathol 

Histol 2002; 8(1):80-9. 

Notes: NRQ 

Slotman BJ, Njo KH, de Jonge A, Meyer OW, Karim 

AB. Consolidative thoracic radiotherapy and 

prophylactic cranial irradiation in limited disease 

small cell lung cancer. Lung Cancer 1993; 10(3-

4):199-208. 

Notes: NSD 

Smythe WR, Estrera AL, Swisher SG, et al. Surgical 

resection of non-small cell carcinoma after treatment 

for small cell carcinoma. Ann Thorac Surg 2001; 

71(3):962-6. 

Notes: NSD 

Socinski MA, Neubauer MA, Olivares J, et al. Phase 

II trial of paclitaxel, ifosfamide, and carboplatin in 

extensive-stage small cell lung cancer. Lung Cancer 

2003; 40(1):91-7. 

Notes: NRQ 

Sorensen JB. The role of prophylactic brain 

irradiation in small cell lung cancer treatment. 

Monaldi Arch Chest Dis 2003; 59(2):128-33. 

Notes: NRA 

Soria JC, Johnson BE, Chevalier TL. Imatinib in 

small cell lung cancer. Lung Cancer 2003; 41 Suppl 

1:S49-53. 

Notes: NRQ 
D-28

Souhami RL. Neuroendocrine phenotype, 

chemosensitivity and prognosis in adenocarcinoma of 

the lung. Ann Oncol 1991; 2(5):323-4. 

Notes: NPD 

Souhami RL, Spiro SG, Rudd RM, et al. Five-day 

oral etoposide treatment for advanced small-cell lung 

cancer: randomized comparison with intravenous 

chemotherapy. J Natl Cancer Inst 1997; 89(8):577-

80. 

Notes: NRQ 

Spiro SG, Porter JC. Lung cancer--where are we 

today? Current advances in staging and nonsurgical 

treatment. Am J Respir Crit Care Med 2002; 

166(9):1166-96. 

Notes: NRA 

Spiro SG, Souhami RL, Geddes DM, et al. Duration 

of chemotherapy in small cell lung cancer: a Cancer 

Research Campaign trial. Br J Cancer 1989; 

59(4):578-83. 

Notes: NRQ 

Sportelli G, Loffredo L, Lupi M, et al. A 

multidisciplinary approach to the treatment of smallcell lung cancer: the role played by surgery. Eur Rev 

Med Pharmacol Sci 1999; 3(6):261-3. 

Notes: SCS 

Steele JP. Gemcitabine/carboplatin versus 

cisplatin/etoposide for patients with poor-prognosis 

small cell lung cancer: a phase III randomized trial 

with quality-of-life evaluation. Semin Oncol 2001; 

28(3 Suppl 10):15-8. 

Notes: NRQ 

Stephens RJ, Girling DJ, Machin D. Treatmentrelated deaths in small cell lung cancer trials: can 

patients at risk be identified? Medical Research 

Council Lung Cancer Working Party. Lung Cancer 

1994; 11(3-4):259-74. 

Notes: NRQ 

Steward WP, von Pawel J, Gatzemeier U, et al. 

Effects of granulocyte-macrophage colonystimulating factor and dose intensification of V-ICE 

chemotherapy in small-cell lung cancer: a 

prospective randomized study of 300 patients. J Clin 

Oncol 1998; 16(2):642-50. 

Notes: NRQ 

Stiess J, Kiricuta IC, Mueller G, Bohndorf W. 

[Usefulness of prophylactic whole brain irradiation in 

small-cell bronchial carcinoma]. Strahlenther Onkol 

1995; 171(5):284-9. 

Notes: NSD 

Stuschke M. [Accelerated hyperfractionated 

compared with conventional radiotherapy in limited 

small-cell lung carcinoma, with concurrent 

chemotherapy]. Strahlenther Onkol 1999; 

175(6):296-8. 

Notes: NPD 

Sugio K, Ishida T, Kaneko S, et al. Surgically 

resected lung cancer in young adults. Ann Thorac 

Surg 1992; 53(1):127-31. 

Notes: NSP NSD 

Sugita T, Matsunaga K, Kobayashi H, et al. [Phase II 

study of a continuous five-day intravenous infusion 

of cisplatin and etoposide with concurrent chest 

radiation therapy in limited stage small cell lung 

cancer]. Gan To Kagaku Ryoho 1994; 21(14):2479-

83. 

Notes: NSD 

Sundstrom S, Bremnes RM, Kaasa S, et al. Cisplatin 

and etoposide regimen is superior to 

cyclophosphamide, epirubicin, and vincristine 

regimen in small-cell lung cancer: results from a 

randomized phase III trial with 5 years' follow-up. J 

Clin Oncol 2002; 20(24):4665-72. 

Notes: NRQ 

Szczesny TJ, Szczesna A, Shepherd FA, et al. 

Surgical treatment of small cell lung cancer. Semin 

Oncol 2003; 30(1):47-56. 

Notes: NRA 

Takigawa N, Fujiwara K, Ueoka H, et al. 

Fractionated administration of irinotecan and 

cisplatin for treatment of extensive-disease small-cell 

lung cancer: a phase II study. Anticancer Res 2003; 

23(1B):557-60. 

Notes: NRQ 

Tannock IF. Combined modality treatment with 

radiotherapy and chemotherapy. Radiother Oncol 

1989; 16(2):83-101. 

Notes: NRA 
D-29

Thatcher N, Clark PI, Girling DJ, et al. Comparison 

of oral etoposide and standard intravenous multidrug 

chemotherapy for small-cell lung cancer: a stopped 

multicentre randomised trial. Medical Research 

Council Lung Cancer Working Party. Lancet 1996; 

348(9027):563-6. 

Notes: NRQ 

Thatcher N, James RD, Steward WP, et al. Three 

months' treatment with cyclophosphamide, VP-16-

213 followed by methotrexate and thoracic 

radiotherapy for small cell lung cancer. Cancer 1985; 

56(6):1332-6. 

Notes: NSD 

Thatcher N, Lorrigan P, Burt P, Stout R. Intensive 

combined-modality therapy in small cell lung cancer. 

Semin Oncol 1994; 21(3 Suppl 6):9-22. 

Notes: NRA 

The Prophylactic Cranial Irradiation Overview 

Collaborative Group. Cranial irradiation for 

preventing brain metastases of small cell lung cancer 

in patients in complete remission. Cochrane Database 

Syst Rev 2000; (4):CD002805. 

Notes: NPD; exclude, but cite and summarize in 

write-up; systematic review on PCI 

Theuer W, Selawry O, Karrer K. The impact of 

surgery on the multidisciplinary treatment of 

bronchogenic small cell carcinoma (updated review 

including ongoing studies). Med Oncol Tumor 

Pharmacother 1992; 9(3):119-37. 

Notes: NRQ 

Thomas CR Jr, Giroux DJ, Janaki LM, et al. Ten-year 

follow-up of Southwest Oncology Group 8269: a 

phase II trial of concomitant cisplatin-etoposide and 

daily thoracic radiotherapy in limited small-cell lung 

cancer. Lung Cancer 2001; 33(2-3):213-9. 

Notes: NRQ 

Thomas CR Jr, Giroux DJ, Stelzer KJ, et al. 

Concurrent cisplatin, prolonged oral etoposide, and 

vincristine plus chest and brain irradiation for limited 

small cell lung cancer: a phase II study of the 

Southwest Oncology Group (SWOG-9229). Int J 

Radiat Oncol Biol Phys 1998; 40(5):1039-47. 

Notes: NSD 

Thomas CR Jr, Williams TE, Turrisi AT 3rd. Don't 

be mis-guided when the data are silent and the 

editorial misses the mark. J Clin Oncol 1998; 

16(4):1631-2. 

Notes: NPD; exclude, but maybe cite in write-up 

Thomas JP, Moore T, Kraut EH et al. A phase II 

study of CI-980 in previously untreated extensive 

small cell lung cancer: an Ohio State University 

phase II research consortium study. Cancer Invest 

2002; 20(2):192-8. 

Notes: NRQ, FEW 

Thomas P, Castelnau O, Paillotin D, et al. Phase II 

trial of paclitaxel and carboplatin in metastatic smallcell lung cancer: a Groupe Francais de PneumoCancerologie study. J Clin Oncol 2001; 19(5):1320-

5. 

Notes: NRQ 

Thomas P, Rubinstein L. Cancer recurrence after 

resection: T1 N0 non-small cell lung cancer. Lung 

Cancer Study Group. Ann Thorac Surg 1990; 

49(2):242-6; discussion 246-7. 

Notes: NSP NRD (NSCLC) 

Tian DL, Liu HX, Zhang L, et al. Surgery for young 

patients with lung cancer. Lung Cancer 2003; 

42(2):215-20. 

Notes: SCS 

Tobias JS, Spiro SG. Thoracic radiotherapy and 

chemotherapy for small-cell lung cancer: the 

discussion continues. J Clin Oncol 1994; 12(3):643-

4. 

Notes: NPD 

Tourani JM, Jaillon-Abraham C, Coscas Y, et al. 

Feasibility and preliminary results of intensive 

chemotherapy and extensive irradiation in selected 

patients with limited small-cell lung carcinoma--

results of three consecutive phase II programs. Acta 

Oncol 2000; 39(4):501-8. 

Notes: NSD 

Trillet-Lenoir V, Mornex F, Chauvin F, et al. Limited 

disease small cell lung cancer: alternating 

combination of doxorubicin, etoposide, ifosfamide 

and hyperfractionated radiotherapy. Final results of a 

multicentric pilot study for the Groupe Lyonnias 

d'Oncologie Thoracique (GLOT). Lung Cancer 1993; 

10(1-2):35-45. 

Notes: NSD 

Trillet-Lenoir V, Soler P, Arpin D, et al. The limits of 

chemotherapy dose intensification using granulocyte 

colony stimulating factor alone in extensive small 

cell lung cancer. Lung Cancer 1996; 14(2-3):331-41. 

Notes: NSD, NRQ 
D-30

Trillet V, Chauvin F, Champel F, et al. [Small cell 

lung carcinoma. Value of the evaluation of extension 

for the therapeutic strategy]. Presse Med 1990; 

19(14):655-60. 

Notes: NRQ 

Tsubota N, Ayabe K, Doi O, et al. Ongoing 

prospective study of segmentectomy for small lung 

tumors. Study Group of Extended Segmentectomy 

for Small Lung Tumor. Ann Thorac Surg 1998; 

66(5):1787-90. 

Notes: NSP 

Tummarello D, Graziano F, Giordani P, et al. Factors 

influencing response to second-line treatment with 

teniposide (VM26) in patients with progressive small 

cell lung cancer (SCLC). Anticancer Res 1993; 

13(4):1055-8. 

Notes: SCS 

Tummarello D, Guidi F, Torresi U, et al. Teniposide 

(VM26) as second-line treatment for small cell lung 

cancer. Anticancer Res 1990; 10(2A):397-9. 

Notes: SCS NSD (retrospective) 

Tummarello D, Mari D, Graziano F, et al. A 

randomized, controlled phase III study of 

cyclophosphamide, doxorubicin, and vincristine with 

etoposide (CAV-E) or teniposide (CAV-T), followed 

by recombinant interferon-alpha maintenance therapy 

or observation, in small cell lung carcinoma patients 

with complete responses. Cancer 1997; 80 (12):2222-

9. 

Notes: NRQ 

Turrisi AT. Brain irradiation and systemic 

chemotherapy for small-cell lung cancer: dangerous 

liaisons? J Clin Oncol 1990; 8(2):196-9. 

Notes: NPD 

Turrisi AT. Considerations on radiotherapy dose 

intensity for limited small cell lung cancer. Lung 

Cancer 1994; 10 Suppl 1:S167-73. 

Notes: NPD NRA 

Turrisi AT, Sherman CA. The treatment of limited 

small cell lung cancer: a report of the progress made 

and future prospects. Eur J Cancer 2002; 38(2):279-

91. 

Notes: NPD, NRA 

Turrisi AT 3rd. Cisplatin-etoposide based 

chemoradiation treatment for limited small cell lung 

cancer: the current situation. Anticancer Res 1994; 

14(1B):289-93. 

Notes: NRA NPD; but maybe cite in write-up 

Turrisi AT 3rd. Combined platinum etoposide with 

radiation therapy in limited stage small cell lung 

cancer: an effective treatment strategy. Lung Cancer 

1995; 12 Suppl 3:S41-51. 

Notes: NRA 

Turrisi AT 3rd. Innovations in multimodality therapy 

for lung cancer. Combined modality management of 

limited small-cell lung cancer. Chest 1993; 103(1 

Suppl):56S-9S. 

Notes: NRA 

Turrisi AT 3rd. Limited-disease small-cell lung 

cancer research: sense and nonsense. Int J Radiat 

Oncol Biol Phys 2004; 59(4):925-7. 

Notes: NPD; excluded, but cite in write-up 

Turrisi AT 3rd. Platinum combined with radiation 

therapy in small cell lung cancer: focusing like a laser 

beam on crucial issues. Semin Oncol 1994; 21(3 

Suppl 6):36-42. 

Notes: NRA 

Turrisi AT 3rd, Glover DJ. Thoracic radiotherapy 

variables: influence on local control in small cell lung 

cancer limited disease. Int J Radiat Oncol Biol Phys 

1990; 19(6):1473-9. 

Notes: NSD 

Ueoka H. Prophylactic cranial irradiation is a 

standard treatment in patients with small-cell lung 

cancer achieving complete response. Jpn J Lung 

Cancer 2002; 42(7):805-11. 

Notes: NRA 

Ueoka H, Kiura K, Tabata M, et al. A randomized 

trial of hybrid administration of cyclophosphamide, 

doxorubicin, and vincristine (CAV)/cisplatin and 

etoposide (PVP) versus sequential administration of 

CAV-PVP for the treatment of patients with small 

cell lung carcinoma: results of long term follow-up. 

Cancer 1998; 83(2):283-90. 

Notes: NRQ 

Ulsperger E, Karrer K, Denck H. Multimodality 

treatment for small cell bronchial carcinoma. 

Preliminary results of a prospective, multicenter trial. 

The ISC-Lung Cancer Study Group. Eur J 

Cardiothorac Surg 1991; 5(6 ):306-9; discussion 310. 

Notes: NRQ 
D-31

Urban T, Baleyte T, Chastang CL, et al. Standard 

combination versus alternating chemotherapy in 

small cell lung cancer: a randomised clinical trial 

including 394 patients. 'Petites Cellules' Group. Lung 

Cancer 1999; 25(2):105-13. 

Notes: NRQ 

Urban T, Chastang C, Lebas FX, et al. The addition 

of cisplatin to cyclophosphamide-doxorubicinetoposide combination chemotherapy in the treatment 

of patients with small cell lung carcinoma: A 

randomized study of 457 patients. "Petites Cellules" 

Group. Cancer 1999; 86(11):2238-45. 

Notes: NRQ 

Urtasun RC, Belch A, Bodnar D, et al. Radiation as a 

non-cross-resistant systemic agent: experience with 

hemibody and total-body irradiation in patients with 

small cell lung cancer. Cancer Treat Symp 1985; 

2:41-7. 

Notes: NRA 

van de Pol M, ten Velde GP, Wilmink JT, et al. 

Efficacy and safety of prophylactic cranial irradiation 

in patients with small cell lung cancer. J Neurooncol 

1997; 35(2):153-60. 

Notes: NSD 

van de Velde H, Bosquee L, Weynants P, Canon JL, 

Rosier JF, Humblet Y. Moderate dose-escalation of 

combination chemotherapy with concomitant 

thoracic radiotherapy in limited-disease small-cell 

lung cancer: prolonged intrathoracic tumor control 

and high central nervous system relapse rate. Groupe 

d'Oncologie-Pneumologie Clinique de l'Universite 

Catholique de Louvain, Brussels and Liege, Belgium. 

Ann Oncol 1999; 10(9):1051-7. 

Notes: NSD 

van der Linden YM, van Kempen ML, van der Tweel 

I, et al. Prophylactic cranial irradiation in limited 

disease small-cell lung cancer in complete remission: 

a retrospective analysis. Respir Med 2001; 95(3):235-

6. 

Notes: NSD 

Van Houtte P, Mornex F. Is concurrent twice-daily 

thoracic radiotherapy with chemotherapy the 

reference treatment for small cell lung cancer? Lung 

Cancer 2000 Mar;27(3):133-5. 

Notes: NPD; 

van Oosterhout AG, Boon PJ, Houx PJ, et al. Followup of cognitive functioning in patients with small cell 

lung cancer. Int J Radiat Oncol Biol Phys 1995; 

31(4):911-4. 

Notes: NSD 

van Zandwijk N, Groen HJ, Postmus PE, et al. Role 

of recombinant interferon-gamma maintenance in 

responding patients with small cell lung cancer. A 

randomised phase III study of the EORTC Lung 

Cancer Cooperative Group. Eur J Cancer 1997; 

33(11):1759-66. 

Notes: NRQ 

Vansteenkiste J, Gatzemeier U, Manegold C, et al. 

Gemcitabine plus etoposide in chemonaive extensive 

disease small-cell lung cancer: a multi-centre phase II 

study. Ann Oncol 2001; 12(6):835-40. 

Notes: NRQ 

Vansteenkiste J, Tomita D, Rossi G, et al. 

Darbepoetin alfa in lung cancer patients on 

chemotherapy: a retrospective comparison of 

outcomes in patients with mild versus moderate-tosevere anaemia at baseline. Support Care Cancer 

2004; 12(4):253-62. 

Notes: NRQ 

Vieitez JM, Valladares M, Gracia M, et al. Phase II 

study of carboplatin and 1-h intravenous etoposide 

and paclitaxel in a novel sequence as first-line 

treatment of patients with small-cell lung cancer. 

Lung Cancer 2003; 39(1):77-84. 

Notes: NRQ 

Vines EF, Le Pechoux C, Arriagada R. Prophylactic 

cranial irradiation in small cell lung cancer. Semin 

Oncol 2003; 30(1):38-46. 

Notes: NRA 

Viren M, Liippo K, Ojala A, et al. Carboplatin and 

etoposide (CarE) combined with radiotherapy and 

vincristine, doxorubicin and cyclophosphamide 

(VAC) in limited small cell lung cancer. A phase II 

study. Acta Oncol 1992; 31(7):761-5. 

Notes: NSD 

Vitale V, Scolaro T, Orsatti M. Prophylactic brain 

irradiation: still an open question (review). 

Anticancer Res 1994; 14(1B):295-9. 

Notes: NRA 

Voinarevich AO. [Metastatic brain lesion in smallcell lung cancer]. Vopr Onkol 1989; 35 (2):199-203. 

Notes: NRA 
D-32

Vokes EE, Weichselbaum RR. Concomitant 

chemoradiotherapy: rationale and clinical experience 

in patients with solid tumors. J Clin Oncol 1990; 

8(5):911-34. 

Notes: NRA 

von Pawel J, Wilke H, Vallee D, et al. [Phase II study 

with etoposide/vincristine in small cell bronchial 

cancer (extensive disease)]. Pneumologie 1990; 44 

Suppl 1:582-3. 

Notes: NRQ 

Wada H, Tanaka F, Yanagihara K, et al. Time trends 

and survival after operations for primary lung cancer 

from 1976 through 1990. J Thorac Cardiovasc Surg 

1996; 112(2):349-55. 

Notes: SCS NSP 

Waddell TK, Shepherd FA. Should aggressive 

surgery ever be part of the management of small cell 

lung cancer? Thorac Surg Clin 2004; 14(2):271-81. 

Notes: NPD; review (surgery for very early stage 

disease); excluded, but cite in write-up 

Warde P, Payne D. Does thoracic irradiation improve 

survival and local control in limited-stage small-cell 

carcinoma of the lung? A meta-analysis. J Clin Oncol 

1992; 10(6):890-5. 

Notes: NRQ; cite in write-up; systematic review and 

meta-analysis of TRTx versus no TRTx 

Warren WH, Memoli VA, Jordan AG, et al. 

Reevaluation of pulmonary neoplasms resected as 

small cell carcinomas. Significance of distinguishing 

between well-differentiated and small cell 

neuroendocrine carcinomas. Cancer 1990; 

65(4):1003-10. 

Notes: NRQ; but maybe cite in write-up 

Westeel V, Murray N, Gelmon K, et al. New 

combination of the old drugs for elderly patients with 

small-cell lung cancer: a phase II study of the PAVE 

regimen. J Clin Oncol 1998; 16(5):1940-7. 

Notes: NSD 

Wetstein L, Brenner A. Limited resections for lung 

cancer. N J Med 1989; 86(3):197-200. 

Notes: FEW 

White SC, Lorigan P, Middleton MR, et al. 

Randomized phase II study of cyclophosphamide, 

doxorubicin, and vincristine compared with singleagent carboplatin in patients with poor prognosis 

small cell lung carcinoma. Cancer 2001; 92(3):601-8. 

Notes: NSP 

Wiatr E, Bestry I, Danczak-Ginalska Z, et al. [The 

role of radiotherapy in combined treatment of limited 

small cell lung cancer in relation to results of 

induction chemotherapy]. Pneumonol Alergol Pol 

1995; 63(7-8):421-6. 

Notes: NRQ 

Wick MR, Berg LC, Hertz MI. Large cell carcinoma 

of the lung with neuroendocrine differentiation. A 

comparison with large cell "undifferentiated" 

pulmonary tumors. Am J Clin Pathol 1992; 

97(6):796-805. 

Notes: NRQ; large cell neuroendocrine 

Williams CJ, McMillan I, Lea R, et al. Surgery after 

initial chemotherapy for localized small-cell 

carcinoma of the lung. J Clin Oncol 1987; 

5(10):1579-88. 

Notes: SCS 

Willkomm P, Bangard M, Guhlke S, et al. 

Comparison of. Ann Nucl Med 2002; 16(7):503-6. 

Notes: FEW 

Wolf M, Havemann K. Alternating chemotherapy in 

small cell lung cancer. Onkologie 1990; 13(3):157-

64. 

Notes: NRQ 

Wolf M, Havemann K, Holle R, Drings P, Hans K, 

Schroeder M. [Incidence of recurrence and long-term 

survival in small cell bronchial carcinoma]. 

Onkologie 1987; 10(6):357-66. 

Notes: NRQ 

Woll PJ, Hodgetts J, Lomax L, et al. Can cytotoxic 

dose-intensity be increased by using granulocyte 

colony-stimulating factor? A randomized controlled 

trial of lenograstim in small-cell lung cancer. J Clin 

Oncol 1995; 13(3):652-9. 

Notes: NRQ 

Woo IS, Park YS, Kwon SH, et al. A phase II study 

of VP-16-fosfamide-cisplatin combination 

chemotherapy plus early concurrent thoracic 

irradiation for previously untreated limited small cell 

lung cancer. Jpn J Clin Oncol 2000; 30(12):542-6. 

Notes: NSD 

Wood L, Palmer M, Hewitt J, et al. Results of a phase 

III, double-blind, placebo-controlled trial of 

megestrol acetate modulation of P-glycoproteinmediated drug resistance in the first-line management 

of small-cell lung carcinoma. Br J Cancer 1998; 

77(4):627-31. 

Notes: NRQ 
D-33

Wu KL, Jiang GL, Qian H, et al. Three-dimensional 

conformal radiotherapy for locoregionally recurrent 

lung carcinoma after external beam irradiation: a 

prospective phase I-II clinical trial. Int J Radiat 

Oncol Biol Phys 2003; 57(5):1345-50. 

Notes: FEW 

Yoshikawa K, Tsubota N, Kodama K et al. 

Prospective study of extended segmentectomy for 

small lung tumors: The final report. Ann Thorac Surg 

2002 Apr;73(4):1055-8 

Notes: NSP 

Zang DY, Lee KH, Lee JS, et al. Phase II trial of a 

novel platinum analog, SKI 2053R, in patients with 

previously untreated extensive-stage small-cell lung 

cancer. Am J Clin Oncol 1999; 22(5):495-8. 

Notes: NRQ 

Zarogoulidis K, Ziogas E, Papagiannis A, et al. 

Interferon alpha-2a and combined chemotherapy as 

first line treatment in SCLC patients: a randomized 

trial. Lung Cancer 1996; 15(2):197-205. 

Notes: NRQ 

Zatopek NK, Holoye PY, Ellerbroek NA, et al. 

Resectability of small-cell lung cancer following 

induction chemotherapy in patients with limited 

disease (stage II-IIIb). Am J Clin Oncol 1991; 

14(5):427-32. 

Notes: SCS 

Zhang X. [Surgical treatment for small cell 

carcinoma of the lung. Report of 102 cases]. 

Zhonghua Wai Ke Za Zhi 1992; 30(8):492-3, 510. 

Notes: NRQ NSD 

Zvarych IuM, Shevchenko AI. [Intratumoral 

chemotherapy in the treatment of regional 

widespread pulmonary cancer]. Klin Khir 2003; 

(9):32-3. 

Notes: NRQ 
E-1

Appendix E. Technical Expert Panel (TEP) and 

Reviewers 

Technical Expert Panel (TEP) 

Kemp H. Kernstine, M.D., Ph.D. 

Lung Cancer Program 

City of Hope National Medical Center and Beckman Research Institute 

Duarte, CA 

William F. Lawrence, M.D., M.S. 

Center for Outcomes and Evidence 

Agency for Healthcare Research and Quality 

Rockville, MD 

Sandra Zelman Lewis, Ph.D. 

Research Specialist 

American College of Chest Physicians 

Northbrook, IL 

Douglas C. McCrory, M.D., M.H.S. 

Center for Clinical Health Policy Research 

Duke University Medical Center 

Durham, NC 

David Eric Morris, M.D. 

Department of Radiation Oncology 

University of North Carolina Hospitals 

Chapel Hill, NC 

Alan Sandler, M.D. 

Division of Hematology/Oncology 

Vanderbilt University 

Nashville, TN 
E-2

Technical Expert Panel (TEP) 

(continued) 

George R. Simon, M.D., F.C.C.P. 

Thoracic Oncology Program 

H. Lee Moffitt Cancer Center 

Tampa, FL 

Stephen J. Swensen, M.D., M.M.M. 

Department of Radiology 

Mayo Clinic 

Rochester, MN 

Andrew T. Turrisi, III, M.D. 

Gershenson Radiation Oncology Center 

Wayne State University 

Detroit, MI 

Peer Reviewers 

Richard K.J. Brown, M.D. 

Clinical Associate Professor 

University of Michigan 

Department of Radiology 

Division of Nuclear Medicine 

Ann Arbor, MI 

(Nominated by the American College of Radiology) 

Paul Bunn, M.D. 

University of Colorado Cancer Center 

Aurora, CO 

Norman Edelman, M.D. 

Chief Medical Officer 

American Lung Association 

(Nominated by the American Lung Association) 
E-3

Peer Reviewers 

(continued) 

Fergus Macbeth, D.M. 

Director National Collaborating Centre for Cancer 

Cardiff 

UK 

John McArdle, M.D. 

Yale University School of Medicine 

Section of Pulmonary and Critical Care Medicine 

New Haven, CT 

(Nominated by the American Thoracic Society) 

Mary A. Simmonds, M.D., FA.C.P. 

Clinical Professor of Medicine 

Penn State University College of Medicine 

University Park, PA 

(Nominated by the American Cancer Society)