Phase III Comparison of Thoracic Radiotherapy Regimens in Patients With Limited Small Cell Lung Cancer Also Receiving Cisplatin and Etoposide
Phase: PHASE3
Conditions: Lung Cancer
Sponsor: Alliance for Clinical Trials in Oncology

1 
   
Protocol Update #14 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
_________________________________________ 
PROTOCOL UPDATE TO CALGB 30610 
_________________________________________ 
 
PHASE III COMPARISON OF THORACIC RADIOTHERAPY REGIMENS IN PATIENTS WITH LIMITED 
SMALL CELL LUNG CANCER ALSO RECEIVING CISPLATIN OR CARBOPLATIN AND ETOPOSIDE 
 
 
 
 
 
X Update: 
 
 
Status Change: 
 
 
 
 
 
X Eligibility changes 
 
 
Activation 
 
 
 
 
 
 
Therapy / Dose Modifications / Study Calendar changes 
 
 
Closure 
 
 
 
 
 
 
Informed Consent changes 
 
 
Suspension / temporary closure 
 
 
 
 
 
 
 
Scientific / Statistical Considerations changes 
 
 
Reactivation 
 
 
 
 
 
 
X Data Submission / Forms changes 
 
 
 
 
 
 
 
 
X Editorial / Administrative changes 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
Expedited review is allowed. IRB approval (or disapproval) is required within 90 days. Please follow 
your IRB of record guidelines. 
 
UPDATES TO THE PROTOCOL: 
 
Cover Page 
The Respiratory Committee Chair has been updated from 
 
A new Staff Statistician has been added. 
The Data Manager has been updated from Andrew Johnson to Katie Hervey. 
 
CTSU Address and Contact Information Page 
The information under “Submit study data to” has been updated. 
 
Section 4.3 Prior Treatment 
The 4th sentence of the first bullet point: “Registration to CALGB 30610 must take place within 7-21 days 
after the start of the non-protocol therapy” has been moved to Section 5.4 of the registration section. This 
is no longer in the eligibility section. 
 
Section 5.0 Patient Registration 
The entire section has been modified with the updated CTSU language. 
 

2 
Section 5.5 Stratification 
The radiotherapy start time language has been clarified. 
 
Section 6.1 Data Submission 
The first four paragraphs in this section have replaced the previous data submission language. 
In the paragraph following the table information about using CTCAE version 5 for serious AE reporting 
has been added. 
 
Section 16.0 Adverse Event Reporting 
The references to the CTCAE reporting have been updated from version 4.0 to version 5.0 for serious AE 
reporting. CTCAE version 4.0 will continue to be used for routine AE reporting.  
 
Section 16.2 Additional Instructions or Exclusions from CTEP-AERS Expedited Reporting 
Requirements 
The first bullet point regarding death due to progressive disease has been updated. 
The seventh bullet point has new guidelines about reporting pregnancy loss. 
The eighth bullet point replaces the previous AML/MDS and new primary malignancy bullets. 
 
 
 
UPDATES TO THE MODEL CONSENT: 
There are no changes to the model consent. 
 
 
 
 
 
A replacement protocol and model consent have been issued. 
____________________________________________________ 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
_____________________________________________________ 

 
 
  
 
 
 
 
 
Update #14 
Version Date: 08/02/18 
  
 
 
 
 
 
 
 
1
   
Activation Date: March 15, 2008 
Includes Update #14 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
CALGB 30610/RTOG 0538 
 
PHASE III COMPARISON OF THORACIC RADIOTHERAPY REGIMENS IN PATIENTS WITH LIMITED 
SMALL CELL LUNG CANCER ALSO RECEIVING CISPLATIN OR CARBOPLATIN AND ETOPOSIDE 
 
Clinicaltrials.gov Identifier: NCT00632853 
 
Study Chair 
 
 
 
 
   
 
 
Study Co-chair 
RTOG Radiation Oncology Co-chair 
 
 
 
 
 
 
 
RTOG Medical Oncology Co-chair 
RTOG Correlative Science Co-chair 
 
 
 
 
 
 
 
CALGB QOL Co-chair 
RTOG QOL Co-chair 
 
 
 
 
 
 
 
Respiratory Committee Chair 
Respiratory Correlative Science Committee Chair 
 
 
 
 
 
 
 
Faculty Statistician 
Staff Statistician 
 
 
 
 
 
 
 
Data Manager 
Protocol Coordinator 
 
 
 
 
 
 
 

 
 
  
 
 
 
 
 
Update #14 
Version Date: 08/02/18 
  
 
 
 
 
 
 
 
2
Participating NCTN Groups: NRG, ECOG-ACRIN, SWOG 

CALGB 30610 
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Update #14 
Alliance Central Protocol Operations Program Office 
 
 
 
 
  
Adverse Event Reporting 
 
Alliance Biorepository and Ohio State 
 
 
 
 
 
 
Alliance Statistics and Data Center 
 
 
 
CALGB 30610 Pharmacy Contact 
 
 
 
 
CALGB 30610 Nursing Contact 
 
 
 
 
 
 
 

CALGB 30610 
Version Date 08/02/18 
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Update #14 
 
CONTACT INFORMATION 
 
For regulatory requirements: 
For patient enrollments: 
Submit study data to: 
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal. 
Regulatory Submission Portal: 
(Sign in at
            
and select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 
 
to receive further instruction 
and support. 
 
Contact the CTSU Regulatory 
Help Desk at 
 
for regulatory assistance. 
Please refer to the patient 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
 
 
Contact the CTSU Help Desk 
with any OPEN-related questions 
at 
 
 
Data collection for this tudy will 
be done exclusively through 
Medidata Rave. Please see the 
data submission section of the 
protocol for further instructions. 
 
The most current version of the study prot ocol and  all support ing documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at 
  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program 
- Identity and Access Management (CTEP-IAM) registration system and requires user log on with 
CTEP-IAM username and password.  Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the CTSU RSS. 
For clinical questions (i.e. patient eligibility or treatment-related) Contact the Study PI of the Lead 
Protocol Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 
All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at 
 
 
 

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Update #14 
 
PHASE III COMPARISON OF THORACIC RADIOTHERAPY REGIMENS IN PATIENTS WITH LIMITED 
SMALL CELL LUNG CANCER ALSO RECEIVING CISPLATIN OR CARBOPLATIN AND ETOPOSIDE 
 
Patient Eligibility 
Required Initial Laboratory Values 
Histologically or cytologically documented small cell lung 
cancer of limited stage. 
Granulocytes 
Platelets 
≥1,500/µl 
≥100,000/µl 
Measurable disease. 
Total Bilirubin 
≤1.5 x ULN 
No prior chemotherapy or radiotherapy for SCLC, apart from 
1 cycle of chemotherapy (see Section 4.3). 
AST (SGOT) 
≤2.0 x ULN 
No prior mediastinal or thoracic radiotherapy 
Serum Creatinine 
≤ 1.5 x ULN 
Patients with complete surgical resection of disease are not 
eligible. 
  OR 
Calculated CrCl 
 
≥ 70 ml/min 
Age ≥18 years. 
 
 
ECOG Performance status 0-2. 
Non-pregnant and non-nursing. 
Schema (1 cycle = 21 days)  
Patients will receive 4 cycles of chemotherapy 
Part II: Based on the results of Part I, the experimental arm (Arm C) was discontinued and patients are 
randomized (as of 03/11/2013) as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prophylactic cranial irradiation (PCI) should be offered to all patients with a complete or near CR. 
EFFECTIVE MARCH 10, 2013, PART I IS CLOSED TO FURTHER ACCRUAL 
 
Part I: 
 
 
 
 
 
 
 
 
 
Arm A: Same as Arm A in Part II 
 
Register/ 
Randomize 
Arm B: Same as Arm B in Part II 
Arm A: 
Radiotherapy (every day, Monday-Friday, for a total of 3 weeks) 
XRT: 45 Gy BID (1.5 Gy/fx) starting on day 1 of Cycle 1 or 2, every day, for 3 weeks 
Chemotherapy (every 21 days for 4 cycles, for a total of 12 weeks) 
Cisplatin 80 mg/m2 IV on day 1 OR Carboplatin AUC 5 IV day 1, every 21 days 
Etoposide 100 mg/m2 IV on days 1, 2, and 3, every 21 days 
Register/ 
Randomize 
Arm B: 
Radiotherapy (every day, Monday-Friday, for a total of 7 weeks) 
XRT: 70 Gy QD (2.0 Gy/fx), starting on day 1 of Cycle 1 or 2, every day, for 7 weeks 
Chemotherapy (every 21 days for 4 cycles, for a total of 12 weeks) 
Cisplatin 80 mg/m2 IV on day 1 OR Carboplatin AUC 5 IV day 1, every 21 days 
Etoposide 100 mg/m2 IV on days 1, 2, and 3, every 21 days 
Arm C: 
Radiotherapy (every day, Monday-Friday, for a total of 5 weeks) 
XRT: 61.2 Gy Concomitant boost: QD (1.8 Gy/fx), starting on day 1 of Cycle 1 or 2, every day, for 16 
days of treatment; then BID (1.8 Gy/fx) for 9 days of treatment 
Chemotherapy (every 21 days for 4 cycles, for a total of 12 weeks) 
Cisplatin 80 mg/m2 IV on day 1, every 21 days 
Etoposide 100 mg/m2 IV on days 1, 2, and 3, every 21 days 

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Update #14 
 
TABLE OF CONTE NTS 
SECTION 
PAGE 
1.0 
Introduction ......................................................................................................................... 8 
1.1 
Thoracic Radiotherapy .................................................................................................... 8 
1.2 
Timing of Radiotherapy ................................................................................................ 10 
1.3 
Chemotherapy ............................................................................................................... 11 
1.4 
High Dose Thoracic Radiotherapy Concurrent with Cycle 1 Chemotherapy ............... 11 
1.5 
Summary ....................................................................................................................... 12 
1.6 
Inclusion of Women and Minorities ............................................................................. 13 
2.0 
Objectives ......................................................................................................................... 13 
2.1 
Primary Objective ......................................................................................................... 13 
2.2 
Secondary Objectives.................................................................................................... 13 
3.0 
On-Study Guidelines ......................................................................................................... 14 
4.0 
Eligibility Criteria ............................................................................................................. 14 
4.1 
Documentation of Disease ............................................................................................ 14 
4.2 
Measurable Disease ...................................................................................................... 15 
4.3 
Prior Treatment ............................................................................................................. 15 
4.4 
Age Requirement .......................................................................................................... 15 
4.5 
ECOG Performance Status ........................................................................................... 15 
4.6 
Non-pregnant and non-nursing ..................................................................................... 15 
4.7 
Required Initial Laboratory Values .............................................................................. 15 
5.0 
Patient Registration ........................................................................................................... 15 
5.1 
CTEP Registration Procedures ..................................................................................... 15 
5.2 
CTSU Site Registration Procedures .............................................................................. 16 
5.3 
Patient Registration Requirements ................................................................................ 18 
5.4 
Patient Registration/Randomization Procedures........................................................... 18 
5.5 
Stratification .................................................................................................................. 19 
5.6 
Registration to Companion Studies .............................................................................. 19 
6.0 
Data And Sample Submission .......................................................................................... 20 
6.1 
Data Submission ........................................................................................................... 20 
6.2 
Data Submission for QOL ............................................................................................ 22 
6.3 
Specimen Submission for Correlative Studies .............................................................. 22 
7.0 
Required Data ................................................................................................................... 25 
8.0 
Treatment Plan .................................................................................................................. 27 
8.1 
Chemotherapy ............................................................................................................... 27 
8.2 
Radiation Therapy ......................................................................................................... 28 
9.0 
Dose Modifications And Management of Toxicity .......................................................... 35 
9.1 
Hematologic Toxicity ................................................................................................... 35 
9.2 
Gastrointestinal Toxicity ............................................................................................... 36 
9.3 
Hepatic Toxicity............................................................................................................ 36 
9.4 
Nephrotoxicity .............................................................................................................. 36 
9.5 
Hypomagnesemia .......................................................................................................... 36 
9.6 
Neurologic Toxicity ...................................................................................................... 36 
9.7 
Ototoxicity .................................................................................................................... 36 
9.8 
Allergic Reactions ......................................................................................................... 37 

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Update #14 
9.9 
Grade 3/4 Non-Hematologic Toxicity .......................................................................... 37 
9.10 
Radiotherapy Dose Modifications for In-field Non-Hematologic Toxicities ............... 37 
9.11 
Dose Modifications for Obese Patients......................................................................... 38 
10.0 
Companion Studies ........................................................................................................... 38 
10.1 
Correlative Science Substudies (CALGB 150712) ....................................................... 38 
10.2 
Health Related Quality of Life (CALGB 70702) ......................................................... 43 
11.0 
Drug Formulation, Availability, And Preparation ............................................................ 48 
11.1 
Cisplatin ........................................................................................................................ 48 
11.2 
Carboplatin .................................................................................................................... 49 
11.3 
Etoposide....................................................................................................................... 50 
12.0 
Ancillary Therapy ............................................................................................................. 50 
12.1 
Alliance Policy Concerning the Use of Growth Factors ............................................... 50 
13.0 
Criteria For Response, Progression, And Relapse ............................................................ 51 
13.1 
Target Lesions ............................................................................................................... 51 
13.2 
Non-target Lesions ........................................................................................................ 52 
13.3 
Cytology and Histology ................................................................................................ 52 
13.4 
Evaluation of Best Overall Response ........................................................................... 52 
13.5 
Guidelines for Evaluation of Measurable Disease ........................................................ 53 
13.6 
Confirmation Measurement/Duration of Response ...................................................... 54 
14.0 
Removal Of Patients From Protocol Therapy ................................................................... 54 
14.1 
Duration of Treatment................................................................................................... 54 
14.2 
Extraordinary Medical Circumstances:......................................................................... 54 
15.0 
Statistical Considerations .................................................................................................. 55 
15.1 
Endpoints ...................................................................................................................... 55 
15.2 
Stratification Factors ..................................................................................................... 56 
15.3 
Sample Size with Power Justification ........................................................................... 56 
15.4 
Analysis Plan Including Plans for Formal Interim Analysis ........................................ 57 
15.5 
Logistics and Accrual ................................................................................................... 58 
15.6 
Correlative Studies (CALGB 150712).......................................................................... 59 
15.7 
Health Related Quality of Life (CALGB 70702) ......................................................... 61 
15.8 
CDUS Reporting ........................................................................................................... 66 
16.0 
Adverse Event Reporting (Aer) ........................................................................................ 67 
16.1 
CALGB 30610 Adverse Event Reporting Requirements ............................................. 67 
16.2 
Additional Instructions or Exclusions from CTEP-AERS Expedited Reporting 
Requirements: ........................................................................................................................... 68 
17.0 
References ......................................................................................................................... 69 
 
 
 
 

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Update #14 
1.0 
INTRODUCTION 
The integration of thoracic radiotherapy (TRT) with systemic chemotherapy for the treatment of 
limited-stage small cell lung cancer (LSCLC) has been widely studied. Two meta-analyses, 
published in the early 1990s, confirmed that adding TRT to chemotherapy significantly improved 
long-term survival for patients with LSCLC [1, 2]. A recent overview of prospective research in 
LSCLC included 26 randomized clinical trials initiated by cooperative groups in North America 
between 1972 and 1992 and only 5 studies showed statistically significant survival prolongation in 
the experimental arm compared with the control arm [3]. All five positive trials studied some aspect 
of TRT. Although several important questions remain unanswered regarding the optimal 
integration of TRT and chemotherapy in LSCLC, an Intergroup phase III study addressing limited 
stage small cell lung cancer study has not been conducted in more than 13 years. 
1.1 
Thoracic Radiotherapy 
Traditionally, modest total doses of radiation, ranging from 45–50 Gy, were employed because 
of the observed responsiveness of small-cell lung cancer to radiotherapy [4]. Although high 
clinical response rates are expected with combined modality therapy, durable local tumor control 
is poor when modest-dose, conventionally fractionated TRT is employed. For example, 
intrathoracic tumor relapse was observed in the majority of patients treated with 45 Gy once-
daily (QD) radiotherapy concurrent with cisplatin and etoposide chemotherapy in a modern 
prospective phase III trial [5]. 
Intensifying the radiotherapy course by accelerating the time to complete treatment (while 
maintaining the same nominal total radiation dose) appears to be an effective strategy in LSCLC. 
Intergroup trial 0096 (INT 0096) randomized patients to either conventional (180 cGy QD x 25 
fractions [45 Gy in 5 weeks]) or hyperfractionated, accelerated (150 cGy twice daily (BID) x 30 
fractions [45 Gy in 3 weeks]) TRT [5]. TRT was initiated with the first cycle of 
etoposide/cisplatin (PE) chemotherapy. Mature results of this trial demonstrate statistically 
significant improvement in overall survival for the accelerated TRT. Five-year survival was 26% 
with accelerated RT compared with 16% for patients receiving conventional TRT. Patterns of 
recurrence reflected improved local and local plus distant recurrence rates with accelerated TRT, 
suggesting that local treatment has a significant impact on ultimate outcome in LSCLC. The 
cumulative rate of local tumor relapse was 75% with once-daily TRT compared with 42% with 
twice-daily TRT. The major increased toxicity of the accelerated regimen was a doubling of the 
grade 3/4 acute esophagitis rate (e.g., 16% vs 32%). 
INT 0096 was a well-conducted phase III study demonstrating that altering the administration 
of radiotherapy could ultimately influence survival. Despite this result, the 45 Gy BID TRT 
regimen has not been well accepted in clinical practice.  The Patterns of Care Study published 
in 2003 noted that fewer than 10% of patients with LSCLC received this regimen, while more 
than 80% were treated with QD TRT [6]. In addition, recent phase II cooperative group trials in 
LSCLC have not routinely employed 45 Gy BID TRT. The reluctance to accept accelerated TRT 
may be in part due to increased acute toxicity and practical issues involved with treating patients 
twice each day. However, the results of the study have also been questioned due to the inclusion 
of 45 Gy QD TRT as the standard treatment.  The predicted biologic efficacy of 45 Gy QD TRT 
is poor, and a high dose QD TRT arm (e.g., ≥ 60 Gy), which is commonly employed in clinical 
practice, was not included in the INT 0096 study. 
Alternative strategies for increasing the efficacy of treatment include administering either high 
dose QD TRT, or giving concomitant boost therapy, where BID treatment is given only during 
part of the treatment course. The Cancer and Leukemia Group B (CALGB) has extensively 
studied high-dose QD TRT. CALGB 8837, a phase I study, was designed to determine the 
maximum-tolerated dose (MTD) of TRT in both standard QD and accelerated BID schedules 

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Update #14 
[7, 8]. Chemotherapy consisted of three cycles of cisplatin, cyclophosphamide, and etoposide 
followed by two cycles of cisplatin plus etoposide. TRT was initiated with the 4th cycle of 
chemotherapy, although the initial treatment volume (e.g., lung volume receiving 40 Gy) 
included the extent of disease at diagnosis. The TRT volume was reduced to include only the 
post-chemotherapy volume following 40 Gy. The MTD of BID RT was determined to be 45 Gy 
in 30 fractions over 3 weeks, while it was judged to be at least 70 Gy in 35 fractions over 7 
weeks for daily RT. The median survival for QD TRT was 29.8 months compared with 24 
months for BID TRT, and 36% of patients treated with high dose QD RT were alive 6 years 
after therapy compared with 20% for BID RT. Although the number of patients was small, a 
dose response was also suggested for patients receiving high dose QD TRT. A subsequent 
CALGB phase II study (C 39808) employed 70 Gy thoracic RT concurrent with carboplatin and 
etoposide following 2 cycles of induction paclitaxel and topotecan chemotherapy [9]. This 
Group-wide study confirmed the feasibility of delivering 70 Gy TRT. The overall toxic effects 
of therapy were comparable with other recent trials using more modest total doses of TRT, and 
the incidence of severe esophagitis appeared reduced compared with reports of accelerated TRT. 
Although a larger proportion of patients on C 39808 had weight loss > 5% prior to enrolling on 
study (33% versus 18%), outcomes were comparable to the accelerated TRT arm of INT 0096. 
Moreover, median survival on C 39808 was 31 months when the population was limited to 
patients with weight loss  < 5% prior to diagnosis. Two additional CALGB phase II trials 
employing 70 Gy TRT have completed accrual, further confirming the acceptance of this 
regimen. 
The Radiation Therapy Oncology Group (RTOG) has studied a concomitant boost (CB) strategy 
in LSCLC. Concomitant boost radiotherapy has been shown to improve local tumor control in 
head and neck squamous cell carcinoma compared with standard radiotherapy [10]. The 
concomitant boost regimen has been accepted in clinical practice for head and neck cancer, 
which is demonstrated in part by rapid accrual to recent studies combining concomitant boost 
radiotherapy with chemotherapy (RTOG 0129 and RTOG 0522). This approach allows 
acceleration of TRT but only requires hyperfractionated TRT during part of the treatment course. 
Moreover, BID large field TRT can be avoided. A phase I trial has been completed assessing 
the MTD for concomitant boost TRT in LSCLC (R 9712). TRT was initiated with the first of 4 
cycles of PE chemotherapy. Accelerated TRT, 61.2 Gy in 34 fractions of 1.8 Gy/Fx in 5 weeks, 
with BID TRT during the final 9 treatment days, was determined to be the maximum tolerated 
dose (MTD) [11]. A subsequent phase II study, RTOG 0239, employs the 61.2 Gy concomitant 
boost regimen and recently completed accrual [12]. 
The efficacy of radiotherapy can be predicted by calculating the biologic effective dose (BED) 
[13]. The BED reflects the tumor type (doubling time), dose per fraction, nominal total dose and 
may also take into account the time to complete therapy. In comparison to the accelerated 45 Gy 
BID regimen studied in INT 0096, both the CALGB TRT regimen of 70 Gy QD and the RTOG 
concomitant boost approach yield substantially higher BEDs. For example, assuming a potential 
tumor doubling time of 5 days, the predicted increase in BED would range from 1.3 to 1.6 (e.g., 
30% to 60% increase in efficacy) for the CALGB and RTOG experimental regimens compared 
with 45 Gy BID. 

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Update #14 
 
 
Predicted Biologic Effective Dose (BED) of Thorac ic Rad iotherap y Regimens 
 
TRT Regimen 
Nominal Dose 
BED 
BED -Time 
Relative BED 
INT 0096: 
45 Gy (1.5 Gy BID/3 weeks) 
45 Gy 
52 
43 
1.0 
CALGB: 
70 Gy (2.0 QD / 7 weeks) 
70 Gy 
84 
63 
1.4 – 1.6 
RTOG:  
61.2 Gy (1.8 Gy CB /5 weeks) 
61.2 Gy 
72 
57 
1.3 – 1.4 
 
Given the impact of intensified local therapy seen in INT 0096, evaluation of TRT regimens that 
have the potential to further enhance local tumor control and survival is warranted. Importantly, 
the experimental regimens may be better tolerated and more practical to deliver than the 45 Gy 
BID regimen. A positive outcome, reflecting an enhanced therapeutic ratio, should result in 
widespread acceptance in clinical practice.  
1.2 
Timing of Radiotherapy  
The optimal timing of TRT relative to chemotherapy remains controversial. CALGB 8083 
randomly assigned patients to receive initial RT plus chemotherapy, delayed RT plus 
chemotherapy, or chemotherapy alone [14]. Chemotherapy consisted of cyclophosphamide, 
etoposide, and vincristine, with doxorubicin substituting for etoposide during later cycles. RT, 
50 Gy in five weeks, was administered with the 1st cycle (early) or 4th cycle (delayed) of 
chemotherapy. Mature results showed that survival with chemotherapy alone was inferior to 
both TRT arms, and the difference was statistically significant for delayed TRT (p=.002) and 
approached significance for early TRT (p=.082). No significant difference was observed 
between early and delayed RT, although there was a trend favoring delayed TRT (p=0.14). 
Conversely, a phase III trial from the National Cancer Institute of Canada (NCIC) demonstrated 
a benefit for initiating RT, 40 Gy in 3 weeks, with the 2nd chemotherapy cycle compared with 
the 6th cycle of chemotherapy [15]. Five-year survival was 20% in the early TRT cohort 
compared with 11% in the late TRT arm, and the difference was ascribed to a reduction in brain 
metastases, as local tumor control did not differ between arms. Additional studies have 
attempted to address the timing of TRT, including a trial from Japan comparing 45 Gy BID TRT 
during the first cycle of chemotherapy with the same TRT regimen administered following the 
completion of chemotherapy [16]. Median survival was 27 months with early (concurrent) TRT 
and 20 months with late (sequential) TRT, and the difference approached statistical significance. 
Recent meta-analyses have been published addressing this issue [17, 18]. While definitive 
conclusions cannot be reached, there is general consensus that the early initiation of TRT (e.g., 
cycle 1-3) may be beneficial, particularly in the context of intensive TRT.  
Given that the available evidence supports administration of thoracic radiotherapy with either 
the first or second cycle of systemic chemotherapy, the study was amended on September 15, 
2009. Investigators now choose when radiotherapy will start at the time of patient registration. 
This will allow additional time for investigators to perform sophisticated radiotherapy treatment 
planning in select patients without delaying the administration of chemotherapy. The timing of 
radiotherapy delivery (e.g. cycle 1 vs cycle 2) will be incorporated as a stratification factor. 
Additionally, as of February 20, 2013, patients will be allowed to receive one cycle of 
chemotherapy prior to registering on CALGB 30610. These patients will then receive the 
radiotherapy during their second cycle of chemotherapy (their first cycle of protocol therapy). 

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Update #14 
1.3 
Chemotherapy  
SCLC is exquisitely sensitive to systemic chemotherapy with high overall response rates. The 
combination of cisplatin and etoposide (PE) became standard front-line therapy in the 1980s 
given its clinical activity and tolerability in combination with concurrent thoracic irradiation. PE 
proved to be at least equivalent to previous combinations including cyclophosphamide, 
doxorubicin, and vincristine [19, 20]. Recent attempts to find more efficacious regimens by 
either adding or substituting agents have been disappointing. A phase III CALGB trial compared 
paclitaxel/etoposide/cisplatin (PET) with PE as first-line therapy for extensive SCLC [21]. 
Median survival was similar in both arms (5.9 versus 6 months), but toxic deaths increased from 
2.4% with PE to 6.5% with PET. The RTOG conducted a phase II study of PET chemotherapy 
in LSCLC. TRT, 45 Gy BID, was given concurrent with the first of 4 cycles of PE. While the 
regimen was active, the authors of the study concluded that the addition of paclitaxel was 
unlikely to improve survival in LSCLC [22]. The topoisomerase-I inhibitors, topotecan and 
irinotecan, are active agents against SCLC. Topotecan has been studied in combination with 
paclitaxel in both extensive and limited SCLC, but phase II trials did not suggest improved 
outcomes that would warrant study in a phase III setting [23]. In contrast, irinotecan plus 
cisplatin (IP) was superior to PE in a phase III study for extensive SCLC conducted by the 
Japanese Cooperative Oncology Group [24]. Confirmatory trials were subsequently designed in 
North America comparing PE to IP. The preliminary results of the initial confirmatory study 
were recently reported and there was no statistically significant difference in median time to 
progression, median survival or 1-year survival between the EP and IP regimens [25]. A second 
phase III trial testing IP vs PE, coordinated by the Southwest Oncology Group, is ongoing, 
although the results may not be available in the near future. At this time, there is not an obvious 
hypothesis regarding the integration of novel systemic therapy that would merit testing in a 
phase III setting. Importantly, it is necessary to define an optimal TRT regimen for the design 
of future studies that may test the merit of novel cytotoxic agents and molecular targeted agents. 
1.4 
High Dose Thoracic Radiotherapy Concurrent with Cycle 1 Chemotherapy  
RTOG 0241/CALGB 30202 is a recent experience administering high dose QD TRT during the 
initial cycle of chemotherapy in LSCLC [26]. This phase I study evaluated 70 Gy TRT in 
combination with cisplatin (60 mg/m2 day 1) and escalating doses of irinotecan. As noted in the 
table below, 2 dose limiting toxicities have been observed out of 15 patients assigned to receive 
70 Gy TRT; one grade 4 diarrhea and one grade 4 esophageal spasm. 
Although TRT was not administered until the 4th cycle of chemotherapy in CALGB 8837, the 
initial 40 Gy was delivered to the pre-chemotherapy thoracic tumor volume as measured on the 
CT scan obtained at the time of trial entry. Thus, an increased volume of functioning lung was 
irradiated on this trial compared with an approach of immediate chemoradiotherapy. Despite 
treating the pre-chemotherapy lung volume to 40 Gy, grade 3+ pulmonary toxicity was not 
encountered. 
Prospective trials of locally advanced non-small cell lung cancer provide substantial additional 
experience integrating high dose QD TRT with cycle 1 chemotherapy. TRT doses ranging 
between 61 Gy to 74 Gy given in 6.5 to 7.5 weeks have been administered with various 
chemotherapy regimens (table). The proposed study will mandate early interim analyses of both 
experimental treatment arms for assessment of treatment related toxic effects of therapy. 

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Update #14 
Selected Lung Cancer Trials: High Dose Daily Thoracic RT Concurrent with Cycle 1 
Chemotherapy 
Study 
n 
Dose/ # 
fractions 
Chemotherapy 
Toxic Effects 
RTOG 0241/ 
CALGB 30202 (26) 
(phase I LSCLC) 
15 
70 Gy/35 fx 
Cisplatin + 
Irinotecan 
Gr 5 (any) 
0% 
Gr 3/4 esph 
14%/7% 
Gr 3/4 dysp 
7%/0% 
RTOG 0117 (27) 
(phase I/II NSCLC) 
39* 
74 Gy/37 fx 
Carboplatin + 
Paclitaxel 
Gr 5 (any) 
5% 
Gr 3/4 esph 
15%/0% 
Gr 3/4 dysp 
5%/0% 
CALGB 30407 (28) 
(phase II NSCLC) 
26* 
70 Gy /35 fx 
Pemetrexed + 
Carboplatin 
Gr 5 (any) 
4% 
Gr 3/4 esph 
15%/0% 
Gr 3/4 dysp 
4%/4% 
CALGB 39801 (29) 
(phase III NSCLC) 
121 
66 Gy/ 33 fx 
Carboplatin + 
Paclitaxel 
Gr 5 (any) 
1% 
Gr.3/4 esph 
29%/1% 
Gr 3/4 dysp 
9%/2% 
RTOG 9410 (30) 
(phase III NSCLC) 
201 
63 Gy/34 fx 
Cisplatin + 
Vinblastine 
Gr 5 (any) 
2% 
Gr 3/4 esph 
25% 
Gr 3/4 dysp 
11% 
SWOG 9504 (31) 
(phase II NSCLC) 
83 
61 Gy/33 fx 
Cisplatin + 
Etoposide 
Gr 5 (any) 
4% 
Gr 3/4 esph 
12%/5% 
Gr 3/4 dysp 
5%/0% 
SWOG 0023 (32) 
(phase III NSCLC) 
473 
61 Gy/ 33 fx 
Cisplatin + 
Etoposide 
Gr 5 (any) 
3% 
Gr 3/4 esph 
14%/1% 
Gr 3/4 dysp 
3%/1% 
NSCLC = non-small cell lung cancer, Gr = grade, esph = esophagitis, dysp= dyspnea 
1.5 
Summary 
In summary, defining an optimal TRT regimen in LSCLC remains critical and will have a major 
impact on clinical practice. Intergroup study 0096 clearly established that improving the efficacy 
of thoracic radiotherapy can significantly impact survival in patients with LSCLC. Given the 
reluctance for practitioners to adopt 45 GY BID TRT, the validity of this regimen needs to be 
assessed in the context of TRT regimens that have higher predicted biologic efficacy and may 
have improved tolerability and acceptance. Superior outcomes on an experimental arm would 
lead to establishing a change in the standard of care for patients with LSCLC. Conversely, if the 
best outcomes were observed with accelerated 45 Gy BID TRT, then the results of this study 
would provide convincing and definitive evidence for practitioners to adopt this regimen. 
As of December 15, 2012, this trial was updated to include only 2 arms. The Alliance Data 
Safety and Monitoring Board (DSMB) reviewed adverse events for CALGB 30610 on June 29, 
2012. At that time the trial had reached sufficient accrual to trigger a decision regarding dropping 
one of the experimental arms. Toxicity in the 2 arms was found to be similar in the review, and 
the DSMB unanimously recommended that the Respiratory Committee decide which arm should 
continue in conjunction with CTEP. The Alliance Respiratory Committee subsequently 
reviewed the toxicity data and it was noted that while overall toxicity was similar, three on-study 
deaths (4.5%) were observed in arm C compared with no on-study deaths in arm B. Based on 
this review and the study mandate to eliminate one treatment arm, the Alliance Respiratory 

CALGB 30610 
Version Date 08/02/18 
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Update #14 
Committee proposed dropping arm C.  This decision was supported after review and discussion 
with CTEP representatives. 
As of September 15, 2014, the protocol was amended to allow substitution of carboplatin for 
cisplatin at the discretion of the treating physician, and the choice of chemotherapy will be used 
as a stratification factor. It has become clear during the past several years that carboplatin and 
etoposide chemotherapy is a commonly used regimen for patients with limited small cell lung 
cancer, and several investigators have requested that a carboplatin based regimen be allowed. 
Though the choice of chemotherapy has been widely discussed, there is not clear data that 
supports the use of cisplatin over carboplatin in small cell lung cancer. A study randomizing 
patients with small cell lung cancer to receive either cisplatin or carboplatin (with etoposide), 
conducted by the Hellenic Cooperative Oncology Group, did not demonstrate a difference in 
response rates or survival with either regimen (99). Moreover, phase II CALGB studies 
employing a carboplatin and etoposide backbone concurrent  with high dose (7000 cGy ) 
thoracic radiotherapy have accrued well. 
1.6 
Inclusion of Women and Minorities 
Women and minorities will be eligible for this study without alteration in eligibility criteria. 
There is currently no evidence to suggest that differences in response to treatment exist between 
groups on the basis of gender or race. Exploratory analyses will be conducted using Cox's 
proportional hazards model to determine whether treatment differences in survival are consistent 
across men and women, and are also consistent among races. 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
To determine whether administering high dose thoracic radiotherapy, 70 Gy (2 Gy once-daily 
over 7 weeks) or 61.2 Gy (1.8 Gy once-daily for 16 days followed by 1.8 Gy twice-daily for 9 
days), will improve median and 2-year survival compared with 45 Gy (1.5 Gy twice-daily over 
3 weeks) in patients with limited stage small cell lung cancer. 
2.2 
Secondary Objectives 
2.2.1 To compare treatment related toxic effects of thoracic radiotherapy regimens in patients with 
limited stage small cell lung cancer. 
2.2.2 To compare response rates, failure-free survival and toxicity of thoracic radiotherapy 
regimens in patients with limited stage small cell lung cancer. 
2.2.3 To compare rates of local relapse, distant metastases and brain metastases with these 
regimens. 
2.2.4 To compare patients’ quality of life between these treatment regimens in terms of their 
physical symptoms, physical functioning and psychological state. 
2.2.5 To describe the patterns of use of thoracic intensity modulated radiation therapy (IMRT) in 
patients with limited stage small cell lung cancer. 
2.2.6 To examine blood-based biomarkers of response and resistance to cisplatin (or carboplatin) 
and etoposide. 
2.2.7 To evaluate the correspondence between increases in plasma ProGRP concentrations and 
disease progression/recurrence. 

CALGB 30610 
Version Date 08/02/18 
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Update #14 
2.2.8 To evaluate the potential for plasma ProGRP concentrations at baseline, after each cycle of 
chemotherapy and at first evaluation following completion of chemotherapy to predict PFS 
and OS. 
2.2.9 To evaluate the correspondence between longitudinal decreases in plasma ProGRP 
concentrations and clinical response. 
3.0 
ON-STUDY GUIDELINES 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. All 
relevant medical and other considerations should be taken into account when deciding whether this 
protocol is appropriate for a particular patient. Physicians should consider the risks and benefits of 
any therapy, and therefore only enroll patients for whom this treatment is appropriate. Although 
they will not be considered formal eligibility (exclusion) criteria, physicians should recognize that 
the following may seriously increase the risk to the patient entering this protocol: 
• 
Psychiatric illness which would prevent the patient from giving informed consent. 
• 
Medical condition such as uncontrolled infection (including HIV), uncontrolled diabetes 
mellitus or cardiac disease which, in the opinion of the treating physician, would make this 
protocol unreasonably hazardous for the patient. 
• 
Patients with a “currently active” second malignancy other than non-melanoma skin cancers 
and carcinoma in situ of the cervix. Patients are not considered to have a “currently active” 
second malignancy if they have completed therapy and have no evidence of recurrence for at 
least 5 years. 
• 
Women and men of reproductive potential should agree to use an appropriate method of birth 
control throughout their participation in this study due to the teratogenic potential of the therapy 
utilized in this trial. Appropriate methods of birth control include abstinence, oral 
contraceptives, implantable hormonal contraceptives (Norplant), or double barrier method 
(diaphragm plus condom). 
4.0 
ELIGIBILITY CRITERIA 
All questions regarding eligibility criteria should be directed to 
 
 Please note that the Study Chair cannot grant waivers to eligiblity requirements. 
4.1 
Documentation of Disease 
4.1.1 Histologically or cytologically documented small cell lung cancer 
4.1.2 Limited stage disease patients, with disease restricted to one hemithorax with regional 
lymph node metastases, including ipsilateral hilar, ipsilateral and contralateral mediastinal, 
and ipsilateral supraclavicular lymph nodes.  
• 
Patients with disease involvement of the contralateral hilar or supraclavicular lymph 
nodes are not eligible. 
• 
Patients with pleural effusions that are visible on plain chest radiographs, whether 
cytologically positive or not, are not eligible unless they have a negative thoracentesis. 
• 
Patients with cytologically positive pleural or pericardial fluid, regardless of the 
appearance on plain x-ray, are not eligible. 

CALGB 30610 
Version Date 08/02/18 
15 
Update #14 
4.2 
Measurable Disease 
Patients must have measurable disease, which includes lesions that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as ≥ 2 cm with conventional 
techniques or as ≥ 1 cm with spiral CT scan. 
4.3 
Prior Treatment 
• 
Patients may have received one and only one cycle of chemotherapy prior to enrolling on 
CALGB 30610, which must have included carboplatin or cisplatin and etoposide. If a patient 
has had one cycle of cisplatin (or carboplatin)/etoposide prior to registration, the patient 
must have had all of the prior to registration tests outlined in Section 7.0 prior to starting 
their first cycle of chemotherapy. Additionally, these patients also must have met all of the 
eligibility criteria in Section 4.0 prior to receiving the first cycle of chemotherapy. Failing 
to do all of the above will make the patient NOT eligible for CALGB 30610. 
• 
No prior radiotherapy or chemotherapy (except for the chemotherapy described in the bullet 
above) for SCLC 
• 
No prior mediastinal or thoracic radiotherapy  
• 
Patients with complete surgical resection of disease are not eligible 
4.4 
Age Requirement 
Age ≥ 18 years of age   
4.5 
ECOG Performance Status  
PS = 0-2 
4.6 
Non-pregnant and non-nursing 
No patients that are known to be pregnant or nursing. 
4.7 
Required Initial Laboratory Values 
Granulocytes 
≥ 1,500/µl 
Platelet Count 
≥ 100,000/µl 
Total Bilirubin 
≤ 1.5 x ULN 
AST (SGOT) 
≤ 2.0 x ULN 
Serum Creatinine 
  OR 
Calculated Creatinine Clearance 
≤ 1.5 x ULN 
 
≥ 70 ml/min 
5.0 
PATIENT REGISTRATION 
5.1 
CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
(
iam). In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e. clinical site staff 
requiring write access to OPEN, RAVE, or TRIAD or acting as a primary site contact) must 
complete their annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) 
 Documentation requirements per 
registration type are outlined in the table below. 

CALGB 30610 
Version Date 08/02/18 
16 
Update #14 
Documentat ion Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
< 
 >. For questions, please contact 
the RCR Help Desk by email at <
 >. 
5.2 
CTSU Site Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory 
Office before they can be approved to enroll patients.  Assignment of site registration status in 
the CTSU Regulatory Support System (RSS) uses extensive data to make a determination of 
whether a site has fulfilled all regulatory criteria including but not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 

CALGB 30610 
Version Date 08/02/18 
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Update #14 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process. Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRB Manager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
5.2.1 Downloading Site Registration Documents 
Site registration forms may be downloaded from the CALGB 30610 protocol page located 
on the CTSU members’ website.   
• 
Go to 
and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the Alliance link to expand, then select trial protocol (CALGB 30610) 
• 
Click on LPO Documents, select the Site Registration documents link, and download 
and complete the forms provided.   
5.2.2 Requirements for CALGB 30610 Site Registration: 
• 
CTSU Transmittal Sheet (optional) 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, 
an IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted ) 
• 
CTSU RT Facilities Inventory Form 
NOTE:  Per NCI policy all institutions that participate on protocols with a radiation therapy 
component must participate in the Radiological Physics Center (RPC) monitoring program.  
If this form has been previously submitted to CTSU it does not need to be resubmitted unless 
updates have occurred at the RT facility. 
5.2.3 Checking Your Site’s Registration Status 
You can verify your site registration status on the members’ section of the CTSU website.   
• 
Go to 
and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Regulatory tab at the top of your screen 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 

CALGB 30610 
Version Date 08/02/18 
18 
Update #14 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated networks. 
5.2.4 Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS.  
Regulatory Submission Portal: 
  (members’ area)  Regulatory Tab 
Regulatory Submission  
When applicable, original documents should be mailed to: 
 
 
 
  
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 
in order to receive further instruction and 
support. 
5.3 
Patient Registration Requirements 
• 
Informed Consent: The patient must be aware of the neoplastic nature of his/her disease 
and willingly consent after being informed of the procedure to be followed, the experimental 
nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts. If 
local guidelines and regulations permit the enrollment of persons not able to fulfill all of 
these requirements, the registering institution is responsible for complying with all local 
regulations and requirements for obtaining consent from these persons. Modification of the 
model consent form would be required for this purpose Human protection committee 
approval of this protocol and a consent form is required. 
• 
HIPAA requirements 
• 
At registration, the choice of chemotherapy (carboplatin vs. cisplatin) must be entered into 
the OPEN registration system. Following registration, patients must continue on the 
chemotherapy chosen at randomization. 
 
For patients registered to this trial after one cycle of non-protocol therapy, registration to 
CALGB 30610 must take place within 7-21 days after the start of the non-protocol therapy. 
5.4 
Patient Registration/Randomization Procedures 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN).  
OPEN is a web-based registration system available on a 24/7 basis. To access OPEN, the site 
user must have an active CTEP-IAM account (check at < 
 >) and 
a 'Registrar' role on either the LPO or participating organization roster.  Registrars must hold a 
minimum of an AP registration type. 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient in 
the Rave database. OPEN can be accessed at 
or from the OPEN tab on the 
CTSU members’ side of the website at 
To assign an IVR or NPIVR as the 
treating, crediting, consenting, drug shipment (IVR only), or investigator receiving a transfer in 
OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR the IRB number used on 
the site’s IRB approval. 

CALGB 30610 
Version Date 08/02/18 
19 
Update #14 
Prior to accessing OPEN, site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
Note: The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. Please print this confirmation for your records. 
To receive site reimbursement for specific tests and/or bio-specimen submissions, completion 
dates must be entered in the OPEN Funding screen post registration. Please refer to the protocol-
specific funding page on the CTSU members’ website for additional information. Timely entry 
of completion dates is recommended as this will trigger site reimbursement. 
Further instructional information is provided on the OPEN tab of the CTSU members’ side of 
the CTSU website at 
or at 
For any additional 
questions contact the CTSU Help Desk at 1
 
5.5 
Stratification 
• 
Gender: male vs. female 
• 
Weight loss (6 months prior to study entry): ≤5% of body weight vs >5% of body weight 
• 
ECOG Performance Status: 0 vs 1 vs 2 
• 
Planned Radiotherapy Technique: IMRT vs. 3D conformal 
• 
Radiotherapy Start Time (choose 1, 2 or 3):  
For patients receiving 1 cycle of non-protocol therapy prior to registration: 
1) Start radiotherapy at the first cycle of protocol chemotherapy, after one cycle of prior 
non-protocol chemotherapy 
For patients starting treatment right after registration (no non-protocol therapy):  
2) Start radiotherapy at the first cycle of protocol chemotherapy, without prior non-
protocol chemotherapy 
3) Start radiotherapy at the second cycle of protocol chemotherapy, without prior non-
protocol chemotherapy 
• 
Chemotherapy backbone: carboplatin vs. cisplatin 
5.6 
Registration to Companion Studies 
There are two substudies within CALGB 30610. The correlative science study must be offered 
to all patients enrolled on CALGB 30610; the quality of life study must be offered to all English-
speaking patients enrolled on CALGB 30610 (although patients may opt to not participate). 
These substudies do not require separate IRB approval. Note: The quality of life substudy, 
CALGB 70702, closed to accrual on August 30, 2017. Therefore, no further patients will 
be enrolled on the quality of life substudy. 
The substudies included within CALGB 30610 are: 
• 
CALGB 150712: Correlative Science Studies in CALGB 30610 (Section 10.1) 
If a patient answers “yes” to “My specimen(s) may be used for the research described above” 
question #1 in the model consent, they have consented to participate in the substudy 
described in Section 10.1. The patient should be registered to CALGB 150712 at the same 
time they are registered to the treatment trial (30610). Samples should be submitted per 
Section 6.3. 
• 
CALGB 70702: Quality of Life Studies in CALGB 30610 (Section 10.2) 

CALGB 30610 
Version Date 08/02/18 
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Update #14 
As of August 30, 2017, accrual to CALGB 70702 has been met. Therefore, after August 
30, 2017, not further patients will be registered to CALGB 70702. 
Only English-speaking patients may participate in the QOL companion. If a patient answers 
“yes” to “I choose to take part in the Quality of Life study and agree to complete the Quality 
of Life questionnaires” question #5 in the model consent, they have consented to participate 
in the substudy described in Section 10.2. The patient should be registered to CALGB 70702 
at the same time they are registered to the treatment trial (CALGB 30610). 
Note: Patients that are registered on CALGB 30610 after they receive one cycle of chemotherapy 
are NOT eligible for the companion studies. 
6.0 
DATA AND SAMPLE SUBMISSION 
6.1 
Data Submission 
As of March 15, 2018, this study uses Medidata Rave® for remote data capture (RDC) of all 
data collection. If necessary, data originally submitted to the SDC electronically can be amended 
via the Medidata Rave® system 
The Rave system can be accessed through the iMedidata portal at 
 
For additional information regarding account setup or training, please visit the training section 
of the Alliance website. Forms should be submitted in compliance with the table below, and a 
copy of the All Forms Packet can be downloaded from the Alliance and CTSU websites. 
Site personnel with Rave roles assigned on the appropriate roster may receive a study invitation 
e-mail from iMedidata. To accept the invitation, site users must log into the Select Login 
(
) using their CTEP-IAM user name and password, and 
click on the “accept” link in the upper right-corner of the iMedidata page. Please note, site users 
will not be able to access the study in Rave until all required Medidata and study specific 
trainings are completed. Trainings will be in the form of electronic learnings (eLearnings), and 
can be accessed by clicking on the link in the upper right pane of the iMedidata screen. Personnel 
who did not receive an invitation should contact the Alliance Service Center. 
Users who have not previously activated their iMedidata/Rave account at the time of an initial 
site registration approval for a study in RSS will also receive a separate invitation from 
iMedidata to activate their account. Account activation instructions are located on the CTSU 
website’s Rave tab under the Rave Resource Materials heading (Medidata Account Activation 
and Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the 
CTSU members’ website under the Rave tab at 
or by contacting the 
CTSU Help Desk at 
 

CALGB 30610 
Version Date 08/02/18 
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Update #14 
For 
the 
most 
up-to-date 
data 
forms, 
please 
visit 
the 
Alliance 
Web 
site 
at 
 
. 
Form* 
Submission Schedule 
C-1727 
30610 On-Study Form 
Within one month of registration 
C-660 
Solid Tumor Measurement Form 
Report 
CT scan report (chest and abdomen) 
Report 
Bone or PET scan report 
Report 
MRI or CT report (brain) 
 
Pathological/cytological documentation of 
SCLC 
 
 
 
 
 
RT Quality Assurance Documentation 
See Radiation Therapy section 
 
 
 
 
 
 
 
QOL Data 
For patients consenting to 70702: see Data 
Submission for QOL section 
 
 
 
C-1728 
30610 Treatment and Response Form 
Every 2 cycles during protocol treatment 
(including the non-protocol cycle of chemo, 
if applicable). 
C-660  
Solid Tumor Evaluation Form 
Report 
CT scan reports 
 
 
 
C-1729 
Adverse Event Form 
Every cycle during protocol treatment 
 
 
 
C-1742 
Confirmation of Lost to Follow-up Form 
Follow form directions. 
 
 
 
 
 
After the end of protocol treatment submit 
every 3 months for 2 years, then every 6 
months for 3 years, then every year for an 
additional 5 years until progression. After 
progression submit only the C-1730 every 6 
months to report survival, new malignancy, 
and non-protocol treatment data. Report new 
malignancy on the C-1001. 
 
 
C-1730 
Follow-up and Response Form 
C-660 
Solid Tumor Evaluation Form 
Report 
CT scan reports 
C-1001 
New Malignancy Form 
 
 
This study will use NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 for 
routine toxicity reporting on study forms. However, CTCAE version 5.0 will be used for serious AE 
reporting through CTEP-AERS as of April 1, 2018; see Section 16.0. 
* Use CALGB Remarks Addenda (C-260) if additional comments are necessary or additional writing 
space is needed. 
 

CALGB 30610 
Version Date 08/02/18 
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Update #14 
6.2 
Data Submission for QOL 
All participating institutions must ask patients for their consent to participate in the Quality of 
Life Studies in CALGB 30610 (CALGB 70702), although patient participation is optional. 
Patients registered to CALGB 30610 after they receive one cycle of chemotherapy will not 
participate in the QOL study. Rationale and methods for this study are described in Section 10.2. 
For patients who consent to participate, assessments will be collected at the following time 
points: 
Form 
Baseline 
Weekly 
during 
RT 
Week 
3* 
Week 
5* 
Week 
7* 
Week 
12* 
Week 
26* 
Week 
52* 
(Assessment No.) 
(#0) 
 
(#3) 
(#5) 
(#7) 
(#12) 
(#26) 
(#52) 
C-1732 
FACT-L  
X 
 
X 
X 
X 
X 
X 
X 
C-1734 
FACT Eating and 
Swallowing Subscales 
X 
 
X 
X 
X 
X 
X 
X 
C-1733 
ECOG Acute Esophagitis 
Scale 
X 
X 
X 
X 
X 
X 
X 
X 
C-1736 
Difficulty Swallowing 
X 
X 
X 
X 
X 
X 
X 
X 
C-458 
HADS 
X 
 
X 
X 
X 
X 
X 
X 
C-903 
EQ-5D 
X 
 
X 
X 
X 
X 
X 
X 
C-616 
Subjective Significance 
Questionnaire 
 
 
X 
X 
X 
X 
X 
X 
C-419 
QOL Assessment Form 
X 
 
X 
X 
X 
X 
X 
X 
C-1735 
Treatment Inconvenience 
 
 
X 
X 
X 
 
 
 
C-187 
Sociodemographic 
Characteristics 
X 
 
 
 
 
 
 
 
* 
The assessment should be done at 3, 5, 7, 12, 26 or 52 weeks after the start of radiation therapy. The 
assessment number entered on the forms should be the same as the week number of the assessment. 
6.3 
Specimen Submission for Correlative Studies 
All participating institutions must ask patients for their consent to participate in the correlative 
science studies in CALGB 30610 (CALGB 150712), although patient participation is optional. 
Patients registered to CALGB 30610 after receiving one cycle of chemotherapy will not 
participate in the correlative science substudy. Rationale and methods for the scientific 
components of these studies are described in Section 10.1. 
6.3.1 Plasma Collection for both Correlative Science Studies (see Section 10.1) 
For patients who consent to participate, 20 ml of whole blood (in two 10 ml purple top tubes) 
will be collected at the following time points:  
• 
Baseline (before treatment initiation) 
• 
Day 1 of Cycles 2, 3 and 4 (pre-chemotherapy), 
• 
At first follow-up after completion of all protocol treatment,  
• 
At each post-treatment follow-up visit (Follow-up is every 3 months for 2 years, then 
every 6 months for 3 years, and then yearly. Note: If follow-up is completed more often 
than required a plasma sample is preferred by is not required.) 
• 
At the time of recurrence. 

CALGB 30610 
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Update #14 
6.3.2 Plasma Sample Processing 
The purple top tubes should be kept on ice for no more than 30 minutes after venipuncture. 
Spin down the blood at 1500 x g for 10 minutes at room temperature. Collect plasma at the 
top of the tube with at least 0.5 cm distance from the buffy coat. Put 1.0 ml aliquots of 
plasma into 2 ml cryovials. Store aliquots at -80˚C until shipment. 
The Alliance strongly recommends the usage of 2 ml cryovials for storage of plasma 
specimens. Acceptable cryovials include: 
Company name 
Catalog number 
Nalgene 
03-337-7Y (through Fisher) 
NNI No.: 5012-0020 
Fisher brand 
05-669-57 (through Fisher) 
Corning 
03-374-21 (through Fisher) 
CLS430659 (through Sigma) 
Corning: 430488 
VWR 
16001-102 
Specimen registration and tracking 
USE OF THE ALLIANCE BIOSPECIMEN MANAGEMENT SYSTEM (BioMS) IS 
MANDATORY AND ALL SPECIMENS MUST BE LOGGED AND SHIPPED VIA THIS 
SYSTEM.  
BioMS is a web-based system for logging and tracking all biospecimens collected on Alliance 
trials. 
Authorized 
individuals 
may 
access 
BioMS 
at 
the 
following 
URL: 
using most standard web browsers (Safari, 
Firefox, Internet Explorer). For information on using the BioMS system, please refer to the 
‘Help’ links on the BioMS web page to access the on-line user manual, FAQs, and training 
videos. To report technical problems, such as login issues or application errors, please contact: 
For assistance in using the application or questions or problems related to 
specific specimen logging, please contact: 
 
After logging collected specimens in BioMS, the system will create a shipping manifest. This 
shipping manifest must be printed and placed in the shipment container with the specimens. 
Shipment of samples 
• 
All samples should be labeled with study number, patient ID number, patient initials, sample 
collection date and time, and be accompanied by the completed specimen submission 
shipping manifest which will be generated by BioMS.  
Note for CRA – The following PHI must be removed or blacked out for all specimens or 
reports: signature, name, date of birth, other identifying information, except initials and 
study identification number. 
• 
All samples should be shipped to the Alliance Biorepository at Ohio State. 
• 
Specimens may be sent to the Alliance Biorepository on Monday through Thursday for next 
day delivery. The Bank cannot receive specimens on Saturdays, Sundays or holidays. 
Do not send specimens the day before a holiday. 
• 
The institution is expected to pay the cost of mailing specimens and will be reimbursed 
through capitation fees set for each individual study. 
• 
Arrange for express courier pick-up through your usual institutional procedure. Ship 
specimens to the address below: 
 
 

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On the day that specimens are sent to the specimen bank, please contact the bank by phone or 
e-mail to notify what is being sent and when the shipment is expected to arrive. 
 

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7.0 
REQUIRED DATA 
Pre-Study Testing Intervals 
To be completed within 16 DAYS before registration: 
- 
All blood work 
- 
History and physical 
To be completed within 28 DAYS before registration: 
- 
Any X-ray, scan of any type or ultrasound which is utilized for tumor measurement per 
protocol. 
To be completed within 42 DAYS before registration: 
- 
Any baseline exams used for screening,  
- 
Any X-ray, scan of any type or ultrasound of uninvolved organs which is not utilized for 
tumor measurement. 
Patients registering to CALGB 30610 after 1 cycle of therapy must adhere to the “prior to 
registration” test requirements at the timepoints listed above, with the requirement that the test be 
done “before first cycle of chemotherapy” rather than “before registration.” If the tests and 
observations, laboratory studies and staging are not obtained within the timeframes specified, prior 
to the first cycle of therapy, patients will not be eligible to register to CALGB 30610. For patients 
receiving 1 cycle of non-protocol therapy prior to registering, that first cycle is considered “Cycle 
1” for reporting purposes. Once they register and start the chemoRT that will be considered Cycle 
2. 
Exception: It is acceptable to obtain the following tests prior to Cycle 2 to satisfy eligibility 
requirements for patients who have received Cycle 1 prior to registration: pulmonary function, 
LDH, Bili, LDH, AST, Cr, BUN, Mg, Na, Ca. 
 
 

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Prior to 
Registration 
 
Day 1 of Each 
Cycle* 
Time of 
Restaging  
(q 2 cycles) 
Post 
Treatment 
Follow up*** 
Tests & Observations 
 
 
 
 
Physical Examination 
X 
X 
 
X 
Pulse, Blood Pressure 
X 
X 
 
X 
Height 
X 
 
 
 
Weight†**/Body Surface Area 
X 
X 
 
X 
Performance Status 
X 
X 
 
X 
Tumor Measurements 
X 
 
X 
X 
Drug Toxicity Assessment 
 
X 
 
X 
Laboratory Studies 
 
 
 
 
CBC, Differential, Platelets 
X 
B 
 
 
Bili, LDH, AST, Cr, BUN, Mg, 
Na, Ca 
X 
X 
 
 
Pulmonary Function (DLCO, 
FEV-1, FVC) 
X 
 
 
D 
Pregnancy test in women of child-
bearing potential 
X 
 
 
 
Staging 
 
 
 
 
Spiral CT Scan of ChestA 
X 
 
X 
X 
Spiral CT Scan of AbdomenA 
X 
 
 
 
Bone or PET Scan 
X 
 
 
 
MRI (or CT) of Brain 
X 
 
C 
 
Companion (or sub) Studies 
 
 
 
 
QOL (70702) 
See Section 6.2 for further information. 
Correlative Studies (150712) 
See Section 6.3 for further information. 
* 
Pre-registration labs may be used for day 1 of cycle 1 tests if obtained within 14 days prior 
to day 1 of Cycle 1. For subsequent cycles labs may be obtained within 48 hours prior to day of 
treatment. Patients receiving treatment on a Monday may have labs obtained within 72 hours. 
** 
Weight must be recorded weekly during thoracic radiotherapy 
*** 
At least every 3 months for 2 years, then every 6 months for 3 years, then every year for 
an additional 5 years until disease progression. After progression, follow every 6 months for 
survival and new malignancy. 
† 
The dose of chemotherapy need not be changed unless the calculated dose changes by ≥ 
10%. 
A 
See Section 13.5.3 for CT instructions. Note that a CT scan made as part of the PET-CT is 
acceptable if it meets all the criteria in Section 13.5.3. Any CT scan that does not meet these 
requirements must be repeated. 
B 
Obtain on days 1 and 8 of each cycle. 
C 
Obtain MRI or CT of brain prior to initiating prophylactic cranial irradiation. 
D 
Obtain 6 and 12 months from the start of treatment, then as clinically indicated. 
 
For those patients who consent to participate in the substudies. 

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Update #14 
8.0 
TREATMENT PLAN 
Patients registered to CALGB 30610 prior to the start of cycle 1 protocol treatment will start therapy 
within 7 days of registration.  
Questions regarding treatment should be directed to the Alliance Study Chair. 
Protocol therapy will consist of 4 cycles of cisplatin and etoposide or carboplatin and etoposide 
chemotherapy administered every 21 days. Thoracic radiotherapy will begin either on the first day 
of the first cycle of chemotherapy OR on the first day of the second cycle of chemotherapy. 
Patients may be registered to CALGB 30610 following one cycle of chemotherapy. Patients must 
receive the second cycle of therapy following registration, on day 22-24, so that the patient adheres 
to a 3-week treatment cycle. Patients not able to be treated within 3 days of day 22 should not be 
registered to CALGB 30610. For patients registered to CALGB 30610 after 1 cycle of 
chemotherapy, the thoracic radiotherapy must begin with the second cycle of chemotherapy (the 
first cycle of protocol chemotherapy after the patient was registered). Additionally, the cycle of 
chemotherapy given prior to registration will be considered “cycle 1.” Therefore, patients registered 
following 1 cycle of chemotherapy will receive three cycles of therapy after registration. 
The original design was a randomized phase III trial including two experimental treatment arms 
(70 Gy once daily radiotherapy and 61.2 Gy concomitant boost radiotherapy) and a standard 
treatment arm (45 Gy twice daily radiotherapy). An interim analysis, conducted after accrual of a 
pre-determined number of patients, selected one experimental arm based upon a comparison of 
treatment related toxicity. The most toxic experimental arm, which was Arm C, was discontinued, 
and the trial now compares standard therapy to the selected experimental regimen. 
8.1 
Chemotherapy 
Patients will be treated with cisplatin and etoposide or carboplatin and etoposide chemotherapy 
as described below. Standard anti-emetic therapy including steroids such as dexamethasone and 
a 5-HT3 antagonist is recommended. The use of aprepitant should be considered. 
Cisplatin 80 mg/m2 by IV on day 1 of each 21-day cycle. Prior to each cisplatin treatment 
prehydrate with at least 1000 ml normal saline and use diuretics per institutional guidelines OR 
Carboplatin AUC 5 by IV on day 1 of each 21-day cycle 
Etoposide 100 mg/m2 by IV on days 1, 2, and 3 of each 21-day cycle. 
 
 

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8.2 
Radiation Therapy 
Questions regarding Radiation Therapy should be directed to 
preferably via e-mail. 
8.2.1 Required Benchmarks and Pre-approval of 3D Treatment Plans 
• 
CT-based conformal planning is required on this study. In accordance with current 
guidelines for use of IMRT in clinical trials (see
), IMRT may be 
used only if the degree of tumor motion is assessed and can be limited to 1.0 cm. If 
required to achieve this goal, techniques for managing or suppressing tumor motion 
shall be applied. 
 • Institutions that have been credentialed for participation in RTOG protocol 0617 using 
3D conformal techniques will be considered credentialed for use of 3D conformal 
techniques in this protocol as well. Likewise those institutions credentialed for use of 
IMRT in RTOG 0617 will be considered credentialed for use of IMRT in this study. A 
copy of the approval letter from RTOG should be submitted to QARC. Institutions using 
3D conformal techniques and not credentialed for RTOG 0617 must complete the 3D 
Conformal Benchmark. Those treating with IMRT and not credentialed for RTOG 0617 
must complete the IMRT Benchmark and IMRT Questionnaire. The benchmark 
material is available from the Quality Assurance Review Center (
) and 
must be submitted before patients on this protocol can be evaluated. The IMRT 
credentialing requirement may also be satisfied by successful irradiation of the RPC’s 
head and neck IMRT phantom.  Contact the RPC for information about their phantoms. 
If techniques are used to compensate for or limit respiratory motion, the QARC 
questionnaire on respiratory motion management will also be submitted. 
• 
Treatment plans must be reviewed and approved by QARC during the initial week of 
treatment. 
• 
Equipment 
- 
Modality: Use external beam radiation. 
- 
Geometry: The distance from the radiation source to the prescription point should 
not be less than 100 cm. 
- 
Energy: Use radiation of megavoltage quality, i.e., X-ray beams with a nominal 
energy of 4-18 MV. Co-60 treatment is not allowed for treatment on this protocol. 
- 
Calibration: All radiation units used for protocol therapy must have their 
calibration verified by the RPC. 
- 
Field Shaping - Field shaping shall be done with blocks, which are at least 5 HVL 
thick, or with multileaf collimation. 
8.2.2 Target Dose 
• 
Prescription Point: Dose is to be prescribed to an isodose line that encompasses the 
PTV and that satisfies the dose uniformity criteria in section 8.2.5. The minimum PTV 
dose must not fall below 95% of the prescription dose. The MTD will be quoted as the 
PTV minimum target dose. The maximum and minimum point doses (within the PTV) 
will be reported. 
• 
Dose Definition: Dose is to be specified in centigrays (cGy)-to-water. 
• 
Tissue Heterogeneity: All radiation doses will be calculated with inhomogeneity 
corrections that take into account the density differences within the irradiated volume 
(i.e., air in the lung and bone). 

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• 
Prescription Dose and Fractionation:  
Arm A:  45 Gy in 3 weeks  
Patients on Arm A will receive treatment 5 days per week, in twice daily fractions, 1.5 
Gy per fraction. The total dose will be 45 Gy in 30 fractions. There are no field 
reductions on this arm and a single PTV (PTV-1) will be used throughout the entire 
treatment. All fields must be treated daily and the entire PTV must be treated daily. The 
treatment plan will limit direct irradiation of the spinal cord during the afternoon 
treatment for the final 10 days of therapy. Radiation therapy (RT) commences on either 
day 1 of the first cycle of chemotherapy or day 1 of the 2nd cycle of chemotherapy. There 
will be a minimum of 6 hours between the morning and afternoon fractions. 
Arm B: 70 Gy in 7 weeks 
Patients on Arm B will receive treatment 5 days per week, in once daily fractions, 2 Gy 
per fraction. The total dose will be 70 Gy in 35 fractions. There will be a field reduction 
following 44 Gy. The initial 44 Gy will be directed towards PTV-1 and the subsequent 
26 Gy will be directed towards PTV-2. All fields must be treated daily and the entire 
PTV must be treated daily. Radiation therapy (RT) commences on either day 1 of the 
first cycle of chemotherapy or day 1 of the 2nd cycle of chemotherapy. A second 
simulation is allowed to determine PTV-2. 
Arm C: 61.2 Gy in 5 weeks (DISCONTINUED AS OF 03/10/13) 
Patients on Arm C will receive treatment 5 days per week, in once daily fractions during 
the initial 16 days of treatment and twice daily fractions during the final 9 days of 
treatment, 1.8 Gy per fraction. The total dose will be 61.2 Gy in 34 fractions. There will 
be a field reduction (i.e., PTV-2) for the afternoon treatment when twice-daily 
treatments begin, and the morning treatment during the final 5 days of therapy will also 
be directed towards PTV-2. Thus, the initial 20 morning treatments will be directed at 
the PTV-1 and the remaining 14 fractions (9 afternoon treatments and the final 5 
morning treatments) will encompass the PTV-2. The treatment plan will limit direct 
irradiation of the spinal cord during the afternoon treatment when 2 daily treatments are 
given. All fields must be treated daily and the entire PTV must be treated daily. 
Radiation therapy (RT) commences on either day 1 of the first cycle of chemotherapy 
or day 1 of he 2nd cycle of chemotherapy. A second simulation is allowed to determine 
PTV-2. There will be a minimum of 6 hours between the morning and afternoon 
fractions when 2 daily treatments are given. 
8.2.3 Treatment Technique 
• 
Conformal (Three Dimensional) Planning is required on this protocol. Both planar 
and non-coplanar field arrangements are acceptable. Fields should be chosen to 
minimize the dose to the normal tissues while encompassing the target volume. The 
treatment plan used for each patient will be based on an analysis of the volumetric dose 
including DVH analyses of the PTV and critical normal structures.  Each field is to be 
treated daily. 
• 
Intensity Modulated Radiation Therapy (IMRT):  IMRT is allowed as long as the 
participating institution is credentialed for use of IMRT in RTOG 0617 or has 
completed the IMRT Benchmark and IMRT Questionnaire. The credentialing 
requirement may also be satisfied by successful irradiation of the RPC’s head and neck 
IMRT phantom. If IMRT is used, the degree of tumor motion shall be assessed and shall 
be limited to 1.0 cm. If required to achieve this goal, techniques for managing or 
suppressing tumor motion shall be applied. Acceptable approaches include abdominal 

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Update #14 
compression, automatic breath-hold (i.e., Elekta ABC device) or a gating approach (e.g., 
Varian RPM system) or other technologies. Each institution must document both the 
method used for limiting motion as well as the efficacy of their approach. The motion 
management questionnaire shall be submitted. 
8.2.4 Localization, Simulation, and Immobilization 
• 
A volumetric treatment planning CT study will be required to define gross tumor 
volume (GTV), clinical target volume (CTV), and planning target volume (PTV)(see 
definitions below). Each patient will be positioned in an immobilization device in the 
treatment position on a flat table. Contiguous CT slices, having 3-5 mm thickness 
through the regions harboring gross tumor and grossly enlarged lymph nodes and 8-10 
mm thickness of the remaining regions are to be obtained starting from the level of the 
cricoid cartilage and extending inferiorly through the entire liver volume. The GTV, 
CTV, and PTV and normal organs will be outlined on all appropriate CT slices. 
• 
The initial treatment planning CT may be obtained either prior to the first cycle or 
second cycle of chemotherapy, depending on when thoracic radiotherapy is initiated. If 
the initial planning CT is obtained after chemotherapy has been initiated, all sites of 
disease involvement on the prechemotherapy diagnostic CT and /or PET-CT will be 
designated as GTV. However, treatment planning will take into account changes in 
tumor size and volume.   
• 
A second volumetric treatment planning CT study is allowed on Arm B (70 Gy QD) 
and Arm C (DISCONTINUED AS OF 03/10/13) of the study for defining PTV-2. This 
study should take place approximately one week prior to the initiation of PTV-2 to allow 
sufficient time for treatment planning. 
• 
Intravenous (IV) contrast during the planning CT is optional provided a diagnostic chest 
CT was done with contrast to delineate the major blood vessels. If not, IV contrast 
should be given during the planning CT. If contrast is used, the densities can be over-
ridden or the contrast scan must be registered to a non-contrast scan for planning 
purposes. 
• 
Optimal immobilization is critical for this protocol. Immobilization to assure 
reproducibility of the set up is necessary. 
• 
The use of four-dimensional radiation treatment planning is highly encouraged. 
Acceptable methods of accounting for tumor motion include: design of the PTV to cover 
the excursion of the lung primary cancer and nodes during breathing such as an ITV 
approach, a maximum intensity projection (MIP) approach, automatic breath-hold (i.e., 
Eleckta ABC device) or a gating approach (e.g., Varian RPM system). 
8.2.5 Treatment Planning/Target Volumes 
The nomenclature and definitions of ICRU Reports 50 and 62 shall be followed in this study. 
• 
Gross Target Volume (GTV) is the volume occupied by visible or palpable disease. 
This generally includes sites seen on CT/MRI scan, FDG-PET imaging or biopsy 
positive sites. 
• 
Clinical Target Volume (CTV) is the GTV plus any sites that warrant irradiation 
because of potential occult tumor involvement. 
• 
Planning Target Volume (PTV) is the CTV plus a margin added in order to 
compensate for variability in treatment setup, breathing, or motion during treatment. 
PTV is the volume used for treatment planning. 

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Definition of the GTV: The primary tumor and clinically positive lymph nodes seen 
either on the pretreatment CT (> 1 cm short axis diameter) or pretreatment PET scan (SUV 
> 3) will constitute the GTV. This volume(s) may be disjointed. The ITV includes the 
envelope that encompasses the tumor motion for a complete respiratory cycle. In Arm B and 
Arm C (DISCONTINUED AS OF 03/10/13) the volume of the GTV may be revised to 
determine CTV-2 and PTV-2, based on a second CT simulation performed approximately 
one week prior to the start of the boost field (see Section 8.2.2). 
Definition of the CTV: 
CTV-1 will include the GTV plus potential occult disease as defined below. 
• 
Potential occult disease: 
a. 
Ipsilateral hilum (i.e., level 10 lymph node station) 
Elective treatment of the mediastinum and supraclavicular fossae will not be done. 
CTV-2 = GTV for the purposes of this protocol. Revised volumes based on a second 
simulation may be used to determine CTV-2. 
Definition of the PTV: 
Free-breathing non-ITV approach (i.e., standard CT simulation without 4DCT or fusion of 
inhalation and exhalation scans): 
There are two components to the PTV expansion. The internal motion (IM margin) which 
should be at least 1 cm in the inferior-superior direction, and 0.5 cm in the axial plane and 
an additional set-up margin of 0.5 cm. Thus, the PTV-1 includes the CTV-1 plus a total 
margin of at least 1.5 cm to the superior-inferior dimensions and at least 1.0 cm in the axial 
plane and the PTV-2 includes the CTV-2 plus a total margin of at least 1.5 cm to the 
superior-inferior dimensions and at least 1.0 cm in the axial plane. 
Breath-hold or gating non-ITV approach: 
For breath-hold or gating approaches, the PTV margin should be at least 1 cm in the inferior-
superior direction and 0.5 cm in the axial plane. It is expected that daily imaging will be 
used for both breath-hold and gating techniques. 
ITV approach: 
If the ITV approach is used, then the PTV margin should account for setup uncertainties and 
may be individualized but should not be less than 1.0 cm. If daily imaging is used to align 
the vertebral bodies, then the margins for setup margins may be reduced to 0.5 cm. 
For institutions not using 4DCT, the use of fluoroscopy to determine the margin for motion 
in the inferior superior direction is encouraged. 
For institutions with gating technology, the use of respiratory gating is encouraged. 
Normal anatomy to be identified: The normal anatomy to be outlined on each CT image 
will include the lungs (right and left done separately), heart, skin, esophagus and spinal cord. 
The heart should be contoured from its base to apex, beginning at the CT slice where the 
ascending aorta originates. The esophagus should be contoured from the bottom of the 
cricoid to the gastroesophageal junction. The skin and spinal cord should be contoured on 
each CT slice. 
8.2.6 Critical Structures 
Normal tissue constraints shall be prioritized in the following order for treatment planning: 
1=spinal cord, 2=lungs, 3=esophagus, 4= heart 
• 
Spinal Cord: 

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Update #14 
Arm A 
The treatment plan will avoid (> 20%) direct irradiation of the spinal cord during the 
afternoon treatment for the final 10 days of therapy. The spinal cord dose limitation is 
the highest priority dose constraint and thus must be met irrespective of other 
constraints. Total “direct” plus “scatter” dose to the spinal cord must not exceed 41 Gy. 
Arm B 
The spinal cord dose limitation is the highest priority dose constraint and thus must be 
met irrespective of other constraints. Total “direct” plus “scatter” dose to the spinal cord 
must not exceed 50.5 Gy. 
Arm C (DISCONTINUED EFFECTIVE 03/10/13) 
The treatment plan will avoid (> 20%) direct irradiation of the spinal cord during the 
afternoon treatment for the final 9 days of therapy such that the spinal cord is not directly 
treated twice daily. The spinal cord dose limitation is the highest priority dose constraint 
and thus must be met irrespective of other constraints. Total “direct” plus “scatter” dose 
to the spinal cord must not exceed 50.5 Gy. 
• 
Lungs: The dose-volume constraint to the lungs is the second highest priority and must 
be met, except if it conflicts with the cord dose constraints. The volume of both lungs 
that receive more than 20 Gy (the V20) should not exceed 40 % of the total. Alternatively, 
the mean lung dose should optimally be  20 Gy. (By total lung volume we mean the 
total lung minus the CTV.) 
If either of these constraints is exceeded, several solutions can be entertained. 
• 
First, one might increase the weighting of AP / PA treatments by one and reduce the 
obliques. This can be done as long as the cord dose (above), which takes precedence, is 
not exceeded. 
• 
Second, one can reduce the CTV to the minimum range suggested above. 
• 
Third, one can try to reduce the PTV by using respiratory gating techniques. 
• 
If after all attempts to decrease the V20 to below 40%, the V20 value still exceeds this 
limit, the patient should still be treated to the dose and fractionation on the arm to which 
they were randomized. 
• 
Esophagus: The mean dose to the esophagus is optimally kept below 34 Gy. This is not 
an absolute requirement, but is strongly recommended unless other, more critical 
constraints force the situation. 
• 
Heart: The following limits are recommended: 60 Gy to <1/3, 45 Gy to <2/3, and 40 
Gy to <100% of the heart. 
8.2.7 Definitions of Deviations in Protocol Performance 
Prescription Dose 
• 
No Deviation: ≥ 99% of the PTV receives ≥ 93% of the prescribed dose, and a 
contiguous volume of no more than 2cc inside PTV exceeds 20% of the prescribed dose. 
• 
Minor Deviation: Deviations of this magnitude are not desirable, but are acceptable. 
Coverage that is equal to 93% of the prescribed dose and falls between 99% and 95% 
of the PTV, or a contiguous volume of no more than 2cc inside the PTV exceeds 20-
25% of the prescribed dose. 
• 
Major Deviation: Doses in this region are not acceptable. More than 1 cm3 of tissue 
outside the PTV receives ≥ 120% of the prescribed dose, or 93% of the prescribed dose 

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Update #14 
falls below 95% of the PTV, or a contiguous volume of no more than 2cc inside the 
PTV exceeds 25% of the prescribed dose. 
Volume 
• 
Minor Deviation: Margins less than specified, or field(s) 1-3 cm greater than specified. 
• 
Major Deviation: Fields transect tumor or specified target volume(s), or fields are more 
than 3 cm greater than specified. 
Critical Organ 
• 
Major Deviation: The maximum dose to the spinal cord exceeds the limits in section 
8.2.6. 
8.2.8 Quality Assurance Documentation: 
Digital Submission: 
Submission of treatment plans in digital format (either Dicom RT or RTOG format) is 
encouraged. Instructions for data submission are on the QARC Web site at 
Any 
items on the list below that are not part of the digital submission should be submitted in hard 
copy form. 
Note: Black and white copies of color data may be submitted, provided lines are clearly 
labeled and the copy is legible. Otherwise, only color copies will be accepted. 
• 
Within three days of the start of radiotherapy, the following data shall be submitted for 
on-treatment review. 
a. 
Copies of all diagnostic materials (including diagnostic CT) and surgical reports. 
b. 
Copies of treatment planning CT used in defining the target volumes. 
c. 
Copies of simulator films and /or digitally reconstructed radiographs (DRRs) for 
each field. The GTV, CTV, PTV should be drawn on the simulator films. 
d. 
Copies of verification (portal) films (or hard copy of real time portal images) for 
each field. 
e. 
Copies of worksheets and/or printouts used for calculations of monitor units. 
f. 
Color hard copy isodose distribution for the total composite dose plan in the axial, 
sagittal, and coronal planes, which includes the isocenter of the planning target 
volume. 
g. 
RT-1 or IMRT Dosimetry Summary Form. 
h. 
One set of orthogonal anterior/posterior and lateral films for isocenter localization 
for each group of concurrently treated beams. If portals being submitted contain 
an orthogonal set, this is sufficient. 
i. 
Beam's Eye Views (BEVs) for all fields and showing the PTV and critical 
structures. BEV hard copies must be in color to enable reviewers to identify 
structures. 
j. 
Dose volume histograms for the total treatment for the target volumes, lungs, heart, 
and spinal cord. If IMRT is used, a DVH shall also be submitted for a category of 
tissue called “unspecified tissue,” which is defined as tissue contained within the 
skin, but which is not otherwise identified by containment within any other 
structure. 
k. 
Documentation of an independent check of the calculated dose if IMRT is used. 
l. 
If IMRT is used for tumors in the thoracic region, a description of the steps taken 
to suppress/manage motion to achieve appropriate simulation. 

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Update #14 
• 
Within one week of the completion of radiotherapy, the following data shall be 
submitted. 
• 
Copies of additional simulation films and verification (portal) films for any field 
modifications made subsequent to the initial reporting of data for on-treatment 
review. 
• 
A "RT-1 or IMRT Dosimetry Summary" form if changes have been made 
subsequent to submission of on-treatment data. 
• 
The "RT-2 Radiotherapy Total Dose Record" form. 
• 
A copy of the patient's radiotherapy record including the prescription, and daily and 
cumulative doses to all required areas and reference points. 
• 
Copies of calculations performed subsequent to the submission of the on-treatment 
data. 
• 
Copies of isodoses. 
• 
All data should be forwarded to: 
 
  
 
 
 
 
• 
Questions regarding the completion of RT-1 and RT-2 data forms, dose calculations 
or documentation should be directed to: 
 
  
 
 
 
 
• 
Questions regarding the radiotherapy section of this protocol, including treatment 
interruptions, should be directed to: 
 
 
 
 
 
 
 
OR 
 
 
 
 
 
 
 
8.2.9 Prophylactic Cranial Irradiation 

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Update #14 
• 
Prophylactic cranial irradiation (PCI) should be offered to all patients with a complete 
tumor response (CR) or near complete response (very good PR) with only residual chest 
abnormalities of indeterminate nature following completion of combined modality 
therapy. This will be determined based on the re-staging studies obtained following all 
four cycles of chemotherapy and thoracic irradiation. PCI should start approximately 3-
6 weeks following the final cycle of chemotherapy. No concurrent chemotherapy is 
given with PCI. For patients with a response to therapy that is less than CR or very good 
PR, the use of PCI is at the investigator’s discretion. 
• 
Treatment should be delivered with megavoltage radiation. 
• 
The dose and fractionation scheme for PCI is 2500 cGy given in 250 cGy fractions. An 
RT-2 Form must be completed indicating the start and end date of treatment, fraction 
dose, number of fractions and total dose. This form should be mailed or faxed to QARC 
at the address in section 8.2.8. 
• 
The treatment field should encompass the entire cranial contents. The base of the field 
will extend from the supraorbital ridge, the lateral canthus of the orbit, through the tip 
of the mastoid process, which is 1.5-2 cm below the external auditory meatus, back to 
the C1-C2 vertebral interspace. 
9.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY 
If different percentages of dose reductions for a given drug are required because of two different 
types of toxicities, the greater percentage dose reduction should be employed. 
9.1 
Hematologic Toxicity 
Granulocyte or Platelet Counts for Day 1: Based on counts within 2 days of the start of each 
cycle, give the following: 
Granulocytes/µl 
 
Platelets/µl 
Cisplatin, Carboplatin and Etoposide 
≥ 1,500 
and 
≥ 100,000 
100% 
< 1,500 
and/or 
< 100,000 
0* 
* 
Hold protocol therapy; repeat counts twice weekly and reinstitute therapy at 100% when 
granulocytes ≥ 1,500/microliter and platelets ≥ 100,000/microliter. If counts do not reach 
these levels within 3 weeks of the next scheduled treatment, discontinue all protocol 
therapy. 
Neutropenia or Febrile Neutropenia: 
For nadir neutropenia in the absence of fever or with fever that is successfully treated by oral 
antibiotics, there will be no dose adjustment. Filgrastim, sargramostim, or pegfilgrastim are 
allowed for patients with neutropenia that delays day 1 chemotherapy by one week or more for 
cycles 3 and 4 (after the completion of radiation therapy). WBC growth factors may not be 
used during radiation therapy. Filgrastim, sargramostim, or pegfilgrastim may then be given 
after chemotherapy to prevent future treatment delays in subsequent cycles at the discretion of 
the treating physician (after the completion of radiation therapy). Any use of colony stimulating 
factors should be documented on the Remarks Addenda Form (C-260). 
For chemotherapy delays of more than 7 days on any subsequent cycle of treatment, both 
chemotherapy drugs should be dose-reduced by 25% for all subsequent cycles of chemotherapy. 
For neutropenic fever (ANC ≤ 500/microliter and temperature ≥ 100.5) requiring intravenous 
antibiotics, the doses of all chemotherapy drugs should be reduced by 25% for the next cycle 
and all subsequent cycles. 

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For grade 4 nadir thrombocytopenia (platelets ≤ 25,000), the dose of all chemotherapy drugs 
should be reduced by 25% from the previous dose for the next cycle and for all the subsequent 
cycles of chemotherapy.  
9.2 
Gastrointestinal Toxicity 
Nausea and Vomiting 
All patients should receive antiemetics to prevent nausea and vomiting. Specific antiemetic 
therapy is left to the discretion of the physician treating the patient (steroids and 5-HT3 
antagonists should be used). If vomiting is severe, consider hospital admission and/or use of 
aprepitant if possible. Do not modify dose. 
9.3 
Hepatic Toxicity 
Bilirubin 
Etoposide 
<1.5 x ULN 
100% 
1.5-3.0 x ULN 
50% 
>3.0 x ULN 
30% 
  
9.4 
Nephrotoxicity  
(based on measured or calculated creatinine clearance) 
Creatinine Clearance (ml/min) 
Cisplatin 
≥ 70 
100% 
70-50 
67% 
< 50 
0* 
* 
If serum creatinine clearance is < 50 ml/min on day 1 of the next cycle, delay the start of 
that cycle for up to 2 weeks (check creatinine at least weekly). If CrCl decrease persists 
beyond 2 weeks, omit cisplatin for that cycle. If CrCl does not recover to ≥ 50 ml/min after 
3 weeks, remove patient from protocol therapy. 
9.5 
Hypomagnesemia  
Hypomagnesemia is not an indication for stopping therapy. Oral or parenteral magnesium 
supplementation is indicated for serum magnesium levels ≤ 1.5 mEq/l. 
9.6 
Neurologic Toxicity 
Grade 
Cisplatin/Carboplatin 
0-1 
100% 
2 
75%* 
3 
0** 
* 
Patients with grade 2 neurotoxicity should recover to grade 1 or better prior to retreatment 
with this (75%) dose reduction. If grade 2 neurotoxicity recurs with 75%, drug will be given 
at 50% upon resolution of neurotoxicity to grade 0-1. If grade 2 neurotoxicity persists for 3 
weeks, remove the patient from protocol therapy (see section 14.2). 
** Discontinue drug for neurotoxicity  grade 3. 
9.7 
Ototoxicity 
Remove patient from therapy for ≥ grade 3 ototoxicity. 

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9.8 
Allergic Reactions 
Discontinue treatment promptly if ≥ grade 3 anaphylaxis develops. 
9.9 
Grade 3/4 Non-Hematologic Toxicity 
If a patient develops grade 3 or 4 non-hematologic toxicity not detailed above (excluding 
anorexia, fatigue, fever without grade 3/4 neutropenia, and alopecia), hold all therapy. Therapy 
can be restarted if the toxicity has resolved to ≤ grade 1 by the time of the next treatment. Doses 
of all chemotherapy should then be reduced by 25%. If therapy is held for more than 3 weeks, 
remove the patient from protocol therapy. 
9.10 
Radiotherapy Dose Modifications for In-field Non-Hematologic Toxicities 
Radiation treatment will be interrupted for grade 4 in-field toxicity and/or grade 4 neutropenia 
with fever. 
Aggressive supportive care is encouraged throughout the course of radiotherapy. If the patient 
is near completion of therapy, then every attempt should be made to complete treatment despite 
acute toxicity. Otherwise, treatment should be restarted when the accompanying toxicity 
declines to ≤ grade 2. 
If treatment is interrupted for more than 3 weeks due to non-hematologic toxicity, remove the 
patient from protocol treatment. 
Use the following treatment modification table for in-field non-hematologic toxicity: 
In-field 
CTCAE 
Toxicity 
Grade 
XRT 
Cisplatin/Carboplatin 
Etoposide 
Esophagus/pharynx  
(on day of 
treatment) 
4 
Hold treatment 
until ≤ grade 2 
Hold treatment until ≤ 
grade 2 
Hold treatment 
until 
≤ grade 2 
Esophagus/pharynx 
(on day of chemo) 
3 
No change  
Hold treatment until ≤ 
grade 2 
Hold treatment 
until 
≤ grade 2 
Esophagus/pharynx 
(on day of chemo) 
2 
No change 
No change 
No change 
Pulmonary 
4 
Discontinue 
Hold treatment until ≤ 
grade 2 
Hold treatment 
until 
≤ grade 2 
Pulmonary 
3 
Hold treatment 
until ≤ grade 2 
Hold treatment until ≤ 
grade 2 
Hold treatment 
until 
≤ grade 2 
Skin 
4 
Hold treatment 
until ≤ grade 2 
Hold treatment until ≤ 
grade 2 
Hold treatment 
until 
≤ grade 2 
Skin 
3 
No change 
No change 
No change 
 

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9.10.1 For grade 4 infield esophagitis, radiotherapy and chemotherapy should be interrupted as 
detailed in the table above. Re-evaluate patient weekly. 
9.10.2 For grade  3 esophagitis/pharyngitis, dermatitis, or other in-field radiotherapy- related 
toxicity, on day of chemotherapy administration during any treatment week, omit 
cisplatin/carboplatin and etoposide until toxicity resolves to grade  2 as detailed in the 
table above. 
9.10.3 Radiotherapy should be interrupted only for grade 4 in-field toxicity and resumed when 
that toxicity has decreased to grade  2 as detailed in the table above. If the patient 
experiences esophagitis so that IV fluid support is needed, insertion of a feeding tube 
should be considered. 
9.10.4 For grade 3 esophagitis, radiotherapy can be continued with pain management and IV 
support. 
9.11 
Dose Modifications for Obese Patients 
There is no clearly documented adverse impact of treatment of obese patients when dosing is 
performed according to actual body weight. Therefore, all dosing is to be determined solely 
by (1) the patient’s BSA as calculated from actual weight or (2) actual weight without any 
modification unless explicitly described in the protocol. This will eliminate the risk of 
calculation error and the possible introduction of variability in dose administration. Failure to 
use actual body weight in the calculation of drug dosages will be considered a major 
protocol deviation. Physicians who are uncomfortable with administering chemotherapy dose 
based on actual body weight should not enroll obese patients on Alliance protocols. 
10.0 
COMPANION STUDIES 
There are two substudies within CALGB 30610.  Patients who receive one cycle of chemotherapy 
prior to registering on CALGB 30610 will NOT be offered participation in either companion study. 
The correlative science and the quality of life studies must be offered to all patients enrolled on 
CALGB 30610 (although patients may opt to not participate). These substudies do not require 
separate IRB approval. The substudies included within CALGB 30610 are: 
• 
CALGB 150712: Correlative Science Studies in CALGB 30610 
• 
CALGB 70702: Quality of Life Studies in CALGB 30610, closed to accrual as of 8/30/17 
10.1 
Correlative Science Substudies (CALGB 150712) 
10.1.1 Exploratory Investigation of Circulating Biomarkers 
The goal of the first correlative study is to use the multiplex bead assay to systematically 
examine potential blood-based biomarkers of anti-tumor response and therapeutic resistance 
to the two chemoradiotherapy regimens, with a focus on circulating cytokines and 
angiogenic factors. 
This correlative study will be performed at MD Anderson Cancer Center in the laboratory 
of 
 
Rationale: Previous studies have established that both the tumor response to radiotherapy 
and radiation-induced gastrointestinal toxicity are dependent on the induction of tumor 
endothelial apoptosis and angiogenesis [27, 28]. Furthermore, radiation induces 
compensatory pathways, including hypoxia inducible factor-1 (HIF-1), which affect 
endothelial survival and tumor radiosensitivity through mediators such as VEGF and basic 

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FGF [29]. Interestingly, the sequencing and frequency of radiotherapy had a significant 
impact on the activation of these pathways [29]. Assessing the treatment-induced changes 
in circulating angiogenic factors and cytokine expression, particularly HIF-regulated 
factors, may therefore provide important information regarding the tumor response to 
different treatment regimens. In this study we will investigate a biomarker profile consisting 
of circulating potential blood-based biomarkers of response and resistance, including 
proangiogenic cytokines (i.e., EGF, bFGF, IL-8) and markers of endothelial damage 
(soluble E-selectin, soluble VEGFR-2). 
Objectives: The exploratory objectives of the correlative study are: 
1. To determine whether the baseline biomarker profile, or changes in the profile during 
treatment, correlate with clinical outcome as judged by objective response rate, 
progression free survival, and overall survival. 
2. To compare the changes in the biomarker profile between the two treatment arms. 
Hypotheses 
1. Higher-dose, accelerated radiation therapy will cause a larger rise in circulating markers 
of endothelial damage than hyperfractionated and accelerated radiotherapy (HFXART) 
due to a greater induction of tumor endothelial apoptosis. 
2. Other circulating biomarkers may be useful for helping to identify patients most likely 
to benefit from therapy, monitor antitumor responses, and understand mechanisms of 
therapeutic resistance. 
Method for Multiplex Bead Assay 
Plasma will be used for the assay. We will use the multiplexed bead suspension arrays for 
33 C/AFs (BiosourceTM Human Cytokine 30-Plex for LuminexTM panel, Biosource, 
Camarillo, 
CA; 
LincoplexTM 
Human 
Cardiovascular 
Disease 
I 
kit, 
LINCO 
Research/Millipore, St. Charles, MO). The Luminex Multiplex Cytometric Bead Array 
(Multiplex) assay is ideal for exploratory investigations using statistical support. The assay 
has many advantages. It requires as little as 50 µl of plasma, rather than the 100-200 µl that 
is required for the routine ELISA procedures. In addition, the Multiplex has an advantage 
over the ELISA in its ability to measure up to 25-33 cytokines in one run using a single 
sample, thereby providing relative concentrations among 25-33 cytokines and also 
minimizing the variance of the data. 
10.1.2 Biomarkers Specific for Small Cell Lung Cancer 
The second correlative study will propose correlative translational studies to investigate 
known promising circulating markers in the plasma in small cell lung cancer. These studies 
will utilize the standard ELISA assay, and will be performed at the University of Rochester 
Cancer Center in the laboratory of 
 
Rationale: Several serum/plasma markers have been found promising in the prognostic 
value for small cell lung cancer. These include neuron-specific enolase (NSE), 
carcinoembryonic antigen (CEA), BB isoenzyme of creatine kinase (CK-BB), angiogenic 
factors Interleukin 8 (IL-8) and Vascular Endothelial Growth Factor (VEGF). There are also 
new markers worth investigation, which include the stem cell factor (SCF), granulocyte-
macrophage-colony stimulating factor (GM-CSF), and tumor hypoxia marker osteopontin. 
Background information of these serum/plasma biomarkers is briefly summarized as 
follows: 
Carcinoembryonic antigen (CEA): A number of reports suggested that CEA elevations are 
more prevalent in SCLC patients with extensive disease (40%-65%) than limited stage (0-

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38%) [30, 31]. Some reports suggested a prognostic value for monitoring response to 
chemotherapy and predicting disease recurrence [32]. 
Neuron-specific enolase (NSE): SCLC is a neoplasm with neuroendocrine origin. Serum 
NSE is thought to be the most sensitive tumor marker of SCLC at the time of diagnosis. 
While one study reported a correlation of NSE with disease extent and disease outcome [33], 
many other reports confirmed that NSE was a strong independent prognostic factor for 
complete response, remission duration and overall survival [34, 35]. In a multivariate 
analysis, NSE, followed by performance status and serum albumin, was the best independent 
predictor for survival [36]. 
BB isoenzyme of creatine kinase (CK-BB): CK-BB is also a neuroendocrine marker. It was 
found to have the best correlation with regard to predicting response and survival when 
compared with NSE and CEA in the same cohort of patients [33]. 
Interleukin-8 (IL-8): Tumor angiogenesis is one of the most important biologic features 
related to tumor growth and metastasis. IL-8 is a cytokine marker with angiogenic property 
and has been found in at least one study that the serum level was significantly increased in 
SCLC patients compared with healthy controls [37]. 
Vascular Endothelial Growth Factor (VEGF): VEGF is considered the most potent 
angiogenic factor in promoting growth of tumor vasculature. Tumor expression of VEGF as 
well as circulating VEGF have been demonstrated to be of prognostic significance, 
correlating with tumor progression or patient survival [38-40]. One study showed that high 
pretreatment serum VEGF level was an adverse prognostic factor for survival independent 
of tumor stage [40], other studies found a correlation between serum VEGF level and stage 
progression [41]. 
Stem cell factor (SCF): SCF, the ligand for c-Kit receptor, has been implicated in the 
regulation of angiogenesis in hematopoietic and nonhematopoietic malignancies. At least 
70% of SCLC tumor specimens and cell lines co-express SCF and c-Kit [42]. SCF/c-Kit 
pathway is functional in an autocrine or paracrine fashion in SCLC [43-46]. One study found 
that patients with SCLC have significantly increased levels of SCF when compared with the 
control [47]. 
Granulocyte-macrophage-colony stimulating factor (GM-CSF): GM-CSF is a known 
cytokine for the proliferation of hematopoietic cells. At least one study found significantly 
increased levels of GM-CSF in patients with SCLC when compared with the control [47]. 
Osteopontin (OPN): Tumor hypoxia has been shown to affect the malignant progression of 
tumors, as well as being one of the leading causes of cancer resistance to chemotherapy 
and/or radiotherapy. Studies have indicated that hypoxia increases tumor invasiveness and 
dissemination in human solid tumors [48, 49]. Hypoxia also regulates VEGF expression by 
enhancing transcription of the VEGF gene and by stabilizing its mRNA. It is now clear that 
the transcription factor hypoxia-inducible factor (HIF) 1a is the major regulator of VEGF 
transcription in response to hypoxia [50, 51]. Molecular laboratory work has suggested that 
OPN may be linked to tumor hypoxia and plasma OPN level was increased in patients with 
hypoxic tumors of head and neck, and the levels correlated with clinical outcomes [52]. 
In addition to analyzing the small cell lung cancer specific biomarkers as described above, 
we will also include two additional groups of proteins. First, we will assess factors that we 
have already established to be modulated by radiotherapy or endothelial damage, including 
VEGF, soluble VEGFR-2, and E-selectin [53-55]. The second set of factors will be 
proangiogenic cytokines that may contribute to resistance by promoting the proliferation 
and survival of tumor endothelial cells. First, several selected proangiogenic cytokines 

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known to play a role in angiogenesis in lung cancer, including VEGF, basic fibroblast 
growth factor (bFGF), transforming growth factor  (TGF-), and interleukin-8 (IL-8). 
Objectives: The objectives of the correlative studies for small cell specific circulating 
markers are: 
1. To investigate the value of the published markers specific to small cell lung cancer in 
the large phase III clinical study setting. We will analyze the baseline biomarker profile, 
changes in the profile during treatment at the time of recurrence to correlate with the 
response rate, progression free survival, and overall survival of these patients. 
2. To compare the differences in the biomarker profile between the two treatment arms. 
Hypotheses 
1. Circulating biomarkers may have prognostic or predictive value of small cell lung 
cancer. 
2. The differences in circulating biomarkers between the two treatment arms may reveal 
information correlating with efficacy of treatments. 
Method for the ELISA Assay 
ELISA is a standard laboratory analytical method for protein quantification in the plasma or 
serum (R&D Systems, Minneapolis, MN). This assay requires a significant volume of 
sample (100-200 µl) for each biomarker. The ELISA assay has high sensitivity and high 
precision, and thus has been the standard assay of cytokine measurement. 
10.1.3 ProGRP as a Marker to Monitor the Response to Therapy and for the Prediction of 
Relapse Following Therapy 
The goal of this correlative study is to evaluate the performance of proGRP as a biomarker 
in SCLC lung cancer.  In addition, this study will provide an opportunity to better understand 
the role proGRP to monitor the response to therapy and the relapse following therapy. 
This correlative study will be performed at an Abbott Center of Excellence, which are 
clinical laboratories chosen for their expertise in assay evaluation and biomarker evaluation.  
The target Center of Excellence for this study is the clinical laboratory at Johns Hopkins run 
by 
This is a CLIA approved laboratory. 
Rationale: Gastrin releasing peptide (GRP) is a gut hormone and is widely distributed in 
the mammalian gastrointestinal tract, nervous system and pulmonary tract. GRP is an 
autocrine growth factor, and binding of GRP to cell surface receptors leads to altered 
expression of the c-fos oncogene and cell proliferation. 
Tumor tissues from SCLC patients show amplification of GRP mRNA and protein. 
However, serum GRP was not useful for clinical diagnosis due to its very poor stability in 
specimens.  In 1994, an assay to detect a ProGRP fragment (residues 31-98) in serum was 
developed because the molecule was more stable than GRP. Approximately two thirds of 
patients with SCLC have elevated concentrations of ProGRP in their serum. The clinical 
usefulness of the ProGRP 31-98 measurements has been widely reported for the diagnosis, 
the prediction of prognosis, and the monitoring of treatment in patients with SCLC (94). 
Neuron-specific enolase (NSE) has been also used as a tumor marker of SCLC, however 
compared to NSE, ProGRP has relatively high sensitivity, specificity and early recognition 
of relapse in patients with SCLC (95).  The progression of SCLC in patients under therapy 
in small cohorts of 44 patients and 66 patients has been reported.  The majority of patients 
under treatment showed decreased levels of ProGRP, particularly those with objective 
responses.  The sensitivity for detection of responses ranged from 70-79.7% and the addition 

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of NSE was found to improve sensitivity to 85.9%.  The trend of ProGRP in patients with 
progressive disease was generally upward. 
There have been many publications over the years showing the clinical utility of proGRP as 
a marker for SCLC. Some important reviews of the literature (96-98) have demonstrated the 
proGRP was the best tumor marker in his evaluation for patients with SCLC. In addition, 
the National Academy of Clinical Biochemists Practice Guidelines and Recommendations 
for the Use of Tumor Markers in Lung cancer recognize the clinical use of proGRP in the 
differential diagnois of lung masses and in the monitoring of therapy response and detection 
of recurrent disease (Stieber et al, manuscript in review, Clin Chem.)  From the multiple 
reports, it is clear that proGRP is a valuable tumor marker for SCLC, but it has not been 
validated in a prospective study. 
Objectives: The objectives of this correlative study are: 
Primary: 
1) To evaluate the correspondence between increases in plasma ProGRP concentrations 
and disease progression/recurrence. 
Secondary: 
1) To evaluate the potential for plasma ProGRP concentrations at baseline, after each cycle 
of chemotherapy and at first evaluation following completion of chemotherapy to 
predict PFS and OS. 
2) To evaluate the correspondence between longitudinal decreases in plasma ProGRP 
concentrations and clinical response. 
Exploratory: 
1) To evaluate novel biomarkers for their ability to improve correspondence and prediction 
of response to therapy in patients with SCLC.  This may involve the use of multiple 
biomarkers, including ProGRP, in conjunction with the biomarkers specific for small 
cell lung cancer being studied by 
 
Hypotheses 
1) ProGRP will have a relatively high sensitivity, specificity and early recognition of 
relapse in patients with SCLC. An increase in proGRP level may be detected 
approximately a month prior to clinical evidence of relapse 
2) The majority of patients under treatment will show decreased levels of ProGRP, 
particularly those with objective responses. NSE and proGRP together may be a 
combination of biomarkers that most accurately predicts response to therapy. 
Methods 
Plasma is the sample type that will be used for the assay. The plasma levels of ProGRP will 
be assayed on the ARCHITECT ProGRP assay.  The ARCHITECT ProGRP assay is a 
automated two-step, sandwich format.  Analyte capture is with paramagnetic microparticles 
coated with two mouse monoclonal anti-ProGRP 31-98 antibodies: 3G2 (amino acids of 
ProGRP 84-88) and 2B10 (amino acids of 71-75), which can capture the C-terminal side of 
ProGRP 31-98.  Detection of the ProGRP analyte microparticle complex is by an acridinium 
labeled mouse monoclonal antibody conjugate.  The mouse monoclonal antibody of 3D6-2 
can capture the N-terminal side of the protein (amino acids of ProGRP 40-60). Exposing the 
reaction mixture to on-board trigger reagents containing peroxide at alkaline pH causes the 
release of light that is proportional to the ProGRP level in the specimens, calibrators, or 
controls.  The ARCHITECT ProGRP assay calibrators range from 0 to 5 000 pg/mL (0, 20, 
80, 320, 1 250, and 5 000 pg/mL).  A 1:10 autodilution is used to extend the measurable 

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range up to 50 000 pg/mL.  ARCHITECT ProGRP control concentrations are 40, 160, and 
2 500 pg/mL.  To minimize the risk of interference from human-anti-mouse antibodies, 
heterophilic antibodies, and rheumatoid factor, blocking agents and murine mAbs of 
different isotypes are used in the assay.  Furthermore, the F(ab’)2 portion of the antibody 
with  Fc portion eliminated by pepsin digestion is used to produce the conjugate.  The assay 
is fully automated and measurement is completed within 30 minutes with 200 tests / hour 
throughput.  
The ARCHITECT ProGRP assay is available CE Marked for sale in Europe and approved 
for sale in Japan and has been fully validated.  The performance was defined by multisite 
studies in Japan, Germany and the US.  These results are in press (Clinical Chemistry and 
Laboratory Medicine) and is summarized as follows: The total precision %CV for 9 analyte 
levels was between 2.9-5.7.  The analytical sensitivity of the assay was between 0.20-0.88 
pg/mL. The functional sensitivity at 20%CV was between 0.66-1.73 pg/mL.  The assay was 
linear up to 50 000 pg/mL with a 1:10 autodilution protocol. The calibration curve was stable 
for 30 days. The comparison with Fujirebio microtiter plate EIA ProGRP assay gave a slope 
of 0.93 and a correlation coefficient (r) of 0.99.  No interference was seen with 
chemotherapeutic agents or common interfering substances (bilirubin, hemoglobin, 
triglycerides, high protein, etc.).   
The goal of this correlative study is to obtain information on the clinical value of ProGRP 
in the US to support an FDA submission and to provide information on its clinical utility to 
the medical professionals responsible for treating patients with SCLC. 
10.2 
Health Related Quality of Life (CALGB 70702) 
As early as 1956, the World Health Organization defined quality of life as “a complete physical, 
mental and social well-being and not merely the absence of disease or infirmity” [56]. Thirty-
four years later, the definition had not changed, with the major areas of quality of life consisting 
of physical/occupational status, psychological state, social interaction and somatic sensation 
[57]. These areas may be the most likely to be impacted by different cancer treatment regimens, 
with disease factors and treatment toxicity affecting physical symptoms and functioning, and 
consequently, psychological state and social functioning. 
In this dose-response thoracic radiotherapy trial in limited small cell lung cancer, three different 
doses are being compared in terms of their response rates, failure-free survival and toxicity: 70 
Gy (2 Gy once-daily for 7 weeks), 61.2 Gy (1.8 Gy once-daily for 16 days followed by 1.8 Gy 
twice daily for 9 days), and 45 Gy (1.5 Gy twice-daily over 3 weeks). In Turrisi’s study [5], the 
major increased toxicity for the hyperfractionated dose of 45 Gy in 3 weeks was a doubling of 
the severe (grades 3 and 4) acute esophagitis rate. Esophagitis typically limits oral intake, 
requires a change in diet (soft-liquid), may necessitate frequent IV hydration and may be 
associated with significant fatigue, decreased activity and functioning (and possibly not be able 
to work) and pain. The impact of these side effects on patient’s psychological state and 
potentially social interaction for those with esophagitis can be significant. In Mehta et al.’s [58] 
phase II trial, 30 non-small cell lung cancer patients were administered hyperfractionated 
accelerated radiotherapy: 54 Gy over 12 consecutive treatment days, with three fractions 
administered daily with a 6 hour interval between fractions. Of the 28 patients who completed 
treatment, 22% had grade 3 and 4 esophagitis [58]. All esophagitis resolved after treatment. 
However, in Auchter et al.’s [59] quality of life study of these patients, there were statistically 
significant declines in physical and functional well-being at treatment completion, with a return 
to baseline levels occurring at 4 weeks post-treatment completion.  Emotional state improved 
by the time of treatment completion and at 4 weeks post-treatment completion. In Bonner et al.’s 
[60] phase III trial involving limited stage small-cell lung cancer, while there were no differences 

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in overall progression rates or overall survival between the once-daily thoracic radiation (50.4 
Gy) and twice-daily (48 Gy twice-daily with a two week break after 24 Gy) dose groups, those 
who received the twice-daily dose had significantly greater esophagitis (grade 3 or greater) than 
those receiving the once-daily dose. However, there were no significant differences in quality-
adjusted life years between patients receiving once-daily versus twice-daily thoracic radiation 
[61]. In a study by Bailey et al. [62], non-small cell lung cancer patients were randomized to 
continuous hyperfractionated accelerated radiotherapy (54 Gy, 1.5 Gy three times daily for 12 
days) or conventional radiotherapy (60 Gy: 2 Gy in 30 fractions for 6 weeks). Apart from 
patients in the hyperfractionated accelerated group reporting transient pain on swallowing and 
heartburn, there was little difference between the two arms of the trial. To date, there is no 
prospective, longitudinal data on the impact of hyperfractionated accelerated dose at the level 
proposed in this study on patients’ quality of life. 
10.2.1 Objective: To compare patients’ quality of life between these regimens in terms of 
their physical symptoms, physical functioning and psychological state 
Hypothesis A: Patients in the hyperfractionated accelerated dose (45 Gy) group will 
experience worse lung cancer specific physical symptoms and physical functioning, as 
measured by the FACT TOI (Trial Outcome Index)-Lung Cancer and FACT-Esophageal 
Cancer Eating and Swallowing Indices, than those in the high dose daily (70 Gy) and 
concomitant boost radiotherapy (61.2 Gy) groups when all RT has been completed in each 
arm of the study at 12 weeks after the start of radiation therapy. This hypothesis will be 
revised to reflect the change in the research design due to the elimination of one of the 
experimental arms (high dose daily or the concomitant boost radiotherapy arm), due to 
greater toxicity. 
Hypothesis B: Patients in the hyperfractionated accelerated dose (45 Gy) group will 
experience worse esophagitis (measured by the ECOG Acute Esophagitis Scale and 
difficulty swallowing item), and as a consequence worse psychological state, (measured by 
the Hospital Anxiety and Depression Scale), and lower quality-adjusted life years (measured 
by the EQ-5D) than those in the high dose daily (70 Gy) and concomitant boost radiotherapy 
(61.2 Gy) groups when all RT has been completed in each arm of the study at 12 weeks after 
the start of radiation therapy. This hypothesis will be revised to reflect the change in the 
research design due to the elimination of one of the experimental arms (high dose daily or 
the concomitant boost radiotherapy arm), due to greater toxicity. 
Hypothesis C: Patients in the high dose daily 70 Gy arm of the study will experience greater 
treatment inconvenience (measured by a single item developed for this study), than those in 
the other two arms of the study, due to having to come into clinic for 7 weeks, the longest 
duration of the three arms.  If the 70 Gy arm is eliminated due to greater treatment toxicity, 
than this hypothesis will be revised to reflect that those in the 61.2 Gy arm will experience 
greater treatment inconvenience than those in the 45 Gy arm, due to having to come into 
clinic for 5 weeks. 
10.2.2 Methods 
English-speaking patients who consent will be given a packet of quality of life 
questionnaires to be completed in the clinic. The CRA will be available to answer any 
questions that the patients have, and review the questionnaires for completeness when 
handed in. If the questionnaires are not complete, patients will be asked if they left out 
answering the question by mistake or because they didn’t wish to answer the question. If the 
former, patients will be asked to answer those questions; if the latter, patients will not be 
asked anything further. Patients will be assessed at baseline, 3, 5, 7, 12, 26, and 52 weeks 

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after the start of radiation therapy (see schedule outlined below). By 7 weeks, RT will have 
been completed for all arms of the study. The 12, 26, and 52 week assessments will allow 
us to examine the longer term effects of toxicity on patients’ quality of life. The CRAs at 
the institutitions will be called by the centralized CRA at the Psycho-Oncology Research 
Office at Dana-Farber Cancer Institute at each timepoint to remind them to administer the 
questionnaires to the patients. The schedule of assessments is outlined below: 
a) Baseline 
b) 3 weeks after the start of radiation therapy (completion of RT on 45 Gy, 1.5 Gy twice 
daily over 3 weeks. Mid-RT for 70 Gy once daily over 7 weeks; and 61.2 Gy, 1.8 Gy 
daily for 16 days, followed by 1.8 Gy twice daily for 9 days); cycle 2 chemotherapy 
[Cisplatin and Etoposide]) 
c) 5 weeks after the start of radiation therapy (completion of 61.2 Gy; mid-treatment for 
70 Gy); mid-cycle 2 chemotherapy [Cisplatin and Etoposide]) 
d) 7 weeks after the start of radiation therapy (RT completed for all arms; cycle 3 
chemotherapy [Cisplatin and Etoposide]) 
e) 12 weeks after the start of radiation therapy (5 weeks post-completion of 70 Gy arm; 
6.5 weeks post completion of 61.2 Gy arm; 9 weeks post-completion of 45 Gy.  
Completion of chemotherapy (Cisplatin and Etoposide])  
f) 26 weeks after the start of radiation therapy to assess longer-term consequences of 
patients’ radiotherapy treatment on their quality of life 
g) 52 weeks after the start of radiation therapy to assess long-term consequences of 
patients’ radiotherapy treatment on patient’s quality of life 
h) Weekly during RT: ECOG Acute Esophagitis Scale and Difficulty Swallowing Item 
The FACT-L, the FACT Eating and Swallowing Subscales, and the HADS are the only 
patient-reported quality of life measures that are translated into Spanish. Therefore, the 
quality of life component will be restricted to English-speaking patients only. 
10.2.3 Measures 
The Quality of Life battery will include measures of lung cancer-related physical symptoms, 
esophagitis, physical functioning, psychological state, quality-adjusted life years, treatment 
inconvenience, and sociodemographic characteristics, all of which (with the exception of 
sociodemographic characteristics) are hypothesized as being sensitive to differences in the 
treatment arms (see the table in Section 6.2). Acute esophagitis toxicity ratings will be 
obtained from the oncologist; all other quality of life data will be obtained from patient-
completed questionnaires which will take the patient approximately 25 minutes to complete 
(see the table in Section 6.2 for the frequency of administering the different scales). Several 
measures that have been included in our study (FACT-Lung Cancer TOI, EQ-5D, difficulty 
swallowing item, all described below) are also being used in a radiation therapy trial in the 
RTOG (R0617) of 60 Gy versus 74 Gy in non-small cell lung cancer patients. This will 
create a large database by which to examine the effect of RT on the quality of life of both 
non-small cell and small cell lung cancer patients. The majority of patients in the study will 
have prophylactic cranial irradiation (PCI). The effect of PCI on quality of life measures is 
not clear. In the meta-analysis of PCI for limited stage small cell lung cancer [63] 
neuropsychological evaluation was performed in two trials [64, 65]. The initial 
neuropsychological assessment, performed in 350 patients, revealed that many patients had 
abnormalities prior to PCI. The results of repeated tests during the first years of follow-up 
revealed that the changes in neuropsychological function and the frequency of abnormalities 

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on CT scans of the brain did not differ between the treated and untreated patients. 
Consequently, an in-depth neuropsychological assessment of patients and the potential 
impact of cognitive deficits on physical functioning and psychological state were not 
deemed necessary. Moreover, the primary Quality of Life endpoints are determined prior to 
PCI administration. Whether patients received PCI will be noted in the analyses of 
secondary endpoints that occur in the follow-up period after completion of all therapy. 
• 
ECOG Acute Esophagitis Toxicity Criteria (C-1733) 
The ECOG Acute Esophagitis Criteria consist of 4 items involving patients’ assessment of 
sore throat/dysphagia, analgesics required, nutrition/hydration, and weight loss [58]. The 
scoring system integrates multiple objective and subjective criteria in the determination of 
an overall esophagitis grade. Using this point system, an ECOG grade 0 equals 0 points, 
grade 1 equals 1-3 points, grade 2 equals 4-6 points, grade 3 equals 7-9 points and grade 4, 
10-12 points. This will be completed by the oncologist on a weekly basis while the patient 
is receiving RT in each of the arms, and then at all subsequent assessments. 
• 
Difficulty Swallowing (Form C-1736) 
At the time of each assessment, patients will report swallowing difficulties based on their 
response to the following item: “Have you had any problem with swallowing today?” The 
responses are made on the following 5-point scale: 1=none; 2=mild soreness; 3=can swallow 
solids with some difficulty; 4=cannot swallow solids; 5=cannot swallow solids or liquids. 
Time of assessment is less than a minute. 
• 
FACT-Esophagus Eating and Swallowing Subscales (Form C-1734) 
The FACT-Esophagus Subscale consists of 17 items that are specific to patients with 
esophageal cancer, including eating, appetite, swallowing, pain, talking/communicating, 
mouth dryness, breathing difficulty coughing and weight loss [66]. All items are rated on a 
5-point Likert scale ranging from 0, “not at all,” to 4, “very much.” For purposes of this 
study, in which esophagitis is one of the primary symptoms of radiotherapy, the Eating and 
Swallowing subscales will be used. The Swallowing Index consists of 5 items, and the 
Eating Subscale consists of 3 items. Internal consistency of both subscales is excellent, with 
the Eating Index having alpha coefficients of .84-.88, and the Swallowing Index having 
alpha coefficients of .82-.86. Evidence for validity was found in that for patients in the 
neoadjuvant chemoradiotherapy group, there was a significant improvement in the Eating 
and Swallowing Indices from time in treatment to post-treatment completion. It takes 
approximately 2-3 minutes to complete the scales. 
• 
Functional Assessment of Cancer Therapy Scale: Lung Cancer (FACT-L) 
(Form C-1732) 
The FACT-L [67] consists of the FACT-G [68] and the lung cancer subscale.  The FACT-
G (version 4.0), developed by Cella and colleagues [68] is an overall cancer-specific quality 
of life questionnaire. It is a 27-item core quality of life measure grouped into four subscales: 
physical well being, social/family well-being, emotional well-being, and functional well-
being. The Lung Cancer subscale consists of 10 items, involving lung cancer-specific 
physical symptoms and regret about smoking. All items are rated on a 5-point Likert scale, 
ranging from 0, “not at all,” to 4, “very much.” The FACT-G has been tested on 545 patients 
with mixed cancer diagnoses. The internal consistency of the subscales ranges from 
moderate to excellent, from .65-.82, with excellent internal consistency of the total score, 
with an alpha coefficient of .89. Test-retest reliability is excellent within a 7-day period, 
with correlations ranging from .82-.92. Convergent validity has been demonstrated, with the 
FACT correlating significantly with other quality of life measures (FLIC, r=.79), and related 
constructs of psychological distress (e.g., Brief POMS,    r=-.68), and the ECOG 

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performance rating (r=-.52) [68]. The FACT-G has been able to distinguish between patients 
with metastatic and non-metastatic disease. It has been determined that a 2 point difference 
on the FACT-G subscales and a 5 point difference on the FACT-G total score was associated 
with meaningful differences on clinical and subjective indicators [69]. In a review of the 
literature, Butt et al. [70] reported that the FACT-L scale has been used with more than 
5,000 patients and been found to be sensitive to change in performance status over time, 
treatment response and correlate with dyspnea. The FACT-L is frequently used in clinical 
trials and studies of cancer patients’ quality of life and is available in 20 foreign languages. 
The FACT-L will take approximately 10 minutes to complete. 
The FACT-Lung Cancer (FACT-L) Trial Outcome Index (TOI) consists of the Physical 
Well-Being, Functional Well-Being and Additional Concerns (lung cancer-specific physical 
symptoms) subscales, for a total of 24 items [71]. It is a shortened version of the FACT-
Lung Cancer Scale, which also includes Emotional and Social Well-Being. All items are 
rated on a 5-point Likert Scale, ranging from 0, “not at all,” to 4, “very much.” Evidence for 
validity of the FACT-L TOI was provided by finding that those with a significantly lower 
performance status had lower FACT-L TOI scores. Further, those patients with progressive 
disease had significantly lower TOI scores than those in the complete and partial responders 
groups. Last, those patients who progressed early had significantly larger negative declines 
in TOI scores than those who progressed later. Cella et al.’s [71] study has determined that 
a 5-7 point change in the FACT-Lung Cancer TOI is a clinically meaningful difference. 
• 
Hospital Anxiety and Depression Scale (Form C-458) 
The Hospital Anxiety and Depression Scale (HADS) [72] is a 14-item self-administered 
measure, which has been well tested in cancer populations. It has two 7-item subscales 
assessing depression and anxiety. The scale is considered particularly appropriate for use 
with medically ill patients because of the absence of somatic items, which often confound 
the determination of psychiatric problems in this population. Reported anxiety and 
depression cutoff scores on the HADS have varied from eight [73] to eleven [74]. The total 
cutoff score for psychological distress has ranged from 13, reflecting adjustment disorder, 
to 19, reflecting major depressive disorders [75]. Ibbotson and colleagues [76] found that 
for patients in active treatment, an overall cutoff score of 15 or greater resulted in 85% 
sensitivity, 77% specificity and a positive predictive value of 47%. For purposes of this 
study, 15 or greater on the HADS total score and 11 or greater on the HADS Anxiety and 
Depression subscales [74] will be used as the cutoff score indicative of a possible psychiatric 
disorder. The HADS will take approximately 8 minutes to complete. 
• 
Subjective Significance Questionnaire (Form C-616) 
In order to better interpret the clinical significance of changes in quality of life scores, Osoba 
et al. [77] developed the Subjective Significance Questionnaire (SSQ), consisting of 4 items 
in which patients rated the degree to which they saw an improvement in their physical 
condition, emotional state, ability to enjoy their social life and overall quality of life since 
their last quality of life assessment. All items are rated on a 7-point Likert scale, ranging 
from “very much worse” to “very much better,” with each point on the scale anchored. The 
SSQ will be used to examine their scores in relation to corresponding changes in the FACT-
L domains of quality of life. When used in relation to the EORTC QLQ C-30, increasing 
SSQ ratings were found to correspond with increasing EORTC scores in both breast and 
lung cancer patients, with small, moderate or large changes in quality of life defined in 
relation to changes in EORTC scores [78]. This will take 1 minute to complete. 
• 
EQ-5D (Form C-903) 

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EQ-5D is a measure of health status for use in evaluating health and healthcare. It provides 
a simple descriptive profile of 5 functional dimensions and generates a single utility value 
for health status on which best imaginable health is assigned a value of 1 and worst 
imaginable health a value of 0. Thus, the index can be used to obtain a utility for these 
dimensions for use in economic analyses. The EQ-5D has been specially designed to 
complement other quality of life measures such as the SF-36, or cancer-specific measures. 
Descriptively, the EQ-5D consists of 5 dimensions, mobility, self-care, usual activity, 
pain/discomfort, and anxiety/depression. Each dimension has 3 levels designated simply as 
“no problem,” “some problem,” or “extreme problem,” with patients checking the level most 
descriptive of their current level of function on each dimension. Five dimensions, each with 
three levels, yield 243 possible distinct health states comprising the classification system. 
The classification system has been assigned different standardized scores derived through 
population-based samples of respondents who assign values to subsets of the 243 states 
using the anchoring labels noted above [79]. A set of valuation weights has thus been derived 
from a U.S. sample more recently [79, 80]. The Agency for Healthcare Research and Quality 
has funded a study to develop definitive weights. EQ-5D is designed for self-completion by 
patients and has been used extensively in mailed surveys. It is cognitively simple, taking no 
more than a few minutes to complete. Quality-adjusted life years can be calculated from 
using the EQ-5D in conjunction with a utility scale of health states. 
• 
Treatment Inconvenience (Form C-1735) 
The different treatment arms have different dose schedules for different lengths of times, 
which may impact the satisfaction with treatment due to the inconvenience posed. 
Therefore, an item will be added as to the inconvenience of going for therapy at the different 
dose schedules. 
• 
Sociodemographic Characteristics (Form C-187) 
Demographic data, including education, marital status, employment and household 
composition, will be obtained at baseline only using the CALGB Background Information 
Form [81] (CALGB Form C-187). Age, gender, and ethnicity will be obtained upon patients' 
registration to the study. 
• 
QOL Assessment Form (Form C-419, revised) 
In order to track data collection, and reasons for missing data, a QOL Assessment Summary 
Form will be completed for each patient by the CRA, for each assessment, coding whether 
the assessment was conducted and data collected, and if not, the reason why. 
11.0 
DRUG FORMULATION, AVAILABILITY, AND PREPARATION 
• 
Qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and safe 
disposal of chemotherapeutic agents in a self-contained, protective environment. 
• 
Discard unused portions of injectable chemotherapeutic agents that do not contain a 
bacteriostatic agent or are prepared with unpreserved diluents (i.e., Sterile Water for Injection 
USP or 0.9% Sodium Chloride for Injection USP) within eight hours of vial entry to minimize 
the risk of bacterial contamination. 
• 
The total administered dose of chemotherapy may be rounded up or down within a range of 
5% of the actual calculated dose. 
11.1 
Cisplatin 
Please refer to the FDA approved package insert for additional information. 

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Cisplatin (DDP): Cisplatin (Platinol; cDDP; Platinum, Platinol AQ; cis-DDP; cis-
Diamminedichloroplatinum; cis-Platinum II. 
Availability 
Platinol (Bristol-Myers Oncology Division) is commercially available as an aqueous solution 
(platinol AQ 1 mg/ml injection in 50 ml and 100 ml vials). 
Compatibility 
Incompatible with dextrose solutions (or any solution) containing less than 0.2% sodium 
chloride. Y-site incompatibility: Chlorpromazine, Piperacillin/Tazobactam. 
Storage and Stability 
Reconstituted vials are stable for 20 hours at room temperature. Vials reconstituted with 
bacteriostatic solutions are stable for 72 hours. Intact vials of cisplatin for injection and powder 
for injection should be stored at room temperature and protected from light. 
Do not refrigerate. 
Aluminum reacts with cisplatin to form black precipitates and loss of potency; do not prepare or 
administer with aluminum needles or IV sets; stainless steel or plated brass hubs may be used. 
Toxicities 
Nephrotoxicity (dose related and severe); electrolyte abnormalities (increased excretion of Mg, 
K, Ca, PO4, Na); hyperuricemia; ototoxicity (30%, particularly high frequency hearing); 
nausea/vomiting; anaphylaxis/hypersensitivity; cardiotoxicity (rare: bradycardia, CHF); 
neurotoxicity (peripheral neuropathies, myasthenic-like syndrome); myelosuppression 
(moderate and reversible; infrequent at low dose); elevations in liver enzymes; optic neuritis; 
SIADH; seizures; cortical blindness (rare); loss of taste. 
11.2 
Carboplatin 
Availability 
Carboplatin is commercially available and supplied as a sterile lyophilized powder available in 
single-dose vials containing 50 mg, 150 mg, 450 mg, or 600 mg of carboplatin. Each vial 
contains equal parts by weight of carboplatin and mannitol. 
Refer to the package insert for further information. 
Preparation 
Prepare according to institutional standards. 
Storage and Stability 
Unopened vials of carboplatin are stable for the life indicated on the package when stored at 
controlled room temperature and protected from light. 
Administration 
AUC dosing will be used to determine carboplatin dosing. The protocol permits use of the 
Cockcroft-Gault formula to estimate creatinine clearance. However, in markedly obese patients, 
the Cockcroft-Gault formula will tend to overestimate the creatinine clearance. The actual body 
weight (in kilograms) will be utilized in the Cockcroft-Gault formula. However, if the calculated 
creatinine clearance exceeds an upper limit for creatinine clearance, as specified below, then this 
ceiling value for creatinine clearance, rather than the calculated creatinine clearance, will be 
used in the Calvert formula to calculate the dose of carboplatin.  
The maximum allowable creatinine clearance for males and females is 125 ml/min. 

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Alternatively, at the treating physician's discretion, a measured 24 hour creatinine clearance can 
be obtained. In this case, the measured creatinine clearance can be used to calculate the 
carboplatin dose in the Calvert formula. 
Toxicities 
Myelosuppression, nausea and vomiting, peripheral neuropathy, nephrotoxicity, hepatotoxicity, 
electrolyte imbalance, hypomagnesemia, hypocalcemia, and allergic reactions. 
11.3 
Etoposide 
Please refer to the FDA approved package insert for additional information. 
Availability 
Intravenous etoposide is commercially available (VePesid Injection from Bristol-Myers 
Oncology) in ampules containing 1000 mg/50 ml, 500 mg/25 ml, 150 mg/7.5 ml, and 100 mg/5 
ml. It is now available from generic sources and is available in a 20 mg/ml, 1 gm vial. 
Preparation 
The dose of etoposide should be further diluted with D5W or Normal Saline for Injection to a 
final concentration of less than 0.4 mg/ml. 
Storage and Stability 
Unopened vials are stable at room temperature for 24 months. Vials diluted up to a concentration 
of 0.2 or 0.4 mg/ml are stable for 96 and 24 hours, respectively, at room temperature under 
normal light.  
Administration 
Administer the diluted infusion solution at a maximum rate of 500 mg/hr; an administration that 
is too rapid may be associated with hypotension. 
Toxicities  
Myelosuppression, anorexia, nausea and vomiting, headaches, alopecia, phlebitis, fever, and 
peripheral neuropathy may occur. Acute arterial hypotension may result from rapid intravenous 
infusion. Anaphylaxis, somnolence and fatigue, rash, pigmentation, urticaria and pruritis may 
also occur. 
12.0 
ANCILLARY THERAPY 
• 
Patients should receive full supportive care, including transfusions of blood and blood products, 
erythropoetin, antibiotics, antiemetics, etc., when appropriate. The reason(s) for treatment, 
dosage, and the dates of treatment should be recorded on CALGB Form C-260 (Remarks 
Addenda). 
• 
Treatment with hormones or other chemotherapeutic agents may not be administered except 
for steroids given for adrenal failure; hormones administered for non-disease-related conditions 
(e.g., insulin for diabetes); and intermittent use of dexamethasone as an antiemetic. 
12.1 
Alliance Policy Concerning the Use of Growth Factors 
The following guidelines are applicable unless otherwise specified in the protocol: 
12.1.1 Epoetin (EPO) 
The use of EPO is permitted at the discretion of the treating physician. 
12.1.2 Filgrastim (G-CSF) and sargramostim (GM-CSF) 

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1. Filgrastim (G-CSF), pegfilgrastim and sargramostim (GM-CSF) treatment is 
discouraged. 
2. Filgrastim/pegfilgrastim and sargramostim may not be used: 
a. 
to avoid dose reductions, delays or to allow for dose escalations specified in the 
protocol, 
b. 
prophylactically because of concern about myelosuppression from prior 
chemotherapies 
3. For the treatment of febrile neutropenia the use of CSFs should not be routinely 
instituted as an adjunct to appropriate antibiotic therapy. However, the use of CSFs may 
be indicated in patients who have prognostic factors that are predictive of clinical 
deterioration such as pneumonia, hypotension, multi-organ dysfunction (sepsis 
syndrome) or fungal infection, as per the ASCO guidelines. Investigators should 
therefore use their own discretion in using the CSFs in this setting. The use of CSF 
(filgrastim/pegfilgrastim or sargramostim) must be documented and reported on 
CALGB Form C-260 (Remarks Addenda). 
4. If filgrastim/pegfilgrastim or sargramostim are used, they must be obtained from 
commercial sources. 
13.0 
CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE   
For the purposes of this study, patients should be reevaluated every 6 weeks. In addition to a 
baseline scan, confirmatory scans should also be obtained ≥ 4 weeks following initial 
documentation of objective response. 
13.1 
Target Lesions 
All measurable lesions up to a maximum of 10 lesions representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and their 
suitability for accurate repetitive measurements (either by imaging techniques or clinically). A 
sum of the longest diameter (LD) for all target lesions will be calculated and reported as the 
baseline sum LD. The baseline sum LD will be used as reference to further characterize the 
objective tumor response of the measurable dimension of the disease. 
13.1.1 Complete Response: Disappearance of all target lesions. Where response is the primary 
endpoint, changes in tumor measurements must be confirmed by repeat studies performed 
no less than 4 weeks after the criteria for response are first met. 
13.1.2 Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) 
of target lesions taking as reference the baseline sum LD. Where response is the primary 
endpoint, changes in tumor measurements must be confirmed by repeat studies performed 
no less than 4 weeks after the criteria for response are first met. 
13.1.3 Progression (PD): At least a 20% increase in the sum of the LD of target lesions taking as 
references the smallest sum LD recorded since the treatment started or the appearance of 
one or more new lesions. 
13.1.4 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD taking as references the smallest sum LD since the treatment started. 
Patients having a documented response with no reconfirmation of the response will be 
listed with stable disease. 

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13.2 
Non-target Lesions 
All other lesions (or sites of disease) not included in the “target disease” definition should be 
identified as non-target lesions and should also be recorded at baseline. Measurements are not 
required and these lesions should be followed as “present” or “absent.” 
13.2.1 Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
13.2.2 Non-complete response (non-CR)/Non-progression (non-PD): Persistence of one or 
more non-target lesion and/or maintenance of tumor marker level above the upper limits 
of normal. 
13.2.3 Progression (PD): Appearance of one or more new lesions. Unequivocal progression of 
existing non-target lesions. Although a clear progression of non-target lesions is 
exceptional, in such circumstances, the opinion of the treating physician should prevail and 
the progression status should be confirmed later on by the study chair. 
13.3 
Cytology and Histology 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
These techniques can be used to differentiate between PR and CR in rare cases (for example, 
residual lesions in tumor types such as germ cell tumors, where known residual benign tumors 
can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect 
of the treatment) and progressive disease. 
13.4 
Evaluation of Best Overall Response 
The best overall response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). In general, the patient’s best response assignment will 
depend on the achievement of both measurement and confirmation criteria (see Section 13.6.1). 
 
 

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Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Note: 
• 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration” on the Off-treatment Form (C-300) under “other.” Every effort 
should be made to document the objective progression even after discontinuation of 
treatment. 
• 
Conditions that may define “early progression, early death and inevaluability” are study 
specific and should be clearly defined in each protocol (depending on treatment duration, 
treatment periodicity). 
For example: Conditions that may define early death include patients that have died without 
documentation of disease progression and before it was time to conduct the first tumor 
reassessment. Inevaluable patients have received protocol treatment (regardless of how 
much was received) and did not have any follow-up assessment completed before initiation 
of alternative treatment.  
• 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
13.5 
Guidelines for Evaluation of Measurable Disease 
13.5.1 Clinical Lesions will only be considered measurable when they are superficial (e.g., skin 
nodules, palpable lymph nodes). For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is recommended. 
13.5.2 Chest X-ray: Lesions on chest X-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
13.5.3 Conventional CT and MRI: Sections of 5 mm thickness (or less) will be obtained using 
spiral/helical technique. Reconstruction intervals must be equal of less than the section 
thickness. Anatomic coverage will extend from lung apices through the adrenal glands. IV 
contrast enhancement is required, unless the patient has significant history of contrast 
allergy. A CT scan performed at a site other than a study site may be acceptable for study 
purposes; otherwise, it should be repeated at the study site. In particular, a repeat CT scan 
should be performed if the investigator at the study site considers the outside CR scan to 
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13.5.4 Ultrasound (US) should not be used to measure tumor lesions that are clinically not easily 
accessible when the primary endpoint of the study is objective response evaluation. It is a 
possible alternative to clinical measurements of superficial palpable nodes, subcutaneous 
lesions, and thyroid nodules. US might also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination. 
13.5.5 Endoscopy and Laporascopy for objective tumor evaluation has not yet been fully and 
widely validated. Their uses in this specific context require sophisticated equipment and a 
high level of expertise that may only be available in some centers. Therefore, the utilization 
of such techniques for objective tumor response should be restricted to validation purposes 
in reference centers. However, such techniques can be useful to confirm complete 
pathological response when biopsies are obtained. 
13.5.6 Tumor Markers alone cannot be used to assess response. If markers are initially above 
the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response. 
13.6 
Confirmation Measurement/Duration of Response 
13.6.1 Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat studies that should be performed 4 weeks after the criteria for response are first met. 
In the case of SD, follow-up measurements must have met the SD criteria at least once after 
study entry at a minimum interval of 6 weeks. 
13.6.2 Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
The duration of overall complete response is measured from the time measurement criteria 
are first met for CR until the first date that recurrent disease is objectively documented. 
13.6.3 Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression 
are met, taking as reference the smallest measurements recorded since the treatment started. 
14.0 
REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
14.1 
Duration of Treatment 
14.1.1 CR, PR, or SD: Continue treatment at the highest tolerable dose for up to 4 cycles until 
the appearance of disease progression. 
14.1.2 Disease Progression: Remove from protocol therapy any patient with rapid disease 
progression. Document details, including tumor measurements, on data forms. 
14.2 
Extraordinary Medical Circumstances:  
If, at any time the constraints of this protocol are detrimental to the patient's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
• 
Notify the Study Chair. 

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• 
Document the reason(s) for discontinuation of therapy on CALGB Form C-260. 
• 
Follow the patient for progression, survival, new primaries or secondary malignancy for a 
total of 10 years following registration. 
15.0 
STATISTICAL CONSIDERATIONS 
15.1 
Endpoints 
15.1.1 Primary Endpoint 
The primary objective of this study is to determine whether administering high dose thoracic 
radiotherapy, 70 Gy (2 Gy once-daily over 7 weeks) or 61.2 Gy (1.8 Gy once-daily for 16 
days followed by 1.8 Gy twice-daily for 9 days), will improve overall survival compared 
with 45 Gy (1.5 Gy twice-daily over 3 weeks) in patients with limited stage small cell lung 
cancer. Overall survival time is measured from randomization until death from any cause. 
15.1.2 Interim Endpoint 
An interim endpoint will be utilized to select between the experimental treatment arms. 
Treatment related grade 3+ non-hematologic toxicity, grade 4 hematologic toxicity and any 
grade 5 toxicity will be used in this determination. Discontinuing the experimental arm with 
higher toxicity will not only protect patients but also substantially reduce the study size. The 
rationale of eliminating an experimental arm based on acute toxic effect of therapy is well 
founded given that the acute toxicity of the standard regimen (e.g., 45 Gy BID TRT) appears 
to have substantially limited its acceptance into clinical practice. Moreover, both 
experimental arms have greater predicted biologic efficacy compared with standard 
treatment. The focus will be on grade 3+ treatment related non-hematologic toxicity, grade 
4 hematologic toxicity, failure to complete 4 cycles of chemotherapy and any grade 5 
toxicity. The following scoring system will be used to define the severity of adverse events. 
For each patient, only the highest grade of relevant toxicities will be counted and multiple 
relevant toxicities of the same grade will be counted once. 
Any grade 2 or less toxicity or grade 3 hematologic 
toxicity  
0 point 
Grade 3 non-hematologic toxicity or grade 4 hematologic 
toxicity 
1 point 
Grade 4 non-hematologic toxicity or failure to complete 4 
cycles of chemotherapy 
2 points 
Any grade 5 toxicity 
3 points 
In the initial stage of the study, eligible patients will be randomized to arms 1, 2 and 3 with 
probability ratio of 1:1:1. A blocking design with 30/30/30 patients will be used to compare 
toxicity between the experimental arms. Specifically, after 30 patients have been accrued to 
each experimental arm, the Alliance Statistics and Data Center will computerize and analyze 
all treatment related toxicities and report findings to the study team and the DSMB. For the 
60 patients treated by experimental regimens, permutation t test will be used to compare 
toxicity severity scores between experimental arms. If the 2-sided p value of the permutation 
test is less than 0.05, a decision will be made to drop the experimental arm with higher 
toxicity; otherwise, the study will continue and adverse events will be analyzed again after 
20 additional patients have been treated in each experimental arm. For the 100 patients 
treated by experimental regimens so far, if statistically significant difference of adverse 
events is found between the experimental arms, a decision will be made to drop the 

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experimental arm with higher toxicity; otherwise, the study will continue after 20 additional 
patients have been treated in each experimental arm. For the first 140 patients treated by 
experimental regimens, the experimental arm with the highest cumulative numerical toxicity 
score will be discontinued following review by the study team and the DSMB. 
A notice will be broadcast to all Alliance and CTSU institutions for the discontinuation of 
an experimental arm. In the initial stage of the trial, while the toxicity profiles of treated 
patients are being evaluated, the study accrual will not be suspended. In the second stage, 
the study will proceed with the remaining experimental arm and the standard treatment arm 
with 1:1 allocation. 
15.1.3 Secondary Endpoint 
Secondary endpoints will include complete and partial response rates, failure-free survival, 
local tumor progression according to RECIST criteria, and rates of distant metastases and 
intracranial metastases. Failure free survival is the time from randomization to death of all 
causes or disease progression, whichever comes first. Second primary tumors will not be 
viewed as disease progression. 
15.2 
Stratification Factors 
• 
Gender: male vs. female 
• 
Weight loss (6 months prior to study entry): <= 5 % vs > 5% 
• 
ECOG Performance Status: 0 vs 1 vs 2 
• 
Radiotherapy Technique: IMRT vs. 3D 
• 
Radiotherapy Start Time (choose one):  
-At first cycle of protocol chemotherapy, after one cycle of prior non-protocol chemotherapy 
-At first cycle of protocol chemotherapy, without prior non-protocol chemotherapy 
-At second cycle of protocol chemotherapy, without prior non-protocol chemotherapy 
• 
Chemotherapy Backbone: carboplatin vs. cisplatin 
15.3 
Sample Size with Power Justification 
This randomized phase III study is to determine the efficacy of 70 Day QD RT (arm 2) or 61.2 
Gy concurrent boost RT (arm 3) as compared to the standard therapy 45 Gy BID RT (arm 1) in 
patients with limited small cell lung cancer. The primary endpoint is overall survival, which is 
measured from the date of randomization to the date of death from any cause. 
The implementation of the study will be divided into two stages. In the first stage, eligible 
patients will be randomized with a 1:1:1 allocation to arm 1, 2 and 3. The toxicity profiles of 
two experimental arms (arm 2 and arm 3) will be analyzed after 30 patients have been treated to 
each of the experimental arms. If no statistically significant difference of adverse events is found 
between experimental arms, additional 20 patients will be treated by each experimental arm. 
The pattern will be repeated until a significant difference is found or 70 patients have been 
treated by each experimental arm, whichever comes first. In the second stage, after the decision 
of dropping the experimental arm with higher toxicity is made, the study will continue with two 
remaining arms with 1:1 allocation. All randomization will be made using a permuted-block 
scheme, stratified by gender (female vs. male), ECOG PS (0 vs. 1 vs. 2), weight loss within 6 
months before entry (weight loss ≤5% vs. >5%), radiotherapy technique: IMRT vs. 3D, timing 
of first chemotherapy treatment (prior to randomization vs. post-randomization with the start of 
radiotherapy on the first cycle vs. post randomization with the start of radiotherapy on the second 
cycle), and chemotherapy backbone (carboplatin vs. cisplatin) [82]. In the end, the study will 

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randomize 303 patients to arm 1, 303 to Arm 2 and 30-70 patients to the discontinued 
experimental arm. As of November 20, 2012, the discontinued experimental arm (Arm 3) 
randomized 88 patients due to a delayed final toxicity interim decision. With an allowance of 
5% of patients canceling or ineligible for randomization, the study will accrue a total of 729 
patients over a period of 6 years at about 10 patients per month. All randomized patients will be 
followed for at least 2.5 years after enrollment 
The trial is designed to have adequate power to test the null hypothesis H0: log(λ1 / λ2/3 )=0 
versus the alternative hypothesis Ha: log(λ1 / λ2/3 ) ≥ 1.3 for the comparison of overall survival 
between the remaining experimental arm (arm 2) and the standard arm (arm 1). The power 
analysis is based on the following assumptions: (1) the 2-year overall survival rate of the 
remaining experimental arm (arm 2) is 57.3% and that of arm A is 48.5%. Under exponential 
survival distribution, the median survival for the remaining experimental arm is 29.9 months 
and for the standard arm is 23 months, or a hazard ratio of 1.3 (λ1 / λ2) for the standard arm to 
the remaining experimental arm; (2) an accrual length of 6 years; (3) 303 eligible patients in the 
standard arm and 303 eligible patients in the remaining experimental arm; (4) additional follow-
up of 2.5 years after the last enrollment; (5) a two-sided significance level of 0.05. Under these 
assumptions, at the time of final analysis, at least 483 deaths are anticipated under alternative 
hypotheses for the two remaining comparative arms. Without taking into account the expected 
minimal loss of power due to interim analyses, the power in detecting the survival improvement 
for the remaining experimental arm (arm 2) as compared to the standard arm is at least 81.9% 
using a stratified log-rank test. 
15.4 
Analysis Plan Including Plans for Formal Interim Analysis 
Both short term and long term toxic effects of therapy will be captured and monitored closely. 
Severe toxic events will be reported and monitored as per NCI guidelines for clinical studies 
(e.g., CTEP-AERS). These data will be critical in the assessment of each of the treatment 
regimens. In addition, the Alliance DSMB will perform a formal review of the available data at 
each of its semiannual meetings. This review will include both acute and late toxicity. 
After discontinuing one of the experimental arms with worse toxicity profile, in the second stage 
of the study, the first formal interim analysis for efficacy will occur once 78 deaths are observed 
in the remaining study arms. After that, formal interim analyses will be conducted annually, with 
the final analysis at year 8.5, corresponding to approximately 140, 213, 292, 374, 437 and 483 
deaths. The trial is subject to stopping early for either superiority or inferiority of the 
experimental relative to the standard arm if either arm was markedly superior in terms of overall 
survival. The main reason is that if both arms were roughly equal in terms of overall survival, 
the final conclusion might be to recommend the experimental arm for future use because of less 
toxicity or more convenience. Using S+SeqTrial [83], we will construct two-sided symmetric 
monitoring boundaries in the spirit of O’Brien and Fleming [84]. To maintain overall 1-sided 
alpha level of 0.025 for each boundary and be conservative in the initial looks, we will truncate 
alpha level at 0.0005 for the first look and at 0.0025 for other interim looks [85]. The final 
analysis at 8.5 years after study activation will conclude superiority (inferiority) of the remaining 
experimental arm to the standard arm if the p-value of a one-sided log rank test for superiority 
(inferiority) is less than 0.0220. The following table displays the operating characteristics, 
including power, average study size, stopping probabilities under true hazard ratios of 0.75, 1.0, 
1.3, and 1.5. The exact performance of the study design, especially under different allocation 
ratios in the first and the second stage of the study, will be investigated using simulation. 
 

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Hazard Ratio 
(λ1/ λ2/3) 
Expected 
Number of 
Deaths 
Prob. to Reject 
H0: λ1 / λ2/3 =1 
(Power)  
Early Stop Prob. 
for Superiority  
Early Stop Prob. 
for Inferiority 
0.75 
354 
0.8763 
0.0000 
0.6348 
1.0 
479 
0.0250 
0.0081 
0.0081 
1.3 
377 
0.8106 
0.5357 
0.0000 
1.5 
245 
0.9928 
0.9385 
0.0000 
 
The Alliance DSMB will review the data available from the trial at each of its semiannual 
meetings. This will include toxicity, disease recurrence and survival information. The DSMB 
will determine which of its biannual meetings most appropriately fits the protocol-dictated one-
year formal interim analysis. This determination will be based on a recommendation of the study 
statistician. In determining whether the trial should be continued, the DSMB will consider the 
results at each interim analysis, as described above. The DSMB will use its discretion in 
weighing the combined impact of treatment-related morbidity, disease recurrence and overall 
survival. 
Overall survival (OS) is defined as the time between randomization and death from all causes. 
Overall survival curve will be estimated by the Kaplan-Meier method. The primary analysis is 
to test the survival benefit of the experimental therapy over the standard therapy using stratified 
log rank test in the intent-to-treat (ITT) population. Six stratification factors, including Gender, 
Weight loss, ECOG Performance Status, Radiotherapy Technique, Radiotherapy Start Time, 
and Chemotherapy Backbone, have been used in randomization. As a total of 144 stratums have 
been defined by these factors and many of the stratum may end up of small number of patients. 
For the primary analysis, the stratified log rank test will only stratify on patient subgroups 
defined by Performance Status (0 vs 1/2) and Chemotherapy Choice (entry prior to the option 
to use carboplatin, choice of carboplatin among those patients for which this is an option, and 
choice of cisplatin among those patients for which this is an option). Cox’s proportional hazards 
model will be used to estimate hazard ratio between treatments with and without adjusting for 
other prognostic factors.  
Failure free survival (FFS) is the time from randomization to death of all causes or disease 
progression, whichever comes first. In this study, second primary tumors will not be viewed as 
disease progression. FFS will be analyzed in a similar manner to overall survival (OS). 
The rates of local relapse, distant metastases and brain metastases with the regimens will be 
evaluated using logistic regression with treatment and other prognostic factors in the model. . 
Contingency tables will be used to summarize the frequency of toxicity by severity, type and 
treatment. For comparison of the frequency of toxic events, the Cochran-Mantel-Haenszel test 
will be used to take advantage of the trend effect among toxicity grades. 
 
15.5 
Logistics and Accrual 
An estimated 174,000 patients will be diagnosed with lung cancer in 2006. Small cell lung 
cancer comprises approximately 16-20% of all lung cancer, and accounts for 22% of all lung 
cancer cases accrued to cooperative group clinical trials. According to the National Cancer Data 
Base, 42% of staged patients had limited stage disease in 2000, and 11,000 to 14,000 new cases 
of limited stage small cell lung cancer are expected annually. The total accrual goal is 729 
patients. To complete accrual in 6 years, the accrual rate will be approximately 10 patients per 
month (120 patients per year). We anticipate this trial to be opened by all major Alliance and 
RTOG sites, and several additional adult cooperative groups including SWOG and ECOG have 

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agreed to participate in this trial. The accrual goal should be achievable given the track record 
of accrual to limited stage small cell lung cancer trials in these Groups. Given the uncertainty in 
clinical practice regarding the optimal thoracic radiotherapy regimen in limited stage small cell 
lung cancer, we expect that the question addressed by this study will lead to a high level of 
interest and participation. In addition, there are few competing cooperative group, industry, or 
institutional studies in this patient population. 
15.6 
Correlative Studies (CALGB 150712) 
In the main treatment study, a total of 303 patients will be randomized to the standard control 
arm (arm A) and the remaining experimental arm (arm B or arm C, depending on the toxicity 
data from an initial cohort, the more toxic experimental arm will be dropped). These patients 
will be followed for disease progression and survival for at least 3 years after enrollment. All 
patients will be invited to join the correlative science substudies. Samples from consenting 
patients will be collected at baseline (before treatment initiation), day 21 (pre-chemotherapy), at 
first follow-up after completion of all protocol treatment, and at the time of disease recurrence. 
The laboratory data, including measures of all biomarkers described in the protocol, will be sent 
to the Alliance Statistics and Data Center, where the laboratory data will be merged with the 
clinical data and analyzed by Alliance statisticians. 
Power Analysis for the First Correlative Science Substudy (Section 10.1.1): 
The primary objectives of this first correlative science substudy are (i) to test whether higher-
dose, accelerated radiation therapy (arm B or C) will cause a larger rise in circulating markers 
of endothelial damage than hyperfractionated and accelerated radiotherapy (arm A), and (ii) to 
determine whether the baseline biomarker profile, or changes in the profile during treatment, 
correlate with clinical outcome as judged by objective response rate, progression free survival, 
and overall survival. 
With allowance of 20% patient loss due to consent, ineligibility, and specimens of poor quality, 
we assume that 264 patients on arm A and 264 patients on arm B/C will provide evaluable 
circulating biomarkers for final analysis. With regards to the first primary objective, we assume 
the transform of biomarker count difference between post-treatment initiation and baseline 
follows approximately a normal distribution so that a 2-sample t test would be appropriate. At a 
2-sided significance level of 0.05, the study has 90% power to detect a 0.274 standard deviation 
of cell count difference between the two treatment arms on log scale. With regards to the second 
primary objective, for the purpose of power analysis, the correlation of the biomarker (baseline 
or change scores of post-initiation of treatment against baseline) with response rate, 2-year FFS 
and 2-year OS will be tested for each arm using logistic regression with a single continuous 
predictor. At a 2-sided significance level of 0.05, the study has at least 90% power to detect a 
6% increase of response rate from 80% at the mean of the biomarker to 86% at one standard 
deviation above of the mean. Similarly, the study has at least 90% power to detect an 11% 
increase of 2-year FFS from 40% at the mean to 51% at one standard deviation above of the 
mean, to detect an 11% increase of 2-year OS from 50% at the mean of a biomarker to 61% at 
one standard deviation above of the mean. 
Power Analysis for the Second Correlative Science Substudy (Section 10.1.2): 
The primary objective of the second correlative substudy is to evaluate the correlation of several 
serum markers at baseline or their changes against baseline with response rate (RR), failure free 
survival (FFS), and overall survival (OS) in small cell lung cancer. They include neuron-specific 
enolase (NSE), carcinoembryonic antigen (CEA), BB isoenzyme of creatine kinase (CK-BB), 
angiogenic factors Interleukin 8 (IL-8) and Vascular Endothelial Growth Factor (VEGF), stem 
cell factor (SCF), granulocyte-macrophage-colony stimulating factor (GM-CSF), and tumor 

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hypoxia marker osteopontin. The correlation tests are considered exploratory and the Type I 
errors will not be adjusted for multiple comparisons. 
It is assumed that 230 randomized patients (70%) on each arm will consent and provide valid 
measures for these biomarkers. These biomarkers are concentration in the blood. The baseline 
measures and the change at different time points – day 21; at first follow-up after completion of 
all protocol treatment; and at the time of disease recurrence – against baseline are continuous 
variables. For the purpose of power analysis, logistic regression with a single continuous 
predictor will be used to test a measure’s correlation with RR, 2-year FFS, and 2-year OS, 
separated by study arm. At a 2-sided significance level of 0.05, the study has at least 90% power 
to detect a 6% increase of response rate from 80% at the mean of the biomarker to 86% at one 
standard deviation above of the mean. Similarly, the study has at least 90% power to detect a 
12% increase of 2-year FFS from 40% at the mean to 52% at one standard deviation above of 
the mean, to detect a 12% increase of 2-year OS from 50% at the mean of a biomarker to 62% 
at one standard deviation above of the mean. 
Power Analysis for the Third Correlative Science Substudy (Section 10.1.3): 
Most studies of proGRP have reported that approximately 70-80% of patients have increased 
levels of proGRP in their serum or plasma.  The primary endpoint examines the correlation of 
increases in the plasma proGRP levels with changes in disease status.  This strategy is based on 
the analyses performed for tumor markers used for monitoring and approved by the FDA, such 
as CA19-9, CA15-3, CA125 and CEA.  Changes above a cutoff are compared for to clinical 
evaluation of stable disease vs. progression.  In the secondary studies, the correlation of 
decreases in proGRP level will be compared to stable disease vs. regression and/or remission 
designations.  The data is analyzed as concordance of 2 X 2 table of clinical outcome vs. a 
defined change in cutoff levels.  For proGRP, 3 levels will be evaluated initially a) the percent 
increase that is 2.5 times the assay’s observed total percent coefficient of variation (CV), b) a 
percent change that is 2.5 times the assay and biological variation, and c) a change of >25% 
based on changes used with other cancer biomarkers.  The change in disease state is evaluated 
per sequential pair and per patient.  Secondary analyses can determine whether a different cutoff 
functions better than these 3 cutoffs.  Individual patients will be evaluated by following their 
sequential proGRP values and their clinical status via tables and graphs.   
Based on the numbers of patients and samples sufficient for these evaluations for other 
monitoring biomarkers as submitted to and approved by the FDA, it is recommended that 
between 150 and 200 patients be enrolled in this study. A sample size of approximately 150 and 
200 patients will provide a sufficient number of evaluable patients with 95% confidence and 
80% to 90% statistical power for evaluating the association of the change in ProGRP assay 
values and change in disease status. 
For the primary study and the secondary studies of the relationship of proGRP levels at baseline 
and at each round of chemotherapy and at the end of therapy will be analyzed as defined above. 
Analytic Methods 
All data from eligible patients with evaluable measures of the biomarker of interest will be 
included in final analysis. A 2-sided significance level of 0.05 will be used for all tests. 
Descriptive statistics will used to characterize biomarker count or distribution over time and 
changes against baseline. The change of biomarker count or mean between treatment arms will 
be tested using a 2-sample t test on a transformed scale such as the use of t test is appropriate. If 
the normal assumption is violated, Wilcoxon rank sum test, a nonparametric test, will be used. 
As supplementary analysis, the difference of biomarker count and mean change will be modeled 
using generalized linear model using appropriate link function. 

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The correlation of the baseline measure or the change of the biomarker measure relative to 
baseline with response rate (RR) will be evaluated using logistic regression [86] with and 
without adjusting for significant confounding variables at baseline. The correlation of the 
biomarker with failure free survival (FFS) and overall survival (OS) will be evaluated using 
Cox’s proportional hazard model [87] for time to event data without and with adjusting for 
confounding variables. These analyses will reveal whether the baseline biomarker or its change 
against baseline during treatment is predictive to RR, FFS, or OS, or whether the correlation is 
dependent on which treatment is given. In the pooled analysis of all patients on the treatment 
arms, the interaction between treatment and baseline or change score of the biomarker will be 
tested to evaluate the predictive value of the biomarker to different treatments. 
If a continuous biomarker is significantly correlated with FFS or OS, an optimal threshold for 
classifying patients into subgroups will be identified by searching the dichotomized level of the 
continuous predictor at which yields the maximal log rank statistic. Both the raw p-value from 
the log rank test as well as the adjusted p-value from the maximal log rank statistic [88], which 
takes the randomness of the maximally selected cutoff point into account, will be provided. 
Kaplan-Meier curves [89] will be used to describe survival difference for different subgroups of 
patients classified by predictive biomarker at its optimal cutoff point. 
To assess the correspondence between increases in plasma ProGRP and disesase progression or 
recurrence, patients will be considered evaluable if they have at least five blood draws, one at 
baseline and the remaining draws at 3, 6, 9 and 12 months, respectively with the corresponding 
scans at those time points.  Patients with CR, PR, and SD will be grouped together as non-
progressive disease for the statistical analysis.  Since each patient contributes a unique set of 
visit pairs to the data, this must be controlled by using techniques developed for generalized 
linear models.  GENMOD procedure in SAS will be used to obtain the estimates of the 
concordances.  The relationship between the concordance estimate C and the parameter estimate 
b is given by C = (1 + e-b)-1.  95% confidence limits will be determined for all concordance 
proportion. 
To evaluate the ability of ProGRP at baseline, after each cycle of chemotherapy and at first 
evaluation post-treatment, patients will be grouped into two different groups based on their 
ProGRP concentrations.  At each of those intervals, they will be grouped as negative if (ProGRP 
 50 pg/mL) or as positive if (ProGRP > 50 pg/mL).  In addition, changes in ProGRP 
concentrations starting at baseline and after the first or second dose of chemotherapy will also 
be explored.  The log-rank test will be used to determine if the PFS for patients with positive 
values (or changes) are different from the negatives. 
15.7 
Health Related Quality of Life (CALGB 70702) 
Hypothesis A: Patients in the hyperfractionated accelerated dose (45 Gy) group will experience 
worse lung cancer specific physical symptoms and physical functioning, as measured by the 
FACT TOI (Trial Outcome Index) -Lung Cancer and FACT-Esophageal Cancer Eating and 
Swallowing Indices, than those in the high dose daily (70 Gy) and concomitant boost 
radiotherapy (61.2 Gy) groups when all RT has been completed in each arm of the study at 12 
weeks after the start of radiation therapy. This hypothesis will be revised to reflect the change 
in the research design due to the elimination of one of the experimental arms (high dose daily or 
the concomitant boost radiotherapy arm), due to greater toxicity. 
Hypothesis B: Patients in the hyperfractionated accelerated dose (45 Gy) group will experience 
worse esophagitis (measured by the ECOG Acute Esophagitis Scale and difficulty swallowing 
item), and as a consequence worse psychological state, (measured by the Hospital Anxiety and 
Depression Scale), and lower quality-adjusted life years (measured by the EQ-5D) than those in 
the high dose daily (70 Gy) and concomitant boost radiotherapy (61.2 Gy) groups when all RT 

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has been completed in each arm of the study. This hypothesis will be revised to reflect the change 
in the research design due to the elimination of one of the experimental arms (high dose daily or 
the concomitant boost radiotherapy arm), due to greater toxicity. 
Hypothesis C: Patients in the high dose daily 70 Gy arm of the study will experience greater 
treatment inconvenience (measured by a single item developed for this study), than those in the 
other two arms of the study, due to having to come into clinic for 7 weeks, the longest duration 
of the three arms. If the 70 Gy arm is eliminated due to greater treatment toxicity, then this 
hypothesis will be revised to reflect that those in the 61.2 Gy arm will experience greater 
treatment inconvenience than those in the 45 Gy arm, due to having to come into clinic for 5 
weeks. 
Overview: 
In the quality of life companion, patients will be assessed by multiple HRQOL (Health-related 
quality of life) scales at baseline, 3, 5, 7, 12, 26 and 52 weeks (see Table 1 for details). 
Investigators are interested in evaluating the change of quality of life assessments from baseline 
to multiple time points during and after treatment and comparing the differences of such changes 
between treatment regimens. It is expected that patients in arm 1 (45 Gy) experience worse 
physical and functional well being, worse esophagitis than those in the remaining study arm 
(arm 2 or 3), and that patients in arm 2 (70 Gy) experience worse treatment inconvenience than 
those in arm 1 (45 Gy) or arm 3 (61.2 Gy). The HRQOL scores changed from baseline to 12 
week are of the primary scientific interest. The size of the HRQOL companion is chosen such 
that one has adequate power to test three sets of scientific hypotheses as shown in Table 2). The 
companion will register 415 patients (57%) from the 729 patients consenting to the main 
treatment study. Of the 415 patients, 394 patients are expected to meet the eligibility criteria. Of 
the 394 patients on the companion study, 188 patients are expected in each of the two remaining 
study arms and 18 patients are in the discontinued study arm. 
 
 

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Table 2 
Quality of Life Assessment 
QoL Endpoint 
Variable 
Hypothesis 
Measure 
Statistical Analysis 
Primary 
Endpoints 
    Physical Well-
being, Functional 
Well-Being, Lung 
Cancer physical 
symptoms 
 
    FACT 
Esophageal Eating 
and Swallowing 
Subscales  
Hypothesis A: At 12 
weeks after the start 
of XRT, patients in 
the 45Gy arm will 
report worse 
physical symptoms 
and functioning than 
those in the high 
dose daily (70Gy) 
and concomitant 
boost RT (61.2 Gy) 
groups. 
 
 
 
FACT-L (TOI) 
 
FACT 
Esophageal 
Eating and 
Swallowing 
Subscales 
 
Continuous 
scores/outcomes 
 
T test; 
Analysis of covariance; 
Linear mixed effect 
model or general linear 
model with generalized 
estimating equations 
Secondary 
Endpoints 
 
 
Esophagitis 
Hypothesis B: At 12 
weeks after the start 
of XRT, patients in 
the 45Gy arm will 
experience worse 
esophagitis than 
those in the high 
dose daily (70Gy) 
and concomitant 
boost RT (61.2 Gy) 
groups. 
 
 
ECOG Acute 
Esophagitis 
Scale 
 
Difficulty 
swallowing 
 
Dichotomized or 
ordinal 
scores/outcomes 
 
Chi-square test;  
Logistic regression; 
Nonlinear mixed effect 
or generalized linear 
model with generalized 
estimating equations 
using log or multi-log 
link. 
 
 
 
 
Psychological 
state 
Hypothesis B: At 12 
weeks after the start 
of XRT, patients in 
the 45Gy arm will 
report a worse 
psychological state 
than those in the 
high dose daily 
(70Gy) and 
concomitant boost 
RT (61.2 Gy) 
groups. 
 
 
 
Hospital 
Anxiety and 
Depression 
Scale (HADS) 
 
Continuous 
scores/outcomes 
 
T test; 
Analysis of covariance; 
Line mixed effect 
model or general linear 
model with generalized 
estimating equations 
 
 
 
 
Quality-adjusted 
Life Years 
(QALY) 
Hypothesis B: At 12 
weeks after the start 
of XRT, the QALY 
of those in the 45 Gy 
will be worse than 
those in the high 
dose daily (70Gy) 
and concomitant 
 
 
 
 
 
 
 
 
EQ-5D 
 
Quality adjusted time 
to event 
variable/outcome 
 
Generalized log rank 
test for QALY data  
 
 

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boost RT (61.2 Gy) 
groups. 
 
 
 
 
Treatment 
Inconvenience 
Hypothesis C: At 7 
weeks after the start 
of XRT, treatment 
inconvenience will 
be greatest for those 
receiving 70Gy QD 
in 7 weeks.   
 
 
 
Single item 
developed for 
the study 
 
Dichotomized or 
ordinal 
scores/outcomes 
 
Chi-square test;  
Logistic regression; 
Nonlinear mixed effect 
or generalized linear 
model with generalized 
estimating equations 
using log or multi-log 
link. 
Refusal and attrition rates have been found to vary by disease site, stage, type of treatment, 
method of data collection, and length of follow-up. Osoba and Zee [78] conducted a review of 
completion rates in health–related quality of life assessments of the National Cancer Institute of 
Canada Clinical Trials Group, in which data were collected by self-administered questionnaires. 
In seven completed trials, quality of life completion rates were high with more than 93% of 
patients completing questionnaires at baseline and while on treatment. The rate of completion 
off treatment was 85%. In Ganz et al.’s [90] study of the quality of life of early stage Hodgkin’s 
disease patients, in which data was collected by mailed questionnaires, the completion rate by 
the second year was 70%. In a Gynecologic Oncology Group study of the quality of life of 
endometrial cancer patients randomized to either laparoscopy vs. laparotomy, in which data 
were collected by self-administered questionnaires, the completion rate by 6 months was 85% 
[91]. In a Cancer and Leukemia Group B study of patients with myelodysplastic syndrome 
treated by 5-Azacytidine (CALGB 9221) in which patients were interviewed by telephone about 
their quality of life, only 5% refused to continue the quality of life assessments over a 6 month 
study period [92]. In the Gynecologic Oncology Group trial of IP versus IV chemotherapy in 
ovarian cancer patients, where patients completed questionnaires in the clinic, 82% of IV and 
79% of IP patients completed self-administered questionnaires at 12 months after treatment. 
Therefore, given these findings, it is reasonable to assume a completion rate of quality of life 
data of at least 80% at both baseline and 12 weeks after the start of radiation therapy, which 
ensures adequate statistical power in conducting the planned comparisons at the designated 
levels of effect size and Type I errors. 
Power Analysis: 
The following assumptions are made in the power calculations: (1) Based on the literature and 
previous CALGB studies, we expect that at least 80% of eligible patients who register to the 
companion will complete the HRQOL assessments at both baseline and 12 weeks after the start 
of radiation therapy. That is, of the 394 eligible patients on the companion study, 150 patients 
in the two remaining study arms and 15 in the discontinued study arm will have complete 
HRQOL assessments at both baseline and 12 weeks after the start of radiation therapy; (2) 
Within each set of hypothesis (A, B, C), Type I error will be controlled at the level of 0.05. The 
Bonferroni method is used to address the issue of multiple comparisons for simplicity and 
reasonable performance with a small number of comparisons; and (3) Two-sided tests will be 
used. 
Hypothesis A 

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Three planned comparisons will be made to address Hypothesis A. The total TOI score from 
FACT TOI, the eating score and the swallowing score will be calculated from the FACT-
Esophagus Subscale. The change scores between baseline and 12 weeks after the start of 
radiation therapy are of interest. A size of 150 patients with complete assessments at baseline 
and 12 weeks after the start of radiation therapy in each of the two remaining arms will have 
85% power to detect an effect size of 0.397 s.d. unit on the scale of change score using a two 
group t-test at a significance level of 0.0167 (0.05/3). The effect size of 0.397 s.d. is usually 
associated with a moderate effect in quality of life literature. 
Hypothesis B 
Five comparisons will be made to address this hypothesis - ECOG esophagitis score (severe/≥7 
vs moderate/<7), difficulty swallowing (severe/≥4 vs. moderate/<4), HADS depression score, 
HADS anxiety score, and quality-adjusted life year (QALY). 
The ECOG esophagitis score ranges from 0 to 12 points. We will define patients with scores of 
≥7 as “Severe” and score <7 as “Moderate.” With 150 patients in each remaining arm with 
complete assessments at baseline and 12 weeks after the start of radiation therapy, a two group 
continuity corrected Chi-square test at a 2-sided significance level of 0.01 (0.05/5) will have 
80% power to detect the 18% difference of the proportions of patients with severe symptoms 
between the two remaining study arms, assuming 35% of patients in arm 1 report severe 
symptoms and 17% in the other remaining arm (odds ratio of 2.625). 
We define swallowing difficulty score as 4 or 5 as “Severe” and scores 1, 2, or 3 as “Moderate.” 
Similar to the ECOG esophagitis score, with 150 patients in each study arm, we have 80% power 
to detect a 18% difference of severe swallowing difficulty between the two study arms, assuming 
35% swallowing difficulty for arm 1 and 17% in the other arm. 
The depression and anxiety scores of HADS are of primary interest. Consider the change score 
between baseline and 12 weeks after the start of radiation therapy. With 150 in each of the two 
remaining arms, one has 85% power to detect an effect size of 0.419 s.d. unit on the scale of 
change score using a two group t-test at a significance level of 0.01. 
Quality-adjusted life years (QALY) is calculated as EQ-5D utility score weighted survival time. 
For the purpose of power calculation, consider a patient with a QALY greater than 12 weeks as 
“success” and less than 12 weeks as “failure.” With a size of 150 patients having EQ-5D score 
at baseline and 12 weeks, we have 90% power to detect a 20% difference of 12-week success 
rate, assuming the 12-week success rate is 65% for arm 1 (45 Gy) and 85% for the remaining 
experimental arm. 
Hypothesis C 
The different treatment arms have different dose schedules for different lengths of times, which 
may impact the satisfaction with treatment due to the inconvenience posed. Patients with an 
inconvenience rating of 1 or 2 will be defined as “Inconvenient” and those with a rating of 3 or 
4 as “Convenient.” If the remaining experimental arm is arm 2 (70 Gy), with 150 patients having 
inconvenience measure on each arm at baseline and 12 weeks after the start of radiation therapy, 
a two group continuity corrected Chi-square test at a significance level of 0.05 will have 81% 
power to detect the 16% difference of the proportion of patients reporting treatment 
inconvenience between the two remaining study arms, assuming 60% of patients in arm 1 report 
treatment inconvenience and 76% of patients in arm 2 report inconvenience. If arm 2 is 
discontinued after 30 patients have been accrued to the main study, with about 150 patients in 
arm 1 and 15 patients in arm 2 having complete assessment at baseline and 12 weeks, we will 
have 74% power to detect the 30% difference of the proportion of patients reporting treatment 
inconvenience between the two remaining study arms, assuming 60% of patients in arm 1 report 
treatment inconvenience and 90% of patients in arm 2 report inconvenience. 

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Analytic Methods: 
For continuous HRQOL (Health-Related Quality of Life) scores, including Physical Well-
Being, Functional Well-Being, Lung Cancer Physical Symptoms subscale scores from the 
FACT-TOI, Eating and Swallowing subscale scores from the FACT-Esophagus Subscale, and 
depression and anxiety subscale scores from HADS, two-group t test and analysis of covariance 
will be the primary method used to analyze and test the planned comparisons for the change 
scores from baseline to 12 weeks after the start of radiation therapy with and without adjusting 
for other prognostic factors. In analysis of covariance, in addition to study arm, significant 
baseline prognostic factors will be included in the model to adjust for confounding effects. These 
planned tests results will be reported at the significance level designated in the section of power 
analysis. Similar exploratory univariate analyses will be conducted for the change score from 
baseline to other assessment points at 3, 5, 7, 26, and 52 weeks after the start of radiation therapy. 
Multivariate analyses for evaluating the trend of HRQOL scores varying over time will be 
conducted using a linear mixed effect model and linear model with generalized estimating 
equation (GEE) with all valid measures from multiple time points included in the analysis. 
For binary dichotomized endpoints, such as ECOG esophagitis severity (severe/≥7 vs 
moderate/<7), difficulty swallowing (severe/≥4 vs. moderate/<4) and ordinal endpoints, such as 
treatment inconvenience (inconvenient/≤2 yes vs. convenient/≥3), Chi-square test and 
generalized linear model with a logit or multi-logit link will be used to test the planned 
comparisons. In regression analysis, baseline prognostic factors besides study arm will be 
included. Again, these planned tests will be reported at the significance level as designated in 
the section of power analysis. Similar multivariate analyses for evaluating the trend of HRQOL 
scores varying over time will be conducted using a nonlinear mixed effect model and generalized 
linear model with generalized estimating equation (GEE) with all valid measures from multiple 
time points included, in which logit link for dichotomized scores and multi-logit link for ordinal 
scores will be specified. In the analysis of ordinal scores, proportional odds assumptions will be 
tested. 
It is expected that a proportion of quality of life data collected at follow-up assessments will be 
missing due to various reasons, including failing health of patients. However, the percentage is 
expected to be less than 10% above and beyond that missing due to death. If the dominant 
missing mechanism is missing completely at random (MCAR) above and beyond the effect of 
study condition assignment, then the results based on complete data analysis will be unbiased. 
However, sensitivity analyses using different statistical methods and assuming different missing 
mechanisms (MCAR, MAR and NMAR) will be used to evaluate the robustness of main study 
findings from multivariate data analyses. 
The quality-adjusted overall survival will be calculated for each study arm based on the utility 
score from EQ-5D and the subgroup difference will be tested using the method developed by 
Zhao and Tsiatis [93]. 
15.8 
CDUS Reporting 
The Alliance Statistics and Data Center will submit quarterly reports to CTEP by electronic 
means using the Clinical Data Update System (CDUS). 

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16.0 
ADVERSE EVENT REPORTING (AER) 
Investigators are required by Federal Regulations to report serious adverse events as defined below. 
Investigators are required to notify the Alliance Central Office, the Study Chair, and their 
Institutional Review Board (IRB) if a patient has a reportable serious adverse event. The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for serious AE reporting beginning April 1, 
2018. This study will utilize version 4.0 for routine toxicity reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 
can be downloaded from the CTEP web site 
 All reactions determined to 
be “reportable” in an expedited manner must be reported using the NCI Adverse Event Expedited 
Reporting System (CTEP-AERS). 
16.1 
CALGB 30610 Adverse Event Reporting Requirements 
Phase 2 and 3 Trials: CTEP-AERS Expedited Reporting Requirements for Adverse Events 
That Occur Within 30 Days1 of the Last Dose of Treatment 
 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpect
ed  
and 
Expected 
 
 
Unexpecte
d 
 
 
Expecte
d 
Unexpected 
Expected 
Unexpect
ed  
Expecte
d 
with  
Hospital
i-zation 
without 
Hospital
i- zation 
with  
Hospita
li- 
zation 
without 
Hospita
li- 
zation 
Unrelat
ed 
Unlikel
y 
Not 
Required 
Not 
Required 
Not 
Require
d 
Not 
Require
d 
Not 
Require
d 
Not 
Require
d 
Not 
Require
d 
10 
Calendar 
Days 
10 
Calendar 
Days 
Possible 
Probabl
e 
Definite 
Not 
Required 
Not 
Required 
Not 
Require
d 
Not 
Require
d 
Not 
Require
d 
Not 
Require
d 
Not 
Require
d 
10 
Calendar 
Days 
10 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 
days after the last dose of treatment require reporting as follows: 
 
CTEP-AERS 10 calendar day report: 
• 
Grade 4 unexpected events 
• 
Grade 5 expected or unexpected events 
 
March 2005 
Note: All deaths on study require both routine and expedited reporting regardless of 
causality. Attribution to treatment or other cause should be provided. 
• 
Expedited AE reporting timelines defined: 
➢ "10 calendar days" - A complete CTEP-AERS report on the AE must be submitted 
within 10 calendar days of the investigator learning of the event. 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS. 

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• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
16.2 
Additional Instructions or Exclusions from CTEP-AERS Expedited Reporting 
Requirements: 
• 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in 
the system organ class (SOC) “General disorders and administration site conditions.” 
Evidence that the death was a manifestation of underlying disease (e.g., radiological changes 
suggesting tumor growth or progression: clinical deterioration associated with a disease 
process) should be submitted. 
Any death occurring within 30 days of the last dose, regardless of attribution to the 
investigational agent/intervention requires expedited reporting within 24 hours.  
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is possibly, 
probably, or definitely related to the investigational agent/intervention. 
• 
All grade 4 events that are unexpected and that are at least possibly related to treatment must 
be reported via CTEP-AERS within 10 calendar days. 
• 
Grade 4 events that are expected do not require CTEP-AERS expedited reporting, even if 
they result in hospitalization. 
• 
Adverse events include those listed in Section 11.0 and in the package inserts. 
• 
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB. 
• 
The reporting of adverse events described in the table above is in addition to and does not 
supplant the reporting of adverse events as part of the report of the results of the clinical 
trial, e.g., study summary forms or cooperative group data reporting forms (see Section 6.1 
for required CALGB forms). 
• 
Pregnancy loss is defined in CTCAE as “Death in utero.” Any Pregnancy loss should be 
reported expeditiously, as Grade 4 “Pregnancy loss” under the Pregnancy, puerperium and 
perinatal conditions SOC. A Pregnancy loss should NOT be reported as a Grade 5 event 
under the Pregnancy, puerperium and perinatal conditions SOC, as currently CTEP-AERS 
recognizes this event as a patient death. 
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under the 
General disorders and administration SOC. 
• 
All new malignancies must be reported via CTEP-AERS whether or not they are thought to 
be related to either previous or current treatment. All new malignancies should be reported, 
i.e. solid tumors (including non-melanoma skin malignancies), hematologic malignancies, 
myelodysplastic syndrome/acute myelogenous leukemia, and in situ tumors. In CTCAE 
version 5.0, the new malignancies (both second and secondary) may be reported as one of 
the following: (1) Leukemia secondary to oncology chemotherapy, (2) Myelodysplastic 
syndrome, (3) Treatment-related secondary malignancy, or (4) Neoplasms benign, 
malignant and unspecified-other. Whenever possible, the CTEP-AERS reports for new 
malignancies should include tumor pathology, history or prior tumors, prior 
treatment/current treatment including duration, any associated risk factors or evidence 
regarding how long the new malignancy may have been present, when and how the new 
malignancy was detected, molecular characterization or cytogenetics of the original tumor 
(if available) and of any new tumor, and new malignancy treatment and outcome, if 
available. 

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17.0 
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