A Phase II Randomized Study of 2 Stereotactic Body Radiation Therapy (SBRT) Regimens for Medically Inoperable Patients With Node Negative, Peripheral Non-Small Cell Lung Cancer
Phase: PHASE2
Conditions: Lung Cancer
Sponsor: Roswell Park Cancer Institute

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A Phase II Randomized Study of 2 Stereotactic Body Radiation 
Therapy (SBRT) Regimens for Medically Inoperable Patients with 
Node Negative, Peripheral Non-Small Cell Lung Cancer
Protocol #: I 124407
Roswell Park Cancer Institute
Elm & Carlton Streets
Buffalo, New York 14263
Principal Investigator
Anurag K. Singh, MD
Final Version:  4/23/08
Amendment #1: 6/3/08
Amendment #2: 8/7/08
  Amendment #3: 10/9/08
 Amendment #4: 2/2/09
Amendment #5: 5/19/09
Amendment #6: 7/26/11
Amendment #7: 2/3/14
Amendment #8: 7/18/17
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NCT#00843726

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Network Investigator Signature Page
Protocol #: I 124407
A Phase II Randomized Study of 2 Stereotactic Body Radiation 
Therapy (SBRT) Regimens for Medically Inoperable Patients with 
Node Negative, Peripheral Non-Small Cell Lung Cancer
PROTOCOL APPROVAL AND INVESTIGATOR AGREEMENT
I have read and familiarized myself with this protocol and I agree to conduct the study as 
described according to GCP and ICH guidelines.
Principal Investigator
Signed
Date
Printed
Address:
Phone:
Fax:
E-mail:
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NOTE: Please see Appendix III for Network-specific instructions that will 
apply to your site.
ABSTRACT

Principal Investigator: Anurag K. Singh, M.D.

Co-Investigators: Heinz Baumann, PhD; Todd Demmy, MD; Jorge 
Gomez, MD; Dominick Lamonica, MD; C.E. Nwogu, MD;  Harish Malhotra, 
PhD;  Austin Miller, PhD;  Sai Yendamuri, MD and Hua Zhao, PhD 

Phase: II Randomized

Objectives:  To determine the incidence of RTOG grade 3 or higher 
toxicity with 2 different radiation therapy regimens.

Treatment Overview:  Randomized between 30 Gy once or 20 Gy x 3.

Eligibility Criteria:  Medically inoperable patients with node negative, 
peripherally located, histologically proven NSCLC ≤ 5 cm are eligible.

Subjects and target study duration:  The trial will accrue 98 patients 
over 12 years.

Endpoints:  Incidence of RTOG grade 3 or higher toxicity, overall 
survival, correlations between blood and serum markers and survival and 
toxicity.

Statistics:  This is a phase II randomized study to compare incidence of 
RTOG grade 3 or higher toxicity associated with 2 different, established 
SBRT regimens for NSCLC. Group sample sizes of 49 in group one (Gy x 
3) and 49 in group two (Gy x 1) achieve 81% power to detect a difference 
between the group incidences of toxicity of 0.17. The incidence of toxicity  
in group one (the treatment group) is assumed to be 0.03 under the null 
hypothesis and 0.2000 under the alternative hypothesis. The proportion in 
group two (the control group) is 0.03. The test statistic used is the one-
sided Z test with continuity correction and unpooled variance. The 
significance level of the test was targeted at 0.05. The significance level 
actually achieved by this design is 0.0037.
Descriptive statistics will be presented for each group. Incidence of toxicity 
will be compared using Z test.  Disease free survival and overall survival 
will be compared between two groups using log-rank test statistics. 
Correlation analysis will be performed to explore the relationship between 
outcomes and toxicities with tumor biomarkers. The estimate of acute and 
long term toxicity associated with SBRT for NSCLC will be reported.
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SCHEMA
ARM 2
SBRT 20 Gy x 3 fractions = 60 Gy
1.
Obtain Imaging (PET/CT)
2.
Labs, PFT’s (Full spirometry and 
DLCO)
3.
OPTIONAL Collect: 
a.
blood 
b.
urine
↓
ELIGIBILITY:
(1) Medically inoperable, 
(2) node negative, 
(3) peripherally located, 
(4) histologically proven NSCLC ≤ 5 cm
REGISTER
STRATIFY by: Performance status, treatment center
Follow Up
1)
Obtain Imaging
2)
Labs, PFT’s (Full spirometry and 
DLCO)
3)
OPTIONAL Collect: 
a.
blood 
b.
urine
ARM 1
SBRT 30 Gy x 1 fraction
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Table of Contents
1.0  BACKGROUND and RATIONALE ........................................................................6
1.1 Sterotactic Body Radiation Therapy (SBRT) .......................................................6
1.2 Predictors of Outcomes (Imaging, Biomarkers, etc) ..........................................10
1.3 Roswell Park Cancer Institute Experience to Date ............................................11
2.0  STUDY PURPOSES AND OBJECTIVES.............................................................13
2.1  Primary..................................................................................................................12
2.2  Secondary:.............................................................................................................12
3.0  ELIGIBILITY CRITERIA......................................................................................12
3.1  Inclusion criteria...................................................................................................12
3.2  Exclusion Criteria.................................................................................................12
4.0  PRE-TREATMENT EVALUATION .....................................................................13
4.1  Clinical Evaluation ...............................................................................................13
4.2  Pre-treatment Data Acquisition ..........................................................................13
5.0  INFORMED CONSENT..........................................................................................13
6.0  TREATMENT PLAN...............................................................................................13
6.1   Study Design.........................................................................................................13
6.2  Protocol Administration...........................................................................................14
7.0  STUDY CALENDAR ...............................................................................................29
8.0 TREATMENT MODIFICATIONS.........................................................................30
8.1  Radiation Treatment Modifications....................................................................30
8.2  Off Study Criteria.................................................................................................30
9.0  RESPONSE CRITERIA ..........................................................................................30
10.0  ADVERSE EVENTS ..............................................................................................33
10.1  Adverse Events Reporting .................................................................................33
10.2 Serious Adverse Events (SAE)............................................................................33
10.3 Reporting Serious Adverse Events.....................................................................34
10.4 SAE Follow-up .....................................................................................................34
11.0   DATA SAFETY AND MONITORING PLAN ...................................................34
12.0  STATISTICAL ANALYSIS ..................................................................................34
13.0  REFERENCES .......................................................................................................36
APPENDIX I - COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS (CTCAE) 
APPENDIX II - QUALITY OF LIFE QUESTIONNAIRES
APPENDIX III - INSTRUCTIONS FOR NETWORK SITES
APPENDIX IV - KARNOFSKY PERFORMANCE STATUS
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1.0  BACKGROUND and RATIONALE
Lung cancer remains the leading cause of cancer death with an estimated 
213,380 new cases diagnosed in 2007 with 160,390 deaths1.  Approximately 
75% of lung cancers are non-small cell lung cancer (NSCLC) and 15-20% of 
NSCLC patients are diagnosed with localized disease1.  With improved 
screening, the percent of patients diagnosed with localized disease is expected 
to rise2.
Surgery is the mainstay of treatment for localized NSCLC with favorable 5 year 
survival rates of 65-70%3.  However, NSCLC often occurs in patients with 
compromised lung function. Thus, many patients with localized disease are 
termed medically inoperable4.  
Radiation using conventional techniques has been used extensively5, 6.  
However, outcomes have been inferior to surgery alone. Rates of 5 year survival 
with definitive RT have ranged from 10-30%6-9, well inferior to rates of 65-70% 
achieved with surgery alone3, 10.
Many factors have been suggested to explain this discrepancy in outcomes. 
Notably, cause-specific survivals are 10-20% higher than overall survivals in 
medically inoperable patients due to mortality from competing causes8, 9, 11, 12. 
Additionally local failures, up to 85% biopsy proven13, have continued to be a 
problem following curative radiation therapy.
High rates of local failure have spurred several trials in dose escalation with 
conventional fractionation. Several have shown improved outcomes with higher 
doses 9, 14-18. However, not all series have shown improved survival with higher 
doses11, 19. 
Such mixed results and overall suboptimal outcomes with conventional 
fractionation have prompted evaluation of alternate fractionation schemes17, 20, 21. 
Alternate fractionation schemes employing conventional treatment margins have 
shown significantly increased toxicity20. 
Efforts to increase the dose per fraction to the tumor while limiting the dose to 
surrounding normal tissues has lead to the development of stereotactic body 
radiation therapy (SBRT.) SBRT used has been the topic of a growing number of 
single institution and cooperative group studies22-25.
1.1 Sterotactic Body Radiation Therapy (SBRT)
As shown below, SBRT has been shown to have excellent results and low 
toxicity with either single or multiple fraction schemes. The data suggest 
that 30 Gy in a single fraction is superior to doses less than 30 Gy. For 
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multiple fraction schemes, 20 Gy times 3 fractions appears to be a safe 
and effective dose.
1.1.1 Multiple Fraction SBRT (for peripheral lesions)
Onishi et al. reported outcomes among 257 patients treated in 14 
Japanese centers with SBRT using many dosing schemes (1-22 fractions 
at 3-12 Gy per fraction).  Total dose ranged from 18 to 75 Gy. With 38 
months median follow-up, patients receiving a biologically equivalent dose 
(BED) of >100 Gy experienced fewer local recurrences than those patients 
receiving < 100 Gy BED (42.9 vs 8.1%, p<0.001.) Similarly, survival was 
significantly improved with higher BED doses, 70.8 vs. 30.2% (p<0.05.) 
grade 3 or higher toxicity was observed in 5.4% 26.  
Echoing these results, Wulf et al. studied the dose-response for local 
tumor control after SBRT in 92 pulmonary tumors (36 NSCLC and 56 
metastases.). Short course irradiation of 1-8 fractions with different 
fraction doses was used. After a median follow-up of 14 months (2-85 
months) 11 local recurrences were observed. A BED dose of 94Gy at the 
isocenter and 50Gy at the PTV-margin were demonstrated to give 50% 
probability of tumor control (TCD50). Multivariate analysis revealed the 
dose at the PTV-margin as the only significant factor for local control. No 
severe toxicity was observed27.
While the initial experience with multi-fraction SBRT regimens as 
summarized above showed very little toxicity, more recent publications 
have shown higher rates of toxicity, likely somewhat secondary to more 
rigorous reporting of toxicities in more recent trials.
Baumann et al. reported on 138 patients with stage I NSCLC treated with 
SBRT delivered using a 3D conformal multifield technique and a 
stereotactic body frame. Doses delivered were 30-48 Gy (65% isodose at 
the periphery of PTV) in 2-4 fractions. Equivalent dose in 2 Gy fractions 
(EQD2) was in the range of 50-100 Gy. Three- and 5-year overall survival 
was 52 and 26% respectively. Lung cancer specific 3- and 5-year overall 
survival was 66 and 40% respectively. EQD2 (> vs <55.6 Gy) showed a 
statistically significant survival benefit for the higher doses. Fifty nine 
percent (83/138) of the patients had no side effects. Fourteen patients 
(10%) experienced RTOG grade 3-4 toxicity28.
1.1.2 Multiple Fraction SBRT (the Indiana Univiersity Experience)
Investigators at Indiana University conducted a Phase I study among 47 
patients with Stage IA or IB NSCLC. The study began at a dose of 8Gy in 
3 fractions and escalated to a dose of 24 Gy in 3 fractions.  Significantly 
decreased rates of LR (only 1 of 9) were noted among patients receiving 
>16 Gy per fraction. No significant toxicities were reported at 20 Gy per 
fraction. The maximum tolerated dose was realized at 72 Gy for tumors 
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larger than 5 cm. Dose-limiting toxicity included bronchitis, pericardial 
effusion, hypoxia, and pneumonitis 29.
Timmerman et al. carried out a prospective, phase II, 70 patient trial using 
stereotactic body radiation therapy (SBRT) to doses of 60 to 66 Gy in 
three fractions during 1 to 2 weeks. With a median follow-up of 17.5 
months, the 3-month major response rate was 60%. Kaplan-Meier local 
control at 2 years was 95%. Grade 3 to 5 toxicity occurred in a total of 14 
patients. Six patients died as a consequence of treatment related toxicity. 
Median overall survival was 32.6 months and 2-year overall survival was 
54.7%. Among patients experiencing toxicity, the median time to 
observation was 10.5 months. Tumors with GTV volume of more than 10 
mL had an eight-fold risk of high-grade toxicity compared with smaller 
tumors (P = .017). Patients treated for tumors in the peripheral lung had 2-
year freedom from severe toxicity of 83% compared with only 54% for 
patients with central tumors30.
Based on the early experience from Indiana University31, the Radiation 
Therapy Oncology Group (RTOG) opened a prospective trial of SBRT in 
2004 (RTOG study 0236.)  This study enrolled 52 medically inoperable 
patients with peripherally located, node negative NSCLC measuring ≤5cm. 
Patients received three 20 Gy fractions over 10-14 days. The trial was 
closed to accrual in October 2006.  Early results in abstract form show 
15% grade 3-4 toxicity. Specifically, with median follow-up of 8.7 months, 
there was one (2%) grade 4 and 7 (13%) grade 3 pulmonary/upper 
respiratory adverse events reported as related to protocol treatment. Two 
of the 7 pts reported pulmonary function test decreased, 1 pt reported 
cough/dyspnea, 1 pt reported hypoxia, 1 pt reported pneumonitis, 1 pt 
reported cough/forced expiratory volume, and 1 pt reported 
pneumothorax. There was also a grade 3 dermatitis and a grade 3 
syncope reported as related to protocol treatment. No treatment related 
deaths have been reported32. As the median time to toxicity was 
previously reported to be 10.5 months in the previous Timmerman 
publication30, the observed toxicity reported in this RTOG abstract (with 
only 8.7 months of follow-up) can be expected to rise. 
1.1.3 Single Fraction SBRT (for peripheral lesions)
Hof et al. reported outcomes among 42 patients with stage I or II NSCLC 
treated with single dose SBRT (dose range 19-30 Gy.)  With a median 
follow-up of 15 months, overall survival and disease free survival at 12, 
24, and 36 months were 74.5%, 65.4%, 37.4% and 70.2%, 49.1%, and 
49.1% respectively.    Local tumor control was 89.5%, 67.9%, and 67.9% 
at the same time points.  Local tumor control was significantly improved in 
those patients receiving 26-30 Gy (n=32) versus lower doses (p=0.032)33. 
Regarding toxicity, follow up CT scan normal tissue changes (including 
pneumonitic changes and fibrosis) were noted in the treatment area in 
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64.3% of patients.  However, no CTC grade 3 or 4 toxicities were noted.  
Minor cough and slightly increased dyspnea were the only clinical 
toxicities observed.  
Hara et al reported outcomes among 59 patients with malignant lung 
tumors (11 primary lung tumors, 48 metastases) treated for localized 
disease within the lung or metastatic disease to the lung and noted one 
and two year local progression free rates of 93 and 78%.  All patients were 
treated with single dose SBRT and improved local control was noted 
among patients receiving >30 Gy versus 26-30 Gy (9 patients.) Local 
regrowth of the irradiated tumor was a direct cause of death in two 
patients. Only the minimal radiation dose to the reference target volume 
tended to have an influence on the LPFR (P = 0.068). RTOG Grade 3 
respiratory symptoms were noted in one patient34.
1.1.4 Rationale for the Current Study Design
From the aforementioned studies, we can conclude that single fraction 
and multi-fraction SBRT regimens are feasible and yield excellent local 
control.  Most studies have used the multi-fraction regimen and no prior 
study has compared the two regimens in terms of efficacy and toxicity.
With multi-fraction regimens, the severe toxicity of 17% for those with 
peripheral lesions reported by Indiana University30 is greater than 
suggested by the data summarized in section 1.1.1, which includes 
previous data from Indiana. For this reason, even in patients with 
peripheral lesions, it is imperative that SBRT be performed in the setting of 
a clinical trial (as opposed to routine clinical practice) so that the true 
incidence of toxicity can be captured and reported.
Of interest, no studies have yet shown major toxicity with single fraction 
regimens of 30 Gy. However, toxicities have been more rigorously 
monitored and reported in studies of multi-fraction regimens.  
Given excellent reported control rates for both regimens, and absent any 
significant reported toxicity for single fraction therapy, a comparison of 30 
Gy in one fraction versus 60 Gy in 3 fractions is warranted.  Comparison 
of these regimens via a randomized prospective trial will allow for 
collection of a wealth of valuable information including, but not limited to, 
toxicity, outcomes, cost, patient comfort, and radiobiologic and dosimetric 
comparisons.
Interestingly, the Radiation Therapy Oncology Group (RTOG,) has chosen 
not to pursue single fraction regimens. Even, for central lesions where 
toxicity is high with the RTOG’s preferred 20 Gy x 3 regimen, currently 
planned studies hope to reduce toxicity by increasing the number of 
fractions and reducing dose. A similar strategy appears to taking hold in 
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Japan. Certainly, reimbursement is less for a single fraction treatment and 
the effect of this variable is difficult to ascertain. Only in Germany does 
there appear to be interest in single fraction regimens. Consequently, it 
appears unlikely that many other institutions would be interested in the 
study design proposed here.
1.2 Predictors of Outcomes (Imaging, Biomarkers, etc) 
Although studies have demonstrated improved outcomes among patients 
treated with SBRT versus conventional techniques, patients continue to 
fail and some experience significant toxicity. 
A well delineated, uniformly staged, and followed prospective cohort would 
be invaluable at interrogating and validating known predictors of toxicity 
and outcome. Also, analysis of data from such a cohort may identify novel 
predictors of outcome following SBRT. 
Additionally, serial PFTs, imaging data, dosimetry data, blood and urine 
samples will be collected for these analyses . 
The study team members will perform clinical data collection and utilize 
the RPCI Data Bank and BioRepository (DBBR) infrastructure to 
companion bank blood and urine samples points alongside the trial.  
Network sites will not be participating in this companion study.    
At the time of trial consent, at the discretion of the treating physician and 
PI, patients may be asked to simultaneously enroll in the DBBR as a 
companion banking study (RPCI protocol I 03103).  Study team members 
will register the banking consent and associated enrollment information 
with DBBR, provide patients with the baseline DBBR epidemiologic 
questionnaire, and schedule blood and urine sample collection using the 
DBBR shared resource laboratory calendar, following standard work 
instructions for companion banking.
The DBBR is a shared institutional core resource where participants are 
asked to donate blood for research (prior to and following treatments), to 
complete an epidemiologic questionnaire, and to give permission to have 
their blood specimens linked to the questionnaire and clinical data 
including diagnosis and laboratory test results for research.  Collected 
biospecimens and/or data are provided to investigators with RPCI IRB 
approved research protocols.  
Patients that have already donated and banked appropriate pre-treatment 
specimens through another RPCI service and are usable for this study, 
will not be asked to donate additional pre-treatment (baseline) specimens. 
All samples and associated sample data from DBBR will be linked to the 
clinical data collected by the trial Coordinators, and de-identified prior to 
receipt for analysis.  Per protocol, the DBBR will maintain the key between 
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the participant's PHI and study ID. Only designated DBBR personnel 
associated with operating the bank have access to this link.  The key will 
never be given to the investigator of this study.
Participation in sample collection with the DBBR is optional.
1.2.1 Future Potential Studies
A variety of blood and urine markers have been found to be associated 
with outcomes and treatment effects. At the time of completion of this 
study, we will identify the most promising of these markers and 
retrospectively review some of the samples banked at the DBBR.  Patients 
will be consented for this possibility.
1.2.2 FDG-PET staging and follow-up
The value of FDG-PET in NSCLC staging has been established and is 
accepted35. FDG-PET for staging is even accepted by the NCCN 
guidelines. Recent publications suggest that FDG-PET can be a predictor 
of response following conventional radiation therapy36 and SBRT37, 38. 
Though fewer than fifty patients were involved in these studies, in practice 
FDG-PET is widely used and reimbursed for follow-up.
1.2.3 Pulmonary Function Testing
Paludan et al. analyzed the association of dose-volume histogram 
parameters with changes in dyspnea. Of 28 medically inoperable stage I 
NSCLC patients that received SBRT to 45 Gy/3 fractions over 5-8 days, 
aggravated dyspnea was registered in 11 patients (40%). Disturbingly, no 
association between DVH parameters and changes in dyspnea was 
found. Upon further analysis, the authors found observed that aggravation 
of dyspnea following SBRT reflected underlying COPD rather than 
treatment-related toxicity. The authors concluded that concern about 
pulmonary toxicity should not be prohibitive for future studies targeting 
limitations to dose and volume39.
This experience highlights the need for close follow-up of pulmonary 
function following radiation therapy.
1.3 Roswell Park Cancer Institute Experience to Date
Since March 2006 we have treated 23 NSCLC patients with SBRT (60 Gy 
in 3 fractions.) No significant toxicities have been seen. 
In addition, Cleveland Clinic is a high volume center for SBRT. They have 
expressed an interest in joining this study. The administrative process is 
underway. For this reason the stratification variables were changed to 
performance status and treatment center.
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2.0  STUDY PURPOSES AND OBJECTIVES
2.1  Primary:
2.1.1 To compare incidence of toxicity with two established SBRT 
regimens for NSCLC 
2.2  Secondary:
2.2.1 To compare QOL, patterns of failure, disease free survival, 
and overall survival associated with 2 two established SBRT 
regimens for NSCLC 
2.2.2 To correlate outcomes and toxicities with imaging and patient 
and tumor biomarkers
3.0  ELIGIBILITY CRITERIA
3.1  Inclusion criteria

Histologically confirmed NSCLC

T1-T2, N0 measuring ≤ 5 cm (T3 based on chest wall involvement is 
excluded)

Surgically resectable primary, however patient evaluated by thoracic 
oncologist and deemed medically inoperable or patient refuses 
surgical resection

Age ≥ 18
3.2  Exclusion Criteria

Prior Thoracic Radiation Therapy 

T2 or T3 tumor greater than 5 cm or T3 tumor based on chest wall 
involvement

Node positive or metastatic disease

Tumor location within the zone of the proximal bronchial tree. The 
proximal bronchial tree is defined as the carina, right and left main 
bronchi, right and left upper lobe bronchi, bronchus intermedius, right 
middle lobe bronchus, lingular bronchus, and right and left lower lobe 
bronchi. The zone of the proximal bronchial tree is defined as a volume 
2cm in all directions around the proximal bronchial tree.

Other conditions deemed by the PI or associates to make the patient 
ineligible for protocol investigations, procedures, and high-dose 
external beam radiotherapy. This includes the inability to cooperate 
with any aspect of SBRT such as the inability to lie still and breathe 
reproducibly.

Pregnant or unwilling to use adequate contraception.
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4.0  PRE-TREATMENT EVALUATION
4.1  Clinical Evaluation 

Evaluation by thoracic surgical oncologist

Evaluation by radiation oncologist

Performance status
4.2  Pre-treatment Data Acquisition

PFT’s (Full spirometry and DLCO)

Urine pregnancy test for women of child bearing potential

PET-CT 

CT of the Chest/Abdomen/Pelvis (CT Simulation is acceptable. The 
abdomen and pelvis CT studies may be omitted if the PET-CT covers 
the abdomen and pelvis.)

Tumor Biopsy

Specimens for banking: blood and urine (will be requested but is 
optional)

Toxicity evaluation

Quality of Life Questionnaire
5.0  INFORMED CONSENT
An informed consent for this trial meeting Federal and Institutional requirements 
will be obtained from each patient prior to enrollment in the study.  The informed 
consent will inform each patient of what is involved, the risks, alternatives, who to 
contact for questions and that participation is voluntary.  Additionally, patients will 
be asked to consent to the RPCI Data Bank and BioRepository as a companion 
study for future analyses (I 03103). Participation in this DBBR companion study, 
though encouraged, is at the discretion of the treating physician and PI. 
Participation in the DBBR is not required for participation in this trial. Patients 
who have already consented to the DBBR companion study will not need to be 
re-consented or have their pre-treatment samples re-drawn if done previously. 
Network sites will not be participating in this DBBR companion study.
6.0  TREATMENT PLAN
6.1   Study Design
Medically inoperable patients with node negative, peripherally located, 
biopsy proven NSCLC measuring ≤5 cm will be enrolled, stratified, and 
randomized to receive multi-fraction or single fraction SBRT.   
Patients will be stratified by KPS into one of three groups (See Appendix 
IV) and treatment center. (100, 90, 80 and below). 
Prior to SBRT delivery, patients will undergo baseline imaging using 
PET/CT and will undergo formal pulmonary function testing.  Blood and 
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urine samples will also be formally collected and stored for future 
correlative studies.  
Patients randomized to the multi-fraction arm will receive 3 high dose 
fractions of radiation to the primary lung tumor.  Those randomized to the 
single fraction arm will receive a single high dose fraction using SBRT. 
Overall treatment time for one fraction is one day, for three fractions is 8-
24 days. Treatment may start within 4 weeks after registration.
SBRT is a technique that allows for improved precision of radiation 
delivery.  In order to deliver stereotactic radiotherapy, precise mechanisms 
of patient immobilization, tumor localization, and beam delivery are 
required and discussed in detail below.  
Following SBRT delivery, imaging and pulmonary function studies will be 
regularly performed to monitor tumor status and toxicity.  Blood and urine, 
samples may also be formally collected and stored, as described above, 
following SBRT and in the event of tumor recurrence such that correlative 
studies can be performed.  
           6.2  Protocol Administration
6.2.1  Dose Specifications
Note: Intensity Modulated RT (IMRT) Is Not Allowed without approval of PI.
 6.2.1.1 Stereotactic Targeting and Treatment 
The term “stereotactic” for the purposes of this protocol implies the 
targeting, planning, and directing of therapy using beams of radiation 
along any trajectory in 3-D space toward a target of known 3-D 
coordinates. This differs from conventional radiation therapy in which 
therapy is directed toward skin marks or bony landmarks that are 
indirectly referenced to the tumor. This protocol will require treatments to 
be conducted with the use of a fixed 3-D coordinate system defined by 
fiducials. The coordinate system defined by the fiducials should be 
directly related to the radiation producing device (e.g., couch and gantry) 
in a reproducible and secure fashion. Capability should exist to define 
the position of targets within the patient according to this same 3-D 
coordinate system. As such, the patient is set up for each treatment with 
the intention of directing the radiation toward an isocenter or target 
according to the known 3-D coordinates as determined in the process of 
treatment planning. The nature of the fiducials themselves may include 
radio-opaque markers or rods placed at known locations in a frame or 
fixed structure adjacent to the patient as well as use of the tumor itself as 
a fiducial (e.g. acquiring tomographic views of the tumor simultaneously 
with the treatment). Metallic “seeds” placed within the tumor will not 
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generally be allowed to constitute a fiducial unless the site employing 
this technique provides satisfactory validation to the Study Chair 
indicating no seed migration and reproducibility of target positioning from 
treatment to treatment and obtains permission in writing from the Study 
Committee (Principal Investigator and Co-Chairs) prior to treatment. 
6.2.1.2 Dose Fractionation 
Patients will receive 1 (30 Gy) or 3 (20 Gy) fractions of radiation. A 
minimum of 40 hours and a maximum of 8 days should separate each 
treatment. No more than 2 fractions will be delivered per week (7 
consecutive days). The dose for all patients per fraction will be to the 
prescription line at the edge of the PTV. If giving 3 fractions, treatment 
will be delivered as above over 8-24 days for a total of 60 Gy. Overall 
treatment time for one fraction is one day, for three fractions is 8-24 
days. Treatment may start within 4 weeks after registration.
6.2.1.3 Premedications 
Unless contraindicated, it is recommended that all patients receive 
corticosteroid premedication (e.g. Decadron 4 mg p.o. in a single dose, 
or equivalent) 15-60 minutes prior to each of the treatment for the 
intended purpose of modulating immediate pulmonary inflammatory 
effects. Analgesic premedication to avoid general discomfort during long 
treatment durations also is recommended when appropriate. 
6.2.2 Technical Factors
6.2.2.1 Physical Factors 
Only photon (x-ray) beams produced by linear accelerators, betatrons, or 
microtron accelerators with photon energies 6-23 MV will be allowed. 
Cobalt-60 and charged particle beams (including electrons, protons, and 
heavier ions) are not allowed. Photon beam energies greater than 6 MV 
but not more than 23 MV will only be allowed for a limited number (≤ 2) 
beams that must travel more than a cumulative distance of 10 cm 
through soft tissue (not lung) to reach the isocenter. 
6.2.2.2 Minimum Field Aperture (Field Size) Dimension 
Due to uncertainties in beam commissioning resulting from electronic 
disequilibrium within small beam apertures, a minimum field dimension 
of 3.5 cm is required for any field used for treatment delivery. It is 
understood that this may exceed the technical requirements listed in 
Section 6.4 for small lesions (< 2.5 cm axial GTV dimension or < 1.5 cm 
cranio-caudal GTV dimension). In such cases, the prescription dose is 
still prescribed to the edge of the defined PTV. This minimum field 
dimension does not apply to centers using tomotherapy or multiple 
pencil beam delivery systems. 
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6.2.2.3 Dose Verification at Treatment 
Personal dosimeter measurements (e.g. diode, TLD, etc.) may be 
obtained for surface dose verification for accessible beams as per 
institutional preference. This information is not required by the protocol. 
6.2.3 Localization, Simulation, and Immobilization 
6.2.3.1 Patient Positioning
Patients will be positioned in a stable position capable of allowing 
accurate reproducibility of the target position from treatment to 
treatment.  Positions uncomfortable for the patient should be avoided so 
as to prevent uncontrolled movement during treatments.
It is very important that a rigid immobilization device be prepared in the 
CT Simulator to ensure reproducible set up of the patient during his/her 
treatment.  Selection of an appropriate immobilization device will be 
done after consulting with the physician who may elect to use one or 
many such immobilization devices together [e.g. BodyFix along with 
vaclock system etc.] for a particular patient. 
   6.2.3.2 Internal Organ Motion/ Tumor Localization
Patients will undergo simulation using a respiratory gating technique 
which synchronizes radiation delivery to an individual’s breathing cycle.  
Image acquisition takes place only during a pre-specified portion of the 
respiratory cycle (maximum inhalation or end-expiration) thus helping to 
determine margins needed to encompass tumor motion throughout the 
breathing cycle.  Respiratory gating will be used only for determination of 
ITV and is not used for actual treatment delivery.
Due to significant intrafraction motion of the tumor, it is proposed to use 
respiratory gating to determine the maximum extent of tumor motion by 
taking at least 2 additional scan sets/series viz. exhale and inhale phase.  
The gated CT image set can cover a much smaller superior-inferior 
extent.  These limits will be defined by the radiation oncologist and are 
usually 2 cm beyond the GTV limits defined earlier utilizing the 
topogram/scout view. The patient is now instructed to breathe in a 
reproducible manner. Using the RPM system, appropriate threshold 
levels are then generated for phase based gating enabling gated CT-
data acquisition in the inhale and exhale stage.  It is very important to 
ensure that the couch parameters and the patient position remain 
unchanged in all the three series acquisitions [normal breathing, 
exhale & inhale state]. The necessary gating parameters, as well as 
the other series identification information will be recorded in the 
conventional free-breathing gating sheet in use for such patients and will 
be attached with the patient’s chart.  It is important to remember that the 
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above procedure mentioned for determining the ITV is strictly true only 
for the single-slice CT scanner allowing prospective gating scans.
In some lung SBRT cases, it may not be possible to use RPM gating 
system to acquire the additional scans in inhale and exhale phase as the 
patient may be having very shallow breathing pattern.  In those type of 
circumstances, it might be easier to acquire a cone beam CT scan 
(CBCT). The CBCT will then be co-registered with regular normal 
breathing CT simulation image series and will be used instead of the 
inhale and exhale image series obtained through respiratory gating.  
Cone beam CT images will be taken just prior to delivery of each 
radiation fraction while the patient is in the treatment position on the 
linear accelerator.  These CT images can be compared with the original 
treatment planning CT and adjustments can be made as necessary to 
precisely conform treatment delivery to the original plan.  This process 
may be repeated during RT more than once per physician discretion.
Cone beam CT will give an idea about the average tumor motion as the 
CBCT image is reconstructed using 550+ planar images acquired in 
around 1 minute.  Such an image can either be acquired directly using 
CBCT application or can also be generated through the regular process 
of 3D/3D match.  Please note that prior to acquiring these CBCT images, 
the patient will be repositioned on the Trilogy couch exactly the same 
way as it was on the CT Simulator.  The reconstructed CT images can 
then be imported and registered in Eclipse.  Since OBI station is on its 
own network, a direct transfer of the patient files which are in 
D:\patient\MR# directory is not possible but Compact disks [CDR] can be 
used to burn the images.  Virus free flash drives may also be used for 
this purpose.  
Tumor localization methods are constantly evolving. As other accepted 
methods of tumor localization become available, including image based 
and implantable fiducial marker based methods, these may be 
substituted at the PI’s discretion. 
6.2.4  Treatment Planning/Target Volumes 
6.2.4.1  Image Acquisition
Computed Tomography (CT) will be the primary image platform for 
targeting and treatment planning. The planning CT scans must allow 
simultaneous view of the patient anatomy and fiducial system for 
stereotactic targeting.  If IV contrast dye is used, then 1) 2 sets of 
images one without the dye and one with the dye should be done or 2) a 
bulk density must be defined in the treatment planning system for the 
region of dye.  Axial acquisitions with gantry 0 degrees will be required 
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with spacing ≤ 3.0 mm between scans. Images will be digitally 
transferred to the treatment planning computers. 
Once images have been transferred to the planning system, the target lesion and 
surrounding normal tissue structures will be outlined by the treating physician.  
The target will generally be drawn using CT pulmonary windows; however, soft 
tissue windows with contrast may be used to avoid inclusion of adjacent vessels, 
atelectasis, or mediastinal or chest wall structures within the GTV. The Gross 
Tumor Volume (GTV) is defined as the visible tumor on CT.  No margin will be 
added for presumed microscopic extension.  The Clinical Target Volume (CTV) 
and GTV are thus identical.  
There are 2 acceptable methods to define the PTV depending on the method of 
CT simulation:
(a)
Conventional (helical) CT-simulation (non-4DCT): The 
PTV will include the GTV plus an additional 0.5 cm margin 
in the axial plane and 1.0 cm margin in the longitudinal 
plane (craniocaudal).
(b)
4D CT-simulation: An internal target volume (ITV) 
around the GTV, accounting for tumor motion may be 
defined from the 4D CT dataset. The PTV will include the 
ITV plus an additional 0.5 cm margin uniformly applied to 
the ITV.
These margins will be used at all institutions, even if a particular institution uses 
equipment or techniques felt to be more accurate. 
6.2.4.2 Dosimetry 
Three-dimensional coplanar or non-coplanar beam arrangements will be 
custom designed for each case to deliver highly conformal prescription 
dose distributions. Non-opposing, non-coplanar beams are preferable. 
Typically, 7-10 beams of radiation will be used with roughly equal 
weighting. Generally, more beams are used for larger lesion sizes. When 
static beams are used, a minimum of 7 non-opposing beams should be 
used. For arc rotation techniques, a minimum of 340 degrees 
(cumulative for all beams) should be utilized. For this protocol, the 
isocenter is defined as the common point of gantry, collimator, and 
couch rotation for the treatment unit. Field aperture size and shape 
should correspond nearly identically to the projection of the PTV along a 
beam’s eye view (i.e. no additional “margin” for dose build up at the 
edges of the blocks or MLC jaws beyond the PTV). The only exception 
will be when observing the minimum field dimension of 3.5 cm when 
treating small lesions. As such, prescription lines covering the PTV will 
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typically be the 60-90% line (rather than 95-100%); however, higher 
isodoses (hotspots) must be manipulated to occur within the target and 
not in adjacent normal tissue. The isocenter in stereotactic coordinates 
will be determined from system fiducials (or directly from the tumor) and 
translated to the treatment record. 
The treatment dose plan will be made up of multiple static beams or arcs 
as described above. The plan should be normalized to a defined point 
corresponding closely to the center of mass of the PTV (COMPTV). 
Typically, this point will be the isocenter of the beam rotation; however, it 
is not a protocol requirement for this point to be the isocenter. 
Regardless, the point identified as COMPTV must have defined 
stereotactic coordinates and receive 100% of the normalized dose. 
Because the beam apertures coincide nearly directly with the edge of the 
PTV (little or no added margin), the external border of the PTV will be 
covered by a lower isodose surface than usually used in conventional 
radiotherapy planning, typically around 80% but ranging from 60-90%. 
The prescription dose of 60 Gy in three fractions will be delivered to the 
margin of the PTV and fulfill the requirements below. As such, a “hot 
spot” will exist within the PTV centrally at the COMPTV with a magnitude 
of 60 Gy times the reciprocal of the chosen prescription isodose line (i.e., 
60-90%). 
Tissue heterogeneity corrections will not be used for the patient’s 
treatment.  For purposes of dose planning and calculation of monitor 
units for actual treatment, all tissues within the body, including lung, will 
be assumed to have unit (water) density (no correction for tissue 
heterogeneity). 
Once a treatment plan has been approved, an additional treatment plan 
will be generated with inhomogeneity correction ON.  However, this plan 
will be altered in such a way that it carries the monitor units of the 
inhomogeneity OFF treatment plan.  The dose to various critical 
structures and dosimetric indices will be recorded for documentation 
purposes in another worksheet which will have all the parameters as 
specified earlier as well as following parameters [volume of PTV 
receiving 60 Gy {or 30 Gy in case of single dose SBRT} or more [V60]  
and D95].  The exact inhomogeneity correction algorithm to be used for 
these patients will be the same which is being used for rest of the 
patients being treated at RPCI.  Of note, the calculation grid utilized 
should be as small as possible.  
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Successful treatment planning will require accomplishment of all of the 
following criteria: 
1) Normalization 
The treatment plan should be normalized such that 100% 
corresponds to the center of mass of the PTV (COMPTV). 
This point will typically also correspond (but is not required to 
correspond) to the isocenter of the treatment beams. 
2) Prescription Isodose Surface Coverage 
The prescription isodose surface will be chosen such that 
95% of the target volume (PTV) is conformally covered by 
the prescription isodose surface (i.e., 20 Gy per fraction = 60 
Gy total; 30 Gy single fraction = 30 Gy total)), and 99% of 
the target volume (PTV) receives a minimum of 90% of the 
prescription dose (i.e., 18 Gy per fraction = 54 Gy total for 3 
fraction regimen; 27 Gy for single fraction regimen). 
3) Target Dose Heterogeneity 
The prescription isodose surface selected in number 2 
(above) must be ≥ 60% of the dose at the center of mass of 
the PTV (COMPTV) and ≤ 90% of the dose at the center of 
mass of the PTV (COMPTV). The COMPTV corresponds to the 
normalization point (100%) of the plan as noted in 1) above. 
4) High Dose Spillage 
a) Location 
Any dose greater than 105% of the prescription dose 
(> 21Gy per fraction = 63 Gy total for 3 fraction 
regimen; >31.5 Gy for single fraction) should occur 
primarily within the PTV itself and not within the 
normal tissues outside of the PTV. Therefore, the 
cumulative volume of all tissue outside of the PTV 
receiving a dose greater than 105% of prescription 
dose (> 21Gy per fraction = 63 Gy total for 3 fraction 
regimen; >31.5 Gy for single fraction) should be no 
more than 15% of the PTV volume. 
b) Volume 
Conformality of PTV coverage will be judged such 
that the ratio of the volume of the prescription isodose 
meeting criteria 1) through 4) to the volume of the 
PTV is ideally < 1.2 (See table below). These criteria 
will not be required to be met in treating very small 
tumors (< 2.5 cm axial GTV dimension or < 1.5 cm 
cranio-caudal GTV dimension) where the required 
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minimum field size of 3.5 cm results in the inability to 
meet a conformality ratio of 1.2. 
5) Low Dose Spillage 
The falloff gradient beyond the PTV extending into normal 
tissue structures must be rapid in all directions and meet the 
following criteria: 
a) Location
The maximum total dose over all 3 fractions in Gray 
(Gy) to any point 2 cm or greater away from the PTV 
in any direction be no greater than D2cm where D2cm is 
given by the table below. 
b) Volume 
The ratio of the volume of 50% of the prescription 
dose (10 Gy per fraction = 30 Gy total for 3 fraction 
regimen; 15 Gy for single fraction) isodose to the 
volume of the PTV must be no greater than R50% 
where R50% is given by the table below. 
TABLE 1: Conformality Criteria and Lung Radiation Limits
Ratio of 
Prescription 
Isodose Volume 
to PTV
Ratio of 50% 
Prescription 
Isodose Volume 
to PTV (R50%)
Maximum Dose 
2cm from PTV in 
any Direction (in 
Gy)
Percent of 
Lung receiving 
20 Gy total or 
more  V20 (%)
Deviation
Deviation
Deviation
Deviation
Maximum 
PTV 
Dimension 
(cm)
None
Minor
None
Minor
None
Minor
None
Minor
PTV 
volume 
(in cc)
2.0
<1.2
1.2 – 
1.4
< 3.9
3.9 – 
4.1
< 28.1
28.1 – 
30.1
< 10
10 - 15
1.8
2.5
<1.2
1.2 – 
1.4
< 3.9
3.9 – 
4.1
< 28.1
28.1 – 
30.1
< 10
10 – 
15
3.8
3.0
<1.2
1.2 – 
1.4
< 3.9
3.9 – 
4.1
< 28.1
28.1 – 
30.1
< 10
10 - 15
7.4
3.5
<1.2
1.2 – 
1.4
< 3.9
3.9 – 
4.1
< 28.1
28.1 – 
30.1
< 10
10 – 
15
13.2
4.0
<1.2
1.2 – 
1.4
< 3.8
3.8 – 
4.0
< 30.4
30.4 - 
32.4
< 10
10 – 
15
21.9
4.5
<1.2
1.2 – 
1.4
< 3.7
3.7 – 
3.9
< 32.7
32.7 – 
34.7
< 10
10 – 
15
33.8
5.0
<1.2
1.2 – 
1.4
< 3.6
3.6 – 
3.8
< 35.1
35.1 – 
37.1
< 10
10 – 
15
49.6
5.5
<1.2
1.2 – 
1.4
< 3.5
3.5 – 
3.7
< 37.4
37.4 – 
39.4
< 10
10 – 
15
69.9
6.0
<1.2
1.2 – 
1.4
< 3.3
3.3 – 
3.5
< 39.7
39.7 – 
41.7
< 10
10 – 
15
95.1
6.5
<1.2
1.2 – 
1.4
< 3.1
3.1 – 
3.3
< 42.0
42.0 – 
44.0
< 10
10 – 
15
125.8
7.0
<1.2
1.2 – 
1.4
< 2.9
2.9 – 
3.1
< 44.3
44.3 – 
46.3
< 10
10 – 
15
162.6
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7.5
<1.2
1.2 – 
1.4
< 2.7
2.7 – 
2.9
< 46.6
46.6 – 
48.6
< 10
10 – 
15
8.0
<1.2
1.2 – 
1.4
< 2.5
2.5 – 
2.7
< 48.9
48.9 – 
50.9
< 10
10 – 
15
Note 1: For values of PTV dimension or volume not specified, linear 
interpolation between table entries is required. 
Note 2: Protocol deviations greater than listed here as ‘minor’ will require 
approval of the treating physician or PI prior to treatment. 
Note 3: These limits will apply to both treatment arms.
6) Respect all critical organ dose-volume limits listed in Section 
6.5.1 below. 
6.2.5 Critical Structures 
6.2.5.1 Critical Organ Dose-Volume Limits 
The following table lists maximum dose limits to a point or volume within 
several critical organs. These are absolute limits, and treatment delivery 
that exceeds these limits will constitute a major protocol violation. 
The limits for 20Gy x 3 are taken from RTOG 0236 and were formulated 
with the approval of the RTOG study committee (Principal Investigators 
and Co-Chairs) including Dr. Jack Fowler, international authority on 
radiobiology 
and 
radiotolerance, 
using 
known 
tolerance 
data, 
radiobiological conversion models, norms used in current practice at 
academic centers,
16-22 and the experience of several years of irradiation 
using these large fractions at Indiana University
26,30,31 and centers in 
Sweden,
24,25,27 Germany, and Japan.  With the exception of the spinal 
cord limit which is conservatively set from experience with irradiation of 
vertebral body metastases, the dose limits for 30 Gy were scaled from 
the limits at 20 Gy per fraction. However, even for the 30 Gy arm, we 
will endeavor to meet the single fraction dose limits of the 20 Gy 
arm. 
In order to verify each of these limits, the organs must be contoured 
such that appropriate dose volume histograms can be generated. 
Instruction for the contouring of these organs will follow below. 
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TABLE 2a: DOSE LIMITS TO CRITICAL STRUCTURES for 20 Gy x3
Organ 
Volume 
20 Gy x 3 Arm 
Spinal Cord 
Any point 
18 Gy (6 Gy 
per fraction) 
Esophagus 
Any point 
27 Gy (9 Gy 
per fraction) 
Ipsilateral 
Brachial Plexus 
Any point 
24 Gy (8 Gy 
per fraction) 
Heart 
Any point 
30 Gy (10 Gy 
per fraction) 
Trachea and 
Ipsilateral 
Bronchus 
Any point 
30 Gy (10 Gy 
per fraction) 
Whole Lung 
(Right & Left) 
(See table in 
Section 6.4.2) 
(See table 
below) 
TABLE 2b: DOSE LIMITS TO CRITICAL STRUCTURES for 30 Gy x1
Serial Tissue
  Volume
Volume Max 
(Gy)
Max Point Dose 
(Gy)
Endpoint (≥Grade 
3)
Spinal Cord 
<0.35 cc
<1.2 cc
10 Gy
7 Gy
14 Gy
myelitis
Esophagus*
<5 cc
11.9 Gy
15.4 Gy
stenosis/fistula
Brachial Plexus
<3 cc
14 Gy
17.5  Gy
neuropathy
Heart/Pericardi
um
<15 cc
16 Gy
22 Gy
pericarditis
Great vessels
<10 cc
31 Gy
37 Gy
aneurysm
Trachea and 
Large 
Bronchus*
<4 cc
10.5 Gy
20.2 Gy
stenosis/fistula
Rib
<1 cc
22 Gy
30 Gy
Pain or fracture
Skin
<10 cc
23 Gy
26 Gy
ulceration
Stomach
<10 cc
11.2 Gy
12.4 Gy
ulceration/fistula
Parallel Tissue
 Critical 
Volume 
(cc)
Critical Volume 
Dose Max (Gy)
Endpoint (≥Grade 
3)
Lung (Right & 
Left)
1500 cc
7 Gy
Basic Lung 
Function
Lung (Right & 
Left)
1000 cc
7.4 Gy
Pneumonitis
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6.2.5.2 Contouring of Normal Tissue Structures 
6.2.5.2.1 Spinal Cord 
The spinal cord will be contoured based on the bony limits of 
the spinal canal. The spinal cord should be contoured starting 
at least 10 cm above the superior extent of the PTV and 
continuing on every CT slice to at least 10 below the inferior 
extent of the PTV. 
6.2.5.2.2 Esophagus 
The esophagus will be contoured using mediastinal windowing 
on CT to correspond to the mucosal, submucosa, and all 
muscular layers out to the fatty adventitia. The esophagus 
should be contoured starting at least 10 cm above the superior 
extent of the PTV and continuing on every CT slice to at least 
10 below the inferior extent of the PTV. 
6.2.5.2.3 Brachial Plexus 
The defined ipsilateral brachial plexus originates from the 
spinal nerves exiting the neuroforamina on the involved side 
from around C5 to T2. However, for the purposes of this 
protocol only the major trunks of the brachial plexus will be 
contoured using the subclavian and axillary vessels as a 
surrogate for identifying the location of the brachial plexus. This 
neurovascular complex will be contoured starting proximally at 
the 
bifurcation 
of 
the 
brachiocephalic 
trunk 
into 
the 
jugular/subclavian veins (or carotid/subclavian arteries) and 
following along the route of the subclavian vein to the axillary 
vein ending after the neurovascular structures cross the 2
nd rib. 
6.2.5.2.4 Heart 
The heart will be contoured along with the pericardial sac. The 
superior aspect (or base) for purposes of contouring will begin 
at the level of the inferior aspect of the aortic arch (aorto-
pulmonary window) and extend inferiorly to the apex of the 
heart. 
6.2.5.2.5 Trachea and Proximal Bronchial Tree 
The trachea and proximal bronchial tree will be contoured as 
two separate structures using mediastinal windows on CT to 
correspond to the mucosal, submucosa and cartilage rings and 
airway channels associated with these structures. For this 
purpose, the trachea will be divided into two sections: the 
proximal trachea and the distal 2 cm of trachea. The proximal 
trachea will be contoured as one structure, and the distal 2 cm 
of trachea will be included in the structure identified as proximal 
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bronchial tree. Differentiating these structures in this fashion 
will facilitate the eligibility requirement for excluding patients 
with tumors within 2 cm of the proximal bronchial tree (see 
section 6.5.2.8 below). 
6.2.5.2.5.1 Proximal Trachea 
Contouring of the proximal trachea should begin at least 10 cm 
superior to the extent of the PTV or 5 cm superior to the carina 
(which ever is more superior) and continue inferiorly to the 
superior aspect of the proximal bronchial tree (see definitions 
below). 
6.2.5.2.5.2 Proximal Bronchial Tree 
The proximal bronchial tree will include the most inferior 2 cm of 
distal trachea and the proximal airways. The following airways 
will be included according to standard anatomical relationships: 
the distal 2 cm of trachea, the carina, the right and left mainstem 
bronchi, the right and left upper lobe bronchi, the intermedius 
bronchus, the right middle lobe bronchus, the lingular bronchus, 
and the right and left lower lobe bronchi. Contouring of the lobar 
bronchi will end immediately at the site of a segmental 
bifurcation. 
6.2.5.2.6 Whole Lung 
Both the right and left lungs should be contoured as one 
structure. Contouring should be carried out using pulmonary 
windows. All inflated and collapsed lung should be contoured; 
however, gross tumor (GTV) and trachea/ipsilateral bronchus 
as defined above should not be included in this structure. 
6.2.5.2.7 PTV Plus 2 cm 
As part of the QA requirements for “low dose spillage” listed in 
6.2.4.2 above, a maximum dose to any point 2 cm away in any 
direction is to be determined. To facilitate this QA requirement, 
an artificial structure 2 cm larger in all directions from the PTV 
is required. Most treatment planning systems have automatic 
contouring features that will generate this structure without 
prohibitive effort at the time of treatment planning. 
6.2.5.2.8 Proximal Bronchial Tree Plus 2 cm 
As part of adhering to the ineligibility requirements for not 
enrolling patients with tumors in the zone of the proximal 
bronchial tree, it is convenient to define an artificial structure 2 
cm larger in all directions from the proximal bronchial tree. If 
the GTV falls within this artificial structure, the patient should 
not be treated with the protocol therapy. Most treatment 
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planning systems have automatic contouring features that will 
generate this structure without prohibitive effort at the time of 
treatment planning. This structure is not required by the 
protocol, but its construction is suggested to facilitate 
appropriateness of patient selection. Alternately, ruler tools in 
the treatment planning software may be used to ensure 
protocol compliance. 
6.2.6 Documentation Requirements 
In general, treatment interruptions should be avoided by preventative 
medical measures and nutritional, psychological, and emotional 
counseling. Treatment breaks, including indications, must be clearly 
documented on the treatment record and communicated to the PI. The 
total treatment time following the first fraction, must not exceed 10 weeks.
6.2.6.1 Quality of Life Measures
Health related quality of life (HRQOL) will be assessed by study team 
members using 2 frequently used and validated questionnaires. The 
European Organisation for Research and Treatment of Cancer Quality of 
Life Questionnaire [EORTC-QLQ] C30) is a generic HRQOL 
questionnaire. A lung cancer-specific questionnaire (EORTC QLQ-LC13) 
will also be used40-42. Patient responses to these questionnaires will be 
used to analyze and quantify differences, if any, in HRQOL from each 
SBRT regimen. See Appendix II.
6.2.7 Compliance Criteria 
6.2.7.1 Dosimetry Compliance 
Section 6 describes appropriate conduct for treatment planning 
dosimetry. Criteria for both major and minor deviations are 
provided in the table in Section 6.2.4. In addition to the criteria in 
section 6.2.4, the table in Section 6.2.5 lists dose volume limits for 
specific organs and structures. Exceeding these limits by more 
than 2.5% constitutes a minor protocol violation. Exceeding these 
limits by more than 5% constitutes a major protocol violation. 
6.2.7.2 Treatment Delivery Compliance 
Set-up films will be compared to digitally reconstructed 
radiographs from the same beam’s eye view. Deviations of less 
than 0.5 cm in the transverse plane and 1.0 cm in the cranio-
caudal plane will be considered compliant. Deviations from 0.5-
1.0 cm in the transverse plane and 1.0-1.25 cm in the 
craniocaudal plane will be considered minor protocol deviations. 
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Deviations greater than those listed as minor will be considered 
major protocol deviations. 
6.2.8  Radiation Toxicity
The most commonly reported side effects from lung SBRT have been 
pulmonary side effects, likely attributable to radiation induced inflammation 
(radiation pneumonitis) of surrounding normal lung. The constellation of 
symptoms associated with radiation pneumonitis includes fatigue, fever, 
shortness of breath, nonproductive cough, and pulmonary infiltrates on 
chest x-ray.  
Among 37 patients evaluated in a Phase I dose escalation study 
performed by Timmerman et al., all patients reported fatigue.  Six patients 
reported worsening shortness of breath and non-productive cough and 
were treated with steroids, inhalers cough medicines, and oxygen therapy.  
On imaging studies, one patient was noted to have worsening pulmonary 
infiltration and 25 patients had worsening fibrotic changes.  Following 
SBRT, 10 patients had documented decline of at least 10% predicted in at 
least one measure of pulmonary function.  Other reported toxicities in this 
Phase I trial included chest wall tenderness and discomfort from the 
abdominal compression device and one report of grade 3 radiation 
dermatitis.
An update of this Phase I trial evaluating 47 patients, Grade 2 toxicities 
reported included pneumonitis, pericardial effusion, pneumonia, and 
bronchitis.  Grade 3 toxicities reported included pneumonitis, hypoxia, 
dermatitis, pericardial effusion, pneumonitis, and tracheal necrosis.  
Timmerman et al later reported the results of a Phase II trial that included 
70 patients with a median follow-up of 17.5 months.  58 of 70 patients 
experienced grade 1-2 toxicity, most commonly fatigue, musculoskeletal 
discomfort, and radiation pneumonitis.  Eight grade 3-4 toxicities were 
reported including decline in PFT’s, pneumonia, pleural effusion, apnea, 
and skin reaction.  Six grade 5 toxicities (deaths) were reported, 4 
secondary to bacterial pneumonia, 1 from pericardial effusion, and 1 from 
massive hemoptysis following local recurrence adjacent to the carina.  
Further analysis of patients experiencing high grade toxicity revealed that 
tumor location was a significant predictor.  Patients treated for tumors in 
the peripheral lung had 2-year freedom from severe toxicity of 83% 
compared with only 54% for patients with central tumors30.
In a retrospective analysis of 138 patients reported by Baumann et al., 
60% of patients reported no toxicity.  Fourteen patients experienced grade 
3-4 toxicity including lung atelectasis, rib fracture, pneumonitis, thoracic 
pain, pneumonia, decreased lung function, and decreased performance 
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status.  The most commonly reported toxicities included lung fibrosis 
(n=21), skin rash (n=12), lung atelectasis (n=10), cough (n=9), rib fracture 
(n=8), thoracic pain (n=6), esophagitis (n=5), and pleural exudates (n=4).  
Hara et al reported toxicity outcomes among 59 patients treated for 
malignant lung tumors with single fraction SBRT ranging from 20-34 Gy.  
In one patient, grade 2 respiratory symptoms were reported and in one 
patient with active tuberculosis and interstitial pneumonia, Grade 3 
respiratory toxicity requiring oxygen supplementation was reported.  Two 
patients experienced skin erythema.
In another trial of single fraction SBRT, Hof et al reported outcomes 
among 42 patients treated with a single fraction ranging from 19-30 Gy.  
Follow up CT scan normal tissue changes (including pneumonitic changes 
and fibrosis) were noted in the treatment area in 64.3% of patients.  
However, no CTC grade 3 or 4 toxicities were noted.  Minor cough and 
slightly increased dyspnea were the only clinical toxicities observed.  
The Japanese experience was reported retrospectively by Onishi et al.  
Among 257 patients treated with various dosing schemes (1-22 fractions 
at 3-12 Gy per fraction).  NCI-CTC pulmonary toxicities ≥ grade 2 were 
reported in 10.9% of patients.  Grade 3 or 4 toxicities were observed in 
5.4% and included bronchitis, esophagitis, dermatitis, and rib fracture.  
The vast majority of patients experiencing symptomatic pulmonary 
complications had baseline pulmonary fibrosis or emphysema.  
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7.0  STUDY CALENDAR
Pre-
Treatment11
Rx 
#110
Rx #2
Rx 
#39
6 wks 
post-
rx
12 
wks 
post-
rx
f/u1,11
H&P8
X
X
X
X
X
X
X
Performance 
Status
X
X
X
X
X
X
X
Evaluation by 
Thoracic 
Oncologist
X
Evaluation by 
Radiation 
Oncologist
X
Pregnancy 
test
X
CT C/A/P7
X
PET-CT scan7
X
X2
PFT’s6
X
X3
Tumor Biopsy
X
X4
Blood and 
urine, 
collection for 
DBBR, future 
analyses5 
X
Toxicity Eval
X
X
X
X
X
X
X
QOL 
questionnaire
X
X
X
X
X
X
X
1 At week 6 and 12 post SBRT as noted above, then every 3 months for 1 year, 
and every 6 months for the next 4 years. Patients will be followed for a total of 5 
years.
2 PET-CT will be done at 6 months and then as clinically indicated
3 PFTs will be done at 6 months, and annually in follow-up
4 Biopsies will be done only if clinically indicated.  
5 Blood and urine will be collected through the DBBR at pre-treatment. Patients 
may refuse this and still participate in the study. This will not be offered at 
network sites.  
6 Full Spirometry and DLCO
7 Any one of these pre-treatment imaging studies should be done within 6 weeks 
of registration:  CT Chest, PET or CT Simulation 
8 H&P within 2 weeks of treatment start
9Overall treatment time for one fraction is one day, for three fractions is 8-24 
days. 
10Treatment may start within 4 weeks after registration.
11Pre-treament and follow up assessments may be waived at the discretion of the 
Principal Investigator.
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8.0 TREATMENT MODIFICATIONS
8.1  Radiation Treatment Modifications
Modifications to the radiation treatment will be discussed with the Principal 
Investigator.  
8.2  Off Study Criteria
8.2.1 Patients may be taken off study for the following non-medical or 
administrative reasons:

Patient refuses the procedure or further treatment

It is deemed in the patient’s best interest as determined by the PI.

Serious protocol violation as determined by the PI.
8.2.2   Development of a concurrent serious medical condition that 
precludes the completion of fiducial marker placement, radiation therapy 
or follow-up. 
8.2.3   Tumor progression (if occurs during treatment, at the end of 
radiation therapy unless the completion of local therapy is not indicated)
8.2.4   Initiation of cytotoxic chemotherapy (if occurs during treatment, at 
the end of radiation therapy unless the completion of local therapy is not 
indicated)
8.2.5    Development of a concurrent serious medical condition during 
active treatment and not attributable to therapy that precludes the 
completion of active treatment.
8.2.6   The completion of 60 months (5 years) follow-up. 
9.0  RESPONSE CRITERIA
This protocol will use a modified version of the international criteria proposed by 
the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 
92(3): 205-216, 2000] See http://ctep.info.nih.gov/guidelines/recist.html for further 
details. Additional definitions beyond the RECIST guidelines specific to this 
protocol are incorporated to define local control as described below. 
9.1 Baseline documentation of “Target” and “Non-Target” Lesions 
Patients enrolled to this protocol should have clinical stage I (T1 or T2, N0, 
M0) or clinical stage II (non-small cell lung cancer. At time of treatment, 
they should only have one site of gross disease in the lung with no 
metastases. The primary lung tumor should be identified as the target 
lesion and recorded and measured at baseline and with each follow-up 
imaging evaluation. 
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The longest diameter (LD) for the target lesion will be calculated from the 
treatment planning CT scan using pulmonary windowing and reported 
as the baseline LD. The baseline LD will be used as reference by which to 
characterize the objective tumor. For follow-up assessment, diagnostic CT 
scans performed using a 5 mm contiguous reconstruction algorithm using 
pulmonary windowing taken as part of scheduled protocol follow-up are 
preferred as the method of evaluation for response. When CT scans are 
not available, chest x-ray determination will be allowed as long as the 
target lesion is clearly visible. Changes in serum tumor markers will not be 
allowed for assessment of either local tumor progression or metastatic 
progression. 
Local treatment effects in the vicinity of the tumor target may make 
determination of tumor dimensions difficult. For example, bronchial or 
bronchiolar damage may cause patchy consolidation around the tumor 
that over time may coalesce with the residual tumor. In cases where it is 
indeterminate whether consolidation represents residual tumor or 
treatment effect, it should be assumed that abnormalities are residual 
tumor. A treating radiation oncologist will review films as well as a 
radiologist at each site.
All other lesions (or sites of disease) that appear after treatment (e.g., 
regional lymph nodes and distant metastases) should be identified as 
non-target lesions and should also be recorded at the point of their 
appearance and with each follow up. Non-target lesions should constitute 
measurable disease, which by definition requires having an appearance 
suspicious for carcinoma and having a dimension of at least 1.0 cm. 
Assessment of regional lymphatic or metastatic progression will be made 
in comparison to the required pretreatment staging studies or any other 
pretreatment imaging evaluations available. Only non-target lesions 
appearing at the margin of the PTV (i.e., within 1.0 cm) will have recorded 
measurements (see Marginal Failure in the table below). Recorded 
measurements of all other non-target lesions are not required, but the 
presence or absence of each should be noted throughout follow-up. 
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9.2  Response Criteria 
Evaluation of Target Lesions
Complete Response (CR) 
Disappearance of the target lesion; 
ideally, this determination will be made 
based on CT image evaluation. 
Partial Response (PR) 
At least a 30% decrease in the LD of the 
target lesion, taking as reference the 
baseline LD; ideally, this determination 
will be made based on CT image 
evaluation. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for 
CR/PR above nor sufficient increase to 
qualify for LE below, taking as reference 
the smallest LD since the treatment 
started 
Local Enlargement (LE) 
At least a 20% increase in the LD of 
target lesion, taking as reference the 
smallest 
LD 
recorded 
since 
the 
treatment 
started; 
Ideally, 
this 
determination will be made based on CT 
image evaluation. 
Local Failure (LF) 
Refers to the primary treated tumor after 
protocol therapy and corresponds to 
meeting both of the following two 
criteria: 1) Increase in tumor dimension 
of 20% as defined above for local 
enlargement (LE); 2) The measurable 
tumor with criteria meeting LE should be 
avid on Positron Emission Tomography 
(PET) imaging with uptake of a similar 
intensity as the pretreatment staging 
PET, OR the measurable tumor should 
be biopsied confirming viable carcinoma. 
For outcome analysis, Marginal Failures 
(MF; see below) will also be counted as 
LF; 
however, 
they 
should 
be 
distinguished specifically as MF, not LF, 
on all report forms. The EORTC criteria 
for post-treatment PET evaluation will be 
used as a basis for evaluation in cases 
more difficult to assign as to whether the 
uptake 
is 
pathological 
for 
cancer 
recurrence vs. inflammation.
46
Local Control (LC) 
The absence of Local Failure. 
Progressive Disease (PD)
Progression will be defined by any 
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imaging and clinical findings which 
support development of disease outside 
the chest, in the mediastinum or first 
echelon lymph nodes, and by PET +/- 
biopsy consistent with progression at the 
target lesion.
10.0  ADVERSE EVENTS
Network sites refer to Appendix III for AE and SAE reporting instructions.
10.1  Adverse Events Reporting
Investigators are required by Federal Regulations to report serious adverse 
events to the Study Chair and Clinical Research Services. CRS will notify the 
Institutional Review Board if a patient has a reportable serious adverse event. 
This study will utilize the Common Toxicity Criteria version 3.0 to determine 
the severity of the reaction for adverse event reporting. (Appendix I)
Reporting requirements and procedures depend upon: (1) whether procedure 
is suspected of causing the adverse event, (2) whether the possibility of such 
an adverse event was reported in the protocol, consent form, or 
manufacturer's literature (expected or unexpected adverse event), (3) the 
severity or grade of the adverse event, (4) the phase of the study and 
attribution (the determination of whether an adverse event is related to a 
medical treatment or procedure). All reactions in a "reportable" category must 
be reported. 
10.2 Serious Adverse Events (SAE)

A serious adverse event (SAE) is any experience that suggests a 
significant hazard, contraindication, side effects or precaution.  This 
includes any experience that:

Results in death.

Is a life-threatening adverse drug experience.

Requires 
inpatient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization.
For the purpose of this study, hospitalizations for protocol-scheduled 
procedures, blood product transfusions, or for social reasons (i.e., 
awaiting transport home) will not be considered SAE’s.

Results in persistent or significant disability/incapacity.

Is a congenital anomaly/birth defect.

Requires medical or surgical intervention to prevent one of the 
outcomes listed above.
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10.3 Reporting Serious Adverse Events
All serious adverse events will be reported to the IRB and Data Safety 
Monitoring Board according to the established guidelines. A cumulative 
summary of all adverse events occurring on this study will also be submitted 
to the IRB with the continuing review. Toxicity is reported, as required, to the 
FDA and study sponsors. All study data reviewed and discussed during these 
meetings will be kept confidential. Any breech in subject confidentiality will be 
reported to the IRB. In addition, all Roswell Park Cancer Institute initiated 
trials will be monitored periodically by the Compliance Monitor.
10.4 SAE Follow-up
For all SAE’s occurring during the study or within 30 days of the last 
administration of study procedure, the investigator must submit follow-up 
reports the Study Chair and Clinical Research Services, CRS will notify 
Institutional Review Board regarding the patient’s subsequent course until the 
SAE has subsided, or until the condition stabilizes, the patient dies, or 
receives alternative therapy.
Local reporting for data and safety monitoring for the protocol will require 
SAE’s to be reported to the IRB, via the Clinical Research Service Office, 
using the Adverse Event Reporting form and the FDA MEDWATCH SAE 
reporting form.
On the anniversary date of the approved protocol at RPCI, the principal 
investigator will be required to report to the IRB the number of patients 
entered on the trial, the number of patients treated, a summary of all adverse 
events reported to date using CTC 3.0 grading, a specific list of serious 
adverse events requiring immediate reporting, and significant literature 
reporting developments that may affect the safety of participants or the ethics 
of the study.
11.0   DATA SAFETY AND MONITORING PLAN

PI will assume primary responsibility for monitoring the progress of the trial 
and the safety of participants.

Data will be submitted to the RPCI IRB annually for continuing review and 
at the completion of the study. 

Data integrity and protocol adherence are assured by regular data 
verification and protocol compliance checks performed by the research 
team (PI, research nurse, data manager and clinic nurse).
The IRB will review annual data and safety monitoring reports, as well as an 
interim analysis performed after 49 patients have been enrolled, and make 
recommendations on whether the study should continue unchanged, require 
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modification/amendment, or be closed based on unacceptable risk to 
participants.
12.0  STATISTICAL ANALYSIS
This is a phase II randomized study to compare incidence of RTOG grade 3 or 
higher toxicity associated with 2 different, established SBRT regimens for 
NSCLC. 
Group sample sizes of 49 in group one (Gy x 3) and 49 in group two (Gy x 1) 
achieve 81% power to detect a difference between the group incidences of 
toxicity of 0.17. The incidence of toxicity in group one (the treatment group) is 
assumed to be 0.03 under the null hypothesis and 0.2000 under the alternative 
hypothesis. The proportion in group two (the control group) is 0.03. The test 
statistic used is the one-sided Z test with continuity correction and unpooled 
variance. The significance level of the test was targeted at 0.05. The significance 
level actually achieved by this design is 0.0037.
Descriptive statistics will be presented for each group. Incidence of toxicity will be 
compared using Z test.  Disease free survival and overall survival will be 
compared between two groups using log-rank test statistics. Correlation analysis 
will be performed to explore the relationship between outcomes and toxicities 
with tumor biomarkers. The estimate of acute and long term toxicity associated 
with SBRT for NSCLC will be reported.
13.0  SAMPLE HANDLING
13.1 Blood and Urine Samples
Forty (40) ml of blood will be collected, processed, and stored in the RPCI 
Data Bank and BioRepository at the time points specified in the study 
calendar.  The DBBR will distribute the de-identified samples to the study 
investigators using established DBBR procedures.  
At least 20 and up to 100 ml of spot urine samples will also be collected 
and stored at -20 oC in the RPCI Data Bank and BioRepository at the time 
points specified in the study calendar.  The DBBR will distribute the de-
identified samples to the study investigators using established DBBR 
procedures.  
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14.0  REFERENCES
1.
Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin 
2007;57:43-66.
2.
Cilli A, Ozkaynak C, Onur R, et al. Lung cancer detection with low-dose spiral 
computed tomography in chronic obstructive pulmonary disease patients. Acta 
Radiol 2007;48:405-411.
3.
Mountain CF. Revisions in the International System for Staging Lung Cancer. 
Chest 1997;111:1710-1717.
4.
Zierhut D, Bettscheider C, Schubert K, et al. Radiation therapy of stage I and II 
non-small cell lung cancer (NSCLC). Lung Cancer 2001;34 Suppl 3:S39-43.
5.
Dosoretz DE, Galmarini D, Rubenstein JH, et al. Local control in medically 
inoperable lung cancer: an analysis of its importance in outcome and factors 
determining the probability of tumor eradication. Int J Radiat Oncol Biol Phys 
1993;27:507-516.
6.
Foote RL, Robinow JS, Shaw EG, et al. Low-versus high-energy photon beams in 
radiotherapy for lung cancer. Med Dosim 1993;18:65-72.
7.
Perez CA, Pajak TF, Rubin P, et al. Long-term observations of the patterns of 
failure in patients with unresectable non-oat cell carcinoma of the lung treated 
with definitive radiotherapy. Report by the Radiation Therapy Oncology Group. 
Cancer 1987;59:1874-1881.
8.
Dosoretz DE, Katin MJ, Blitzer PH, et al. Radiation therapy in the management 
of medically inoperable carcinoma of the lung: results and implications for future 
treatment strategies. Int J Radiat Oncol Biol Phys 1992;24:3-9.
9.
Sibley GS, Jamieson TA, Marks LB, et al. Radiotherapy alone for medically 
inoperable stage I non-small-cell lung cancer: the Duke experience. Int J Radiat 
Oncol Biol Phys 1998;40:149-154.
10.
Martini N. Operable lung cancer. CA Cancer J Clin 1993;43:201-214.
11.
Slotman BJ, Njo KH, Karim AB. Curative radiotherapy for technically operable 
stage I nonsmall cell lung cancer. Int J Radiat Oncol Biol Phys 1994;29:33-37.
12.
Hayakawa K, Mitsuhashi N, Saito Y, et al. Limited field irradiation for medically 
inoperable patients with peripheral stage I non-small cell lung cancer. Lung 
Cancer 1999;26:137-142.
13.
Le Chevalier T, Arriagada R, Quoix E, et al. Radiotherapy alone versus combined 
chemotherapy and radiotherapy in unresectable non-small cell lung carcinoma. 
Lung Cancer 1994;10 Suppl 1:S239-244.
14.
Zhang HX, Yin WB, Zhang LJ, et al. Curative radiotherapy of early operable 
non-small cell lung cancer. Radiother Oncol 1989;14:89-94.
15.
Kaskowitz L, Graham MV, Emami B, et al. Radiation therapy alone for stage I 
non-small cell lung cancer. Int J Radiat Oncol Biol Phys 1993;27:517-523.
16.
Chen M, Hayman JA, Ten Haken RK, et al. Long-term results of high-dose 
conformal radiotherapy for patients with medically inoperable T1-3N0 non-small-
cell lung cancer: is low incidence of regional failure due to incidental nodal 
irradiation? Int J Radiat Oncol Biol Phys 2006;64:120-126.
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17.
Cox JD, Azarnia N, Byhardt RW, et al. A randomized phase I/II trial of 
hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 Gy: 
possible survival benefit with greater than or equal to 69.6 Gy in favorable 
patients with Radiation Therapy Oncology Group stage III non-small-cell lung 
carcinoma: report of Radiation Therapy Oncology Group 83-11. J Clin Oncol 
1990;8:1543-1555.
18.
Kong FM, Hayman JA, Griffith KA, et al. Final toxicity results of a radiation-
dose escalation study in patients with non-small-cell lung cancer (NSCLC): 
predictors for radiation pneumonitis and fibrosis. Int J Radiat Oncol Biol Phys 
2006;65:1075-1086.
19.
Sandler HM, Curran WJ, Jr., Turrisi AT, 3rd. The influence of tumor size and pre-
treatment staging on outcome following radiation therapy alone for stage I non-
small cell lung cancer. Int J Radiat Oncol Biol Phys 1990;19:9-13.
20.
Saunders M, Dische S, Barrett A, et al. Continuous hyperfractionated accelerated 
radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung 
cancer: a randomised multicentre trial. CHART Steering Committee. Lancet 
1997;350:161-165.
21.
Nagata Y, Matsuo Y, Takayama K, et al. Current status of stereotactic body 
radiotherapy for lung cancer. Int J Clin Oncol 2007;12:3-7.
22.
Uematsu M, Shioda A, Suda A, et al. Computed tomography-guided frameless 
stereotactic radiotherapy for stage I non-small cell lung cancer: a 5-year 
experience. Int J Radiat Oncol Biol Phys 2001;51:666-670.
23.
Onishi H, Kuriyama K, Komiyama T, et al. Clinical outcomes of stereotactic 
radiotherapy for stage I non-small cell lung cancer using a novel irradiation 
technique: patient self-controlled breath-hold and beam switching using a 
combination of linear accelerator and CT scanner. Lung Cancer 2004;45:45-55.
24.
Timmerman R, Galvin J, Michalski J, et al. Accreditation and quality assurance 
for Radiation Therapy Oncology Group: Multicenter clinical trials using 
Stereotactic Body Radiation Therapy in lung cancer. Acta Oncol 2006;45:779-
786.
25.
Timmerman R, Abdulrahman R, Kavanagh BD, et al. Lung cancer: a model for 
implementing stereotactic body radiation therapy into practice. Front Radiat Ther 
Oncol 2007;40:368-385.
26.
Onishi H, Shirato H, Nagata Y, et al. Hypofractionated stereotactic radiotherapy 
(HypoFXSRT) for stage I non-small cell lung cancer: updated results of 257 
patients in a Japanese multi-institutional study. J Thorac Oncol 2007;2:S94-100.
27.
Wulf J, Baier K, Mueller G, et al. Dose-response in stereotactic irradiation of lung 
tumors. Radiother Oncol 2005;77:83-87.
28.
Baumann P, Nyman J, Lax I, et al. Factors important for efficacy of stereotactic 
body radiotherapy of medically inoperable stage I lung cancer. A retrospective 
analysis of patients treated in the Nordic countries. Acta Oncol 2006;45:787-795.
29.
McGarry RC, Papiez L, Williams M, et al. Stereotactic body radiation therapy of 
early-stage non-small-cell lung carcinoma: phase I study. Int J Radiat Oncol Biol 
Phys 2005;63:1010-1015.
30.
Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when 
treating central tumors in a phase II study of stereotactic body radiation therapy 
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for medically inoperable early-stage lung cancer. J Clin Oncol 2006;24:4833-
4839.
31.
Timmerman R, Papiez L, McGarry R, et al. Extracranial stereotactic 
radioablation: results of a phase I study in medically inoperable stage I non-small 
cell lung cancer. Chest 2003;124:1946-1955.
32.
Timmerman R. Toxicity Analysis of RTOG 0236 Using Stereotactic Body 
Radiation Therapy to Treat Medically Inoperable Early Stage Lung Cancer 
Patients. Intl J Rad Onc Biol Phys 2007;69:S86.
33.
Hof H, Muenter M, Oetzel D, et al. Stereotactic single-dose radiotherapy 
(radiosurgery) of early stage nonsmall-cell lung cancer (NSCLC). Cancer 
2007;110:148-155.
34.
Hara R, Itami J, Kondo T, et al. Clinical outcomes of single-fraction stereotactic 
radiation therapy of lung tumors. Cancer 2006;106:1347-1352.
35.
MacManus MP, Hicks RJ, Matthews JP, et al. High rate of detection of 
unsuspected distant metastases by pet in apparent stage III non-small-cell lung 
cancer: implications for radical radiation therapy. Int J Radiat Oncol Biol Phys 
2001;50:287-293.
36.
Kong FM, Frey KA, Quint LE, et al. A pilot study of [18F]fluorodeoxyglucose 
positron emission tomography scans during and after radiation-based therapy in 
patients with non small-cell lung cancer. J Clin Oncol 2007;25:3116-3123.
37.
Hoopes DJ, Tann M, Fletcher JW, et al. FDG-PET and stereotactic body 
radiotherapy (SBRT) for stage I non-small-cell lung cancer. Lung Cancer 
2007;56:229-234.
38.
Ishimori T, Saga T, Nagata Y, et al. 18F-FDG and 11C-methionine PET for 
evaluation of treatment response of lung cancer after stereotactic radiotherapy. 
Ann Nucl Med 2004;18:669-674.
39.
Paludan M, Traberg Hansen A, Petersen J, et al. Aggravation of dyspnea in stage 
I non-small cell lung cancer patients following stereotactic body radiotherapy: Is 
there a dose-volume dependency? Acta Oncol 2006;45:818-822.
40.
Bergman B, Aaronson NK, Ahmedzai S, et al. The EORTC QLQ-LC13: a 
modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-
C30) for use in lung cancer clinical trials. EORTC Study Group on Quality of 
Life. Eur J Cancer 1994;30A:635-642.
41.
Movsas B, Scott C, Langer C, et al. Randomized trial of amifostine in locally 
advanced non-small-cell lung cancer patients receiving chemotherapy and 
hyperfractionated radiation: radiation therapy oncology group trial 98-01. J Clin 
Oncol 2005;23:2145-2154.
42.
Janda M, Newman B, Obermair A, et al. Impaired quality of life in patients 
commencing radiotherapy for cancer. Strahlenther Onkol 2004;180:78-83.
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APPENDIX I
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE) VERSION 
3.0
Pulmonary/Upper Respiratory
Adverse Event
Short 
Name
1
2
3
4
5
Adult 
Respiratory 
Distress 
Syndrome
ARDS
-
-
Present, 
intubation 
not indicated
Present, 
intubation 
indicated
Death
Aspiration
-
Asymptomatic 
(“silent 
aspiration”); 
endoscopy or 
radiographic 
(e.g., barium 
swallow) 
findings
Symptomatic 
(e.g., altered 
eating habits, 
coughing or 
choking 
episodes 
consistent with 
aspiration); 
medical 
intervention 
indicated(e.g., 
antibiotics, 
suction or 
oxygen)
Clinical or 
radiographic 
signs of 
pneumonia 
or 
pneumonitis; 
unable to 
treat aliment 
orally
Life-threatening 
(e.g., aspiration 
pneumonia or 
pneumonitis)
Death
Atelectasis
-
Asymptomatic
Symptomatic 
(e.g., dyspnea, 
cough), medical 
intervention 
indicated (e.g., 
bronchoscopic 
suctioning, 
chest 
physiotherapy, 
suctioning)
Operative 
(e.g., stent, 
laser) 
intervention 
indicated
Life-threatening 
respiratory 
compromise
Death
Bronchospasm, 
wheezing
-
Asymptomatic
Symptomatic 
not interfering 
with function
Symptomatic 
interfering 
with 
function
Life-threatening
Death
Carbon 
monoxide 
diffusion 
capacity
DLCO
90-75% of 
predicted 
value
<75-50% of 
predicted value
<50-25% of 
predicted 
value
<25% of 
predicted value
Death
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Chylothorax
-
Asymptomatic 
Symptomatic; 
thoracentesis or 
tube drainage 
indicated
Operative 
intervention
Life-threatening 
(e.g., 
hemodynamic 
instability  or 
ventilatory 
support 
indicated)
Death
Cough
-
Symptomatic, 
non-narcotic 
medication 
only indicated
Symptomatic 
and narcotic 
medication 
indicated
Symptomatic 
and 
significantly 
interfering 
with sleep or 
activities of 
daily living 
(ADL)
-
-
Adverse Event
Short 
Name
1
2
3
4
5
Dyspnea
-
Dyspnea on 
exertion, but 
can walk 1 
flight of stairs 
without 
stopping
Dyspnea on 
exertion but 
unable to walk 1 
flight of stairs or 
1 city block 
(0.1km) without 
stopping
Dyspnea with 
ADL
Dyspnea at rest; 
intubation/ventilator 
indicated
Death
Edema, larynx
-
Asymptomatic 
edema by 
exam only
Symptomatic 
edema, no 
respiratory 
distress
Stridor; 
respiratory 
distress; 
interfering 
with ADL
Life-threatening 
airway 
compromise; 
tracheotomy, 
intubation, or 
laryngectomy 
indicated
Death
FEV1
-
90-75% of 
predicted value
<75-50% of 
predicted value
<50-25% of 
predicted 
value
<25% of predicted 
value
Death
Fistula*
-
Bronchus
-
Larynx
-
Lung
-
Oral 
cavity
-
Pharynx
-
Pleura
-
Trachea
-
Asymptomatic, 
radiographic 
findings only
Symptomatic, 
tube 
thoracostomy or 
medical 
management 
indicated; 
associated with 
altered 
respiratory 
function but not 
Symptomatic 
and 
associated 
with altered 
respiratory 
function 
interfering 
with ADL; or 
endoscopic 
(e.g., stent) or 
Life-threatening 
consequences; 
operative 
intervention with 
thoracoplasty, 
chronic open 
drainage or multiple 
thoracotomies 
indicated
Death
APPROVED RPCI IRB
10/10/2017

interfering with 
ADL
primary 
closure by 
operative 
intervention 
indicated
Hiccoughs 
(hiccups, 
singultus)
-
Symptomatic, 
intervention 
not indicated
Symptomatic, 
intervention 
indicated
Symptomatic, 
significantly 
interfering 
with sleep or 
ADL
-
-
Hypoxia
-
-
Decreased O2 
saturation with 
exercise (e.g., 
pulse oximeter 
<88%); 
intermittent 
supplemental 
oxygen
Decreased O2 
saturation at 
rest; 
continuous 
oxygen 
indicated
Life-threatening; 
intubation or 
ventilation 
indicated
Death
Nasal 
cavity/paranasal 
sinus reactions
-
Asymptomatic 
mucosal 
crusting, 
blood-tinged 
secretions
Symptomatic 
stenosis or 
edema/narrowing 
interfering with 
airflow
Stenosis with 
significant 
nasal 
obstruction; 
interfering 
with ADL
Necrosis of soft 
tissue or bone
Death
APPROVED RPCI IRB
10/10/2017

Adverse Event
Short 
Name
1
2
3
4
5
Obstruction/stenosis of 
airway
- Bronchus
- Larynx
- Pharynx
- Trachea
Airway 
obstruction
Asymptomatic 
obstruction or 
stenosis on 
exam, 
endoscopy, or 
radiograph
Symptomatic 
(e.g., noisy 
airway 
breathing), but 
causing no 
respiratory 
distress; 
medical 
management 
indicated (e.g., 
steroids)
Interfering with 
ADL; stridor or 
endoscopic 
intervention 
indicated (e.g., 
stent, laser)
Life-
threatening 
airway 
compromise; 
tracheotomy or 
intubation 
indicated
Death
Pleural effusion (non-
malignant)
-
Asymptomatic
Symptomatic, 
intervention 
such as 
diuretics or up 
to 2 
therapeutic 
thoracenteses 
indicated
Symptomatic 
and 
supplemental 
oxygen, >2 
therapeutic 
thoracenteses, 
tube drainage, 
or pleurodesis 
indicated
Life-
threatening 
(e.g., causing 
hemodynamic 
instability or 
ventilatory 
support 
indicated)
Death
Pneumonitis/pulmonary 
infiltrates
-
Asymptomatic, 
radiographic 
findings only
Symptomatic, 
not interfering 
with ADL
Symptomatic, 
interfering with 
ADL; O2 
indicated
Life-
threatening; 
ventilatory 
support 
indicated
Death
Pneumothorax
-
Asymptomatic, 
radiographic 
findings only
Symptomatic; 
intervention 
indicated (e.g., 
hospitalization 
for 
observation, 
tube placement 
without 
sclerosis)
Sclerosis and/or 
operative 
intervention 
indicated
Life-
threatening, 
causing 
hemodynamic 
instability (e.g., 
tension 
pneumothorax); 
ventilatory 
support 
indicated
Death
Prolonged chest tube 
drainage or air leak 
after pulmonary 
resection
-
-
Sclerosis or 
additional tube 
thoracostomy 
indicated
Operative 
intervention 
indicated (e.g., 
thoracotomy 
with stapling or 
sealant 
application)
Life-
threatening; 
debilitating; 
organ resection 
indicated
Death
APPROVED RPCI IRB
10/10/2017

Prolonged intubation 
after pulmonary 
resection (>24 hours 
after surgery)
-
-
Extubated 
within 24-72 
hrs 
postoperatively
Extubated >72 
hrs 
postoperatively, 
but before 
tracheostomy 
indicated
Tracheostomy 
indicated
Death
Adverse Event
Short 
Name
1
2
3
4
5
Pulmonary 
fibrosis** 
(radiographic 
changes)
-
Minimal 
radiographic 
findings (or 
patchy or bi-
basilar 
changes) with 
estimated 
radiographic 
proportion of 
total lung 
volume that is 
fibrotic of 
<25%
Patchy or bi-
basilar 
changes with 
estimated 
radiographic 
proportion of 
total lung 
volume that is 
fibrotic of 25-
<50%
Dense or widespread 
infiltrates/consolidation 
with estimated 
radiographic 
proportion of total lung 
volume that is fibrotic 
of 50-<75%
Estimated 
radiographic 
proportion of 
total lung 
volume that is 
fibrotic is 
≥75%; 
honeycombing
Death
Vital Capacity
-
90-75% of 
predicted 
value
<75-50% of 
predicted 
value
<50-25% of predicted 
value
<25% of 
predicted value
Death
Voice 
changes/dysarthria 
(e.g., hoarseness, 
loss or alteration 
in voice, 
laryngitis)
-
Mild or 
intermittent 
hoarseness or 
voice change, 
but fully 
understandable
Moderate or 
persistent 
voice changes, 
may require 
occasional 
repetition but 
understandable 
on telephone
Severe voice changes 
including 
predominantly 
whispered speech; may 
require frequent 
repetition or face-to-
face contact for 
understandability; 
requires voice aid (e.g., 
electrolarynx) for 
≤50% of 
communication
Disabling; 
non-
understandable 
voice or 
aphonic; 
requires voice 
aid (e.g., 
electrolarynx) 
for >50% 
written 
communication
Death
Pulmonary/Upper 
Respiratory – 
Other
-
Mild
Moderate
Severe
Life-
threatening; 
disabling
Death
*A fistula is defined as an abnormal communication between two body cavities, potential spaces, 
and/or the skin.  The site indicated for a fistula should be the site from which the abnormal process is 
believed to have arisen.  
APPROVED RPCI IRB
10/10/2017

**Fibrosis is usually a “late effect” seen >3 months after radiation or combined modality therapy 
(including surgery).  It is thought to represent scar/fibrotic lung tissue.  It may be difficult to 
distinguish from pneumonitis that is generally seen within 3 months of radiation or combined 
modality therapy.
APPROVED RPCI IRB
10/10/2017

                                 APPENDIX II: QUALITY OF LIFE QUESTIONNAIRES
EORTC QLQ-C30 (version 3)
We are interested in some things about you and your health. Please answer all of the questions yourself by circling the 
number that best applies to you. There are no "right" or "wrong" answers. The information that you provide will remain 
strictly confidential.
Please fill in your initials:   
Your birthdate (Day, Month, Year): 
Today's date (Day, Month, Year):        31
__________________________________________________________________________________________
Not at 
   A 
      Quite   
     Very    
   All 
Little 
      a Bit                 Much
1. Do you have any trouble doing strenuous activities,
    like carrying a heavy shopping bag or a suitcase?
 1 
2 
3 
 4
2. Do you have any trouble taking a long walk? 
 1 
2 
3
 4
3. Do you have any trouble taking a short walk 
    outside of the house? 
 1 
2 
3 
 4
4. Do you need to stay in bed or a chair during the day? 
 1 
2 
3  
 4
5. Do you need help with eating, dressing, washing
    yourself or using the toilet? 
 1 
2 
3 
 4
During the past week: 
              Not at 
   A 
      Quite
      Very
   All 
Little 
      a Bit                  Much
6. Were you limited in doing either your work or 
    other daily activities?
 1 
2
3 
 4
7. Were you limited in pursuing your hobbies or other
    leisure time activities? 
 1 
2   
3 
 4
8. Were you short of breath? 
 1 
2 
3
 4
9. Have you had pain? 
 1 
2 
3
 4
10. Did you need to rest? 
 1 
2 
3
 4
11. Have you had trouble sleeping?
 1 
2 
3
 4
12. Have you felt weak?
 1 
2 
3
 4
13. Have you lacked appetite?
 1 
2 
3
 4
14. Have you felt nauseated? 
 1 
2 
3
 4
15. Have you vomited?
 1 
2 
3
 4
16. Have you been constipated?
 1 
2 
3
 4
                                                                           Please go on to the next page
APPROVED RPCI IRB
10/10/2017

During the past week: 
              Not at 
   A 
      Quite
     Very
   All 
Little 
       a Bit                Much
17. Have you had diarrhea?
 1 
2 
3
 4
18. Were you tired?
 1 
2 
3
 4
19. Did pain interfere with your daily activities?
 1 
2 
3
 4
20. Have you had difficulty in concentrating on things,
      like reading a newspaper or watching television?
 1 
2 
3
 4
21. Did you feel tense? 
1 
2 
3
 4
22. Did you worry? 
1 
2 
3
 4
23. Did you feel irritable?
 1
2 
3
 4
24. Did you feel depressed?
 1 
2 
3
 4
25. Have you had difficulty remembering things?
 1 
2 
3
 4
26. Has your physical condition or medical treatment
      interfered with your family life? 
 1 
2 
3
 4
27. Has your physical condition or medical treatment
      interfered with your social activities?
 1 
2 
3
 4
28. Has your physical condition or medical treatment
      caused you financial difficulties?
 1 
2 
3
 4
For the following questions please circle the number between 1 and 7 that best applies to you
29. How would you rate your overall health during the past week?
1 
2 
3 
4 
5 
6 
7
             Very poor  
              Excellent
30. How would you rate your overall quality of life during the past week?
1 
2 
3 
4 
5 
6 
7
             Very poor  
              Excellent
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0
APPROVED RPCI IRB
10/10/2017

EORTC QLQ - LC13 
Patients sometimes report that they have the following symptoms or problems. Please indicate the 
extent to which you have experienced these symptoms or problems during the past week. Please 
answer by circling the number that best applies to you.
______________________________________________________________________________________
During the past week: 
Not at 
   A 
      Quite
   Very
   All 
Little       a Bit              Much
31. How much did you cough? 
1 
2 
3 
4
32. Did you cough up blood?
1 
2 
3 
4
33. Were you short of breath when you rested? 
1 
2 
3 
4  
34. Were you short of breath when you walked? 
1 
2 
3 
4
35. Were you short of breath when you climbed stairs? 
1 
2 
3 
4
36. Have you had a sore mouth or tongue? 
1 
2 
3 
4
37. Have you had trouble swallowing? 
1 
2 
3 
4
38. Have you had tingling hands or feet? 
1 
2 
3 
4
39. Have you had hair loss? 
1 
2 
3 
4
40. Have you had pain in your chest? 
1 
2 
3 
4
41. Have you had pain in your arm or shoulder? 
1 
2 
3 
4
42. Have you had pain in other parts of your body? 
1 
2 
3 
4
       If yes, where__________________________
43. Did you take any medicine for pain?
       1                    No                         2                   Yes
       If yes, how much did it help? 
1 
2 
3 
4
 QLQ-C30-LC13 Copyright 1994 EORTC Study Group on Quality of life. All rights reserved
APPROVED RPCI IRB
10/10/2017

APPENDIX III:  INSTRUCTIONS FOR NETWORK SITES
1.
CONTACT INFORMATION
All questions related to the protocol or study implementation should be directed to:
Roswell Park Cancer Institute
CRS Network Office
ASB K 102B
Buffalo, New York 14263
Telephone:
716-845-8084 or 716-845-1203 - M-F; 8:00 AM to 5:30 PM 
716-845-2300 - After hours, Weekends and Holidays: request the RPCI Principal Investigator
Fax: 716-845-8743
2.
INFORMED CONSENT

Informed Consent must be obtained by the Investigator from any patients wishing to participate, 
prior to any procedures or change in their treatment

An informed consent template is provided by RPCI and can be amended to reflect institutional 
requirements

All consent changes must be reviewed by Roswell Park Cancer Institute Network Office prior to 
submission to the site IRB.

The informed consent must be IRB approved

Always check that you are using the correct date and version of the IRB approved consent.
3.
PATIENT REGISTRATION 
The Subject Enrollment Log must be faxed to the CRS Network Office within 24 hours of the date the 
patient is consented. Once the Principal Investigator has determined that the eligibility criteria have been 
met, complete the Patient Registration Form and fax it to the RPCI Network Coordinator at (716) 845-
8743.  
Note: The patient completes the Gender, Race, and Ethnicity form and this is placed in the study 
binder.
Roswell Park Cancer Institute does not grant exceptions to eligibility criteria.
4.
STUDY DEVIATIONS

If a deviation has occurred to eliminate hazard, this should be reported to the RPCI Network, site IRB 
and any other regulatory authority involved in the trial.

ANY study deviation will be recorded on the Study Deviation Log

Patients who are inadvertently enrolled, with significant deviation(s) from the study- specified 
criteria, will be removed from the study

Notify RPCI of any early patient withdrawal and appropriately document the discontinuation and the 
reason why.
5.
STUDY DOCUMENTATION

Study documents must be filled out completely and correctly. Ditto marks are not allowed.

If an entry has been documented in error put a single line through the entry and initial and date the 
change. The auditor must be able to read what has been deleted. 
o
Do NOT use white-out, magic marker, scratch-outs
APPROVED RPCI IRB
10/10/2017

o
Do NOT erase entries 

Use only black ink for documentation on the accountability form and any other study forms.
6.
DRUG ACCOUNTABILITY
Drug accountability will be strictly maintained, recording quantities of study drug 
received, dispensed to patients and wasted, lot number, date dispensed, patient ID 
number and initials, quantity returned, balance remaining, manufacturer, expiration 
date, and the initials of the person dispensing the medication. 

Responsibility rests solely with the Principal Investigator but can be delegated as appropriate (e.g. to 
pharmacy personnel)

Records must be maintained regarding receipt, dispensing, return, waste and disposition of all 
investigational agents

Study drug supply should only be used in accordance with the IRB approved study

Drug accountability forms are protocol and agent specific, they are study source documents and will 
be used to verify compliance with the study

Any discrepancies shall be documented and explained

An inventory count should be performed with each transaction

Drug accountability forms shall be stored with study related documents

Each medication provided for this study and each dosage form and strength must have its own Drug 
accountability. 

Do NOT “transfer”, “borrow” or “replace” supplies between studies

Dispensing the wrong study supply is considered a medication error

Never replace investigational agents with commercial product
7.
SERIOUS ADVERSE EVENT REPORTING:
The site Investigator or designated research personnel will report all serious adverse events, whether 
related or unrelated to the study drug(s) to the IRB in accordance with their local institutional 
guidelines.  The site will notify the CRS Network Office within one business day of being made aware of 
the SAE.  A preliminary written report must follow within 24 hours (1 business day) of the oral 
notification using the following forms:
o
SAE report form 
o
MEDWATCH 3500
A complete follow-up report must be filed within 10 working days.
8.
UNANTICIPATED PROBLEM REPORTING:
An Unanticipated Problem (UAP) is any incident, experience, or outcome that meets all of the following 
criteria:
1. Unexpected (in terms of nature, severity, or frequency) given:
(a) the research procedures that are described in the study- related documents, including study 
deviations, as well as issues related to compromise of patient privacy or confidentiality of 
data; 
(b) the characteristics of the subject population being studied;
2. Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research);
APPROVED RPCI IRB
10/10/2017

3. Suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized;
For all adverse events occurring that are unanticipated and related or possibly related to the research drug, 
biologic or intervention the participating physician or delegated research staff from each site will notify 
their local IRB in accordance with their local institutional guidelines.  The site must also notify the 
CRS Network Office within 24 hours of being made aware of the Unanticipated Problem by completing 
the RPCI Unanticipated Problem Report Form and faxing it to the CRS Network office.
APPROVED RPCI IRB
10/10/2017

 
 APPENDIX IV
KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS RATING (%) 
CRITERIA
  100  Normal no complaints; no evidence of 
disease.
90
Able to carry on normal activity; minor 
signs or symptoms of disease.
Able to carry on normal activity and to work; no 
special care needed.
80
Normal activity with effort; some signs 
or symptoms of disease. 
70
Cares for self; unable to carry on normal 
activity or to do active work.
60
Requires occasional assistance, but is 
able to care for most of his personal 
needs.
Unable to work; able to live at home and care for 
most personal needs; varying amount of assistance 
needed.
50
Requires considerable assistance and 
frequent medical care. 
40
Disabled; requires special care and 
assistance.
30
Severely disabled; hospital admission is 
indicated although death not imminent.
20
Very sick; hospital admission necessary; 
active supportive treatment necessary.
10
Moribund; fatal processes progressing 
rapidly.
Unable to care for self; requires equivalent of 
institutional or hospital care; disease may be 
progressing rapidly.
0
Dead
References:
Crooks, V, Waller S, et al. The use of the Karnofsky Performance Scale in determining outcomes 
and risk in geriatric outpatients. J Gerontol. 1991; 46: M139-M144.
de Haan R, Aaronson A, et al. Measuring quality of life in stroke. Stroke. 1993; 24:320- 327.
Hollen PJ, Gralla RJ, et al. Measurement of quality of life in patients with lung cancer in multicenter 
trials of new therapies. Cancer. 1994; 73: 2087-2098.
O'Toole DM, Golden AM. Evaluating cancer patients for rehabilitation potential. West J Med. 1991; 
155:384-387.
Oxford Textbook of Palliative Medicine, Oxford University Press. 1993;109.
Schag CC, Heinrich RL, Ganz PA. Karnofsky performance status revisited: Reliability, validity, and 
guidelines. J Clin Oncology. 1984; 2:187-193.
APPROVED RPCI IRB
10/10/2017