POSTILV: A RANDOMIZED PHASE II TRIAL IN PATIENTS WITH OPERABLE STAGE I NON-SMALL CELL LUNG CANCER: RADICAL RESECTION VERSUS ABLATIVE STEREOTACTIC RADIOTHERAPY - This is a Limited Participation Study.
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer
Sponsor: Radiation Therapy Oncology Group

RTOG FOUNDATION 
 
 
RTOG 3502 
 
(ClinicalTrials.gov NCT #: 01753414) 
 
 
POSTILV:  A RANDOMIZED PHASE II TRIAL IN PATIENTS WITH 
OPERABLE STAGE I NON-SMALL CELL LUNG CANCER: RADICAL 
RESECTION VERSUS ABLATIVE STEREOTACTIC RADIOTHERAPY 
 
 
Amendment 2:  August 6, 2018 

  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RTOG Foundation Collaboration with Varian 
 
RTOG 3502 
A Limited Participation Study 
 
POSTILV: A RANDOMIZED PHASE II TRIAL IN PATIENTS WITH OPERABLE STAGE I NON-
SMALL CELL LUNG CANCER: RADICAL RESECTION  
VERSUS ABLATIVE STEREOTACTIC RADIOTHERAPY  
Protocol Version Date: August 6, 2018 
Sponsor: RTOG Foundation 
 
Co-Principal Investigators/Radiation 
Oncology 
China: Jinming Yu, MD, PhD  
U.S: Feng-Ming (Spring) Kong, MD, PhD 
 
Study Co-Chairs 
 
China Thoracic Surgery 
Yilong Wu, MD  
Jie He, MD  
Weimin Mao, MD  
Haiquan Chen, MD 
China Radiation Oncology 
Luhua Wang, MD  
Xiaolong Fu, MD, PhD 
China Medical Physics 
Jianrong Dai, PhD 
Yong Yin, PhD 
China Medical Oncology 
Meilin Liao, MD 
Shun Lu, MD 
China Medical Oncology/Pulmonary 
Chunxue Bai, MD, PhD 
U.S. Thoracic Surgery 
Andrew Chang, MD 
Mark Orringer, MD  
Thomas D’Amico, MD 
U.S. Medical Physics 
Fang-Fang Yin, PhD  
Ying Xiao, PhD  
Ning Jeff Yue, PhD 
U.S. Radiation Oncology 
Zhongxing Liao, MD 
Joe Chang, MD, PhD 
U.S. Medical Oncology 
Gregory P. Kalemkerian, MD 
U.S. Senior Statistician 
James Dignam, PhD 
Protocol Acceptance 
On behalf of the RTOG Foundation, Inc. 
 
August 6, 2018 
Walter J. Curran, Jr., MD 
RTOG Foundation Chairman  
 
Date 

  
 
 
 
 
1 
 
 
 
 
 
 
3502 
 
RTOG FOUNDATION STUDY 3502 
 
POSTILV: A RANDOMIZED PHASE II TRIAL IN PATIENTS WITH OPERABLE STAGE  
I NON-SMALL CELL LUNG CANCER: RADICAL RESECTION  
VERSUS ABLATIVE STEREOTACTIC RADIOTHERAPY  
 
This is a limited participation study.  
 
 
 
Participating Sites (6-AUG-2018) 
 
Shandong Cancer Hospital, Jinan, Shangdong 250117, China 
Cancer Hospital of Chinese Academy of Medical Science, Beijing 10021, China 
Wenzhou University First Affiliated Hospital, Zhejiang 325011, China  
Shanghai Cancer Center/Fudan University, Shanghai 200032, China 
Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China 
 
 
 
 
 
 
 
Document History 
 
Version/Update Date 
Broadcast Date 
Amendment 2 
August 6, 2018 
N/A 
Amendment 1 
October 22, 2014 
November 5, 2014 
Update  
September 12, 2013 
September 12, 2013 
Update 
June 6, 2013 
June 6, 2013 
Activation 
December 17, 2012 
February 14, 2013 
 
 
 
 
 
 
RTOG Headquarters Contact Information (6-AUG-2018) 
Data Manager:   For questions concerning eligibility or 
data submission 
Jeff Serianni, jserianni@acr.org 
Amy Krystkiewicz, akrystkiewicz@acr.org 
 
 
 
RTQA:  For questions concerning dosimetry or RT data 
submission 
Jennifer Presley, jpresley@acr.org 
RTQA general e-mail, RTOG-RTQA@acr.org 
 
 
Clinical Trials Administration: For questions 
concerning contracts 
and reimbursement 
Sharon Hartson Stine, shartson@acr.org 
 
 

  
 
 
 
 
2 
 
 
 
 
 
 
3502 
RTOG FOUNDATION STUDY 3502 
 
POSTILV: A RANDOMIZED PHASE II TRIAL IN PATIENTS WITH OPERABLE STAGE 
I NON-SMALL CELL LUNG CANCER: RADICAL RESECTION 
VERSUS ABLATIVE STEREOTACTIC RADIOTHERAPY 
 
Study Team (6-AUG-2018) 
 
China Co-Principal Investigator/Radiation Oncology 
U.S. Co-Principal Investigator/Radiation Oncology 
Jinming Yu, MD, PhD 
Feng-Ming (Spring) Kong, MD, PhD 
Shandong Cancer Hospital 
Jinan, Shandong 250117, China 
86-531-87984729/FAX 86-531-87984079 
yujinmingsd@yahoo.com.cn 
Case Western Reserve University 
11100 Euclid Avenue, Suite B812 
Cleveland, OH 44106 
216-983-4703 /FAX 216-201-6623 
fxk132@case.edu  
China Thoracic Surgery Co-Chair  
U.S. Thoracic Surgery Co-Chairs 
Yilong Wu, MD 
Andrew Chang, MD and Mark Orringer, MD 
Guangdong General Hospital 
University of Michigan Cancer Center 
Guangzhou, Guangdong 510080, China 
Ann Arbor, MI 48109, USA 
86-20-83827812*21187 
734-763-7418/FAX 734-615-2656 
syylwu@live.cn 
andrwchg@umich.edu and orrin@umich.edu 
 
 
China Thoracic Surgery Co-Chair 
U.S. Thoracic Surgery Co-Chair 
Jie He, MD 
Thomas D’Amico, MD 
Chinese Academy of Medicine/Qinhua University 
Duke University Medical Center, Box 3295 
Beijing 100021, China 
Durham, NC 27710, USA 
86-10-877888207/67713359  
919-68404891/FAX 919-684-8500 
Prof.hejie@263.com 
damic001@mc.duke.edu 
 
 
China Thoracic Surgery Co-Chair 
U.S. Medical Physics Co-Chair 
Weimin Mao, MD 
Fang-Fang Yin, PhD 
Zhejiang Cancer Hospital 
Duke University Medical Center, Box 3295 
38 Guangii Road 
Durham, NC 27710, USA 
Hangzhou, Zhejiang 310022 
919-660-2185/FAX 919-681-7183 
86-571-881-22568 
fangfang.yin@duke.edu 
Maowm1218@163.com 
 
 
 
China Thoracic Surgery Co-Chair 
U.S. Medical Physics Co-Chair 
Haiquan Chen, MD 
Ying Xiao, PhD 
Shanghai Cancer Center/Fudan University 
Shanghai 200032, China 
86-21-64175590 
Hospital of the University of Pennsylvania  
Perelman Center for Advanced Medicine 
3400 Civic Center Blvd TRC-2 
hqchen1@yahoo.com 
Philadelphia, PA 19104 
 
 215-615-2247 
 
Ying.Xiao@uphs.penn.edu 
 
 
China Radiation Oncology Co-Chair 
U.S. Medical Physics Co-Chair 
Luhua Wang, MD  
Ning Jeff Yue, PhD 
Chinese Academy of Medicine/Qinhua University 
Cancer Institute of New Jersey 
Beijing 100021, China 
195 Little Albany Street 
86-10-87788799/8610-87716559  
New Brunswick, NJ 08903 
wlhwq@yahoo.com  
732-253-3939/FAX 732-253-3477 
 
yuenj@umdnj.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Team continued on next page. 

  
 
 
 
 
3 
 
 
 
 
 
 
3502 
RTOG FOUNDATION STUDY 3502 
 
POSTILV: A RANDOMIZED PHASE II TRIAL IN PATIENTS WITH OPERABLE STAGE 
I NON-SMALL CELL LUNG CANCER: RADICAL RESECTION 
VERSUS ABLATIVE STEREOTACTIC RADIOTHERAPY 
 
Study Team Continued 
 
China Radiation Oncology Co-Chair 
U.S. Radiation Oncology Co-Chairs 
Xiaolong Fu, MD, PhD  
Zhongxing Liao, MD and Joe Chang, MD, PhD 
Shanghai Cancer Center/Fudan University 
MD Anderson Cancer Center 
Shanghai 200032, China 
Houston, TX 77030 
86-21-64175590  
713-563-2349/FAX 713-563-2331 
xlfu1964@126.com   
zliao@mdanderson.org 
 
 
China Medical Physics Co-Chair 
U.S. Medical Oncology Co-Chair 
Jianrong Dai, PhD 
Gregory P. Kalemkerian, MD 
Chinese Academy of Medical Science 
University of Michigan Cancer Center 
Beijing 10021, China 
Ann Arbor, MI 48109, USA 
86-10-8778-8893/ Fax: 86-10-6770-6153 
734-615-4762/FAX 734-647-8792 
jianrong_dai@yahoo.com 
kalemker@umich.edu 
 
 
China Medical Physics Co-Chair 
U.S. Senior Statistician 
Yong Yin, PhD 
James Dignam, PhD 
Shandong Cancer Hospital and Institute 
Jinan, Shandong 250117, China 
Radiation Therapy Oncology Group/ACR  
and University of Chicago 
86-531-67626427/FAX 86-531-87984079 
1818 Market Street, Suite 1720 
yinyongsd@yahoo.com.cn 
Philadelphia, PA 19103 
 
215-574-3174/FAX 215-928-0153 
 
jdignam@acr.org 
China Medical Oncology Co-Chairs 
 
Meilin Liao, MD and Shun Lu, MD 
 
Shanghai Lung Cancer Center/Jiaotong University 
 
Shanghai 200030, China 
 
086-13601813062 
 
lushun@csco.org.cn 
 
 
 
 
China Medical Oncology/Pulmonary Co-Chair 
 
Chunxue Bai, MD, PhD 
 
Zhongshan Hospital/Fudan University 
 
Shanghai, China 
 
862 16404-1990-3077FAX 862 164-187-165 
 
cxbai@fudan.edu.cn 
 
 
 

  
 
 
 
 
4 
 
 
 
 
 
 
3502 
  TABLE OF CONTENTS 
 
 
 
Schema  
 
Eligibility Checklist  
 1.0 
Introduction 
 2.0 
Objectives 
 3.0 
Patient Selection  
 4.0 
Pretreatment Evaluations/Management 
 5.0 
Registration Procedures 
 6.0 
Radiation Therapy 
 7.0 
Drug Therapy 
 8.0 
Surgery 
 9.0 
Other Therapy 
10.0 
Tissue/Specimen Submission 
11.0 
Patient Assessments 
12.0 
Data Collection 
13.0 
Statistical Considerations 
 
References 
 
 
Appendix I 
- Sample Consent Form 
 
Appendix II  
- Study Parameters 
 
Appendix III 
- Performance Status Scoring 
 
Appendix IV 
- Staging System 
 
Appendix V 
- Thoracic Surgeon Credentialing Form 
 
Appendix VI 
- Nodal Atlas 
 
 
 
 
  

  
 
 
 
 
5 
 
 
 
 
 
 
3502 
RTOG FOUNDATION STUDY 3502 
 
POSTILV: A Randomized Phase II Trial in Patients with Operable Stage I Non-Small Cell Lung Cancer:  
Radical Resection versus Ablative Stereotactic Radiotherapy  
 
 
 
SCHEMA 
 
 
 
 
 
 
 
 
R 
 
R 
 
Follow up for  
 
E 
 
A 
Arm 1: R0 resection with  
Arms 1 and 2 
Patients with  
G 
FDG-PET/CT  
N 
nodal dissection/sampling 
 
pathologically 
I 
staging 
D 
(RODS) 
If recurrence then  
proven, medically 
S 
to confirm 
O 
 
salvage treatment:  
operable CT-staged 
T 
T1N0 disease* 
M 
Arm 2: SBRT given every other day 
surgery, radiation,  
T1N0 NSCLC 
E 
 
I 
11 Gy in  5 fractions to a total dose 
or systemic therapy 
 
R 
 
Z 
of 55 Gy in 10-15 days with an  
 
 
 
 
E 
inter-fraction interval of 2-3 days 
 
 
 
 
 
 
 
*Patients with T > 3 cm or N+ disease will be treated off study per standard of care and will not be followed. 
 
Note:  All participating institutions must be credentialed for participating surgeons, a dry-run case, 
phantom irradiation, IGRT, and 3DCRT (or IMRT, if used) prior to registering patients to the study; 
see Section 5.1. 
 
 
 
 
 
Patient Population:  (See Section 3.0 for Eligibility)  
Patients must have histologically proven CT and PET/CT confirmed Stage I, T1N0M0 non-small cell lung cancer 
(NSCLC); patients must be medically operable 
 
 
 
 
Required Sample Size: 76  
 

  
 
 
 
 
6 
 
 
 
 
 
 
3502 
Institution #  
 
 
3502 
 
 
 
 
ELIGIBILITY CHECKLIST – STEP 1 (10/22/14) 
Case #  
 
 
 
     (page 1 of 4) 
 
 
PRE-REGISTRATION CREDENTIALING for participating surgeons, a dry-run case, phantom irradiation, 
IGRT, AND 3DCRT (or IMRT, if used) IS REQUIRED. 
 
 
(Y)    1. 
Was stage I non-small cell lung cancer (NSCLC) confirmed by biopsy (strongly recommended) 
or is the mass suspicious for NSCLC based on 2 or more criteria listed in Section 3.1.1? 
 
            (Y)  
 Is the cancer one of the types eligible for the study as specified in Section 3.1.1?  
 
            (N)  
 Any histologic evidence of pure bronchioloalveolar cell carcinoma subtype? 
 
            (N) 
2.    Is the primary tumor > 3 cm? 
 
            (Y) 
3. Is patient nodal status N0 per definition in Section 3.1.2. ? 
 
        (Y/N)   
Are there hilar or mediastinal lymph nodes > 1 cm on computed tomography (CT) or any size 
lymph nodes demonstrating suspicious uptake on positron emission tomography (PET) scan? 
 
           (Y) 
If yes, are all lymph nodes > 1 cm on CT or demonstrating suspicious uptake on PET scan 
negative for NSCLC on biopsy? 
 
______(N) 
4. Does the patient have metastatic disease (M1)? 
 
______ (Y)  
5. Is the primary tumor predicted to be technically resectable with high likelihood of negative 
surgical margins by a thoracic surgeon?   
 
 
 
 
(Y) 
6. Is the patient medically operable as defined in Section 3.1.3?   
 
 
(Y) 
7. Do the patient’s PFTs meet the criteria specified in Section 3.1.3? 
 
          (Y/N)    8. Is pleural effusion present? 
 
             (Y) 
If yes, is the effusion too small to tap under CT guidance and not evident on chest x-ray? 
(Pleural effusion that appears on chest x-ray and only after thoracotomy or other invasive 
thoracic procedure will be permitted.) 
 
 
(Y) 
9.  Is the patient’s Zubrod Performance Score 0-1? 
 
 
(Y) 
10. Is patient ≥ 18 years of age?  
 
       (Y/NA)    11.  If a female of childbearing potential or an sexually active male, has the patient agreed to use an 
effective method of contraception?                                                                  
 
 
(Y) 
12. Have the required pretreatment evaluations and staging studies been obtained as specified in 
Section 3.0 and are results compatible with required parameters for registration to this study?  
 
 
(N)  13. Is there direct evidence of regional or distant metastases or synchronous primary or prior 
invasive malignancy within the past 3 years? 
 
 
 
 
 
 
 
 
 
 
 
 
Continued on next page

  
 
 
 
 
7 
 
 
 
 
 
 
3502 
Institution #  
 
 
3502  
 
 
 
 
ELIGIBILITY CHECKLIST – STEP 1 (2/14/13) 
Case #  
 
 
 
     (page 2 of 4)  
 
 
_______(N) 14.  Any prior radiotherapy for any other cancer which would overlap the planned SBRT fields? 
 
              (N)   15.  Any previous chemotherapy or thoracic surgery involving lobectomy or pneumonectomy? 
 
 
(N)    16. Is there evidence of active systemic, pulmonary, or pericardial infection? 
 
       (N/NA)    17.  If a female of childbearing potential, is the patient pregnant? 
 
 
The following questions will be asked at Study Registration:  
CREDENTIALING for participating surgeons, a dry-run case, phantom irradiation, IGRT, AND 3DCRT (or 
IMRT, if used IS REQUIRED BEFORE REGISTRATION. 
 
 
         
1. 
Institutional person randomizing case. 
 
                  (Y) 2. 
Has the Eligibility Checklist been completed? 
 
                  (Y) 3. 
In the opinion of the investigator, is the patient eligible? 
 
 
         
4. 
Date informed consent signed 
 
 
         
5. 
Patient’s Initials (First Middle Last) 
 
 
         
6. 
Verifying Physician 
 
 
         
7. 
Patient ID  
 
 
         
8. 
Date of Birth 
 
 
         
9. 
Race 
 
 
         
10. 
Ethnicity 
 
 
         
11. 
Gender 
 
 
         
12. 
Country of Residence 
 
 
         
13. 
Method of Payment 
 
 
         
14. 
Calendar Base Date 
 
 
         
15. 
Randomization date 
 
 
         
16. 
Thoracic Surgeon 
 
 
 
Continued on next page. 
 

  
 
 
 
 
8 
 
 
 
 
 
 
3502 
Institution #  
 
 
3502  
 
 
 
 
ELIGIBILITY CHECKLIST –STEP 1 (2/14/13) 
Case #  
 
 
 
     (page 3 of 4)  
 
 
 
              (Y/N) 17. 
Have you obtained the patient's consent for his or her tissue to be kept for use in 
research to learn about, prevent, treat, or cure cancer?  
 
              (Y/N) 18.  
Have you obtained the patient's consent for his or her blood to be kept for use in  
research to learn about, prevent, treat, or cure cancer?  
 
              (Y/N) 19. 
Have you obtained the patient's consent for his or her tissue to be kept for use in  
research about other health problems (for example: causes of diabetes, Alzheimer's 
disease, and heart disease)?   
 
              (Y/N) 20. 
Have you obtained the patient's consent for his or her blood to be kept for use in  
research about other health problems (for example: diabetes, Alzheimer's disease, or 
heart disease).  
 
              (Y/N) 21. 
Have you obtained the patient's consent to allow someone from this institution to contact  
him or her in the future to take part in more research?  
  
______ (Y/N)    22.        Specify use of IMRT. 
 
 
 
 
The Eligibility Checklist must be completed in its entirety prior to web registration. The completed, signed, and 
dated checklist used at study entry must be retained in the patient’s study file and will be evaluated during an 
institutional RTOG audit. 
 
Completed by  
 
 
 
 
 
Date 
 
 
 
 
 
 
 

  
 
 
 
 
9 
 
 
 
 
 
 
3502 
Institution #  
 
 
3502  
 
 
 
 
ELIGIBILITY CHECKLIST –STEP 2 (2/14/13) 
Case #  
 
 
 
     (page 4 of 4)  
 
 
 
 
 
 
1. Institutional person randomizing case 
 
 
(Y/N) 
2. Is the patient able to continue protocol treatment? 
 
 
  
3. If no, specify the reason the patient cannot continue to Step 2:  
1) FDG-PET/CT not done;  
2) T > 3 cm; 
3) N+;  
4) T > 3 and N+;  
5) Patient refusal; 
6) Other* 
 
 
 
 
*Specify the reason the patient cannot continue to Step 2. 
 
 
 
4. Patient’s Initials 
 
 
 
5. Verifying Physician 
 
 
 
6. Patient ID  
 
 
 
 
7. Calendar Base Date (for Step 2) 
 
 
 
 
8. Randomization date: (for Step 2) 
 
 
 
 
 

  
 
 
 
 
10 
 
 
 
 
 
 
3502 
1.0 
INTRODUCTION 
Lung cancer remains the leading cause of cancer death in both men and women in the U.S. [1], Asian 
countries [2], and the world [3].  Based on WHO report, there were 1.4 million lung cancer-related deaths 
in the world in 2008. The incidence is expected to increase with an expected doubling of the incidence of 
all cancers by 2030.   
 
Approximately 85% of lung cancers are non-small cell lung cancer (NSCLC), and 16% of these present 
with localized disease (stage I and node-negative stage II are generally considered as local disease). For 
patients with local disease, radical resection, i.e. R0 resection with nodal dissection or sampling (RODS) 
has been the standard care for decades, with a 5-year survival rate of 70-80% [4]. Based on SEER data 
from 1973-2007, approximately 70% of early stage patients underwent surgical resection. The remaining 
patients were either medically inoperable or declined surgical intervention. Among this group, 
conventional fractionated radiation therapy (RT) was the mainstay of treatment with a 10-30% 5-year 
survival rate. In the 1990s, advances in technology allowed for the implementation of 3D conformal RT 
(3DCRT) with associated dose escalation and improved local control and long-term survival. Further 
advances in target motion definition, image-guidance, and stereotactic localization, have allowed for the 
development of stereotactic radiotherapy (SBRT). This modality has a reported 90% 3-year local control 
rate and 60-80% long-term survival rate. These rates are comparable to those obtained from surgery.  
The primary aim of this trial is to determine if the efficacy of SBRT is comparable to that of standard 
surgical interventions for patients with T1N0 NSCLC. 
 
1.1 
Treatment Outcome of Surgery 
1.1.1 
Efficacy 
Currently, RODS remains the standard of care for stage I (T1-2a N0) NSCLC with 5-year 
survival rates of 60-70%. [5-13]. The preferred surgical procedure is a lobectomy with or without 
hilar/mediastinal lymph node dissection [14-21]. A less extensive operation such as a wedge 
resection or a segmentectomy with or without postoperative brachytherapy often is performed 
when a patient is unable to tolerate a lobectomy either because of inadequate respiratory 
reserve, cardiac dysfunction, vascular disease, general poor performance status, or other co-
morbidities. In general, wedge resection is not considered to be a radical resection. Table 1a 
summarizes the tumor control rates after surgical resection in this patient population. According 
to the International Association for the Study of Lung Cancer staging project [4], the 5-year 
survival rates were 77% and 71% after radical excision of pT1N0 tumors <2 cm (n=1,816 
patients) and pT1bN0 tumors (2–3 cm), (n=1,653 patients), respectively. For patients clinically 
staged N0, 5-year survival was 53% for cT1a and for cT1b, 43%. After RODS, there is a 10-
35% rate of local recurrence [22-27]. Salvage options after resection are available but tend to 
have poor outcomes.   
 
Table 1a: Survival Outcomes in T1-2N0M0 NSCLC Patients Treated with Surgery 
Reference 
N  
Patient 
Category 
Treatment 
Local control 
(%) 
Overall survival 
(%) 
Postoperative 
complications 
Errett, et al. 
(1985)[28] 
97 
100 
Poor risk 
Lobectomy 
Wedge resection 
NR 
74 (2yr), 75 (6yr) 
72 (2yr), 69 (6yr) 
2.1%,3% (30 day 
operative mortality) 
Ginsberg, et 
al. (1995)[11] 
125 
122 
Standard 
risk 
Lobectomy 
Limited resection 
~80 (5yr) 
~55 (5yr) 
~65% (5yr) 
~45% (5yr) 
2 postoperative deaths 
1 postoperative death 
Kodama, et 
al. (1997)[29] 46/77 
 
Standard 
risk 
Segmentectomy 
or Lobectomy 
91.3 (5yr) 
93 (5yr) 
NR 
Koike, et al. 
(2003)[30] 
159 
74 
 
Standard 
risk 
Lobectomy 
Limited resection 
~150/159 (5yr) 
~69/74 (5yr) 
97.0 (3yr), 90.1 
(5yr) 
94.0 (3yr), 89.1 
(5yr) 
(tumor <=2cm) 
no severe 
cardiovascular or 
comorbid factors  in 
either groups 

  
 
 
 
 
11 
 
 
 
 
 
 
3502 
Landreneau, 
et al. 
(1997)[31] 
42 
60 
117 
Stage I 
Poor risk 
Open wedge 
resection 
Video-assisted 
wedge resection 
Lobectomy 
76 (5yr) 
84 (5yr) 
91 (5yr) 
58  (5yr) 
65 (5yr) 
70 (5yr) 
0 operative death in 
wedge resection 
3% operative mortality 
in lobectomy group 
Martini, et al. 
(1995)[32] 
511 
25 
62 
T1-2 
Lobectomy 
Pneumonectomy 
Wedge resection 
or segmentectomy 
 
 
50 (5yr) 
77 (5yr), 70 (10yr) 
 
59 (5yr), 35 (10yr) 
14 postoperative death 
in lobectomy group 
Miller, et al. 
(2002)[33] 
75 
25 
T<1cm 
Lobectomy or 
bilobectomy 
Limited resection 
85.3 (5yr) 
72 (5yr) 
71 (5yr) 
33 (5yr) 
4 postoperative death 
Okada, et al. 
(2006)[34] 
262 
305 
Standard 
risk 
(<2cm) 
Segmentectomy or 
Lobectomy 
 
82 (5yr) 
85 (5yr) 
89.1 (5yr) 
89.6 (5yr) 
 
6.6% 
7.3%  
 
Pastorino, et 
al. (1991)[35] 
411 
61 
Stage I 
Standard 
risk 
Lobar resection 
Sublobar resection 
64 (5yr) 
62 (5yr) 
T1:55 (5yr) 
T2:46(5yr) 
T1:73 (5yr) 
T2: 35 (5yr) 
3% peri-operative 
death lobar resection  
Warren, et al. 
(1994)[36] 
105 
68 
Standard 
risk 
T1-2 
Lobectomy 
Segmentectomy 
95.1 (5yr) 
77.1 (5yr) 
NR 
NR 
Birdas, et al. 
(2006)[37] 
126 
41 
IB 
High risk 
Lobectomy 
Sublobar + I-125 
brachytherapy 
96.8 
95.2 
51.8 (4yr) 
54.9 (4yr) 
NR 
Fernando, et 
al. (2005)[38] 
167 
124 
IA 
High risk 
Lobectomy 
Sublobar resection 
(60+ 
brachytherapy) 
90 (<2cm), 
96.5 (>2cm) 
82.5 (T2cm) 
95.6 (T2cm) 
96.7 with 
brachytherapy 
85 
m(<2cm),68.7m(>
2cm) 
55.8m(<2cm),50.
6m(>2cm 
 
NR 
Santos, et al. 
(2003)[39] 
102 
101 
T1-2 
High risk 
Sublobar resection 
Resection + 
brachytherapy 
81.4 
98 
NR 
NR 
d'Amato, et 
al. (1998)[40] 
14 
T1 
High risk 
VATS wedge 
resection 
+ brachytherapy 
100 at 7m fu 
NR 
NR 
Lee, et al. 
(2003)[41] 
33 
T1-2 
High risk 
Limited resection 
+ brachytherapy 
2 local 
recurrence 
47(5yr) 
NR 
McKenna, et 
al. (2008)[42] 
48 
I-III 
 High risk 
Wedge resection 
+ brachytherapy 
3 local 
recurrence 
NR 
2 death in 30 day 
postoperatively 

  
 
 
 
 
12 
 
 
 
 
 
 
3502 
 
Attempts to minimize the extent of resection have demonstrated worse outcomes in general 
[10, 11, 31, 43, 44]. The only randomized trial comparing lobectomy with sublobar resection 
reported a significantly higher recurrence rate for sublobar resection (p=0.02). There also was a 
trend toward worse survival in the sublobar resection group, but this did not reach statistical 
significance (p=0.08) [11]. One meta-analysis and several non-randomized comparisons have 
confirmed these results. Local recurrence after wedge resection is higher than after 
segmentectomy. However, for tumors ≤ 2 cm, segmentectomy is equivalent to lobectomy.  
Survival after segmentectomy is worse for larger tumors [45, 46].  For patients aged > 71 years, 
lobectomy and wedge resection may be associated with similar survival. 
1.1.2 
Toxicity 
Surgical treatment is invasive and associated with significant mortality and morbidity [47-52]. 
The reported mortality rates are 7.2% in China (for T4 tumors) [53], 2.4~4.9% in Europe [49, 
54], and 4.5% in the U.S. within 30 days post-lobectomy. In 128 patients with screen-detected 
peripheral lung nodules who underwent a video-assisted thoracic surgical (VATS) lobectomy, 
grade 3 or greater complications were seen in 7.4% (out of 95 patients) and the 30-day 
perioperative mortality was 2.7% [55]. Similarly, operative complications occurred in 27% of 
patients with screen-detected lung nodules who underwent a thoracotomy, and the 
corresponding operative mortality was 1.7%. [56]. While morbidities may vary from report to 
report [48, 57-59], most of the studies reported mortality rates of 1-7% associated with surgical 
intervention (Table 1a). 
 
1.2 
Treatment Outcome of Stereotactic Body Radiation Therapy (SBRT) 
SBRT is an emerging radiation (RT) technique that targets very high-dose RT precisely to a 
tumor while minimizing dose to adjacent normal tissue. SBRT derived from stereotactic 
radiosurgery, which was first developed in the late 1950’s for the treatment of intracranial lesions. 
Stereotactic radiosurgery, normally with high-dose RT delivered in 1 fraction under stereotactic 
targeting, provides equivalent treatment results as a craniotomy with surgical resection. Recent 
advances in RT planning, such as 3DCRT and intensity modulated radiation therapy (IMRT), 
motion control, and on board image (OBI), and image guided radiation therapy (IGRT) during 
treatment delivery in the last decade have led to the application of this technique to extracranial 
sites. While stereotactic RT refers to high-dose RT in a fractionated fashion to any organ sites 
(intra- or extracranial sites), SBRT has been adopted for stereotactic RT to extracranial body sites 
including lung. The U.S. National Cancer Institute defines SBRT as “a type of external radiation 
therapy that uses special equipment to position a patient and precisely deliver radiation to tumors 
in the body (except the brain). The total dose of radiation is divided into smaller doses given over 
several days. This type of radiation therapy helps spare normal tissue.” 
 
SBRT techniques were initially developed at Karolinska University Hospital in Sweden in the early 
1990s for the treatment of tumors in the liver using a body stereotactic frame method [116]. 
Investigators there reported that the reproducibility of localization in the stereotactic system for 
tumors in the liver and the lung was within 5-8 mm for 90% of the patient set-ups. Diaphragmatic 
movements were reduced to 5-10 mm, by applying pressure on the abdomen. A non-coplanar 
treatment technique of 8 individually shaped beams was proposed [116]. The first clinical report 
also was from the same group in 31 patients with solitary tumors in the liver, lung, or 
retroperitoneal space with clinical target volumes ranging from 2 to 622 cm3 (mean 78 cm3). With 
a total mean PTV dose of 41 Gy (8-66 Gy), fraction dose of 14.2 Gy (7.7-30 Gy), and minimum 
PTV dose of  30.2 Gy (7.7-45 Gy) with treatment delivered in 1-4 fractions, the authors reported 
that 50% of patients had tumor reduction or complete resolution [117]. Later, a Japanese group 
developed an SBRT unit consisting of a linear accelerator, X-ray simulator, computed 
tomography scanner, and table [118]. A dose of 30-75 Gy was delivered in 5-15 fractions at the 
80% isodose line over 1-3 weeks, with or without conventional radiation therapy. The gantry axes 
of the 3 machines were coaxial and could be matched by rotating the table. Patients were 
instructed to perform shallow respiration with oxygen. The motion of the tumor was monitored 
with the x-ray simulator. Between 1994 and 1997, 45 patients with 23 primary tumors and 43 
metastatic lung tumors were treated. During a median follow-up of 11 months, local progression 
occurred in only 2 of 66 lesions with no or minimal toxicity.  
 

  
 
 
 
 
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The first prospective dose escalation SBRT trial performed in the U.S. was from the University of 
Indiana, led by Timmerman [119]. This study of 37 patients with stage I NSCLC demonstrated 
that a very high dose (60 Gy in 3 fractions BED 180 Gy) could be delivered safely to peripheral 
tumors, and that a dose less than 18 Gy per fraction was associated with more frequent local 
failure. 
 
Modern SBRT is the result of multiple advanced RT techniques, including IMRT, 4DCT/ABC, OBI, 
high accurate image fusion capability, and precise treatment delivery. Specifically, SBRT is a 
form of high-precision radiotherapy delivery characterized by (a) highly reproducible 
immobilization to avoid patient movement during treatment sessions; (b) highly conformal 
radiation dose tightly covering the tumor, with rapid dose falloff in surrounding normal tissues in 
order to reduce toxicity; c) measures to individually account for tumor motion during imaging, 
treatment planning, and radiation delivery; d) use of OBI and 3D IGRT to secure precise radiation 
delivery; and e) the use of extremely high biological doses of RT usually delivered in 3 to 8 
treatment fractions within a 2-week period [120]. The tumor control and overall survival (OS) rates 
for SBRT (Table 1b) are remarkably better than that of 3DCRT. In patients with medically 
inoperable stage I NSCLC, SBRT generated 3-year local control and OS rates of 66-90% and 43-
90%, respectively. Results from RTOG 0236, a multicenter trial in medically inoperable NSCLC, 
have just been published [121].  Of 55 evaluable patients with stage I NSCLC (44 stage IA, 11 
IB), the 3-year primary tumor and involved lobe (local) control rate was 90.6% (95% CI, 76.0%-
96.5%). The local-regional control rate was 87.2% (95% CI, 71.0%-94.7%). The 3-year rate of OS 
was 55.8% (95% CI, 41.6%-67.9%), and the median OS was 48.1 months (95% CI, 29.6 months 
to not reached).  
 
The survival outcome of SBRT in stage I NSCLC is associated with multiple factors including 
comorbidities, tumor size, RT dose, and patient fitness. One of the most common causes of death 
in this group of patients was intercurrent diseases [122]. This is in marked contrast to the 
experience reported in 3DCRT series, in which the major cause of death was progression from 
lung cancer [85, 123, 124].   
 
Patients with operable disease had overall survival (OS) rates of over 80% in most series after 
SBRT.  However, the data on SBRT in operable stage I NSCLC is relatively limited [125-130]. In 
a retrospective study, Hiraoka, et al. reported that for tumors that received a BED of more than 
100 Gy, OS at 3 years was 91% for operable patients [130]. This included 98 patients who 
refused surgery [129], and whose 5-year OS rate of 70.8% after a BED of 100 Gy was at least 
equivalent to that reported historically after surgery [131]. A recent study from Washington 
University retrospectively compared treatment results in patients with clinical stage I disease 
treated with SBRT and RODS [132]. The 3-year local tumor control rates were 89% with SBRT 
and 96% with surgery (p = .04) for stage IA. There was no difference in local tumor control in 
stage IB disease (p = .89). No disease-specific survival differences were found in patients with 
stage 1A (p = .33) or IB disease (p = .69). Results from a propensity score matched analysis in 57 
high-risk surgical patients to 57 patients undergoing SBRT reported no difference in freedom from 
local recurrence (88% vs. 90%), disease-free survival (77% vs. 86%), and OS (54% vs. 38%) at 3 
years. A study from William Beaumont Hospital compared outcomes between SBRT (n=58) and 
wedge resection (n=69) for patients with stage I NSCLC. At 30 months, no significant differences 
were identified in regional recurrence, locoregional recurrence, distant metastasis, or freedom 
from any failure between the 2 groups (p > .16). SBRT reduced the risk of local recurrence by 4% 
versus 20% for wedge resection (p = .07). OS was higher with wedge resection, but cause-
specific survival (CSS) was identical. Results from a phase II randomized study reported at 
ASTRO 2010 showed that OS is comparable between SBRT and RODS in patients with operable 
stage I NSCLC. In patients with operable NSCLC, a retrospective study of 87 patients stage I 
NSCLC reported 5-year tumor control of 92%, OS 72% from 14 Japanese centers [265]. Results 
from a phase II single arm study from Japan reported at ASTRO 2010 showed that OS of SBRT 
is comparable to RODS in patients with operable stage I NSCLC [266].   
 
 
 
 
 

  
 
 
 
 
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Table 1b: Results of SBRT in the Treatment of Stage I Non-Small Cell Lung Cancer 
Reference 
# Pts 
Stage 
Dose & 
Fraction (Gy) 
Treatment 
Duration 
(Days) 
Median 
follow-
up(months) 
% local 
tumor 
control 
% overall 
survival 
Toxicity 
Uematsu, et al. 
2001[125] 
50 (29 
operable) 
I 
50-60 in 5-10fx 
<12 
 
94 (3yr) 
66 (all 
cases, 3 yr) 
86 
(operable 
cases, 3 yr) 
2 minor bone 
fracture, 
6 temporary 
pleural pain 
Koto, et al. 
2007[133] 
31 
I 
45/3fx, 68/8fx 
 
32 
77.9 (T1,3yr) 
40.0 (T2,3yr) 71.7 (3yr) 
5 grade 2 
 lung toxicity 
Timmerman, et 
al. 2006[134] 
70 
I 
24-60 in 3fx 
<12 
17.5 
95 (2yr) 
54.7 (2yr) 
14 grade 3-5 
toxicity for both 
central and 
peripheral 
disease 
Lagerwaard, et 
al. 2008[135] 
206 
I 
60/3fx,60/5fx, 
60/8fx 
5-14 
34 
91 (2yr) 
64 (2yr) 
3% ≥ grade 3 
pneumonitis, 4 rib 
fracture 
Hiraoka, et al. 
2004[136] 
254 
IA,IB 
48 in 4 fx 
5-12 
 
80 
(BED<100) 
93.5 
(BED>100) 
46 
(BED>100,
3 yr) 
42 
(BED<100,
3 yr) 
NR 
Zimmermann, 
et al. 2005[137] 
30 
I 
24.0-2737.5 in 
3-5 fx 
<12 
18 
93 (1.5 yr) 
70 (1.5yr) 
1 grade 3 acute 
pneumonitis, 1  
rib fracture 
Wulf, et al. 
2004[138] 
20 
I, II 
30-37.5 in 3fx 
or 26 Gy in 1 fx 
<12 
11 
92 (1yr) 
32 (2yr) 
2 grade 2 
pneumonitis 
Nagata, et al. 
2005[139] 
45 
IA, 
IB<4cm 
48 in 4 fx 
5-12 13 
30 
72 (3 yr dfs) 
71 (3 yr 
dfs)98 
83 (IA, 3yr) 
72 (IB, 3yr) 
2 grade 2 
pneumonitis 
Onishi, et al. 
2004[140] 
235 
IA, IB 
60 in 10 fx 
5-8 
13 
NR, 94 
83 (2yr) 
5 grade 2 lung 
toxicity 
Zimmermann, 
et al. 2006 
[141] 
68 
I 
24-40 in 3-5 fx 
3-10 
17 
88 (3 yr) 
53 (3yr) 
3% grade 3 acute 
pneumonitis, 1% 
grade 3 late 
pneumonitis, 3% 
rib fractures, 2 
benign pleural 
effusion 
Takeda, et al. 
2009[142] 
121 
IA/IB 
50 in 5fx 
<12 
31 
93 (IA)/96 
(IB) (3yr) 
90 (IA)/63 
(IB) 
(3 yr) 
3 >2 grade 
pneumonitis, 
1 fatal bacterial 
pneumonia 
Guckenberger 
& Wulf,  et al. 
2009[143] 
124 
(118 met) 
I/II 
(Met) 
26-326 in 1-
68fx 
<12 
14 
62 
(BED<100) 
89 
((BED>100) 
(3yr) 
37 
(primary) 
16 (mets) 
3yr 
1 grade 3 
pneumonitis 
1 grade 3 
esophageal 
ulceration 
Chang, et al. 
2008[144] 
27 
I & 
recurre
nt 
40-50 in 4 fx 
4 
17 
100 (17mo) 
(50Gy) 
47 (40Gy) 
NA 
3 grade 2-3 
dermatitis and 
chest wall pain. 

  
 
 
 
 
15 
 
 
 
 
 
 
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Baumann, et al. 
2008 & 
2009[126, 145] 60 (2008) 
/57 
(2009) 
IA/ 
IB 
45 in 3 fx 
<12 
36 
92(3yr) 
50/60 (3yr) 
21% grade 3 
toxicity 
0%grade 4-5 
toxicity 
Salazar, et al. 
2008[146] 
60 
IA/IB 
 
40-53 Gy in 4 fx 
(73%) or 
EBRT45 Gy 
+3SBRTx3 fx 
(27%) 
BED=120 Gy 
6+ weeks 
NR 
70/74 (CSS) 
82 
5yr CSS 74 
(IA) 
5yr CSS 64 
(IB)NA 
 
7% grade 2 
toxicity 
Le, et al. 
2006[147] 
32 
I 
15-30 Gy/1fx 
1 
12 
91 (>20 
Gy,1yr) 
54 (<20 Gy, 
1yr) 
NR 
12.5% grade 3-5, 
3/4 central 
lesions, all >20Gy 
Fakiris, et al. 
2009[148] 
70 
IA/IB 
60-66/3fx 
<12 
50.2 
88.1 (3yr) 
42.7 (3yr) 
Grade 3-
5:10.4%(peripher
al); 27.3% 
(central) 
Gomi, et al. 
2007 [149] 
56 
IA 
62.5/5fx 
5<12 
32 
95 (3yr) 
81.3 (3yr) 
1 grade 4 
pneumonitis, 
 1 grade 4 
dermatitis,  
1 grade 3 
esophagitis and 1 
rib fracture 
Gril, et 
al.2010[150] 
58 
IA/IB 
48/4fx, 60/5fx 
<12 
30 
96 
72 (3yr) 
11% > grade 2 
pneumonitis 
Timmerman, et 
al. [121] 
55 
IA/IB 
60 in 3fx 
10-14 
24.8 
93.7 (2yr) 
72 (2yr) 
24% grade 3, 4% 
grade 4 
Onishi, et al. 
2007 [129] 
257 
IA/IB 
18-75/1-22fx 
 
38 
86 
70.8 
(BED>100
Gy, 5yr), 
30.2 
(BED<100
Gy, 5yr) 
5.4% >grade 2 
lung toxicity 
 
1.2.1 
Dose Fractionations in SBRT 
Similar to 3DCRT, adequate biologic equivalent dose (BED) is essential for optimal tumor 
control with SBRT [129, 130, 140, 143, 151-154]. SBRT normally delivers much higher BED 
than conventionally fractionated 3DCRT (typically BED of 70-85 Gy). Studies from Japan, 
Germany, and China all reported that SBRT with BED ≥ 100 Gy was associated with 
significantly better local control and long-term survival. For patients who received a BED ≥ 100 
Gy, local tumor control was over 90%. The largest series [129] retrospectively reviewed 257 
patients treated at 14 institutions in Japan using a number of different treatment doses and 
delivery approaches. At a median follow up of 38 months, the local recurrence rate was 8.4% in 
patients who were treated to a BED ≥ 100 Gy. A recent Germany study also reported that a 
BED > 100 Gy is critical for achieving good local control [143]. A Chinese study applied daily 
fractionated SBRT with a total BED up to 115 Gy and reported 3- and 5-year OS rates for T1-3 
patients of 57.3% and 35.1%, respectively, and for stage T1-2 patients of 60.2 and 36.5%, 
respectively [151]. Studies from the U.S. also suggested that patients who received 16 Gy x 3 
(BED=124 Gy) had significantly better local control than those who received lower doses. Dose 
response analysis showed that the outcome plateaued around 120 Gy BED. 
 

  
 
 
 
 
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The effect of fractionation is complicated for SBRT, and fractionation regimens vary from center 
to center. A number of fractionation schedules are undergoing evaluation [155]. In the U.S., a 
frequently used schedule for peripheral lung tumors is 60 Gy in 3 fractions with a total BED of 
180 Gy. In Europe, Japan, and China, however, a BED >100 Gy is more commonly delivered in 
4-10 fractions. Particularly in China, regimens with fraction size less than 12 Gy have been 
preferred. Selection of fractionation should maximize the therapeutic ratio of tumor control 
versus normal tissue toxicity by taking the tumor size and location into consideration for an 
optimized therapeutic gain [156] [157]. Overall, for tumors less than 3 cm, there is no significant 
difference in tumor control rates between various fractionation regimens as long as more than 
100 Gy BED is given [150, 158]. For tumors larger than 3 cm, higher doses (BED of 120 Gy or 
above) may be needed. Similar to RODS, distant failure is the main cause of death [159]. 
Fractionation regimens with tumor BED around 120 Gy in 3-5 fractions include 16 Gy x 3, 13 
Gy x 4, and 11 Gy x 5. The available data are compelling enough for SBRT to be considered an 
established treatment option in patients who are medically inoperable or for those patients who 
have refused surgical resection [132, 150, 160]. 
1.2.2 
Toxicity of SBRT 
Toxicity following SBRT has been limited. Reported long-term toxicity exceeding grade 2 
Common Toxicity Criteria (CTC v. 3.0) is seen in less than 10% of patients and was mainly 
observed in patients with large or centrally located tumors [121, 135, 161, 162] when doses to 
the proximal bronchial tree were not strictly limited.  In the series by Onishi [129], pulmonary 
complications exceeding grade 2 were observed in 14 patients (5.4%). Timmerman, et al. 
reported the need for caution when a BED of 180–210 Gy was administered for centrally 
located tumors adjacent to the mediastinum [134]. In the patients treated by Lagerwaard, et al., 
using a ‘risk-adapted’ approach with the BED limited to 105 Gy for central tumors, early toxicity 
was mild with fatigue (32%), nausea (10%), and chest pain (8%) as the most frequently 
encountered acute side effects [135]. Late toxicity was uncommon with radiation pneumonitis 
exceeding grade 2 in 6 patients (3%). Rib fractures and chronic pain syndromes located at the 
chest wall were observed in 4 and 3 patients, respectively. 
1.2.3 
Quality of Life After SBRT 
Data on quality of life (QOL) is limited after SBRT for NSCLC. For stage I NSCLC, QOL was 
assessed in 39 patients treated with SBRT by using The European Organization for Research 
and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30 and the QLQ LC13 
lung cancer-specific questionnaire. Assessments were done before treatment, at 3 weeks, and 
at 2, 4, 6, 9, and 12 months after treatment, and until death or progressive disease. Toxicity 
was evaluated using CTCAE, v. 3.0. Emotional functioning improved significantly after 
treatment. Other functional scores, QLQ C30, and QLQ LC13 lung symptoms (such as dyspnea 
and cough) showed no significant changes. [164]. These results may be better than those 
reported for 3DCRT, RFA, and surgical resection. Using Markov model analysis, a recent cost 
effectiveness study report indicates that SBRT may offer comparable OS and quality-adjusted 
life expectancy as compared with surgical resection [266]. Randomized prospective studies 
comparing surgery vs. SBRT in early-stage lung cancer are warranted to further investigate the 
relative survival, quality of life, and cost characteristics of both treatment paradigms [266].  
 
In this trial, quality of life endpoints will not be evaluated; however, provided that the primary 
hypothesis and performance metrics are satisfied, the subsequent phase III trial will incorporate 
detailed QOL measures in order to definitively and comprehensively evaluate SBRT for larger 
scale clinical utility.  
 
1.3 
Translational Research 
1.3.1 
Background/Hypothesis  
Severe pulmonary complications occur in about 10-20% patients after lobectomy [192-198]. 
After SBRT, 10% of patients experience grade ≥ 3 radiation-induced lung toxicity (RILT) [199-
201].  Currently, there are no well-established methods to predict which patients will experience 
lung toxicity. In general, the risk of pulmonary toxicity increases with decreasing pulmonary 
reserve, larger radiation treatment volumes, and the use of concurrent chemotherapy. Many 
dosimetric factors, such as mean lung dose, V20, and D30 [202-209], have been associated 
with the risk of lung toxicity after radiation.  However, these associations have not enabled 
prediction of which patients will experience lung toxicity.  The mechanisms of RILT are not well 
understood; however, several reports have suggested a possible role of pro-fibrogenic and pro-

  
 
 
 
 
17 
 
 
 
 
 
 
3502 
inflammatory cytokines such as Interleukin-1 (IL-1), IL-6, IL-8, IL-10, TNF-α, platelet-derived 
growth factor and transforming growth factor beta 1 (TGFβ1) [210-218]. Among these factors, 
TGFβ1 has been the most extensively studied. TGFβ1 stimulates connective tissue formation 
and decreases collagen degradation resulting in fibrosis.  It also plays an important role in the 
inhibition of epithelial cell proliferation.  Researchers from Duke University have reported that 
the plasma TGFβ1 at the end of radiation correlates with symptomatic lung toxicity in patients 
treated with definitive radiation therapy [219, 220]. Kong, et al. further demonstrated that the 
loss of mannose 6-phosphate insulin-like growth factor-2 receptor contributes to increased 
TGFβ1 levels and subsequent radiation-induced pneumonitis [221]. In patients treated with an 
escalated dose of radiation, Anscher, et al. found a significant correlation between TGFβ1 
levels and late grade ≥ 3 non-pulmonary radiation toxicity [222]. Additional reports have shown 
that elevated plasma levels of TGFβ1 4 weeks into the course of conventionally fractionated 
conformal radiation therapy are highly correlated with the occurrence of grade ≥ 2 RILT [210, 
223]. A combined analysis of University Michigan and Peking Union of Medical College data 
further confirmed this finding [224]. 
 
Data also has been published demonstrating an association between RILT and levels of IL-1, 
IL-6, and IL-8 [215, 216, 225-228]. IL-1 (IL-1ra and IL-1β) is produced by macrophages, 
monocytes, fibroblasts, and dendritic cells and is an important mediator of the inflammatory 
response of many tissues [229-232]. IL-1β promotes inflammation in injured lung tissue, and 
has been reported to be significantly associated with RILT [216, 233].  IL-6 also is a major 
mediator of the acute-phase inflammatory response and is synthesized by a variety of cells in 
the lung parenchyma. Researchers have demonstrated a trend toward increased plasma 
concentrations of IL-6 after thoracic RT [212, 216]. Animal models also have confirmed these 
trends [228, 237, 238]. In addition, IL-8, a member of the CXC chemokine family, is believed to 
serve as a chemical signal that attracts neutrophils to the site of inflammation [239-241]. 
Significant differences in the median values of IL-8 were observed between patients with and 
without symptomatic RILT [225]. Overall, plasma IL1, IL-6, and IL-8 levels may serve as a 
predictor for RILT after conventionally fractionated radiation therapy [212, 216].  Most recently, 
it was reported that the plasma level of IL-8 prior to and during conventionally fractionated 
radiation therapy is significantly associated with grade ≥ 2 RILT [242]. 
 
Genomic markers also have shown promise in helping to elucidate the mechanism of RILT. The 
single nucleotide polymorphisms (SNP) of several specific genes found in white blood cells 
have been shown to be elevated in the setting of radiation-induced injury in several organs 
[243-245]. CT/CC genotypes of TGFβ1 rs1982073:T869C genes are associated with a lower 
risk of RILT in patients with NSCLC treated with definitive chemoradiation [246]. It also recently 
was demonstrated that the frequency of the 7351C allele of Tissue Plasminogen Activator, 
which is associated with TGF β1 activation is increased in patients with grade ≥ 2 RILT when 
compared to historical controls (0.73 vs. 0.68, p = 0.01)[247]. 
 
Protein elevations also may hold cues as to the mechanism of RILT. It has been demonstrated 
that there are differential changes in protein-associated pathways between animals sensitive to 
and resistant to radiation lung damage [248]. Using a multiplexed quantitative proteomics 
approach involving ExacTag labeling, RP-HPLC, and LC-ESI-MS/MS, over 100 proteins have 
been identified and quantified in platelet-poor plasma. C4b-binding protein alpha chain, 
complement C3, and vitronectin have significantly higher expression levels in patients with 
grade ≥ 2 RILT. Interestingly, all of these proteins are associated with inflammatory pathways 
that interact with IL-1 ß, TNF, and TGF-ß1 [249].  
 
Given these previous studies, we hypothesize that blood-based biomarkers, including plasma 
TGFβ1, will be able to predict which patients will develop grade ≥3 pulmonary complications 
after treatment with either SBRT or surgery, and specimens will be banked for future 
translational research. Translational research endpoints will not be evaluated in this trial. If the 
primary hypothesis and performance metrics are satisfied, the subsequent phase III trial will 
incorporate translational research endpoints. 
 
 
 

  
 
 
 
 
18 
 
 
 
 
 
 
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1.4 
Study Rationale/Hypothesis 
Standard therapy for stage I NSCLC has been R0 resection, consisting primarily of lobectomy 
with lymph node dissection/sampling (RODS), generating 3-5 year OS rates of 50-80%, local 
control rates of 70-90%, grade 3 complication rates of 10-30%, and hospital stays of 1-3 weeks. A 
significant number of patients are either medically inoperable or refuse surgical intervention. 
Historically, conventional fractionated 2DRT or 3DCRT (60-70 Gy over 5-7 weeks) has been 
reserved for medically inoperable patients with a 5-year cause-specific survival rate of ~30%, 
local control rate of 15-50%, grade 3 toxicity rate of 5%, radiation therapy cost of $20,000 to 
$30,000, and outpatient treatment duration of 6-7 weeks. With advancement of radiation 
technology, SBRT has become available at most of the large centers and generates local tumor 
control rates of 85% to 95% in both medically inoperable and operable patients [127] with relative 
rare adverse events, such as pneumonitis and rib fracture. The role of SBRT in patients who are 
operable candidates is being evaluated in a phase II clinical trial, RTOG 0618, which was initiated 
in 2008 and completed accrual as of March 1, 2010. 
 
The central hypothesis of this study is that SBRT, although potentially yielding a lower local-
regional tumor control rate will provide equivalent OS and significantly better QOL than RODS in 
patients with stage I NSCLC. The study population includes medically operable patients with 
PET/CT staged T1N0 (Stage IA) NSCLC. Eligible patients will be randomized to 2 arms.   
Patients enrolled to Arm 1 will be treated with surgical resection.  Patients enrolled to Arm 2 will 
be treated with SBRT of 55 Gy in 5 fractions (BED 118 Gy) for both peripheral and central 
tumors. We selected this fractionation as it is also a safe regimen [280, 281]. Three-year OS, 3-
year local progression-free survival, disease-specific survival, treatment cost, duration of hospital 
stay, and time to local progression will be compared between the 2 arms. By completing this trial, 
we hope to be able to provide necessary preliminary information to continue to a definitive trial to 
determine whether high-dose SBRT will generate outcomes comparable to those of surgical 
resection in patients with stage I NSCLC. 
 
1.5 
Study Significance 
The outcome of this study will be clinically significant for several reasons:  If SBRT is proven to be 
at least equivalent to RODS, patients with stage I NSCLC (approximately 20,000 new cases 
annually worldwide) would have a non-invasive treatment option that may offer significant 
advantages. With respect to advancing the SBRT approach: 
 
1. This trial will provide important data regarding potential differences in local-regional tumor 
control and patterns of failure between SBRT and RODS. These endpoints are critical to 
establishing equivalence of the 2 approaches with respect to survival. 
2. A key secondary objective of this trial is to qualitatively and quantitatively assess the logistical 
feasibility of joint clinical trial conduct between the RTOG and institutions in China. 
Parameters measuring feasibility include pre-registration requirements, patient accrual rate, 
eligibility rate, randomization conduct, baseline forms completion, follow-up forms 
completion/delinquency, and loss to follow-up rate. This study will serve to motivate the 
building and evaluation of logistics for international collaboration in the cooperative group 
setting, and serve to develop a critical means of expanding participation and conducting trials 
more rapidly, as well as delivering an advantageous therapy to populations of great need. 
3. The banking of biological specimens will provide for future identification of molecular 
prognostic factors for response to these very different therapeutic modalities.  
 
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objective 
2.1.1 
The primary aim of this study is to determine whether SBRT provides local-regional tumor 
control that is not more than 15% lower than RODS. This difference is considered a threshold 
deficit at which overall survival (OS) will not be compromised. 
 
 
 

  
 
 
 
 
19 
 
 
 
 
 
 
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2.2 
Secondary Objectives  
2.2.1 
To qualitatively and quantitatively assess feasibility of this joint RTOG-China clinical trial. 
Parameters to be assessed include satisfaction of pre-registration requirements (e.g. surgical 
and RTQA credentialing), patient accrual rate, patient eligibility rate, randomization conduct 
baseline forms completion and timeliness, follow-up forms completion/delinquency, and loss to 
follow-up rate; 
2.2.2 
To compare overall survival and disease-free survival between study arms; 
2.2.3 
To estimate and compare time to local-regional failure, time to distant metastases, and patterns 
of failure between study arms; 
2.2.4 
To compare treatment toxicities using the Common Terminology Criteria for Adverse Events 
(CTCAE, v. 4) between study arms; specific comparisons will include adverse events at 1, 3, 
12, 24, and 36 months post-therapy; 
 
 
3.0 
PATIENT SELECTION 
 
 
3.1 
Conditions for Patient Eligibility (10/22/14) 
3.1.1 
Stage I NSCLC (AJCC, 7th ed.), T1N0M0; note: T1N0 disease must be confirmed by FDG-
PET/CT (see Section 3.1.5).  
 
Biopsy confirmation of diagnosis is strongly recommended but not required. If the biopsy is 
attempted and non-diagnostic, if the patient refuses biopsy, or if the risk of biopsy is considered 
too high, patients may be enrolled if the mass is suspicious for NSCLC based on 2 or more of 
the following criteria: 
 
Positive smoking history; 
 
Absence of benign calcifications within suspicious nodule; 
 
Activity on PET greater than normal tissue; 
 
Evidence of growth compared to previous imaging; 
 
Presence of spiculation. 
 
 
The following primary cancer types are eligible: squamous cell carcinoma; adenocarcinoma; 
large cell carcinoma/ large cell neuroendocrine carcinoma; non-small cell carcinoma not 
otherwise specified. 
3.1.2 
Patients with hilar or mediastinal lymph nodes ≤ 1 cm and no abnormal hilar or mediastinal 
uptake on PET and CT will be considered N0.  Mediastinal lymph node biopsy is required for 
patients with visible nodes: patients with > 1 cm hilar or mediastinal lymph nodes on CT or with 
nodes appearing as abnormal on PET (including suspicious but nondiagnostic uptake). Such 
patients will not be eligible unless directed biopsies of all abnormal lymph nodes are negative 
for cancer or these nodes demonstrate a lack of change during the prior 6 months and thus are 
considered to be non-malignant. 
3.1.3 
The patient must be considered a reasonable candidate for surgical resection using a 
lobectomy or pneumonectomy of the primary tumor within 6 weeks prior to registration, 
according to the following criteria based on the American College of Chest Physicians 
guidelines [165]:   
 A qualified thoracic surgeon should make the determination that there would be a high 
likelihood of negative surgical margins;  
 Baseline FEV1 >60% predicted, postoperative predicted FEV1 >40%  predicted; 
 Diffusion capacity of the lung for carbon monoxide (DLCO) >60% predicted, 
postoperative predicted DLCO > 40 % predicted;  
 No baseline hypoxemia and/or hypercapnia;  
 If the estimated postoperative FEV1 or DLCO <40% predicted indicates an increased risk 
for perioperative complications, including death, from a standard lung cancer resection 
(lobectomy or greater removal of lung tissue), then cardiopulmonary exercise testing to 
measure maximal oxygen consumption (VO2max) must be >60%;  
 No severe pulmonary hypertension; 
 No severe cerebral, acute or chronic cardiac, or peripheral vascular disease; 

  
 
 
 
 
20 
 
 
 
 
 
 
3502 
3.1.4 
Pleural effusion, if present, must be deemed too small to tap under CT guidance and must not 
be evident on chest x-ray. Pleural effusion that appears on chest x-ray will be permitted only if 
there is no evidence of malignancy after invasive cytologic assessment. 
3.1.5 
Appropriate stage for protocol entry, including no distant metastases, based upon the following 
minimum diagnostic workup: 
 
History/physical examination, including documentation of weight within 6 weeks prior to 
registration; 
 
Evaluation by an experienced thoracic surgeon within 6 weeks prior to registration; 
 
FDG-PET/CT scan for staging and RT plan within 4 weeks prior to registration; 
 
CT scan (preferably with intravenous contrast, unless medically contraindicated) within 4 
weeks prior to registration to include the entirety of both lungs, the mediastinum, liver, 
and adrenal glands; primary tumor dimension will be measured on CT scan. 
3.1.6 
Zubrod Performance Status 0-1 within 6 weeks prior to registration;  
3.1.7 
Age ≥ 18; 
3.1.8 
For women of childbearing potential, a serum or urine pregnancy test must be negative within 
72 hours prior to registration; 
3.1.9 
Women of childbearing potential and male participants who are sexually active must practice 
adequate contraception during treatment if assigned to treatment with SBRT. 
3.1.10 
Patients must provide study specific informed consent prior to study entry. 
 
3.2 
Conditions for Patient Ineligibility 
3.2.1 
Direct evidence of regional or distant metastases after PET and surgical staging studies, or 
synchronous primary malignancy or prior invasive malignancy in the past 3 years, with the 
following exceptions:  
 carcinoma in situ; 
 early stage skin cancer that has been definitively treated; 
 when an invasive malignancy has been treated definitively and the patient has remained 
disease free for ≥ 3 years; 
3.2.2 
Primary tumors >3 cm; 
3.2.3 
Prior systemic chemotherapy or thoracic surgery involving lobectomy or pneumonectomy; 
3.2.4 
Prior radiotherapy to the region of the study cancer that would result in overlap of radiation 
therapy fields; 
3.2.5 
Pure bronchioloalveolar carcinoma subtype of non-small cell lung cancer; 
3.2.6 
Active systemic, pulmonary, or pleural pericardial infection; 
3.2.7 
Pregnancy or women of childbearing potential and men who are sexually active and not 
willing/able to use medically acceptable forms of contraception; this exclusion is necessary 
because the treatment involved in this study may be significantly teratogenic.  
 
 
4.0 
PRETREATMENT EVALUATIONS/MANAGEMENT 
NOTE: This section lists baseline evaluations needed before the initiation of protocol treatment that do 
not affect eligibility. 
 
4.1 
Required Evaluations/Management 
4.1.1 
EBUS is required within 4 weeks prior to treatment if there are suspicious nodes on the CT or 
PET/CT scan and/or if there was no prior mediastinoscopy. Patients who already have had 
mediastinoscopy, chamberlain procedure, or VATS are eligible for this trial if they meet the 
eligibility criteria. 
 
 
5.0 
REGISTRATION PROCEDURES 
Note: This is a limited institution study. 
 
5.1 
Regulatory Pre-Registration Requirements (6/6/2013) 
5.1.1 
Prior to the recruitment of a patient for this study, investigators at participating institutions must 
obtain IRB/REC approval for this protocol, and submit IRB/REC approval and supporting 
documentation to the RTOG Headquarters (FAX 267-940-9409) or e-mail them to 
RTOG3502Regulatory@acr.org.   

  
 
 
 
 
21 
 
 
 
 
 
 
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The following documents also are required:  
 
Site contract; 
 
RT Credentialing (see Section 5.2 for details) 
 
Surgeon credentialing (see Section 5.3 for details) 
 
FDA 1572 (Investigator’s agreement to follow FDA regulations and comply with the 
protocol) 
 
Investigator’s current CV 
 
Investigator’s completion of the American College of Radiology’s Conflict of Interest form. 
This document can be found on the RTOG website: 
http://www.rtog.org/Researchers/PoliciesManuals/ConflictofInterestPolicy.aspx  
 
Documentation of investigator’s completion of Human Subject Protection Training 
(information about the National Institutes of Health (NCI) training can be accessed at 
http://grants.nih.gov/grants/policy/hs/training.htm; comparable training is acceptable); 
 
IRB/REC initial approval letter, annual continuing review approvals, and approvals of 
each amendment of the protocol; 
 
IRB/REC approved consent (English and native language versions*); *Note: Institutions 
must provide certification/verification of IRB/REB consent translation to RTOG 
Headquarters (described below); 
 
All Regulatory submissions must also include a completed IRB certification Form as a 
cover sheet, with the following information documented on the form: 
 Site NCI code; 
 Investigator’s CTEP ID, if available; 
 IRB/REC registration number; 
 FWA number. 
5.1.1.1 
Translation of documents is critical. The institution is responsible for all translation costs. All 
regulatory documents, including the IRB/REC approved consent, must be provided in 
English and in the native language. Certification of the translation is optimal but due to the 
prohibitive costs involved RTOG will accept, at a minimum, a verified translation. A verified 
translation consists of the actual REC approved consent document in English and in the 
native language, along with a cover letter on organizational/letterhead stationery that 
includes the professional title, credentials, and signature of the translator as well as signed 
documentation of the review and verification of the translation by a neutral third party. The 
professional title and credentials of the neutral third party translator must be specified as 
well. 
 
5.2 
Pre-Registration Requirement: RT Credentialing (6-AUG-2018) 
 
5.2.1 
For participating institutions from China, a specific credentialing process will be arranged by a 
Medical Physics Co-Chair, Fang Fang Yin, PhD, or Ying Xiao, PhD, prior to registration of 
patients.  
 
 
Since the participating Chinese institutions have not completed the RTOG membership 
application process, a special credentialing document has been created that combines 
requirements from the RTOG membership application, American College of Radiology (ACR) 
practice guidelines, and specific benchmark credentialing for special procedures, such as 
downloadable tests from the American Association of Physics in Medicine (AAPM) Task Group 
119 (www.aapm.org). This credentialing document is available to participating sites on the 
RTOG web site, www.rtog.org, under RTOG Foundation Study 3502. 
 
The credentialing process for this study is distinctively different from the standard RTOG 
procedure in that a comprehensive review similar to that of ACR accreditation is performed by 
the Medical Physics Co-Chairs or their designees at each participating institution. The 
institution is required to prepare the documents specified in the credentialing document 
(summarized in Section 5.2.5 below) and have them ready for an onsite visit. More than one 
visit and/or follow-up submission of documentation may be needed for the completion of the 
credentialing. A phantom study with the MD Anderson Dosimetry Lab (MDADL)  must be 
successfully completed. Close interactions between the Medical Physics Co-Chairs and 
participating institutions are necessary for this pioneering trial. 

  
 
 
 
 
22 
 
 
 
 
 
 
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A summary of the credentialing requirements is provided below in Table 5.2 and in Sections 
5.2.2 to 5.2.5. It is mandatory for institutions to complete the credentialing document (on the 
RTOG web site under RTOG Foundation Study 3502) to confirm that the institution has fulfilled 
all requirements. Institutions must have the completed questionnaire and requested data on 
site for review by the visiting Medical Physics Co-Chair, Fang Fang Yin, PhD, or Ying Xiao, 
PhD, who will initial each page, sign the document, and deliver it to RTOG Headquarters for 
filing/storage. 
 
Table 5.2 
 
Summary of Radiation Therapy Quality Assurance Credentialing Requirements 
 
Components 
Document & Data for 
Onsite Visit 
Document & Data 
Submission  
Facility Information 
 
 
Delivery System(s) and QA 
 
 
Planning System(s) and QA 
 
 
Policy and Procedure(s) 
 
 
Treatment & Other Records 
 
 
IGRT (including 4D imaging) 
 
 
Motion Management 
        
 
IMRT 
 
 
3D-CRT 
 
 
Dry-Run Case  
 
 
Phantom irradiation 
 
 
 
5.2.2 
The delivery system for participating institutions includes a linear accelerator which can 
produce 6MV photon beams. An in-room IGRT system should be available using 3D (kV or MV 
Cone-beam CT or CT on-rail system) images, for localization and verification purposes.  
CyberKnife and Tomotherapy units, or equivalent, also are allowed if proper motion 
management is implemented and credentialed by Medical Physics Co-Chair.  The quality 
assurance program should be implemented following TG 142 or equivalent, including the 
supplemental information in TG 142, as judged by visiting Medical Physics Co-chair. 
5.2.3 
The treatment planning system should have a 3D inhomogeneity dose calculation method. 
Convolution/superposition algorithms are required for this protocol.  Monte Carlo calculation 
algorithms are also allowed.  Acceptance testing and commissioning reports/documents should 
be available for the visiting Medical Physics Co-chair. Proper QA for the planning system 
should be done as outlined in Section 5.2.5. 
5.2.4 
Dry-Run Case  
Participating institutions in China are required to download a dry-run case. Directions are 
accessible on the RTOG web site: 
http://www.rtog.org/ClinicalTrials/RTOGFoundationStudies/RTOGFoundationStudy3502.aspx 
  
 
Sites are to submit the completed case to the RTOG RTQA Center for review by the Principal 
Investigators. The dry-run case is a mock case provided by RTOG and should be planned 
exactly following the guidelines of the protocol.  
5.2.5 
Evaluation Criteria 
A summary of the evaluation criteria and required documentation from the credentialing 
document (on the RTOG web site under RTOG Foundation Study 3502) is included below. The 
participating site needs to prepare these documents and have them ready for onsite review. 
 
The most recent calibration reports (less than 2 years) for primary standard ion chamber 
and electrometer should be submitted to visiting Medical Physics Co-Chair to review. TLDs 
or equivalent dosimeters comparison reports for the last 3 years (if the machine is less than 
3 years old, the commissioning report and the latest calibration report will serve the 
purpose) for each energy in all linear accelerators used for SBRT protocol should be 
available for the visiting medical physics co-chair. A Pass should be indicated (or onsite 

  
 
 
 
 
23 
 
 
 
 
 
 
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measurements ≤ 5%). 
 
Criteria for Delivery System(s) QA 
Follow the AAPM TG 142 Standards for SBRT/IMRT. 
 
Criteria for Treatment Planning QA 
Each site should present all treatment planning system commissioning/acceptance/upgrade 
report(s) for superposition/convolution algorithm or better as described in TG 53.  
 
All QA recommendations and acceptance criteria in TG 53 (or equivalent as judged by the 
visiting Medical Physics Co-Chair) should be used as the standard, including CT 
Houndsfield number to electronic density table. The site should also have error log books.  
 
Documents for Policy and Procedure/Treatment Records 
Each site should have a Policy and Procedures manual, treatment record and/or chart 
(either in electronic or paper version), and consent form, equivalent to those developed by 
the American College of Radiology (ACR). 
 
Documents for IMRT commissioning 
Each site should present acceptance testing and commissioning report as described by TG 
119 or equivalent. The acceptance testing criteria for IMRT dose delivery equipment and 
QA protocol should follow standards as described in TG 142 or equivalent. When tracking 
or gating strategies are used for motion management, a moving phantom must be used for 
the benchmark cases described by TG 119. 
 
Documents for 4D and IGRT 
A respiratory management procedure/sample chart should be developed to reflect that 
breathing motion is appropriately managed or appropriately accounted for target motion 
larger than 15 mm in one direction and presented to the visiting Medical Physics Co-Chair. 
The simulation CT system should have a QA program following AAPM TG-66 or equivalent. 
4D imaging protocols and/or 3-phase 3D CT plus fluoroscopic imaging protocols should be 
available for inspection. The acceptable deviation from the review also should be less than 
5 mm.  
 
 
5.2.6 
Digital RT Data Submission to RTOG Using TRIAD (6-AUG-2018) 
TRIAD is the image exchange application used by the RTOG Foundation.  All required digital 
RT planning data will be uploaded using this application.  See the study-specific webpage on 
the RTOG website at www.rtog.org for details regarding TRIAD account and installation. 
 
5.3 
Pre-Registration Requirement: Surgeon Credentialing  
 
Only teaching hospitals performing over 100 lung cancer surgeries each year are eligible to 
participate in this study.  
 
 
Participating surgeons must complete and sign the credentialing form, Appendix V, prior to the 
institution entering any patients onto this study. The institution will e-mail the completed form to 
Andrew Chang, MD, Thoracic Surgery Co-Chair, at andrwchg@umich.edu for review and 
approval. Dr. Chang will then e-mail the reviewed form to RTOG.  Institutions should allow 
adequate processing time (7-10 days) before registering the first patient.   
 
5.4 
Registration 
5.4.1 
Summary of Procedures 
 
 
This study incorporates a two-step registration process. 
 
All patients can be registered after completing the Eligibility Checklist, STEP 1 via online 
registration; see the text below for online registration instructions. 
 
All patients must be staged by FDG-PET/CT to confirm T1N0 disease. At this point, patients with 
confirmed T1N0 disease may be randomized.  
 
Note: Sites must complete the Eligibility Checklist, STEP 2 via online registration for ALL 
patients, even for patients found not to have T1N0 disease, to indicate whether or not patients are 
able to continue protocol treatment and if not, to specify the reason.  
 

  
 
 
 
 
24 
 
 
 
 
 
 
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Patients found not to have T1N0 disease on PET/CT will be treated off study per standard of care 
and will not be followed. 
5.4.2 
Online Registration 
 
Patients can be registered only after eligibility criteria are met.   
 
 
Special assistance for institutions from China can be obtained from the following web site: 
http://www.rtog.org/ClinicalTrials/RTOGFoundationStudies/RTOGFoundationStudy3502.aspx 
 
Each individual user must have an RTOG user name and password to register patients on the 
RTOG web site. To get a user name and password: 
 
The investigator and research staff must have completed Human Subjects 
Training 
and 
been 
issued 
a 
certificate 
(Training 
is 
available 
via 
http://phrp.nihtraining.com/users/login.php). 
 
A representative from the institution must complete the Password Authorization 
Form  
(http://www.rtog.org/LinkClick.aspx?fileticket=-BXerpBu5AQ%3d&tabid=219) and 
fax it to 215-923-1737.  RTOG Headquarters requires 3-4 days to process 
requests and issue user names/passwords to institutions. 
 
 
An institution can register the patient by logging onto the RTOG web site (http://www.rtog.org), 
going to “Data Center Logon" and selecting the link for new patient registrations.  The system 
triggers a program to verify that all regulatory requirements (OHRP assurance, IRB approval) 
have been met by the institution. The registration screens begin by asking for the date on which 
the eligibility checklist was completed, the identification of the person who completed the 
checklist, whether the patient was found to be eligible on the basis of the checklist, and the 
date the study-specific informed consent form was signed. 
 
 
Once the system has verified that the patient is eligible and that the institution has met 
regulatory requirements, it assigns a patient-specific case number. The system then moves to a 
screen that confirms that the patient has been successfully enrolled.  This screen can be 
printed so that the registering site will have a copy of the registration for the patient’s record.  
Two e-mails are generated and sent to the registering site:  the Confirmation of Eligibility and 
the patient-specific calendar. The system creates a case file in the study’s database at the 
DMC (Data Management Center) and generates a data submission calendar listing all data 
forms, images, and reports and the dates on which they are due.  
 
 
If the patient is ineligible or the institution has not met regulatory requirements, the system 
switches to a screen that includes a brief explanation for the failure to register the patient.  This 
screen can be printed. 
 
 
Institutions can contact RTOG web support for assistance with web registration: 
websupport@acr.org. 
 
 
In the event that the RTOG web registration site is not accessible, participating sites can 
register a patient by calling RTOG Headquarters, at (215) 574-3191, Monday through Friday, 
8:30 a.m. to 5:00 p.m. ET. The registrar will ask for the site’s user name and password. This 
information is required to assure that mechanisms usually triggered by web registration (e.g., 
confirmation of registration and patient-specific calendar) will occur. 
  
 
  
6.0 
RADIATION THERAPY 
Note: All participating institutions will be credentialed for a dry-run case, phantom irradiation, 
IGRT, and 3DCRT (or IMRT, if used) as described in Section 5.1 prior to registering patients to the 
study. Centers not credentialed for IMRT are not permitted to enroll and treat patients with this 
approach. 
 
Protocol treatment must begin within 14 calendar days after randomization. 
 
The protocol procedures associated with SBRT will respect updated guidelines set by ACR/ASTRO [182].  

  
 
 
 
 
25 
 
 
 
 
 
 
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6.1 
Simulation/Immobilization 
6.1.1 
Positioning/Immobilization 
The patient will be scanned in the supine position with both arms raised above the head to 
allow beams from multiple directions. Securing a comfortable position is critical as it allows 
accurate reproducibility of the target localization from treatment to treatment.  Uncomfortable 
positions should be avoided as they will most likely cause uncontrolled movement during 
scanning or treatment. A variety of immobilization systems may be used, including vac-bag, 
alpha cradle, and stereotactic frames. While frames are intended to index the patient to a 
stereotactic coordinate, their use alone (i.e. without image guided positioning) is insufficient for 
this trial. 
 
Immobilization should be sufficient to maintain the intra-fraction patient position (tumor and 
adjacent skeletal) to within 3 mm. A post-treatment verification image should be taken to 
document the intra-fraction error for set up. The comparison between these images with 
reference images should be quantitatively analyzed and must not be > 5 mm. The institution 
should store these datasets on site for possible review/audit by the Principal Investigators. 
6.1.2 
CT Simulation and Motion Management 
Target motion will be managed appropriately to ensure target localization and reproducibility.  
Tumor motion will be assessed by using fluoroscopy, 3-phase CT scanning or optimally 4D-CT 
scanning of 10 breathing phases. For CT scanning, intravenous contrast is not mandatory. If IV 
contrast is used, CT images without IV contrast should also be acquired and used for dose 
calculations. The slice spacing between reconstructed CT images should be ≤3 mm 
encompassing the entire lung volume.  
 
An internal target volume (ITV) approach can be used up to a limit of 1.5 cm movement in one 
direction.  
 
   When the tumor motion is more than 1.5 cm in any one direction, as demonstrated using one of 
the techniques described above, special measures should be applied to reduce internal organ 
motion. Acceptable maneuvers for motion control include reliable abdominal compression, 
accelerator beam gating with the respiratory cycle, tumor tracking using fiducial markers, and 
active breath-holding techniques. Regardless of the tumor motion management method 
applied, image guidance for target localization is required for initial positioning at the start of 
each treatment fraction. 
6.1.3 
Localization/Verification 
Localization images or Cone Beam CT (CBCT) should be obtained at each treatment on the 
treatment unit. ITV from 3D CBCT should be compared to the ITV from the planning CT. 
4DCBCT also can be used for target verification, if available, but it is not required. These 
images should be taken immediately before treatment to ensure proper alignment of the 
geometric center (i.e., isocenter) of the simulated fields. Verification images (3D) should be 
taken if more than 3 mm shifts are performed before treatment, as indicated by image guidance 
and after treatment to document the patient positioning accuracy. 
6.1.4 
SBRT Dose Fractionations 
SBRT is given every other day. A total dose of 55 Gy will be given in 5 fractions within 10-15 
days with an inter fraction interval of 2-3 days. The dose for all patients will be prescribed to the 
isodose line that covers 95% of the PTV. Treatment duration up to 20 days is permitted to allow 
for circumstances such as holidays or unanticipated medical conditions. Tissue heterogeneity 
corrections must be applied for dose calculation using convolution/superposition calculation 
techniques or a Monte Carlo algorithm. Planes should be normalized to provide 95% coverage 
of the planning target volume with the prescription dose. Dose constraints are provided in 
Tables 6a and 6b. 
6.1.5 
SBRT Target Delineation 
The gross tumor volume (GTV) will be delineated by an appropriately trained physician using 
CT pulmonary windows for tumor surrounded by lung parenchyma. Soft tissue windows should 
be used for tumors adjacent to chest wall, or centrally located IV contrast may be used to avoid 
inclusion of adjacent vessels or chest wall structures within the GTV. The correctness of the 
GTV delineation should be checked in axial, sagittal and coronal views. This target will not be 
enlarged whatsoever for prophylactic treatment (including no “margin” for presumed 

  
 
 
 
 
26 
 
 
 
 
 
 
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microscopic extension); rather, include only an abnormal CT signal consistent with 
gross tumor (i.e. the GTV and the clinical target volume [CTV] are identical). An additional 
0.5 cm in the axial plane and 1.0 cm in the longitudinal plane (craniocaudal) will be added to 
the GTV to constitute the PTV.  
 
As an alternative, sites equipped with 4D CT scanning equipment may generate an Internal 
Target Volume (ITV) using the inspiration and expiration images or maximum intensity 
projections (MIP) as appropriate. Sites should be aware that the MIP reconstruction may 
erroneously define an ITV in cases of significant irregular breathing or when tumors abut soft 
tissue structures (e.g. the diaphragm, great vessels). The 4D scan acquired for planning, 
however, should be obtained after initial assessment of tumor motion confirming that the tumor 
motion will be no greater than 0.5 cm in the axial plane and 1.0 cm in the craniocaudal plane. If 
4D CT is not available, the composite GTV should be based on either the CT data covering the 
whole tumor trajectory taken over multiple breathing cycles or the summation of GTVs drawn 
on multiple rapid planning scans. Regardless of the method of ITV generation, if a PET scan is 
also acquired, the PET target should be compared to the ITV to ensure sufficient target size for 
coverage of the moving tumor. In general, an ITV should NOT be defined by the merger of a 
deep inspiration CT scan and a deep expiration CT scan, as such would typically overestimate 
tumor motion. The ITV, then, is generated using a CT dataset where motion control maneuvers 
are already successfully employed. This ITV can be expanded by the institution’s geometric 
set-up uncertainty (e.g. 4-5 mm) to generate the PTV. 
 
6.2 
Delineating Organs at Risk and Dosimetric Limits (6-AUG-2018) 
Please see the atlas on the RTOG web site, www.rtog.org, on the page for RTOG 1106.   All 
required structures must be named according to naming convention provided on RTOG 
website.  See list available at 
http://www.rtog.org/ClinicalTrials/RTOGFoundationStudies/RTOGFoundationStudy3502.as
px 
 
6.2.1 
Lung 
Lung contours should be limited to active alveolar regions without inclusion of fluid and 
atelectasis. Automated contouring tools may be used but appropriate thresholds, specific to 
each CT scan, should be chosen. Editing of autotracked contours is always required.  The 
proximal bronchial tree should be excluded, and small sized vessels (less than 1cm, or vessels 
beyond the hilar region) should be included. The right and left lungs should be contoured as 
separate structures, and the DVH of whole lung should be generated by inclusion of both lungs. 
Normally the lung dose limits are based on the DVHs of both lungs with exclusion of composite 
GTV. Special attention should be paid that only the GTV overlapping normal lungs is subtracted 
(i.e., only the component of the GTV existing within the lung); the GTVs outside of lung such as 
the mediastinal nodal GTVs should not be subtracted. All inflated and collapsed lung should be 
contoured; trachea/ bronchus as defined below should not be included in this structure. When 
there is collapsed lung, the use of IV contrast and/or PET scanning may be very helpful at 
distinguishing collapsed lung from tumor extension. 
6.2.2 
Proximal Tracheal Bronchial Tree  
The proximal bronchial tree should be contoured using mediastinal windows on CT to 
correspond to the mucosal, submucosa and cartilage rings and airway channels associated 
with these structures.  The proximal tracheal bronchial tree should be contoured as one 
structure, should include the most inferior 2 cm of distal trachea and the proximal airways on 
both sides. The following airways should be included according to standard anatomic 
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 
should end immediately at the site of a segmental bifurcation, as recommended by RTOG 
0618. 
6.2.3 
Esophagus 
The esophagus should 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 the level of cricoid and continuing on every CT slice to the 
gastroesophageal junction. 
6.2.4 
Spinal Cord 

  
 
 
 
 
27 
 
 
 
 
 
 
3502 
For specifically treating lung tumors, the spinal cord should be contoured based on the bony 
limits of the spinal canal. The spinal cord should be contoured starting at the same cranial level 
as esophagus to L2, when the cord ends. RTOG studies recommend at least 10 cm above the 
superior extent of the PTV and continuing on every CT slice to at least 10 cm below the inferior 
extent of the PTV, as such definition may go beyond the true cord ends for inferior tumors. 
6.2.5 
Ribs and Chest Wall 
Delineation of ribs and chest wall will be contoured by using corrected lung contours with a 2 
cm expansion at lateral, anterior and posterior directions.  Intercostal muscles are to be 
included, while other muscles and skin are excluded.  This is a result of combined consideration 
of previous methods of including ribs alone or comprehensive inclusion of the chest wall [185, 
186]. One can also confine the rib contours to the relevant tissue that exists within a 3 cm 
range from the PTV. 
6.2.6 
Brachial Plexus 
The brachial plexus originates from the spinal nerves exiting the spinal canal through the neural 
foramina from the C4/5 (C5 nerve roots) to the T1/2 (T1 nerve roots) level. Using high quality 
CT scanning with IV contrast, it is possible to identify the actual roots and trunks of the brachial 
plexus directly with no need of a surrogate. We recommend outlining this structure starting from 
C5 root (within the C4/5 neural foramen) and ending at the subclavian neurovascular bundle 
without including the vessels. To contour the brachial plexus correctly, it is critical to first identify 
the anterior and middle scalene muscles, the subclavian and axillary arteries and veins, and 
relevant cervical and thoracic vertebrae on axial CT.   
6.2.7 
Heart/Pericardium 
The heart will be contoured along with the pericardial sac.  The superior aspect (or base) for 
purposes of contouring will begin at one slice below the level of the inferior aspect of the 
pulmonary artery trunk crossing the midline and extend inferiorly to the apex of the heart. 
6.2.8 
Skin OAR 
The skin will be defined as the outer 0.5 cm of the body surface.  As such it is a rind of uniform 
thickness (0.5 cm) which envelopes the entire body in the axial planes.  The cranial and caudal 
surface of the superior and inferior limits of the planning CT should not be contoured as skin 
unless skin is actually present in these locations (e.g., the scalp on the top of the head).   
6.2.9 
Great Vessels 
 
The great vessels (aorta and vena cava, not the pulmonary artery or vein) will be contoured 
using mediastinal windowing on CT to correspond to the vascular wall and all muscular layers 
out to the fatty adventitia.  The great vessel 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 cm below the 
inferior extent of the PTV.  For right sided tumors, the vena cava will be contoured, and for left 
sided tumors, the aorta will be contoured. 
6.2.10 
Structures are to be labeled exactly according to the “Standard DICOM Name” in the left 
column of the table below. Additional structures will be deleted and if any missing structures are 
noted, the case will be requested for resubmission.  
 
STANDARD DICOM NAME 
Description 
GTV 
Gross Tumor Volume 
ITV 
Internal Target Volume 
PTV 
Planning Target Volume 
PTV_20 
PTV + 2cm 
Lung_R 
Right Lung 
Lung_L 
Left Lung 
Lungs 
(Right + Left Lung) minus GTV 
BronchialTree 
Proximal Bronchial Tree 
BroncTree_20 
Proximal Bronchial Tree + 2cm 
Esophagus 
Esophagus 
SpinalCord 
Spinal Cord 
Rib 
Ribs & Chest Wall 
BrachialPlexus 
Brachial Plexus 
GreatVessels 
Great Vessels 
Heart 
Heart & Pericardium 
SkinOAR 
Skin (outer .5cm rind) 

  
 
 
 
 
28 
 
 
 
 
 
 
3502 
SkinOAR-PTV 
Skin (outer 0.5 cm rind) minus PTV 
SkinOAR-PTV_20 
Skin (outer 0.5 cm rind) minus PTV_20 
External 
Entire Body/External Contour 
External-PTV 
External Contour minus PTV 
External-PTV_20 
External Contour minus PTV_20 
Trachea 
Trachea 
 

  
 
 
 
 
29 
 
 
 
 
 
 
3502 
 
6.3 
Radiation Planning/Dose Conformality Requirements (9/12/13) 
6.3.1 
General Guidelines 
The dose to the target should be maximized while the dose to the adjacent OARs minimized. 
Both co-planar and non-coplanar beam arrangements are allowed. All dose calculations and 
Monitor Unit calculations should include tissue heterogeneity corrections as available in the 
planning system based on the CT data. A superposition/convolution algorithm or better is 
required. Photons of 6 MV to 10 MV will be allowed to optimize the dose plan. 10 MV photons 
only will be used when there is adequate soft tissue before the tumor at the beam entrance 
direction.  
 
Dose calculations should be performed on the 3D CT scan reconstruction generated without 
breathing phase binning (i.e. an average scan or untagged scan reconstruction).  
 
A hot spot is allowed within the ITV. The prescription isodose line shouldn’t be below 60% as 
specified in Section 6.3.4. 
 
Successful treatment planning will require accomplishment of all of the following 
criteria:  
6.3.2 
Normalization 
An initial treatment plan used to select the isodose line for PTV coverage should be normalized 
such that 100% corresponds to the center of mass of the PTV. This point will typically also 
correspond (but is not required to correspond) to the isocenter of the treatment beams.   
6.3.3 
Prescription Isodose Surface Coverage 
The dose prescription will be chosen such that 95% of the target volume (PTV) receives the 
prescribed dose of 55 Gy, and 99% of the target volume (PTV) receives a dose that does not 
fall below a minimum dose that is defined as 90% of this dose, 99% of ITV and 100% of 
composite GTV should receive the prescribed dose.  
6.3.4 
Target Dose Heterogeneity 
The prescription isodose surface selected using the initial plan must be ≥ 70%. It is preferred to 
keep the max dose to a 30% maximum increase of the dose at the center of mass (COM) of the 
PTV and ≤ 90% of the dose at the center of mass of the PTV. The COMPTV corresponds to the 
normalization point (100%) of the plan. 
6.3.5 
Hot Spot Consideration 
a) 
Location: Any dose > 105% of the prescription dose should occur primarily within the 
PTV itself and not within the normal tissues outside the PTV. 
b) 
Volume: Conformality of PTV coverage will be judged to meet criteria in Sections 6.3.2 to 
6.3.5, with ratio of the volume of the prescription dose 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 craniocaudal GTV dimension) in 
which the required minimum field size of 3.5 cm results in the inability to meet a 
conformality ratio of 1.2. 
6.3.6 
  Conformality and Dose Fall Off Gradient 
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 treatment in Gy to any point 2 cm or greater 
away from the PTV in any direction must be no greater than D2cm where D2cm is given 
by the table below. 
b) 
Volume: The ratio of the volume of the 50% of prescription dose in this trial as the volume 
of 27.5 Gy to the volume of the PTV must be no greater than R50% given by the table 
below, modified from RTOG 0618.  
 

  
 
 
 
 
30 
 
 
 
 
 
 
3502 
Table 6a: Dosimetric Guidelines for SBRT Plan Evaluation  
PTV 
Volume 
(cc) 
Ratio of 
Prescription 
Isodose Volume 
to the PTV 
Volume 
Ratio of 50% 
Prescription 
Isodose Volume 
to the PTV 
Volume, R50% 
Maximum Dose (in % 
of dose prescribed) @ 
2 cm from PTV in Any 
Direction, D2cm (Gy) 
Percent of Lung 
Receiving 20 Gy 
Total or More, 
V20 (%)   
Deviation 
Deviation 
Deviation 
Deviation 
None 
Minor 
None 
Minor 
None 
Minor 
None 
Minor 
1.8 
<1.2 
<1.5 
<5.9 
<7.5 
<50.0 
<57.0 
<10 
<15 
3.8 
<1.2 
.<1.5 
<5.5 
<6.5 
<50.0 
<57.0 
<10 
<15 
7.4 
<1.2 
<1.5 
<5.1 
<6.0 
<50.0 
<58.0 
<10 
<15 
13.2 
<1.2 
<1.5 
<4.7 
<5.8 
<50.0 
<58.0 
<10 
<15 
22.0 
<1.2 
<1.5 
<4.5 
<5.5 
<54.0 
<63.0 
<10 
<15 
34.0 
<1.2 
<1.5 
<4.3 
<5.3 
<58.0 
<68.0 
<10 
<15 
50.0 
<1.2 
<1.5 
<4.0 
<5.0 
<62.0 
<77.0 
<10 
<15 
70.0 
<1.2 
<1.5 
<3.5 
<4.8 
<66.0 
<86.0 
<10 
<15 
95.0 
<1.2 
<1.5 
<3.3 
<4.4 
<70.0 
<89.0 
<10 
<15 
126.0 
<1.2 
<1.5 
<3.1 
<4.0 
<73.0 
>91.0 
<10 
<15 
163.0 
<1.2 
<1.5 
<2.9 
<3.7 
<77.0 
>94.0 
<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” (Variation Acceptable) will be 
classified as “major” (Deviation Unacceptable) for protocol compliance. 
 
6.3.7 
Dose Limits of Organs at Risk 
This trial will follow the dose constraints of National Comprehensive Cancer Network (NCCN) 
2010 guidelines for treatment of non-small cell lung cancer, under 5 fractions. These are 
simplified limits found in recent RTOG trials  
 
Table 6b: Dose Volume Constraints for Organs at Risk 
 
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose 
(Gy) 
Avoidance 
Endpoint  
Spinal Cord 
<0.25 cc 
<0.5 cc 
22.5 Gy (4.5 
Gy/fx) 
13.5 Gy (2.7 
Gy/fx) 
30 Gy (6 Gy/fx) 
myelitis 
Ipsilateral Brachial 
Plexus 
<3 cc 
30 Gy (6 Gy/fx) 
32 Gy (6.4 Gy/fx) 
neuropathy 
Skin 
<10 cc 
30 Gy (6 Gy/fx) 
32 Gy (6.4 Gy/fx) 
ulceration 
Parallel Tissue 
Critical 
Volume  
Critical Volume 
Dose Max (Gy) 
 
Avoidance 
Endpoint  
Lung (Right & Left) 
1500 cc 
12.5 Gy (2.5 
Gy/fx) 
 
Basic Lung 
Function 
Lung (Right & Left) 
1000 cc 
13.5 Gy (2.7 
Gy/fx) 
 
Pneumonitis 
 
 
Serial Tissue* 
Volume 
Volume Max (Gy) 
Max Point Dose 
(Gy) 
Avoidance 
Endpoint  
Esophagus, non-
adjacent wall 
<5 cc 
27.5 Gy (5.5 
Gy/fx) 
105% of PTV 
prescription 
stenosis/fistula 
Heart/Pericardium 
<15 cc 
32 Gy (6.4 Gy/fx) 
105% of PTV 
prescription 
pericarditis 
Great vessels, non-
adjacent wall 
<10 cc 
47 Gy (9.4 Gy/fx) 
105% of PTV 
prescription 
aneurysm 

  
 
 
 
 
31 
 
 
 
 
 
 
3502 
Proximal tracheal 
bronchial tree, non-
adjacent wall  
<4 cc 
18 Gy (3.6 Gy/fx) 
105% of PTV 
prescription 
stenosis/fistula 
Note: The volume maximum column shows suggested limits for these structures for planning 
purposes.   Exceeding these limits is not a protocol violation.   
 
6.4 
3D-CRT, IMRT, IGRT Treatment Delivery Verifications 
6.4.1 
3D-CRT/Intensity Modulated Radiation Therapy (IMRT) 
3D-CRT should be the first choice of treatment technique. However, IMRT is allowed if 
necessary as long as the participating institution has passed the dry run case using IMRT 
planning.  
 
3D-CRT fields should not be smaller than 3.5 cm except for the use of IMRT where a 2x2 mm 
limit is used. If multiple segments per beam are given, this minimum requirement holds for all 
segments separately.  
6.4.2 
Image Guided Radiation Therapy (IGRT) for Treatment Delivery Verifications 
Image guidance should be used to guide precise treatment delivery. ACR/ASTRO guidelines 
for IGRT should be followed [187]. Pre-registration IGRT credentialing requirements are 
specified in the credentialing document (on the RTOG web site under RTOG Foundation Study 
3502). After any set-up correction is performed, the appropriateness of the correction should be 
verified by imaging. This can be performed directly after the set-up correction is made, but this 
may also be performed after the treatment itself. The procedure is described in Section 6.1.3. 
There are small enough dose contributions with only one imaging study done per treatment 
session, and this is not expected to have any clinical relevance to the patient. However, the 
imaging dose to the patient may become significant if repeated studies are done. Caution is 
advised with excessive localization imaging. 
 
6.5 
SBRT QA Procedures (6-AUG-2018) 
6.5.1 
Submission of Treatment Plan 
In order to be able to document the actual delivered dose on an individual basis, the treatment 
plans, images, and delineated structures used for treatment planning will be submitted to the 
RTOG via a TRIAD (see Section 12.2) (exported using the Dicom RT protocol) as well as 
centrally stored securely on site. This will also allow a retrospective derivation of dose-effect 
relations. See Section 12.0 for data submission details. 
 
6.6 
R.T. Quality Assurance Reviews 
The Principal Investigators, Jinming Yu, MD, PhD, and Feng-Ming (Spring) Kong, MD, PhD, and 
Physics Co-Chairs Ying Xiao, PhD, and Fang-Fang Yin, PhD will oversee quality assurance 
reviews. These reviews will be ongoing and performed remotely. RT quality assurance reviews 
will be facilitated by RTOG RTQA.  
 
6.7 
Radiation Therapy Adverse Events 
 
Note: All adverse events will be scored according to CTCAE, v. 4, which can be accessed on 
the RTOG web site: http://www.rtog.org/ResearchAssociates/AdverseEventReporting.aspx 
(scroll to the bottom of the page). 
6.7.1 
Potential Adverse Events Associated with SBRT 
Potential adverse events associated with SBRT include pneumonitis, fibrosis, atelectasis, 
bronchial obstruction, bronchial stricture, bronchopleural fistula, chest wall pain, fracture, 
changes in pulmonary function tests (e.g. reductions in FEV1, DLCO or FVC) pulmonary 
fibrosis, burn, dermatitis radiation, alopecia, cough (may be productive), dyspnea, fever, 
fatigue, pericarditis, pericardial effusion, chest pain – cardiac, palpitations, heart failure, 
myocardial infarction, paresthesias, generalized muscle weakness, esophagitis, dysphagia, 
aortic or arterial injury, hemoptysis, pain of skin. 
 
Radiation pneumonitis is a subacute inflammation of the end bronchioles and alveoli, which can 
occur weeks to months after completion of treatment. For radiation pneumonitis, it is very 
important that a Radiation Oncologist participate in the care of the patient, as the clinical picture 
may be very similar to acute bacterial pneumonia, with fatigue, fever, shortness of breath, 
nonproductive cough, and a pulmonary infiltrate on chest x-ray.  The infiltrate on chest x-ray 

  
 
 
 
 
32 
 
 
 
 
 
 
3502 
should include the area treated to high dose, but may extend outside of these regions.  The 
infiltrates may be characteristically “geometric” corresponding to the radiation portal, but may 
also be ill defined. 
 
Patients reporting symptoms as above will be promptly evaluated and treated. Mild radiation 
pneumonitis may be treated with nonsteroidal anti-inflammatory agents or steroid inhalers.  
More significant pneumonitis will be treated with systemic steroids, bronchodilators, and 
pulmonary toilet.  Supra- and concurrent infections should be treated with antibiotics.  
Consideration 
of 
prophylaxis 
of 
opportunistic 
infections 
should 
be 
considered 
in 
immunocompromised patients. 
 
It is unlikely that symptomatic pneumonitis will occur during the weeks radiation is actually 
delivered to the patients.  However, if a patient experiences pneumonitis before completing 
therapy, therapy will be put on hold until symptoms resolve.  At that point, a clinical decision 
whether to finish therapy will be made in conjunction with the treating physician in conjunction 
with the study Principal Investigator.  When symptomatic pneumonitis resolves to grade 0, 
CTCAE, v. 4 , the treating physician will contact a Co-Principal Investigator (Dr. Yu or Dr. Kong) 
for a decision to continue or terminate protocol therapy. 
6.7.2 
Bronchial Injury 
The vast majority of patients have radiographic changes during follow-up scan, such as 
experienced some degree of atelectasis (collapse) of lung downstream from the area of 
treatment.  This was felt to be related to bronchial injury of bronchi or bronchioles within or near 
the treated tumor.  By unknown mechanisms over a period of 3-6 months, pulmonary 
parenchyma distal to the site of bronchial injury results in this focal lung collapse.  The majority 
of patients are asymptomatic.  In others, the injury apparently correlated to a drop in diffusing 
capacity and arterial oxygen tension on pulmonary function tests.  This process of collapse may 
not be reversible, is mostly likely associated with large fraction sizes, as reported from Indiana 
University. This is the justification of using smaller fraction sizes in this study.  
 
Bronchial injury with subsequent focal collapse of lung may impair overall pulmonary status. 
The consequences of bronchial toxicity, e.g. cough, dyspnea, hypoxia, impairment of 
pulmonary function test parameters, pleural effusion or pleuritic pain (associated with collapse), 
will be graded and reported on adverse event forms based on CTCAE, 4. 
 
Bronchial injury also makes further assessment of tumor response more difficult as the 
collapsed lung approximates the treated tumor. Because atelectatic lung and tumor have 
similar imaging characteristics, radiology reports will often describe the overall process as 
progressive disease while the actual tumor may be stable or shrinking.  A PET scan can be 
very useful to minimize and avoid such mischaracterization. As indicated, endoscopic exam can 
be applied for further assessment. 
6.7.3 
Changes in Pulmonary Function Tests  
Patients enrolled to this study should have pulmonary function tests (PFTs), including Forced 
Expiratory Volume in 1 second (FEV1), Forced Vital Capacity (FVC), and Diffusing Capacity for 
Carbon Monoxide (DLCO). The CTCAE, v. 4 includes specified criteria for grading adverse 
events related to PFT parameters.  The grading criteria for PFT changes use the “percent 
predicted” values from 0-100% which are recorded on the patient’s PFT report. A percent 
predicted of 90% conveys that the patient is able to perform the PFT test to a result that is 90% 
of what would be expected for the normal general population of the same height, age, and sex.  
The CTCAE, v. 4 grading criteria for PFTs assumes that all patients have normal baseline 
pulmonary function, which is often not true for lung cancer patients.  In this study we will use 
RTOG protocol specific toxicity classification for PFTs that adjusts for baseline abnormalities.  
Changes that occur after therapy will be referenced to the baseline for a given patient, which 
will be abnormal for most patients.  This scale defines a proportional decline from the baseline.  
Grade 1 toxicity will be a decline from baseline to a level 0.90 times the baseline, grade 2 will 
be a decline to a level 0.75 x baseline, grade 3 will be a decline to a level 0.5 of baseline, grade 
4 will be a decline to a level 0.25 x baseline, and grade 5 will be death.  This scheme is 
depicted in the table below. 
 

  
 
 
 
 
33 
 
 
 
 
 
 
3502 
As an example, a patient who enters the study with a percent predicted DLCO of 55% who 
experiences a post treatment decline to a percent predicted DLCO of 40% would have a grade 
4 event in the original CTCAE, v. 4 criteria; however, under the modified PFT toxicity 
classification for patients with abnormal baseline, his decline would constitute a decrease to 
0.72 of the baseline value which is between 0.75 and 0.5 or a grade 2 event. 
 
RTOG Pulmonary Function Test Toxicity Scale 
 
Grade 
Adverse Event 
1 
2 
3 
4 
5 
FEV-1 Decline 
0.90-0.75 
times the 
patient’s 
baseline 
value 
 
<0.75-0.50 
times the 
patient’s 
baseline 
value 
<0.50-0.25 
times the 
patient’s 
baseline 
value 
<0.25 times 
the patient’s 
baseline 
value 
Death 
FVC Decline 
0.90-0.75 
times the 
patient’s 
baseline 
value 
 
<0.75-0.50 
times the 
patient’s 
baseline 
value 
<0.50-0.25 
times the 
patient’s 
baseline 
value 
<0.25 times 
the patient’s 
baseline 
value 
Death 
DLCO Decline 
0.90-0.75 
times the 
patient’s 
baseline 
value 
 
<0.75-0.50 
times the 
patient’s 
baseline 
value 
<0.50-0.25 
times the 
patient’s 
baseline 
value 
<0.25 times 
the patient’s 
baseline 
value 
Death 
 
6.7.4 
Radiation-Induced Lung Toxicity (RILT)  
RILT includes pneumonitis and fibrosis. Radiation pneumonitis is a subacute (weeks to months 
from treatment) inflammation of the end bronchioles and alveoli.  Radiation fibrosis is a late 
(months to years) complication due to fibroblast proliferation and scar formation in the lung 
parenchyma. It can be difficult to distinguish fibrosis from pneumonitis on CT scans, though 
clinically fibrosis often present with shortness of breath from pulmonary function reduction 
without significant cough, fever or other signs of inflammation. Table 6c below described the 
diagnosis and grading system of pneumonitis and fibrosis. 
 
Table 6c: Diagnosis and Grading System for Radiation Pneumonitis and Clinical Fibrosis 
 
 
 
 
 
 
Radiation Pneumonitis 
Clinical Fibrosis 
Grade 1 
Minimal or mild symptoms of dry cough 
and/or 
dyspnea 
on 
exertion, 
without 
evidence of tumor progression or other 
etiology, with radiographic evidence of 
acute pneumonitis  
Radiographic evidence of radiation fibrosis 
without or with minimal dyspnea 
Grade 2 
Persistent dry cough requiring narcotic 
antitussive 
agents 
or 
steroid, 
and/or 
dyspnea with minimal effort but not at rest, 
without evidence of tumor progression or 
other etiology, with radiographic evidence 
of acute pneumonitis, and requiring steroid 
for treatment  
Radiographic evidence of radiation fibrosis 
causing dyspnea with minimal effort but not 
at rest, not interfering with activities of daily 
living  
Grade 3 
Severe cough, unresponsive to narcotic 
antitussive agent and /or dyspnea at rest, 
with 
radiographic 
evidence 
of 
acute 
pneumonitis, 
and 
requiring 
oxygen 
(intermittent or continuous)  for treatment 
Radiographic evidence of radiation fibrosis 
causing dyspnea at rest, interfering with 
activities of daily living, and home oxygen 
indicated 

  
 
 
 
 
34 
 
 
 
 
 
 
3502 
Grade 4 
Radiation pneumonitis causes respiratory 
insufficiency, requiring assisted ventilation 
Radiation 
fibrosis 
causes 
respiratory 
insufficiency, requiring assisted ventilation 
Grade 5 
Radiation pneumonitis directly contributes 
to the cause of the death 
Radiation fibrosis directly contributes to the 
cause of the death 
 
6.7.5 
Chest Wall Pain and/or Rib Fracture 
Chest wall pain presents either as a result of intercostal neuropathy, inflammation, or rib 
fracture (focal radiation induced osteoporosis can result in both occult and obvious rib fractures 
generally propagated by severe coughing/sneezing episodes or chest wall trauma). The pain 
typically occurs several months after treatment and may last several more months.  The chest 
pain will be scored per CTCAE, v. 4. 
6.7.6 
Radiation-Induced Toxicity of Heart and Esophagus 
Radiation-induced toxicity of heart and esophagus will be scored per CTCAE, v. 4. 
 
6.8 
Radiation Therapy Adverse Event Reporting 
 
All AE reporting on the study case report forms (CRFs) should follow grading criteria 
instructions on the specific CRF. Note: All adverse events will be scored according to 
CTCAE, 
v. 
4, 
which 
can 
be 
accessed 
on 
the 
RTOG 
web 
site: 
http://www.rtog.org/ResearchAssociates/AdverseEventReporting.aspx 
(scroll 
to 
the 
bottom of the page). 
 
6.8.1 
Adverse Events (AEs)  
 
Definition of an AE: Any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medical treatment or 
procedure regardless of whether it is considered related to the medical treatment or procedure 
(attribution of unrelated, unlikely, possible, probable, or definite).  
 
AEs, as defined above, experienced by patients accrued to this protocol should be reported on 
the AE section of the appropriate case report form (see Section 12.1).  
 
NOTE: If the event is a Serious Adverse Event (SAE) [see next section], further reporting 
will be required. Reporting AEs only fulfills Data Management reporting requirements.  
6.8.2 
Serious Adverse Events (SAEs)  
 
Definition of an SAE: Any serious adverse experience occurring during any part of protocol 
treatment and 30 days after whether or not related to the study drug that results in any of the 
following outcomes: 
 
Death; 
 
A life-threatening adverse drug experience; 
 
Inpatient hospitalization or prolongation of existing hospitalization; 
 
A persistent or significant disability/incapacity; 
 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE, when, based upon medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition.  
 
 
SAE reporting is safety related and separate and in addition to the Data Management 
reporting requirements as outlined in the previous AE reporting section.  
 
6.9 
Serious Adverse Event (SAE) Reporting Requirements 
It is the responsibility of the investigator to document all adverse events which occur during the 
study.  
 
In addition to standard practice of recording AEs and SAEs on the case report form, this study will 
utilize an RTOG SAE Report Form for reporting of SAEs. The SAE Report Form, SAE Reporting 
Guidelines, and SAE Report Form Instructions are available on the RTOG web site, 
www.RTOG.org.  
 
 

  
 
 
 
 
35 
 
 
 
 
 
 
3502 
 
6.9.1 
Reporting SAEs  
Any SAE that occurs during any part of protocol treatment and 30 days after whether or not 
related to the study treatment must be reported by the investigator. In addition, any SAEs which 
occur as a result of protocol specific diagnostic procedures or interventions also must be 
reported.   
 
The SAE report should comprise a full written summary, detailing relevant aspects of the SAEs 
in question. The SAE summary also must include the investigator’s assessment of 
expectedness and relatedness to specific protocol treatment (e.g. radiation or surgery). When 
applicable, information from relevant hospital case records and autopsy reports should be 
included. Initial and follow-up information, when it becomes available, should be faxed to the 
RTOG SAE Fax Line 215-940-8918 or e-mailed to RTOG3502AE@acr.org. Each participating 
site must report the SAE to their regulatory authority. RTOG will report the SAE to the FDA. 
 
SAEs brought to the attention of the investigator at any time after cessation of treatment and 
considered by the investigator to be related or possibly related to treatment also must be 
reported.  
 
All SAEs must be reported to RTOG by facsimile to the RTOG SAE Fax Line 215-940-
8918 or e-mailed to RTOG3502AE@acr.org within 24 hours. RTOG will complete a 
preliminary review of the SAE details and may contact the site with suggested revisions.  
6.9.2 
Assessment of Causality and Expectedness 
Every effort should be made by the investigator to explain each SAE and assess its 
expectedness and relationship, if any, to study treatment.  Causality should be assessed using 
the following categories: no (not related), or yes (reasonable possibility). 
 
The investigator may change his/her opinion of expectedness and/or causality in light of follow-
up information, by amending the SAE Report Form. 
 
 
 
7.0 
DRUG THERAPY 
Not applicable to this study. 
 
 
8.0 
SURGERY (10/22/14) 
8.1  
Surgical Resection Guidelines 
8.1.1 
Resection Procedures 
Anatomic resection, i.e.lobectomy, bilobectomy, or pneumonectomy, will be performed at the 
discretion of the responsible thoracic surgeon. The final goal of surgery is complete resection, 
i.e., removal of the primary tumor with at least a 2 cm margin together with mediastinal and hilar 
nodal dissection or systematic mediastinal and hilar nodal sampling. 
 
A radical resection is defined as a complete resection if all of the following apply: 
 Free resection margins proven microscopically: resection margins should be considered 
to be the bronchial, venous and arterial stumps, peribronchial soft tissue, any peripheral 
margin near the tumor or any additionally resected tissue; 
 There should be no extracapsular extension of tumor in lymph nodes removed separately 
or those at the margin of the main lung specimen; 
 The highest mediastinal lymph node that has been removed must be negative. 
 
The resection is considered an incomplete resection if any of the following apply: 
 Tumor involvement of resection margins; 
 Extracapsular extension of tumor in lymph nodes removed separately, or those at the 
margin of the main lung specimen;  
 Lymph nodes known to be positive but not removed (this would be an R2 resection if 
recognized by the surgeon);  
 Positive cytology of pleural or pericardial effusions. 

  
 
 
 
 
36 
 
 
 
 
 
 
3502 
 
The lung resection is considered an uncertain resection if the resection margins are proved to 
be free of disease microscopically, but one of the following applies: 
 The intraoperative lymph node evaluation has been less rigorous than systematic nodal 
dissection or lobe-specific systematic nodal dissection as described below; 
 The highest mediastinal lymph node removed is positive; 
 The bronchial margin shows carcinoma in situ;  
 Pleural lavage cytology is positive. 
8.1.2 
Intra-Operative Nodal Staging 
According to the guidelines of the American and European Societies of Thoracic Surgeons, a 
systematic nodal dissection is recommended in all cases [167]. All the nodal stations are 
excised and put in different vials with separate labeling. The highest removed mediastinal node 
should be identified. After pathological examination of the lymphatic tissue specimens, the 
number of involved lymph nodes and nodal stations, and the status of the nodal capsule should 
be documented.  
 
Systematic nodal sampling with a lobe-specific systematic nodal approach will only be 
acceptable for a peripheral squamous T1 tumor. A lobe-specific systematic nodal dissection 
implies dissection and histological examination of intrapulmonary (lobar-level 11, interlobar-
level 12 and segmental-level 13-14) and hilar nodes (level-10) and, at least, three of the 
following mediastinal nodal stations depending on the lobar location of the primary tumor. 
 The right upper and middle lobes: the subcarinal (level-7) and right superior/inferior 
pretracheal nodes (level-2 and -4) 
 The right lower lobe: the subcarinal (level-7) and right inferior pretracheal nodes (level- -
4) and either the paraesophageal (level-8) or pulmonary ligament (level-9) nodes.  
 The left upper lobe: subcarinal (level-7), subaortic (level-5)/paraaortic (level-6), left 
inferior pretrachial (level-4) and anterior mediastinal nodes (level-3a). 
 The left lower lobe, subcarinal, left inferior pretrachial (level-4), paraesophageal (level-8) 
and pulmonary ligament nodes (level-9). 
8.1.3 
Mediastinal Nodal Sampling 
Mediastinal nodal sampling is allowed.[168]. When sampling is elected, hilar and 3 high risk 
nodal regions should be sampled based on the location of the primary tumor: 
 The  right upper and middle lobes: the subcarinal (level-7) and right superior/inferior 
pretracheal Nodes (level-2 and -4); 
 The right lower lobe: the subcarinal (level-7) and right inferior pretracheal nodes (level- -
4) and either the paraesophageal (level-8) or pulmonary ligament (level-9) nodes; 
 The left upper lobe: subcarinal (level-7),subaortic (level-5)/paraaortic (level-6), left inferior 
pretrachial (level-4)  and anterior mediastinal nodes (level-3a); 
 The left lower lobe, subcarinal, left inferior pretrachial (level-4), paraesophageal (level-8) 
and pulmonary ligament nodes (level-9). 
 
Both nodal dissection and sampling specimens should include, at least, 6 nodes, 3 removed 
from intrapulmonary and/or hilar stations and 3 removed from mediastinal stations, one of 
which must be the subcarinal station. Numbering and /or nomenclature outlined in the regional 
nodal stations / lymph node map definitions should follow nodal zones defined by IASLC/AJCC 
[169; 270] in Appendix VI. 
8.1.4 
Pathology Assessment Guidelines 
The surgeon needs to report the time of excision out of the body on the Surgery/Pathology 
Study Form. 
 
Primary tumor tissue and normal lung tissue will be submitted to trial Tissue Bank within 14 
days after surgery for those patients who have consented to banking their tissues (Appendix I) .  
 
The removed lymph nodes undergo histopathological evaluation as follows [167]:   
1. As a first step, all resected intrapulmonary, hilar, and mediastinal nodes should be 
examined macroscopically. In the presence of gross tumor, one hematoxylin-eosin 
(HE) stained section should be performed at the most macroscopically suspicious site 
to demonstrate the metastasis and its possible extracapsular extension.  

  
 
 
 
 
37 
 
 
 
 
 
 
3502 
2. If the macroscopic evaluation does not show any suspicion of metastasis, a single 
section of a node should be avoided. The probability to detect a metastasis on center 
section is related to the size of the lymph node, the size of the lesion, and the location 
of the tumor within the node. To avoid this problem, it is recommended to perform 
several sections of the nodes, 2-mm slices in the longitudinal plane and to examine 
each block separately. Thin sections of 2 mm may increase the workload of the 
pathologist but increase the detection rate of metastases. Small nodes can be sliced 
and embedded in one block if possible. 
3. There are different methods to detect additional metastatic deposits in lymph nodes like 
serial sectioning or immunohistochemistry (IHC). IHC using a cocktail of cytokeratins 
such as the anti-epithelial antibody mAb Ber-Ep4, AE1/AE3 is a sensitive and specific 
method for detecting isolated tumor cells or clusters of cells. Three levels of section are 
enough for this analysis.  
8.1.5 
Treatment for Unexpected N1 and N2 disease  
If a patient has unexpected nodal positive disease, his/her further care should be discussed by 
a multidisciplinary team. Based on the results of phase III randomized trials and recent meta-
analyses, cisplatin-based adjuvant chemotherapy improves survival in patients with stage II or 
III NSCLC [170-177] and such treatment should be offered if the patient is medically fit.  
Considering that the literature is evolving, the consideration of adjuvant chemotherapy should 
follow NCCN guidelines.   
8.1.6 
Post-Operative Care and Follow Up 
The patient should undergo inpatient pulmonary rehabilitation [178] and receive prophylactic 
doses of low molecular weight heparin (LMWH) until discharge [179, 180]. The patient should 
be followed-up for complications related to surgery, and undergo surveillance at regular 
intervals with imaging and review of symptoms. Smoking cessation after curative intent therapy 
to prevent a second primary lung cancer is strongly supported by the available evidence [181]. 
 
8.2 
Surgical Quality Assurance Reviews 
The Surgical Oncology Co-Chair, Andrew Chang, MD, will perform a Quality Assurance Review 
after complete data for the first 20 cases enrolled has been received at RTOG Headquarters. Drs. 
Wu, Chang, Orringer, and D’Amico will perform the next review after complete data for the next 
20 cases enrolled has been received at RTOG Headquarters. The final cases will be reviewed 
within 3 months after this study has reached the target accrual or as soon as complete data for all 
cases enrolled has been received at RTOG Headquarters, whichever occurs first. 
 
8.3 
Adverse Events Associated with RODS 
Atelectasis, lung infection, pneumonitis, dyspnea, adult respiratory distress syndrome, pleural 
infection, thromboembolic event, myocardial infarction, ventricular arrhythmia, arterial injury, 
venous injury, wound infection, bronchopleural fistula, postoperative hemorrhage, sepsis, 
recurrent laryngeal nerve palsy, intraoperative respiratory injury, changes in pulmonary function 
tests (e.g. forced expiratory volume (FEV1) decreased; carbon monoxide diffusion capacity 
(DLCO) decreased; vital capacity abnormal). 
 
8.4 
Surgery Adverse Event Reporting Requirements 
 
See Section 6.9 for details. 
 
 
9.0 
OTHER THERAPY 
9.1 
Permitted Supportive Therapy 
 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and documented on 
each site’s source documents as concomitant medication.  
9.1.1 
Cytotoxic Therapy 
Cytotoxic therapy is not recommended for patients with stage IA (T1N0) disease.  Patients with  
unexpected pathologic stage II or III disease should be offered adjuvant cisplatin-based 
chemotherapy, although there will be no primary, chemotherapy-related endpoints for this trial. 
Adjuvant chemotherapy for patients with stage IB NSCLC is controversial [188-191] but is 
sometimes offered to patients with higher-risk T2 tumors (> 4 cm) in routine clinical practice.  
To be consistent for trial treatment, adjuvant therapy is not recommended for patients with 

  
 
 
 
 
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3502 
clinical stage T1N0 and pathologic stage T2N0 tumors. The adjuvant chemotherapy regimen 
and the timing of chemotherapy will be at the discretion of the treating oncologist. However, 
docetaxel and gemcitabine containing regimens should be avoided due to concerns of 
exacerbating radiation lung injury. Otherwise, any cisplatin/carboplatin-based 2-drug regimen is 
considered acceptable (e.g. cisplatin/etoposide, carboplatin/paclitaxel, cisplatin/paclitaxel, 
cisplatin/pemetrexed, carboplatin/pemetrexed, cisplatin/vinorelbine).   
9.1.2 
Salvage Therapy 
If a patient has disease progression after trial treatment (either RODS or SBRT), salvage 
therapy should be implemented per standard of care. Salvage therapy could include 
multimodality care, such as surgical resection, radiation (including SBRT) and systemic therapy 
based on the stage of the disease, per NCCN guidelines.  
 
9.2 
Non-permitted Supportive Therapy 
9.2.1 
Molecularly Targeted Therapy 
No molecularly targeted therapy is planned for the patients treated on this trial.  The addition of 
molecularly targeted therapy is not permitted, except in the setting of another clinical trial or 
progression of disease.  Patients may be entered on appropriate trials of adjuvant therapy with 
either cytotoxic or molecularly targeted therapy.  
9.2.2 
Other Cancer Therapy 
Aside from the therapy outlined above for surgical resection, SBRT, and systemic therapy, 
patients must not receive other concomitant local or regional antineoplastic therapy (including 
standard fractionated radiotherapy, non-approved systemic therapy, and surgery except as 
described in this protocol) except at disease progression. 
 
 
10.0 
TISSUE/SPECIMEN SUBMISSION  
NOTE: Patients must be offered the opportunity to participate in the correlative components of the study, 
such as tissue/blood submission. Sites are not permitted to delete the tissue/specimen component from 
the protocol or from the sample consent.  
 
10.1 
Tissue/Blood Submission  
 
In this study, tissue and blood will be collected from consenting patients (see Appendix I) for 
banking at Qinhua University, Beijing. Collection and banking are highly recommended, but 
optional. 
 
Tissue will be collected pre-treatment.  
 
Patients enrolled to the surgical arm (Arm 1) will undergo a venous or arterial blood draw at the 
following time points:  
 
In the clinic prior to surgery OR pre-operatively OR prior to surgical removal of the tumor; 
 
Intra-operatively, after surgical removal of the tumor; 
 
Prior to discharge; 
 
4-6 weeks post-op. 
 
Patients enrolled to the SBRT arm (Arm 2) will undergo a venous blood draw at the following time 
points: 
 Prior to the 1st fraction of SBRT; 
 After the 3rd fraction of SBRT; 
 After all SBRT (the last day); 
 4-6 weeks after the end of SBRT. 
 
10.2 
Specimen Collection for Banking (6-AUG-2018) 
Specimens should be collected, documented, and submitted to Qinhua University, Beijing.  
Nan Bi, MD, PhD /Jie He, MD 
Chinese Academy of Medicine 
Qinhua University 
Beijing 100021, China 
86-10-87788799 

  
 
 
 
 
39 
 
 
 
 
 
 
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wlhwq@yahoo.com 
 
[Drs. Bi and He will specify the following for participating sites]:  
 
What specimens (e.g. H & E slides, block, serum) will be collected; 
 
At what time point (e.g. pretreatment, preoperatively, intraoperatively) will specimens be 
collected; 
 
How specimens will be stored (e.g. frozen, ambient); 
 
How specimens will be shipped (on dry ice, overnight). 
 
11.0 
PATIENT ASSESSMENTS 
 
11.1 
Study Parameters: See Appendix II. 
11.1.1 
Details of Follow-Up Evaluations 
11.1.1.1 
In follow up, PET and CT scans are required to document disease relapse/progression. 
Biopsy of the relapse/progression site is encouraged, but not required. Submission of the 
biopsy report (if applicable) and scan reports is required (see Schedule of Forms). 
Submission of imaging studies (scans with recurrent disease and the scans used for 
reference) is required for patients with recurrent disease.  
 
Chest CT with IV contrast will be performed at least at 3, 6, 9, 12, 18, 24, and 36 months 
after completion of treatment (the date of surgery or at the last day of SBRT) per current 
standard of care. Response evaluation after SBRT can sometimes be difficult as fibrosis and 
subclinical radiographic changes are observed in a majority of patients. A solid pattern of 
fibrosis often may be misinterpreted as recurrent disease [267]. Regular radiological follow-
up is required to establish local control. 18F-FDG PET can be helpful in distinguishing 
fibrosis from tumor recurrence, but treated volumes can show 18F-FDG uptake related to 
therapy for at least 12 months after treatment [162]. Careful radiological follow-up of patients 
is paramount in patients treated by RODS, as salvage surgery or definitive 
chemoradiotherapy might still be possible in case of local or regional recurrence [268-269]. 
11.1.1.2 
In follow up, pulmonary function tests should be done per the treating physician’s discretion. 
11.1.1.3 
After treatment is completed, patients will be seen in follow up every 3 months for years 1-2 
years, every 6 months for year 3, then annually until publication of study results. 
 
 
11.2 
Measurement of Response  
11.2.1 
Guidelines for Assessing Treatment Response after SBRT 
11.2.1.1 
CT Tumor Response 
Tumor response on CT will be assessed per RECIST 1.1, as described below; see 
http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf for additional details. 
 
 Complete Response (CR): Disappearance of all target lesions.  Any pathologic lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm) 
 Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 
 Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progression). 
 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study. 
11.2.1.2 
PET Tumor Response 
Guidelines for assessing post-SBRT changes on PET/CT will be per the table below, defined 
by Kong, et al. at the University of Michigan [257], using the blood pool in the aortic arch as 
a reference.  This system is considered to be more reproducible than that of PERECIST 
[258] which uses the liver as a reference. The aortic arch is also less likely to be confounded 
by disease conditions in the liver which may increase FDG-activity. Metabolic tumor volumes 
will also be assessed and recorded. 
 

  
 
 
 
 
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3502 
PET Tumor Response of Irradiated Target Lesions 
Complete Metabolic 
Response (CMR) 
Tumor FDG-activity decreased to less than mean background of 
the aortic arch blood pool. 
Partial Metabolic 
Response (PMR) 
At least a 30% decrease in the maximum of relative tumor FDG-
activity of target lesions  
Progressive 
Metabolic Disease 
(PMD) 
At least a 20% increase in the maximum of relative tumor FDG-
activity of target lesions  
Stable Metabolic 
Disease (SMD) 
Neither sufficient reduction to qualify for MPR nor sufficient 
increase to qualify for MPD 
 
The percentage of decrease or increase was globally estimated based on readings of 
(tumor activity-aorta activity)/aorta activity. 
 
11.2.2 
Local regional tumor control is defined as freedom from local-regional recurrence after RODS 
and freedom from progression of local primary tumor and disease occurrence at nodal regions 
after SBRT.  
 
Local-regional recurrence after RODS includes recurrence, defined by CT, confirmed by 
PET/CT whenever possible, i.e., development of tumor masses at the site of resection, or hilum 
(N1 nodal region), mediastinum (N2-N3 nodes), or ipsilateral supraclavicular fossa for upper 
lobe tumors (N3 nodes), or within 3 cm of the staple line of RODS. 
 
Local regional progression after SBRT includes tumor progression on CT per RECIST criteria, 
confirmed by PET/CT, within the same lobe, hilum (N1 nodes), mediastinum (N2-N3 nodes), or 
ipsilateral supraclavicular fossa for upper lobe tumors (N3 nodes), or within 3 cm of original 
PTV. 
 
 
 
Local progression is defined as at least a 20% increase in the sum of diameters of the target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is 
the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new 
lesions is also considered progression). 
11.2.3 
Guidelines for Assessing Failure Patterns After SBRT and RODS 
The definition of local failure is critical; recurrence rates may vary just due to varying definitions 
[259]. Participating physicians should be trained in the use of a standardized recording system. 
The distance between the center of recurrent tumor and the edge of the treated lesion will be 
measured as part of the following classification. 
 
Type of Recurrence 
Modality 
Description 
(after treatment effects have subsided) 
Local Failure 
Primary tumor failure 
(PLF) 
SBRT 
Appearance of residual tumor located within the 
extent of the primary targeted tumor. 
Marginal failure (MF) 
 
RODS/SBRT 
RODS: Appearance of tumor < 2 cm in any 
direction of the staple-line or the structures 
immediately adjacent to prior tumor site (chest wall/ 
mediastinum/ diaphragm/ spine). 
SBRT: Appearance of tumor < 2 cm in any direction 
of the primary tumor PTV* or structures 
immediately adjacent to primary tumor (lung/ chest 
wall, mediastinum/ diaphragm/ spine). 
Involved Lobe failure 
(ILF) 
RODS/SBRT 
RODS: Appearance of tumor > 2 cm in any 
direction of the staple-line or the structures 

  
 
 
 
 
41 
 
 
 
 
 
 
3502 
 
immediately adjacent to prior tumor site (chest wall/ 
mediastinum/ diaphragm/ spine). 
SBRT: Appearance of tumor > 2 cm in any direction 
of the primary tumor or structures immediately 
adjacent to primary tumor (lung/ chest wall, 
mediastinum/ diaphragm/ spine). 
Port site/wound failure 
(PWF) 
 
RODS 
Appearance of tumor at a port or incision site after 
VATS or open resection. 
Regional Nodal Failure 
Hilar nodal failure (HNF) 
 
RODS/SBRT 
Appearance of tumor in ipsilateral hilar nodal 
regions 
Ipsilateral mediastinal 
nodal failure (MNF) 
 
RODS/SBRT 
Appearance of tumor in ipsilateral mediastinal 
and/or subcarinal nodal regions. 
Contra-lateral mediastinal 
nodal failure (CNF) 
RODS/SBRT 
Appearance of tumor in contralateral mediastinal 
nodal regions. 
Contralateral hilar nodal 
failure (CNF) 
 
RODS/SBRT 
Appearance of tumor in contralateral hilar nodal 
regions 
Supraclavicular nodal 
failure (SNF)* 
RODS/SBRT 
Appearance of tumor in ipsilateral and contralateral 
supraclavicular nodal regions 
 
 
 
Distant Failure 
 
 
Non-primary lobe failure 
(NLF)# 
 
RODS/SBRT 
Appearance of tumor within another ipsilateral 
(non-primary) lobe, ≥ 2 cm from the original 
planning target volume 
Distant metastatic failure 
(DMF)  
RODS/SBRT 
Appearance of tumor deposits characteristic of 
NSCLC metastasis (chest wall other than incision 
sites, mediastinal structures/diaphragm, malignant 
pleural/pericardial effusion), contralateral lung 
and/or other distant sites. 
 *This is classified as distant nodal failure in RTOG 1021/ACOSOG Z4099. 
#This is classified as local-regional failure in RTOG 1021/ACOSOG Z4099. 
 
11.3 
Criteria for Discontinuation of Protocol Treatment 
 
Protocol treatment will be discontinued if the patient  
 
has progression of disease so that SBRT is not a reasonable treatment; 
 
becomes inoperable for radical surgical resection; 
 
cannot tolerate SBRT treatment;  
 
wants to withdraw from the study 
 
 
If protocol treatment is discontinued, follow up and data collection will continue as specified in the 
protocol. 
 
 
12.0 
DATA COLLECTION (6-AUG-2018) 
Translation of data forms is critical. The institution is responsible for all translation costs. All data forms 
below must be provided in English and in the native language. Certification of the translation is optimal 
but due to the prohibitive costs involved, RTOG will accept, at a minimum, a verified translation. A verified 
translation consists of the actual data form in English and in the native language, along with a cover letter 
on organizational/letterhead stationery that includes the professional title, credentials, and signature of 
the translator as well as signed documentation of the review and verification of the translation by a neutral 

  
 
 
 
 
42 
 
 
 
 
 
 
3502 
third party. The professional title and credentials of the neutral third party translator must be specified as 
well. 
 
Data should be submitted to: 
RTOG Headquarters* 
 1818 Market Street, Suite 1720 
 Philadelphia, PA  19103 
 
*If a data form is available for web entry, it must be submitted electronically. 
 
Patients will be identified by initials only (first middle last); if there is no middle initial, a hyphen will be 
used (first-last). Last names with apostrophes will be identified by the first letter of the last name. 
 
12.1 
Summary of Data Submission (6-AUG-2018) 
 
 
 
Item 
Due 
Initial Evaluation Form (I1) 
Pathology Report (P1) 
Within 2 weeks of registration 
 
 
Radiotherapy Form (T1) 
Within 1 week of RT end 
 
 
Surgical Form (S1) 
Surgical Procedure Report (S2) 
Surgical Pathology Report (S5) 
NOTE: The S2 and S5 should be de-identified 
and emailed to jserianni@acr.org as PDF files 
Within 4 weeks after protocol surgery 
 
 
Follow-up Form (F1) 
Every 3 months for years 1-2 years, every 6 
months for year 3, then annually until publication 
of study results 
 
12.2 
Summary of Dosimetry Digital Data Submission (Submit to RTOG Headquarters; see Section 
12.2.1) (6-AUG-2018) 
 
Item 
Due 
Preliminary Dosimetry Information (DD) 
 
Digital 
Data 
Submission 
– 
Treatment 
Plan 
submitted in DICOM format to RTOG via TRIAD, 
exported from treatment planning machine by 
Physicist 
 
Digital data submission includes the following: 
 
Planning CT 
 
RT Structure File including all required  
tumor 
volumes 
and 
critical 
normal 
structures  
 
RT Plan File  for final plan 
 
RT Composite Dose File for treated beams 
 
Digital DVH data including all required  
tumor volume and critical normal structures 
 
Digital Data Submission Form (DDSI) [on 
the RTOG website, Foundation study 
3502, under Forms] 
Within 1 week of start of RT  
 
 

  
 
 
 
 
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Final Dosimetry Information 
Radiotherapy Form (T1)  
Daily Treatment Record (T5) [Copy of daily 
treatment chart submitted via email to RTOG-
RTQA@acr.org.] 
Within 1 week of end of RT 
 
 
PET and/or CT progression scans (MR)                     
PET and/or CT progression reports (ME) 
Digital Data Submission Form (DDSI) [on the 
RTOG web site, Foundation study 3502, under 
Forms] 
At time of progression 
 
 
NOTE: 
For 
all 
digital 
data 
submissions 
(preliminary, final Dosimetry or PET/CT scans 
for progression), sites must complete a Digital 
Data Submission Form (DDSI) via the RTOG 
web site. 
Also, sites will notify RTOG via e-mail RTOG-
RTQA@acr.org 
after 
any 
digital 
data 
is 
submitted. The e-mail must include study 
number, site name, and case numbers. 
 
        Modified digital patient data as required by RTOG will be submitted via TRIAD. 
 
12.2.1 
Digital Data Submission to RTOG Headquarters  
Digital data will be submitted to RTOG via TRIAD.  
12.2.2 
Method of Plan Submission 
Sites will follow directions for establishing a TRIAD account for the purpose of submitting digital 
RT data.  Refer to the RTOG website for instructions. 
http://www.rtog.org/ClinicalTrials/RTOGFoundationStudies/RTOGFoundationStudy3502.aspx,  
 
 
13.0 
STATISTICAL CONSIDERATIONS 
13.1 
Primary Endpoint 
13.1.1 
Two-year local-regional tumor control, which is defined as freedom from local-regional 
recurrence after RODS and freedom from progression of local primary tumor and disease 
occurrence at nodal regions after SBRT (see Section 11.2.2) 
 
13.2 
Secondary Endpoints 
13.2.1 
Overall survival; 
13.2.2 
Disease-free survival; 
13.2.3 
Frequency of site-specific failure (patterns of failure); 
13.2.4 
Time to local-regional tumor failure and distant metastases; 
13.2.5 
PET tumor response; 
13.2.6 
Frequency of adverse events, graded by CTCAE, v. 4; 
13.2.7 
Trial feasibility parameters. 
 
13.3 
Sample Size 
This randomized phase II trial will compare SBRT and RODS among patients with T1N0M0 
NSCLC. 
 
The trial is designed to determine whether there is a 15% or smaller absolute decrement in local- 
regional tumor control at 2 years for SBRT relative to RODS. Specifically, we assume  that 
patients treated with RODS will have 90% of 2 year local regional control, and aim to demonstrate 
that those with SBRT would have no greater than 15% lower local-regional control largely due to 
lack of nodal dissection, or 75% local-regional control. The rationale for permitting up to 15% 
lower 2-year local tumor control for the SBRT arm is that SBRT is expected to have equivalent 
survival as such local failure would be effectively salvaged by surgery, radiation, chemotherapy or 
combined trimodality therapy [252]. Additionally, we expect the patients treated with SBRT would 

  
 
 
 
 
44 
 
 
 
 
 
 
3502 
have a better quality of life and more favorable toxicity profiles (less severe treatment 
complications such as inter-operative death). The null hypothesis is that SBRT has a > 15% lower 
local-regional control rate, and the alternative is that the difference is 15% or less. To ensure 
probability of 0.80 for correctly concluding that the difference is 15% or less (that is, when this is 
the true state) and probability 0.20 of falsely concluding that the difference exceeds 15%, 36 
patients per treatment arm is required, a total of 72 patients. To account for ineligible patients and 
attrition of the cohort during the 24-month follow up, a 5% inflation of the sample size is applied, 
leading to a total of 76 patients. With 24 months of accrual and a minimum follow-up of 24 
months, the trial will be completed. 
 
13.4 
Accrual 
Five institutions will participate in this trial. It is estimated that 100 patients in each participating 
center will undergo a complete resection for stage I NSCLC each year. Of these patients, 5-10% 
are expected to consent to enroll on this trial. Thus, we anticipate that enrollment will be 
completed in 24 months. We plan to report primary results at a maximum of 2 years after the last 
patient has been enrolled (i.e. when all patients have accumulated either 2 years of follow up or a 
primary endpoint failure event). 
 
13.5 
Analysis Methods 
13.5.1 
Primary Endpoint 
A test of binomial proportions will be used to compare local-regional failure proportions 
between treatment arms. If despite randomization, there are imbalances in important patient 
and disease covariates, then logistic regression will be used to estimate the effect of treatment 
accounting for other covariates [253]. Survival analysis methods, specifically the Cox 
proportional hazards model and the cumulative incidence function, will be used to evaluate the 
time to local-regional failure hazard by treatment arm and the cumulative probability of local-
regional failure events over time by treatment arm [254]. 
13.5.2 
Other Time-to-Event Endpoints and Sites of Failure 
The Kaplan-Meier estimator and logrank test will be used to estimate survival distributions and 
compare survival by treatment arm. The hazard rate ratio with 95% confidence interval will be 
estimated via the Cox proportional hazards model. If the proportionality assumption is not met, 
then other models will be considered as appropriate. Contingency table methods and logistic 
regression will be used for discrete endpoints such as site-specific failure proportions and PET 
response. Cumulative incidence of time to local-regional failure, other site-specific failure (i.e., 
distant metastases), and cause-specific survival will be estimated using appropriate competing 
risks methods. Models for cause-specific hazards and cumulative incidence of these events will 
used to estimate different aspects of the relative event-specific failure risk between groups 
[255] [256]. PET tumor response (Section 11.2.1.2) and an evaluation of assessment of failure 
patterns after SBRT and RODS (Section 11.2.3) will be investigated. 
13.5.3 
Adverse Events 
Frequency distributions of specific adverse events of interest will be compared between 
treatment arms using Fisher’s exact test. If there appear to be imbalances in patient or disease 
characteristics by treatment arm, then stratified methods or logistic regression modeling will be 
used to compute adjusted tests. Logistic regression modeling will be used to explore the 
relationship between treatment toxicities and other factors in addition to treatment. 
13.5.4 
Trial Feasibility Parameters 
Trial feasibility parameters will be summarized using descriptive statistics. Formal hypothesis 
testing will not be conducted; rather, observed quantities will be compared to performance 
benchmarks based on typical RTOG trials. Some specific expectations are as follows: 
 
 
Credentialing: 100% credentialing completed and documented before patient 
enrollment;  
 
Eligibility: Among screened and enrolled patients, 95% retain eligibility status after 
central review by RTOG Headquarters staff; 
 
Baseline forms: Completed and provided within 30 days of registration; 
 
Follow-up forms and delinquency: Follow-up loss < 3% where follow-up loss is defined 
as the proportion of patients unavailable to be evaluated for the primary endpoint due 
to loss of contact, follow-up assessment provided within 60 days of evaluation time 
point. 

  
 
 
 
 
45 
 
 
 
 
 
 
3502 
 
13.6 
Data Monitoring Committee, Interim Analyses, and Stopping Criteria 
An independent Data Monitoring Committee will be constituted to oversee this trial. Accrual, other 
study conduct parameters, and adverse events will be reviewed at semi-annual meetings of this 
committee. 
 
One formal analysis for futility with respect to demonstrating noninferiority will be performed after 
completion of enrollment and follow up to 1 year, including only those patients who have reached 
the 2-year follow-up time point. Early reporting will be considered if the estimated 2-year local-
regional control rate in the SBRT arm (Arm 2) is less than 60% (in which case the exact upper 
one-sided 95% confidence bound would fall below 75%, the threshold noninferiority value for this 
trial), and if this rate is more than 15% lower than the observed rate in the RODS arm (Arm 1). 
 
Results for dissemination will be developed, and a manuscript drafted for review, approval, and 
submission. After manuscript acceptance, patient follow up will be discontinued and the trial 
terminated. It is anticipated that termination will occur approximately 5.5 years from initiation of 
patient entry. This time-frame may be extended depending on factors such as the observed 
accrual and event rates, in which case a new trial termination date will be established. 

  
 
 
 
 
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radiotherapy for centrally located lung tumors. Radiother Oncol. 2012 Jan 20. [Epub ahead of print] 
PubMed PMID: 22265734. 
 
 
 
 
 

 
  
 
 
 
 
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3502 
 
APPENDIX I (6-AUG-2018) 
 
The consent form is a separate document from the protocol and has been reviewed by the new RTOG 
Foundation−contracted IRB vendor, Advarra. 

 
  
 
 
 
 
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APPENDIX II:  STUDY PARAMETER TABLE: *See section 11.1 for details and exceptions 
 
Assessments 
Within 6 wks 
prior to 
registration, 
unless 
otherwise noted 
Arm 1 
Arm 2 
Both Arms 
Prior to 
surgery in 
clinic OR 
Pre-Op OR 
prior to 
surg.removal 
of tumor 
Intra-Op 
after 
surgical 
removal 
of tumor 
Prior to 
dis- 
charge 
4-6 
wks 
Post-
Op 
Prior to  
1st 
fraction 
of SBRT   
 
After 3rd 
fraction of 
SBRT 
After all 
SBRT (the 
last  day) 
4-6 weeks 
after end of 
SBRT 
q 3 mos. for years 1-2, 
6 mos. for  year 3, then 
annually* 
History & Physical 
X 
 
 
 
X 
 
 
 
X 
X 
Thoracic Surgeon 
evaluation 
X 
 
 
 
 
 
 
 
 
 
Document weight 
X 
 
 
 
X 
 
 
 
X 
X 
Performance Score 
X 
 
 
 
X 
 
 
 
X 
X 
PFTs (with DLCO) 
X 
 
 
 
 
 
 
 
 
X* 
FDG-PET/CT scan 
Within 4 wks 
 
 
 
X 
 
 
 
 
At 3, 12, 24 mos. 
CT of chest/upper 
abdomen, with 
contrast 
Within 4 wks 
 
 
 
X 
 
 
 
 
Chest CT with contrast 
at 3,6.9, 12, 18, 24, 36 
mos. 
EBUS 
Within 4 wks 
prior to 
treatment 
 
 
 
 
 
 
 
 
 
Adverse event 
assessment 
 
 
 
 
X 
 
 
X 
X 
X 
Pregnancy test, if 
applicable 
Within 72 hrs. 
 
 
 
 
 
 
 
 
 
†Blood for research 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
†Tissue for banking 
For Both Arms: 
prior to 
treatment 
 
 
 
 
 
 
 
 
 
†For patients who consent to participate in the specimen banking component of the study; see Appendix I. 
 
 
 

 
  
 
 
 
 
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APPENDIX III 
 
ZUBROD PERFORMANCE SCALE 
 
0 
Fully active, able to carry on all predisease activities without restriction  
 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
work of a light or sedentary nature.  For example, light housework, office 
work  
 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours  
 
3 
Capable of only limited self-care, confined to bed or chair 50% or more of 
waking hours  
 
4 
Completely disabled. Cannot carry on self-care. Totally confined to bed  
 
5 
Death  
 
 
 

 
  
 
 
 
 
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APPENDIX IV 
Edge, SB, ed. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010. 
 
LUNG 
 
Primary Tumor (T) 
TX 
Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or 
bronchial washings but not visualized by imaging or bronchoscopy 
T0 
No evidence of primary tumor.   
Tis 
Carcinoma in situ 
T1 
Tumor 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without 
bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main 
bronchus)* 
T1a 
Tumor 2 cm or less in greatest dimension 
T1b 
Tumor more than 2 cm but 3 cm or less in greatest dimension 
T2 
 
Tumor more than 3 cm but 7 cm or less with any of the following features (T2 tumors with these 
features are classified T2a if 5 cm or less):  Involves main bronchus, 2 cm or more distal to the 
carina; Invades the visceral pleura PL1 or PL2);  Associated with atelectasis or obstructive 
pneumonitis that extends to the hilar region but does not involve the entire lung 
T2a 
Tumor more than 3 cm but 5 cm or less in greatest dimension 
T2b 
Tumor more than 5 but 7 cm or less in greatest dimension 
T3 
Tumor more than 7 cm or one that directly invades any of the following:  parietal (PL3), chest wall 
(including superior sulcus tumors),  diaphragm, phrenic nerve, mediastinal pleura, parietal 
pericardium; or tumor in the main bronchus (less than 2 cm distal to the carina* but without 
involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung or 
separate tumor nodule(s) in the same lobe 
T4 
Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, 
recurrent laryngeal nerve, esophagus, vertebral body, carina, separate tumor nodules in a different 
ipsilateral lobe 
*The uncommon superficial spreading tumor of any size with its invasive component limited to the bronchial wall, 
which may extend proximally to the main bronchus, is also classified as T1a. 
 
 
Regional Lymph Nodes (N) 
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph nodes metastasis 
N1 
Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and intrapulmonary nodes 
including involvement by direct extension 
N2 
Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s) 
N3 
Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or 
supraclavicular lymph node(s) 
 
 
Distant Metastasis   (M) 
M0 
 
No distant metastasis 
M1 
 
Distant metastasis  
M1a 
Separate tumor nodule(s) in a contralateral lobe tumor with pleural nodules or malignant pleural (or 
pericardial) effusion* 
M1b 
Distant metastasis 
* Most pleural (and pericardial effusions with lung cancer are due to tumor. In a few patients, however, multiple 
cytopathologic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and is 
not an exudate. Where these elements and clinical judgment dictate that the effusion is not related to the tumor, 
the effusion should be excluded as a staging element, and the patient should be classified as M0. 

 
  
 
 
 
 
62 
 
 
 
 
 
 
3502 
 
STAGE GROUPING  
Occult Carcinoma 
TX, N0, M0 
Stage 0 
Tis, N0, M0 
Stage IA 
T1a-b, N0, M0 
Stage IB 
T2a, N0, M0 
Stage IIA 
T2b, N0, M0 
 
T1a-b, N1, M0 
 
T2a, N1, M0 
Stage IIB 
 
T2b, N1, M0 
 
T3, N0, M0 
Stage IIIA 
T1a-b, N2, M0 
 
T2a-b, N2, M0 
 
T3, N1-2, M0 
 
T4, N0-1, M0 
Stage IIIB 
T1a-b, N3, M0 
 
T2a-b, N3, M0 
 
T3, N3, M0 
 
T4, N2-3, M0 
Stage IV 
Any T, Any N, M1a-b 
 
 
 
 
 
 
  

 
  
 
 
 
 
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3502 
  
APPENDIX V (10/22/14) 
 
THORACIC SURGEON'S CREDENTIALING FORM 
 
Please complete this questionnaire following a careful review of the eligibility (Section 3.0) and surgical (Section 
8.0) sections of RTOG Foundation 3502 and return this form to your Research Associate. Surgeon credentialing 
is a pre-registration requirement (Section 5.3). 
 
 
1.  
This study recommends careful documentation of stage of disease. Systematic mediastinal sampling or 
mediastinal lymph node dissection is strongly recommended for all patients at the time of lung resection. 
Is this a procedure that you perform routinely and would you agree to do for this protocol? 
 
 
YES ________ NO 
 
 
 
Comments: 
 
 
 
2. 
This protocol recommends systematic nodal sampling or dissection at thoracotomy at all levels of hilar 
and mediastinal nodes according to the American Thoracic Society Lymph Node Map.  
 
 
Are you familiar with this nodal mapping system? 
 
YES________ NO 
 
 
 
Comments: 
 
 
 
Do you routinely perform systemic mediastinal nodal sampling or dissection at the time of pulmonary 
resection? 
 
YES________   NO 
 
 
 
Comments: 
 
 
 
Do you agree to perform systematic nodal sampling or nodal dissection as specified in the protocol?   
Section 8.0 of the protocol specifies removal of lymph nodes from stations 2R, 4R, 7, 9R and 10R for right 
sided resections and from stations 5, 6, 7 9L, and 10L for left sided resections. 
 
YES________ NO 
 
 
 
Comments: 
 
 
 
3. 
This study requires anatomic pulmonary resection for all patients in surgery arm.  Do you agree to attempt 
radical resection (lobectomy or pneumonectomy) of all patients if the patient is randomized to surgery? 
 
YES________ NO 
 
 
 
Comments: 
 
(Continued on the next page) 
 
 
 
 
 
 
 

 
  
 
 
 
 
64 
 
 
 
 
 
 
3502 
APPENDIX  V (Continued) 
 
 
 
4. Please check the item that best describes the scope of your practice: 
 
 
 
 
General Surgery plus Thoracic Surgery 
 
 
 
Primarily Thoracic Surgery; some Cardiac Surgery 
 
 
 
Primarily Cardiac Surgery; some Thoracic Surgery 
 
 
 
Equal mix of Thoracic and Cardiac Surgery 
 
 
 
Only Thoracic Surgery 
 
 
 
5. Please estimate the number of lobectomies and/or pneumonectomies you perform per year. _ 
 
 
6. Please estimate the number of lobectomies and/or pneumonectomies you perform per year. _______ 
 
NOTE: Surgeons must have performed a minimum of 10 lobectomies/pneumonectomies per year in order 
to participate in RTOG Foundation 3502.  
 
 
 
7. If there are other surgeons at your institution who will be participating in this program, have they also 
completed one of these forms? 
 
 
YES_______ NO_______  
 
 
 
If you have any specific questions about this form or other aspects of the trial, please contact: 
 
Andrew Chang, MD  
University of Michigan Cancer Center 
Ann Arbor, MI 48109, USA 
734-763-7418/FAX 734-615-2656 
andrwchg@umich.edu  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_________________________________          _________________________________ 
 
Signature of Surgeon completing this form 
Institution Name 
 
 
__________________________________ 
________________________________ 
Printed Name of Surgeon 
 
 
Telephone number of Surgeon  
 
 
 
__________________________________         __________________/______________ 
Physician's Fax Number 
 
 
Site RTOG Institution Number 
 
 
 
(Continued on the next page) 

 
  
 
 
 
 
65 
 
 
 
 
 
 
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APPENDIX  V (Continued)  
 
Return this form to your Research Associate. 
 
 
RTOG Research Associates: E-mail the completed form to Dr. Chang: andrwchg@umich.edu.  
 
Dr. Chang will e-mail the reviewed form, indicating the decision (via the box below) to RTOG HQ, 
RTOG3502@acr.org  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Reviewed and approved  
 
 
 
 
   Reviewed and not approved: Dr. Chang also will contact the site. 
 
 
______________________________ 
 
 
_________________ 
Andrew Chang, MD, 
 
 
 
 
Date 
Thoracic Surgery Co-Chair 
 
 
 

 
  
 
 
 
 
66 
 
 
 
 
 
 
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APPENDIX  VI 
 
AJCC NODAL ATLAS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continued on next page 
 
 
 
 
 
 
 
 
169. Pisters 2007 
270. Rusch VW 2009.  
  

 
  
 
 
 
 
67 
 
 
 
 
 
 
3502 
APPENDIX  VI (Continued) 
 
AJCC NODAL ATLAS 
 
 
 
 
 
 
 
 
 
 
169. Pisters 2007 
270. Rusch VW 2009.