institution # 3502 eligibility checklist
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                                                                                                                                                                                                                                                                                                                        | Within 1 week of start of RT |
| 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] |                              |  
| Final Dosimetry Information Radiotherapy Form (T1)  Daily Treatment Record (T5)                                  | [Copy                              | of   | daily   |      |             |
|------------------------------------------------------------------------------------------------------------------|------------------------------------|------|---------|------|-------------|
| treatment chart submitted via email to RTOGRTQA@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 RTOGRTQA@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,
institution # 3502 eligibility checklist
13.0 statistical considerations 13.1 primary

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)
13.3 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 localregional 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  
| 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.                                |  
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).
institution # 3502 eligibility checklist
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 localregional 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.
institution # 3502 eligibility checklist
13.6 data monitoring committee interim

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 localregional 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.
institution # 3502 eligibility checklist
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institution # 3502 eligibility checklist
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.  
| Arm 1                                                                                                                        | Arm 2                                                                        | Both Arms                     |                                                             |    |    |    |    |    |
|------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------|-------------------------------|-------------------------------------------------------------|----|----|----|----|----|
| Within 6 wks  prior to  registration,  unless  otherwise noted                                                               | Prior to  surgery in  clinic OR  Pre-Op OR  prior to  surg.removal  of tumor | Prior to  discharge                               | 4-6 wks  PostOp                                                             |    |    |    |    |    |
| Intra-Op after  surgical  removal  of tumor                                                                                  | Prior to  1st fraction  of SBRT                                              | After 3rd fraction of         | After all                                                   |    |    |    |    |    |
| SBRT                                                                                                                         | 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* |    |    |    |    |    |
| Assessments History & Physical                                                                                               | X                                                                            | X                             | X                                                           | X  |    |    |    |    |
| Thoracic Surgeon                                                                                                             | X                                                                            |                               |                                                             |    |    |    |    |    |
| evaluation 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.      |    |    |    |    |    |
| Within 4 wks  prior to  treatment                                                                                            |                                                                              |                               |                                                             |    |    |    |    |    |
| EBUS Adverse event                                                                                                           | X                                                                            | X                             | X                                                           | X  |    |    |    |    |
| assessment Pregnancy test, if                                                                                                | Within 72 hrs.                                                               |                               |                                                             |    |    |    |    |    |
| applicable †Blood for research                                                                                               | X                                                                            | X                             | X                                                           | X  | X  | X  | X  | X  |
| For Both Arms:  prior to  treatment                                                                                          |                                                                              |                               |                                                             |    |    |    |    |    |
| †For patients who consent to participate in the specimen banking component of the study; see Appendix I. †Tissue for banking |                                                                              |                               |                                                             |    |    |    |    |    |
institution # 3502 eligibility checklist
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
appendix iv edge sb ed.
lung

| 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, |                                                                                                                                                                                                                                                                                                                                                                                                                                                |
appendix iv edge sb ed.
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)
appendix iv edge sb ed.
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.  
| 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                                   |
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)
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)
appendix v (continued)
return this form to your

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
appendix v (continued)
appendix vi

Continued on next page 169. Pisters 2007 270. Rusch VW 2009.
appendixvi (continued)
appendix vi

AJCC NODAL ATLAS  
  
169. Pisters 2007 270. Rusch VW 2009.