NRG ONCOLOGY. RTOG 1308 (ClinicalTrials.gov NCT # )

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1 NRG ONCOLOGY RTOG 1308 (ClinicalTrials.gov NCT # ) PHASE III RANDOMIZED TRIAL COMPARING OVERALL SURVIVAL AFTER PHOTON VERSUS PROTON CHEMORADIOTHERAPY FOR INOPERABLE STAGE II-IIIB NSCLC This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored by the National Cancer Institute (NCI). The trial will be led by NRG Oncology with the participation of the network of NCTN researchers: the Alliance for Clinical Trials in Oncology, ECOG-ACRIN Medical Research Foundation, Inc., and SWOG. Study Team (10/5/15) Principal Investigator/Radiation Oncology Zhongxing Liao, MD The University of Texas MD Anderson Cancer Center 1400 Pressler St., Unit 1422 Houston, TX /FAX Radiation Oncology Co-Chairs Jeffrey Bradley, MD Washington University 4921 Parkview Place St. Louis, MO /FAX Noah Choi, MD Massachusetts General Hospital 55 Fruit Street Boston, MA /FAX Charles B. Simone, II, MD Perelman Center for Advanced Medicine University of Pennsylvania 3400 Civic Center Blvd TRC 2 West Philadelphia, PA /FAX charles.simone@uphs.upenn.edu Radiation Oncology Co-Chairs (continued) Ritsuko Komaki, MD The University of Texas MD Anderson Cancer Center 1515 Holcombe Blvd. Unit 97 Houston, TX / FAX rkomaki@mdanderson.org Bradford Hoppe, MD, MPH University of Florida Proton Therapy Institute 2015 N. Jefferson Street Jacksonville, FL /FAX bhoppe@floridaproton.org Eugen Hug, MD ProCure Proton Therapy Center 103 Cedar Grove Lane Somerset, NJ /FAX Eugen.Hug@procure.com Medical Oncology Co-Chair Charles Lu, MD The University of Texas MD Anderson Cancer Center 1515 Holcombe Boulevard Houston, TX /FAX clu@mdanderson.org Study chairs continued on next page 1

2 NRG ONCOLOGY RTOG 1308 PHASE III RANDOMIZED TRIAL COMPARING OVERALL SURVIVAL AFTER PHOTON VERSUS PROTON CHEMORADIOTHERAPY FOR INOPERABLE STAGE II-IIIB NSCLC Medical Physics Co-Chairs Michael Gillin, PhD MD Anderson Cancer Center 1515 Holcombe Blvd. Unit 94 Houston, TX /FAX Radhe Mohan, PhD Professor, Dept. of Radiation Physics UT MD Anderson Cancer Center Pickens Academic Tower, 1400 Pressler St., Unit 1420 Houston, TX /FAX Translational Research Co-Chair Steven H. Lin, MD, PhD The University of Texas MD Anderson Cancer Center Division of Radiation Oncology 1515 Holcombe Blvd. Unit 97 Houston, TX /FAX Quality of Life Co-Chair Xin Shelley Wang, MD, MPH The University of Texas MD Anderson Cancer Center 1515 Holcombe Blvd. Unit 1450 Houston, TX / /FAX 713/ Outcomes Co-Chair Ben Movsas, MD Henry Ford Health System 2799 West Grand Blvd. Detroit, MI /FAX Comparative Cost Effectiveness Co-Chairs Deborah Watkins Bruner, RN, PhD Neil Hodgson Woodruff School of Nursing Emory University 1520 Clifton Road - RM 323 Atlanta, GA /FAX deborah.w.bruner@emory.edu Gregory Russo, MD Boston University School of Medicine 830 Harrison Avenue, LL Boston, MA /FAX Gregory.Russo@bmc.org Senior Statistician Chen Hu, PhD NRG Oncology 1818 Market Street, Suite 1720 Philadelphia, PA /FAX huc@nrgoncology.org Protocol Agents Agent Supply NSC # IND # Cisplatin Commercial N/A Exempt Carboplatin Commercial N/A Exempt Etoposide Commercial N/A Exempt Paclitaxel Commercial N/A Exempt U.S. Only Canada Only U.S. and Canada Participating Sites 2

3 Approved International Member Sites NRG ONCOLOGY RTOG 1308 PHASE III RANDOMIZED TRIAL COMPARING OVERALL SURVIVAL AFTER PHOTON VERSUS PROTON CHEMORADIOTHERAPY FOR INOPERABLE STAGE II-IIIB NSCLC Document History Version/Update Date Broadcast Date Amendment 2 October 5, 2015 December 7, 2015 Amendment 1 October 23, 2014 January 12, 2015 Activation February 3, 2014 February 3, 2014 Update February 3, 2014 February 3, 2014 Update November 26, 2013 November 26, 2013 Pre-Activation October 24, 2013 November 26, 2013 NRG Oncology , ext This protocol was designed and developed by NRG Oncology. It is intended to be used only in conjunction with institution-specific IRB approval for study entry. No other use or reproduction is authorized by NRG Oncology nor does NRG Oncology assume any responsibility for unauthorized use of this protocol. 3

4 TABLE OF CONTENTS (10/5/15) SCHEMA... 6 ELIGIBILITY CHECKLIST INTRODUCTION Patient-Reported Outcome Study Comparative Cost Effectiveness Analysis Changes in Pulmonary Function After Concurrent Chemoradiation for NSCLC Physics and Technological Considerations OBJECTIVES Primary Objective Secondary Objectives PATIENT SELECTION Conditions for Patient Eligibility Conditions for Patient Ineligibility PRETREATMENT EVALUATIONS/MANAGEMENT Required Pretreatment Evaluations/Management Highly Recommended Evaluations/Management REGISTRATION PROCEDURES RT-Specific Pre-Registration Requirements Digital RT Data Submission to NRG Oncology Using TRIAD Dry Run/Knowledge Assessment Regulatory Pre-Registration Requirements Registration RADIATION THERAPY Dose Specifications Technical Factors [Equipment, Energies] Simulation, Immobilization, Motion Assessment, and Motion Management Target Definitions, Target Delineation, and Normal Anatomy Delineation Treatment Planning and Quality Assurance Compliance Criteria Treatment Delivery R.T. Quality Assurance Reviews Radiation Therapy Adverse Events Radiation Therapy Adverse Event Reporting DRUG THERAPY Treatment Cisplatin Agent Information Etoposide Agent Information Carboplatin Agent Information Paclitaxel Agent Information Dose Modifications Modality Review Adverse Events CTEP-AERS Expedited Reporting Requirements

5 8.0 SURGERY OTHER THERAPY Permitted Supportive Therapy Non-Permitted Supportive Therapy TISSUE/SPECIMEN SUBMISSION Tissue/Specimen Submission Tissue Collection for Banking for Future Research Serum, Plasma, and Whole Blood for DNA Collection for Banking for Future Research Storage Conditions for All Specimens Specimen Collection Summary Submit materials for Banking as follows: Reimbursement Confidentiality/Storage PATIENT ASSESSMENTS Study Parameters Quality of Life/Cost-Effectiveness Response Assessment (RECIST Criteria) Measurement of Response Prior to Study Entry Criteria for Discontinuation of Protocol Treatment DATA COLLECTION Summary of Data Submission Summary of Dosimetry Digital Data Submission STATISTICAL CONSIDERATIONS Primary Endpoint Secondary Endpoints Sample Size and Power Justification Randomization Patient Accrual Statistical Analysis Plan Interim and Final Analysis Gender and Minorities REFERENCES APPENDIX I APPENDIX II APPENDIX III APPENDIX IV

6 S T R A T I F Y NRG ONCOLOGY RTOG 1308 Phase III Randomized Trial Comparing Overall Survival After Photon Versus Proton Chemoradiotherapy for Inoperable Stage II-IIIB NSCLC Stage 1. II 2. IIIA 3. IIIB Histology 1. Squamous 2. Non-Squamous Concurrent Chemotherapy Doublet Type 1. Carboplatin/paclitaxel 2. Cisplatin/etoposide R A N D O M I Z E SCHEMA Arm 1: Photon dose 70 Gy*(RBE), at 2 Gy (RBE) once daily plus platinum-based doublet chemotherapy** Arm 2: Proton dose 70 Gy (RBE), at 2 Gy (RBE) once daily plus platinum-based doublet chemotherapy** Both Arms: Consolidation chemotherapy x 2 cycles required for patients who receive concurrent carboplatin and paclitaxel*** *The total prescribed dose will be 70 Gy [Relative Biological Effectiveness (RBE)] without exceeding tolerance dose-volume limits of all critical normal structures. (See Section when 70 Gy (RBE) is not achieved.) **Chemotherapy delivered concurrently, cisplatin/ etoposide or carboplatin/paclitaxel doublets, is required. The site/investigator must declare the chemotherapy regimen that the patient will receive prior to the patient s randomization. See Section 7.0 for details. ***If carboplatin and paclitaxel is administered concurrently with radiotherapy, 2 cycles of carboplatin and paclitaxel consolidation chemotherapy are required. If cisplatin and etoposide is administered concurrently with radiotherapy, consolidation chemotherapy is not allowed. See Section 5.0 for pre-registration credentialing details. Patient Population: (See Section 3.0 for Eligibility) Untreated histologically or cytologically proven diagnosis of non-small cell lung cancer prior to registration. Clinical AJCC (7 th ed.) stage II-IIIB medically non-operable disease, or surgically unresectable disease, or patients who refuse surgery; patients who present with N2 or N3 disease and an undetectable NSCLC primary tumor also are eligible. Required Sample Size: 560 patients 6

7 NRG Oncology Institution # RTOG 1308 Case # ELIGIBILITY CHECKLIST (10/23/14) (page 1 of 4) (Y) 1. Histologically or cytologically proven diagnosis of non-small cell lung cancer within 90 days of registration (Y) 2. Clinical AJCC (AJCC, 7th ed.) II, IIIA or IIIB (with non-operable disease; non-operable disease will be determined by a multi-disciplinary treatment team, involving evaluation by at least 1 thoracic surgeon) within 60 days prior to registration; Note: For patients who are clearly non-resectable, the case can be determined by the treating radiation oncologist and a medical oncologist, or pulmonologist. Patients who refuse surgery are also eligible. Patients who present with N2 or N3 disease and an undetectable NSCL primary tumor also are eligible. (Y) 3. Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup: History/physical examination within 30 days prior to registration; FDG-PET/CT scan for staging within 60 days prior to registration. MRI scan with contrast of the brain (preferred) or CT scan of the brain with contrast within 60 days prior to registration; FEV1 1.0 Liter or 40% predicted with or without bronchodilator within 90 days prior to registration. o Patients who meet the criterion above without O2, but who need acute (started within 10 days prior to registration) supplemental oxygen due to tumor-caused obstruction/hypoxia are eligible, provided the amount of the O2 needed has been stable. (Y) 4. Zubrod performance status 0-1 within 30 days prior to registration (Y) 5. Age 18 (Y) 6. CBC/differential obtained within 30 days prior to registration, with adequate bone marrow function defined as follows: Absolute neutrophil count (ANC) 1,500 cells/mm3; Platelets 100,000 cells/mm3; Hemoglobin 9.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb 9.0 g/dl is acceptable.) (Y) 7. SGOT or SGPT 1.5 upper limit of normal within 30 days prior to registration (Y) 8. Total bilirubin 1.5 upper limit of normal within 30 days prior to registration (Y) 9. Serum creatinine < 1.5 mg/dl or calculated creatinine clearance 50 ml/min within 30 days prior to registration estimated by the Cockcroft-Gault formula Creatinine Clearance (male) = [(140 age) x (wt in kg)] [(Serum Creatinine mg/dl) x (72)] Creatinine Clearance (female) = 0.85 x Creatinine Clearance (male) (Y) 10. Peripheral neuropathy grade 1 at the time of registration 7

8 NRG Oncology Institution # RTOG 1308 Case # ELIGIBILITY CHECKLIST (10/23/14) (page 2 of 4) (Y) 11. Patients with non malignant pleural effusion are eligible. If a pleural effusion is present, the following criteria must be met to exclude malignant involvement: When pleural fluid is visible on both the CT scan and on a chest x-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative. Exudative pleural effusions are excluded, regardless of cytology; Effusions that are minimal (ie, not visible on chest x-ray) and that are too small to safely tap are eligible. (Y) 12. Patients must have measurable or evaluable disease (Y) 13. Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to registration. (Y) 14. Women of childbearing potential and male participants must practice adequate contraception. (Y) 15. Patient must provide study-specific informed consent prior to study entry. (N) 16. Prior invasive malignancy unless disease free for a minimum of 3 years. However, skin cancer and in situ carcinomas of the breast, oral cavity, cervix, and other organs and are permissible. (N) 17. Patients with prior history of either small cell lung cancer or NSCLC regardless of the treatment received. (N) 18. Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable. See Section (N) 19. Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields. (N) 20. Does the patient have any of the severe, active co-morbidity, defined as follows: Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months; Transmural myocardial infarction within the last 6 months; Chronic obstructive pulmonary disease exacerbation or other respiratory illness other than the diagnosed lung cancer requiring hospitalization or precluding study therapy within 30 days before registration; Acquired immune deficiency syndrome (AIDS) based upon current CDC definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. (N) 21. Unintentional weight loss > 10% within 90 days prior to registration. (N) 22. 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. 8

9 NRG Oncology Institution # RTOG 1308 Case # ELIGIBILITY CHECKLIST (10/23/14) (page 3 of 4) The following questions will be asked at Study Registration: See section 5 for 3DCRT, IMRT, Motion Management, Proton, Dry Run/Knowledge Assessment, and IGRT CREDENTIALING REQUIRED BEFORE REGISTRATION 1. Institutional person randomizing case. (Y) 2. (Y) 3. Has the Eligibility Checklist been completed? In the opinion of the investigator, is the patient eligible? 4. Date informed consent signed 5. Patient s Initials (Last First Middle) 6. Verifying Physician 7. Patient ID 8. Date of Birth 9. Race 10. Ethnicity 11. Gender 12. Country of Residence 13. Zip Code (U.S. Residents) 14. Method of Payment 15. Any care at a VA or Military Hospital? 16. Calendar Base Date 17. Randomization date 18. Medical oncologist s name (Y/N) 19. (Y/N) 20. 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? 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? 9

10 NRG Oncology Institution # RTOG 1308 Case # ELIGIBILITY CHECKLIST (10/23/14) (page 4 of 4) (Y/N) 21. (Y/N) 22. (Y/N) 23. (Y/N) 24. 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)? 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). 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? Did the patient agree to participate in the quality of life component? If no, please specify the reason from the following: 1. Patient refused due to illness 2. Patient refused for other reason: specify 3. Not approved by institutional IRB 4. Tool not available in patient s language 5. Other reason: specify (II/IIIA/IIIB) 25. Stage (Squamous cell carcinoma or Non-squamous cell carcinoma) 26. Histology (Cisplatin and Etoposide or Carboplatin and Paclitaxel) 27. doublet type Concurrent chemotherapy (N/Y) 28. Specify use of IMRT if you are randomized to the photon arm (CTEP code) 29. CTEP code of site delivering photon therapy (CTEP code) 30. CTEP code of site delivering proton therapy 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 NCI/NRG Oncology audit. Completed by Date 10

11 1.0 INTRODUCTION Lung cancer is the leading cause of cancer-related death. A total of 226,160 new cases and 160,340 deaths from lung cancer were estimated in 2012 in the U.S., and 80% to 85% were NSCLC (American Cancer Society 2012). Radiation therapy is a critical component in both curative and palliative treatment because most patients present with regional nodal disease that cannot be cured with surgery. During the past decade, significant advancements have taken place in radiation technology, including the use of image guidance for both radiation planning and delivery, intensity-modulated radiation therapy (IMRT), and tumor-motion management. These advances have translated to improved treatment outcomes with reduced toxicity and improved survival (Yom 2007). However, rates of local tumor failure of up to 50% remain a major problem after definitive concurrent chemoradiation therapy (Dillman 1996, Sause 2000, Kong 2005). Long-term survival has been shown to be better for patients without local-regional recurrence than for those who develop local recurrence after lung cancer treatment (Auperin 2010), and radiation doses of up to 69.6 Gy correlate with better tumor control and survival (Machtay 2012). RTOG 1106/ACRIN 6697, a continuation of the effort to escalate tumor dose with functional image guidance and adaptive re-planning, was recently activated. In this trial, with isotoxicity used to guide treatment planning, the final total tumor dose will be escalated to as high as 85.5 Gy in 30 fractions. However, intensification of the radiotherapy dose to the thorax, especially when concurrent chemotherapy is administered, is often associated with severe toxicity, including treatmentrelated pneumonitis and esophagitis. Three representative RTOG concurrent chemotherapy and radiation dose intensification phase III trials for thoracic cancers (RTOG 0617 and RTOG 9410 for lung cancer and RTOG for esophageal cancer) (Bradley2011, Minsky 2006, Curran 2011) failed to demonstrate any benefit from high-dose radiation; indeed, the high-dose arms had higher mortality. The phase III RTOG 0617 trial was originally designed to test standard-dose (60 Gy) with high-dose radiation (74 Gy) with chemotherapy for stage III NSCLC. However, the radiation dose-escalation component of this trial was closed in June 2011 when a planned interim analysis showed that the 2 high-dose arms crossed a futility boundary. The median survival times were 21.7 months for the control arms and 20 months for the high-dose arms (Bradley 2011). In RTOG 94-10, a 3-arm study comparing induction versus concurrent chemoradiation therapy at a standard dose of Gy and at 69.6 Gy, the survival of the 69.6 Gy arm was worse than the 60 Gy arm; both were given with concurrent chemotherapy (Curran 2011). RTOG was a phase III trial of combined modality therapy for esophageal cancer comparing standard dose (50.4 Gy) with high-dose (64.8 Gy) radiation; the 2-year survival rates in this study were 31% in the high-dose versus 40% in the standard-dose arms (Minsky 2006). The reasons for the failure of the high-dose treatments to produce a survival difference in RTOG 94-10, RTOG 0617, and RTOG remain to be determined, and treatment-related toxicity might have contributed to the early deaths that occurred in these trials. Nonetheless, based on the results of RTOG 0617, 74 Gy would not be considered an acceptable dose for photon radiation, and therefore, 70 Gy (RBE) will be used in this study for both the photon and proton arms. Furthermore, upon review by the study PIs, if normal tissue constraints cannot be met at the 70 Gy (RBE) level, the dose will be decreased to as low as 60 Gy (RBE). In terms of dosimetry, the use of protons as a source of therapeutic radiation provides a substantial improvement over the dose distributions that can be achieved with conventional sources of radiation such as high-energy x-rays. Because of the poor outcome of conventional radiotherapy for most lung cancers and the high sensitivity of the adjacent normal tissues to radiation, proton therapy has the potential for significant clinical gain owing to the unique physical and dosimetric characteristics of protons, particularly the fact that large volumes of critical organs at risk (OARs), such as the lung and heart, may receive greatly reduced or no radiation dose. For example, this proton advantage can be exploited by reducing heart dose. On multivariate analysis of RTOG 0617 for factors associated with overall survival between 11

12 standard dose and high dose radiation, lower heart V5 (heart V5= the volume of heart receiving 5 Gy) was associated with improved overall survival. Heart doses with proton beam therapy are lower compared to the heart doses with IMRT. The Figure below shows the heart V5 value for 103 patients on an ongoing trial. The mean value for Heart V5 is 14.6% (±13.6% SD) with protons, and 44.3% (±33.3% SD) with IMRT. A t-test verifies a statistically significant (p<0.0001) lower dose for protons than IMRT for Heart V5 values. 100 Heart V5 Relative Volume [%] PSPT IMRT Box-plot shows the maximum and minimum values (whisker) and 75 th and 25 th percentile (box) and mean (center line) for 103 lung patients that were randomized between passive scattering proton therapy (PSPT) or IMRT Furthermore, in a previous study (Tucker and Liao 2012), investigators at MD Anderson hypothesized that heart dose affects overall survival (OS) of patients with non-small cell lung cancer (NSCLC) receiving definitive concurrent chemoradiotherapy. These investigators tested this hypothesis by investigating the impact of mean heart dose (MHD) on OS in a retrospective study including 532 patients with NSCLC treated with concurrent chemoradiation. The range of radiation dose to tumor was 60 to Gy, with most patients receiving 60, 63, 66, 69.6, 70, or 74 Gy. The techniques used for treatment delivery were 3-dimensional radiation (3DCRT, n= 332), intensity modulated radiation (IMRT, n=141), and passive scattering proton beam therapy (PBT, n=59). Mean heart doses ranged from 0 to 55.4 Gy, with 25th, 50th, and 75th percentiles corresponding to 9.9 Gy, 18.4 Gy, and 28.7 Gy, respectively. The median MHD was 22.3 Gy, 15.1 Gy and 6.5 Gy for 3DCRT, IMRT, and PBT, respectively. The median follow-up time was 18.6 months for the entire group and 36.1 months for surviving patients. By multivariate analysis, mean heart doses above the 25% percentile were significantly associated with an increased risk of death, with a hazard ratio (HR) of 1.4 compared to patients with MHD in the lowest quartile (see Figure below). Other factors selected by the model as being independently associated with survival were prescribed dose <63 Gy (HR=1.6), stage IV disease (HR=1.6), and GTV, with a hazard ratio of 1.5 for tumors larger than the median GTV, and an additional HR of 1.4 for tumors above the 75th percentile in size. 12

13 OS in patients with mean heart doses above or below the median per radiation dose subgroups. There was a consistent trend for shorter survival with higher mean heart doses in all 4 groups, and the difference in OS reached statistical significance in the Gy group. These investigators also noted that a bi-institutional prospective trial, A Bayesian Randomized Trial of Image-Guided Adaptive Conformal Photon (74 Gy) vs. Proton Therapy (74 Gy), with Concurrent Chemotherapy, for Locally Advanced Non-Small Cell Lung Carcinoma: Radiation Pneumonitis and Locoregional Recurrence (MDACC , Clinicaltrials.gov identifier NCT ), currently being conducted jointly by MD Anderson and Mass General, demonstrates the feasibility of multiinstitutional trials of proton therapy for patients with lung cancer. The investigators also compared mean heart dose in 103 randomized patients between the proton and IMRT arms and found that the mean heart dose has been consistently lower in the proton arm (see Figure below). Mean heart dose between patients randomized to proton versus IMRT 13

14 Additional preliminary clinical studies have recently demonstrated that the 18-month overall survival rate after concurrent chemoradiotherapy for NSCLC was strongly influenced by both mean dose to heart (MHD) and lung V20 (Liao 2012), suggesting that the unwanted dose to heart and lung during radiation therapy may contribute to the early death of patients with NSCLC treated with concurrent chemoradiation. In the MD Anderson study, the potential association between MHD and lung V20 and OS up to 18 months after start of radiotherapy was assessed using a Cox proportional hazards analysis with forward stepwise selection of factors significant at p<0.05. Patients surviving longer than 18 months were censored for OS at this time point. The following factors also were considered for inclusion in the model to correct for their potential effects on OS and/or their association with MHD and lung V20: tumor stage and histology, gross tumor volume (GTV), patient s Karnofsky status, treatment technique, and prescribed radiotherapy dose. By multivariate analysis, the risk factors for survival included GTV, lung V20, and MHD. Patients with GTV, MHD, and lung V20 above the median for each factor had 36% survival at 18 months, whereas survival among patients with all three of these factors below the median was 83%. Patients with one factor or two factors above the median had intermediate survival levels at 18 months: 58% and 50% respectively (Figure below). Preliminary analysis of RTOG 0617 further showed the heart V5 also to be associated with OS, supporting the hypothesis of this concept that reduced dose to heart using proton beam therapy would improve OS (Bradley 2011). Association of OS and GTV, heart, and lung dose Dosimetric treatment planning studies have shown that proton beam therapy can significantly spare the critical organs in thorax, including normal lung, heart, esophagus, and spinal cord (Chang 2006). Retrospective studies from MD Anderson and elsewhere seem to indicate that chemotherapy given with proton beam therapy led to less severe treatment-related toxicity among patients with locally advanced NSCLC relative to patients given chemotherapy plus photon RT. Reductions in toxicity were observed for the lung, heart, esophagus, and bone marrow (Sejpal 2011). Other retrospective studies from MD Anderson on stage II-IIB NSCLC also seem to indicate an increase in OS rate from 20.3% to 35.1% (P=0.038) and an extension of median survival time from 16.2 months with IMRT to 20.7 months with proton beam therapy, both given with concurrent chemotherapy (Cox, personal communication, 2012).A study from Japan also confirmed the advantage of high-dose proton beam therapy for NSCLC (Oshiro 2012). 14

15 A phase II single-arm prospective trial from MD Anderson confirmed the potential advantage from high-dose proton therapy [74 cobalt Gray equivalents (CGE)] versus historical IMRT with regard to treatment-related pneumonitis and OS: the median survival time in this study was 29.4 months (Chang 2011). The RTOG 1308 trial will keep the maximum tumor dose at 70 Gy [relative biological effect (RBE)] based on the results of this phase II trial and the early results from RTOG Based on pilot work at MD Anderson, an increase in median survival time from 21 months in the photon arm to 28 months in the proton arm is expected. The proposed study uses 28 months as the median survival time as the primary objective for 2 reasons: first, because expecting a median survival time of 29.4 months for the proton arm would be quite aggressive, especially in the less-tightly-controlled setting of a multicenter trial, and second, because the highest dose will be 70 Gy (RBE), not 74 Gy (RBE). Furthermore, the normal tissue constraints at 70 will be the same as those acceptable for 60 Gy (RBE). Other evidence in support of proton beam therapy for locally advanced NSCLC comes from early findings of an NCI-sponsored P01, A Bayesian Randomized Trial of Image-Guided Adaptive Conformal Photon vs. Proton Therapy, with Concurrent Chemotherapy, for Locally Advanced Non-Small Cell Lung Carcinoma: Radiation Pneumonitis and Locoregional Recurrence (MDACC , clinicaltrials.gov identifier NCT ), currently being conducted jointly by MD Anderson and Massachusetts General. This trial is proceeding smoothly according to the trial design. This trial mandates motion management with 4D CT simulation and, when appropriate, gating. (RTOG 1308 will permit any type of motion management methods used by participating institutions). The P01 trial requires the development of both IMRT and proton plans before randomization. Patients are randomized only when both IMRT and proton plans can meet the dose-volume constraints of OARs. All treatment plans are initially attempted at dose level of 74 Gy (RBE) for both IMRT and protons. If one of the plans cannot meet the normal tissue dose constraints for ALL OARs, a second set of plans is attempted at the 66 Gy (RBE) level. Weekly 4D CT is acquired to access the need for adaptive re-planning, and PET scans are obtained at mid-treatment as well. (In the RTOG 1308 study, mid-treatment PET will not be required). This ongoing P01 trial has provided the investigators with invaluable insights for conducting a randomized trial of proton therapy. These investigators have learned the following so far: 1) peer review of all contours is critical; 2) image guidance with daily kv imaging and weekly CT scans is very important; 3) modifications to treatment plans to adapt to changes in tumor or anatomy were needed in 20% of the IMRT cases and 55% of the proton cases; 4) ~ 70% of all patients who consented to this trial could be randomized, and among the randomized patients, 75% were at 74 Gy (RBE) and 25% at 66 Gy (RBE) dose levels; 5) five patients withdrew consent after having been randomized to the IMRT arm (to date, no patients randomized to the proton arm have withdrawn consent) and 9 patients were denied insurance coverage after having been randomized to the proton arm; 6) among patients for whom the plan could not meet the stipulated dose constraints, the modality that achieved higher target dose without violating dosevolume constraints was used to deliver the treatment, and 7) the rate of treatment interruption or incompletion has been extremely low. Of the 103 randomized patients, there have been 3 (2 disease progression, 1 esophagitis) patients who received less than 60 Gy due to treatment interruption. Finally, early findings suggest that the outcomes in both the IMRT and proton groups are better than those of historical controls. With much discussion amongst the existing lung cancer experts at proton centers within the U.S., this proposal differs from strategies used in RTOG 0617 in the following: a) This protocol will allow the patient s dose to be individualized to the highest achievable dose (within normal tissue organs-at-risk [OAR] constraints) between Gy; b) The protocol will maintain strict organs-at-risk constraints for this trial; and c) The protocol will perform preliminary quality assurance review as patients are entered on the trial to monitor dose prescriptions and dose/contouring compliance. The prescribed dose for this study is 70 Gy. The study is designed to allow lower doses in situations for which critical structure constraints cannot be met. Before treatment can begin 15

16 using lower doses, a pre-treatment review of the case must be performed by one of the radiation oncologist study chairs. The rationale for testing proton therapy in stage III NSCLC in this trial is to determine if proton therapy can improve overall survival by reducing the risk of severe toxicity to organs at risk compared to photon-based IMRT. Local tumor recurrence contributes to both morbidity and mortality in locally advanced NSCLC, and increasing local control translates to survival benefits, especially in the era of effective systemic therapy. Radiation therapy is a mainstay of treatment for locally advanced NSCLC, and current therapy includes chemotherapy. Radiation dose escalation may improve local-regional disease control and OS in patients with stage III NSCLC. Results from several groups (Kong 2005, Bradley 2002, Rengan 2004, Wang 2006) and a recent RTOG secondary analysis (Machtay 2012) of more than 1,300 cases treated with chemoradiation in the dose range of Gy have demonstrated that use of high-dose radiation is associated with improvements in both these variables. However, these improvements come at the cost of increased treatment-related toxicity (Curran 2011). Further improvements in OS for patients with NSCLC have been challenging because of the difficulty in escalating radiation doses to the tumor further without increasing the radiation dose to proximal critical organs. Advancements in technology such as IGRT, IMRT, and in particular, proton beam therapy make it possible to reduce the radiation dose and the volumes of OARs exposed and thus, to reduce toxicity. Therefore, these advanced technologies and techniques have the potential to intensify radiation doses without increasing side effects to unacceptable levels. The physical and dosimetric characteristics of proton therapy make it an ideal radiation modality for lung cancer, having the potential to reduce toxicity, improve patient quality of life (QOL), increase tumor dose, and improve OS of patients with lung cancer. This potential has generated very high interest in the use of proton beam therapy for cancer, and the number of proton facilities has increased steadily worldwide. However, the lack of level I evidence of the effectiveness of proton therapy and concerns regarding its cost and benefits have remained problematic. In April 2012, the NCI issued Guidelines for the Use of Proton Radiation Therapy in NCI-Sponsored Cooperative Group Clinical Trials which provided some much-needed guidance for the radiation community. However, no standards or guidelines have been established specifically for aspects of quality assurance, treatment planning, and delivery of proton radiation therapy. Given the rapid proliferation of new proton treatment facilities, it is a critical time to objectively and scientifically assess the potential of protons versus photons for the treatment of lung cancer. RTOG 1308, being a phase III randomized trial, will help to establish such evidence, which clinicians can use to guide treatment recommendations. The results of this trial have the potential to change the current standard of care for unresectable NSCLC. On the basis of the published and preliminary information summarized in this section, the design and radiation dose chosen for this trial is considered ethical, safe, and feasible. 1.1 Patient-Reported Outcome Study: Health-Related Quality of Life (HRQOL), Symptom Burden, and Health Utility Analysis As noted above, two key toxicities of concern from definitive chemoradiation for locally advanced NSCLC are treatment-related pulmonary toxicity (ie, clinical pneumonitis and lung fibrosis) and esophageal toxicity (ie, esophagitis). Thus, these two clinical toxicities will form the basis of the main patient reported outcomes to be analyzed. Of these two main toxicities, the primary QOL outcome of this study will focus on the pulmonary toxicity, as this is a typically a chronic effect of treatment that can have long term negative effects on QOL. Esophagitis, on the other hand, which will be followed as a secondary QOL outcome, is an acute/subacute effect which is largely transient. 16

17 This randomized study aims to provide information on a clinically meaningful QOL benefit from proton therapy over photon therapy in NSCLC patients. Our primary QOL hypothesis is that, compared with patients receiving either 3DCRT or IMRT (Arm 1), patients on the proton arm (Arm 2) will have less-severe shortness of breath (as measured by the validate MDASI-Lung instrument) 6 months after the end of concurrent chemoradiation therapy (representing late adverse response to radiation), and that the differences in symptom ratings between Arms will be clinically meaningful, after controlling for disease progression. The second QOL hypothesis is that, compared with patients receiving either 3DCRT or IMRT (Arm 1), patients in the proton arm (Arm 2) will have less severe sore throat (as measured by the validated MDASI lung instrument) at the end of chemoradiation therapy (at 6 weeks of therapy, representing acute response) and that the differences in symptom ratings between Arms will be clinically meaningful. Beyond analyzing the key patient reported outcomes related to shortness of breath and sore throat, this study will also follow a variety of other QOL items and symptoms using the MDASI- Lung and UCSD Shortness of Breath Questionnaire (SOBQ) instruments to better understand the differences in QOL and breathing functioning between proton and photon therapy. Time points and rationale are as follows: 1. Baseline: to serve as a control measurement for each patient weeks during therapy: which is at the end of CXRT, as the peak of acute phase sore throat symptoms related to esophagitis; 3. At the first follow-up visit (4-8 weeks) after CXRT: to document the initial change on lung symptom burden related to acute adverse effects of therapy between arms months post-cxrt document the difference in shortness of breath related to adverse pulmonary effects of therapy between arms, months post-cxrt: document long-term difference in shortness of breath between the two arms. As noted above, dosimetric treatment planning studies have shown that proton beam therapy can significantly spare the critical organs in thorax, particularly normal lung and esophagus (Chang 2006). Retrospective studies also suggest that chemotherapy given with proton beam therapy led to less severe treatment-related toxicity among patients with locally advanced NSCLC relative to patients given chemotherapy plus photon RT. Key reductions in toxicity were observed for the lung and esophagus (Sejpal 2011). Why is it important to collect prospective HRQOL data? Why not simply collect the NCI-CTC toxicity information? More and more, studies are demonstrating a disconnect between physician and patient reported outcome (PROs). This was evident from RTOG 98-01, a phase III trial of amifostine, a radioprotector, in patients with stage III NSCLC receiving concurrent chemotherapy and hyperfractionated radiation. Sarna et al (2008) found that patients receiving amifostine reported significantly greater pain reduction after chemoradiation (34% vs. 21%), less difficulty swallowing during chemoradiation, and less weight loss than patients not receiving amifostine. However, physician-rated assessments of dysphagia were not significantly different by treatment arm. This disconnect illustrates the critical role of patient reported outcomes (PRO) in this setting MDASI-Lung The lung cancer-specific module of the MDASI has also been validated (Mendoza 2011). In addition to the key QOL endpoints of shortness of breath (the primary QOL endpoint) and sore throat (the secondary QOL endpoint), this instrument also will capture patient reported outcomes related to pain, fatigue, coughing, etc. In addition to collecting esophagitis-related symptoms, we will add a difficulty swallowing item from a patient-reported symptom severity with the same 0-10 scale. This item was validated under MDASI-GI (Wang et al, 2010). The radiation-induced difficulty swallowing was documented as the second-worst symptom overtime of chemoradiation therapy in esophagus cancer patients (Wang et al, 2012). A clinically meaningful difference will 17

18 be defined as an effect size greater than 0.5 standard deviation (SD) (Cohen 1988) on the MDASI-Lung symptoms, as indicated by preliminary results from retrospective studies conducted at MD Anderson (McLeod 2011). The post-chemoradiation QOL effects of shortness of breath and difficulty swallowing are likely related to the development of lung and esophagus tissue damage over time in response to therapy. In an ongoing phase II longitudinal study in NSCLC patients treated by proton or photon therapy at MD Anderson, investigators observed the following trends of symptom severity from 1 month to 6 months post-chemoradiation (N=96), see Table below. Of note, of these symptoms, only the pulmonary symptoms (ie, shortness of breath and coughing) continually worsened over time. The symptoms related to difficulty swallowing, sore throat, pain, and fatigue peaked at 1-3 months after treatment and then began to improve by 6 months. Moreover, the early pilot review of shortness of breath at 6 months post-cxrt in a smaller sample (N=40) showed that mean severity was lower for patients treated with protons (2.5) than for patients treated with for IMRT (3). MDASI Symptom Severity in NSCLC Patients undergoing Proton or Photon Therapy (N=96) Time Point_ Fatigue Shortness of Breath Coughing Difficulty Swallowing Pain Sore Throat Pre CXRT Mean SD month Mean SD months Mean SD months Mean SD Total Mean SD ANOVA, P-value On the basis of the pilot data, the critical time point for capturing acute adverse events, which will be evidenced by ratings on the MDASI-Lung item sore throat, is 6 weeks after the initiation of chemoradiation therapy (at the end of treatment); the optimal time point for capturing lung tissue damage related late adverse events, which could be evidenced by ratings of the MDASI-Lung symptom item shortness of breath and coughing, is 6 months after the end of chemoradiation therapy. During the active component of the chemoradiation treatment course itself, Wang, et al. (2006) found that esophagitis-related symptoms, including sore throat and pain, increased in a linear fashion as the radiation dose accumulated (see left Figure below) and then began to decrease following completion of the chemoradiation. Interestingly, a previous non-randomized longitudinal study of patients with NSCLC at MD Anderson (unpublished data) documented that the MDASI sore throat scores differed significantly among 3 different radiation treatments (3DCRT, IMRT, and proton) during the course of chemoradiation. The area under the curve (AUC) of mean sore throat (right Figure below) depicts a symptom burden in the proton therapy patients that was significantly lower than in patients receiving IMRT (effect size =.74) than in patients receiving 3D- 18

19 Symptoms Steady increase during CXRT Non-randomized study: AUC, mean MDASI sore throat 3DCRT IMRT PROTON Weeks from radiation start AUC (3DCRT) = 148; AUC (IMRT) = 96; AUC (Proton) = 33.5 CRT (effect size =1.3). The end of CXRT time point presents the worst symptom burden related to esophagitis. In a pilot work in NSCLC patients with symptom measures pre and end of CXRT from a nonrandomized study (Wang 2013), the proton patients showed the lowest probability to report an increase in esophagitis symptoms (pain and sore throat); see Figure below. Compared with proton patients, a significantly higher percentage of 3DCRT patients reported any increase in esophagitis symptoms (P<.0001). The probability of IMRT patients to report an increase in esophagitis symptom was lower than 3DCRT patients (P=0.013) but higher than proton patients (P=0.0001) UCSD Shortness of Breath Questionnaire (SOBQ) The SOBQ is a shortness of breath instrument (Eakin et al, 1998), which involves a 24 item patient-reported outcome scale. Item 22 is the symptom severity measure on 0-5. The other 23 items rate impaired functioning on 0 to 5, with 0 being not at all and 5 representing the maximally or unable to do because of breathlessness. While the shortness of breath question will be captured on MDASI as the primary outcome, we will also use SOBQ to more fully understand the many related functional impairments secondary to shortness of breath. Kupferberg (2005) reported the minimal clinical important difference for SOBQ and reported moderate to large effect sizes between the SOBQ and SF-36 subscales (physical functioning, role-physical, energy/fatigue and health change). Of note, this tool was also utilized in another phase III NSCLC study (RTOG 1021). 1.2 Comparative Cost Effectiveness Analysis We will calculate the area under the EuroQol (EQ-5D) utility curve from data points gathered at treatment start (baseline), at week 6 after chemoradiation and at 3, 6, and 12 months after 19

20 chemoradiation to determine quality adjusted life years (QALYs) for photon beam and proton beam radiotherapy. QALYs will be considered in the context of the differences in costs associated with the interventions (i.e., incremental costs per QALY) to determine cost effectiveness of each intervention Background Lung cancer patients are sick, and it is estimated that it costs roughly 15 times more to care for them than it does for healthy controls. The main costs associated with caring for lung cancer patients in the initial treatment phase are inpatient hospitalizations (49%), outpatient office visits (35%), and radiology and laboratory tests (13%) (Kutikova 2005). First-line treatment for patients with inoperable, locally advanced NSCLC is generally considered very cost effective when compared to best supportive care as an alternative treatment (Chouaid 2009). Three modelbased analyses done in Canada and Europe show that treatment with more intense multi-agent chemotherapy, concurrent (as opposed to sequential) chemoradiotherapy, and hyperfractionated (as compared to standard fractionated) radiotherapy are all cost-effective interventions from the perspective of absolute dollars, dollars per life-year gained (LYG), and dollars per quality adjusted life year (QALY), respectively (Evans 1997, Lievens 2005, Vergnenegre 2006). Among treatment costs, radiotherapy is the most costly cancer treatment approach during the initial and terminal care phases, responsible for 6 and 13% of total costs, respectively (Kutikova 2005). Technological advances in radiotherapy delivery (e.g. IMRT) hold potential for improved cure rates and reduction in acute and late treatment-related toxicity, as compared to their predecessor technologies. Such technological advances almost always come with incremental increases in monetary cost. In the case of IMRT for lung cancer treatment, single-institution series and small clinical trials shown reduction in treatment-related toxicity when compared to historical controls (Yom 2007); however, the rapid dissemination and adoption of this technology never allowed for a prospective assessment of its cost effectiveness. IMRT has resulted in extreme increases in the amount of money spent by the healthcare system overall on radiotherapy for cancer patients (Nguyen 2011). The incremental costs of proton beam radiotherapy (PBT) (over IMRT) for the treatment of localized prostate cancer is estimated to be approximately $14,000 for a standard course of 44 radiation treatments; a similar increase is expected for the treatment of NSCLC (ICER 2009). To inform resource allocation decisions, differences in QALYs between PBT and IMRT must be considered in the context of the differences in costs associated with the interventions (i.e. incremental costs per QALY) (Drummond 2001) EQ-5D The EQ-5D is a method for obtaining valuations of health-related QOL, which also can be used for quality-adjusted survival and cost-utility analyses (Glick 1999, Johnson 1998, Johnson 1998b, Johnson 2000). It is a 2-part questionnaire that takes approximately 5 minutes to complete (Schulz 2002). The first part of the EQ-5D consists of 5 items addressing 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension can be graded on 3 or 5 levels whether one is utilizing the EQ-5D-3L vs. EQ-5D-5L. This modification of the original instrument has been validated alongside the EQ-5D-3L for use in cancer patients and shown to be have less ceiling effect and have greater ability to discriminate different levels of health and changes in health than the EQ-5D-3L (Pickard 2007). For the sake of comparison, the two versions of the instrument can be mapped one onto the other with the aid of the crosswalk index value calculator which is available on the euroqol website ( For the purpose of this study we plan on using the EQ-5D-5L. The EQ-5D-5L response levels are: 1-no problems, 2-slight problems, 3-moderate problems, 4-a lot of problems, and 5-extreme problems. Health states are defined by the combination of the response levels for each of the 5 dimensions, generating 243 health states to which unconsciousness and death are added (Badia 1998). The second part of the EQ-5D is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm 10-point-interval scale. Worst imaginable health state is scored as 0 at the bottom of the scale, and best imaginable health state is scored as 100 at the top. Both the 5-item index score and the VAS score are 20

21 transformed into a utility score between 0- worst health state and 1- best health state. Either the index score or the VAS score can be used in the quality-adjusted survival analysis, or the costutility equation can be entered, depending on the health state(s) of interest (Wu 2002). The area under the EQ-5D curve yields predicted QALYs (Glick 2007). QALY differences of 0.03 are considered important, and QALY differences of as little as 0.01 potentially meaningful and important for several prevalent diseases, including cancer, diabetes, and heart disease (Samsa 1999; Walters 2003). Although developed in Europe, the EQ-5D has been used in the United States and Canada (Glick 1999, Johnson 1998, Johnson 1998b, Johnson 2000). The EQ-5D web site, lists multiple languages in which the instrument has been validated. There have been few studies published reporting on the incorporation of the EQ-5D into the evaluation of patients with NSCLC. Trippoli et al (2001) used the EQ-5D in the evaluation of 95 patients with NSCLC treated at 15 Italian hospitals. The mean utility score was 0.58 in the selfclassifier version and 0.58 in the VAS version. Both the self-classifier version and the VAS version showed statistically significant correlation with each of the eight domains of the Short Form-36 (SF-36). 1.3 Changes in Pulmonary Function After Concurrent Chemoradiation for NSCLC Thoracic RT is associated with significant alterations in lung function as assessed by objective pulmonary function tests (PFTs) [Cerfolio 2009, Kepka 2011, Semrau 2011, Theuws 1999, Bishawi 2012]. The extent of residual lung function is a major determinant of a patient s functional status after treatment, particularly in patients with lung cancer who frequently have pretreatment pulmonary compromise secondary to both malignancy and coexisting lung disease [Sundar 2011]. It is increasingly important to understand the relationship between thoracic RT and the decline in lung function in the setting of aggressive concurrent chemoradiation. Studies by Gopal 2003 and others [Cerfolio 2009; Takeda 2006] have shown that the largest and most consistent changes in PFT values after definitive radiation for NSCLC occur in diffusing capacity of the lung for carbon monoxide (DLCO). Additionally, the decrease in DLCO after neoadjuvant chemotherapy or chemoradiotherapy has been associated with an increased risk for postoperative complication [Cerfolio 2009, Takeda 2006]. Lopez ( 2012) reported that 85% patients were found to have decreased DLCO after RT with a median reduction of 20% in the percent predicted value. Those patients who had grade 0, 1, 2 and 3 RP experienced a median 10.7, 13, 22.1, and 35.2% change in DLCO after treatment, respectively (P = ; Figure below 21

22 Comparison between radiation-induced pneumonitis grades and the median of percent reductions in diffusing capacity of the lung for carbon monoxide tests. The 25 th and 75 th percentile range is represented by the thin line of the lung for carbon monoxide tests. The 25 th and 75 th percentile range is represented by the thin line. There was a significant association between the percentage reduction in DLCO and grade 1 vs. grade 2 RP (P = ; correlation coefficient, 0.30). Similar results were observed for the DLCO change in patients with a pre-rt FEV1 < 60% of predicted with a median DLCO reduction of 10.8% for those cases with RP grade 1 and 24.2% if the patients experienced grade 2 RP (P = ). Additionally, when patients with V20 and MLD below the median values were evaluated for the change of DLCO according to RP grade, again a higher DLCO reduction was observed in the symptomatic cases (10% vs 20%; P = 0.11 for both V20 < 30% and MLD < 17Gy cases). RTOG 1308 provides a unique opportunity to further explore the utilization of PFT as a functional endpoint as a measure of patient QOL and the possibility of using PFT as an objective measurement for treatment-related lung toxicities. 1.4 Physics and Technological Considerations Relative to photons, the physical characteristics of proton beams are appealing for cancer therapy. The technology associated with proton delivery is still evolving, and there are many practical challenges associated with the planning and delivery of this treatment modality. [Martijn 2013] With the introduction of intensity-modulated photon delivery and the use of a drastically increased number of beam angles, the dose deposition advantage of standard proton therapy is not so obvious. [Seco 2012] The distal penumbra of protons is much sharper than the lateral penumbra, especially when using uniform scanning. As a consequence of range uncertainties, the sharp finite range of proton beams can change from a major advantage to a significant risk of inaccurate delivery. [Lu 2011] There are many factors contributing to delivery inaccuracies: the cumulative uncertainty in treatment planning and treatment delivery associated with changes in patient geometries. It is essential to investigate the physics aspects of proton therapy and photon therapy to determine the most appropriate and clinically relevant technological parameters, to ensure quality and effectiveness throughout radiation therapy processes, including imaging, simulation, patient immobilization, target and critical structure definition, treatment planning, image guidance and delivery. [Nitin 2013] This would ensure collection of quality technical data and a meaningful clinical trial outcome. 22

23 2.0 OBJECTIVES 2.1 Primary Objective To compare the overall survival (OS) in patients with stage II-IIIB NSCLC after image guided, motion-managed photon radiotherapy (Arm 1) or after image guided, motion-managed proton radiotherapy (Arm 2) both given with concurrent platinum- based chemotherapy. 2.2 Secondary Objectives To compare 2-year progression-free survival (PFS) between the 2 arms; To compare the development of grade 3 or higher adverse events definitely, probably, or possibly related to treatment (see Section 13.2 for specific adverse events) To compare differences between the two arms in QOL based primarily on the development of shortness of breath at 6 months and secondarily on the development of sore throat at the end of chemort (as measured by the lung cancer module of the MD Anderson Symptom Inventory [MDASI-Lung]), as well as breathing related functioning impairments as measured by the Shortness Breath Questionnaire [SOBQ]; To compare cost-effectiveness outcomes between the 2 arms; To compare pulmonary function changes by treatment arms and response; To explore the most appropriate and clinically relevant technological parameters to ensure quality and effectiveness throughout radiation therapy processes, including imaging, simulation, patient immobilization, target and critical structure definition, treatment planning, image guidance and delivery. 3.0 PATIENT SELECTION NOTE: PER NCI GUIDELINES, EXCEPTIONS TO ELIGIBILITY ARE NOT PERMITTED 3.1 Conditions for Patient Eligibility For questions concerning eligibility, please contact the study data manager Histologically or cytologically proven diagnosis of non-small cell lung cancer Clinical AJCC (AJCC, 7 th ed.) II, IIIA or IIIB (with non-operable disease; non-operable disease will be determined by a multi-disciplinary treatment team within 60 days prior to registration; Note: For patients who are clearly nonresectable, the case can be determined by the treating radiation oncologist and/or a medical oncologist or pulmonologist. Patients who present with N2 or N3 disease and an undetectable NSCLC primary tumor are eligible. Patients who refuse surgery are eligible Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup: History/physical examination within 30 days prior to registration; FDG-PET/CT scan for staging within 60 days prior to registration. MRI scan with contrast of the brain (preferred) or CT scan of the brain with contrast within 60 days prior to registration; FEV1 1.0 Liter or 40% predicted with or without bronchodilator within 90 days prior to registration. o Patients who meet the criterion above without O2, but who need acute (started within 10 days prior to registration) supplemental oxygen due to tumor-caused obstruction/hypoxia are eligible, provided the amount of the O2 needed has been stable Zubrod performance status 0-1 within 30 days prior to registration; Age CBC/differential obtained within 30 days prior to registration, with adequate bone marrow function defined as follows: Absolute neutrophil count (ANC) 1,500 cells/mm 3 ; Platelets 100,000 cells/mm 3 ; 23

24 Hemoglobin 9.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb 9.0 g/dl is acceptable.); SGOT or SGPT 1.5 upper limit of normal within 30 days prior to registration Total bilirubin 1.5 upper limit of normal within 30 days prior to registration Serum creatinine < 1.5 mg/dl or calculated creatinine clearance 50 ml/min within 30 days prior to registration estimated by the Cockcroft-Gault formula: Creatinine Clearance (male) = [(140 age) x (wt in kg)] [(Serum Creatinine mg/dl) x (72)] Creatinine Clearance (female) = 0.85 x Creatinine Clearance (male) Peripheral neuropathy grade 1 at the time of registration Patients with non malignant pleural effusion are eligible. If a pleural effusion is present, the following criteria must be met to exclude malignant involvement: o o o When pleural fluid is visible on both the CT scan and on a chest x-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative. Exudative pleural effusions are excluded, regardless of cytology; Effusions that are minimal (ie, not visible on chest x-ray) that are too small to safely tap are eligible Patients must have measurable or evaluable disease Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to registration Women of childbearing potential and male participants must practice adequate contraception Patient must provide study-specific informed consent prior to study entry. 3.2 Conditions for Patient Ineligibility Prior invasive malignancy unless disease free for a minimum of 3 years. However, skin cancer and in situ carcinomas of the breast, oral cavity, cervix, and other organs and are permissible Patients with prior history of either small cell lung cancer or NSCLC regardless of the treatment received Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable. See Section Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields; Severe, active co-morbidity, defined as follows: Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months; Transmural myocardial infarction within the last 6 months; Chronic obstructive pulmonary disease exacerbation or other respiratory illness other than the diagnosed lung cancer requiring hospitalization or precluding study therapy within 30 days before registration; Acquired immune deficiency syndrome (AIDS) based upon current CDC definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive Unintentional weight loss > 10% within 90 days prior to registration 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. 24

25 4.1 Required Pretreatment Evaluations/Management (NOTE: See Sections 3.1 and 3.2 for evaluations required for eligibility) Glucose, electrolytes, LDH, aspartate alkaline phosphatase, total protein, albumin, calcium, blood urea nitrogen (BUN), and serum magnesium level within 30 days before concurrent chemotherapy start date. Serum creatinine and CBC with differential within 10 days before concurrent chemotherapy start date. DLCO within 90 days of treatment start. 4.2 Highly Recommended Evaluations/Management Note that these evaluations/interventions are highly recommended as part of good clinical care of patients on this trial but are not required MRIs of the thorax 90 days before treatment start, if there is a medical justification, especially for superior sulcus tumors CT or MRI scans of the abdomen, with or without contrast within 90 days before treatment start if medically indicated Cardiac Single-Photon Emission CT (SPECT) for patients with lower lung tumor when medically indicated as determined by the treating radiation oncologist within 90 days before treatment start Quantitative lung ventilation/perfusion scan +/- CT scan if FEV1 1.4 liters within 90 days before treatment start Bone scan within 90 days before treatment start if there is a medical justification; Comprehensive pulmonologist consultation within 90 days before treatment start; EKG and/or echocardiogram within 90 days before treatment start Nutritional assessment, including evaluation of the need for prophylactic gastrostomy tube placement (if the patient is 10% below ideal body weight) within 90 days before treatment start 5.0 REGISTRATION PROCEDURES (10/23/14) Access requirements for OPEN, Medidata Rave, and TRIAD: Site staff will need to be registered with CTEP and have a valid and active CTEP Identity and Access Management (IAM) account. This is the same account (user id and password) used for the CTSU members' web site. To obtain an active CTEP-IAM account, go to NOTE: All sites must submit a Letter of Intent (LOI) to NRG Oncology Regulatory to receive approval to participate in this trial. For more details see the regulatory tab on the NRG Oncology/RTOG website next to the RTOG 1308 protocol link. The RT treatment modalities are either photon (3DCRT and/or IMRT) or proton therapy. Image- Guided Radiotherapy (IGRT) is required for all patients enrolled on this trial. In order to be eligible to enroll patients onto this trial, centers must be credentialed for photons (3D-CRT and/or IMRT) AND protons in addition to Lung image-guided radiotherapy (IGRT). Institutions not having credentialed for IMRT/3D-CRT and proton treatment must credential for each of the modalities being used for this protocol. Credentialing for IMRT allows the institution to also use 3D-CRT. As part of this credentialing, institutions intending to use gating or tracking for motion management must be credentialed using the IROC Houston phantom placed on a moving table supplied by the IROC Houston. If this credentialing has not been obtained previously as part of IMRT or 3D-CRT credentialing, the process must be repeated. There is a required knowledge assessment for both photons and protons for this protocol, which is in addition to the Facility Questionnaire and the credentialing requirements. This must be successfully completed prior to the enrollment of the first patient. Details for the knowledge assessment can be found on the IROC Houston website at 25

26 Protons Photons 5.1 RT-Specific Pre-Registration Requirements For detailed information on the specific technology requirement required for this study, please refer to the table below and utilize the web link provided for detailed instructions. The check marks under the treatment modality columns indicate whether that specific credentialing requirement is required for this study. Specific credentialing components may require you to work with various QA centers. However, the NRG Oncology will be the entity to notify your institution when all credentialing requirements have been met and the institution is RT credentialed to enter patients onto this study. Proton centers wishing to participate in this study must comply with the NCI proton guidelines for the Use of Proton Radiation Therapy in NCI Sponsored Cooperative Group Clinical Trials, which are available on the IROC Houston website ( These requirements include, but are not limited to, completion of a proton facility questionnaire, a successful IROC Houston site visit, which identifies the proton technique(s) which can be used, annual monitoring of the proton beam calibration, e.g. IROC Houston s monitoring program, and successful digital data submission to the TRIAD. Once these requirements are successfully met, the proton center is approved to use proton therapy in NCI sponsored clinical trials. Each trial may require additional proton therapy credentialing steps prior to being allowed to enter a patient treated with protons onto a specific study. The IROC Houston QA Center will coordinate the completion of the proton therapy use approval process in conjunction with the appropriate other Quality Assurance Offices for any additional protocol specific credentialing requirements. See the table below for the credentialing requirements of this study. Web Link for Procedures and Instructions: RT Credentialing Requirements Treatment Modality Key Information Facility Questionnaire Knowledge Assessment Phantom Irradiation IGRT Verification Study X X X X X X X X If questionnaire was previously completed for another trial, update Section 2A of the existing questionnaire to add this trial number. The Knowledge Assessment Form will be available on the IROC Houston website at See Section 5.0 above describing phantom irradiation requirements for specific motion management techniques. Questions may be directed to IROC Houston. For details, see the RTOG website at px?study= Digital RT Data Submission to NRG Oncology Using TRIAD (10/5/15) TRIAD is the American College of Radiology s (ACR) image exchange application and it is used by NRG Oncology. TRIAD provides sites participating in NRG Oncology clinical trials a secure method to transmit DICOM RT and other objects. TRIAD anonymizes and validates the images as they are transferred. 26

27 TRIAD Access Requirements: Site physics staff who will submit images through TRIAD will need to be registered with The Cancer Therapy Evaluation Program (CTEP) and have a valid and active CTEP Identity and Access Management (IAM) account. Please refer to Section 5.0 of the protocol for instructions on how to request a CTEP-IAM account. To submit images, the site physics user must have been assigned the 'TRIAD site user' role on the relevant Group or CTSU roster. NRG Oncology users should contact your site Lead RA to be added to your site roster. Users from other cooperative groups should follow their procedures for assignment of roster roles. RAs are able to submit standard of care imaging through the same method. TRIAD Installations: When a user applies for a CTEP-IAM account with proper user role, he/she will need to have the TRIAD application installed on his/her workstation to be able to submit images. TRIAD installation documentation can be found on the NRG Oncology/RTOG website Core lab tab. This process can be done in parallel to obtaining your CTEP-IAM account username and password. If you have any questions regarding this information, please send an to the TRIAD Support mailbox at TRIAD-Support@acr.org. 5.3 Dry Run and Knowledge Assessment There is a required dry-run and knowledge assessment for both photons and protons for this protocol, which is in addition to the Facility Questionnaire and the credentialing requirements. This must be successfully completed prior to the enrollment of the first patient. Details for this dry-run/knowledge assessment can be found on the IROC Houston website at Regulatory Pre-Registration Requirements (10/5/15) This study is supported by the NCI Cancer Trials Support Unit (CTSU). Prior to the recruitment of a patient for this study, investigators must be registered members of a lead protocol organization. Each investigator must have an NCI investigator number and must maintain an active investigator registration status through the annual submission of a complete investigator registration packet (FDA Form 1572 with original signature, current CV, Supplemental Investigator Data Form with signature, and Financial Disclosure Form with original signature) to the Pharmaceutical Management Branch (PMB), CTEP, DCTD, NCI. These forms are available on the CTSU registered member web site: investigator_registration.htm. For questions, please contact the CTEP Investigator Registration Help Desk by at pmbregpend@ctep.nci.nih.gov. The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) application is a web-based application intended for use by both Investigators (i.e., all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates (i.e., all staff involved in the conduct of NCI-sponsored clinical trials). Associates will use the CTEP-IAM application to register (both initial registration and annual re-registration) with CTEP and to obtain a user account. Investigators will use the CTEP-IAM application to obtain a user account only. (See CTEP Investigator Registration Procedures above for information on registering with CTEP as an Investigator, which must be completed before a CTEP-IAM account can be requested.) An active CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications, including the CTSU members website. Additional information can be found on the CTEP web site at: 27

28 registration.htm. For questions, please contact the CTEP Associate Registration Help Desk by at IRB Approval Each investigator or group of investigators at a clinical site must obtain IRB approval for this protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office before they can enroll patients. Study centers can check the status of their registration packets by querying the Regulatory Support System (RSS) site registration status page of the CTSU member web site by entering credentials at For sites under the CIRB initiative, IRB data will automatically load to RSS. Sites participating on the NCI CIRB initiative and accepting CIRB approval for the study are not required to submit separate IRB approval documentation to the CTSU Regulatory Office for initial, continuing or amendment review. This information will be provided to the CTSU Regulatory Office from the CIRB at the time the site s Signatory Institution accepts the CIRB approval. The Signatory site may be contacted by the CTSU Regulatory Office or asked to complete information verifying the participating institutions on the study. Other site registration requirements (i.e., laboratory certifications, protocol-specific training certifications, or modality credentialing) must be submitted to the CTSU Regulatory Office or compliance communicated per protocol instructions. Site registration forms may be downloaded from the RTOG-1308 protocol page located on the CTSU members web site. Go to and log in to the members area using your CTEP-IAM username and password Click on the Protocols tab in the upper left of your screen Click on the (state organization type e.g. P2C, CITN, NCTN Group name) link to expand, then select trial protocol, RTOG-1308 Click on the Site Registration Documents link Requirements for RTOG 1308 site registration: CTSU IRB Certification (for sites not participating via the NCI CIRB) CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the NCI CIRB) CTSU RT Facilities Inventory Form (if applicable) NOTE: Per NCI policy all institutions that participate on protocols with a radiation therapy component must participate in the Radiological Physics Center (RPC) monitoring program. For non-lead group institutions an RT Facilities Inventory Form must be on file with CTSU. If this form has been previously submitted to CTSU it does not need to be resubmitted unless updates have occurred at the RT facility. IRB/REB approval letter (for sites not participating via the NCI CIRB) IRB/REB approved consent IRB/REB assurance number renewal information as appropriate. 28

29 Submitting Regulatory Documents: Submit completed forms along with a copy of your IRB Approval and Informed Consent to the CTSU Regulatory Office, where they will be entered and tracked in the CTSU RSS. CTSU Regulatory Office 1818 Market Street, Suite 1100 Philadelphia, PA Phone: Fax: CTSURegulatory@ctsu.coccg.org (for regulatory document submission only) Checking Your Site s Registration Status: Check the status of your site s registration packets by querying the RSS site registration status page of the members section of the CTSU website. (Note: Sites will not receive formal notification of regulatory approval from the CTSU Regulatory Office.) Go to and log in to the members area using your CTEP-IAM username and password Click on the Regulatory tab at the top of your screen Click on the Site Registration tab Enter your 5-character CTEP Institution Code and click on Go 5.5 Registration OPEN Registration Instructions Patient registration can occur only after evaluation for eligibility is complete, eligibility criteria have been met, and the study site is listed as approved in the CTSU RSS. Patients must have signed and dated all applicable consents and authorization forms. Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access OPEN, the site user must have an active CTEP-IAM account (check at < >) and a 'Registrar' role on either the LPO or participating organization roster. All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient position in the Rave database. OPEN can be accessed at or from the OPEN tab on the CTSU members web site Prior to accessing OPEN site staff should verify the following: All eligibility criteria have been met within the protocol stated timeframes. Site staff should use the registration forms provided on the group or CTSU web site as a tool to verify eligibility. All patients have signed an appropriate consent form and HIPPA authorization form (if applicable). The OPEN system will provide the site with a printable confirmation of registration and treatment information. Please print this confirmation for your records. Further instructional information is provided on the OPEN tab of the CTSU members side of the CTSU website at or at For any additional questions contact the CTSU Help Desk at or ctsucontact@westat.com. In the event that the OPEN system is not accessible, participating sites can contact web support for assistance with web registration: websupport@acr.org or call the Registration Desk at (215) , Monday through Friday, 8:30 a.m. to 5:00 p.m. ET. The registrar will ask the site to fax 29

30 in the eligibility checklist and will need the registering individual s address and/or return fax number. This information is required to assure that mechanisms usually triggered by the OPEN web registration system (e.g. drug shipment and confirmation of registration) will occur. 6.0 RADIATION THERAPY (10/23/14) Notes: Both Intensity Modulated RT (IMRT) and 3D-Conformal Radiation (3DCRT) are allowed for photon planned cases. The proton centers should use their standard proton planning and delivery techniques in the respective center for proton treatment. See Section 5.2 for information on installing TRIAD for submission of digital RT data prior to enrolling patients. Protocol treatment must begin within 30 calendar days after registration and within 21 calendar days after simulation. Proton dose will be reported in Gy (relative biological effectiveness, RBE), where 1 Gy (RBE) = proton dose Gy x RBE, RBE = 1.1. Radiation doses shall be prescribed using the protocol specified definitions for igtv, ITV, and PTV. Proton treatment plans will be based upon scans obtained with a CT scanner for which the institution has defined an imaging protocol for protons which establishes the relationship between the CT number and the stopping power ratios. The pre-treatment PET or PET/CT study will be used to assist the treatment planning process. It is highly recommended that institution perform follow-up PET or PET/CT studies at 3 months after the completion of chemoradiation treatment. It is recommended that these studies be performed on the same equipment used for the pre-treatment study. These studies will not be collected. Institutions should archive this information for possible future collection. 6.1 Dose Specifications (10/5/15) Dose Prescription Patients in both proton and photon arms will receive treatments 5 days per week using 2 Gy (RBE) per fraction. RBE used will be 1.1 for protons and 1 for photons. The total prescribed dose will be 70 Gy (RBE) without exceeding tolerance dose-volume limits of all critical normal structures. (See Section when 70 Gy (RBE) is not achieved.) Dose distribution will be normalized to cover 95% of the PTV with the prescription dose. A volume of no more than 0.03 cc inside PTV should exceed 120% of the prescribed dose. 100% of the ITV (motion-incorporated CTV) must be covered by the prescription dose Acceptable Variations and Unacceptable Deviations From the Prescription Dose Per Protocol: See Section Variation Acceptable: Deviations of this magnitude are not desirable but are acceptable for situations where a patient s geometry (target and critical structure positions within the body) makes treatment planning more challenging.. o 95% of the PTV is covered by 95% of the prescription dose, o A volume of no more than 0.03 cc inside the PTV exceeds 120% but not 125% of the prescribed dose; o The minimum PTV dose to a volume of 0.03 cc falls below 85% but not below 75% of o the prescription dose; Less than 100% of the ITV (motion incorporated CTV) is covered by the prescription dose but no less than 99% is covered. Deviation Unacceptable: A Deviation Unacceptable occurs when any of the Variation Acceptable dose limits stated above are not met. Dose distributions falling in this region are not acceptable, and plan modifications should be attempted to improve results. A Deviation 30

31 Unacceptable occurs when any of the Variation Acceptable dose limits stated above are not met Failure To Achieve 70 Gy (RBE) If the prescription dose of 70 Gy (RBE) cannot be achieved within the normal tissue constraints, the treatment plan must be submitted for pre-treatment review (See Section 6.8) Failure To Achieve 60 Gy (RBE) If the prescription dose of at least 60 Gy (RBE) cannot be achieved within the normal tissue constraints, the treatment will be deemed Deviation Unacceptable. 6.2 Technical Factors [Equipment, Energies] Photon beam energies of 6-10 MV may be used. IMRT or 3DCRT may be used, but IMRT is strongly preferred. IMRT may be delivered using multiple fixed fields employing dynamic multi-leaf collimator, helical arc therapy or volumetric modulated arc therapy using any of the commercially available delivery systems. Proton therapy may be delivered using passively scattered protons or using scanning beam. o Selected proton energies should be high enough to adequately provide target coverage. Range shifters may be used to make fine adjustment to the maximum proton range. o Both passive scattering and scanning beams may employ apertures and/or compensators, as appropriate, to shape the fields laterally and distally. 6.3 Simulation, Immobilization, Motion Assessment, and Motion Management Simulation Motion assessment must be performed on all patients to determine the motion management technique (see Section 6.3.3) and the appropriate type of treatment planning CT required. A motion management technique-specific treatment planning CT (e.g., 4D, breath-hold, with ABC device, etc.) will be required during simulation to define gross tumor volume (GTV), clinical target volume (CTV), and planning target volume (PTV) (see definitions in Section 6.4). Contiguous CT slices, having no more than 3 mm thickness are to be obtained starting from the level of the cricoid cartilage and extending inferiorly through the entire liver volume. The field of view must be large enough so that none of the patient s anatomy along the path of the treatment beams is cut off. A CT scanner unit calibrated for proton treatments with the appropriate proton relative linear stopping power (RLSP) vs. HU conversion function shall be used for simulation of patients randomized to the proton arm. A treatment planning FDG PET/CT scan (or FDG-PET alone) with the patient in the treatment position is encouraged for treatment planning. In the case where the PET/CT is obtained in the treatment position, the CT from this study may be used as the planning CT scan. Intravenous contrast during the planning CT is optional provided a diagnostic chest CT was done with contrast to delineate the major blood vessels. If not, intravenous contrast should be given during the planning CT. If contrast is used, the densities should be over-ridden or the contrast scan must be registered to a non-contrast scan for planning purposes Immobilization Patients will be positioned in a stable position capable of allowing accurate reproducibility of the target position. Positions uncomfortable for the patient should be avoided so as to prevent uncontrolled movement during treatments. A variety of immobilization systems customized to the participating institutions standard of practice may be used, including using an alpha-cradle or vac-bag. Stereotactic frames that surround the patient on 3 sides and large rigid pillows (conforming to patients external contours) may be used as indicated. 31

32 6.3.3 Motion Assessment and Motion Management Motion assessment is mandatory for this protocol. As a first step, it is required that each site quantify the specific target motion for each patient, so as to determine if management strategies are needed (motion management strategies are not needed for patients with endto-end target motion 10 mm). Instead, an ITV (see Section 6.4.1) can be developed for treatment planning and DVH analysis. Options for motion assessment include real time fluoroscopy (using either the treatment unit table when an IGRT system with fluoroscopy capability is available or a conventional simulator with fluoroscopy), or 4-D CT scanning. Examples of acceptable methods of accounting for tumor motion include: design of the target volume to cover the excursion of the lung primary cancer and nodes during breathing (the ITV approach ), active breathing control (e.g. Elekta ABC device), abdominal compression, active breath hold, free-breathing gating (e.g. with Varian RPM system), or gated breath hold. If the necessity of special respiratory management with a specific technique (e.g., ABC) is obvious to the treating physician, simulation CT specific to that technique must be acquired. The impact of motion and need for motion management will be assessed with 4D CT simulation combined with initial dose calculation for at least end inhale and end exhale phases. If dose constraints are met with the ITV approach (Section 6.4.1), no further motion management is needed. If dose constraints are not met, then one of the volume-reduction motion management approaches mentioned above must be employed before reducing the dose below 70 Gy. Note: If end-to-end tumor motion is > 10 mm (+/-5 mm relative to the mean position), the use of ITV approach is discouraged. 6.4 Target Definitions, Target Delineation, and Normal Anatomy Delineation (10/5/15) Target Definition GTV: Gross tumor volume, including the primary tumor and involved lymph nodes, is all known gross disease ( 1 cm short axis diameter) as demonstrated on the single phase planning CT, and modified as deemed necessary based on PET and other imaging studies. GTV of the nodal disease is all known gross nodal disease (>1 cm short axis diameter) as demonstrated on the single phase planning CT or smaller nodes considered PET avid, or otherwise suspicious clinically. igtv: GTV plus margin for tumor motion, which is the union of the GTVs on all respiratory correlated images, or the gross tumor volume contoured directly on maximum intensity projection (MIP) images. The delineated igtv will be compared with the actual position of the GTV on each of the respiratory correlated CTs and modified, if necessary, to encompass the extent of motion of the GTV (hence igtv). The igtv may also be modified as deemed necessary based on PET and other clinical studies that may better distinguish the true GTV from other near unit density tissues. (If a breath-hold technique is used, igtv is the union of the GTVs on 3 breath hold scans - see table below CTV: Clinical target volume is the subclinical involvement around the GTV. The CTV is the GTV plus an 8-mm margin for micro extensions of the tumor (CTV=GTV+8 mm) without extending into uninvolved organs, such as the esophagus, heart, or bone. ITV: ITV=iGTV+8mm Internal target volume is the union of the CTV plus motion or igtv plus 8 mm CTV. The ITV may equivalently be created in one of two ways: (1) by expanding the igtv by 8 mm to include subclinical microscopic disease without extending into uninvolved organs, such as the esophagus, heart, or bone; or (2) by combining all CTVs in all respiratory phases. This volume will be reviewed and edited according to patient s anatomy by the treating radiation oncologist, according to the prevailing current clinical practice standard. PTV: Planning target volume is ITV plus a margin to ensure that the prescribed dose is actually delivered to the ITV. This margin accounts for variations in treatment delivery, including variations in setup between treatments. The ITV is expanded isotropically by 5 mm to generate the PTV. The PTV, defined in this manner, is relevant to photon planning and for 32

33 plan evaluation for both protons and photons. For proton planning, the PTVs are beam specific and defined differently (see Section 6.5.3) Target Delineation The simulation CT scan images will be used for target delineation and treatment planning. The proper lung window should be used for target delineation in the lung parenchyma, and proper soft tissue window should be used to delineate the nodal disease. igtv should be contoured on the maximum intensity projection (MIP) images when 4D CT simulation is done. Or, the igtv should be created by combining the GTV contours delineated in inhale and exhale scans. Pretreatment PET/CT and/or contrast CT images should be fused with the simulation images to help target delineation Normal Anatomy Delineation (See The normal anatomy to be outlined on each CT image will include both right and left lungs, heart, brachial plexus for upper lobe tumors, esophagus and spinal canal. Liver and kidneys will also be contoured if these organs will be in the beam path. Lungs should be contoured on the average image of the 4D CT scans for free-breathing based treatments or the mid position of gated planning CTs for gated treatments, or on the selected breath-hold CT for breath-hold treatments. The heart should be contoured from its base to apex, beginning at the CT slice where the ascending aorta originates. The esophagus should be contoured from the bottom of the cricoid to the gastro-esophageal junction. The spinal canal should be contoured on each CT slice in the region included in the simulation scan Required Structures Standard Names for Digital RT Submission Note: All required structures must be labeled as listed in the table below for digital RT data submission. Resubmission of data may be required if labeling of structures does not conform to the standard DICOM name listed. The following table outlines the naming/definition of the various target volumes. igtv/itv/ptv are for the motion management scenarios as specified in the table below: Motion Management Scans Scan to be used for dose calculation 4-D CT simulation with free breathing 4-D CT simulation with free breathing gating 1 free breathing scan, 1 4D scan (10 imaging data sets) 1 free breathing scan, 1 4D scan (10 imaging data sets) AVG of all phases AVG of the beam-on phases (e.g %) Images from which the target volume contours are to be generated MIP or union of the GTVs of all phases used to generate gross tumor plus tumor motion=igtv, igtv+ CTV (8mm)=ITV ITV+5mm =PTV Union of GTVs contoured at each breathing phase while the beam will be on (e.g %) =igtv igtv+ CTV (8mm)=ITV 33

34 4D CT simulation with breath hold (with or without ABC) Repeat breath hold scan 3 times to assess reproducibility of the breath hold. Select one scan for dose calculation ITV+5mm =PTV Union of GTVs contoured at each breath hold scan =igtv igtv+ CTV (8mm)=ITV ITV+5mm =PTV The following table outlines the naming of the various normal and critical structures for submission to TRIAD. All structures must be submitted and labeled according to the specifications in the table below or resubmission will be required. This includes capitalization, spacing, etc. Please note: For Tumor Volumes, select the three appropriate tumor volumes required for your motion management technique selected for your patient as described in Section 6.1 and the above table. For Arms 1 and Arm 2 NOTE: For Tumor Volumes, you will contour and submit either GROUP A ( igtv, ITV, PTV) -or- GROUP B (GTV, CTV, PTV). You will choose either one group or the other for your tumor volume structures. GROUP A: TUMOR VOLUMES FOR 4DCT IS USED TO ENCAPSULATE ENTIRE BREATHING CYCLE VOLUME Gross Tumor Volume with motion Internal Target Volume Planning Target Volume igtv ITV PTV GROUP B: TUMOR VOLUMES FOR FREE BREATHING / ABDOMINAL COMPRESSION / ACTIVE BREATH HOLD / GATING MOTION MANAGEMENT TECHNIQUES Gross Tumor Volume Clinical Target Volume Planning Target Volume GTV CTV PTV CRITICAL STRUCTURES FOR ALL PLANS, as indicated Spinal Canal Right + Left Lung minus GTV (or igtv) Right Lung Left Lung SpineCanal Lungs Lung_R Lung_L 34

35 Esophagus Esophagus Brachial Plexus BrachialPlexus Required for upper lobe tumors Heart Heart Liver Liver *Required if in the beam path Right Kidney Left Kidney Kidney_R Kidney_L *Required if in the beam path *Required if in the beam path 6.5 Treatment Planning and Quality Assurance Target Contour Quality All contours and treatment plans for the first 3 proton cases and the first 3 photon cases from each participating institution will have pretreatment review by the protocol PIs or a radiation oncologist designee. Additional reviews for the first 3 cases for which adaptive replanning is necessary are required as well Planning Procedures Photons For IMRT (multiple fixed fields or arc therapy, see Section 6.2) or 3DCRT planning, the PTV will be treated with any combination of coplanar, non-coplanar, or dynamically arcing fields. Please refer to Section 5 above for credentialing requirements. For 3DCRT plans, forward planning with optimized beam orientation and shaping is expected. Margins to be used are stated in Section For protons, average of all scans used will be employed for dose calculations, compensator and aperture design and plan evaluation. However, individual phases may also be used for evaluating dose distributions Planning Procedures Protons Passively scattered proton therapy (PSPT) or scanned proton beams will be used for patients enrolled in the proton arm. For proton planning, each beam has an individual and unique PTV expansion from the ITV. In the plane perpendicular to the proton beam axis, the PTV expansion from the ITV is according to the method used for photons. However, along the direction parallel to the proton beam axis, the distal and proximal margins to expand the ITV will be computed using established algorithms based on range uncertainty of the beam. For multiple ITVs, the most distal edge of the collection of ITVs is assigned range uncertainty margin. To compensate for the perturbation of the proton dose distribution due to misalignment of the compensator and the anatomy, the compensator is smeared. The smearing radius will be calculated using the algorithms established at each participating institution (Moyers 2001). The compensator may be smoothed to reduce hot spots. A block margin must be assigned depending on the penumbra specific to the proton beam being used. Note that proton beam penumbra is a function of proton energy and the distance between aperture + compensator and patient s anatomy. It may vary significantly from one clinical situation to another. Note: While the treatment planning parameters, including distal and proximal margins, block margin and the smearing radius may be calculated based on published formulae, (Moyers 2001) they may be modified for the local machine characteristics and practice. Variation of magnitudes in these parameters from one institution to another is acceptable; however, the parameters selected must ensure specified target coverage and normal tissue sparing in the face of range and set up uncertainties Critical Structures Constraints Dose volume constraints for normal critical structures are given in the Table below. These dose values can be used as guidelines for constraining the optimization process during treatment planning, and they are also used for scoring each case for protocol compliance (see Section 6.6). 35

36 For superior sulcus tumor or upper lobe tumors where the brachial plexus is part of the target volume, the volume receiving 70 Gy (V70) can be as large as 10 cc with significant areas within receiving doses as high as 74 Gy. If any portion of cardiac structure is part of the planning target volume (PTV), respiratory gating or another technique to separate cardiac structures from the PTV and allowing the full prescription dose to be delivered should be the first step. Doses exceeding the limits of variation acceptable listed in the Table below will be considered a deviation unacceptable. Critical Structure Dose Constraints and Compliance Criteria Note: Must label structures per DICOM Standard Name as listed above. See Table in Section Per Protocol Variation Acceptable* Normal lung (right lung + left lung minus GTV) V20 37%; MLD 20 Gy (RBE); lung V5 60% V20 40 % or MLD 22 Gy (RBE); lung V5 65% Esophagus Brachial Plexus** Max dose: 74 Gy (RBE) 1cc of partial circumference V cc V cc V cc Max dose: 74 Gy (RBE) 1.5 cc of partial circumference V cc Spinal Cord*** V50 < 0.03 cc V52 < 0.03 cc Heart V30 50% V30 55% V45 35% V45 40% * Doses not meeting the Variation Acceptable limits will be classified as Deviation Unacceptable. ** See first bullet in the list just above the Table for exception to the values for this critical structure. *** See the last bullet in the list just above the Table for exception to the values for this critical structure. **** When this value cannot be achieved, treatment plans must be modified to move dose distribution hotspots away from the heart to avoid having the case scored as a Deviation Unacceptable. Also refer to the 3 rd bullet in Section Dose Distribution Calculations Dose matrix grid size must be 3 mm x 3 mm x 3 mm or smaller Plan Review and Evaluation For IMRT, traditional DVHs and dose distribution displays will be used for plan review and evaluation. DVHs will also be used for retrospective outcomes analyses. For proton planning, additional plan review procedures are required to ensure adequacy of dose distributions. o At a minimum, beam-by-beam review of dose distributions is required to ensure that CTV plus the lateral, distal and proximal margins are covered. For the ITV approach, adequacy of coverage in both end-inhale and end-exhale phases must be reviewed. o While it is understood that DVHs derived from composite dose distribution of all beams have limitations, they are to be used for plan evaluation for comparison of competing plans. o Robustness of dose distributions should be evaluated to ensure that the target and critical normal tissue constraints are not violated in the face of set-up and range uncertainties and breathing motion. 6.6 Compliance Criteria Compliance criteria for targets can be found in Section Compliance criteria for critical structures are found in the Table in Section

37 Target doses not meeting either the Per Protocol or the Variation Acceptable criteria are classified as Deviation Unacceptable and are considered non-compliant. Any of the critical normal tissue dose and dose-volume indices that are not Per Protocol or classified as Variation Acceptable will be considered non-compliant Missed Treatment Days/Elapsed Days Per Protocol: No missed treatments (other than holidays). Variation Acceptable: Total consecutive missed or interrupted treatments (not including holidays) 5 total days. Total elapsed time exceeding 7 weeks but less than 9 weeks will be considered Variation Acceptable. Deviation Unacceptable: Treatment break or missed treatments (other than holidays, weekends) >5 total days. Total elapsed time exceeding 9 weeks Temporary Unavailability of Proton Machine Patients randomized to the proton therapy arm may receive up to 5 fractions with photons in the event the proton machine is not available. 6.7 Treatment Delivery Image Guided Treatment Image-guided radiation therapy (IGRT), consisting of images and appropriate image alignment software tool, is required for both photon and proton treatments on this protocol. It is expected that investigators will be familiar with those concepts presented in the ASTRO IGRT White paper (Jaffray in press). Patients will be treated only on units with image guidance capabilities. Such units include ones with on-board imaging, CT-on-rails, or other dedicated imaging system for patient positioning. At a minimum, these units must include orthogonal x-ray imaging systems for patient positioning and employ software tools for image registration. To achieve compliance with the PTV expansions stated in the protocol, daily imaging is required. Image Guidance for IGRT (see Section 5.2.2): Daily image guidance of IGRT may be achieved using any one or more of the following techniques: o Orthogonal kilovoltage (KV) images, e.g. ExacTrac; on-board imagers (OBI) or similar systems; o Linear-accelerator mounted kv and MV conebeam CT images; o Linear-accelerator mounted MV CT images (e.g., Tomotherapy); The institution s procedure to register treatment day image dataset with the reference dataset should comply with the following recommendations: o Region-of-Interest (ROI) or clip box for fusion should be set to encompass the high dose PTV and adjacent vertebral bodies. (Note: The same strategy should be used for repeat CT scans required for verification, QA or replanning.) o If the fusion software allows the user to create an irregular ROI (e.g., ExacTrac), o treatment room objects seen on in-room X-rays should be excluded from the registration. Automatic (e.g., based on mutual information bone or soft tissue fusion) types of registration should be used; the result of the fusion must be visually checked for alignment of the target or bony structures, such as vertebral bodies when appropriate. Manual adjustments (using drag-and-drop capabilities) should be made when necessary. Following the registration, the translational and (if the appropriate technology is available) rotational corrections should be applied to the treatment couch. If all the variances are less than 3 mm, the treatment can proceed without correction. If one or more corrections are 3-5 mm, adjustment is necessary prior to treatment; however, re-imaging is not recommended. If one or more of the corrections are larger than 5 mm, the imaging can be repeated in addition to performing table/positioning adjustments. If orthogonal projection imaging is used for setup, this fact should be communicated to the therapists (i.e. bony anatomy or fiducial). The relationship between the image surrogate of internal anatomy and the soft tissue targets shall be verified, at a minimum, as part of the repeat CTs done for QA, verification or replanning. If in room CT is available but orthogonal projection X-ray imaging is used for daily setup, weekly verification of soft tissue with setup surrogate is recommended. 37

38 If in-room CT is used for daily setup, the setup surrogate needs to be communicated to the therapists (i.e. bony anatomy, GTV, or other). If, due to changing anatomy, a compromise must be made between multiple target structures, the therapists shall be guided by the treating physician as to the best compromise Mid-Course Repeat CT Scans to Adapt Radiotherapy to Anatomic Changes (10/5/15) Repeat CT acquisition In addition to the CT datasets obtained for initial planning of treatment, repeat CT scans will be performed to assess whether a patient requires modifications to their treatment plan due to anatomic changes. The initial simulation planning scan should be scheduled to occur as close as possible to the starting date and no more than 21 days prior to the estimated treatment start date. If the starting date is 14 days or more from the simulation date, a pretreatment verification CT scan is strongly recommended. Additional repeating studies must be obtained during the time the dose delivered is between Gy (during week 3 of treatment) and between 46-50Gy (during week 5 of treatment). Repeat CTs will be of the same type (4D, breath-hold, etc.) as the initial planning CT depending upon the motion management strategy being used. Determination of the need for replanning The repeat CT scan will undergo a rigid fusion with planning-ct and the targets from the original simulation scan and OARs will be transferred to the repeat CT scan. The same fusion technique used for daily IGRT (bone matching, soft tissue matching, drag-and-drop) will be used for image registration of the repeat CT scans. Rotational changes to the fusion should only be done if the institution has the equipment needed to implement this type of adjustment as part of its daily IGRT system. The GTV or igtv, spinal canal, lungs and other OARs will be reviewed by a physician and will be modified as needed. Any modifications to an OAR must be denoted by the structure name (see Table in Section 6.4.4) followed by the sequence number of the scan (1 for the 3 rd week repeat scan or 2 for the scan from the 5 th week of treatment, depending on which of the two repeat scans is currently being evaluated). GTV or igtv do not require modifications, unless they lie > 3mm outside the originally contoured GTV or igtv. GTV or igtv should be re-contoured if tumor regression develops within the previously contoured region, but the CTV (or ITV) and PTV should remain the same. Re-contouring may also be necessary if the GTV shifts relative to other anatomy or deforms. In this case the CTV should be adjusted to the new igtv/gtv + margin, and a new PTV should be created. Important note: Even though the GTV may shrink substantially during the course of radiotherapy, the CTV is assumed to retain its volume. Therefore, the CTV (or ITV) should not be reduced even if the GTV or igtv has regressed in the repeat CT scans. The assumption is that there is likely to be microscopic disease present where GTV or igtv was initially positioned. The CTV (or ITV) shape may change depending on changes in the surrounding anatomy. The beam configuration (beam directions, energies, SOBPs, weights, compensators, apertures, etc.) from the previously approved treatment plan will be transferred to the repeat CT and appropriately weighted for the already delivered dose, the dose distribution will then be recalculated for the projected continuation of treatment, and a new set of DVHs will be created for the OARs and target structures. The technique used to generate the plan for continuation of treatment is described in detail below. Verification plan and replanning (adaptive planning) For planning purposes, the institution is expected to generate verification treatment plans that will not be submitted for review. A verification plan is a plan with dose distribution computed using a new repeat CT dataset and the original (current beam) configuration to verify whether the dose distribution is still acceptable. When unacceptable differences are detected, an adaptive plan must be generated and submitted for review as described here. An adaptive plan is a new plan designed to meet the specified criteria. It will very likely have a different beam configuration. 38

39 The treating physician should evaluate the verification plan and decide on the need of replanning. When there is an unfavorable change in dose distribution to an OAR or target in the verification plan, every effort is made to restore the DVH for that structure to the previous/original plan's DVH. At times this is not achievable, but that is the goal of replanning. The following steps should be taken to evaluate verification plans and create the adaptive plans: i. Use the original plan on the original scan to full prescription dose as reference ii. Create the dose distribution from the original plan with the full prescription dose on the replanning scan. This is done to evaluate if there is any change in DVH on the replanning scan under the conditions where original beam configuration is used to deliver the full dose. iii. If replan is indicated, the institution must create an adaptive plan on the new scan with the remaining dose and this will be used to deliver the rest of the treatment or until another replan is indicated. iv. Submission of this plan will be for the full Rx dose and not just the remaining dose. See Sec for submission details. Target coverage: Replanning of a treatment plan based on under coverage of the target must be performed if the target coverage shows Deviation Unacceptable for the verification plan. OAR overdose: Replanning of a treatment plan based on higher doses to the OARs must be performed if the spinal canal D max (0.03cc)>52 Gy, lung V20>40%, or mean lung dose >22Gy. Inferior dose distribution compared with the original plan: Replanning of a treatment plan should be done when the verification plan is inferior to the original plan. For example, MLD 17 Gy in the verification plan when MLD was 12 Gy in the original plan in the event that the tumor becomes cavitary or had significant reduction causing overshooting into the normal lung. Another example would be proton overshoot to heart due to tumor regression. For other, less critical tissues, if the dose calculated with the original beam configuration to the new image indicates unacceptable deviation based on criteria specified in the Table in Section 6.5.4, replanning will be at the discretion of the treating physician. Dose distributions displayed on each of the modified plans are used for evaluation and delivery of the remainder of the treatments. The dose delivered to date is not considered in the design and optimization of the new plan. The new plan, on its own, should meet the specified target coverage and normal tissue criteria. For patients requiring adaptive plans, the following procedure is to be used to estimate the summed dose distributions. Beam configurations for the original and the adaptive replans used for treatments will be applied to the CT image of week 5, assumed to represent an average anatomy over the course of radiotherapy. The dose distributions computed for each of the configurations will be summed weighted according to the number of fractions each distribution used. All plans developed and used for treatments and the corresponding CT images will be submitted to IROC Philadelphia-RT Core Lab. NRG Oncology will not collect repeat CT study information when a replan is not necessary. Submission of DICOM RT Planning data NRG will not collect repeat CT study information when replanning was not performed. All treatment plans including any adaptive replans will be submitted for evaluation and scoring. Adaptive plans will be submitted for the full prescribed dose. These plans will be used to score the quality of the plan by comparing to the compliance criteria stated in the protocol. If the dose constraints cannot be met and scaling the prescribed dose to less than 70 Gy/GyE, the treatment plan should be scaled to this lower dose value. For example, if a treatment plan cannot meet the 70 Gy/GyE prescription dose and reducing the dose to 68 Gy/GyE is necessary, the initial and the adaptive plan each should be submitted for the full prescribed dose of 68 Gy/GyE. The initial plan will be submitted for 68 Gy/GyE and the adaptive plan will be submitted for 68 Gy/GyE). 39

40 6.7.3 Management of IGRT and Repeat CT Radiation Dose to the Patient According to the IGRT literature, estimates of patient dose per imaging study for different imaging systems vary considerably. The doses are in the range of 1 mgy for Cyberknife s and BrainLab s ExacTrac planar kv-systems and can be considered negligible compared with doses from MV portal imaging and kv and MV CT. The doses from helical MV cone-beam CT scan on a tomotherapy unit are estimated to be in range of 1 to 3 cgy for head and neck studies, similar to doses reported for kv cone beam CT on Elekta Synergy machine. The doses for MV cone beam CT are reported to be in range from 10 cgy for a pelvis study to 6 cgy for a head and neck study. Thus, the doses for 3D imaging systems are in the range from 1 to 6 cgy for head and neck imaging and can contribute from 0.5 to 3% to the daily dose of 2.0 Gy. These are small enough dose contributions that if there is only one imaging study done per treatment session, the dose does not need to be incorporated into treatment planning and 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 for patients with severe set up problems (e.g., requiring frequent corrections of more than 5 mm). It is recommended that patients demonstrating severe set up problems during the first week of treatment be moved to a treatment with larger margins. 6.8 R.T. Quality Assurance Reviews Pre-Treatment Review Pre-treatment reviews will be performed for the first 3 cases of proton treatment as well as the first 3 cases of photon treatment from each participating institution. Pre-treatment reviews will also be performed for the first 3 adaptive replans. When a facility partners with one or more outside facilities to provide the treatment modality not available at the enrolling institution, this facility will be required to submit their first 3 cases for pre-treatment review on behalf of the enrolling site. These reviews will be performed by the PI of the protocol (Zhongxing Liao, MD) or a radiation oncology co-chair. If the prescribed dose of 70 Gy (RBE) is not achievable If the prescription dose of 70 Gy (RBE) cannot be achieved within the stated normal tissue constraints, the treatment plan must be submitted for pre-treatment review Post-Treatment Review For cases not requiring pre-treatment review, the Radiation Oncology Co-Chairs, will perform an RT Quality Assurance Review after complete data for the first 20 cases enrolled has been received at NRG Oncology. The Radiation Oncology Co-Chairs will perform the next review after complete data for the next 20 cases enrolled has been received at NRG Oncology. 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 NRG Oncology, whichever occurs first. These reviews will be ongoing and performed remotely or at the NRG Oncology semi-annual meetings as needed. 6.9 Radiation Therapy Adverse Events All radiation therapy adverse events will be graded according to CTCAE, v. 4.0 (see Section 7). Treatment-related acute adverse event is defined as any side effect occurring within 90 days from the start of treatment. Treatment-related late toxicity is defined as any side effect occurring after or persisting beyond 90 days from the start of treatment. Radiation pneumonitis will be evaluated for 12 months after the start of radiation treatment. Also see Section 7.6 for treatment modifications for hematologic and non-hematologic toxicity Potential Adverse Events Reversible or permanent alopecia, bone marrow toxicity, skin reactions, pneumonitis, pleural effusion, fibrosis of the AORs in the path or radiation, esophagitis, odynophagia, dysphagia, and sometimes esophageal stricture are expected side effects of radiation therapy. Radiation-induced myocarditis or transverse myelitis rarely occurs at doses lower than 50 Gy Acute Esophageal Toxicities (AET) 40

41 Acute esophageal toxicities include esophagitis, odynophagia, dysphagia. Esophageal complaints are common with combined modality therapy. AET does not constitute a reason to interrupt or delay radiotherapy or chemotherapy provided oral intake is sufficient to maintain hydration. Patients should be advised to avoid alcoholic, acidic, or spicy foods or beverages. Viscous Xylocaine, Carafate, or other medications should be used for symptomatic relief. Quite often, narcotics may be required. Acute esophagitis may persist for 4-6 weeks. If grade 4 esophagitis occurs, all treatments including chemotherapy and radiation therapy should be put on hold until patient is stable enough to continue with the same or modified treatment. Esophagitis Grading System Please refer to CTCAE v.4 for the diagnosis and grading of esophagitis. Treatment should be interrupted for grade 4 or greater dysphagia or odynophagia. Acute esophageal toxicity, which typically can occur within 2 weeks of the initiation of treatment and manifests as dysphagia, odynophagia, reflux symptoms, etc. should be pharmacologically managed with the following approach and should be initiated at the first signs or symptoms of esophageal toxicity. Suggested Management of Radiation Esophagitis 1. Ketoconazole 200 mg PO q day OR Fluconazole 100 mg PO q day until the completion of radiation; 2. Mixture of 2% viscous lidocaine: 60 cc; Mylanta: 30 cc; sucralfate (1 gm/cc): 10 cc. Take cc PO q3-4 hrs prn. (Contraindications: patients taking Dilantin, Cipro, Digoxin); 3. Ranitidine 150 mg PO BID (or other H2 blocker or a proton pump inhibitor such as omeprazole) until the completion of radiation; 4. Grade 4 esophagitis: hold RT + chemotherapy until grade 2 or less. A significant portion of patients is expected to experience grade 2 esophagitis. Treatment of esophagitis varies with the severity of the patient s symptoms; for example, diet adjustment and narcotic management may be sufficient for grade 2 esophagitis. Nutritional support via gastric tube or jejunostomy tube may be initiated upon development of grade 3-4 esophagitis, per mutual preference of the treating physician and patient. Severe acute esophageal toxicity is defined as persistent grade 3 or higher esophageal toxicity occurring within 3 months of the start of radiation therapy, defined as severe dysphagia or odynophagia with dehydration or weight loss > 15% from treatment baseline, requiring a feeding tube, intravenous fluids for more than 3 consecutive days, or hyperalimentation. Grade 4 is defined as esophagitis causing life-threatening consequences, such as perforation, obstruction, or fistula formation. Grade 5 is severe esophagitis directly contributing to death. Persistent grade 3 esophageal toxicity is defined as esophageal toxicity dependent on a feeding tube, intravenous fluids, or hyperalimentation longer than 6 weeks after the completion of radiation therapy Changes in Pulmonary Function Tests Patients enrolled to this study are allowed to have some degree of impaired pulmonary function as measured by pulmonary function tests (PFTs), including Forced Expiratory Volume in 1 second (FEV1), Forced Vital Capacity (FVC), and Diffusing Capacity for Carbon Monoxide (DLCO). The Common Toxicity Criteria (CTCAE), v. 4 includes specified criteria for grading adverse events related to these PFT parameters under the system organ class of Investigations. The grading criteria for these 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 version 4 specified grading criteria for PFTs assumes that all patients have normal baseline pulmonary function. This assumption is not appropriate for this protocol enrolling patients with abnormal baseline function. 41

42 As a remedy to monitor treatment effects on PFTs, we will define a 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. We have defined 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 of 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 of baseline, and grade 5 will be death. This scheme is depicted in the Table below and graphically represented in the Figure below. 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 3 event in the original CTCAE, v. 4 criteria; however, under this 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. 42

43 Percent Predicted Pulmonary Toxicity Scale Grade Adverse Event FEV-1 Decline times the patient s baseline value < times the patient s baseline value < times the patient s baseline value <0.25 times the patient s baseline value Death Forced Vital Capacity Decline times the patient s baseline value < times the patient s baseline value < times the patient s baseline value <0.25 times the patient s baseline value Death DLCO Decline times the patient s baseline value < times the patient s baseline value < times the patient s baseline value <0.25 times the patient s baseline value Death PFT(FEV-1, FVC, DLCO) Decline Baseline Grade 1 Grade 2 Grade 3 Grade

44 6.10 Radiation Therapy Adverse Event Reporting (See Section 7.8) 7.0 DRUG THERAPY Concurrent chemotherapy treatment must begin within 24 hours of radiation therapy start. 7.1 Treatment Concurrent Chemotherapy Concurrent chemotherapy is one treatment course during the 7 weeks of radiotherapy. A single platinum-based doublet chemotherapy regimen is to be administered during radiotherapy. The choice of the chemotherapy regimen is at the discretion of the treating physician. One of the following recognized standard, protocol-allowed regimens must be given with radiation therapy: OR Paclitaxel (50 mg/m 2 ) intravenous over 1 hour followed by Carboplatin AUC = 2 mg/min/ml intravenous weekly (every 7 days) during radiotherapy (Belani 2005, NCCN 2012) Standard premedications with steroids, diphenhydramine, H2 receptor antagonist, and 5- HT3 receptor antagonist antiemetics must be administered per individual institutional guidelines. Etoposide (50 mg/m 2 /d) intravenous on days 1 to 5 and days 29 to 33 Cisplatin (50 mg/m 2 /d) intravenous on days 1, 8, 29, and 36 (Albain 2002, NCCN 2012) Standard premedications with steroids and 5-HT3 receptor antagonist antiemetics must be administered per individual institutional guidelines. Standard intravenous hydration ( 1.5 liters) must be administered in conjunction with cisplatin. Filgrastim and pegfilgrastim may not be used during concurrent chemoradiotherapy. Erythropoiesis-stimulating agents (epoetin alfa, darbepoietin alfa) may not be used during concurrent chemoradiotherapy. Chemotherapy dosing for all patients will be based on actual body weight, in accordance with ASCO guidelines (Griggs 2012). Chemotherapy scheduling modifications of +/- 48 hours are allowed due to weekends and holidays Consolidation Chemotherapy The treating physician will administer 2 cycles of consolidation chemotherapy 4-6 weeks after concurrent chemoradiotherapy has ended, only if patients receive concurrent carboplatin and paclitaxel with radiotherapy. Each cycle length is 21 days. The consolidation chemotherapy regimen is carboplatin and paclitaxel. Paclitaxel (200 mg/m 2 ) intravenous over 3 hours on day 1 Carboplatin at an area under the plasma concentration time curve (AUC) = 6 mg/min/ml intravenous on day 1 A second cycle of paclitaxel and carboplatin will be administered on day 22. Standard premedications with steroids, diphenhydramine, H2 receptor antagonist and 5- HT3 receptor antagonist antiemetics must be administered per individual institutional guidelines. Patients who receive concurrent cisplatin and etoposide with radiotherapy are not allowed to receive consolidation chemotherapy. 44

45 Filgrastim and pegfilgrastim may be used in accordance with ASCO guidelines during consolidation chemotherapy (Smith 2006). Erythropoiesis-stimulating agents (epoetin alfa, darbepoietin alfa) may be used in accordance with ASCO guidelines during consolidation chemotherapy (Rizzo 2010). Chemotherapy scheduling modifications of +/- 48 hours is allowed due to weekends, holidays, and other scheduling constraints. 7.2 Cisplatin Agent Information Refer to package insert for detailed pharmacologic and safety information Formulation Each vial contains 10 mg of DDP, 19 mg of sodium chloride, 100 mg of mannitol, and hydrochloric acid for ph adjustment. One vial is reconstituted with 10 ml of sterile water. The ph range will be 3.5 to 4.5. Cisplatin injection also is available from the manufacturer in aqueous solution, each ml containing 1 mg cisplatin and 9 mg NaCl and HCL or NaOH to adjust ph. Cisplatin also is available in vials containing 50mL or 100mL of a 1mg/mL solution Storage and Stability Reconstituted solution of cisplatin is stable for 20 hours when stored at 25 C and should be protected from light if not used within 6 hours. The vials and injection should not be refrigerated. Cisplatin has been shown to react with aluminum needles, producing a black precipitate within 30 minutes. Therefore, needles or intravenous sets containing aluminum parts that may come in contact with the drug must not be used for the preparation or administration of cisplatin Adverse Events Human toxicity includes nausea, vomiting, anaphylaxis, neuropathies, ocular disturbances, renal toxicity (with an elevation of BUN and creatinine and impairment of endogenous creatinine clearance, as well as renal tubular damage, which appears to be transient), ototoxicity (with hearing loss that initially is in the high-frequency range, as well as tinnitus), and hyperuricemia. Much more severe and prolonged toxicity has been observed in patients with abnormal or obstructed urinary excretory tracts. Myelosuppression, often with delayed erythrosuppression, is expected Supply Commercially available. The use of drug(s) or combination of drugs in this protocol meet the criteria described under Title 21 CFR 312.2(b) for IND exemption. 7.3 Etoposide Agent Information Refer to package insert for detailed pharmacologic and safety information Storage and Stability Store the unopened vials under refrigeration 2º to 8º C (36º-46º F). Retain in original package to protect from light Adverse Events Hematologic: Myelosuppression is dose related and dose limiting with granulocyte nadirs occurring 7 to 14 days after drug administration and platelet nadirs occurring 9 to 16 days after drug administration. Bone marrow recovery is usually complete by day 20. Acute myeloid leukemia has been reported in rare instances. Gastrointestinal: Nausea and vomiting are the major gastrointestinal toxicities. Nausea and vomiting can usually be controlled with standard antiemetic therapy. Hypotension: Transient hypotension following rapid intravenous administration has been reported in 1% to 2% of patients. It has not been associated with cardiac toxicity or electrocardiographic changes. No delayed hypotension has been noted. Allergic Reactions: Anaphylactic-like reactions characterized by chills, fever, tachycardia, bronchospasm, dyspnea and hypotension have been reported to occur in less than 1% of the patients treated with the oral capsules. These reactions have usually responded promptly to the 45

46 cessation of the drug and to the administration of pressor agents, corticosteroids, antihistamines or volume expanders as appropriate. One fatal acute reaction associated with bronchospasm has been reported. Alopecia: Reversible alopecia, sometimes progressing to total baldness was observed in up to 66% of patients. Other: The following adverse reactions have been infrequently reported: aftertaste, hypertension, rash, fever, pigmentation, pruritus, abdominal pain, constipation, dysphagia, transient cortical blindness, and a single report of radiation recall dermatitis Supply Commercially available. The use of drug(s) or combination of drugs in this protocol meet the criteria described under Title 21 CFR 312.2(b) for IND exemption. 7.4 Carboplatin Agent Information Refer to package insert for detailed pharmacologic and safety information. Refer to the package insert for additional information Formulation Carboplatin is available as a sterile lyophilized powder in single-dose vials containing 50 mg, 150 mg, or 450 mg of carboplatin. Each vial contains equal parts by weight of carboplatin and mannitol. Carboplatin also is available as a 10 mg/ml solution in 50, 150, and 450 mg vials Preparation When available, prediluted vials of carboplatin should be utilized. Otherwise, the preparation of carboplatin should proceed as described below: Immediately before use, the contents of a carboplatin vial must be reconstituted with either sterile water for injection, USP, 5% dextrose in water, or 0.9% sodium chloride injection, USP. The following shows the proper diluent volumes to be used to obtain a carboplatin concentration of 10 mg/ml: Vial size Diluent volume 50 mg 5mL 150 mg 15 ml 450 mg 45 ml Carboplatin reacts with aluminum to form a precipitate and cause a loss of potency. Therefore, needles or intravenous sets containing aluminum parts that may come in contact with the drug must not be used for the preparation or administration of carboplatin Storage and Stability Intact vials of carboplatin are stable for the period indicated on the package when stored at room temperature (15-30 C or F) and protected from light. When prepared as described above, carboplatin solutions are stable for 8 hours at room temperature if protected from light. The solution should be discarded after 8 hours since no antibacterial preservative is contained in the formulation Adverse Events Hematologic: Myelosuppression is the major dose-limiting toxicity. Thrombocytopenia, neutropenia, leucopenia, and anemia are common but typically resolve by day 28 when carboplatin is given as a single agent. Allergic Reactions: Hypersensitivity to carboplatin has been reported in 2% of patients receiving the drug. Symptoms include rash, urticaria, erythema, pruritus, and rarely bronchospasm and hypotension. The reactions can be successfully managed with standard epinephrine, corticosteroid, and antihistamine therapy. Desensitization per the allergy team is allowed. Neurologic: Peripheral neuropathies have been observed in 4% of patients receiving carboplatin with mild paresthesia being the most common. 46

47 Gastrointestinal: Nausea and vomiting are the most common gastrointestinal events; both usually resolve within 24 hours and respond to antiemetics. Other gastrointestinal events include diarrhea, weight loss, constipation, and gastrointestinal pain. Hepatic: Elevated alkaline phosphatase, total bilirubin, and SGOT have been reported. Other: Pain and asthenia are the most common miscellaneous adverse events. Alopecia has been reported in 3% of the patients taking carboplatin Supply Commercially available. The use of drug(s) or combination of drugs in this protocol meet the criteria described under Title 21 CFR 312.2(b) for IND exemption. 7.5 Paclitaxel Agent Information Refer to package insert for detailed pharmacologic and safety information Preparation Paclitaxel injection is a sterile solution concentrate, 6 mg/ml in 5, 16.7, and 50 ml vials (30, 100, and 300 mg/vial) in polyoxyethylated castor oil (Cremophor EL) 50% and dehydrated alcohol, USP, 50%. Paclitaxel will be diluted to a final concentration of 0.3 to 1.2 mg/ml in D 5 W, NS, or D 5 NS, in glass or polyolefin containers due to leaching of diethylhexphthalate (DEHP) plasticizer from polyvinyl chloride (PVC) bags and intravenous tubing by the Cremophor vehicle in which paclitaxel is solubilized. Each bag/bottle should be prepared immediately before administration. NOTE: Formation of a small number of fibers in solution (NOTE: acceptable limits established by the USP Particular Matter Test for LVPs) have been observed after preparation of paclitaxel. Therefore, in-line filtration is necessary for administration of paclitaxel solutions. In-line filtration should be accomplished by incorporating a hydrophilic, microporous filter of pore size not greater than 0.22 microns (e.g.: Millex-GV Millipore Products) into the intravenous fluid pathway distal to the infusion pump. Although particulate formation does not indicate loss of drug potency, solutions exhibiting excessive particulate matter formation should not be used Storage and Stability Paclitaxel vials should be stored between C (68-77 F). When prepared as suggested ( mg/ml), the solution is stable for 27 hours Adverse Effects Hematologic: Myelosuppression; Gastrointestinal: Nausea, diarrhea, vomiting, abdominal pain; Heart: Arrhythmias, heart block, hypertension; Neurological: Sensory and peripheral neuropathy; Allergy: Severe anaphylactic reactions; Other: Alopecia, fatigue, arthralgia, myopathy, myalgia, infiltration (erythema, induration, tenderness, rarely ulceration), hypotension, irritation to the injection site, mucositis Supply Commercially available. The use of drug(s) or combination of drugs in this protocol meet the criteria described under Title 21 CFR 312.2(b) for IND exemption. 7.6 Dose Modifications Dose Modifications During Concurrent Chemoradiotherapy With Weekly Carboplatin and Paclitaxel Hematologic Toxicity Absolute neutrophil count (ANC) and platelet count (plt) must be obtained within 72 hours prior to each dose of carboplatin and paclitaxel, except for on day 1, as specified in Appendix I. If ANC < 1000 or plt < 75,000, omit weekly carboplatin and paclitaxel. Restart weekly carboplatin and paclitaxel at same dose if ANC > 1000 and plt > 75,000. Doses that are omitted are not made up. 47

48 Dysphagia/Radiation Esophagitis If radiation is interrupted for grade 3 or 4 dysphagia or radiation esophagitis, hold weekly carboplatin and paclitaxel. If radiation is interrupted for grade 3 dysphagia or radiation esophagitis and radiation is to be restarted, it is the investigator s decision whether or not to restart chemotherapy. If the decision is made to restart chemotherapy in this setting, weekly carboplatin and paclitaxel must be dose reduced to 50%. If radiation is interrupted for grade 4 dysphagia or radiation esophagitis, do not restart chemotherapy even if radiation is restarted. Neurologic Toxicity Carboplatin and paclitaxel doses will be modified for neurologic toxicity: If grade 1 neurologic toxicity, no dose modification If grade 2 neurologic toxicity, reduce dose to 75%. If grade > 2 neurologic toxicity, hold chemotherapy until neurologic toxicity improves to grade 2, then either reduce dose to 50% or discontinue chemotherapy, at the physician s discretion. Renal Toxicity Carboplatin dose will be modified for renal toxicity. Serum creatinine must be obtained within 72 hours prior to each dose of weekly carboplatin, except for day 1. Serum creatinine is required within 10 days prior to day 1 carboplatin, as specified in Appendix I. If serum creatinine 1.5 mg/d, give full carboplatin dose. If serum creatinine > 1.5 mg/d, calculate creatinine clearance (Cockcroft-Gault formula). If calculated creatinine clearance is 50 ml/min give full carboplatin dose. If serum creatinine > 1.5 mg/d and calculated creatinine clearance is ml/min, reduce carboplatin dose to 50%. If serum creatinine > 1.5 mg/d and calculated creatinine clearance is 25 ml/min hold carboplatin dose. Reassess creatinine and creatinine clearance weekly. If creatinine clearance improves to > 25 ml/min, restart carboplatin at a dose of 50%. Neutropenic Fever [defined as temperature 38.3 C (101 F) and ANC < 500] If neutropenic fever occurs and the patient subsequently meets criteria for further chemotherapy, the doses are reduced to 75% Other Toxicities Not Defined Above If toxicities grade 2, then manage symptomatically, if possible, and retreat without dose reduction. If toxicities grade 3, the suspected drug should be withheld until resolution to grade 1 or baseline, if baseline was > grade 1, then reinstitute if medically appropriate and reduce dose to 50%. If carboplatin or paclitaxel doses are reduced, all future weekly doses are reduced Dose Modifications During Concurrent Chemoradiotherapy With Cisplatin and Etoposide Hematologic Toxicity As specified in Appendix I: ANC and plt must be obtained within 72 hours prior to day 29 chemotherapy. For day 1 and day 29 cisplatin and etoposide: If ANC 1250 and plt 100,000, give full dose If ANC < 1250 or plt < 100,000, hold chemotherapy and recheck ANC and plt in 1 week. If after a 1 week delay ANC 1250 and plt 100,000, give full dose. If after a 1-week delay ANC < 1250 or plt < 100,000, hold chemotherapy and recheck ANC and plt in 1 more week (total of a 2-week delay). If after a 2-week delay ANC 1250 and plt 100,000, reduce dose of chemotherapy by 25%. If after a 2-week delay ANC < 1250 or plt < 100,000, omit chemotherapy. For day 8 and day 36 cisplatin: 48

49 ANC and plt must be obtained within 72 hours prior to day 8 and 36 chemotherapy, as specified in Appendix I. If ANC 1000 and plt 75,000, give full dose If ANC < 1000 or plt < 75,000, hold chemotherapy and recheck ANC and plt in 1 week. If after a 1-week delay ANC 1000 and plt 75,000, give full-dose cisplatin. If after a 1- week delay ANC < 1000 or plt < 75,000, hold chemotherapy and recheck ANC and plt in 1 more week (total of a 2-week delay). If after a 2-week delay ANC 1000 and plt 75,000, reduce dose of cisplatin to 75%. If after a 2-week delay ANC < 1000 or plt < 75,000, omit the dose of cisplatin. Dysphagia/Radiation Esophagitis If radiation is interrupted for grade 3 or 4 dysphagia or radiation esophagitis, hold cisplatin and etoposide. If radiation is interrupted for grade 3 dysphagia or radiation esophagitis and radiation is to be restarted, it is the investigator s decision whether or not to restart chemotherapy. If the decision is made to restart chemotherapy in this setting, cisplatin and etoposide doses must be reduced to 50%. If radiation is interrupted for grade 4 dysphagia or radiation esophagitis, do not restart chemotherapy even if radiation is restarted. Neurologic Toxicity Cisplatin dose will be modified for neurologic toxicity: If grade 1 neurologic toxicity, no dose modification If grade 2 neurologic toxicity, reduce dose to 75%. If grade > 2 neurologic toxicity, hold cisplatin until neurologic toxicity improves to grade 2, then either reduce dose to 50% or discontinue cisplatin, at the physician s discretion Renal Toxicity Cisplatin dose will be modified for renal toxicity. Serum creatinine must be obtained within 72 hours prior to each dose of cisplatin, except for day 1. Serum creatinine is required within 10 days prior to day 1 cisplatin. See Appendix I. If serum creatinine 1.5 mg/d, give full cisplatin dose. If serum creatinine mg/d, calculate creatinine clearance. If calculated creatinine clearance is 50 ml/min give full cisplatin dose. If serum creatinine mg/d and calculated creatinine clearance is < 50 ml/min, omit cisplatin dose and recheck serum creatinine at next scheduled cisplatin dose. If creatinine is < 2.0 and creatinine clearance has improved to 50 ml/min, reduce cisplatin dose to 75%. If serum creatinine > 2.0 mg/d, omit cisplatin dose, and recheck serum creatinine at next scheduled cisplatin dose. If creatinine is < 2.0 and creatinine clearance 50 ml/min, reduce dose to 50%; otherwise continue to omit cisplatin dose, recheck serum creatinine again at next scheduled cisplatin dose, and follow the same guidelines. Neutropenic Fever [defined as temperature 38.3 C (101 F) and ANC < 500] If neutropenic fever occurs and the patient subsequently meets criteria for further chemotherapy, the doses are reduced by 25%. Other Toxicities Not Defined Above If toxicities grade 2, then manage symptomatically, if possible, and retreat without dose reduction. If toxicities grade 3, the suspected drug should be withheld until resolution to grade 1 or baseline; if baseline was > grade 1, then reinstitute if medically appropriate and reduce dose by 50%. If cisplatin or etoposide doses are reduced, all future doses are reduced Dose Modifications for Consolidation Chemotherapy With A Carboplatin and Paclitaxel Regimen 49

50 Hematologic Toxicity ANC and plt must be obtained within 72 hours prior to each dose of carboplatin and paclitaxel, as specified in Appendix I. If ANC 1500 and plt 100,000, give full dose If ANC < 1500 or plt < 100,000, hold chemotherapy and repeat ANC and plt in 1 week. If ANC 1500 and plt 100,000, give full dose. If ANC < 1500 or plt < 100,000, hold chemotherapy again and repeat ANC and plt in 1 week (total of a 2-week delay). If ANC 1500 and plt 100,000, give full dose; otherwise omit chemotherapy dose. Neurologic Toxicity Carboplatin and paclitaxel doses will be modified for neurologic toxicity: If grade 1 neurologic toxicity, no dose modification If grade 2 neurologic toxicity, reduce dose to 75%. If grade > 2 neurologic toxicity, hold chemotherapy until neurologic toxicity improves to grade 2, then either reduce dose to 50% or discontinue chemotherapy, at the physician s discretion. Renal Toxicity Carboplatin dose will be modified for renal toxicity. Serum creatinine must be obtained within 72 hours prior to each dose of carboplatin, as specified in Appendix I. If serum creatinine 1.5 mg/d, give full carboplatin dose. If serum creatinine > 1.5 mg/d, calculate creatinine clearance. If calculated creatinine clearance is 50 ml/min give full carboplatin dose. If serum creatinine > 1.5 mg/d and calculated creatinine clearance is ml/min, reduce carboplatin dose to 50%. If serum creatinine > 1.5 mg/d and calculated creatinine clearance is 25 ml/min hold carboplatin dose. Reassess creatinine and creatinine clearance weekly. If creatinine clearance improves to > 25 ml/min within 14 days, restart carboplatin at a dose of 50%. Neutropenic Fever [defined as temperature 38.3 C (101 F) and ANC < 500] If neutropenic fever occurs and the patient subsequently meets criteria for further chemotherapy, the doses are reduced to 75%. Other Toxicities Not Defined Above If toxicities grade 2, then manage symptomatically, if possible, and retreat without dose reduction. If toxicities grade 3, the suspected drug should be withheld until resolution to grade 1 or baseline; if baseline was > grade 1, then reinstitute if medically appropriate and reduce dose to 50%. If carboplatin or paclitaxel doses are reduced, all future doses are reduced. 7.7 Modality Review The Medical Oncology Co-Chair, Charles Lu, M.D., will perform a Chemotherapy Assurance Review of all patients who receive or are to receive chemotherapy in this trial. The goal of the review is to evaluate protocol compliance. The review process is contingent on timely submission of chemotherapy treatment data as specified in Section The scoring mechanism is: Per Protocol/Acceptable Variation, Unacceptable Deviation, and Not Evaluable. A report is sent to each institution once per year to notify the institution about compliance for each case reviewed in that year. Failure to deliver consolidative chemotherapy will be considered an acceptable variation. Dr. Lu will perform a Quality Assurance Review after complete data for the first 20 cases enrolled has been received at NRG Oncology. Dr. Lu will perform the next review after complete data for 50

51 the next 20 cases enrolled has been received at NRG Oncology. 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 NRG Oncology, whichever occurs first. 7.8 Adverse Events This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 for adverse event (AE) reporting. The CTCAE version 4.0 is located on the CTEP website at All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. Adverse events (AEs) that meet expedited reporting criteria defined in the table(s) below will be reported via the CTEP-AERS (CTEP Adverse Event Reporting System) application accessed via the CTEP web site at In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to , ext. 4189, for instances when Internet fails. Once internet connectivity is restored, an AE report submitted by phone must be entered electronically into CTEP-AERS. NRG Oncology is responsible for adverse event reporting to the FDA Adverse Events (AEs) Definition of an AE: Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product (attribution of unrelated, unlikely, possible, probable, or definite). (International Conference on Harmonisation [ICH], E2A, E6). [CTEP, NCI Guidelines: Adverse Event Reporting Requirements. February 29, 2012; Serious Adverse Events (SAEs) Serious adverse events (SAEs) that meet expedited reporting criteria defined in the table in section 7.9 will be reported via CTEP-AERS. SAEs that require 24 hour CTEP-AERS notification are defined in the expedited reporting table in section 7.9. Contact the CTEP-AERS Help Desk if assistance is required. Definition of an SAE: Any adverse drug event (experience) occurring at any dose 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. Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the pregnancy of a study participant must be reported via CTEP-AERS in an expedited manner Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) AML or MDS that is diagnosed as a secondary malignancy during or subsequent to treatment in patients on NCI/CTEP-sponsored clinical trials must be reported via the CTEP-AERS within 30 days of AML/MDS diagnosis. Secondary Malignancy 51

52 A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered a metastasis of the initial neoplasm. Three options are available to describe the event: Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML]) Myelodysplastic syndrome (MDS) Treatment-related secondary malignancy Any malignancy possibly related to cancer treatment (including AML/MDS) should also be reported via the routine reporting mechanisms outlined in each protocol. Second Malignancy A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a metastasis from the initial malignancy). Second malignancies require ONLY routine reporting via CDUS unless otherwise specified. 7.9 CTEP-AERS Expedited Reporting Requirements All serious adverse events that meet expedited reporting criteria defined in the reporting table below will be reported via CTEP-AERS, the CTEP Adverse Event Reporting System, accessed via the CTEP web site, Submitting a report via CTEP-AERS serves as notification to NRG Oncology and satisfies NRG Oncology requirements for expedited adverse event reporting. CTEP-AERS provides a radiation therapy-only pathway for events experienced that involve radiation therapy only. These events must be reported via the CTEP-AERS radiation therapy-only pathway. In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to NRG Oncology at , ext. 4189, for instances when Internet fails. Once internet connectivity is restored, an AE report submitted by phone must be entered electronically into CTEP-AERS. CTEP-AERS-24 Hour Notification requires that an CTEP-AERS 24-hour notification is electronically submitted within 24 hours of learning of the adverse event. Each CTEP-AERS 24-hour notification must be followed by an CTEP-AERS 5 Calendar Day Report. Serious adverse events that require 24 hour CTEP-AERS notification are defined in the expedited reporting table below. Supporting source document is not mandatory. However, if the CTEP-AERS report indicates in the Additional Information section that source documentation will be provided, then it is expected. If supporting source documentation accompanies an AdEERS report, include the protocol number, patient ID number, and CTEP-AERS ticket number on each page, and fax supporting documentation to the NRG Oncology dedicated SAE FAX, A serious adverse event that meets expedited reporting criteria outlined in the following table but is assessed by the CTEP-AERS System as expedited reporting NOT required must still be reported to fulfill NRG Oncology safety reporting obligations. Sites must bypass the NOT Required assessment; the CTEP-AERS System allows submission of all reports regardless of the results of the assessment. CTEP defines expedited AE reporting requirements for phase 2 and 3 trials as described in the table below. Important: All AEs reported via CTEP-AERS also must be reported on the AE section of the appropriate case report form (see Section 12.1). 52

53 Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events that Occur on Studies Utilizing Commercial Drug within 30 Days of the Last Administration of the Commercial Drug 1, 2 FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are considered related to the investigational agent(s)/intervention (21 CFR ) An adverse event is considered serious if it results in ANY of the following outcomes: 1) Death 2) A life-threatening adverse event 3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for 24 hours 4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 5) A congenital anomaly/birth defect. 6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR ; ICH E2A and ICH E6). ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-AERS within the timeframes detailed in the table below. Hospitalization Resulting in Hospitalization 24 hrs Not resulting in Hospitalization 24 hrs Grade 1 Timeframes Not required Grade 2 Timeframes 10 Calendar Days Grade 3 Timeframes 10 Calendar Days Grade 4 & 5 Timeframes 24-Hour 5 Calendar Days NOTE : Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR Expedited AE reporting timelines are defined as: o 24-Hour; 5 Calendar Days - The AE must initially be reported via CTEP-AERS within 24 hours of learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. o 10 Calendar Days - A complete expedited report on the AE must be submitted within 10 calendar days of learning of the AE. 1 Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have an attribution of possible, probable, or definite require reporting as follows: Expedited 24-hour notification followed by complete report within 5 calendar days for: All Grade 4, and Grade 5 AEs Expedited 10 calendar day reports for: Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization Grade 3 adverse events 2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half lives, rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote 1 above applies after this reporting period. Effective Date: May 5,

54 Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements The following are protocol specific exceptions to expedited reporting via CTEP-AERS. Report the following AEs in an expedited manner only if they exceed the grade in parentheses next to the AE: esophagitis (gr 2); dysphagia (gr 2); nausea (gr 3); vomiting (gr 3); dehydration (gr 3). Routine adverse event reporting on the case report form fulfills safety reporting requirements for these events at the aforementioned grades. 8.0 SURGERY Not applicable to this trial. 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 Filgrastim, pegfilgrastim, and erythropoiesis-stimulating agents (epoetin alfa, darbepoietin alfa) may be used in accordance with ASCO guidelines during consolidation chemotherapy (Smith 2006; Rizzo 2010). Per Section below, they are not permitted during concurrent chemoradiotherapy See Sections and7.1.2, for premedication regimens for chemotherapy administration. 9.2 Non-Permitted Supportive Therapy Filgrastim, pegfilgrastim and erythropoiesis-stimulating agents (epoetin alfa, darbepoietin alfa) may not be used during concurrent chemoradiotherapy TISSUE/SPECIMEN SUBMISSION (10/5/15) NOTE: Patients must be offered the opportunity to participate in the correlative components of the study, such as tissue/specimen submission. If the patient consents to participate in the tissue/specimen component of the study, the site is required to submit the patient s specimens as specified in Section 10.0 of the protocol. Note: Sites are not permitted to delete the tissue/specimen component from the protocol or from the sample consent Tissue/Specimen Submission The NRG Oncology Biospecimen Bank at the University of California San Francisco acquires and maintains high quality specimens from NRG Oncology trials. Tissue from each block is preserved through careful block storage and processing. NRG Oncology encourages participants in protocol studies to consent to the banking of their tissue. The NRG Oncology Biospecimen Bank provides tissue specimens to investigators for translational research studies. Translational research studies integrate the newest research findings into current protocols to investigate important biologic questions. In this study, it is strongly encouraged that tumor tissue and blood will be submitted to the NRG Oncology Biospecimen Bank for the purpose of specimen banking for future research Tissue Collection for Banking for Future Research (optional but strongly encouraged) The following must be provided in order for the case to be evaluable for the NRG Oncology Biospecimen Bank: One H&E stained slide per positive biopsy site (slide can be a duplicate cut stained H&E of the diagnostic slide (block); it does not have to be the diagnostic slide itself) A corresponding paraffin-embedded tissue block of the tumor (preferred; the block must match the H&E being submitted) or a 2-mm diameter core of tumor tissue, punched from the tissue 54

55 block containing the tumor with a punch tool and submitted in a plastic tube labeled with the surgical pathology number; or 10 unstained sections on adherent slides. Note: A kit with the punch, tube, and instructions can be obtained free of charge from the NRG Oncology Biospecimen Bank. Block or core must be clearly labeled with the pathology identification number and block number that corresponds to the Pathology Report. The submitted material must be from malignant tumor, not necrotic or fibrotic tissue. If the submitted material is reviewed and is not tumor, the site may be assessed a protocol violation A Pathology Report documenting that the submitted block or core contains tumor. The report must include the NRG Oncology and patient s case number. The patient s name and/or other identifying information should be removed from the report. The surgical pathology numbers and information must NOT be removed from the report A Specimen Transmittal Form clearly stating that tissue is being submitted for the NRG Oncology Biospecimen Bank; if for translational research, this should be stated on the form. The form must include the NRG Oncology protocol number and patient s case number Serum, Plasma, and Whole Blood for DNA Collection for Banking for Future Research (optional but strongly encouraged) The following materials must be provided to the NRG Oncology Biospecimen Bank: A Specimen Transmittal Form documenting the date of collection of the biospecimen; the NRG Oncology protocol number, the patient s case number, time point of study, and method of storage, for example, stored at -80 C, must be included Specimens will be collected per Section Storage Conditions for All Specimens Store frozen specimens at -80 C (-70 C to -90 C) until ready to ship. If a -80 C Freezer is not available: Samples can be stored short term in a -20 C freezer (non-frost free preferred) for up to one week (please ship out Monday-Wednesday only). OR: Samples can be stored in plenty of dry ice for up to one week, replenishing daily (ship out Monday-Wednesday only). OR: Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only Please indicate on Specimen Transmittal (ST) Form the storage conditions used and time stored Specimen Collection Summary (10/5/15) Specimens for Banking for Future Research (optional but strongly encouraged) Specimens taken from Collected when: Submitted as: Shipped: patient: Representative H&E stained slides of the primary tumor Pre-treatment H&E stained slide Pre-treatment Slide shipped ambient A paraffin-embedded tissue block of the primary tumor taken before initiation of treatment or a 2 mm diameter core of tissue, punched from the tissue block with a punch tool SERUM: 5-10 ml of whole blood in 1 red-top tube and centrifuge Pre-treatment 1) Pre-treatment; 2) During treatment: at 4 weeks after initiation of treatment; Paraffin-embedded tissue block or punch biopsy (must match the H&E slide being submitted). If site cannot provide block then 10 unstained slides are permitted as an alternative. Frozen serum samples containing a minimum of 0.5 ml per aliquot in 1 ml cryovials (five to Block or punch shipped ambient. Include a cold pack during warm weather. Serum sent frozen on dry ice via overnight carrier 55

56 PLASMA: 5-10 ml of anticoagulated whole blood in EDTA tube #1 (purple/ lavender top) and centrifuge Whole blood for DNA: 5-10 ml of anticoagulated whole blood in EDTA tube #2 (purple/lavender top) and mix 3) Post-treatment: at first follow-up visit after completion of concurrent chemoradiotherapy 1) Pre-treatment; 2) During treatment: at 4 weeks after initiation of treatment; 3) Post-treatment: at first follow-up visit after completion of concurrent chemoradiotherapy Pre-treatment Note: If site missed this collection time point they may collect whole blood for DNA at a later time point instead but must note this on the ST Form. eight) Frozen plasma samples containing a minimum of 0.5 ml per aliquot in 1 ml cryovials (five to eight) Frozen whole blood samples containing a minimum of 1 ml per aliquot in 1ml cryovials (three to five) Plasma sent frozen on dry ice via overnight carrier Whole blood sent frozen on dry ice via overnight carrier 10.6 Submit materials for Banking as follows: U. S. Postal Service Mailing Address: For Non-frozen Specimens Only NRG Oncology Biospecimen Bank San Francisco University of California San Francisco UCSF Box Sutter Street, Room S341 San Francisco, CA Courier Address (FedEx, UPS, etc.): For Trackable FFPE and ALL Frozen and Trackable Specimens NRG Oncology Biospecimen Bank San Francisco University of California San Francisco 2340 Sutter Street, Room S341 San Francisco, CA Questions: /FAX ; NRGBB@ucsf.edu 10.7 Reimbursement Please note that with the start of the new NCI National Clinical Trials Network (NCTN) Program, NCI funds for reimbursement for protocol-specified biospecimen materials will be distributed per the requirements/methods specified by the new NCTN Program. This information will be made available with the other registration materials in the Oncology Patient Enrollment Network (OPEN) portal system. OPEN will serve as the registration system for all patient enrollments onto NCIsponsored NCTN trials, including this study, which will be transitioned into the new Program from the NCI-sponsored Cooperative Group Clinical Trials Program Confidentiality/Storage (See the RTOG Patient Tissue Consent Frequently Asked Questions, for further details.) Upon receipt, the specimen is labeled with the NRG Oncology protocol number and the patient s case number only. The NRG Oncology Biospecimen Bank database only includes the following information: the number of specimens received, the date the specimens were received, documentation of material sent to a qualified investigator, type of material sent, and the date the specimens were sent to the investigator. No clinical information is kept in the database. 56

57 Specimens for banking will be stored for an indefinite period of time. If at any time the patient withdraws consent to store and use specimens, the material will be returned to the institution that submitted 11.0 PATIENT ASSESSMENTS 11.1 Study Parameters See Appendix I 11.2 Quality of Life/Cost-Effectiveness NOTE: Patients must be offered the opportunity to participate in the correlative components of the study, such as quality of life assessment. If the patient consents to participate in the quality of life (QOL) component of the study, sites are required to administer the baseline QOL and functional assessments prior to the start of protocol treatment, during treatment, and in follow-up per the Appendix I schedule Instructions for Administration of the Instruments Patients will be given the 4 instruments (MDASI-Lung, SOBQ, EQ-5D, and Medical Service Use Survey) to be completed in the clinic at specified visits per Appendix I. A research assistant will be available to answer any questions that the patients have and review the questionnaire for completeness. If the questionnaires are not complete, patients will be asked if they left out answering the question by mistake or because they did not wish to answer the question. If the former, patients will be asked to answer those questions; if the latter, patients would not be asked anything further. If a patient does not come in to clinic (and/or if requested), the questionnaires will be mailed to the patient. If the questionnaires have not been received in 2 weeks after the due date, another set will be sent to the patients, reminding them to complete the questionnaire. If the patient prefers, he or she will be interviewed by the research assistant over the telephone at that time Response Assessment (RECIST Criteria) Measurement of Response (10/5/15) Response will be evaluated in this study using the revised RECIST guideline, v. 1.1 [European Journal of Cancer. 45: , 2009]. See for further details. Response Criteria: Evaluation of Target Lesions Complete Response (CR): Partial Response (PR): Progressive Disease (PD): Stable Disease (SD): Disappearance of all target lesions; Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters 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 progressions). Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study 11.4 Criteria for Discontinuation of Protocol Treatment Progression of disease (Further treatment will be given at the discretion of the treating physician); Pregnancy; Protocol-specified adverse event that precludes continuation of treatment; 57

58 Any clinical adverse event, laboratory abnormality, or intercurrent illness that, in the opinion of the Investigator, indicates that continued treatment with all study therapy is not in the best interest of the patient; A delay in protocol treatment of greater than 21 days during the concurrent phase and more than 6 weeks in the consolidation chemotherapy phase; and Unacceptable toxicity; see Section 6.0 and Section 7.0 for further information. If protocol treatment is discontinued, follow up and data collection will continue as specified in the protocol DATA COLLECTION (10/23/14) This study will utilize Medidata Rave for remote data capture (RDC) of all data. Access to the trial in Rave is granted through the imedidata application to all persons with the appropriate roles in RSS. To access imedidata/rave, see Section 5.0 of the protocol. Each person responsible for data entry must be on the NRG Oncology roster in order to receive access to Medidata Rave. Upon initial site registration approval for the study in RSS (Regulatory Support System), all persons with Rave roles assigned on the appropriate roster will be sent a study invitation from imedidata (imedidata-notification@mdsol.com) to activate their account. To accept the invitation, site users must log into the Select Login ( using their CTEP-IAM user name and password, and click on the accept link in the upper right-corner of the imedidata page. Once an account is activated, elearning modules will be available for Rave RDC instructions. Please note, site users will not be able to access the study in Rave until all required Medidata and study specific trainings are completed. Trainings will be listed in the upper right pane of the imedidata screen. Users that have not previously activated their imedidata/rave accounts will also receive a separate invitation from imedidata to activate their account. Account activation instructions are located on the CTSU website, Rave tab under the Rave resource materials (Medidata Account Activation and Study Invitation Acceptance). Additional information on imedidata/rave is available on the CTSU website under the Rave tab at or by contacting the CTSU Help Desk at or by at ctsucontact@westat.com Summary of Data Submission (11/26/13) Adverse event data collection and reporting, which are required as part of every clinical trial, are done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using similar agents. Adverse events are reported in a routine manner at scheduled times during the trial using Medidata Rave. Additionally, certain adverse events must be reported in an expedited manner for more timely monitoring of patient safety and care. The following sections provide information about expedited reporting. For this trial the Adverse Events Form is used for routine AE reporting in Rave. For reporting of secondary cancers or other report forms available in Rave: Folder Registration via the OPEN System Enrollment When pushed into RAVE there will be 4 forms representing registration Form/Item Subject Enrollment Eligibility Checklist Step Information Treatment Assignment Demography 58

59 Baseline Baseline Labs Diagnostic Staging Exclusion Criteria Lymph Node Assessment Pathology Report Patient History (formerly known as the A5) Work Up RT Plan Upload Digital Data-(Upload of confirmation from TRIAD submission required) Concomitant Medications Concomitant Medication (only required if patient is taking concomitant medications) Concurrent Treatment RT Administration RT Treatment-if was radiation therapy given = yes Protocol Specific RT Questions Any Adverse Events? Adverse Events if any adverse events? = yes Carboplatin (if selected during registration) Paclitaxel (if selected during registration) Cisplatin (if selected during registration) Etoposide (if selected during registration) On Treatment Labs 01 (up to 11 additional weeks may be added by user if needed) End of Chemo/RT End of Chemo/RT (this form should be completed for all patients after their final day of concurrent Chemo/RT) Consolidation Treatment* Any Adverse Events? *Only appears if paclitaxel and carboplatin are selected during registration Year Week Follow-Up 3 Month Follow-Up 6 Month Follow-Up 9 Month Follow-Up 1 Year Follow-Up 18 Month Follow-Up 2 Year Follow-Up Years Year Follow-Up 4 Year Follow-Up 5 Year Follow-Up 6 Year Follow-Up 7 Year Follow-Up 8 Year Follow-Up 9 Year Follow-Up Adverse Events if any adverse events? = yes Carboplatin (consolidation) Paclitaxel (consolidation) On Treatment Labs 01 (up to 11 additional weeks may be added by user if needed) Any Adverse Events? Adverse Events if any adverse events? = yes Patient Contacted Follow-up - if Patient able to be Contacted = yes Disease Assessment- if Documented clinical assessment = yes New Primary Cancer- If New Primary Cancer= yes Non-Protocol Treatment- if non-protocol cancer therapy= yes Pulmonary Function Tests if PFTs performed = yes Primary Cause of Death If Vital Status = dead 59

60 10 Year Follow-Up CTEP-AERS CTEP-AERS Upload Form used by HQ to upload CTEP-AERS reports, sites have read only access to this folder/form Source Documentation Upload Source Documentation Upload used by sites in the event that source documentation needs to be uploaded to HQ Quality of Life Coversheets will Difficulty Swallowing Coversheet appear in the following folders if the Difficulty Swallowing* patient has consented to the EQ-5D Coversheet Quality of Life component: EQ-5D* Baseline MDASI-LC Coversheet Concurrent Treatment MDASI-LC* 4-8 Week Follow-Up Medical Service Use Coversheet 6 Month Follow-Up Medical Service Use Survey* 12 Month Follow-Up UCSD SOB Coversheet UCSD Shortness of Breath Form* *These quality of life forms only appear if the corresponding coversheet is submitted and was the patient questionnaire completed was answered as YES Summary of Dosimetry Digital Data Submission (10/5/15) (Submit to TRIAD; see Section 5.2 for account access and installation instructions)) Item Dosimetry Information ALL DIGITAL RT DATA REQUIRED IN DICOM format via TRIAD The initial and each adaptive plan used for treatment must be submitted, each one individually for the full prescription dose (see Sec for details) All plans developed and used for treatments and the corresponding CT images will be submitted. If replanning is done, each dataset used for treatment must be submitted at the full prescription dose, not the given dose. CT Files (NOTE: Per Section do not submit repeat CT study information when a re-plan is not necessary) Due Cases requiring Pre- Treatment review: Must submit prior to beginning RT for first 3 cases of each modality, including Initial, Adaptive and Composite planning data Cases for Post-Treatment review: Within one week of RT end RT Dose Files RT Plan Files RT Structure Files (must be labeled exactly as shown in Table in Section or resubmission will be required) Digital DVH data for all required tumor volumes and critical normal structures RTOG 1308 Datasheet, located on the RTOG website at 60

61 px?study=1308 (submit via TRIAD with Digital RT Data listed above) Upon submission of any digital data via TRIAD, complete an online digital data submission form (DDSI) located on the NRG Oncology/RTOG web site at dy=1308 Final Dosimetry Information Radiotherapy Form Protocol Specific Form Within 1 week of RT end Daily Treatment Chart Upload NOTE: ALL SIMULATION AND PORTAL IMAGES WILL BE STORED BY THE INSTITUTION AND ONLY SUBMITTED UPON REQUEST STATISTICAL CONSIDERATIONS 13.1 Primary Endpoint Overall survival (OS); failure defined as death due to any cause 13.2 Secondary Endpoints year progression-free survival (PFS); failure defined as occurrence of local or regional progression, distant metastases or death from any cause, whichever occurs first; The development of grade 3 or higher adverse events definitely, probably, or possibly related to treatment for the following adverse events within 1 year of concurrent chemoradiation therapy completion: Grade 3-5 Cardiac Disorders o Acute coronary syndrome o Atrial fibrillation o Atrial flutter o Conduction disorder o Pericardial effusion o Pericarditis o Restrictive cardiomyopathy Grade 4-5 Gastrointestinal Disorders o Dysphagia o Esophagitis o Esophageal fistula o Esophageal obstruction o Esophageal perforation o Esophageal stenosis o Esophageal ulcer o Esophageal hemorrhage Grade 3-5 Injury, Poisoning, and Procedural Complications o Dermatitis radiation o Fracture (to be limited to rib fractures only) Grade 3-5 Nervous System Disorders o Brachial plexopathy o Recurrent laryngeal nerve palsy o Myelitis Respiratory, Thoracic, and Mediastinal Disorders, Grade 3-5, except as noted below 61

62 o Atelectasis (grade 4-5 only) o Bronchopulmonary hemorrhage o Mediastinal hemorrhage o Pleural hemorrhage o Tracheal hemorrhage o Bronchial fistula o Pulmonary fistula o Bronchopleural fistula o Tracheal fistula o Hypoxia (provided grade 3 is worse than baseline) o Bronchial obstruction o Tracheal obstruction o Pleural effusion o Pneumonitis o Pulmonary fibrosis Grade 3-5 Skin and Subcutaneous Disorders o Skin ulceration (thorax only) Changes in Pulmonary Function Tests per the RTOG Pulmonary Toxicity Scale (see Section 6.9.3), Grade 3-5 o FEV1 decline o Forced Vital Capacity decline o DLCO decline Any Grade 5 Adverse Event Attributed to Treatment To compare the development of symptom burden and quality of life (QOL) as measured by the single esophagitis and shortness of breath items and the entire lung cancer module of the MD Anderson Symptom Inventory (MDASI-Lung), and the SOBQ, and the EuroQol (EQ-5D) derived health utility score; To compare cost-effectiveness outcomes between the 2 arms; To compare pulmonary function changes by treatment arms and response; To explore the most appropriate and clinically relevant technological parameters to ensure quality and effectiveness throughout radiation therapy processes, including imaging, simulation, patient immobilization, target and critical structure definition, treatment planning, image guidance and delivery Sample Size and Power Justification Treatment Comparison The sample size calculation will address the primary hypothesis that proton therapy will improve OS in stage II-IIIB NSCLC patients. The survival times are exponentially distributed with (at least approximately) constant hazards in both treatment arms. The proposed design is based on the primary hypothesis that the median OS will be improved from 21 months (monthly hazard λ=0.0330) with photon therapy, Gy (RBE), (Arm 1) to 28 months (monthly hazard λ=0.0248) with proton therapy, (RBE), (Arm 2), i.e., hazard ratio (HR) equals to 0.75, which translates to a 25% relative hazard reduction. The statistical power is set as 80% and the significance level is (1-sided). Using a group sequential design, a total of 390 deaths is required to detect a 25% relative hazard reduction. Three interim analyses will be performed when 25%, 50%, and 75% cumulative information for OS is available. A total of 504 analyzable patients are required to be accrued uniformly with 10 patients per monthly accrual and an additional 24 months of follow-up is needed to meet the required number of deaths. Guarding against up to a 10% ineligibility and lost to follow-up rate, the final targeted accrual for this study will be 560 cases. Given the potential impacts of treatment crossovers such as patient preferences or insurance denial, the rate of treatment crossovers will be closely monitored. The table below shows the impact for 5% and 10% crossover rates. The adjusted type 1 error, power, and additional accrual 62

63 time are derived by assuming the other original design parameters remain the same. NRG Oncology will discuss with NCI possible protocol amendments and feasibility of continuing the trial if the treatment crossover truly becomes an issue. Impacts of Crossover Crossover Rate Adjusted Hazard Adjusted Adjusted Type Adjusted Add. Accrual Arm 2 to 1 Arm 1 to 2 Arm 1 Arm 2 HR 1 Error Power Time (month) 0% 0% % 0 5% 5% % 8.5 5% 10% % 16 10% 5% % 15 10% 10% % Statistical Power for Quality of Life (QOL) Endpoint (10/5/15) Our primary QOL hypothesis is that, compared with patients receiving photon therapy (Arm 1), patients on the proton arm (Arm 2) will have less severe shortness of breath 6 months after the end of concurrent chemoradiation therapy (representing late adverse response to therapy), and that the differences in symptom ratings (based on MDASI shortness of breath item) between arms will be clinically meaningful. Patients are strongly encouraged to provide PRO/QOL assessments regardless of disease status (e.g., progression or stable). However, the primary QOL analysis of MDASI shortness of breath item will include patients only if they have provided symptom-assessment data at both baseline and 6 months post concurrent chemoradiation therapy without local or regional disease progression, as local or regional progression may confound the evaluation of shortness of breath and the corresponding comparison. Based on preliminary results from retrospective studies conducted at MDACC, as well as Cohen s widely used rules of thumb for interpreting the magnitude of difference (Cohen 1988), an effect size greater than 0.4 standard deviation (SD) in the MDASI-lung shortness of breath symptom is considered as clinically meaningful. This discussion is also very applicable to the MDASI-lung and specific symptom items as well as the UCSD SOBQ. Based on past RTOG trials, we expect about 70% patients (176 per arm) to consent to PRO-QOL data collection. Depending on the proportion of patients who become ineligible for QOL analysis (ineligible due to insufficient measurements, drop-out, disease progression, death etc.), the following table summarizes the powers to detect different effect sizes. Briefly, with sample sizes of 106, 123, and 144 (corresponding to 60%, 70%, and 80% evaluable (with both pre- and post-treatment assessments) rate among patients consenting to QOL) per treatment arm, we will have 82%, 87%, and 91% power to detect an effect difference of 0.4 between the two treatment groups at the significance level of 0.05 (2-sided) in the MDASI-lung shortness of breath item. Other comparisons in scores/subscales of the MDASI-Lung, as well as the UCSD SOBQ, may be evaluated similarly. These treatment comparisons will be considered exploratory for planning in nature, and no effort will be made to control for the overall significance level. Effect size detection in standard deviation Power of the Treatment Comparison at a Significance Level 0.05 (2-sided) Proportion of randomized patients with MDASI-Lung SOBQ (corresponding number of eligible patients per treatment arm) 60% (106) 70% (123) 80% (141) Randomization Patients will be enrolled and randomized 1:1 to either photon therapy (Arm 1) or proton therapy (Arm 2). The treatment allocation scheme described by Zelen (1974) will be used, as it balances patient factors other than institution. The following factors will be stratified Tumor stage (II, IIIA, IIIB); 63

64 Histology (squamous, non-squamous); Concurrent chemotherapy doublet type (carboplatin/paclitaxel, cisplatin/etoposide) Patient Accrual RTOG 0617 (phase III trial for stage IIIA/B NSCLC) accrued approximately 130 patients per year, or 11 patients per month. With the increasing interests and number of proton centers available in United States, the monthly accrual rate is projected to be 10 patients and the trial is projected to accrue uniformly in 56 months. During the first 6 months following activation, little accrual is anticipated while the trial is being approved by institutional review boards (IRBs). If the total accrual during months 13 through 18 of the study is 20% of the targeted accrual ( 2 cases per month) the protocol will be discontinued per NCI-CTEP accrual guidelines for phase III studies. If the total accrual is between 21% and 49%, the protocol will continue to accrue subject to approval of the NRG Oncology Data Monitoring Committee (DMC) and NCI-CTEP. If the trial remains open to accrual, the study must accrue at least 50% of targeted accrual (> 5 cases per month) during months 22 through 24 to remain open beyond 2 years Statistical Analysis Plan Overall Survival The primary analysis will be performed on an intent-to-treat basis, such that all eligible cases will be included in the treatment arm to which they were randomized regardless of what treatment the patients actually received. Patients who cannot receive 60 Gy will be included, while ineligible patients or patients who withdrew consent to participate before receiving any protocol treatment will be excluded. OS will be measured from the date of randomization to the date of death or the last follow-up date on which the patient was reported alive. OS rates will be estimated using the Kaplan-Meier method (1958), and the differences between arms will be tested using a stratified log-rank test by adjusting for stratification factors (Mantel 1966). A multivariate analysis with the Cox proportional hazard model (1972) for OS will be performed with the stratification variables as fixed variables to assess the treatment effect adjusting for patient-specific risk factors. Proportional hazard assumptions will be checked using different graphical or time-varying coefficients testing methods (Kalbfleisch 2002). If the data clearly do not support the proportional hazard assumption, other statistical models will be used to fit the data if applicable. A step-down procedure that consists of dropping the least significant covariates, one at a time, will be used to obtain a more parsimonious model Progression-Free Survival (PFS) PFS is defined as the time from randomization to disease progression or death of any cause, whichever occurs first. A rigorous definition of disease progression is provided in Section Due to the limitations of PFS in solid tumors (Bhattacharya 2009), efforts will be made to minimize any potential bias introduced in assessment during study conduct, and appropriate sensitivity analyses (FDA 2007) may be conducted accordingly to assure the robustness of analysis results. As both OS and PFS can be considered as time-to-event endpoints, the distribution of PFS will be similarly summarized using the product limit estimator developed by Kaplan and Meier (1958) by treatment arm. From the product limit estimates, median PFS, 2-year PFS as well as their 95% confidence intervals will be estimated. Comparisons between arms will be conducted using a log rank test. The Cox proportional hazards model will be used to estimate the hazard ratio and its 95% confidence interval of Arm 2 relative to Arm 1. Appropriate methods for competing risks will also be applied on other progression-related endpoints (e.g., distant metastasis, local-regional failure) when applicable; specifically, cumulative incidence functions (Kalbfleisch 2002) for estimation of cumulative cause-specific event probabilities with associated testing for differences (Gray 1988) as well as regression methods for cause-specific hazards (Kalbfleisch 1978) and subdistribution hazards underlying cumulative incidence functions (Fine 1999) may be applied accordingly for exploratory purposes Toxicity Endpoints 64

65 The analysis for reporting the initial results of treatment will be undertaken when each patient has been potentially followed for a minimum of 1 year from the end of concurrent chemoradiation therapy. Only patients that meet the eligibility requirements of this protocol and start protocol treatment will be included. Analyzable patients are defined as eligible patients who received any protocol treatment. The rate of treatment-related adverse events using NCI Common Terminology Criteria for Adverse Events (CTCAE, v. 4) and RTOG Pulmonary Toxicity Scale (see Section 6.9.3) will be reported with the frequency and severity (e.g., type, grade, and attribution) by arm. The analysis will be performed at the time of primary endpoint analysis. Logistic regression (Agresti 1990) will be used to model the distribution of adverse events with and without adjustment for covariates. Both unadjusted and adjusted odds ratios and the respective 95% confidence intervals will be computed and tested at a significance level of 0.05 (2-sided) Statistical Methods for Symptoms and Quality of Life The mean severity score changes for the MDASI-Lung item shortness of breath will be calculated. Comparisons between arms [photon (3DCRT/IMRT) versus proton] at 6 months after the end of chemoradiation will be made using the two-sample t-test. If the parametric assumptions are not met, the Mann-Whitney test will be used. Effect size will be calculated through dividing the difference between arms in mean score changes by the pooled standard deviation of the pretreatment score means. The mean score changes from different tools, including MDASI-lung scores and SOBQ, will be similarly calculated at baseline and key subsequent assessment time points, for the proton arm and photon arm separately. Among these tools and subscales, mean score changes of MDASIlung item sore throat at end of chemoradiation, as well as local symptoms (coughing, difficulty swallowing, pain) and systemic symptoms (fatigue, total symptom interference) at subsequent key time points, may also be examined and compared between the 2 arms (among the therapies). In addition, the relationship between high symptom burden and specific toxicities could be explored. Due to the exploratory nature, no multiplicity adjustment will be applied. For MDASI Shortness of Breath item and SOBQ, cases with local or regional progression are excluded for analysis purposes to avoid any potential confounding. Symptom worsening will be calculated as the difference of before and after CXRT (week 0 vs. week 6 for pain and sore throat, baseline vs. 6 months for lung symptoms) and the significance of the differences will be tested between the 2 arms using a paired t-test. The cumulative proportion of patients reporting symptom worsening in each chemoradiation technique will be plotted and compared among the 2 arms using the Kolmogorov Smirnov test (McLeod et al, 2011). A longitudinal analysis will also be conducted with a focus on the patterns of scores over time points (baseline, 6 weeks, 6 months, 12 months) of PRO instruments (MDASI-Lung and SOBQ). Following the descriptive statistics on assessments, repeated measures for analysis of covariance (ANCOVA) will be used on scores/subscales for the assessment measures, where time points are considered the within-patient factor and treatment groups is considered the between-patient factor (Diggle 1994). While scales for the individual instrument questions are quantitative, they represent ordinal values on a bounded range rather than continuous quantities. Nonetheless, in aggregate these approximate continuous distributions and appropriate transformations will be applied to improve consistency with model assumptions. The hierarchical analytic approach described below permits tests of omnibus hypotheses that control for multiple comparisons among time points and treatment groups. The analysis will be conducted as follows: (1) The ANCOVA model will be used to carry out an omnibus test of the hypothesis that there is a common mean score across time points within the treatment groups: H 0 : it = 65

66 i., where i = treatment group 1 or 2, t = time point (baseline and subsequent time points) and it is the mean score in treatment group i at time t. (2) If the hypothesis in (1) is rejected, individual comparisons of the post-radiation and subsequent scores will be conducted within treatment groups. Additional modeling and graphical methods to determine trends or patterns of change in scores over time points will be conducted. (3) The ANCOVA model will be used to carry out an omnibus test of the hypothesis that there is a common mean score at each time point among the treatments: H 0 : it =.t, where again it is the mean score in treatment group i at time t. (4) Assuming the result of the hypothesis test in (3) is significant (H 0 rejected), individual tests will be carried out to determine differences between treatment groups at specific time points. If there are no significant treatment differences identified in (3), an overall test of trend in scores can be aggregated over treatment groups. Additional modeling to characterize patterns of change over time will be conducted. Following the above analysis, the linear mixed model will also be used to analyze the symptom outcomes collected over time, taking into account potential confounding factors in addition to treatment groups and time. This analysis could be done when all time points of PRO data have been collected in a desired study period, either in the acute phase or in long-term follow-up. Patient participation in the QOL component is not mandatory in this study, but sites must offer all patients the opportunity to participate. If patients agree to participate in this component, patients adherence to the component assessment schedule will be encouraged through reminders sent to the patient from participating institutions. Completion of all scheduled assessments is part of the routine delinquency assessment for institutions with patients participating. The Statistics and Data Management Center staff will monitor the proportions of missing quality of life information in each treatment arm at different assessment points. In spite of these efforts, missing data is to a certain extent expected. The information from patients with missing data will be reviewed to determine whether the data analyses will be biased. Patients with missing data will be reviewed for the distributions of treatment arms and patient characteristics (patient exclusion is not considered as missingness). Mean scores by assessment time for cohorts stratified by baseline score quartile will also be compared to investigate if the missingness is consistent with an ignorable missing data process (missing at random). If a missing-at-random (MAR) mechanism is reasonable, the data will be analyzed with appropriate likelihood-based analysis methods such as linear mixed effect models. If a missing-at-random (MAR) mechanism is suspected, multiple imputations for missing values and sensitivity analyses will be conducted to control for the potential bias. The possible strategies for imputation and analyses will depend on the severity of the missing data problem and may include: worse-case scenario, use of mean response for individuals who withdraw from the trial from either all or similar (matched) patients remaining in the trial, last observation carried forward, or multiple imputations. The data can also be analyzed using pattern mixture models to estimate separate estimates for the outcome within strata based on the missing data pattern, and then combining estimates in a specialized way to yield an appropriate overall effect estimate (Little 2002). Sensitivity analyses based on the varying assumptions about the missing data mechanisms will also be conducted. Quality-adjusted survival can be defined by the weighted sum of different time episodes added up to a total quality-adjusted life-year [U= sum of quality (qi) of health states K times the duration (si) spent in each health state] (Glasziou 1990): U K i 1 q i s i 66

67 The area under the EQ-5D curve yields predicted Quality-Adjusted Life Years (QALYs) (Glick 2007). QALY differences of 0.03 are considered important, and QALY differences of as little as 0.01 are considered potentially meaningful and important for several prevalent diseases, including cancer, diabetes, and heart disease (Samsa 1999; Walters 2003). We will use Glasziou s multiple health-state (Q-TwiST) models to use the repeated measures of EQ-5D. Because Glasziou s method incorporates longitudinal QOL data into an analysis of qualityadjusted survival, the health state model must be constructed on the following assumptions: A1) QOL is independent from treatment. A2) A health state is independent from previous states. A3) Proportionality of quality-adjusted duration and duration of the actual state of health Assumption A1 can be checked by plotting QOL scores over time according to treatment, and the t-test can be used to compare the mean QOL scores of each treatment arm. Assumption A2 can be checked by comparing the QOL scores for patient groups in a given health state where the groups are defined by duration of previous health state experience using a regression model. A suitable check for assumption A3 at a minimum would be a simple plot. If data do not support these assumptions, we will use a method that uses the longitudinal QOL data directly. We will use the 5-item utility score in EQ-5D for the cost-utility analysis. We will use the Z-test to test the hypothesis that the cost-utility in the 2 treatment arms is the same at 1 year after initiation of treatment with a significance level of 0.05 (2-sided). The remaining time points at which the EQ- 5D is collected will also be assessed using similar longitudinal analysis techniques as described for the other QOL endpoints Statistical Methods for Cost-Effectiveness Analysis Only direct medical costs will be estimated. These fall into 3 categories: 1) initial therapy costs; 2) costs of managing the most common side effects as determined by this study; and 3) costs of managing recurrence. Costs for external beam radiotherapy will be determined using CPT coding and Medicare reimbursement rates. Cost of common management strategies of the most common side effects documented in this study will be estimated from regional costs per unit. Costs for managing recurrence will assume the following salvage therapies: second-line chemotherapy or biological therapy in selected patients, radiotherapy for cancer recurrence (e.g. whole-brain radiation for central nervous system recurrence), or hospice/supportive care depending on individual patient preference. We will make an attempt to estimate other medical costs including that of emergency room/inpatient admissions, radiology and laboratory tests, and subsequent medical management of treatment-related toxicity including medications (and RedBook costs) by polling patients at the same time points as above (pre-treatment, at 6 weeks, and at 3, 6, and 12 months posttreatment) regarding medical service use by utilizing a modification of the Medical Service Use Form being used to collect similar data in an active Massachusetts General/University of Pennsylvania trial of proton versus IMRT for localized prostate cancer that is being used ( The form is used to document utilization of specific medical services including inpatient hospitalizations, specialist physician visits, radiology/laboratory services, and homecare. As part of this analysis we will formulate a Markov model of cost-utility. We will take the societal perspective to assess the comparative effectiveness of photon versus proton radiation therapy in this randomized trial. Model cycles will be 3 or 6 months long, to coincide with the primary clinical trial s follow-up scheme. The model s primary outcome will be incremental cost-utilities expressed in dollars per quality-adjusted life year (QALY). We will run the primary model as a Monte Carlo probabilistic sensitivity analysis, in which each parameter (e.g., cost of treatment, cost of additional medical services utilized, probability of survival/death) is modeled based on its characteristics in the trial population. This modeling allows simultaneous variation in all model parameters and allows us to determine the confidence intervals around our model s results, expressed as an incremental cost utilities ratio (cost/qaly). 67

68 Acceptability curves will then be performed to determine, at a specified willingness to pay ICUR level, the percentage of simulations in which photon or proton radiation therapy is considered cost-effective for treating patients with inoperable stage II-III NSCLC PFT Change The descriptive statistics of changes in FEV1 and diffusion capacity before and after treatment will be reported by treatment arm and by response categories (complete response; partial response; stable disease; progressive disease). Linear regression will be used to model PFT changes with adjustment for treatment arms and possibly other baseline covariates, if applicable. The Grade 3-5 NRG Oncology Pulmonary Toxicity Scale (see Section 6.9.3) for PFT changes will be reported with the frequency and grade by arm. Logistic regression (Agresti 1990) will be used to model the distribution of the NRG Oncology Pulmonary Toxicity Scale by arms with and without adjustment for covariates. Both unadjusted and adjusted odds ratios between arms and the respective 95% confidence interval will be computed and tested at a significance level of Adherence to the PFT assessment schedule will be required, and reminders from participating institutions will be sent to patients to facilitate adherence. Similar to the QOL component, completion of all scheduled assessments is part of the routine delinquency assessment for participating institutions. The Statistics and Data Management Center staff will monitor the proportions of missing PFT information in each treatment arm at different assessment points. In spite of these efforts, missing data is to a certain extent expected. The information from patients with missing data will be reviewed to determine whether the data analyses will be biased. Patients with missing data will be reviewed for the distributions of treatment arms and patient characteristics. As described in Section , a missing data mechanism will be appropriately evaluated, and methods for assessing and adjusting the impacts of missing data will be adopted accordingly Interim and Final Analysis Special Interim Toxicity Analysis Treatment-related adverse events (AEs) experienced by patients on both arms will be closely monitored throughout the study. The following grade 3-5 (CTCAE, v. 4) treatment-related AEs occurring within 90 days after the start of chemoradiation defined as possibly, probably, or definitely related to treatment are of particular interest: Pneumonitis, esophagitis, dysphagia, esophageal ulcer, dermatitis radiation, pericarditis, pericardial effusion, brachial plexopathy, myelitis, recurrent laryngeal nerve palsy. An interim analysis of AEs is planned after 30 evaluable patients have been accrued and randomized to each arm and have been followed for a minimum of 90 days after the start of chemoradiation. Patients will be considered evaluable if they are eligible and receive at least 1 fraction of radiation. The interim analysis will include all of the specified unacceptable treatmentrelated AEs reported at the time of the interim analysis, and the interim analysis results for each arm will be discussed with the study chairs and CTEP accordingly to assure patient safety Special Interim Analysis for Treatment Completion Similarly, treatment completion rates of both arms will be closely monitored throughout the trial. An interim analysis of treatment completion rates is planned after 50 evaluable patients have been accrued and randomized to each arm. The interim analysis results will be discussed with the study chairs and CTEP accordingly to assure that treatment completion rates are balanced Interim Analysis for Early Termination and Reporting Interim treatment comparisons will be performed when we observe 25% (98 deaths), 50% (195 deaths), and 75% (292 deaths) of the 390 required maximum number of deaths. The 3 analyses will be done on an intent-to-treat analysis basis, with all eligible cases included in the treatment arm to which they were randomized regardless of what treatment the patients actually received. The primary endpoint, OS, will be tested in each interim analysis. A conservative upper superiority bound, based on a Lan-DeMets approximation to the O Brien-Fleming boundary 68

69 (DeMets 1994; O'Brien 1979) provides test critical values used in the sequential analyses and preserves an overall alpha level of (1-sided) for the study. An interim futility analysis will be based on the rule of Freidlin (2010), with a Linear 20% Inefficacy Boundary (LIB20). This rule provides the opportunity to terminate early for evidence that the experimental arm will not prove superior, but protects against aggressive early termination for treatment effect sizes smaller than planned. The following Table summarizes the interim efficacy/futility monitoring schedule with respect to the primary endpoint: Interim and Final Analysis for OS Analysis Projected Time (month) Percent Information Number of Events Efficacy boundary Futility boundary Z> P< Z< P> Interim % * 0.05* Interim % Interim % Final % Early look for detriment in experimental arm, left-tail p<0.05 will prompt stopping. At each protocol-planned interim analysis, the results from the test assessing the treatment efficacy and futility will be reported to the NRG Oncology Data Monitoring Committee (DMC). The responsible senior statistician may recommend early reporting of the results and/or stopping accrual (if applicable) of the trial if the critical value exceeds the specified boundary in a sequential design for either efficacy or futility. The accrual rate, treatment compliance, treatment safety, and the importance of the study are also considered in making such a recommendation. The results will be reported to the NRG Oncology DMC with the treatment blinded. The DMC will then make a recommendation about the trial to the NRG Oncology Group Chair Significance Testing for Final Analysis The major analysis will occur after at least 390 deaths have been observed, unless an early stopping rule is satisfied. It will include: Tabulation of all cases entered and those excluded from the analyses with the reasons for exclusion given; Distributions of important prognostic baseline variables; The frequencies and severity of AEs by treatment arms; Compliance rate of treatment delivery; Observed results with respect to the primary and secondary endpoints. All eligible patients randomized will be included in the comparison and will be grouped by assigned treatment in the analysis. The primary hypothesis of treatment benefit will be tested using the stratified log-rank statistic with a significance level of (1-sided), given that the 3 interim analyses will have been carried out. Additional analyses of treatment effect will be performed using the Cox proportional hazards model with the stratification factors included as fixed covariates, as well as any factors that show an imbalance between the arms Interim Analysis to Monitor Study Progress Phase III trials are required by NCI National Clinical Trials Network (NCTN) Guidelines to be reviewed by a data and safety monitoring committee. This study will be reviewed by the NRG Oncology Data Monitoring Committee (DMC) on a semi-annual basis, and an interim study summary report will be prepared twice per year accordingly until the initial study results have been presented to the scientific community. In general, the interim reports will contain information about the patient accrual rate, a projected completion date for the accrual phase, patient exclusion rates and reasons following registration, compliance rate of treatment delivery, 69

70 distributions of pretreatment characteristics and important prognostic baseline variables, and the frequencies and severity of treatment-related adverse events. The interim reports will not contain the results from the treatment comparisons with respect to the efficacy endpoints. In general, the interim reports will contain the following information: Patient accrual rate with a projected completion date (while the study is still accruing); Total patients accrued; Distributions of important pretreatment and prognostic baseline variables; The frequencies and severity of AEs by treatment arms; Compliance rates of treatment delivery CDUS Reporting This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. Cumulative CDUS data will be submitted quarterly by electronic means. Reports are due January 31, April 30, July 31, and October Gender and Minorities Projected Distribution of Gender and Minorities Gender Ethnic Category Females Males Total Hispanic or Latino Not Hispanic or Latino Ethnic Category: Total of all subjects Gender Racial Category Females Males Total American Indian or Alaskan Native Asian Black or African American Native Hawaiian or other Pacific Islander White Racial Category: Total of all subjects

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76 APPENDIX I STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS Assessments 90 d prior to registration 30 d prior to registration 14 d prior to registration 90 d prior to treatment start Histologically/ cytologically X proven NSCLC diagnosis AJCC staging 60 days Physical examination/ X performance status FDG-PET/CT 60 days MRI (preferred) or CT of 60 days brain w/ contrast FEV1 X DLCO X CBC/differential including X ANC, platelets, Hgb SGOT or SGPT X Total bilirubin X Serum creatinine or X calculated creatinine clearance Serum pregnancy test X Glucose, electrolytes, 30 d LDH, alkaline phosphatase, total protein, albumin, calcium, BUN, serum magnesium MRI of thorax Recommended* CT or MRI of abdomen, w/ Recommended* or w/o contrast Cardiac SPECT Recommended for pts w/ lower lung tumor when medically indicated* Quantitative lung Recommended ventilation/perfusion scan if FEV /- CT scan liters Bone scan Recommended* Pulmonary consultation Recommended* EKG and/or Recommended* echocardiogram Nutritional assessment HRQOL/Cost- Effectiveness Analysis (for consenting pts): MDASI- Lung, SOBQ, EQ-5D, Medical Service Use Survey Blood collection (for consenting pts) Paraffin-embedded tissue/slides collection (for consenting pts) *See Section 4.2. for details. Taken pre-treatment Taken pre-treatment Recommended if 10% below ideal body weight* X 10 d prior to treatment start X X 76

77 APPENDIX I (continued) (10/5/15) STUDY PARAMETER TABLE: ASSESSMENTS DURING TREATMENT During Concurrent Chemoradiotherapy During Consolidation Chemotherapy (for pts receiving carboplatin/paclitaxel) Physical examination Wkly Within 72 hours prior to day 1 of each cycle of chemotherapy Toxicity assessment Wkly Wkly CBC with differential (including ANC, hgb, plt) Within 72 hours prior to each dose of carboplatin and paclitaxel or each dose of cisplatin, except for day 1 chemotherapy. Within 72 hours prior to day 1 of each cycle of chemotherapy. Glucose, electrolytes, LDH, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, total protein, albumin, calcium, BUN, serum magnesium Serum creatinine: Pts receiving carboplatin/paclitaxel Pts receiving cisplatin/etoposide CT scan Blood collection (for consenting pts) HRQOL/Cost-Effectiveness Analysis (for consenting pts): MDASI-Lung, SOBQ, EQ-5D, Medical Service Use Survey Within 72 hours prior to each dose of carboplatin, except for day 1 carboplatin. Serum creatinine is required within 10 days prior to day 1 carboplatin. Within 72 hours prior to each dose of cisplatin except for day 1 cisplatin. Serum creatinine is required within 10 days prior to day 1 cisplatin. Must occur during the time the dose delivered is between Gy and between Gy. Wk 4 At 6 wks after initiation of treatment Within 72 hours prior to day 1 of each cycle of chemotherapy. Within 72 hours prior to each dose of carboplatin. Not applicable 77

78 APPENDIX I (continued) STUDY PARAMETER TABLE: ASSESSMENTS IN FOLLOW-UP Assessments At 4-8 weeks postchemo/rt end Every 3 months postchemo/rt end for 1 st year, every 6 months for 2 nd year, then annually Physical examination X X Toxicity assessment X X FDG-PET/CT CT Chest, upper abd with contrast or PET/CT FEV1 and DLCO At 3 months (Recommended *please see section 6.0 for further details) To 2 nd year At 6 and 12 months Blood collection (for consenting pts) HRQOL/Cost-Effectiveness Analysis (for consenting pts): MDASI-Lung, SOBQ, EQ- 5D, Medical Service Use Survey X X At 6 and 12 months 78

79 APPENDIX II 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 79

80 APPENDIX III: AJCC STAGING SYSTEM Edge, SB, ed. AJCC Cancer Staging Manual. 7 th ed. New York, NY: Springer; 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) 80

81 APPENDIX III (Continued) AJCC STAGING SYSTEM Edge, SB, ed. AJCC Cancer Staging Manual. 7 th ed. New York, NY: Springer; LUNG 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 Stage 0 Stage IA Stage IB Stage IIA Stage IIB Stage IIIA Stage IIIB Stage IV TX, N0, M0 Tis, N0, M0 T1a-b, N0, M0 T2a, N0, M0 T2b, N0, M0 T1a-b, N1, M0 T2a, N1, M0 T2b, N1, M0 T3, N0, M0 T1a-b, N2, M0 T2a-b, N2, M0 T3, N1-2, M0 T4, N0-1, M0 T1a-b, N3, M0 T2a-b, N3, M0 T3, N3, M0 T4, N2-3, M0 Any T, Any N, M1a-b 81

82 APPENDIX IV (10/5/15) Appendices for NRG Oncology Biospecimen Collection NRG Oncology FFPE Specimen Plug Kit Collection NRG ONcology Blood Collection Kit Instructions Shipping Instructions: U.S. Postal Service Mailing Address: For FFPE or Non-frozen Specimens Only NRG Oncology Biospecimen Bank San Francisco University of California San Francisco UCSF Box Sutter Street, Room S341 San Francisco, CA Courier Address (FedEx, UPS, etc.): For ALL Frozen or Trackable Specimens NRG Oncology Biospecimen Bank San Francisco University of California San Francisco 2340 Sutter Street, Room S341 San Francisco, CA Include all NRG Oncology paperwork in pocket of biohazard bag. Check that the Specimen Transmittal (ST) Form has the consent boxes checked off. Check that all samples are labeled with the NRG Oncology study and case number, and include date of collection as well as collection time point (e.g., pretreatment, post-treatment). FFPE Specimens: o Slides should be shipped in a plastic slide holder/slide box. Place a small wad of padding in top of the container. If you can hear the slides shaking it is likely that they will break during shipping. o FFPE Blocks can be wrapped with paper towel, or placed in a cardboard box with padding. Do not wrap blocks with bubble wrap or gauze. Place padding in top of container so that if you shake the container the blocks are not shaking. If you can hear the block shaking it might break during shipping. o Slides, Blocks, or Plugs can be shipped ambient or with a cold pack either by United States Postal Service (USPS) to the USPS address (94143) or by Courier to the Street Address (94115). Do NOT ship on Dry Ice. Frozen Specimens: o Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and clearly identified. If possible keep Serum, Plasma, and Whole Blood submissions in separate bags. o Place specimens and absorbent shipping material in Styrofoam cooler filled with dry ice (at least 7 lbs). There should be plenty of dry ice under and above the specimens. If the volume of specimens is greater than the volume of dry ice then ship in a larger Styrofoam box, or two separate boxes. Any Styrofoam box can be used, as long as it is big enough. o Specimens received thawed due to insufficient dry ice or shipping delays will be discarded and the site will be notified. o Send frozen specimens on dry ice via overnight courier to the address above. Specimens should only be shipped Monday through Wednesday to prevent thawing due to delivery delays. Saturday or holiday deliveries cannot be accepted. Samples can be stored frozen at -80 C until ready to ship. For Questions regarding collection/shipping please contact the NRG Oncology Biospecimen Bank by RTOG@ucsf.edu or phone: or Fax:

83 NRG ONCOLOGY FFPE SPECIMEN PLUG KIT INSTRUCTIONS This Kit allows sub-sampling of an FFPE block for submission to the NRG Oncology Biospecimen Bank San Francisco. The plug kit contains a shipping tube and a punch tool. Step 1 If the block is stored cold, allow it to equilibrate for 30 minutes at room temperature. Place the punch tool on the paraffin block over the selected tumor area. (Ask a pathologist to select area with tumor.) Push the punch into the paraffin block. Twist the punch tool once around to separate the plug from the block. Then pull the punch tool out of the block. The punch should be filled with tissue sample. Step 2 Label the punch tool with the study #, case #, pathology accession number and block ID. DON T remove specimen from the punch. Use a separate punch tool for every specimen. Call or us if you have any questions or need additional specimen plug kits. Step 3 Once punch tool is labeled, place in shipping tube and mail to address below. Please do not mix specimens in the same tube. We will remove core specimen from the punch, embed in a paraffin block, and label with specimen ID. *NOTE: If your facility is uncomfortable obtaining the plug but wants to retain the tissue block, please send the entire block to the NRG Oncology Biospecimen Bank and we will sample a plug from the block and return the remaining block to your facility. Please indicate on the submission form the request to perform the plug procedure and return of the block. Ship specimen plug kit, specimen in punch tool, and all paperwork to the address below. For Questions regarding collection/shipping or to order an FFPE Specimen Plug Kit, please contact the NRG Oncology Biospecimen Bank by NRGBB@ucsf.edu or call /Fax U.S. Postal Service Mailing Address: For Non-frozen Specimens Only NRG Oncology Biospecimen Bank University of California San Francisco UCSF Box Sutter Street, Room S341 San Francisco, CA Courier Address (FedEx, UPS, etc.): For ALL Frozen Specimens or Trackable shipments NRG Oncology Biospecimen Bank University of California San Francisco 2340 Sutter Street, Room S341 San Francisco, CA

84 NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS (10/5/15) This Kit is for collection, processing, storage, and shipping of serum, plasma, or whole blood (as specified by the protocol): Kit contents: Sites must provide their own blood collection tubes Twenty-five (21) 1 ml cryovials for pre-tx timepoint Thirty-two (32) 1 ml cryovials for other timepoints Biohazard bags (7) and Absorbent shipping material (7) 1 Styrofoam container (inner) and Cardboard shipping (outer) box for batch shipping UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers Specimen Transmittal (ST) Form and Kit Instructions PREPARATION AND PROCESSING OF SERUM, PLASMA AND WHOLE BLOOD: (A) Serum (if requested): Red Top Tube Label as many 1ml cryovials (5 to 8) as necessary for the serum collected. Label them with the NRG Oncology study and case number, collection date, time, and time point, and clearly mark cryovials serum. Process: 1. Allow one red top tube to clot for 30 minutes at room temperature. 2. Spin in a standard clinical centrifuge at ~2500 RPM for 10 minutes at 4 C (preferred). If sites are unable to process samples at 4 C then spinning at room temperature is acceptable if done within 2 hours of draw but must be noted on the ST Form. 3. Aliquot 0.5 ml serum into as many cryovials as are necessary for the serum collected (5 to 8) labeled with NRG Oncology study and case numbers, collection date/time, protocol time-point collected (e.g. pretreatment, post-treatment), and clearly mark specimen as serum. Indicate the volume on the vials if less than 0.5 ml. It is more important to have 0.5 ml per tube than ten tubes with variable amounts. 4. Place cryovials into biohazard bag and immediately freeze at -70 to -90 C, and store frozen until ready to ship. See below for storage conditions. 5. Store serum at -70 to -90 C until ready to ship on dry ice. See below for storage conditions. PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on the ST Form. (B) Plasma (If requested): Purple Top EDTA tube #1 Label as many 1ml cryovials (5 to 8) as necessary for the plasma collected. Label them with the NRG Oncology study and case number, collection date, time, and time point, and clearly mark cryovials plasma. Process: 1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. 2. Centrifuge specimen(s) within one hour of collection in a standard clinical centrifuge at ~2500 RPM for 10 minutes at 4 C (preferred). If sites are unable to process samples at 4 C then spinning at room temperature is acceptable if done within 2 hours of draw but must be noted on the ST Form.. 3. If the interval between specimen collection and processing is anticipated to be more than one hour, keep specimen on ice until centrifuging is performed. 4. Carefully pipette and aliquot 0.5 ml plasma into as many cryovials as are necessary for the plasma collected (5 to 8) labeled with NRG Oncology study and case numbers, collection date/time, time point collected and clearly mark specimen as plasma. Avoid pipetting up the buffy coat layer. Indicate the volume on the vials if less than 0.5 ml. It is more important to have 0.5 ml per tube than ten tubes with variable amounts. (continued on next page) 84

85 NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS (continued) 5. Place cryovials into biohazard bag and immediately freeze at -70 to -90 C. 6. Store frozen plasma until ready to ship on dry ice. 7. See below for storage conditions. PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on the STF. (C) Whole Blood for DNA (if requested): Purple Top EDTA tube #2 Label as many 1ml cryovials (3 to 5) as necessary for the whole blood collected. Label them with the RTOG study and case number, collection date/time, and time point, and clearly mark cryovials blood. Process: 1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. Blood can also be mixed for 5 minutes on a mixer at room temperature. 2. Carefully pipette and aliquot 1.0 ml blood into as many cryovials as are necessary for the blood collected (3 to 5) labeled with RTOG study and case numbers, collection date/time, time point collected and clearly mark specimen as blood. Indicate the volume on the vials if less than 1.0 ml. It is more important to have 1.0 ml per tube than five tubes with variable amounts. 3. Place cryovials into biohazard bag and freeze immediately at -70 to -80 Celsius. 4. Store blood samples frozen until ready to ship on dry ice. 5. See below for storage conditions. PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on ST Form. (continued on next page) 85