January NCCTG Protocol No: N0628 Opened: November 27, 2007 CALGB Protocol No: ECOG Protocol No: R0617

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1 January RTOG Protocol No: 0617 Protocol Status: NCCTG Protocol No: N0628 Opened: November 27, 2007 CALGB Protocol No: ECOG Protocol No: R0617 Title: A Randomized Phase III Comparison of Standard-Dose (60 Gy) Versus High-dose (74 Gy) Conformal Radiotherapy with Concurrent and Consolidation Carboplatin/Paclitaxel +/- (IND #103444) In Patients with Stage IIIA/IIIB Non-Small Cell Lung Cancer Patient Population: Newly diagnosed unresectable Stage III A or B non-small cell lung cancer. Patients with supraclavicular or contralateral hilar adenopathy are ineligible. Objectives: Primary: To compare the overall survival of patients treated with high-dose versus standard-dose conformal radiation therapy in the setting of concurrent chemotherapy. To compare the overall survival of patients treated with cetuximab versus without cetuximab in the setting of concurrent chemotherapy. Secondary: To compare progression-free survival (PFS) and local-regional tumor control between high-dose versus standard-dose radiation therapy and between concurrent cetuximab versus no cetuximab; To compare the toxicity of high-dose versus standard-dose conformal radiation therapy in the setting of concurrent chemotherapy with or without cetuximab; To investigate the prognostic and predictive effects of gross tumor volume on overall survival; To assess quality of life (QOL) between high-dose versus standard -dose conformal radiation therapy; To correlate outcomes (survival, toxicity, QOL) with biological parameters; To analyze the predictive value of pre-treatment SUV of PET scan in predicting survival, distant metastasis, and local-regional control in patients with stage III NSCLC treated with concurrent chemoradiotherapy with conventional radiation dose of 60 Gy and escalated dose of 74 Gy; To explore biological markers to predict clinical outcome including survival, distant metastasis, local-regional control, quality of life including toxicity in patients with stage III NSCLC treated with conventional dose (60 Gy) and high dose (74 Gy) radiation therapy in the setting of concurrent chemotherapy with or without cetuximab;. To prospectively collect and bank tissue specimen, blood and urine samples for future biomarker analyses in predicting clinical outcome including survival, distant metastasis, local regional control, and quality of life in patients with stage III NSCLC treated with conventional dose (60) Gy and high dose (74 Gy) radiation therapy in the setting of concurrent chemotherapy with or without cetuximab; To investigate associations between EGFR expression and toxicity, response, overall survival, and progressionfree survival.

2 January Schema: S T R A T I F Y RT Technique 1. 3D-CRT 2. IMRT Zubrod PET Staging 1. No 2. Yes Histology 1. Squamous 2. Non- Squamous R A N D O M I Z E Concurrent Treatment Arm A Concurrent chemotherapy: Carboplatin & Paclitaxel RT to 60 Gy, 5 x per week for 6 weeks Arm B Concurrent chemotherapy: Carboplatin & Paclitaxel, RT to 74 Gy, 5 x per week for 7.5 weeks Arm C Loading Dose: Week 1, Day 1 then Concurrent chemotherapy, Carboplatin & Paclitaxel, and RT to 60 Gy, 5 x per week for 6 weeks Arm D Loading Dose: Week 1, Day 1 then Concurrent chemotherapy, Carboplatin & Paclitaxel, and : Consolidation Treatment Arm A Consolidation chemotherapy: Carboplatin & Paclitaxel Arm B Consolidation chemotherapy: Carboplatin & Paclitaxel Arm C Consolidation therapy: and Carboplatin & Paclitaxel Arm D Consolidation therapy: and Carboplatin & Paclitaxel RT to 74 Gy, 5 x per week for 7.5 weeks Study Chairs: Radiation Oncology Patients entered through 11/02/09: Jeffrey Bradley, M.D. (Principal Investigator) RTOG Study 164 Hak Choy, M.D. RTOG RTOG 148 Ritsuko Komaki, M.D. RTOG CTSU 15 Jeff Bogart, M.D. CALGB NCCTG 1 William Blackstock, M.D. CALGB Steven Schild, M.D. NCCTG M. Christian Dobelbower, MD, Ph.D. ECOG Medical Physics Ken Forster, Ph.D. Quality of Life Benjamin Movsas, M.D. Jeff Sloan, Ph.D., HSR Medical Oncology Gregory Masters, M.D. George Blumenschein, MD Mark Socinski, M.D. Tien Hoang, MD Alex Adjei, M.D., Ph.D. Outcomes Research Joseph O. Deasy, Ph.D. Translational Research Joe Y. Chang, M.D., Ph.D. RTOG RTOG NCCTG RTOG RTOG CALGB ECOG NCCTG RTOG RTOG

3 January Statisticians: Kyounghwa Bae, Ph.D. [RTOG] Rebecca Paulus, B.S. [RTOG] Research Associate: Mary Gramkowski, R.N., B.A., C.C.R.P. [RTOG] Dosimetrist: Julie McIlvaine, R.T.(T.) [RTOG] Protocol Associate: Linda Walters-Page, M.A. [RTOG] I. Summary: This study opened November 27, Targeted accrual is 500 cases. Expected monthly accrual is 9 patients per month. This study was revised on October 14, 2008, to add two additional arms to evaluate the addition of cetuximab to both arms. As of November 2, 2009, 164 patients have been enrolled to this study, 33 of which were registered prior to the amendment. Adverse event data is shown in Section IV. There has been 2 grade 5 adverse event attributed to protocol treatment, a grade 5 dyspnea occurring on Arm A: 60 Gy 112 days after the start of protocol treatment, and a grade 5 thrombosis occurring on Arm D: 74 Gy + 83 days after the start of protocol treatment (Table 4.2). The numbers in the adverse events (AEs) category frequency tables in Section IV represent the number of patients that experienced that grade AE for a particular category; patients are only counted once for each category using their highest grade experienced. In the listings of AE terms, all AEs of a specified grade or higher are listed by category and term; the days from start of treatment represent the first occurrence of the highest grade reported for that particular AE term. For example, if a patient experienced grade 3 dehydration and grade 4 diarrhea, both of which are in the GI category, this patient would be represented in the grade 4 column of the category main table; however, in the listing of AE terms, both the grade 3 dehydration and grade 4 diarrhea would be listed for this patient (if the listing was for grade 3 or higher). II. Administrative Information: Table 2.1 Patient Accrual Study sample size 500 Total patients entered through November 2, Average monthly accrual for the study 7.1 Average monthly accrual for the last 6 months 14.5 Projected completion date based on last 6 months October 2011

4 January RTOG Full Members and Affiliates (n=99) Table 2.2 Study Accrual MAYO CLINIC 20 MAYO CLINIC SCOTTSDALE 4 ICON- CANCER CENTER OF PUTNAM 3 ICON- ORANGE PARK CANCER CENTER 3 MAYO CLINIC 3 FLORIDA RADIATION ONCOLOGY GROUP / 2 BAPTIST REGIONAL ICON- BAPTIST MEDICAL CENTER SOUTH 1 ICON- FLAGLER CANCER CENTER 1 ICON- SOUTHSIDE CANCER CENTER 1 JOE ARRINGTON CANCER RESEARCH & 1 TREATMENT CENTER MAYO RADIATION ONCOLOGY CENTER 1 THOMAS JEFFERSON UNIV. HOSPITAL 16 EMORY UNIV. 2 NEW YORK ONCOLOGY HEMATOLOGY, P.C. 2 ST. LUKES HOSPITAL 2 SUNY UPSTATE MEDICAL UNIV. 2 THOMAS JEFFERSON UNIV. HOSPITAL 2 EMORY CRAWFORD LONG HOSPITAL 1 KANSAS CITY CANCER CENTER-NORTH 1 ST. AGNES HEALTHCARE 1 US ONCOLOGY 1 USON-KANSAS CITY CANCER CENTER-SOUTH 1 USON-KANSAS CITY CANCER CENTER- 1 SOUTHWEST CLEVELAND CLINIC FOUNDATION 6 CLEVELAND CLINIC FOUNDATION 4 FOX CHASE CANCER CENTER 1 HILLCREST HOSPITAL CANCER CENTER 1 UNIV. OF CALIFORNIA SAN FRANCISCO 6 UNIV. OF CALIFORNIA SAN FRANCISCO 2 KAISER PERMANENTE OAKLAND 1 KAISER PERMANENTE RADIATION ONCOLOGY 1 CENTER ROSEVILLE KAISER PERMANENTE SANTA CLARA 1 MEDICAL CENTER STANFORD UNIV. MEDICAL CENTER 1 RADIOLOGICAL ASSOCIATES OF SACRAMENTO 5 RADIOLOGICAL ASSOCIATES OF 3 SACRAMENTO MERCY SAN JUAN RADIATION ONCOLOGY 2 CENTER UNIV. OF MARYLAND MEDICAL SYSTEMS 5 CENTRAL BAPTIST HOSPITAL 2 UNIV. OF VIRGINIA MEDICAL CENTER 2 UNIV. OF CHICAGO 1 UNIV. OF WESTERN ONTARIO 5 THE OTTAWA HOSPITAL REGIONAL CANCER 4 CENTRE UNIV. OF WESTERN ONTARIO 1 INTERMOUNTAIN MEDICAL CENTER 4 PENROSE CANCER CENTER, PENROSE-ST. 4 FRANCIS HEALTH SERVICES UNIV. OF ALABAMA AT BIRMINGHAM MEDICAL CENTER THE REGIONAL CANCER CENTER AT SINGING RIVER HOSPITAL SYSTEM UNIV. OF ALABAMA AT BIRMINGHAM MEDICAL CENTER UNIV. OF TEXAS SOUTHWESTERN MEDICAL SCHOOL UNIV. OF TEXAS-MD ANDERSON CANCER 4 CENTER THOMPSON CANCER SURVIVAL CENTER 2 UNIV. OF FLORIDA HEALTH SCIENCE CENTER 1 UNIV. OF TEXAS AT SAN ANTONIO 1 WASHINGTON UNIV. 4 MEDICAL COLLEGE OF WISCONSIN 3 MEDICAL COLLEGE OF WISCONSIN 1 METHODIST CANCER CENTER 1 ZABLOCKI VA MEDICAL CENTER-WOOD 1 ROSWELL PARK CANCER INSTITUTE 3 THE REGIONAL CANCER CENTER 3 UNIV. OF UTAH HEALTH SCIENCE CENTER 3 TOM BAKER CANCER CENTRE 2 UNIV. OF ROCHESTER 2 UCSD UNIV. OF CALIFORNIA, SAN DIEGO 2 AKRON CITY HOSPITAL 1 H. LEE MOFFITT CANCER CENTER & 1 RESEARCH INSTITUTE BAY MEDICAL CENTER 1 WAYNE STATE UNIV.-KARMANOS CANCER 1 INSTITUTE CLARIAN HEALTH PARTNERS, INC

5 January RTOG CCOP Members and Components (n=49) MICHIGAN CANCER RESEARCH CONSORTIUM 10 CCOP ST. JOSEPH MERCY HOSPITAL 7 ST. MARY MERCY HOSPITAL 2 GENESYS REGIONAL MEDICAL CENTER 1 SOUTHEAST CANCER CONTROL CONSORTIUM, 7 INC., CCOP PRESBYTERIAN HOSPITAL 3 RALEIGH HEMATOLOGY ONCOLOGY 2 ASSOCIATES CAROLINAS MEDICAL CENTER 1 WELLMONT HOLSTON VALLEY MEDICAL 1 CENTER CHRISTIANA CARE HEALTH SERVICES, INC. 6 KANSAS CITY CCOP 4 MONTANA CANCER CONSORTIUM CCOP 4 NORTHERN ROCKIES RADIATION ONCOLOGY 4 CENTER ST. VINCENT REGIONAL CANCER CENTER 4 CCOP ST. VINCENT REGIONAL CANCER CENTER 3 CCOP DOOR COUNTY CANCER CENTER 1 GEISINGER MEDICAL CENTER 3 MT. SINAI COMPREHENSIVE CANCER CENTER CCOP MAIN LINE CCOP 2 LANKENAU HOSPITAL 2 NATALIE WARREN BRYANT CANCER CENTER AT ST. FRANCIS HOSPITAL LOUISIANA STATE UNIV. HEALTH SCIENCE CENTER MBCCOP NEVADA CANCER RESEARCH FOUNDATION CCOP NORTHERN INDIANA CANCER RESEARCH CONSORTIUM TOLEDO COMMUNITY HOSPITAL ONCOLOGY 1 PROGRAM CCOP FLOWER HOSPITAL CTSU (n=15) GREENVILLE S.C. CCOP 3 IOWA METHODIST MEDICAL CENTER 2 MARGARET & HOWARD HALL RAD CTR/MERCY MEDICAL CTR. MISSOURI BAPTIST MEDICAL CENTER 2 2 MAINE GENERAL MEDICAL CENTER 1 MARTIN MEMORIAL CANCER CENTER 1 MERITCARE HOSPITAL 1 SWEDISH MEDICAL CENTER 1 SANFORD CANCER CENTER 2 NCCTG (n=1) SANFORD CANCER CENTER 1

6 January Table 2.3 Case Status Arm A: 60 Gy Arm B: 74 Gy Arm C: 60 Gy + Arm D: 74 Gy + Total Total patients entered Ineligible Eligible/pending With on-study information With adverse event information No protocol treatment Table 2.4 Cases Excluded Arm D: 74 Gy + (n=2) Arm A: 60 Gy Arm C: 60 Gy Arm B: 74 Gy + (n=1) (n=1) (n=0) Reason n % n % n % n % Ineligible - Brain MRI done > 6 weeks prior to registration Ineligible - Contralateral node present at time of registration Ineligible - Hemoglobin < 10.0 g/dl Ineligible - Unable to confirm no prior chemotherapy or radiotherapy Table 2.4 Cases with Pending Eligibility Arm A: 60 Gy Arm C: 60 Gy Arm B: 74 Gy + Arm D: 74 Gy + (n=5) (n=4) (n=3) (n=5) Reason n % n % n % n % Pending - Verifying patient resectable Pending - Verifying abdominal CT done > 6 weeks prior to registration Pending - Verifying pleural effusion not malignant/not visible on chest X-ray Pending - Verifying COPD, FEV1 (Liters) < 1.2, and FEV1 (% Predicted) < 50% Pending - Verifying PET/bone scan done > 6 weeks prior to registration Pending - Verifying histology confirmed < 12 weeks prior to registration Pending - Verifying patient does not have measurable disease Pending - Verifying patient has stage IIA disease Pending - Verifying patient has stage IIB disease Pending - Verifying weight loss < 10%

7 January III: Pretreatment Characteristics Table 3.1 Pretreatment Characteristics Arm A: 60 Gy Arm B: 74 Gy Arm C: 60 Gy + Arm D: 74 Gy + (n=46) (n=46) (n=28) (n=31) Age Median Range n % n % n % n % Gender Male Female Zubrod RT Technique 3D-CRT IMRT PET Staging No Yes Histology Squamous cell carcinoma Adenocarcinoma Large cell undifferentiated Non-small cell lung cancer NOS AJCC Stage Stage IIA Stage IIB Stage IIIA Stage IIIB

8 January Table 3.2 Gender/Ethnicity/Race Distributions Sex/Gender Ethnic Category Females Males Total Hispanic or Latino Not Hispanic or Latino Unknown (Individuals not reporting ethnicity) Ethnic Category: Total of All Subjects Racial Category Black or African American Native Hawaiian or Other Pacific Islander White Racial Category: Total of All Subjects Table 3.3 Pretreatment QOL Compliance Arm A: 60 Gy Arm B: 74 Gy Arm C: 60 Gy + Arm D: 74 Gy + (n=20) (n=23) (n=4) (n=5) FACT Did not consent to participate in QOL portion of study Completed, prior to start of treatment Completed, after start of treatment Not completed, patient refused for other reason Not completed, institutional error Not received EQ-5D Did not consent to participate in QOL portion of study Completed, prior to start of treatment Completed, after start of treatment Not completed, patient refused for other reason Not completed, other reason Not received

9 January IV. Adverse Events: Adverse events in this section were graded using the CTCAE v. 3.0 Criteria. Table 4.1 Treatment Adverse Events Reported as Definitely, Probably, or Possibly Related to Treatment * Arm A: 60 Gy (n=31) Grade Arm B: 74 Gy (n=28) Grade Category Allergy/immunology Auditory/ear Blood/bone marrow Cardiac arrhythmia Cardiac general Constitutional symptoms Dermatology/skin Gastrointestinal Hemorrhage/bleeding Infection Lymphatics Metabolic/laboratory Musculoskeletal/soft tissue Neurology Ocular/visual Pain Pulmonary/upper respiratory Renal/genitourinary Syndromes Vascular Worst non-hematologic (10%) (39%) (35%) (10%) (3%) (7%) (39%) (25%) (14%) (0%) Worst overall (3%) (19%) (45%) (26%) (3%) (7%) (18%) (39%) (25%) (0%) * Includes adverse events where relationship to treatment is missing

10 January Table 4.1 Treatment Adverse Events Reported as Definitely, Probably, or Possibly Related to Treatment * (continued) Arm C: 60 Gy + (n=13) Grade Arm D: 74 Gy + (n=14) Grade Category Allergy/immunology Auditory/ear Blood/bone marrow Cardiac arrhythmia Cardiac general Constitutional symptoms Dermatology/skin Gastrointestinal Hemorrhage/bleeding Infection Lymphatics Metabolic/laboratory Musculoskeletal/soft tissue Neurology Ocular/visual Pain Pulmonary/upper respiratory Renal/genitourinary Syndromes Vascular Worst non-hematologic (0%) (54%) (38%) (8%) (0%) (0%) (29%) (57%) (7%) (7%) Worst overall (0%) (31%) (46%) (23%) (0%) (0%) (14%) (64%) (14%) (7%) * Includes adverse events where relationship to treatment is missing

11 January Table 4.2 All Grade 3+ Adverse Events from Table 4.1 RX CN Category Adverse Event Days Since Start of Treatment Grade Arm A: 60 Gy 1 Blood/bone marrow Leukopenia Lymphopenia 67 4 Neutrophil count decreased Blood/bone marrow Leukopenia 35 3 Metabolic/laboratory Hyperglycemia Blood/bone marrow Neutrophil count decreased Blood/bone marrow Leukopenia 80 3 Neutrophil count decreased Blood/bone marrow Hemoglobin decreased 23 3 Leukopenia Neutrophil count decreased Gastrointestinal Dehydration 21 3 Infection Pneumonia [with normal or Grade 1-2 ANC] Pulmonary/upper respiratory Dyspnea Pneumonitis Blood/bone marrow Hemoglobin decreased 99 3 Leukopenia 83 3 Lymphopenia 99 4 Neutrophil count decreased 83 3 Cardiac general Hypotension 99 3 Constitutional symptoms Fever 99 3 Gastrointestinal Anorexia 97 3 Dehydration 99 3 Diarrhea 97 3 Nausea 97 3 Infection Urinary tract infection [with normal 99 4 or Grade 1-2 ANC] Metabolic/laboratory Hypokalemia 99 3 Pulmonary/upper respiratory Dyspnea 99 3 Hypoxia Blood/bone marrow Leukopenia Neutrophil count decreased Blood/bone marrow Lymphopenia 11 3 Pulmonary/upper respiratory Cough 93 3 Dyspnea 93 3 Hypoxia Pneumonitis Blood/bone marrow Platelet count decreased 27 3 Constitutional symptoms Fatigue 76 3 Pulmonary/upper respiratory Bronchospasm 38 3 Dyspnea 91 3 Respiratory disorder Blood/bone marrow Leukopenia 28 3 Lymphopenia 35 3 Neutrophil count decreased 35 3 Infection Pneumonia [with normal or 87 3 Grade 1-2 ANC] 38 Blood/bone marrow Lymphopenia 42 3

12 January Table 4.2 All Grade 3+ Adverse Events from Table 4.1 (continued) RX CN Category Adverse Event Days Since Start of Treatment Grade Arm A: 60 Gy 43 Blood/bone marrow Neutrophil count decreased 72 4 Gastrointestinal Diarrhea 70 3 Dysphagia 21 3 Infection Pneumonia [with normal or 93 3 Grade 1-2 ANC] 45 Pulmonary/upper respiratory Dyspnea Pneumonitis Blood/bone marrow Leukopenia 98 3 Neutrophil count decreased Blood/bone marrow Hemoglobin decreased 41 3 Gastrointestinal Dehydration 41 3 Esophagitis Gastrointestinal Vomiting Blood/bone marrow Hemoglobin decreased 91 3 Platelet count decreased Blood/bone marrow Neutrophil count decreased Allergy/immunology Hypersensitivity 22 3 Blood/bone marrow Leukopenia 49 3 Lymphopenia 63 3 Platelet count decreased Infection Pneumonia [with normal or 38 3 Grade 1-2 ANC] Neurology Anxiety Pain Myalgia Constitutional symptoms Fever 20 4 Arm B: 74 Gy 3 Blood/bone marrow Leukopenia 26 3 Lymphopenia 26 3 Gastrointestinal Anorexia 95 3 Dysphagia Esophageal ulcer Neurology Peripheral sensory neuropathy 95 3 Pain Chest pain 95 3 Esophageal pain 95 3 Pulmonary/upper respiratory Dyspnea Blood/bone marrow Neutrophil count decreased 84 3 Gastrointestinal Dysphagia 48 3 Nausea 34 3 Metabolic/laboratory Hypokalemia 56 3 Vascular Thrombosis Blood/bone marrow Leukopenia Blood/bone marrow Leukopenia 84 3 Neutrophil count decreased 77 3

13 January Table 4.2 All Grade 3+ Adverse Events from Table 4.1 (continued) RX CN Category Adverse Event Days Since Start of Treatment Grade Arm B: 74 Gy 14 Blood/bone marrow Leukopenia Lymphopenia 20 3 Neutrophil count decreased Cardiac general Hypotension 55 3 Gastrointestinal Anorexia 61 3 Dehydration 55 3 Dysphagia 26 3 Esophageal stenosis 82 3 Esophagitis 26 3 Nausea 47 3 Infection Febrile neutropenia Pleural infection [with normal or Grade 1-2 ANC] 21 Blood/bone marrow Leukopenia 34 3 Lymphopenia 13 3 Neutrophil count decreased 34 3 Metabolic/laboratory Hyperglycemia Blood/bone marrow Leukopenia Blood/bone marrow Leukopenia 84 3 Neutrophil count decreased Metabolic/laboratory Hyponatremia Blood/bone marrow Neutrophil count decreased Gastrointestinal Esophageal stenosis Esophagitis 58 3 Neurology Depression Blood/bone marrow Leukopenia 42 3 Lymphopenia 50 3 Hemorrhage/bleeding Respiratory tract hemorrhage Blood/bone marrow Lymphopenia Infection Febrile neutropenia 53 4 Musculoskeletal/soft tissue Muscle weakness Pain Headache 33 3 Pulmonary/upper respiratory Pneumonitis Gastrointestinal Dehydration 46 3 Diarrhea 4 3 Pulmonary/upper respiratory Dyspnea Blood/bone marrow Leukopenia 47 3 Metabolic/laboratory Hyponatremia Blood/bone marrow Neutrophil count decreased Blood/bone marrow Leukopenia 42 3 Gastrointestinal Dysphagia 92 4 Arm C: 60 Gy + 46 Allergy/immunology Hypersensitivity Blood/bone marrow Leukopenia 48 3 Neutrophil count decreased Gastrointestinal Esophagitis 77 3 Infection Endocarditis infective [with unknown 98 3 ANC] Pneumonia [with unknown ANC] 98 3

14 January Table 4.2 All Grade 3+ Adverse Events from Table 4.1 (continued) RX CN Category Adverse Event Days Since Start of Treatment Grade 56 Blood/bone marrow Neutrophil count decreased Arm C: 60 Gy + Arm D: 74 Gy + 60 Blood/bone marrow Leukopenia 98 4 Neutrophil count decreased Constitutional symptoms Fatigue 70 3 Metabolic/laboratory Alkaline phosphatase increased 62 3 Neurology Peripheral sensory neuropathy 94 3 Pulmonary/upper respiratory Dyspnea 70 3 Pleural effusion Blood/bone marrow Neutrophil count decreased 84 3 Neurology Peripheral sensory neuropathy Allergy/immunology Hypersensitivity Blood/bone marrow Neutrophil count decreased 42 3 Dermatology/skin Rash desquamating Blood/bone marrow Leukopenia 84 3 Lymphopenia 28 3 Constitutional symptoms Fatigue Fever 28 3 Gastrointestinal Dehydration Blood/bone marrow Leukopenia 56 3 Lymphopenia 56 3 Gastrointestinal Dehydration 56 3 Dysphagia 89 3 Esophagitis 89 3 Nausea Blood/bone marrow Leukopenia Neutrophil count decreased 48 3 Platelet count decreased Cardiac arrhythmia Arrhythmia Gastrointestinal Esophagitis Blood/bone marrow Hemoglobin decreased Leukopenia Lymphopenia Blood/bone marrow Leukopenia Neutrophil count decreased Allergy/immunology Hypersensitivity 98 3 Blood/bone marrow Leukopenia 49 3 Metabolic/laboratory Hyperglycemia Blood/bone marrow Neutrophil count decreased Constitutional symptoms Fatigue 56 3 Gastrointestinal Esophagitis 57 3 Pain Esophageal pain Constitutional symptoms Fatigue 98 3 Weight loss 98 3 Gastrointestinal Anorexia 70 3 Dehydration 70 3 Dysphagia 56 3 Nausea 52 3

15 January Table 4.2 All Grade 3+ Adverse Events from Table 4.1 (continued) RX CN Category Adverse Event Days Since Start of Treatment Grade Arm D: 74 Gy + 84 Gastrointestinal Anorexia 74 3 Dysphagia 49 3 Esophagitis 49 3 Vascular Thrombosis Pulmonary/upper respiratory Pneumonitis Metabolic/laboratory Hyperglycemia 7 3 Pain Chest pain Dermatology/skin Acne 14 3 Table 4.3 Adverse Events Regardless of Relationship to Treatment Arm A: 60 Gy (n=31) Grade Arm B: 74 Gy (n=28) Grade Category Allergy/immunology Auditory/ear Blood/bone marrow Cardiac arrhythmia Cardiac general Coagulation Constitutional symptoms Death Dermatology/skin Endocrine Gastrointestinal Hemorrhage/bleeding Infection Lymphatics Metabolic/laboratory Musculoskeletal/soft tissue Neurology Ocular/visual Pain Pulmonary/upper respiratory Renal/genitourinary Syndromes Vascular Worst non-hematologic (6%) (29%) (45%) (13%) (3%) (7%) (36%) (21%) (21%) (7%) Worst overall (0%) (19%) (45%) (29%) (3%) (7%) (18%) (32%) (29%) (7%)

16 January Table 4.3 Adverse Events Regardless of Relationship to Treatment (continued) Arm C: 60 Gy + (n=13) Grade Arm D: 74 Gy + (n=14) Grade Category Allergy/immunology Auditory/ear Blood/bone marrow Cardiac arrhythmia Cardiac general Coagulation Constitutional symptoms Death Dermatology/skin Endocrine Gastrointestinal Hemorrhage/bleeding Infection Lymphatics Metabolic/laboratory Musculoskeletal/soft tissue Neurology Ocular/visual Pain Pulmonary/upper respiratory Renal/genitourinary Syndromes Vascular Worst non-hematologic (0%) (54%) (38%) (8%) (0%) (0%) (21%) (57%) (14%) (7%) Worst overall (0%) (31%) (46%) (23%) (0%) (0%) (14%) (64%) (14%) (7%) V. Protocol Treatment Reviews: Table 5.1 Status of Protocol Treatment Reviews Arm A: 60 Gy (n=47) Arm B: 74 Gy (n=49) Arm C: 60 Gy + (n=30) Arm D: 74 Gy + (n=34) Radiation therapy Contour reviewed 2 (4%) 2 (4%) 0 (0%) 0 (0%) Dose reviewed 11 (23%) 10 (20%) 0 (0%) 0 (0%) Not reviewed 34 (72%) 37 (76%) 30 (100%) 34 (100%) Chemotherapy Not reviewed 47 (100%) 49 (100%) 30 (100%) 34 (100%)

17 January Table 5.2 Radiotherapy Review Arm A: 60 Gy Tumor Volume Dose Volume Analysis Score Tumor Volume Contouring Score Per protocol Acceptable variation Not reviewed Total Per protocol 0 (0%) 0 (0%) 1 (8%) 1 (8%) Not evaluable 0 (0%) 0 (0%) 1 (8%) 1 (8%) Not reviewed 10 (77%) 1 (8%) 0 (0%) 11 (85%) Total 10 (77%) 1 (8%) 2 (15%) 13 (100%) Arm B: 74 Gy Tumor Volume Dose Volume Analysis Score Tumor Volume Contouring Score Per protocol Acceptable variation Not reviewed Total Not evaluable 0 (0%) 0 (0%) 2 (17%) 2 (17%) Not reviewed 9 (75%) 1 (8%) 0 (0%) 10 (83%) Total 9 (75%) 1 (8%) 2 (17%) 12 (100%) Arm A: 60 Gy Organs at Risk Dose Volume Analysis Score Organs at Risk Contouring Score Per protocol Unacceptable variation Not reviewed Total Per protocol 0 (0%) 0 (0%) 1 (8%) 1 (8%) Acceptable variation 0 (0%) 0 (0%) 1 (8%) 1 (8%) Not evaluable 0 (0%) 0 (0%) 1 (8%) 1 (8%) Not reviewed 7 (54%) 3(23%) 0 (0%) 10 (77%) Total 7 (54%) 3(23%) 3 (23%) 13 (100%) Arm B: 74 Gy Organs at Risk Dose Volume Analysis Score Organs at Risk Contouring Score Per protocol Unacceptable variation Not reviewed Total Not evaluable 0 (0%) 0 (0%) 2(17%) 2 (17%) Not reviewed 8 (67%) 2 (17%) 0 (0%) 10 (83%) Total 8 (67%) 2 (17%) 2(17%) 12 (100%)

18 January Table 5.2 Radiotherapy Review (continued) Arm A: 60 Gy Organs at Risk Contouring Score Tumor Volume Contouring Score Per protocol Acceptable variation Not evaluable Not reviewed Total Per protocol 1 (8%) 0 (0%) 0 (0%) 0 (0%) 1 (8%) Not evaluable 0 (0%) 0 (0%) 1 (8%) 0 (0%) 1 (8%) Not reviewed 0 (0%) 1 (8%) 0 (0%) 10 (77%) 11 (85%) Total 1 (8%) 1 (8%) 1 (8%) 10 (77%) 13(100%) Arm B: 74 Gy Organs at Risk Contouring Score Tumor Volume Contouring Score Not evaluable Not reviewed Total Not evaluable 2 (17%) 0 (0%) 2 (17%) Not reviewed 0 (0%) 10 (83%) 10 (83%) Total 2 (17%) 10 (83%) 12 (100%)