June Arm 1 = Observe R A N D O M I Z E

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1 June RTOG Protocol No: Protocol Status: ECOG Protocol No: R9802 Opened: October 31, 1998 NCCT Protocol No: R9802 Closed: June 27, 2002 SWOG Protocol No: R9802 Title: A Phase II Study of Observation in Favorable Low-Grade Glioma and Phase III Study of Radiation with or without PCV Chemotherapy in Unfavorable Low-Grade Glioma. Patient Population: Histologic proof of a unifocal or multifocal supratentorial WHO grade II astrocytoma (diffuse fibrillary, protoplasmic, or gemistocytic), oligodendroglioma, or oligoastrocytoma. Patients with prior suspected or proven LGG are eligible provided they now have a histologically proven eligible histology. Patients with neurofibromatosis are eligible. Stereotactic biopsies are permitted providing the tissue sample is adequate to make an unequivocal histologic diagnosis. For all patients, tissue must be obtained no more than 12 weeks before the date of registration or randomization. Objectives: Primary: Low Risk Patients To identify the overall (and relapse-free) survival of low-risk adult patients with supratentorial LGG (< 40 years old who undergo gross total resection of a WHO grade II astrocytoma, oligodendroglioma, or mixed oligoastrocytoma) who are observed postoperatively. High Risk Patients To compare the overall (and relapse-free) survival between the two arms of high-risk adult patients with supratentorial LGG ( 40 years old regardless of the degree of surgical resection, or age 18 who undergo subtotal resection or biopsy, of a WHO grade II astrocytoma, oligodendroglioma, or oligoastrocytoma) who receive postoperative external beam radiation therapy with or without PCV chemotherapy. Secondary: To compare the severe or worse toxicities ( grade 3) of unfavorable patients receiving postoperative radiation therapy alone or radiation therapy plus PCV chemotherapy. To compare the neurosurgeon s assessment of gross total resection with that of a postoperative MRI scan interpreted by a neuroradiologist. To collect and store archival, paraffin embedded tissue and peripheral blood samples for concomitant and future correlative studies which will be funded by other mechanisms. Schema: ASSESS RISK LOW RISK Age < 40 AND GROSS TOTAL RESECTION HIGH RISK * Age 40 OR SUBTOTAL RESECTION / BIOPSY Arm 1 = Observe R A N D O M I Z E Arm 2 = Radiation a Alone Arm 3 = Radiation a PCV b x 6 cycles Stratify: Tumor Subtype (astrocytoma [mixed-astro dominant] or equal [astro/oligo mix] vs. oligodendroglioma [mixedoligo dominant]); Age (< 40 vs. > 40); KPS (60-80 vs ); Contrast Enhancement on Pre-Op scan (present vs. absent). Treatment (must begin within 4 weeks after registration) a. Radiation - External Beam Radiation Therapy (EBRT) EBRT: 54 Gy/30 fractions over six weeks, 5 days a week to gross tumor volume defined by a T2 weighted post-op MRI scan (pre-op MRI acceptable if biopsy only) plus a 2 cm margin (tumor edge to block edge. There will be no boost volume. b. PCV Chemotherapy - Procarbazine/CCNU/Vincristine Procarbazine 60mg/m 2 po, Days 8-21 CCNU 110mg/m2 po, Day 1 Vincristine 1.4mg/m 2 iv, Days 8,29 (maximum dose 2 mg) PCV must start within one month following last day of RT. Repeat PCV at 8 week intervals x 6 cycles

2 June Study Chairs: Edward G. Shaw, M.D. (Radiation Oncology) Total patients entered: 370 Jan C. Buckner, M.D. (Medical Oncology) Geoffrey R. Barger, M.D. (Neuro-Oncology) Stephen W. Coons, M.D. (Neuropathology) Peter E. Ricci, M.D. (Neuroradiology) Dennis E. Bullard, M.D. (Neurosurgery) ECOG: Minesh Mehta, M.D. Mark R. Gilbert, M.D. NCCTG: Paul D. Brown, M.D. Jan C. Buckner, M.D. (Radiation Oncology) (Medical Oncology (Radiation Oncology) (Medical Oncology) SWOG: Keith J. Stelzer, M.D., Ph.D. (Radiation Oncology) Geoffrey R. Barger, M.D. (Medical Oncology) Statisticians: Research Associate: Dosimetrist: Protocol Associate: Wendy Seiferheld, M.S. Minhee Won, M.A. Barbara Kaiser, R.N., CCRP Julie McIlvaine, R.T.T. Ellen Aiken, B.A I. Summary: This study opened October 31, 1998, and closed to accrual on June 27, 2002 with 370 patients entered. Two hundred fifty-four high-risk patients were randomized to Arms 2 and 3, while 116 low risk patients were registered to the observation arm. This study used the CTC v. 2.0 and late toxicities were scored using the RTOG/EORTC Late Radiation Morbidity Scoring Schema. Chemotherapy and/or acute radiation toxicities are reported in Tables 4.1 and 4.2. On the RT Alone arm, one patient (1%) had grade 4 toxicity, and eight other patients (6%) had grade 3 toxicity. There were no grade 3 or 4 hematologic toxicities reported. On the RT+PCV arm, 4 patients had non-hematologic grade 4 toxicity (3%), and 29 other patients (23%) had non-hematologic grade 3 toxicity. There were no grade 3 late RT toxicities (Table 4.3). Study chair review of radiation therapy delivery has been completed on 224 patients, 87% of which were determined to be per protocol (Table 5.1). No reviews of chemotherapy delivery have been completed to date. II. Administrative Information: Table 2.1 Patient Accrual Study sample size 370 Total patients entered Arm 1 (Observation) Arm 2 & 3 (Treatment Arms) Average monthly accrual for the study Arm 1 (Observation) Arm 2 & 3 (Treatment Arms)

3 June Table 2.2 Study Accrual by Full Member Institutions RTOG (N=263) Foundation for Cancer Res. and Edu. 49 Cleveland Clinic Foundation 25 Medical College of Wisconsin 23 Notre Dame Hospital/Univ. of Montreal 18 University of Western Ontario 16 Wayne State University 14 Cross Cancer Institute - Univ. of Alberta 12 McGill University 10 Dartmouth Hitchcock Medical Center 8 Univ. of Pennsylvania Medical Center 8 LDS Hospital 7 Univ. of Texas-MD Anderson Cancer Center 7 University of Rochester 6 Wake Forest Univ. Baptist Medical Center 6 Mayo Clinic 5 Metro-MN CCOP 5 Thomas Jefferson Univ. Hospital 5 Radiological Associates of Sacramento 4 Washington University 4 SWOG (N=49) Tumor Institute at Swedish Hospital 11 Univ. of Washington Med. Center 10 St Francis Regional Med Ctr. 9 Grand Rapids CCOP 5 Henry Ford Hospital 4 Louisiana State Univ. Hospital 3 NCCTG (N=37) Rochester Methodist Hospital 11 Des Moines 8 Mayo Clinic - Jacksonville 3 Sioux Falls 3 Cedar Rapids 2 Duluth 2 Peoria CCOP 2 ECOG (N=21) Emory University Affiliated Hospitals 8 West Michigan Cancer Center 4 Vanderbilt University Med. Center 3 St. Vincent Regional Cancer Center CCOP 3 Toledo Comm. Hosp. Oncology Program CCOP 3 Univ. of California San Francisco 3 Univ. of Maryland Med. Systems 3 N. W. Bryant Cancer Center at St. Francis Hosp. 2 SE Cancer Control Consortium, Inc. CCOP 2 Univ. of California Davis Med. Center 2 University of Kentucky Hospital 2 Albert Einstein Medical Center 1 Benefis Healthcare CCOP 1 Colorado Cancer Research Program 1 Fox Chase Cancer Center 1 Greenville S.C. CCOP 1 Gulf Coast MBCCOP 1 Johns Hopkins Hospital 1 Kansas City CCOP 1 Ochsner Clinic CCOP 1 Santa Rosa Memorial Hospital CCOP 1 Univ. of Alabama at Birmingham Med. Ctr. 1 University of Texas Medical Branch 2 City of Hope Medical Center 1 Montana CCOP 1 Multicare - Tacoma General Hospital 1 St. Louis CCOP 1 Wesley Medical Center 1 Bismarck 1 Carle Clinic Association 1 Grand Forks Clinic 1 Rapid City Regional Hospital 1 St Cloud Hospital 1 St Joseph Hospital 1 Yale University-New Haven Hospital 3 West Virginia Univ. Med Center 2 Aultman Hospital 1 Table 2.3a Case Status Observation RT Alone RT+PCV Total Total patients entered Ineligible/canceled* Eligible/pending With on-study information With toxicity information N/A

4 June Table 2.3b *Reasons for Exclusion RX CN Status Reason Observation 337 Canceled Incorrect stratifying registration Observation 369 Ineligible Had hydrea prior to study entry RT Alone 42 Ineligible Central pathology not done prior to randomization RT Alone 59 Ineligible Wrong histology anaplastic astrocytoma RT+PCV 340 Ineligible No pre-operative and post-operative MRI scans Table 2.3c Cases with pending eligibility RX CN Status Reason Observation 368 Pending Missing P4 (central pathology review) RT+PCV 156 Pending No pre-operative and post-operative MRI scans III. Pretreatment Characteristics: Table 3.1 Pretreatment Characteristics Observation (n=114) RT Alone (n=126) RT + PCV (n=125) Age Median Range < (99%) 60 (48%) 56 (45%) 40 1 ( 1%) 66 (52%) 69 (55%) Gender Male 59 (52%) 77 (61%) 65 (52%) Female 55 (48%) 49 (39%) 60 (48%) KPS (12%) 33 (26%) 31 (25%) (88%) 93 (74%) 94 (75%) Neurologic Function 0 69 (61%) 49 (39%) 62 (50%) 1 38 (33%) 67 (53%) 49 (39%) 2 6 ( 5%) 5 ( 4%) 10 ( 8%) 3 1 ( 1%) 5 ( 4%) 4 ( 3%)

5 June Table 3.1 Pretreatment Characteristics Observation (n=114) RT Alone (n=126) RT + PCV (n=125) Surgery Total Resection 111 (97%) 12 (10%) 15 (12%) Subtotal Resection 2 ( 2%) 53 (42%) 48 (38%) Biopsy Only 0 ( 0%) 59 (47%) 59 (47%) Unknown/No Detail/Missing 1 ( 1%) 2 ( 2%) 3 ( 2%) Histology from Central Review Astrocytoma 17 (15%) 29 (23%) 37 (30%) Oligodendroglioma 50 (44%) 57 (45%) 48 (38%) Oligoastrocytoma 46 (40%) 40 (32%) 40 (32%) Pending 1 ( 1%) 0 ( 0%) 0 ( 0%) Contrast Enhancement on Pre-Op Scan Present 54 (47%) 75 (60%) 81 (65%) Absent 60 (53%) 51 (40%) 44 (35%) Pre-Op Non-enhancing Tumor Size (mm) n Mean Median Range Pre-Op Enhancing Tumor Size (mm) n Mean Median Range Risk Low 111 (97%) 1 ( 1%) 1 ( 1%) High 3 ( 3%) 125 (99%) 124 (99%) MMSE n Mean Median Range American Indian or Alaskan Native Table 3.2 Gender/Race Distributions Black, not of Hispanic origin Native Hawaiian or Pacific Islander White, not of Hispanic origin Asian Hispanic Male Female Total Total

6 June IV. Toxicity: Table 4.1 Chemotherapy and Acute Radiotherapy Toxicity RT Alone RT+PCV (n=126) (n=124) Grade Grade Allergy Auditory/hearing Blood/bone marrow Cardiovascular (arrhythmia) Cardiovascular (general) Coagulation Constitutional symptoms Dermatology/skin Endocrine Gastrointestinal Hemorrhage Hepatic Infection/febrile neutropenia Metabolic/laboratory Musculoskeletal Neurology Ocular/visual Pain Pulmonary Renal/genitourinary Sexual/reproductive functions Other tox. From chemotherapy flow sheets Worst non-hematologic (24%) (50%) (6%) (1%) (8%) (46%) (35%) (3%) Worst overall (24%) (50%) (6%) (1%) (4%) (22%) (54%) (12%)

7 June Table 4.2 All Grade 3+ Non-hematologic Toxicities RX CN Group Toxicity Days from RT Start Grade RT Alone 35 Neurology Seizure Gastrointestinal Nausea Vomiting Constitutional Symptoms Weight loss 87 3 Pain Headache 87 3 Chest pain (non-cardiac and non-pleuritic) Neurology Speech impairment Seizure Peripheral motor neuropathy Forgetfulness Constitutional Symptoms Fatigue Neurology Neuropathy cranial Peripheral motor neuropathy Ocular/visual Blurred vision Neurology Ataxia (incoordination) Neurology Seizure Gastrointestinal Nausea Vomiting Cardiovascular (general) Edema RT+PCV 4 Neurology Seizure Hepatic Gama-glutamyltransferase increased Gastrointestinal Nausea 94 3 Metabolic/laboratory Hyponatremia Gastrointestinal Constipation Pain Abdominal Pain Constitutional Symptoms Fatigue Constitutional Symptoms Fatigue 92 4 Dermatology/skin Uriticaria Pain Headache 8 3 Gastrointestinal Nausea 79 3 Vomiting Hepatic SGPT (ALT) Infection/febrile neutropenia Infection with neutropenia Pain Headache Coagulation Thrombotic microangiopathy Gastrointestinal Other-heartburn Vomiting Pain Abdominal Pain or cramping 74 3 Gastrointestinal Diarrhea without colostomy Infection/febrile neutropenia Infection with neutropenia Pulmonary Dyspnea Neurology Seizure 45 3 Constitutional Symptoms Fatigue 98 3

8 June Table 4.2 All Grade 3+ Non-hematologic Toxicities (continued) RX CN Group Toxicity Days from RT Start Grade RT+PCV 125 Hepatic GGT Sexual reproductive function Irregular menses Constitutional Symptoms Weight loss Metabolic/laboratory Hyperglycemia Neurology Speech impairment Gastrointestinal Anal fistula Gastrointestinal Nausea Constitutional Symptoms Fatigue Pain Other-pain in legs Constitutional Symptoms Fatigue Dermatology/skin Alopecia Pulmonary Dyspnea 19 3 Renal/genitourinary Vaginal hemorrhage Dermatology/skin Rash/desquamation Cardiovascular (general) Thrombosis/embolism Metabolic/laboratory Hyperglycemia No RT start date Infection/febrile neutropenia Infection without neutropenia Constitutional Symptoms Weight loss Fever Pain Headache Hepatic SGOT (AST) SGPT (ALT) Alkaline phosphatase Metabolic/laboratory Hyperglycemia/hyponatremia 62 3 Neurology Peripheral motor neuropathy Constitutional Symptoms Fatigue Neurology Insomnia Gastrointestinal Ileus Gastrointestinal Nausea 83 3 Vomiting Gastrointestinal Nausea Vomiting Anorexia Dehydration Constitutional Symptoms Fatigue Weight loss Neurology Peripheral motor neuropathy Hepatic SGPT (ALT) Neurology Speech impairment Neurology Neuralgia 98 3 Pain Neuropathic pain Gastrointestinal Vomiting Constitutional Symptoms Weight loss Allergy/immunology Autoimmune reaction 686 3

9 June Table 4.2 All Grade 3+ Non-hematologic Toxicities (continued) RX CN Group Toxicity Days from RT Start Grade RT+PCV 314 Sexual reproductive function Irregular menses (change from baseline) Dermatology/skin Injection site reaction Endocrine SIADH Hemorrhage Hemorrhage/bleeding Constitutional Symptoms Fatigue Neurology Dizziness/light headedness Hallucinations Memory loss Confusion Mood alternation-anxiety Neuropathy-sensory Constitutional Symptoms Weight loss Gastrointestinal Nausea Table 4.3 Late Radiotherapy Toxicity RT Alone RT+PCV (n=123) (n=118) Grade Grade Brain Skin (within the field) Eye Subcutaneous Tissue Other # Other # Worst overall (28%) (14%) (22%) (16%) V. Modality Reviews: Table 5.1 Radiotherapy Review RT Alone (n=126) RT+PCV (n=125) Not Reviewed 14 (11%) 13 (10%) Reviewed 112 (89%) 112 (90%) Per Protocol 102 (91%) 92 (82%) Variation Acceptable 8 ( 7%) 11 (10%) Deviation unacceptable 1 ( 1%) 5 ( 4%) Incomplete RT/death 0 ( 0%) 2 ( 2%) Not evaluable 1 ( 1%) 2 ( 2%)