June Patient Population:

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1 June RTOG Protocol No: 9802 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 supratentorial WHO grade II astrocytoma, oligodendroglioma, or oligoastrocytoma confirmed by central pathology review prior to randomization. Age > 18 years. KPS > 60. Neurologic Function Score (NFS) < 3. For high risk patients (ARM 2 and 3): * Absolute granulocyte count (AGC) > 1500/mm3. * Platelet count within institutional normal range. * Serum creatinine < 2x institutional normal range. * Total bilirubin, SGOT (AST) or SGPT, and alkaline phosphatase < 2x institutional normal range. Pre-operative and post-operative MRI scans with and without contrast (pos-op MRI not necessary in biopsy only patients) obtained within 4 weeks of date of surgery. CT scans are not acceptable. Signed study-specific informed consent prior to study entry. Objectives: 1. 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. 2. To compare the overall (and relapse-free) survival 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. 3. To compare the severe or worse toxicities (> grade 3) of unfavorable patients receiving postoperative radiation therapy alone or radiation therapy plus PCV chemotherapy. 4. To compare the neurosurgeon s assessment of gross total resection with that of a postoperative MRI scan interpreted by a neuroradiologist. 5. 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.

2 June Schema: ASSESS RISK LOW RISK Age < 40 AND GROSS TOTAL RESECTION Arm 1 = Observe HIGH RISK * Age > 40 OR SUBTOTAL RESECTION / BIOPSY 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] vs. oligodendroglioma [mixed-oligo 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 Study Chairs: Edward G. Shaw, M.D. (Radiation Oncology) Number of Patients: 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. (Radiation Oncology) Mark R. Gilbert, M.D. (Medical Oncology NCCTG: Diana F. Nelson, M.D. (Radiation Oncology) Jan C. Buckner, M.D. (Medical Oncology) SWOG: Keith J. Stelzer, M.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.

3 June I. Summary: This study closed to accrual June 27, 2002 with 370 patients. Two hundred fifty four patients were accrued to the high risk group and randomized to Arms 2 and 3. Pretreatment characteristics are listed in Table 3.1. Toxicities are reported in Table 4.1. On the arm, one patient (1%) had grade 4 toxicity, and eight patients (6%) had grade 3 toxicity. There were no grade 3 or 4 hematologic toxicities reported. On the RT+PCV arm, four patients had non-hematologic grade 4 toxicity (3%), and 27 patients (23%) had non-hematologic grade 3 toxicity. There were no grade 3 late RT toxicities (Table 4.2). Study chair reviews of radiation therapy delivery were done on 72 patients (Table 5.1) and no review has taken place for chemotherapy yet. The second interim report of the primary study endpoint is planned after 40 deaths have occurred. II. Administrative Information: Table 2.1 Patient Accrual Total Patients Randomized 254 Average Monthly Accrual 5.8 Table 2.2 Patient Accrual by Full Member Institutions with Affiliates Included 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 Metro-MN CCOP 5 Thomas Jefferson Univ. Hospital 5 Mayo Clinic 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 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 (continued on next page)

4 June Table 2.2 (continued) 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 Bismarck 1 Carle Clinic Association 1 Grand Forks Clinic 1 Rapid City Regional Hospital 1 St Joseph Hospital 1 St Cloud Hospital 1 Yale University-New Haven Hospital 3 West Virginia Univ. Med Center 2 Aultman Hospital 1 Table 2.3 Case Status Observation RT+PCV Total Entered Ineligible/cancelled/pending* No On-Study Form Eligible and Analyzable Arm *CN Status Reason Observation 337 Cancelled Incorrect strafying registration 364 Pending Missing P4 (central pathology review) 368 Pending No pre-operative and post-operative MRI scans 369 Ineligible Had Hydrea. Prior to study entry 42 Ineligible Central pathology not done prior to randomization 59 Ineligible Wrong histology anaplastic astrocytoma RT+PCV 36 Pending No pre-operative and post-operative MRI scans 156 Pending No pre-operative and post-operative MRI scans 239 Pending Missing P4 (central pathology review) 340 Pending No pre-operative and post-operative MRI scans

5 June III. Pretreatment Characteristics: Table 3.1 Pretreatment Characteristics Observation (N=112) (N=125) RT + PCV (N=120) Age < (99%) 59 (47%) 54 (45%) 40 1 ( 1%) 66 (53%) 66 (55%) Gender Male 58 (52%) 76 (61%) 62 (52%) Female 54 (48%) 49 (39%) 58 (48%) Race White 102 (91%) 115 (92%) 107 (89%) Hispanic 6 ( 5%) 5 ( 4%) 5 ( 4%) Black 3 ( 3%) 5 ( 4%) 5 ( 5%) Asian 1 ( 1%) 0 1 ( 1%) Native American ( 2%) KPS (13%) 33 (26%) 26 (25%) (87%) 92 (74%) 77 (75%) Neurologic Function 0 66 (59%) 48 (38%) 59 (49%) 1 37 (33%) 66 (53%) 48 (40%) 2 6 ( 5%) 5 ( 4%) 10 ( 8%) 3 1 ( 1%) 5 ( 4%) 2 ( 2%) Unknown/Missing 2 ( 2%) 1 ( 1%) 1 ( 1%) Surgery Total Resection 108 (96%) 12 (10%) 15 (13%) Subtotal Reseaction 2 ( 2%) 53 (42%) 44 (37%) Biopsy Only 0 58 (46%) 58 (48%) Unknown/No Detail/Missing 2 ( 2%) 2 ( 2%) 3 ( 2%) Histology from Central Review Astrocytoma 17 (15%) 29 (23%) 35 (29%) Oligodendroglioma 50 (45%) 56 (45%) 48 (40%) Oligoastrocytoma 45 (40%) 40 (32%) 37 (31%) Contrast Enhancement on Pre-Op Scan Present 54 (48%) 74 (59%) 77 (64%) Absent 58 (52%) 51 (41%) 43 (36%) Pre-Op Non-enhancing Tumor Size (mm) N Mean Median Range Pre-Op Enhancing Tumor Size (mm) N Mean Median Range

6 June Table 3.1 (continued) Observation (N=112) (N=125) RT + PCV (N=120) Risk Low Risk 109 (97%) 1 ( 1%) 1 ( 1%) High Risk 3 ( 3%) 124 (99%) 119 (99%) MMSE N Mean Median Range IV. Toxicities: Table 4.1 Toxicities (Late RT Toxicities appear in Table 4.2) (N=125) Grade RT+PCV (N=118) Grade Allergy/immunology * 0 Auditory/hearing Blood/bone marrow Cardiovascular (arrhythmia) Cardiovascular (thrombosis) * Cardiovascular (general) 3 1 1* Coagulation Constitutional symptoms (fatigue) * Constitutional symptoms (other) Dermatology/skin Endocrine Gastrointestinal (constipation) Gastrointestinal (nausea/vomiting) Gastrointestinal (other) Hemorrhage Hepatic * 2* Infection/febrile neutropenia Metabolic/laboratory Musculoskeletal Neurology * 1* * 0 Ocular/visual Pain (headache) Pain (other) Pulmory * 0 Renal/genitourinary Sexual reproductive function Other tox. From chemotherapy flow sheets Maximum Toxicity per Patient Maximum Non-Hematologic Toxicity per Patient *Case details on next page

7 June Table 4.1 (continued) *Arm CN Toxicity Grade Description/Comment Days from RT Start 35 Neurology 3 Seizure Neurology 3 Seizure Neurology 4 Seizure Neurology 3 Ataxia (incoordination) Neurology 3 Seizure Cardio. (general) 3 Edema 118 Neurology 3 Mood alteration depression 101 RT+PCV 4 Neurology 3 Seizure Hepatic 3 Gama-glutamyltransferase increased Neurology 3 Seizure Constitutional Symptoms 4 Fatigue (lethargy, malaise, asthenia) Neurology 3 Mood alteration anxiety Hepatic 3 SGPT (ALT) Neurology 3 Speech impairment Pulmonary 3 Dyspnea Neurology 3 Seizure Hepatic 4 Gamma-glutomyltransferase increased Neurology 3 Speech impairment Pulmonary 3 Dyspnea Allergy/immunology 3 Allergic reaction/ hypersensitivity Cardio. (thrombosis) 4 Thrombosis/embolism Hepatic 4 SGOT (AST), SGPT (ALT) Neurology 3 Neuropathy motor Neurology 3 Memory loss Neurology 3 Neuropathy motor Hepatic 3 SGPT (ALT) Neurology 3 Neuropathic pain Neurology 3 Dizziness/light headache, hallucinations, 260 memory loss, confusion, mood alternation-anxiety 370 Neurology 3 Seizure 51 Table 4.2 Late RT Toxicities* (N=122) Grade RT+PCV (N=113) Grade Brain Skin (within the field) Eye Subcutaneous Tissue Other # Other # Worse toxicity per patient * Using RTOG/EORTC Late Radiation Morbidity Scoring Schema

8 June V. Treatment Evaluation: Table 5.1 RT Review (N=36) RT+PCV (N=36) Per Protocol 32 (89%) 29 (80%) Variation-Acceptable 3 ( 8%) 5 (14%) Deviation-Unacceptable 1 ( 3%) 1 ( 3%) Incomplete RT-Death 0 1 ( 3%)