Radiation Therapy With or Without Temozolomide in Treating Older Patients With Newly Diagnosed Glioblastoma Multiforme

A Randomized Phase III Study of Temozolomide and Short-Course Radiation Versus Short-Course Radiation Alone In The Treatment of Newly Diagnosed Glioblastoma Multiforme in Elderly Patients

RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving radiation therapy together with temozolomide may kill more tumor cells. It is not yet known whether radiation therapy and temozolomide are more effective than radiation therapy alone in treating glioblastoma multiforme.

PURPOSE: This randomized phase III trial is studying radiation therapy and temozolomide to see how well they work compared with radiation therapy alone in treating patients with newly diagnosed glioblastoma multiforme.

Study Overview

• Status: Completed
• Conditions: Brain and Central Nervous System Tumors
• Intervention / Treatment: Drug: temozolomide; Genetic: DNA methylation analysis; Procedure: quality-of-life assessment; Radiation: Radiation

Detailed Description

OBJECTIVES:

Primary

• Compare overall survival rates in older patients with newly diagnosed glioblastoma multiforme treated with short-course radiotherapy with or without temozolomide.

Secondary

• Compare progression-free survival of patients treated with these regimens.
• Compare the nature, severity, and frequency of adverse events in patients treated with these regimens.
• Compare the quality of life of patient treated with these regimens.
• Determine the methylation status of the O6-methylguanine-DNA methyltransferase promoter.

OUTLINE: This is a multicenter, randomized study. Patients are stratified according to center, age (65-70 years vs 71-75 years vs ≥ 76 years), ECOG performance status (0-1 vs 2), and extent of resection at surgery (biopsy only vs complete or incomplete resection). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients undergo radiotherapy once daily on days 1-5, 8-12, and 15-19 in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients undergo radiotherapy as in arm I and receive oral temozolomide once daily on days 1-25.

Beginning 4 weeks after completion of radiotherapy and temozolomide, patients receive adjuvant oral temozolomide once daily on days 1-5. Treatment with temozolomide alone repeats every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.

Patients complete quality of life questionnaires at baseline and periodically during study treatment.

Tissue samples are collected at baseline and analyzed for methylation status of the O6-methylguanine-DNA methyltransferase promoter.

After completion of study treatment, patients are followed every 3 months.

• Study Type: Interventional
• Enrollment (Actual): 562
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Centre
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute
  • British Columbia
    • Surrey, British Columbia, Canada, V3V 1Z2
      • BCCA - Fraser Valley Cancer Centre
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • BCCA - Vancouver Cancer Centre
    • Victoria, British Columbia, Canada, V8R 6V5
      • BCCA - Vancouver Island Cancer Centre
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • New Brunswick
    • Saint John, New Brunswick, Canada, E2L 4L2
      • Atlantic Health Sciences Corporation
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V7
      • QEII Health Sciences Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Juravinski Cancer Centre at Hamilton Health Sciences
    • London, Ontario, Canada, N6A 4L6
      • London Regional Cancer Program
    • Toronto, Ontario, Canada, M4N 3M5
      • Odette Cancer Centre
    • Toronto, Ontario, Canada, M5G 2M9
      • Univ. Health Network-Princess Margaret Hospital
  • Quebec
    • Montreal, Quebec, Canada, H2L 4M1
      • CHUM - Hopital Notre-Dame
    • Montreal, Quebec, Canada, H2W 1S6
      • McGill University - Dept. Oncology
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Centre Hospitalier Universitaire de Sherbrooke
    • Trois-Rivieres, Quebec, Canada, G8Z 3R9
      • Centre Hospitalier Regional de Trois-Rivieres
• Germany
  • Frankfurt, Germany, 60590
    • Klinikum der J.W. Goethe Universitaet
  • Freiburg, Germany, 79106
    • Universitaetsklinikum Freiburg
  • Leipzig, Germany, 04103
    • Universitaetsklinikum Leipzig
  • Tuebingen, Germany, 72076
    • Universitaetsklinikum Tuebingen
• Japan
  • Hiroshima, Japan, 734-8551
    • Hiroshima University Hospital
• Netherlands
  • Maastricht, Netherlands, 6201
    • Maastro - Maastricht Radiation Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years to 120 years (Older Adult)
• Accepts Healthy Volunteers: No

Description

DISEASE CHARACTERISTICS:

• Histopathologically confirmed glioblastoma multiforme

  • Grade IV disease by WHO classification
  • Newly diagnosed disease
• Initial diagnostic surgery or biopsy performed within the past 4 weeks
• Not a candidate for standard radiotherapy (60Gy/30 fractions over 6 weeks) in combination with temozolomide

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Absolute granulocyte count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Creatinine ≤ 1.5 times upper limit of normal (ULN)
• Bilirubin ≤ 1.5 times ULN
• ALT and AST < 2.5 times ULN
• No known hypersensitivity to temozolomide or compounds with similar chemical composition to temozolomide
• No history of other malignancies except adequately treated nonmelanoma skin cancer, curatively treated in situ cancer of the cervix, or other curatively treated solid tumors with no evidence of disease for at least 5 years
• No serious active infection (e.g., wound infection requiring parenteral antibiotics) or other serious underlying medical conditions that would preclude study treatment
• No other condition (e.g., psychological or geographical) that would preclude study compliance

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy
• No prior radiotherapy
• No prior or concurrent investigational therapy
• No concurrent surgical procedures for tumor debulking
• No concurrent stereotactic boost radiotherapy
• No other concurrent chemotherapy, immunotherapy, or biological therapy
• No concurrent epoetin alfa
• Concurrent corticosteroids allowed provided the patient has been on a stable or decreasing dose for at least 14 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Temozolomide; Temozolomide and short course radiation	Drug: temozolomide; Temozolomide (concurrent with radiation) 75 mg/m2 PO 3 weeks once a day, daily, from the first day to the last day of radiotherapy, but for no longer than 28 days, and then adjuvantly for up to 12 cycles (150 mg/m2 for the first 5 days of each cycle). Adjuvant TMZ may be escalated to 200mg/m2 in C2 onward if appropriate.; Genetic: DNA methylation analysis; A stratified log-rank test, adjusting for the stratification factors (except centre) plus MGMT promoter methylation status, will be used as the primary method to compare the overall survival between the two arms; Procedure: quality-of-life assessment; prior to randomization until end of study
Active Comparator: Radiation; Short course radiation alone	Genetic: DNA methylation analysis; A stratified log-rank test, adjusting for the stratification factors (except centre) plus MGMT promoter methylation status, will be used as the primary method to compare the overall survival between the two arms; Procedure: quality-of-life assessment; prior to randomization until end of study; Radiation: Radiation; Short course radiotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Time from date of randomization to the date of death of any causes, or censored at last known alive date.	7 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	Time from date of randomization to the date of disease progression or death whichever came first, or censored at last disease assessment date.	7 years
Adverse Events	Evaluated according to CTCAE V3.0	7 years
Methylation Status of the O6-methylguanine-DNA Methyltransferase Promoter	Overall survival for patients by Methylation status of the O6-methylguanine-DNA methyltransferase promoter	7 years

Collaborators and Investigators

• Sponsor: Canadian Cancer Trials Group
• Collaborators: European Organisation for Research and Treatment of Cancer - EORTC; Trans Tasman Radiation Oncology Group
• Investigators: Study Chair: Alba A. Brandes, MD, Ospedale Bellaria; Study Chair: Normand Laperriere, MD, FRCPC, Princess Margaret Hospital, Canada; Study Chair: James R. Perry, MD, FRCPC, Toronto Sunnybrook Regional Cancer Centre; Study Chair: Johan Menten, MD, PhD, University Hospital, Gasthuisberg

Publications and helpful links

General Publications

• Perry JR, Laperriere N, O'Callaghan CJ, Brandes AA, Menten J, Phillips C, Fay M, Nishikawa R, Cairncross JG, Roa W, Osoba D, Rossiter JP, Sahgal A, Hirte H, Laigle-Donadey F, Franceschi E, Chinot O, Golfinopoulos V, Fariselli L, Wick A, Feuvret L, Back M, Tills M, Winch C, Baumert BG, Wick W, Ding K, Mason WP; Trial Investigators. Short-Course Radiation plus Temozolomide in Elderly Patients with Glioblastoma. N Engl J Med. 2017 Mar 16;376(11):1027-1037. doi: 10.1056/NEJMoa1611977.
• Climans SA, Brandes AA, Cairncross JG, Ding K, Fay M, Laperriere N, Menten J, Nishikawa R, O'Callaghan CJ, Perry JR, Phillips C, Roa W, Wick W, Winch C, Mason WP. Temozolomide and seizure outcomes in a randomized clinical trial of elderly glioblastoma patients. J Neurooncol. 2020 Aug;149(1):65-71. doi: 10.1007/s11060-020-03573-x. Epub 2020 Jul 6.
• Fiorentino A, De Bonis P, Chiesa S, Balducci M, Fusco V. Elderly patients with glioblastoma: the treatment challenge. Expert Rev Neurother. 2013 Oct;13(10):1099-105. doi: 10.1586/14737175.2013.840419.

Study record dates

Study Major Dates

• Study Start (Actual): November 14, 2007
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): August 10, 2016

Study Registration Dates

• First Submitted: June 4, 2007
• First Submitted That Met QC Criteria: June 4, 2007
• First Posted (Estimated): June 5, 2007

Study Record Updates

• Last Update Posted (Actual): August 22, 2023
• Last Update Submitted That Met QC Criteria: August 3, 2023
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: adult glioblastoma; adult giant cell glioblastoma; adult gliosarcoma
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Nervous System Neoplasms; Central Nervous System Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide
• Other Study ID Numbers: CE6; CAN-NCIC-CE6 (Registry Identifier: NCI US - Physician Data Query); EORTC-26062-22061 (Other Identifier: EORTC); TROG 08.02 (Other Identifier: Trans-Tasman Radiation Oncology Group); SPRI-CAN-NCIC-CE.6; CDR0000547163 (Other Identifier: PDQ)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No