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Phase III Trial of Primary Radio- or Chemotherapy in Malignant Astrocytoma of the Elderly (Methusalem)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01502241
Recruitment Status : Completed
First Posted : December 30, 2011
Last Update Posted : December 30, 2011
Information provided by (Responsible Party):
Prof. Dr. Wolfgang Wick, Heidelberg University

Brief Summary:
The study aims to optimize the treatment of elderly subjects (> 65) with anaplastic astrocytoma and glioblastoma. Current treatment policies tend to be no more than palliative. There is no consensus as to how radical the surgery should be. Involved-field radiotherapy is the treatment most likely to be accepted apart from supportive and palliative measures. The role of chemotherapy is barely defined. Study data available to date does not suggest that this patient population would benefit from combined radiochemotherapy. The aim of the study is to verify the hypothesis that first-line chemotherapy with one week on/one week off temozolomide is not inferior to extended-field radiotherapy in the first-line treatment of anaplastic astrocytoma and glioblastoma in the elderly (> 65 age group). The primary endpoint is median survival, as life expectancy is limited to several months. Secondary endpoints are response rates in both arms (CR, PR, MacDonald et al. 1990), median progression-free survival, 1-year and 2-year survival rates, definition of MGMT as molecular genetic prognostic or predictive markers, and quality of life. Theoretically, it should be possible to preserve quality of life in the first-line chemotherapy arm of the study.

Condition or disease Intervention/treatment Phase
Glioblastoma Anaplastic Astrocytoma Drug: Temozolomide Radiation: Radiotherapy of the partial brain. Phase 3

Detailed Description:

This study is a prospective, randomized Phase III intervention study. Following histological documentation of the diagnosis by biopsy or resection of an anaplastic astrocytoma or glioblastoma, patients will be randomized either to receive postoperative extended-field radiotherapy (arm A) or to receive postoperative chemotherapy with temozolomide (arm B). Randomization will be done for all sites at the CRO, Alcedis GmbH.

For patients intending to participate in the study, the procedure is as follows:

  • Request a reference neuropathological review from the brain tumor reference center in Bonn (Prof. Dr. G. Reifenberger) through the local neuropathology department. This review need not be present at randomization because anaplastic astrocytoma and glioblastoma cases are eligible
  • Contact: Prof. Dr. W. Wick, Dep. Neurooncology, National Center for Tumor Diseases and Neurology Clinic, University of Heidelberg, or CRO: Alcedis, Giessen at Alcedis GmbH, I. Helm, Winchester Str. 2, 35394 Gießen, Tel.: 0641 944360, Fax: 0641 94436 70, E-mail:
  • Provide written confirmation that the patient signed the ethics committee-approved consent form
  • Submit the registration form and a copy of the EORTC-QLQ given in Annexes

In subjects with progressive or recurrent disease, the investigating site will verify whether specific tumor treatment is justified. If yes, chemotherapy with temozolomide is recommended in arm A, possibly after further surgery. Subjects in arm B will receive radiotherapy, possible after further surgery. As all-cause mortality is the primary endpoint, all therapeutic measures following first-line therapy should be documented.

If study treatment is discontinued (first-line therapy) because of progressive disease or if progression occurs after completion of study treatment, the pertinent images should be submitted to the reference center for neuroradiology in Tübingen for reference review.

The treatment modalities employed in the study are chemotherapeutic and radiotherapeutic procedures licensed in the Federal Republic of Germany for use in human subjects. Temozolomide is currently licensed for treating subjects with recurrent disease and since 2006 in newly diagnosed glioblastoma together with radiotherapy. The time allotted for the individual treatment sections is 6 weeks for radiotherapy, while chemotherapy will be continued until progression or unacceptable adverse effects occur. The precise chemotherapy sequence is shown in the protocol. The criteria for withdrawal from the study are defined in in the protocol. Four years is the period scheduled for recruiting all patients.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 412 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Temozolomid (One Week on/One Week Off) Versus Strahlentherapie in Der Primärtherapie Anaplastischer Astrozytome Und Glioblastome Bei älteren Patienten: Eine Randomisierte Phase III-Studie (Methvsalem)
Study Start Date : January 2005
Actual Primary Completion Date : November 2010
Actual Study Completion Date : November 2011

Arm Intervention/treatment
Active Comparator: Radiotherapy
6 weeks standard partial brain treatment.
Radiation: Radiotherapy of the partial brain.
60 Gy in 30 fractions à 2 Gy.

Experimental: Temozolomide
Temozolomide in a one week on/one week off schedule per Wick et al. 2004 and A. Wick et al. 2007
Drug: Temozolomide
100 mg/m2 per day on seven out of fourteen days.

Primary Outcome Measures :
  1. Overall survival [ Time Frame: 12 months ]
    The primary endpoint was overall survival, measured in days from surgery to death for any reason. Patients alive at the day of the last contact were censored.

Secondary Outcome Measures :
  1. Event-free survival [ Time Frame: 12 months ]
    Secondary efficacy end points included EFS. EFS was defined as time from surgery to first progression for patients with progression respectively to death for patients without progression. Patients without progression or death were censored at the day of the last contact. Univariate analysis of OS and EFS used Kaplan-Meier estimates21 and a Cox proportional hazard model for evaluating Hazard Ratios (HR) with 95%-confidence intervals and median OS and EFS with 95%-confidence intervals (CI).

  2. Best response [ Time Frame: Within the first 8 months after surgery ]
    Response is assessed according MacDonald Criteria based on regular 3-monthly MRI.

  3. Molecular prognostic or predictive biomarkers [ Time Frame: At 12 months ]
    Tumor tissue, fresh or paraffine-embedded, or DNA/RNA/proteins from tissue are analyzed for the status of known molecular parameters, e.g. MGMT, for a prognostic or predictive role. Further, newly discovered molecular parameters are assessed for their potential to predict outcome.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   65 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Histologically confirmed supratentorial anaplastic astrocytoma or glioblastoma
  • Age > 65
  • Karnofsky performance score > 60%
  • Neutrophilic granulocyte count > 1500/µl
  • Platelet count > 100 000/µl
  • Hemoglobin > 10 g/dl
  • Serum creatinine < 1.5 times the lab's upper normal limit
  • AST or ALT < 3 times the lab's upper normal limit
  • Alkaline phosphatase < 3 times the lab's upper normal limit
  • No previous systemic chemotherapy
  • No previous radiotherapy to the brain
  • Written consent

Exclusion Criteria:

  • Serious medical or neurological condition with a poor prognosis
  • HIV infection
  • Second cancer requiring radiotherapy or chemotherapy (contact the study coordinat if necessary)
  • Hypersensitivity to temozolomide
  • Conditions associated with regular vomiting that might affect oral administration of the drugs
  • Psychological, familial, social or geographical circumstances with major implications for compliance with the study visit schedule
  • Patient was taking part in other intervention studies within a month of starting this study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01502241

Show Show 23 study locations
Sponsors and Collaborators
Heidelberg University
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Study Director: Michael Weller University of Zurich
Principal Investigator: Wolfgang Wick Heidelberg University
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Prof. Dr. Wolfgang Wick, Chairman and Director Neurooncology, Heidelberg University Identifier: NCT01502241    
Other Study ID Numbers: NOA-08
05-01 ( Registry Identifier: German Cancer Society )
First Posted: December 30, 2011    Key Record Dates
Last Update Posted: December 30, 2011
Last Verified: December 2011
Keywords provided by Prof. Dr. Wolfgang Wick, Heidelberg University:
brain tumors
Newly diagnosed
patients > 65 years
Additional relevant MeSH terms:
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Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents