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

Study Overview
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Brief Summary
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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.

Detailed Description
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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, wolfgang.wick@med.uni-heidelberg.de or CRO: Alcedis, Giessen at Alcedis GmbH, I. Helm, Winchester Str. 2, 35394 Gießen, Tel.: 0641 944360, Fax: 0641 94436 70, E-mail: ihe@alcedis.de 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.

Official Title
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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)

Conditions
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Glioblastoma, Anaplastic Astrocytoma

Intervention / Treatment
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* Drug: Temozolomide
* Radiation: Radiotherapy of the partial brain.


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Radiotherapy<br>6 weeks standard partial brain treatment. | Radiation: Radiotherapy of the partial brain.<br>* 60 Gy in 30 fractions à 2 Gy.<br>|
| Experimental: Temozolomide<br>Temozolomide in a one week on/one week off schedule per Wick et al. 2004 and A. Wick et al. 2007 | Drug: Temozolomide<br>* 100 mg/m2 per day on seven out of fourteen days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | 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. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival | 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). | 12 months | 
| Best response | Response is assessed according MacDonald Criteria based on regular 3-monthly MRI. | Within the first 8 months after surgery | 
| Molecular prognostic or predictive biomarkers | 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. | At 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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elderly, brain tumors, MGMT, chemotherapy, Newly diagnosed, patients > 65 years