Comparison of Different Methods to Test MGMT Status in Glioblastoma Patients (ECOM)

Comparative Assessment of Methods to Analyze MGMT as a Predictive Factor of Response to Temozolomide in Glioblastomas.

Treatment for newly diagnosed glioblastomas currently involves surgical resection followed by Temozolomide chemotherapy with concomitant radiotherapy, and then 6 cycles of Temozolomide in adjuvant. According to many studies, only those patients not expressing the enzyme repair MGMT benefit from the adjunction of Temozolomide. Therefore, many patients receive unnecessary treatment. The aim of this project is to compare different techniques for analysis of MGMT in order to choose the approach with the best cost/utility ratio, which will allow the selection of patients likely to respond to TMZ chemotherapy during the first course of GBM treatment.

Study Overview

• Status: Completed
• Conditions: Glioblastoma
• Intervention / Treatment: Drug: Temozolomide; Radiation: Radiation Therapy

Detailed Description

Treatment for newly diagnosed glioblastomas (GBM) currently involves surgical resection followed by Temozolomide (TMZ) chemotherapy with concomitant radiotherapy, and then 6 cycles of TMZ in adjuvant (Stupp schedule). According to many studies, only those patients not expressing the enzyme repair MGMT benefit from the adjunction of TMZ. Therefore, many patients receive unnecessary treatment at an average cost of about 15,000 euros.

The aim of this project is to compare different techniques for analysis of MGMT in order to choose the approach with the best cost/utility ratio, which will allow the selection of patients likely to respond to TMZ chemotherapy during the first course of GBM treatment. Another aspect of this project is to evaluate the extra cost produced by TMZ treatment, and therefore the expected cost saving in the case of using a reliable predictive factor. This kind of evaluation is of great importance, as the MGMT test status is beginning to appear in the decisional care trees of high-grade gliomas The two main techniques for MGMT analysis are currently immunohistochemistry (IH) and molecular analysis of promoter methylation of the gene. Immunohistochemistry is simple and quick, but there is no consensus about labelling or evaluation of the staining, all of which could lead to variability in results. Studies of promoter methylation are currently performed by the MS-PCR technique, in particular the article published in the N Engl J Med in 2005 showing that only patients with a methylated promoter benefit from TMZ adjunction. This technique appears somewhat rudimentary compared to techniques avoiding subjectivity linked to eye reading of the gel after electrophoresis of PCR products.

In phase one of this multicenter national study, IH, MS-PCR, MethyLight, pyrosequencing and MS-HRM will be compared in a retrospective study on 100 samples (frozen for molecular analysis and paraffin-embedded for IH), taken from patients treated according to the Stupp protocol and with a follow-up of 18 months at least. In phase 2, the two techniques with the best cost/efficacy ratio (based on predictive value, analytical quality and feasibility of the test) will be implemented in all the laboratories according to a standard protocol developed by the referral centre for the tests. The dissemination of quality controls will allow us to check that the same results are obtained from one laboratory to another. In phase 3, samples will be analysed prospectively in the different centres and a medico-economic analysis will be undertaken on the integration of MGMT analysis into the standard care of GBM patients. Two types of analysis will be performed: i) on the costs of the techniques, allowing us in particular to estimate the possible additional clinical cost generated and its effect on the cost of a hospital stay, in order to adjust the charging system, and ii) on alternative care strategies for the patients, with or without screening, leading to improve the target of treatments by TMZ, with the aim of improving the definition of "options and recommendations" (cost-utility analysis).

• Study Type: Observational
• Enrollment (Actual): 300

Contacts and Locations

Study Locations

• France
  • Alsace
    • Strasbourg, Alsace, France, 67
      • CHRU Hautepierre
  • Aquitaine
    • Bordeaux, Aquitaine, France, 33000
      • CHU de Bordeaux
  • Basse Normandie
    • Caen, Basse Normandie, France, 14000
      • CHU Côte de Nacre
  • Brittany
    • Rennes, Brittany, France, 35000
      • Center Eugene Marquis
  • Ile de France
    • Paris, Ile de France, France, 75000
      • CHU La Salpetriere
  • Nord Pas-de-Calais
    • Lille, Nord Pas-de-Calais, France, 59000
      • CHRU de Lille
  • Paca
    • Marseille, Paca, France, 13000
      • CHU La Timone
  • Poitou-Charentes
    • Poitiers, Poitou-Charentes, France, 86000
      • CHU de Poitiers
  • Rhone-Alpes
    • Grenoble, Rhone-Alpes, France, 38000
      • CHU de GRENOBLE
    • Lyon, Rhone-Alpes, France, 69000
      • CHU de Lyon

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with glioblastoma, eligible to resection and to a treatment according to the Stupp schedule.

Description

Inclusion Criteria:

• Adult, age from 18 to 70
• Pre-surgical diagnosis compatible with a primary or secondary sub-tentorial glioblastoma than can be resected
• No counter-indication to an adjuvant treatment according to the Stupp schedule
• Free written informed consent

Exclusion Criteria:

• Absence of tumor sample available
• Definite histology not related to a glioblastoma or a main oligodendroglioma component

Study Plan

How is the study designed?

Design Details

• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Stupp protocole; All subjects enrolled must be treated according to the Stupp schedule : surgical resection followed by Temozolomide (TMZ) chemotherapy with concomitant radiotherapy, and then 6 cycles of adjuvant Temzolomide.	Drug: Temozolomide; According to sites procedures; Other Names: Temodal (brand name).; Radiation: Radiation Therapy; According to sites procedures; Other Names: Radiotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival of patients according to their MGMT status.	Predictive MGMT methylation tests values related to mean overall survival.	12 months after last enrollment

Secondary Outcome Measures

Outcome Measure	Time Frame
Progression-Free Survival	12 months

Collaborators and Investigators

• Sponsor: Center Eugene Marquis
• Collaborators: Rennes University Hospital

Publications and helpful links

General Publications

• Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. doi: 10.1056/NEJMoa043330.
• Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005 Mar 10;352(10):997-1003. doi: 10.1056/NEJMoa043331.

Study record dates

Study Major Dates

• Study Start: March 1, 2009
• Primary Completion (Actual): April 1, 2015
• Study Completion (Actual): June 1, 2015

Study Registration Dates

• First Submitted: April 20, 2011
• First Submitted That Met QC Criteria: April 29, 2011
• First Posted (Estimate): May 2, 2011

Study Record Updates

• Last Update Posted (Estimate): January 29, 2016
• Last Update Submitted That Met QC Criteria: January 28, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: Glioblastoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide
• Other Study ID Numbers: ECOM-Glioblastome