Pharmacotherapy
Temozolomide Brings New Hope for Glioblastoma Patients
By European Organisation for Research and Treatment of Cancer
Mar 10, 2005, 07:40

A large international study conducted by the European Organisation for Research and Treatment of Cancer (EORTC) in collaboration with the National Cancer Institute of Canada (NCIC) Clinical Trials Group demonstrated that the addition of a novel chemotherapy agent, Temozolomide (brand name: Temodal(R)) to radiation therapy increases survival in patients suffering from glioblastoma, a very aggressive form of a brain tumour.

Further, molecular analyses of the tumour allowed for the identification of those patients most likely to benefit from this type of treatment. The findings are leading to a new standard of care for patients with this fast growing and devastating cancer. The results of this landmark trial are published in two companion papers in this weeks' edition of the New England Journal of Medicine (publication date: 10 March 2005).

Primary tumours originating in the brain account for less than 5% of all cancer diagnoses. However, brain cancer frequently affects previously healthy younger men and women in the middle of their most active life.

Glioblastoma is the most common type of primary malignant brain tumour in adults with a yearly incidence of 5-7 persons per 100.000. Thus in the European Union approx. 20'000 new patients are diagnosed every year. Glioblastoma is a rapidly growing malignant brain tumour and usually has a fatal outcome.

Prior to the discovery of this new therapy, the average life expectancy of patients with glioblastoma was about 1 year. The results of this study demonstrate a clear improvement of survival. At 2 years only 10% of patients treated with radiotherapy alone were alive, compared to 26% of patients receiving the combination of both radiotherapy and temozolomide chemotherapy.

If patients were to be selected according to their molecular profile -- the investigators analysed the functionality of a gene responsible for DNA repair, the so called MGMT gene -- the improvement is even more dramatic, as almost half of those patients whose tumours carry an inactivated MGMT gene are alive after 2 years.

Importantly, the study also showed that this new combined therapy did not impact negatively on the patients' quality of life. Health- related quality of life has become an increasingly important endpoint in cancer studies.

In this trial, almost 600 patients were randomised within less than one and a half years. This rapid accrual and final success would not have been possible without well-established structures for academic clinical research, like the EORTC and NCIC Clinical Trials Group.

Recently implemented new regulations in Europe with an increased administrative burden, complex liability and insurance issues as well as exploding costs have become a threat for future successful conduct of clinical trials.

This example illustrates that progress in cancer treatment requires well-functioning international collaborative networks and integrated laboratory-based science.

The EORTC also assembled a laboratory research team that succeeded in identifying a molecular change in the tumour that predicts benefit from this new therapy. Future brain tumour trials by the EORTC will continue to integrate clinical and basic research to further refine the molecular basis of brain cancer, find new therapeutic targets, and develop and test new treatments.

The lead investigators comment:

"This is the first trial to demonstrate that we can truly impact this devastating disease with chemotherapy. This is only a first step toward cure of brain cancer patients and should now fuel interest, continued international collaboration and research to further improve the outcome of these patients," says the lead author and trial initiator Roger Stupp, MD for the University Hospital Multidisciplinary Oncology Centre in Lausanne, Switzerland.

"Without the close collaboration between the hospital based research laboratory and the leading clinicians, this interdisciplinary success would never have been possible. I hope this example will stimulate a closer collaboration between basic and clinical research in the future," remarks Monika Hegi, PhD signing author for the translation research work and leader of the laboratory of Tumor Biology and Genetics of the University Hospital Lausanne Neurosurgery department and project leader at the National Center of Competence in Research (NCCR Molecular Oncology).

"In 25 years of academic cancer medicine, it is the first time that I have witnessed such a progress in any of the deadliest forms of human cancers. The study has also been an exceptional model of multidisciplinary as well as international cooperation, with such an outstanding input of so many participants," said co-investigator and radiation therapy protocol leader, Rene-Olivier Mirimanoff MD, at the Radiation Oncology Department of the University Hospital in Lausanne, Switzerland.

"Until now, there have been few treatment options for glioblastoma patients," says Dr. Gregory Cairncross, a pioneer in neuro-oncology research and one of the study's primary investigators and head of the Department of Clinical Neurosciences at the University of Calgary in Alberta, Canada. "The results of this trial will dramatically improve treatment and outcome for many of these patients and will open the door to further trials to expand this treatment combination. The key to the new therapy's effectiveness is that temozolomide causes very few side effects and is well tolerated by patients. This means patients can take the drug every day during their radiation treatment instead of once every eight weeks -- the common dosage for other chemotherapy drugs."

"This landmark study represents the most important advance in the management of glioblastoma since radiotherapy was shown to be of benefit over 35 years ago," comments Dr. Warren Mason, a lead investigators in Canada and head of the neuro-oncology unit at the Princess Margaret Hospital in Toronto, Ontario/Canada. "This study also identified MGMT the first clinically relevant molecular marker for glioblastoma which not only serves as a prognostic factor for survival, but also as a predictor for response to chemotherapy. This observation paves the way for using the unique tumor genetic signature as a guide for individualizing therapy and optimizing outcome."

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