June 2005

From The Lab: Biotech

Continued from page 2

By Monya Baker (edit)

Better Hope for Brain Cancer
More-effective chemo, and who should get it

Context: Patients diagnosed with glioblastoma, a particularly malicious kind of brain cancer, rarely live much longer than a year, even with surgery and radiation therapy. Chemotherapy seems to help some patients but not most. Now, in a large clinical trial, teams led by Roger Stupp and Monika Hegi at the Centre Hospitalier Universitaire Vaudois in Switzerland and the European Organisation for Research and Treatment of Cancer have identified a more-effective form of chemotherapy and a way to single out which patients are likely to benefit from it.

Methods and Results: Patients were randomly assigned to receive radiation either on its own or combined with a drug called temozolomide, which damages DNA. On average, patients receiving the drug lived about 10 weeks longer than patients who did not, a benefit that has been considered significant enough to warrant the approval of other cancer drugs. (In fact, in March, the U.S. Food and Drug Administration approved temozolomide for treating glioblastoma.) When possible, the researchers also examined a DNA-repair gene in patients' tumors to see if it had been silenced by a so-called epigenetic modification, which alters gene expression without changing a gene's sequence. In healthy cells, such silencing is often one of the first steps toward cancer. Ironically, however, the silenced gene repairs the very damage caused by temozolomide. The results were striking: patients with silent DNA-repair genes who received temozolomide and radiation lived nine months longer than patients with active genes who received the same treatment. In fact, in cases where the DNA-repair gene was active, patients who received combination therapy did not live significantly longer than patients receiving radiation therapy alone.

Why it Matters: Chemotherapy makes people feel sick, and physicians are loath to prescribe it when it is unlikely to help a patient live longer. However, in the United States, chemotherapy is often prescribed even if it has only a slight chance of extending life. Stupp and Hegi's results show not only an effective therapy but also a way to pinpoint those patients most likely to benefit from it. The study also illustrates the need to improve the ease of genetic tests, particularly those that look for problems with gene expression rather than changes in DNA sequences. The researchers could tell whether a DNA-repair gene was silent in only 67 percent of the patients for whom tumor material was available, because some tumor samples were of poor quality. With such a promising way to detect which patients should get chemotherapy, researchers need better ways to collect and store samples, as well as tests that work with ill-preserved samples.

Sources: Stupp, R., et al. 2005. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New England Journal of Medicine 352: 987-996.

Hegi, M. E., et al. 2005. MGMT gene silencing and benefit from temozolomide in glioblastoma. New England Journal of Medicine 352:997-1003.