Radiotherapy Offers Modest Glioblastoma Survival Benefit

PARIS, April 12 -- Radiation therapy for older glioblastoma patients extended survival up to three-months without reducing quality of life or cognition, according to researchers here.

In a randomized trial of 81 patients with glioblastoma from 10 French centers, 39 patients who received radiotherapy plus supportive care had a mean 12.2-week survival edge over 42 patients getting only supportive care, the investigators reported in the April 12 issue of the New England Journal of Medicine.

There were no severe adverse events related to radiotherapy and quality of life, and cognitive evaluations over time did not differ significantly between the treatment groups, found Jean-Yves Delattre, M.D., of Hpital de la Salptrire, and colleagues in the Association of French-Speaking Neuro-Oncologists.

Patients 70 or older (median, 73, range, 70 to 85) were enrolled from February 2001 to January 2005 with newly diagnosed glioblastoma and a Karnofsky performance score of 70 or higher.

The focal radiation was delivered in daily fractions of 1.8 Gy given five days a week, for a total dose of 50 Gy. Of the 81 patients, 39 (48%) had undergone debulking surgery.

The dose was selected to minimize an age-related risk of radiation-induced neurotoxicity. Although there were no cases of delayed neurotoxicity, the short survival of these patients may have precluded late toxicity, the researchers noted. So it is unclear whether a total dose of 60 Gy would have increased the survival.

The trial was discontinued at the first interim analysis (January 2005), which showed that according to a preset boundary of efficacy, radiotherapy and supportive care were superior to supportive care alone, the investigators said.

At a median follow-up of 21 weeks, 73 patients (90%) had died. The median survival for the 39 patients who received radiotherapy plus supportive care was 29.1 weeks, versus 16.9 weeks for the 42 patients who received supportive care alone.

The hazard ratio for death in the radiotherapy group was 0.47 (95% confidence interval, 0.29-0.76; P=0.002 by the log-rank test) indicating a 53% relative reduction in the risk of death for the radiotherapy patients compared with supportive care-only patients.

The 16.9 week median survival of the supportive care patients was similar to the median survival for younger patients treated similarly with more than two decades earlier, the researchers wrote.

Conversely, they said, the 12.2-week survival advantage with radiotherapy in the older patients was about half the survival gain in two earlier studies (22 weeks and 24 weeks) that compared conventional radiotherapy (total dose 45 to 60 Gy) with supportive care in a younger population.

Cognitive evaluations over time did not differ significantly between treatment groups (P=0.84). Although the Karnofsky performance measures declined over time as did the health-related quality-of-life measures, there were no significant differences in the groups.

However, the researchers said they did not observe the mild-to-moderate improvement on several scales reported in younger patients after radiotherapy, with or without chemotherapy.

Elderly patients with cancer are underrepresented in clinical trials, often for study-imposed restrictions, as well as co-existing conditions, other concerns, fear of toxicity, and the reluctance of physicians to enroll older patients in trials, Dr. Delattre wrote.

Nevertheless, the researchers said, despite the modest survival benefit, this study showed that these barriers may be overcome, even in trials that involve a rapidly progressive, fatal disease.

In an accompanying editorial Lillian L. Siu, M.D., of the University of Toronto, discussed ageism in cancer therapy trials. In addition to lack of opportunity, logistic and financial barriers, management of coexisting illnesses, or lack of knowledge about clinical trials, many physicians and patients, not unreasonably, associate older age with inferior outcomes and more toxic effects, Dr. Siu wrote.

Yet, she said, clinical trials that have a proportionate representation of the elderly would permit translation of the results of older patients and allow for direct comparisons of younger and older patients who have been treated in similar ways.

From the societal perspective, the graying of the population has substantial implications for the consumption of drugs and health care, she said.

The prescription of therapies to the elderly on the basis of trial information obtained primarily from younger, more fit patients does not constitute good clinical practice, she said. On the other hand, evidence-based data from older patients would ensure that treatment is prescribed for these individuals when it may offer a meaningful gain in survival, quality of life, or both, or be avoided when it may not be beneficial.

"The conduct of randomized controlled trials for the treatment of cancer in older patients is no longer a theoretical concept-it is a reality that has come of age," Dr. Siu concluded.