Nothing Ventured, Nothing Gained: Treatment of Glioblastoma Multiforme in the Elderly

In this issue of the Journal of Clinical Oncology, Roa et al present results of a prospective randomized clinical trial of patients 60 years of age with glioblastoma multiforme (GBM), the most common and lethal of all primary brain tumors in adults. Patients either received a standard course of radiation therapy (RT), 60 Gy in 30 fractions over 6 weeks, or short-course RT, 40 Gy in 15 fractions over 3 weeks, without chemotherapy. The primary end point of the trial was overall survival. Of the 100 patients randomly assigned, 95 were eligible and analyzable. The median survival times and 1-year survival rates were similar between the two regimens; 5.1 months and 9% for standard RT, and 5.6 months and 15% for short-course RT, respectively. All patients had died by 2 years. On the surface, the authors’ conclusion that “the abbreviated course of RT appears to be a reasonable treatment option for older patients with GBM” seems quite reasonable. However, the data require closer scrutiny, and the conclusion needs several qualifications, before all elderly patients with GBM are treated with shortcourse RT alone. A number of prognostic factors play an important role in determining the survival of patients with GBM. In a recent re-analysis of the original Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis database, of 1,672 GBM patients, the most important prognostic factors were age, Karnofsky Performance Status (KPS), extent of surgical resection, and neurologic function. Age had the greatest impact on survival, with “older” defined as 50 years of age. Older GBM patients were divided into two groups. The more favorable group had KPS 70, gross or subtotal resection, and better neurologic function; their median survival time and 1-year survival rates were 11.2 months and 46%, respectively. The less favorable group had either KPS 70, biopsy alone, or poor neurologic function; their median survival time and 1-year survival rates were 7.5 months and 28%, respectively. Both RTOG groups of older GBM patients had better median survival times and 1-year survival rates than either the standard or short-course treatment arms of the Roa et al study. Why did these patients fare so poorly? First, they were a prognostically unfavorable group from the start, with a low median KPS of only 70 in both treatment arms. Second, biopsy alone was performed in 39% of patients, with only 9% of patients undergoing gross total resection, compared to biopsy in 17% and gross total resection in 19% of 645 patients treated on three consecutive RTOG clinical trials. In that study, the median survival time was 6.6 months with biopsy alone, compared to 11.3 months with resection. A similar observation was recently made by the Glioma Outcomes Project in a group of 565 patients with malignant glioma (primarily GBM) diagnosed between 1997 and 2001. The value of debulking GBM in the elderly has also now been shown in a small Finnish randomized clinical trial recently reported by Vourinen et al. In that study, 23 patients 65 years old with malignant glioma (83% with GBM) were randomly assigned to biopsy only or to surgical resection, followed by RT. The median survival time of 5.6 months was significantly longer with resection, compared to 2.8 months with biopsy. When compared to biopsy, resection is also associated with improved quality-of-life in older GBM patients. Third, patients in the Roa et al study were not allowed to have chemotherapy until recurrence. Although the benefit of up-front chemotherapy for malignant glioma is modest, a meta-analysis of 3,004 patients treated on 12 controlled clinical trials of postoperative RT in which patients were randomly assigned to RT, with or without chemotherapy, showed a 6% increase in the 1-year survival rate (from 40% to 46%) with chemotherapy, and a 15% relative decrease in the risk of death— differences which were significant, irrespective of histology, age, performance status, or extent of surgical resection. The value of combined RT and chemotherapy in the elderly with GBM has now been shown in a JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 9 MAY 1 2004