CHICAGO – Adding concomitant and adjuvant temozolomide to a shorter course of radiotherapy (RT) for elderly patients with glioblastoma improves progression-free survival, according to a phase III study presented at the annual meeting of the American Society of Clinical Oncology.
Both patients with and without MGMT methylated promoters in their tumors benefited, with the greatest benefit accruing to patients with promoter methylation, reported Dr. James Perry, head of the division of neurology at Sunnybrook Health Sciences Centre, Toronto.
The age of peak incidence of glioblastoma is 64 years, and the incidence is increasing. Best practice has been surgical resection and 6 weeks of radiation combined with oral temozolomide. A pivotal trial just over 10 years ago was restricted to patients younger than age 70 years and included few patients older than 65 years. It showed decreasing benefit of temozolomide with increasing age. Furthermore, trials in the elderly have compared only head-to-head radiation schedules or radiation alone with temozolomide alone. There has been no evidence on which to base practice for combining radiotherapy with temozolomide, Dr. Perry said.
To address this deficiency, Dr. Perry and his colleagues randomly assigned patients 65 years or older with newly diagnosed glioblastoma either to a short course of RT, consisting of 40 Gy in 15 fractions over 3 weeks or to the same radiotherapy plus 3 weeks of concomitant temozolomide and then adjuvant temozolomide for 12 months or until progression.
Patients (n = 562; 281 in each arm) averaged 73 years (range, 65-90 years), 77% had Eastern Cooperative Oncology Group performance score (PS) 0/1 and the rest PS 2, and 58% had had tumor resection.
Median overall survival was 9.3 months with the combined therapy and 7.6 months with radiation alone. Median progression-free survival was 5.3 vs. 3.9 months, respectively, with a hazard ratio of 0.50 (P less than .0001).
MGMT promoter methylation is a predictive marker for benefit from chemotherapy and a prognostic factor for survival. Forty-six percent of the tumors had this promoter methylation.
Temozolomide use added relatively more benefit if promoters were methylated. Patients with methylated promoters had an overall survival of 7.7 months with radiation alone and 13.5 months with combined radiation and temozolomide (HR, 0.53; P = .0001). For unmethylated promoters, overall survival with radiation alone was 7.9 months and was 10.0 months when temozolomide was added (HR, 0.75; P = .055), suggesting some benefit from temozolomide, although not as great as with tumors with methylated promoters.
“The advantage of this combined treatment with chemoradiation was achieved with minimal side effects,” Dr. Perry reported. Mild nausea and vomiting occurred mostly in the first weeks of therapy, and a slight increase in grade 3/4 hematologic toxicity was seen but occurred in less than 5% of patients. No differences in quality of life were reported between the treatment arms.
Most patients could easily complete the treatment plan, with 97% adherence to the 3 weeks of chemoradiation. “This is quite important because the elderly often have difficulties with mobility, distance from treatment centers, and sometimes don’t have caregivers [who] are able to bring them back and forth for treatment,” Dr. Perry said. He suggested that the shorter course of radiotherapy may have been one factor in the high adherence rate.
Based on these results of higher efficacy using concomitant and adjuvant temozolomide with manageable toxicities and no sacrifice in quality of life, “oncologists now have evidence to consider radiation with chemotherapy in all newly diagnosed elderly patients with glioblastoma,” he said.
Dr. Julie Vose, president of the American Society of Clinical Oncology, said the study was important because it compared the treatments in the appropriate patient population, that is, in the elderly who have the highest incidence of glioblastoma.