Concurrent Radiation and Temozolomide Lowers Risk for Death in Elderly Patients with Glioblastoma
The first study to assess the addition of temozolomide (Temodar) chemotherapy during short-course radiation therapy, followed by monthly maintenance of temozolomide in elderly patients with glioblastoma showed a significantly reduced risk for death, said the study co-author James R. Perry, MD, FRCPC, The Crolla Family Endowed Chair in Brain Tumour Research, Odette Cancer and Sunnybrook Health Sciences Centres, Toronto, Canada, in a plenary session at the 2016 American Society of Clinical Oncology annual meeting.
The incidence of glioblastoma, which is the most common form of brain tumor in adults, is increasing. Glioblastoma disproportionately affects older patients—the average age at diagnosis is 64 years. In addition, glioblastoma is one of the most common causes of cancer-related death. According to Dr Perry, clear treatment guidelines are lacking, and treatment practices vary globally.
The standard treatment for glioblastoma is surgical resection and 6 weeks of radiation therapy combined with chemotherapy (oral temozolomide). However, the 2005 phase 3 clinical trial by Stupp and colleagues that assessed this regimen excluded patients aged >70 years, leading some researchers to question whether chemoradiation with temozolomide may also benefit patients aged >70 years, even when a subgroup analysis found a decreasing benefit for the addition of temozolomide with increasing age.
Previous glioblastoma clinical trials involving elderly patients compared different radiation schedules or evaluated radiation therapy versus temozolomide monotherapy but have never investigated the combination of these 2 options, Dr Perry said.
In the international phase 3 clinical trial, led by the Canadian Cancer Trials Group, 562 patients aged ≥65 years with newly diagnosed glioblastoma were randomly assigned in a 1:1 ratio to short-course radiation therapy (40 Gy in 15 fractions for 3 weeks) with or without concurrent and adjuvant temozolomide (12 cycles).
The primary end point was overall survival (OS), and the secondary end points included progression-free survival and quality of life.
The median OS was 9.3 months in patients who received the combination of radiation plus temozolomide compared with 7.6 months in patients who received radiation therapy alone (hazard ratio, 0.67; 95% confidence interval, 0.56-0.80; P <.0001).
In addition, the median progression-free survival was longer in patients receiving the combination than in patients receiving radiation alone (5.3 months vs 3.9 months, respectively). Dr Perry emphasized that the improvements, although modest, are meaningful. The 1-year and 2-year survival rates with chemoradiation were 37.8% and 10.4%, respectively, compared with 22.2% and 2.8%, respectively, with radiation therapy alone.
A subgroup of 165 patients with O6-methylguanine-DNA methyltransferase promoter methylation, a genetic abnormality that is associated with improved responses to treatment and longer survival, had a longer median OS with chemoradiation than with radiation therapy alone (13.5 months vs 7.7 months, respectively). “Clinical benefit was extended also to some patients with unmethylated tumors, with a hazard ratio of 0.75 (P = .055). That’s the benefit we had been looking for overall in this study,” said Dr Perry.
A quality-of-life questionnaire showed no differences in physical, cognitive, emotional, and social functioning between the treatment groups.
An expected marginal increase in grade 3 and 4 hematologic toxicities was reported in the chemoradiation group. Nausea, vomiting, and constipation were more common in the temozolomide arm than in the radiation therapy arm, especially in the first week of radiation therapy.
“Patients were able to easily complete the treatment plan,” said Dr Perry. Adherence to the 3 weeks of chemoradiation exceeded 97%. “For the elderly who often have difficulties with mobility and challenges getting to treatment centers, the shorter radiation schedule is undoubtedly an advantage,” Dr Perry observed.
“Oncologists now have evidence to consider radiation therapy with temozolomide in all newly diagnosed elderly patients with glioblastoma,” he concluded.