The combination of short-course radiotherapy and temozolomide followed by maintenance with temozolomide significantly improved survival compared with short-course radiotherapy alone in newly diagnosed elderly patients with glioblastoma, according to the results of a global cooperative group trial reported at the plenary session of the 2016 ASCO Annual Meeting.1
James Perry, MD
“There are no clear guidelines for treating elderly patients with glioblastoma. This is the first evidence from a randomized clinical trial that chemotherapy in combination with a shorter radiation schedule significantly extends survival without a detriment to quality of life,” said lead author James Perry, MD, The Crolla Family Endowed Chair in Brain Tumour Research at the Odette Cancer and Sunnybrook Health Sciences Center, Toronto.
The gold standard for treatment of glioblastoma is surgical resection and 6 weeks of radiotherapy plus chemotherapy with temozolomide, but this evidence comes from a pivotal trial in patients younger than age 70. Trials that have included elderly patients have compared radiotherapy schedules head to head and radiotherapy alone vs temozolomide alone.
“Therefore, the only evidence-based choices for elderly patients with newly diagnosed glioblastoma are radiotherapy alone or temozolomide alone,” said Dr. Perry. The need for evidence-based therapy in older patients is clear, since the peak incidence of glioblastoma is age 64.
Study Details
The phase III study was designed to provide evidence for the combination of short-course (hypofractionated) radiotherapy plus temozolomide in 562 newly diagnosed glioblastoma patients over age 65. They were randomized 1:1 to short-course radiotherapy (40 Gy/15 fractions/3 weeks) plus concomitant temozolomide for 3 weeks and monthly adjuvant temozolomide (12 treatment cycles) vs short-course radiotherapy alone.
In an intent-to-treat analysis, the combination of radiotherapy and temozolomide extended overall survival from 7.5 months with radiotherapy alone to 9.3 months, representing a significant 33% improvement in the experimental arm (P < .0001). Radiotherapy plus temozolomide also improved progression-free survival: Median progression-free survival was 5.3 months for the combination vs 3.9 months for radiotherapy alone, representing a significant 50% improvement favoring the combination (P < .0001).
MGMT Promoter Methylation
Tissue was available for MGMT (O6-methylguanine-methyltransferase) methylation analysis in 462 patients. The presence of MGMT promoter methylation predicted the best overall survival. In patients with this marker, median overall survival was 13.5 months for the combination of radiotherapy and temozolomide vs 7.7 months with radiotherapy alone (P = .0001).
“To our surprise, patients with unmethylated tumors also got benefit from the combination vs radiotherapy alone,” Dr. Perry told listeners. In patients with unmethylated tumors, overall survival was 10 months for the combination vs 7.9 months for radiotherapy alone—a 25% improvement. “This was the level of improvement we looked for in the overall trial,” Dr. Perry added.
Combination Therapy in Patients With Glioblastoma
- Short-course radiation therapy plus temozolomide extended survival vs radiation alone in patients over age 65 with newly diagnosed glioblastoma.
- The effect was greatest in patients whose tumors expressed MGMT promoter methylation, but those with unmethylated tumors also benefited.
“Shorter-course radiotherapy plus temozolomide significantly improves survival compared to radiotherapy alone in newly diagnosed elderly patients with glioblastoma,” stated Dr. Perry. “The benefit was more robust in patients with MGMT promoter methylation, but it was also seen in patients with unmethylated tumors, with no sacrifice in quality of life and manageable toxicities. Oncologists now have evidence to consider radiotherapy with temozolomide in all newly diagnosed elderly patients with glioblastoma.”
Toxicity
The advantages of radiotherapy plus temozolomide were achieved with minimal side effects. In the combination arm, nausea and vomiting were increased during the first week, and there was a slight increase in grades 3 and 4 hematologic toxicities observed in fewer than 5% of patients.
“Elderly patients were able to complete the treatment plan. This is important, because elderly often don’t have caregivers and may live far way from the treatment center,” shared Dr. Perry.
Additional Comment
At a press conference where these findings were discussed, ASCO President Julie M. Vose, MD, of the University of Nebraska Medical Center in Omaha, said: “This study is testing a very important question worldwide, and we are testing this in a population that actually gets the disease—the older population.” ■
Disclosure: Dr. Perry has financial relationships with DelMar Pharmaceuticals and VBL Therapeutics.
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