New Standard in Elderly Patients with Glioblastoma Based on Phase 3 Evidence
Short-course (hypofractionated) radiotherapy plus concomitant and adjuvant temozolomide therapy significantly prolonged survival versus short-course radiotherapy alone in elderly patients with newly diagnosed glioblastoma. These results of a global cooperative group phase 3 clinical trial were 1 of 4 presentations selected for the plenary session at ASCO 2016.
“Although glioblastoma disproportionately affects older patients, there are no clear guidelines for treating these patients, and practice varies globally,” said lead investigator James R. Perry, MD, FRCPC, the Crolla Family Endowed Chair in Brain Tumour Research, Odette Cancer Centre and Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
“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,” Dr Perry told attendees.
The accepted standard treatment of glioblastoma is surgical resection and 6 weeks of radiotherapy plus chemotherapy with temozolomide, but this is based on evidence from a pivotal trial that did not include elderly patients.
The only studies conducted in elderly patients compared different radiotherapy schedules head to head and radiotherapy alone versus temozolomide monotherapy, Dr Perry explained.
“Therefore, the only evidence-based choices for elderly patients with newly diagnosed glioblastoma are radiotherapy alone or temozolomide alone,” he emphasized.
The phase 3 study randomized 562 patients with newly diagnosed glioblastoma aged >65 years in a 1:1 ratio to short-course radiotherapy (40 Gy/15 fractions/3 weeks) plus concomitant temozolomide for 3 weeks and monthly adjuvant temozolomide therapy (12 treatment cycles) versus short-course radiotherapy alone.
In an intent-to-treat analysis, the overall survival (OS) was improved from 7.6 months with radiotherapy alone to 9.3 months with radiotherapy plus temozolomide, a significant 33% improvement (P <.001). The progression-free survival (PFS) was also improved with radiotherapy plus temozolomide. The median PFS was 5.3 months for the combination versus 3.9 months for radiotherapy alone, a significant 50% improvement (P <.001).
The 1-year and 2-year survival rates were 37.8% and 10.4%, respectively, with the combination of radiotherapy plus temozolomide versus 22.2% and 2.8%, respectively, for radiotherapy alone.
“Although the difference in median survival seems modest, temozolomide significantly increased the chances of surviving 2 or 3 years,” Dr Perry said. “For an individual patient, that can mean being able to be part of another family holiday or celebration.”
MGMT methylation analysis, which is a marker of response, was assessed in tissue samples from 462 patients. Patients whose tumors showed MGMT methylation had the most robust improvement in OS; in patients with methylated tumors, the median OS was 13.5 months for the combination of radiotherapy and temozolomide versus 7.7 months with radiotherapy alone (P = .001).
In patients with unmethylated tumors, the OS was 10 months in the combination arm versus 7.9 months in the cohort that received radiotherapy alone, for a 25% improvement.
“To our surprise, patients with unmethylated tumors also got benefit from the combination versus radiotherapy alone,” Dr Perry told attendees.
The side effects for radiotherapy plus temozolomide were minimal, including mainly transient increases in nausea and vomiting during the first week and slight increases in grade 3 or 4 hematologic toxicities in <5% of patients.
“Shorter-course radiotherapy plus temozolomide significantly improves survival compared with radiotherapy alone in newly diagnosed elderly patients with glioblastoma,” Dr Perry stated. “The benefit was observed mostly in patients with MGMT promoter methylation, but clinical benefit 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.”
At the plenary session, Deborah Schrag, MD, MPH, of the Dana-Farber Cancer Institute, Boston, MA, said that temozolomide was of “moderate value” in elderly patients with glioblastoma, based on the ASCO and the European Society for Medical Oncology value frameworks.
Furthermore, in the absence of a specific mutation—MGMT promoter methylation—she rated temozolomide as “low value” in this patient population.
Dr Schrag added, though, that the availability of generic temozolomide makes it more likely that the drug will be used in this context.