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Phase 3 Evidence for New Standard in Elderly Glioblastoma Patients

jamesPerry98pxShort-course (hypofractionated) radiotherapy (RT) and temozolomide (TMZ) followed by TMZ significantly prolonged survival versus short-course RT alone in newly diagnosed elderly patients with glioblastoma. These results of a global cooperative group phase 3 trial were 1 of 4 talks selected for the plenary session at the 2016 ASCO Annual Meeting.

“Although glioblastoma disproportionately affects older patients, there are no clear guidelines for treating these patients, and practice varies globally,” 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, 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 listeners.

The accepted standard treatment of glioblastoma is surgical resection and 6 weeks of RT plus chemotherapy with TMZ, but this is based on evidence from a pivotal trial that did not include elderly patients.

The only studies conducted in the elderly compared different RT schedules head to head and RT alone versus TMZ monotherapy, he explained.

“Therefore, the only evidence-based choices for elderly patients with newly diagnosed glioblastoma are RT alone or TMZ alone,” he emphasized.

The phase 3 study randomized 562 newly diagnosed patients with glioblastoma (age >65 years) in a 1:1 ratio to short-course RT (40 Gy/15 fractions/3 weeks) plus concomitant TMZ for 3 weeks and monthly adjuvant TMZ (12 treatment cycles) versus short-course RT alone.

In an intent-to-treat analysis, overall survival (OS) was improved from 7.6 months with RT alone to 9.3 months with RT plus TMZ (P <.0001). Progression-free survival (PFS) was also improved by RT plus TMZ. Median PFS was 5.3 months for the combination versus 3.9 months for RT alone (P <.0001).

The 1-year and 2-year survival rates were 37.8% and 10.4% with the combination of RT plus TMZ versus 22.2% and 2.8%, respectively, for RT alone.

“Although the difference in median survival seems modest, temozolomide significantly increased the chances of surviving 2 or 3 years. For an individual patient, that can mean being able to be part of another family holiday or celebration,” Dr Perry said.

MGMT methylation analysis—a marker of response—was assessed in tissue from 462 patients. Patients whose tumors showed MGMT methylation had the most robust improvement in OS: in patients with methylated tumors, median OS was 13.5 months for the combination of RT and TMZ versus 7.7 months with RT alone (P = .0001).

In patients with unmethylated tumors, OS was 10 months for the combination versus 7.9 months for RT alone, for a 25% improvement.

“To our surprise, patients with unmethylated tumors also got benefit from the combination versus RT alone,” Dr Perry told listeners.

Side effects for RT plus TMZ were minimal: mainly transient increases in nausea and vomiting during the first week and slight increases in grades 3 and 4 hematologic toxicities in less than 5% of patients.

“Shorter-course RT plus TMZ significantly improves survival compared to RT alone in newly diagnosed elderly patients with glioblastoma. 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 with manageable toxicities. Oncologists now have evidence to consider RT with TMZ in all newly diagnosed elderly patients with glioblastoma,” Dr Perry stated.

At the plenary session, Deborah Schrag, MD, MPH, of the Dana-Farber Cancer Institute, Boston, MA, said that TMZ was of “moderate value” in elderly patients with glioblastoma based on the ASCO and ESMO value frameworks.

Further, in the absence of a specific mutation (MGMT promoter methylation), she rated TMZ as “low value.”

She noted that the availability of generic temozolomide makes it more likely that the drug will be used.

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