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CHICAGO -- Short-course radiotherapy plus temozolomide led to significant improvement in overall and progression-free survival (PFS) compared with radiation alone in older patients with glioblastoma, a randomized trial showed.

Median survival was 9.3 months with combined treatment versus 7.6 months for radiotherapy. Median PFS improved from 3.9 months to 5.3 months with combined-modality therapy.

Biomarker analysis for a subgroup of patients showed that patients with tumors expressing the MGMT methylation promoter benefited the most from combined treatment, , of Sunnybrook Health Sciences Center in Toronto, reported here at the American Society of Clinical Oncology (ASCO) meeting.

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

"Oncologists now have evidence to consider radiotherapy with temozolomide in all newly diagnosed elderly patients with glioblastoma," he added.

The addition of temozolomide also added more adverse events, particularly nausea, vomiting, and constipation, but quality of life assessments showed no significant differences between the two treatment arms.

The results are important because they pertain to the patient population most affected by glioblastoma, said ASCO expert , of Dana-Farber Cancer Institute in Boston.

"It's good to have an option to offer patients that we know can have a positive impact," said Alexander. However, he cautioned that clinicians and patients still need to weigh the anticipated benefits against the toxicities that can be expected from more intense treatment.

The results will have the effect of extending standard of care to all adults, regardless of age. Glioblastoma disproportionately affects older individuals, as the median age at diagnosis is 64. Standard of care consists of 6 weeks of radiation therapy in combination with temozolomide. However, that standard was established on the basis of a randomized trial that included no patients ≥70 and few who were older than 65, said Perry.

Clinical trials of glioblastoma in older patients have been limited to comparisons of different radiation therapy schedules and of radiotherapy alone versus temozolomide alone. Oncologists have had no evidence-based options for combined-modality treatment of older patients with glioblastoma, Perry continued.

The , in collaboration with the and the , sponsored a clinical trial to address the issue of combined-modality therapy for older patients with glioblastoma. Enrollment was limited to patients older than 65 with good performance status.

Investigators randomized 562 patients (median age 73) to short-course radiotherapy alone (40 Gy/15 fractions/3 weeks) or to temozolomide chemoradiation with the same radiotherapy schedule and followed by adjuvant temozolomide. The primary endpoint was overall survival. PFS, quality of life, and toxicity were secondary endpoints. Additionally, investigators examined treatment response by tumor MGMT promoter status in a subgroup of patients.

The primary analysis showed a 1.7-month improvement in survival with combined-modality treatment, which translated into a 33% reduction in the survival hazard (HR 0.67, 95% CI 0.56-0.80, P<0.0001). The 1.4-month improvement in PFS with radiation plus temozolomide represented a 50% reduction in the hazard for progression or survival (HR 0.50, 95% CI 0.41-0.60, P<0.0001).

The 1-year survival was 37.8% with combined therapy and 10.4% with radiotherapy alone. The 2-year survival was 22.2% and 2.8% with combined and single-modality therapy, respectively.

Biomarker analysis had been completed for 354 of 462 patients with adequate tissue samples. For patients with MGMT-positive tumors, the combination therapy resulted in a median overall survival of 13.5 months versus 7.7 months for radiotherapy alone (HR 0.53, 95% CI 0.38-0.73, P=0.0001). Patients with MGMT-unmethylated tumors benefited from the combination therapy, but the difference did not achieve statistical significance (10.0 versus 7.9 months, P=0.055).

The increased toxicity associated with combined treatment was generally grade 1/2 severity and could be managed with standard medications. Combined treatment was associated with a small increase in grade 3/4 hematologic toxicity, which was expected, said Perry.

"Patients were able to easily complete the treatment plan, as more than 97% of patients were adherent to the 3 weeks of chemoradiation," he said.

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