James R. Perry, MD

In a phase III trial reported in The New England Journal of Medicine, James R. Perry, MD, of Sunnybrook Health Sciences Centre, Toronto, and colleagues found that adding temozolomide to short-course radiotherapy improved overall survival in patients aged at least 65 years with newly diagnosed glioblastoma.¹ The survival advantage was largest among patients with methylated O⁶-methylguanine–DNA methyltransferase (MGMT) status. 

Study Details

In the open-label trial, 562 patients from sites in Europe, Canada, Australia/New Zealand, and Japan were randomized between November 2007 and September 2013 to receive radiotherapy with concurrent and adjuvant temozolomide (n = 281) or radiotherapy alone (n = 281). Patients were considered by their physicians to be unsuitable for conventional radiotherapy (60 Gy in 30 fractions over 6 weeks) in combination with temozolomide. 

Radiotherapy was planned using three-dimensional planning systems for a total dose of 40.05 Gy given in 15 daily fractions over 3 weeks. Concurrent temozolomide was given at 75 mg/m²/d for 21 consecutive days from day 1 until the final day of radiotherapy; adjuvant temozolomide was given at 150 to 200 mg/m²/d for 5 consecutive days of 28-day cycles for up to 12 cycles or until disease progression. The primary endpoint of the trial was overall survival in the intent-to-treat population.

For the temozolomide vs control groups: 61% of both were male; median age was 73 years, with 29% vs 30% aged ≥ 76 years; Eastern Cooperative Oncology Group performance status was 2 in 23% in both and 0 or 1 in all other patients; median Mini-Mental State Examination score was 27.0 in both; 74% vs 76% were receiving corticosteroid treatment; 68% of both underwent partial or complete resection; 49% vs 45% had methylated MGMT status; and the geographic region was Europe for 44% in both, Canada for 36% vs 35%, Australia/New Zealand for 17% in both, and Japan for 3% in both.

Survival Outcomes

For the small group of surviving patients, median follow-up was 17 months. A total of 86 patients in the temozolomide group did not receive adjuvant temozolomide. 

“In elderly patients with glioblastoma, the addition of temozolomide to short-course radiotherapy resulted in longer survival than short-course radiotherapy alone.”

— James R. Perry, MD, and colleagues

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Median overall survival was 9.3 months (95% confidence interval [CI] = 8.3–10.3 months) in the temozolomide group vs 7.6 months (95% CI = 7.0–8.4 months) in the control group (hazard ratio [HR] = 0.67, P < .001). Median overall survival was 13.5 months vs 7.7 months among 165 patients with methylated MGMT status (HR = 0.53, P < .001) and 10.0 months vs 7.9 months among 189 with unmethylated MGMT status (HR = 0.75, P = .055; P =.08 for interaction). 

Median progression-free survival was 5.3 months vs 3.9 months (HR = 0.50, P < .001). A total of 40% of patients received additional anticancer treatment after progression, with the proportions in each group being similar. A total of 102 patients in the control group subsequently received temozolomide.

Adverse Events

Grade 3 or 4 hematologic adverse events consisted of lymphopenia in 27.2% of the temozolomide group vs 10.3% of the control group, thrombocytopenia in 11.1% vs 0.4%, and neutropenia in 8.3% vs 0.8%. Low-grade opportunistic infection was reported in two patients in the temozolomide group, with no other between-group differences in the incidence of infection. Serious adverse events leading to death occurred in 38 vs 35 patients, with 2 such events in each group considered related to study treatment. Quality of life, assessed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire–Core 30 and EORTC brain module, did not differ between the two groups. 

The investigators concluded: “In elderly patients with glioblastoma, the addition of temozolomide to short-course radiotherapy resulted in longer survival than short-course radio­therapy alone.” ■

Disclosure: The study was funded by the Canadian Cancer Society Research Institute, Schering-Plough (now Merck), and the EORTC Cancer Research Fund from Belgium. For full disclosures of the study authors, visit www.nejm.org.

Reference

1. Perry JR, Laperriere N, O’Callaghan CJ, et al: Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med 376:1027-1037, 2017.