Adding Temozolomide to Short-Course Radiotherapy in Older Patients With Glioblastoma
In a phase III trial reported in The New England Journal of Medicine, Perry et al found that adding temozolomide to short-course radiotherapy improved overall survival in patients aged ≥ 65 years with newly diagnosed glioblastoma. 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 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 in both; 74% vs 76% were receiving corticosteroid treatment; 68% of both underwent partial or complete resection; and 49% vs 45% had methylated MGMT status.
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.
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 disease 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.”
The study was funded by the Canadian Cancer Society Research Institute, Schering-Plough (now Merck), and the EORTC Cancer Research Fund from Belgium.
James R. Perry, MD, of Sunnybrook Health Sciences Centre, and Normand Laperriere, MD, of Princess Margaret Cancer Centre, contributed equally to The New England Journal of Medicine article.
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