PDF: Perry (NCIC CE.6/EORTC 26062)
(2017)Objective
To determine whether adding temozolomide to short-course radiotherapy improves overall survival compared with short-course radiotherapy alone in elderly patients (>=65 years) with newly diagnosed glioblastoma
Study Summary
• Median PFS: 5.3 vs 3.9 months; HR 0.50 (95% CI 0.41-0.60), P<0.001
• Methylated MGMT: median OS 13.5 (RT+TMZ) vs 7.7 months (RT); HR 0.53 (0.38-0.73), P<0.001
• Unmethylated MGMT: median OS 10.0 vs 7.9 months; HR 0.75 (0.56-1.01), P=0.055
• QoL similar between groups
• Grade 3/4 lymphopenia: 27.2% vs 10.3%; thrombocytopenia: 11.1% vs 0.4%
• Established short-course RT + TMZ as standard for elderly GBM patients
Intervention
Short-course radiotherapy (40.05 Gy in 15 fractions over 3 weeks) plus concomitant temozolomide (75 mg/m2/day for 21 consecutive days) followed by adjuvant temozolomide (150-200 mg/m2, days 1-5 of 28-day cycle, up to 12 cycles) vs short-course radiotherapy alone (40.05 Gy in 15 fractions)
Inclusion Criteria
Age >=65 years; newly diagnosed, histologically confirmed glioblastoma (WHO grade IV); deemed not suitable for standard 6-week RT course; ECOG performance status 0-2; stable or decreasing glucocorticoids; adequate hematologic, renal, and hepatic function; surgery or biopsy <28 days before randomization
Study Design
Arms: Array
Patients per Arm: RT+TMZ: 281; RT alone: 281
Outcome
• PFS: 5.3 vs 3.9 months; HR 0.50 (0.41-0.60), P<0.001
• Methylated MGMT OS: 13.5 vs 7.7 months; HR 0.53 (0.38-0.73), P<0.001
• Unmethylated MGMT OS: 10.0 vs 7.9 months; HR 0.75 (0.56-1.01), P=0.055
• Grade 3/4 lymphopenia: 27.2% vs 10.3%
• QoL: no significant difference
Bottom Line
Adding temozolomide to short-course radiotherapy (40 Gy/15 fractions) significantly improved overall survival in elderly GBM patients from 7.6 to 9.3 months (HR 0.67, P<0.001) and PFS from 3.9 to 5.3 months (HR 0.50, P<0.001). The benefit was greatest in patients with methylated MGMT (OS 13.5 vs 7.7 months, HR 0.53), establishing short-course RT+TMZ as the standard of care for elderly GBM patients unsuitable for the full Stupp protocol.
Major Points
- This was the first phase 3 trial to demonstrate a survival benefit from adding temozolomide to short-course hypofractionated radiotherapy in elderly GBM patients — a population excluded from the Stupp trial.
- 562 patients aged 65-90 (median 73 years) were randomized 1:1 at centers in Europe, Canada, Australia/New Zealand, and Japan.
- The primary endpoint — overall survival — showed a 33% reduction in the risk of death with RT+TMZ: median 9.3 vs 7.6 months (HR 0.67; 95% CI 0.56-0.80; P<0.001).
- Progression-free survival was also significantly improved: 5.3 vs 3.9 months (HR 0.50; 95% CI 0.41-0.60; P<0.001).
- MGMT methylation strongly predicted benefit: methylated patients had median OS of 13.5 months (RT+TMZ) vs 7.7 months (RT alone), HR 0.53 (P<0.001). Unmethylated patients had a smaller, borderline benefit: 10.0 vs 7.9 months, HR 0.75 (P=0.055).
- Treatment effect was consistent across age subgroups but appeared to increase with age: HR 0.76 for ages 65-70, HR 0.42 for ages 71-75, and HR 0.53 for ages >=76 (P=0.02 for interaction).
- Quality of life was similar between groups, and there was no clinically meaningful deterioration attributable to chemotherapy.
- Hematologic toxicity was manageable: grade 3/4 lymphopenia 27.2% vs 10.3%, thrombocytopenia 11.1% vs 0.4%, neutropenia 8.3% vs 0.8%.
Study Design
- Study Type
- Randomized, multicenter, open-label, phase 3 trial
- Randomization
- Yes
- Blinding
- Open-label
- Sample Size
- 562
- Follow-up
- Median 17 months for surviving patients; database locked March 2016
- Countries
- Multiple (Canada, Europe, Australia, New Zealand, Japan)
Primary Outcome
Definition: Overall survival: 9.3 vs 7.6 months; HR 0.67 (95% CI 0.56-0.80); P<0.001
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 0.67 (0.56-0.80) | P<0.001 |
Citation
N Engl J Med 2017;376:1027-37