Radiotherapy Plus Temozolomide for GBM

Stupp R, et al. "Radiotherapy plus concomitant and adjuvant temozolomide for Glioblastoma". The New England Journal of Medicine. 2005. 352:987-996.

Clinical Question

In patients with newly diagnosed glioblastoma who have undergone surgical resection, does the addition of concurrent and adjuvant temozolomide (TMZ) to radiation therapy improve overall survival as compared to radiation therapy alone?

Bottom Line

Adding concurrent and adjuvant TMZ to radiation therapy improves survival in patients with GBM who have undergone surgical resection, without excessive toxicity.

Major Points

The previous standard of care for GBM was maximally feasible surgical resection followed by radiation therapy. The role of chemotherapy was uncertain, and no phase III trials to that point had shown a survival advantage to the use of concurrent or adjuvant nitrosurea-based chemotherapy. Temozolomide is an alkylating agent with the potential to deplete levels of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). Low levels of that enzyme had previously been associated with prolonged survival in patients with GBM. The addition of concurrent and adjuvant TMZ, at 75 mg/m2 and 150 mg/m2 respectively, to radiation therapy improved overall survival as compared to radiation therapy alone. A small but manageable increase in grade 3 or 4 hematologic toxicity was seen in patients who received TMZ, though the incidence of cognitive deficits was not studied.

Design

• Multicenter, non-blinded, non-placebo controlled, parallel-group, randomized, controlled trial
• n=573
  • RT alone (n=286)
  • RT with TMZ (n=287)
• Setting: 85 centers institutions in 15 countries, with ~50% of patients at 17 of those institutions
• Enrollment: August 2000 until March 2002
• Median follow-up: 28 months
• Analysis: Intention-to-treat
• Primary endpoint: Overall survival
• 80% power to detect a 33% increase in median survival, assuming 382 deaths occurred

Population

Inclusion Criteria

• Age 18-70 years with newly diagnosed histologically confirmed GBM
• WHO performance status of 2 or less
• If on corticosteroids, on a stable or decreasing dose for at least 14 days

Exclusion Criteria

• Absolute neutrophil count <1500 cells per cubic mm
• Platelt count <100K per cubic mm
• Serum creatinine >1.5x the upper limit of normal
• Total serum bilirubin >1.5x upper limit of normal
• Liver enzymes >3x upper limit of normal

Baseline Characteristics

• Mean age: 72 years
• Mean BMI: 28
• Mean HbA1c: 8.8%
• Units of insulin: 14 units/day

Interventions

• Randomized to intensive (targeting HbA1c <6%) or standard (HbA1c 7-7.9%) glycemic therapy

  • Then 46% were randomized to intensive (SBP <120) vs. standard (SBP <140) blood pressure therapy
  • Remaining 54% randomized to fenofibrate vs. placebo; all received statin
• Intensive glycemic control group attended monthly visits for 4 months, then every 2 months, with additional visits and telephone calls as needed
• Standard therapy group had glycemic control visits every 4 months

Outcomes

Comparisons are intensive therapy vs. standard therapy.

Primary Outcomes

Annual rate of nonfatal MI or nonfatal stroke or cardiovascular death

2.11% vs. 2.29% (HR 0.90; 95% CI 0.78-1.04; P=0.16)

Secondary Outcomes

Annual rate of death from any cause

1.41% vs. 1.14% (HR 1.22; 95% CI 1.01-1.46; P=0.04)

Annual rate of cardiovascular death

0.79% vs. 0.56% (HR 1.35; 95% CI 1.04-1.76; P=0.02)