PDF: RTOG 9802
(2016)Objective
To determine whether adding PCV chemotherapy (procarbazine, CCNU, vincristine) to radiation therapy improves progression-free and overall survival in high-risk grade 2 glioma
Study Summary
• 5-year OS: 72% vs 63%; 10-year OS: 60% vs 40%
• Median PFS: 10.4 years vs 4.0 years; HR 0.50 (95% CI 0.36-0.68), P<0.001
• 5-year PFS: 61% vs 44%; 10-year PFS: 51% vs 21%
• Oligodendroglioma histology: OS HR 0.43 (0.23-0.82), P=0.009; PFS HR 0.36 (0.21-0.62), P<0.001
• IDH1 R132H mutation: OS HR 0.42 (0.20-0.86), P=0.02; PFS HR 0.32 (0.17-0.62), P<0.001
• Survival curves diverged after 2 years; benefit increased over time
Intervention
Radiation therapy (54 Gy in 30 fractions over 6 weeks) followed by 6 cycles of PCV chemotherapy (procarbazine 60 mg/m2 days 8-21, CCNU 110 mg/m2 day 1, vincristine 1.4 mg/m2 [max 2 mg] days 8 and 29; 8-week cycles) vs radiation therapy alone (54 Gy in 30 fractions)
Inclusion Criteria
Supratentorial grade 2 astrocytoma, oligodendroglioma, or oligoastrocytoma confirmed by central pathology review; age 18-39 with subtotal resection or biopsy, or age >=40 with any extent of resection; KPS >=60; neurologic function score <=3
Study Design
Arms: Array
Patients per Arm: RT+PCV: 125; RT alone: 126
Outcome
• 5-year OS: 72% vs 63%; 10-year OS: 60% vs 40%
• PFS: median 10.4 vs 4.0 years; HR 0.50 (0.36-0.68), P<0.001
• 10-year PFS: 51% vs 21%
• Oligodendroglioma OS HR: 0.43 (0.23-0.82), P=0.009
• IDH1 R132H mutant OS HR: 0.42 (0.20-0.86), P=0.02
Bottom Line
With long-term follow-up (median 11.9 years), adding PCV chemotherapy to radiation therapy nearly doubled median overall survival from 7.8 to 13.3 years (HR 0.59, P=0.003) and more than doubled median PFS from 4.0 to 10.4 years (HR 0.50, P<0.001) in high-risk grade 2 glioma. The benefit was most pronounced in oligodendroglioma (OS HR 0.43) and IDH1-mutant tumors (OS HR 0.42), with survival curves diverging after 2 years and continuing to separate over time.
Major Points
- RTOG 9802 was a landmark phase 3 trial providing the first high-level evidence that chemotherapy improves overall survival in low-grade glioma — a result that required over a decade of follow-up to demonstrate.
- 254 patients with high-risk grade 2 glioma (age 18-39 with subtotal resection/biopsy, or age >=40 with any resection) were enrolled from 1998-2002 and followed for a median of 11.9 years.
- The initial report (2012, median 5.9 years follow-up) showed improved PFS but NOT overall survival — demonstrating the critical importance of long-term follow-up in slow-growing tumors.
- With extended follow-up, OS was dramatically improved: median 13.3 years (RT+PCV) vs 7.8 years (RT alone); HR 0.59 (95% CI 0.42-0.83); P=0.003. Five-year OS was 72% vs 63%; 10-year OS was 60% vs 40%.
- PFS was also significantly improved: median 10.4 years vs 4.0 years; HR 0.50 (95% CI 0.36-0.68); P<0.001. The 10-year PFS was 51% vs 21%.
- The benefit was most pronounced in oligodendroglioma (OS HR 0.43; 95% CI 0.23-0.82; P=0.009; PFS HR 0.36; 95% CI 0.21-0.62; P<0.001) — consistent with the known chemosensitivity of 1p/19q-codeleted tumors.
- Among patients with IDH1 R132H mutations (detected in ~62% of tested tumors), the benefit of PCV was even more striking: OS HR 0.42 (95% CI 0.20-0.86; P=0.02); PFS HR 0.32 (95% CI 0.17-0.62; P<0.001).
- Survival curves did not begin to diverge until approximately 2 years after randomization, then continued to separate over the entire follow-up period — a pattern suggesting that PCV prevents or delays malignant transformation rather than simply debulking tumor.
Study Design
- Study Type
- Randomized, multicenter, open-label, phase 3 trial
- Randomization
- Yes
- Blinding
- Open-label
- Sample Size
- 254
- Follow-up
- Median 11.9 years
- Countries
- USA
Primary Outcome
Definition: Overall survival: median 13.3 vs 7.8 years; HR 0.59 (95% CI 0.42-0.83); P=0.003 | 5-year OS: 72% vs 63%; 10-year OS: 60% vs 40%
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 0.59 (0.42-0.83) | P=0.003 |
Citation
N Engl J Med 2016;374:1344-55