Randomized phase III study of sequential radiochemotherapy of oligoastrocytic tumors of WHO-grade III with PCV or temozolomide: NOA-04
Authors: W. Wick Wolfgang, M. Weller
Journal: Journal of Clinical Oncology (2008)

LBA2007 Background: The optimal treatment of anaplastic gliomas is controversial. Standard of care in most centers is still radiotherapy. This phase III study compared the efficacy and safety of radiotherapy vs chemotherapy in patients (pts) with newly- diagnosed, supratentorial gliomas of WHO grade III. Methods: All histological diagnoses (52.6% astrocytoma, 14.2% oligodendroglioma and 33.2% oligoastrocytoma) were centrally confirmed upon study entry. Pts were randomized 2:1:1 (A:B1:B2) between June 1999 and February 2005 in 34 German centers to receive (i) a 6-week course of radiotherapy (1,8–2 Gy fractions, total dose 54–60 Gy) or (ii) four 6-week cycles of CCNU at 110 mg mg/m2 on day 1, vincristine at 2 mg on days 8 and 29 and procarbazine at 60 mg/m2 on days 8–21 or eight 4-week cycles of 200 mg/m2 temozolomide on days 1–5. At occurance of unacceptable toxicity or disease progression, pts in the radiotherapy arm (A) were treated with one of the chemotherapies (1:1 randomization) and pts in the chemotherapy arms (B1, B2) with radiotherapy. The primary endpoint was time-to-treatment-failure (TTF) defined as progression after radiotherapy and one chemotherapy in either sequence, or any time before if further therapy could not be employed. Assuming a 50% improvement in TTF of starting with chemotherapy, 318 pts were to be enrolled to provide 80% power to achieve significance at a one- sided level of 0.05. Results: Pts (N=318) characteristics were balanced between arms. Median TTF [HR=1.2 (0.8–1.8)], PFS [1.0 (0.7–1.3)], and OS [1.2 (0.8–1.9)] were not different between arms (A vs B1/B2). Pts with an astrocytic tumor [HR=3.3 (1.7–6.4)] had a worse TTF. Oligoastrocytic tumors share the same favourable risks of pure oligodendroglioma. Loss of heterozygosity on chromosomal arms 1p and 19q (LOH 1p/19q) [0.3 (0.12–0.77)] and hypermethylation of the methyl-guanyl-methyl-transferase promoter (MGMT+) [0.36 (0.2–0.59)] provided a large risk reduction for TTF irrespective of histology and arm. Both parameters also conferred risk reduction for PFS, both in A and B1/B2. Grade 3–4 hematological toxicities were significantly higher for PCV than for temozolomide (p<0.01). Conclusions: There is an identical clinical course of anaplastic oligodendroglioma and oligoastrocytoma. The favourable impact of an oligodendroglial component was as strong as detecting LOH 1p/19q in the tumor tissue. MGMT promoter methylation was associated with prolonged PFS also in the radiotherapy arm A. There was no difference in TTF between pts started on radiotherapy (A) versus those started on chemotherapy (B1/B2). PCV/Temozolomide(N=158) Radiotherapy(N=161) P-value Discontinuations (therapy-related) 14 (14) 0 (0) Median TTF (95% CI),months 43.8 (37.4-n.r.*) 42.7+ 32.0 0.28 Astrocytoma Oligodendroglioma 29.4 (19.0-n.r.) (23.3-n.r.) Oligoastrocytoma 54+ 54+ 54+ 54+ TTF48** (95% CI), % 46.4 (36.7-56.1) 55.5 (46.3-64.7) 0.51 Median PFS (95% CI), months 31.9 (21.1-37.3) 30.6 (16.3-42.8) 0.87 months Astrocytoma 18.2 (12.1-24.2) 10.8 (8.9-28.3) Oligodendroglioma Oligoastrocytoma 52.7 (33.9-n.r.) 52.7 (33.9-n.r.) 52.1 (36.5-n.r.) 52.1 (36.4-n.r.) Median OS (95% CI), months 60+ 60+ 0.25 OS48 (95% CI), % Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Schering-Plough