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Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide


Wick, W; Roth, P; Hartmann, C; Hau, P; Nakamura, M; Stockhammer, F; Sabel, M C; Wick, A; Koeppen, S; Ketter, R; Vajkoczy, P; Eyupoglu, I; Kalff, R; Pietsch, T; Happold, C; Galldiks, N; Schmidt-Graf, F; Bamberg, M; Reifenberger, G; Platten, M; von Deimling, A; Meisner, C; Wiestler, B; Weller, M (2016). Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. Neuro-Oncology, 18(11):1529-1537.

Abstract

BACKGROUND Optimal treatment and precise classification for anaplastic glioma are needed. METHODS The objective for long-term follow-up of NOA-04 is to optimize the treatment sequence for patients with anaplastic gliomas. Patients were randomized 2:1:1 to receive the standard radiotherapy (RT) (arm A), procarbazine, lomustine and vincristine (PCV) (arm B1), or temozolomide (TMZ) (arm B2). RESULTS Primary endpoint was time-to-treatment-failure (TTF), defined as progression after 2 lines of therapy or any time before if no further therapy was administered. Exploratory analyses examined associations of molecular marker status with TTF, progression-free survival (PFS), and overall survival (OS). At 9.5 (95% CI: 8.6-10.2) years, no difference between arms (A vs B1/B2) was observed: median TTF (4.6 [3.4-5.1] y vs 4.4 [3.3-5.3) y), PFS (2.5 [1.3-3.5] y vs 2.7 [1.9-3.2] y), and OS (8 [5.5-10.3] y vs 6.5 [5.4-8.3] y). Oligodendroglial versus astrocytic histology-but more so the subgroups according to CpG island methylator phenotype (CIMP) and 1p/19q co-deletion status-revealed a strong prognostic value of CIMP(pos) with (CIMP(codel)) versus without 1p/19 co-deletion (CIMP(non-codel)) versus CIMP(neg). but no differential efficacy of RT versus chemotherapy for any of the endpoints. PFS was better for PCV- than for TMZ-treated patients with CIMP(codel) tumors (HR B1 vs B2 0.39 [0.17-0.92], P = .031). In CIMP(neg). tumors, hypermethylation of the O6-methyl-guanyl-DNA methyltransferase promoter (MGMT) provided a risk reduction for PFS with chemotherapy. CONCLUSIONS There is no differential activity of primary chemotherapy versus RT in any subgroup of anaplastic glioma. Molecular diagnosis is superior to histology. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00717210.

Abstract

BACKGROUND Optimal treatment and precise classification for anaplastic glioma are needed. METHODS The objective for long-term follow-up of NOA-04 is to optimize the treatment sequence for patients with anaplastic gliomas. Patients were randomized 2:1:1 to receive the standard radiotherapy (RT) (arm A), procarbazine, lomustine and vincristine (PCV) (arm B1), or temozolomide (TMZ) (arm B2). RESULTS Primary endpoint was time-to-treatment-failure (TTF), defined as progression after 2 lines of therapy or any time before if no further therapy was administered. Exploratory analyses examined associations of molecular marker status with TTF, progression-free survival (PFS), and overall survival (OS). At 9.5 (95% CI: 8.6-10.2) years, no difference between arms (A vs B1/B2) was observed: median TTF (4.6 [3.4-5.1] y vs 4.4 [3.3-5.3) y), PFS (2.5 [1.3-3.5] y vs 2.7 [1.9-3.2] y), and OS (8 [5.5-10.3] y vs 6.5 [5.4-8.3] y). Oligodendroglial versus astrocytic histology-but more so the subgroups according to CpG island methylator phenotype (CIMP) and 1p/19q co-deletion status-revealed a strong prognostic value of CIMP(pos) with (CIMP(codel)) versus without 1p/19 co-deletion (CIMP(non-codel)) versus CIMP(neg). but no differential efficacy of RT versus chemotherapy for any of the endpoints. PFS was better for PCV- than for TMZ-treated patients with CIMP(codel) tumors (HR B1 vs B2 0.39 [0.17-0.92], P = .031). In CIMP(neg). tumors, hypermethylation of the O6-methyl-guanyl-DNA methyltransferase promoter (MGMT) provided a risk reduction for PFS with chemotherapy. CONCLUSIONS There is no differential activity of primary chemotherapy versus RT in any subgroup of anaplastic glioma. Molecular diagnosis is superior to histology. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00717210.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:November 2016
Deposited On:17 Nov 2016 10:39
Last Modified:17 Nov 2016 10:40
Publisher:Oxford University Press
ISSN:1522-8517
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/neuonc/now133
PubMed ID:27370396

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