NOA-04 Randomized Phase III Trial of Sequential Radiochemotherapy of Anaplastic Glioma With Procarbazine, Lomustine, and Vincristine or Temozolomide

Abstract

Initial radiotherapy or chemotherapy achieved comparable results in patients with anaplastic gliomas. IDH1 mutations are a novel positive prognostic factor in anaplastic gliomas, with a favorable impact stronger than that of 1p/19q codeletion or MGMT promoter methylation.

Downregulation of PRDX1 by promoter hypermethylation is frequent in 1p/19q-deleted oligodendroglial tumours and increases radio- and chemosensitivity of Hs683 glioma cells in vitro

“…Combined deletion of chromosomal arms 1p and 19q is a powerful prognostic marker in patients with anaplastic oligodendroglial tumours treated with radiotherapy, alkylating chemotherapy or combined radiochemotherapy (Cairncross et al, 2006;van den Bent, 2006;Wick et al, 2009). To identify genes located on these chromosomal arms that may account for this prognostic effect, we performed microarray-based gene expression profiling comparing oligodendroglial tumours with and without 1p/19q losses (Tews et al, 2006).…”

“…Importantly, we did not only detect frequent 5 0 -CpGisland hypermethylation and reduced expression of PRDX1 in oligodendroglial tumours with 1p and 19q deletions but also provided first evidence that this aberration may be linked to radio-and chemosensitivity of Hs683 glioma cells in vitro. Clinically, it has been well documented in numerous retrospective and prospective studies that 1p/19q deletion in low-grade and anaplastic oligodendroglial tumours predicts response to radiotherapy as well as chemotherapy with TMZ or nitrosourea compounds (Brada et al, 2003;Cairncross et al, 2006;Kouwenhoven et al, 2006;van den Bent, 2006;Wick et al, 2009). The molecular basis for the predictive power of 1p/19q deletion is still unknown.…”

“…The molecular basis for the predictive power of 1p/19q deletion is still unknown. Mo¨llemann et al (2005) reported that 1p/19q-deleted oligodendroglial tumours frequently demonstrate promoter hypermethylation and reduced expression of the O(6)-methylguanine DNA methyltransferase (MGMT) gene, an aberration that has been linked to response to TMZ therapy in glioblastoma patients (Hegi et al, 2005) as well as response to chemo-and radiotherapy in anaplastic glioma patients (Wick et al, 2009). However, although MGMT inactivation undoubtedly is of relevance for TMZ sensitivity (for review see Weller et al, 2010), a mechanistic role of MGMT in mediating radiosensitivity has not been demonstrated, thus suggesting the involvement of genetic/epigenetic alterations in other genes.…”

“…Up to 80% of oligodendrogliomas and B50% of oligoastrocytomas show combined deletions of the chromosomal arms 1p and 19q (Reifenberger and Louis, 2003) mediated by an unbalanced t(1;19)(q10;p10) translocation (Griffin et al, 2006;Jenkins et al, 2006). Deletion of 1p/19q was reported as an independent marker for favourable outcome in patients with anaplastic gliomas treated with chemotherapy and/or radiotherapy (van den Bent et al, 2005;Cairncross et al, 2006;Wick et al, 2009).…”

Significance of complete 1p/19q co-deletion, IDH1 mutation and MGMT promoter methylation in gliomas: use with caution

“…All three markers are considered as indicators of favorable prognosis. [6][7][8][9] MGMT hypermethylation status is already included in the nomogram for predicting survival of patients with newly diagnosed glioblastoma, and IDH1/2 mutation was shown to be a reliable genetic marker of secondary glioblastomas and their precursor lesions. [10][11][12] In contrast, the presence of other markers such as loss of PTEN and CDKN2A and amplification of EGFR are reported to be indicative for more aggressive tumor behavior.…”