NOA-18 / Improve Codel

Improvement of functional outcome for patients with newly diagnosed grade II or III glioma with co-deletion of 1p/19q – Improve Codel: the NOA-20 trial

A simple and reproducible test for co-deletion of chromosomes 1p and 19q in tumor tissue allows for identification of the prognostically most favorable group of patients with WHO grade II and III gliomas. These patients have shown a survival advantage for radiochemotherapy with PCV over radiotherapy alone in studies stratified for WHO grades. Contemporary molecular diagnostics no longer allow for a biological differentiation between WHO grade II and III gliomas, so WHO grade II or III glioma with isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion is used as the molecular inclusion criterion for the present study. This corresponds to the revision of the fourth edition of the WHO classification for brain tumors published in May 2016 (Louis et al, Acta Neuropathologica 2016). The WHO classification represents a cornerstone of the current study design. Subgroup analyses from the NOA-04 trial performed in 2016 suggest that temozolomide treatment appears to be inferior to PCV treatment in the most prognostically favorable subgroup and thus in the NOA-18 trial population.

The value of PCV versus PCV + radiotherapy has never been evaluated in a randomized setting. In the international context, the attempt to show non-inferiority of PCV chemotherapy versus a combination of PCV and radiotherapy has been highly criticized. This question is being evaluated by the French study group of ANOCEF (POLCA). After consultation with this study group in January 2016, we decided against a switch from temozolomide to PCV and established the drug combination of CCNU (lomustine) and temozolomide as experimental intervention.

The goal of the NOA-18 trial is to demonstrate superiority of initial temozolomide plus CCNU chemotherapy followed by partial brain irradiation plus PCV for progression over radiochemotherapy with PCV in overall survival without permanent functional deterioration. The study is in the late design phase. Applications will soon be submitted to regulatory agencies for peer review.