(Improvement of functional results in newly diagnosed glioma grade 2/3 with co-deletion of 1p/19q)

A very simple and reproducible test for the codeletion of chromosomes 1p and 19q in tumor tissue allows the identification of the prognostically most favorable group of patients with WHO grade II and III gliomas. In studies separated by WHO grade, these patients have shown a survival benefit from radiochemotherapy with PCV compared to radiotherapy alone. Updated molecular genetic analyses no longer permit a biological differentiation between WHO grade II and III gliomas; therefore, for the present study, a WHO grade II or III glioma with isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion is used as the molecular inclusion criterion.

This corresponds to the principles of the revision of the fourth edition of the WHO classification of brain tumors published in May 2016 (Louis et al., Acta Neuropathologica 2016). The WHO classification is a cornerstone of the current study design. Subgroup analyses from the NOA-04 trial conducted in 2016 suggest that temozolomide treatment appears to be inferior to PCV treatment precisely in the subgroup with the most favorable prognosis, and thus in the study population of the NOA-18 trial.

The efficacy of PCV compared to PCV plus radiotherapy has never been investigated in a randomized trial. Internationally, the attempt to demonstrate the non-inferiority of PCV chemotherapy compared to a combination of PCV and radiotherapy is viewed with extreme skepticism. This approach is being pursued by the French ANOCEF study group (POLCA). Following discussions with this study group in January 2016, we decided against switching from temozolomide to PCV, both to avoid duplication of the study and, in particular, for substantive reasons. However, the use of temozolomide alone no longer had majority support within the German study group. For this reason, we have selected the drug combination of CCNU (lomustine) and temozolomide, which has a similar mechanism of action to procarbazine, as the combination for the experimental intervention. This combination is being used in the CETEG study, also funded by the German Federal Ministry of Education and Research (BMBF), which is led by Prof. Herrlinger from Bonn.

The aim of the NOA-18 study is to demonstrate the superiority of initial temozolomide plus CCNU chemotherapy followed by partial cerebral irradiation plus PCV in the event of progression, compared to radiochemotherapy with PCV, in terms of overall survival without permanent functional impairment. The study is in the late design phase and will soon be submitted to the regulatory authorities for review.