Efficacy Study of Radiotherapy Alone Versus CCRT With Temozolomide in Grade III Gliomas Without 1p/19q Codeletion

Overview

1. The management of anaplastic gliomas of WHO grade 3 is currently largely based on surgery followed by radiotherapy, of which prognosis remains still dismal with the median survival of 2-5 years. To date, the benefit of chemo for WHO grade 3 gliomas is unclear of modest at best with conventional cytotoxic agents, and the role of temozolomide for these entities still is not elucidated. 2. Codeletion of chromosome 1p/19q is considered the most important marker of prognostic significance in WHO grade 3 gliomas. 3. To project a randomized phase 2 screening trial examining the efficacy of concurrent chemoradiotherapy with temozolomide followed by adjuvant temozolomide for WHO grade 3 gliomas without codeletion of chromosome 1p/19q. 4. The prognostic significance of methylation status of MGMT and IDH1 mutation as molecular markers will be also assessed in each arm as key secondary analysis.

The role of chemotherapy for gliomas has been recently reappraised by the advent of temozolomide, especially for glioblastomas, and further investigation is now being directed to unveiling its optimal indications, dosing protocols, and the most relevant prognostic factors. Meanwhile, the management of anaplastic gliomas of WHO grade 3 (anaplastic astrocytomas, anaplastic oligodendrogliomas, and anaplastic oligoastrocytomas) is currently largely based on surgery followed by radiotherapy, of which prognosis remains still dismal with the median survival of 2-5 years. To date, the benefit of chemo for WHO grade 3 gliomas is unclear of modest at best with conventional cytotoxic agents, and the role of temozolomide for these entities still is not elucidated. Moreover, WHO grade 3 gliomas are now known to consist of heterogeneous groups of different histologic features, biological behaviors, and prognoses. Accordingly, relevant molecular markers are appreciated with the growing body of data that showing their implications on response to therapy and survival, including codeletion of chromosome 1p/19q, methylation status of methylguanine methyl transferase (MGMT), and isocitrate dehydrogenase (IDH) mutation.1,4-6,11 Among those, codeletion of chromosome 1p/19q is considered the most important marker of prognostic significance in WHO grade 3 gliomas. One recent Korean prospective cohort study showed the potential survival benefit and safety of concurrent chemoradiotherapy with temozolomide followed by adjuvant temozolomide for WHO grade 3 gliomas. In this study, however, the role of molecular markers such as codeletion of chromosome 1p/19q and MGMT methylation could not be determined because of small number of patients available. These results prompted this Korean group to project a randomized phase 2 screening trial examining the efficacy of concurrent chemoradiotherapy with temozolomide followed by adjuvant temozolomide for WHO grade 3 gliomas without codeletion of chromosome 1p/19q. The basic concept of the present clinical trial is "a subgroup with expected worse prognosis according to the status of chromosome 1p/19q, i.e. one without codeletion of chromosome 1p/19q is to be managed more aggressively", to investigate the role of temozolomide. An aggressive therapy (surgery + concurrent chemoradiotherapy with temozolomide followed by adjuvant temozolomide) will be compared to the conventional arm (surgery + radiotherapy only) in terms of its efficacy and safety for WHO grade 3 gliomas without chromosome 1p/19q codeletion. The prognostic significance of methylation status of MGMT and IDH1 mutation as molecular markers will be also assessed in each arm as key secondary analysis. Until now, there have been no such trials examining the efficacy and safety of temozolomide for WHO grade 3 gliomas based on prospective molecular stratification.