For the past century, the classification of brain tumors has been based largely on concepts of histogenesis. For the first time, in 2016, the WHO classification of Central Nervous System (CNS) tumors uses molecular parameters in addition to histology to define many tumor entities, leading to greater diagnostic accuracy as well as improved patient management and more accurate determinations of prognosis and treatment response, Louis et al.. For decades, anaplastic glioma has proven not only hard to treat, but also hard to study because it is so rare. Historically, the management of patients with this CNS tumors was based upon results from studies carried out prior to the recognition of the molecular and prognostic differences between glial tumors. The role of chemotherapy for newly diagnosed anaplastic gliomas, particularly when combined with radiotherapy, has long been unresolved.
The Concurrent and Adjuvant Temozolomide Chemotherapy in Non-1p/19q Deleted Anaplastic Glioma (CATNON) trial was an open-label multicentric phase III 2x2 factorial randomized trial that aimed to evaluate the role of temozolomide concurrent with, and adjuvant to, radiotherapy in patients with 1p/19q non-co-deleted anaplastic gliomas, Van Den Bent et al.. Secondary endpoint included progression free survival (PFS), health related quality of life outcomes, adverse events and cognitive effects.
This intention to treat (ITT) interim analysis was planned after 219 (41%) deaths had occurred to test the null hypothesis of no efficacy (threshold for rejection p<0·0084). Up to the time of the analysis, 1400 patients were screened, 745 were randomly assigned to treatment groups, 344 (46%) out of 745 had had disease progression and 221 (30%) had died (129 [35%] of 372 in the groups that did not receive adjuvant TMZ and 92 [25%] of 373 in the groups that did receive adjuvant TMZ). Patients who received 12 cycles of adjuvant TMZ after RT had slower disease progression than those treated without adjuvant therapy. The median time to disease progression was more than double in the adjuvant TMZ group (42.8 vs 19 months). The median OS has not been reached in patients treated with adjuvant TMZ. Long-term survival estimates also support the use of adjuvant TMZ; 56% of patients were alive at 5 years with adjuvant TMZ compared to 44% with RT alone or with TMZ given during radiation therapy. The results of the TMZ treatment given only during RT are not yet available and final data from this study are expected in 2020.
Some issues raised by this report should be considered for reflection. When the study started, in 2007, the molecular insights were not available yet. IDH 1 and IDH2 mutations are the cornerstone of the WHO 2016 classification of glioma, once they are predictive factors for benefit from chemotherapy as well as MGMT promoter methylation. This update of WHO classification incorporated major restructuring of diffuse gliomas, that now incorporate these different molecular profiles. In this trial, results from MGMT promoter methylation testing were not available in 63% of the patients at the time of the randomization, and IDH 1 and 2 was incorporated the study protocol only in 2011. In this interim analysis, the distribution of cases among treatment groups according to IDH1/2 status was not reported and the prognosis of non-co-deleted 1p/19q IDH1/2 wildtype is worse than the mutated counterparts. Questions regarding timing and length remains unanswered by this report. Per protocol adjuvant treatment included 12 cycles of TMZ, whereas for glioblastoma six cycles of adjuvant TMZ are recommended. The available results of this trial did not show increased toxicity in the adjuvant group when comparing those that received concurrent TMZ with the ones that got RT alone. Although 103 out of 373 patients in the adjuvant group discontinued TMZ, it was not reported if this was related with the length of the adjuvant treatment or increased by the concurrent use of TMZ with RT.
Overall, the interim results of this study are promising however ongoing additional research within this trial will help to identify the molecular profile of patients who are most likely to benefit from adjuvant TMZ. On the basis of results from the CATNON study, a phase III randomized trial (CODEL trial) is ongoing and aims to compare RT plus PCV (procarbazine, lomustine, and vincristine) with RT plus temozolomide in 1p19q co-deleted tumors, Jaeckle et al. .
- Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131:803-20.
- Van Den Bent MJ, Erridge S, Vogelbaum MA, Nowak AK, Sanson M, Brandes AA, Wick W, Clement PM, Baurain JF, Mason WP, Wheeler H. Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. The Lancet 2017; Volume 390, No. 10103, p1645–1653
- Jaeckle K, Vogelbaum M, Ballman K, Anderson SK, Giannini C, Aldape K, Cerhan J, Wefel JS, Nordstrom D, Jenkins R, Klein M. CODEL (Alliance-N0577; EORTC-26081/22086; NRG-1071; NCIC-CEC-2): phase III randomized study of RT vs. RT+ TMZ vs. TMZ for newly diagnosed 1p/19q-codeleted anaplastic oligodendroglial tumors. analysis of patients treated on the original protocol design (PL02. 005). Neurology. 2016;86(16 Supplement):PL02-005.
WHO grade II and III diffuse gliomas have similar molecular abnormalities that diverge gradually forming a biological continuum. Roughly 80% present IDH1/2 mutations, making distinction difficult and often judged subjectively. Should we consider adjuvant TMZ also for all patients classified as having grade II non-co-deleted diffuse gliomas?
Leonor Pinto has no actual, potential, real or apparent interest to declare. She has no involvement that might raise the question of bias in the work reported or in the conclusions, implications, or opinions stated.