Background The CeTeG/NOA-09 trial assessed in a randomized phase 3 setting, whether combined treatment of lomustine together with temozolomide was superior to temozolomide treatment alone in newly diagnosed MGMT (O(6)-methylguanine-DNA-methyltransferase) promoter methylated glioblastoma patients. Survival was significantly improved from 31.4 months with temozolomide alone to 48.1 months with the combination of lomustine plus temozolomide. In view of this encouraging data - suggesting this combination could have a significant impact on the survival of newly diagnosed glioblastoma patients - we were curious to assess safety and efficacy of this regimen under real-life conditions. Material and Methods We collected clinical and radiographic data from adult newly diagnosed MGMT promoter methylated IDH (isocitrate dehydrogenase) wildtype glioblastoma patients treated at five neuro-oncology centers in Germany. As a requirement for inclusion, first-line treatment with lomustine plus temozolomide had to be performed for at least six weeks (one course). The available radiographic data was independently reviewed by an experienced board-certified neuro-radiologist. Results In total, 70 patients were included. Median progression-free survival of the full cohort was 14.4 months and median overall survival was 36.0 months. Patients who received TTFields (Tumor Treating Fields) treatment for eight weeks or longer together with the combination of lomustine plus temozolomide (n=22, 31%) had a prolonged progression-free survival compared to those patients who received TTFields treatment less than eight weeks or did not receive treatment with TTFields (n=48, 69%) (21.5 months versus 11.2 months; HR: 2.118, 95% CI: 1.245-3.605; p=0.0105). In a multivariable Cox regression analysis the use of TTFields for eight weeks or longer together with the combination of lomustine plus temozolomide as well as the application of at least five courses of CeTeG therapy emerged as independent prognostic factors for progression-free survival and overall survival. Pseudoprogression occurred in n=16 (33%) of the patients. We observed no treatment related deaths and high-grade hematotoxicity in n=31 (44%) of the patients. Conclusion The results from this multicentric trial that investigated newly diagnosed MGMT promoter methylated IDH wildtype glioblastoma under real-life conditions indicate toxicity and survival estimates comparable to the CeTeG/NOA-09 trial. The use of TTFields for at least eight weeks in combination with this regimen was independently associated with extended progression-free and overall survival.

Background Disease relapse almost inevitably occurs in patients with adult-type diffuse glioma. Standard of care treatment options at tumor relapse are still not well defined. Frequently used drugs for adult-type diffuse glioma recurrence include lomustine (CCNU) and bevacizumab. Few studies indicate that the combination of trofosfamide/etoposide, given their high lipid solubility with good blood-brain barrier penetrance, may be feasible in pediatric glioblastoma patients. In this retrospective analysis, we determined tolerability and feasibility of combined trofosfamide/etoposide treatment at disease recurrence of patients with adult-type diffuse glioma. Material and Methods We collected clinicopathological data from adult patients with adult-type diffuse glioma treated with the combination of trofosfamide/etoposide at the Division of Clinical Neurooncology at the University Hospital Essen. Only those patients were considered eligible who received trofosfamide/etoposide treatment for more than four weeks (one course). Trofosfamide (100mg/m2/day) and Etoposide (25mg/m2/day) was administered orally in a “one week on, one week off” scheme. A cohort of patients receiving empiric treatment at the investigators’ discretion balanced for tumor entity and canonical prognostic factors (number of previous treatments, MGMT promoter methylation, IDH mutation status, KPS, age, extent of resection) served as control. We collected toxicity data as it pertained to CTCAE (Common Terminology Criteria for Adverse Events, version 5.0) and survival data to explore putative efficacy. Results A total of 33 patients were eligible for this analysis. In the IDH wild-type glioblastoma (n=18) subgroup, median progression-free survival (3.8 months versus 2.9 months, HR: 2.09, 95% CI: 1.010-4.312, p=0.0227; PFS-6: 39% versus 6%) and median overall survival (10.4 months versus 5.7 months, HR: 3.05, 95% CI: 1.393-6.655, p=0.0008) were significantly prolonged as compared to the control cohort. In a multivariable Cox regression analysis, treatment with trofosfamide/etoposide emerged as statistically significant prognostic marker regarding progression-free survival and overall survival. We observed high-grade adverse events (CTCAE grade≥III ) in 21 (64%) of all recurrent glioma patients with hematotoxicity comprising most adverse events (n=18, 86%). Lymphopenia was by far the most observed hematotoxic adverse event (n=13, 62%). Among non-hematologic high-grade adverse events was transaminase elevation (n=3, 14%). Conclusion This study provides first indication that the combination of trofosfamide/etoposide is safe in patients with adult-type diffuse gliomas and may be associated with prolonged survival in adult patients with recurrent IDH wildtype glioblastoma. Our data provide a reasonable rationale for follow-up of a larger cohort in a prospective controlled trial.