Protracted Adjuvant Temozolomide in Glioblastoma Multiforme

Abstract

Purpose: Radiotherapy with concurrent temozolomide (TMZ), followed by 6 cycles of adjuvant TMZ, is the standard of care for newly diagnosed Glioblastoma Mulltiforme (GBM). However tumor progression is the role with median survival of almost 14 months. With lack of effective second line chemotherapy, many physicians and some guidelines advocate prolonged use of adjuvant TMZ more than 6 months. We conduct this study to test the efficacy of protracted adjuvant conventional dose TMZ over the standard 6 doses of adjuvant TMZ. Material and Methods: This phase II trial enrolled patients newly diagnosed as GBM, older than age 18 years, with a Karnofsky performance score (KPS) of ≥60, Neurological Performance Scale (NPS) of ≤3. Patients were randomly assigned to the standard concurrent chemoradiotherapy (CCRT) followed by 6 cycles of adjuvant TMZ or the same treatment with more than 6 cycles of adjuvant chemotherapy extended as long as the patient in good performance, with no unacceptable toxicity, no signs of disease progression. The primary end point was OS. Results: A total of 59 patients were recruited in the study and were randomized in two arms. 29 patients joined arm 1 aiming at receiving CCRT followed by adjuvant 6 cycles TMZ (6 cycles arm) and 30 joined arm 2 aiming at receiving the same treatment with more than 6 cycles of TMZ (>6 cycles). 16 patients managed to complete the adjuvant 6 cycles in arm 1. 19 patients in arm 2, completed the 6 cycles with additive more doses with a median of 11 cycles (range: 8-23 cycles). Median PFS was 12.1 months for (6 cycles) arm, and 18.8 months for (>6 cycles) arm, HR 0.88 (95% CI: 1.185-4.901) (P 0.015); the overall survival for (6 cycles) arm was 18.1 months, versus 24.1 months, HR 0.70 (95% CI: 1.007-4.037) (P 0.048). No significant added toxicity was notice and the 4 weekly TMZ was well tolerated. Conclusion: This study concluded that protracted adjuvant TMZ after concurrent chemoradiotherapy could be a feasible strategy for GBM. This strategy warrants a large phase III randomized trial.

Will Extended Adjuvant Temozolomide Treatment Confer a Survival Advantage As Compared to The Standard Six Cycles for Newly Diagnosed Glioblastoma Multiforme Patients?

“…Despite the great advances in multimodality approach for high grade glioma, the optimal treatment remains a challenging issue for the oncologist. Extending the duration of adjuvant TMZ therapy has been evaluated in several studies to optimize treatment and to improve survival [5][6][7][8][9][10][11][12]. In our study, 55/121 patients (45.5%) were eligible and retrospectively analyzed.…”

“…Initially, patients received up to six cycles of adjuvant TMZ therapy according to Stupp protocol (Group 1). However, survival bene t of long term TMZ administration [5,7,8,9], relative tolerability of TMZ and absence of effective second line therapies, were the important elements supporting physicians' decision to allow up to 12 cycles (Group 2) of therapy in patients with good PS (according to ECOG PS) [13] both after surgery and during follow up, manageable toxicity, stable or responsive disease according to Response Assessment in Neuro-Oncology (RANO) criteria [14]. The dose of adjuvant TMZ was 150 mg/m 2 /day for ve days in the rst cycle and increased to 200 mg/m 2 /day for ve days in the subsequent cycles if no hematologic toxicity had occurred.…”

“…Treatment was stopped if neutrophil count was 0.5×10 9 /L, platelet count was < 10×10 9 /L, or ≥ grade 3 non-hematologic toxicity (except for alopecia, nausea, vomiting) was observed. During adjuvant treatment, TMZ dose was reduced from 200 to 150 mg/m 2 or from 150 to 100 mg/m 2 if neutrophil count was < 1×10 9 /L, platelet count was < 50×10 9 /L, or grade 3 non-hematologic toxicity (except for alopecia, nausea, vomiting) was observed.…”

“…At a median follow-up of 28 months, he reported a median overall survival (OS) of 14.6 months with concurrent TMZ and radiotherapy compared to 12.1 months with radiotherapy alone. Aiming at improving the survival in patients with GBM, extending the duration of maintenance TMZ for patients without tumor progression after six cycles of adjuvant TMZ has been evaluated by several randomized trials but the results are con icting [5][6][7][8][9][10][11][12].…”

Re‐inventing the randomized controlled trial in medical oncology: The registry‐based trial

“…Notably, there has been little improvement in the survival outcomes of patients with newly diagnosed glioblastoma since the introduction of chemotherapy following the seminal trial results in 2005 . The justification for a definitive randomized study is that several small retrospective studies and limited randomized phase II studies have suggested that extending post‐radiation chemotherapy up to 12 cycles can improve survival, without an increase in toxicity . The small numbers of patients included in the randomized studies, as well as the multiple confounders in any unselected clinical series create concern regarding the significance of the reported findings.…”