In this study, we showed that 23.4% of patients with IDH1/2-wildtype GBM could complete 12 cycles of maintenance TMZ therapy, their median survival time was 45.1 months, and the 5-year survival rate was 35.5%. Especially, 26 patients with KPS at 12 cycles ≥ 80 had an extremely favorable OS with a median survival of 89.3 months and 5-year survival rate of 57.0%. We did not show that the residual tumor at 12 cycles, maintenance therapy regimen, maintenance TMZ therapy beyond 12 cycles, and MGMT promoter methylation status has an impact on residual PFS and residual OS. In addition, when patients had tumor recurrence, the median survival time after the first progression was 11.9 months.
The clinical effect of long-term TMZ therapy has been investigated by several retrospective studies and two randomized studies with mixed results [7–14, 16, 21, 22]. Darlix et al. reported that extended TMZ treatment of more than nine cycles is associated with better survival durations than the standard six cycles [10]. Bhandari et al. conducted a small prospective randomized trial with 40 patients and showed that the median survival times of patients administered six cycles and those administered 12 cycles were 15.4 and 23.8 months, respectively (p = 0.044), suggesting that extended TMZ therapy confers a survival advantage over the conventional six TMZ cycles [9]. A recent phase II study showed no differences in the 6-month PFS and median survival time between patients continuing beyond six cycles of maintenance TMZ therapy and those discontinuing at six cycles, even for patients with MGMT promoter-hypermethylated tumors [16]. These heterogeneous results indicate that a subset of patients with GBM might benefit from prolonged TMZ use even though most patients with GBM do not.
In this study, we found that the median survival time in patients with IDH1/2-wildtype GBM who completed 12 cycles of maintenance TMZ therapy was 45.1 months, which was better than that of 33.15 months in patients with GBM who completed 6 cycles of maintenance TMZ therapy [22]. This suggests that patients who completed 12 cycles of maintenance TMZ therapy could have a better chance at survival than those who completed 6 cycles. In addition, patients who completed 12 cycles of maintenance TMZ therapy with KPS at 12 cycles ≥ 80 had a median survival time of 89.3 months and 5-year survival rate of 57.0%, indicating that patients completing 12 cycles and KPS at 12 cycles ≥ 80 could have the maximum benefit from the prolonged use of TMZ.
Good preoperative or postoperative performance status is a well-known favorable prognostic factor for patients with GBM [8, 31–33]; however, few studies account for KPS at the given cycle of maintenance TMZ therapy, as in the present study [16]. This emphasizes the importance of not only the perioperative KPS but also high KPS maintenance over the course of treatment. Thus, our finding indicates that KPS at 12 cycles ≥ 80 could be a novel predictive factor for long-term survival. Clinically, sharing our results with patients could be useful in informing them about their possibility of long-term survival.
Long-term TMZ therapy might introduce a hypermutation phenotype and have negative survival effects after tumor progression [23–25]. TMZ is a cytotoxic DNA-alkylating agent with mutagenic potential and could induce cellular apoptosis via mismatch repair (MMR)-mediated futile cycling; however, when tumor cells lose MMR, TMZ exposure induces a hypermutator phenotype [25]. An increased number of TMZ cycles was reported to be associated with an increased risk of a hypermutation phenotype for recurrent tumors [23–25]. Draaisma et al. reported that the frequency of developing a hypermutation phenotype was 6.8% and that the survival time from the second surgery was similar between patients with hypermutated and non-hypermutated tumors with TMZ-treated GBM [23]. In contrast, Yu et al. reported that the frequency of developing a hypermutation phenotype was 57% in patients with transformed IDH-mutant tumors previously exposed to TMZ and that TMZ-induced hypermutation might be associated with shorter survival after transformation [25]. Thus, the frequency of developing a hypermutation phenotype and its effect on survival might be different between IDH-wildtype and IDH-mutation tumors.
In our cohort with long-term TMZ therapy, the median survival time after the first progression was 11.9 months, which was comparable to that in previous reports, in which the median TMZ cycle was 6 [34]. This suggests that long-term TMZ therapy might not be associated with shorter survival after tumor progression. Although we did not assess the hypermutation phenotype in recurrent tumors, long-term TMZ does not appear to have an unfavorable effect on survival time after tumor progression.
Our patient cohort included two different maintenance TMZ cycle groups, those who continued maintenance TMZ therapy beyond 12 cycles until tumor progression or up to 24 cycles and those who discontinued TMZ therapy without progression after the end of cycle 12. Our multivariate analysis did not result in any advantages of continuing maintenance TMZ beyond 12 cycles, with respect to residual PFS or residual OS, over discontinuation at 12 cycles for patients who completed 12 cycles of maintenance TMZ therapy. Our data also showed that the absence or presence of a residual tumor at 12 cycles and the MGMT promoter status do not affect residual PFS and OS. These findings do not support the continuation of maintenance TMZ therapy beyond 12 cycles, regardless of MGMT promoter methylation status or residual tumors.
This study had some limitations. First, it was performed retrospectively and the maintenance therapy regimens were heterogenous. The nature of a retrospective study and the differences in maintenance therapy might affect the results; therefore, we are aware that our results need to be carefully interpreted. Second, the sample size of our cohort was small. We acknowledge that the power of the survival analysis was limited by the sample size; therefore, our results need to be confirmed in large-scale studies. Third, 12 cycles of maintenance TMZ therapy is not current standard care [17, 18]; thus, this result might not be useful in daily practice. However, before the report by Balana et al.[16], approximately 80% cases continued after six cycles [15] and some clinical trials were set to prescribe 6–12 cycles of maintenance TMZ as a control arm [5, 6, 35]; thus, an evaluation of our treatment outcomes could be important to reveal the potential benefits and disadvantages of long-term TMZ therapy.
In conclusion, patients with IDH1/2-wildtype GBM who completed 12 cycles of maintenance TMZ therapy could have favorable outcome. Especially, patients who completed 12 cycles of TMZ with KPS at 12 cycles ≥ 80 had an extremely favorable OS with a median survival of 89.3 months and 5-year survival rate of 57.0%, suggesting these patients could maximally benefit from the prolonged use of TMZ. KPS at 12 cycles ≥ 80 might be a novel predictive factor for long-term survival. Long-term TMZ therapy does not appear to have a negative impact on survival after tumor progression in patients treated with the long-term administration of maintenance TMZ therapy.