The European Organisation for the Research and Treatment of Cancer (EORTC) and the Canadian National Cancer Institute Clinical Trial Team (NCIC) conducted a phase III clinical trial in 2005 (NCT00006353) on the standard treatment protocol of Glioblastoma multiforme. This trial established 6 cycles of adjuvant TMZ chemotherapy as the standard primary glioblastoma treatment protocol post-surgery and concurrent chemoradiotherapy (ie, Stupp protocol). Ultimately, 36.5% (105/287) of patients completed the full adjuvant chemotherapy course. However, there is no effective supplementary treatment after completing the Stupp program. Although six adjuvant TMZ therapy cycles are used in the Stupp regimen, the optimal regimen for such a therapy is debated. In clinical practice, some clinicians adopt a dose-intensive regimen or extend adjuvant treatment cycles beyond 6 weeks. Therefore, establishing a standardized adjuvant TMZ treatment plan is of high importance.
Prolonged exposure to alkylating agents will deplete intracellular MGMT in peripheral blood mononuclear cells, and low levels of MGMT will ensure optimal cytotoxicity of TMZ. To verify whether lower MGMT levels were associated with improved survival, a phase III clinical trial divided patients with primary GBM into standard-dose and dose-dense TMZ treatment groups. The results of this trial revealed a median OS of 16.6 and 14.9 months (HR 1.03; P = 0.63) and median PFS of 5.5 and 6.7 months (HR 0.87; P = 0.06), respectively, with no significant differences between the groups. Extended OS was not observed in the dose-dense group, although the incidence of adverse reactions was greater in this group compared to the standard-dose group (52.5% and 34.1%).
Few large long-term adjuvant chemotherapy studies are present in the published literature. In several retrospective studies[13–15], the median chemotherapy cycle number ranged from 14 to 16 cycles in long-term adjuvant chemotherapy groups. In these studies, patients undergoing long-term TMZ adjuvant chemotherapy treatment exhibited longer PFS and OS than those receiving standard chemotherapy regimens. Such studies indicate that the number of adjuvant TMZ chemotherapy cycles is an independent factor that benefits both PFS and OS; however, our findings suggest otherwise. Long-term adjuvant TMZ chemotherapy improved PFS (HR: 0.454;95%CI 0.244–0.842༛P༚0.01) not OS (HR༚0.628༛95%CI 0.324–1.215༛P༚0.159) based on Cox regression and survival curve analyses in our study. Similar studies have been reported in the literature[16–18]. Gramatzki, D. et al. evaluated 142 newly diagnosed GBM patients between 2004 and 2010. The study determined that long-term adjuvant chemotherapy was independently associated with PFS, but COX regression did not support and benefit to OS. Skardelly et al. studied 107 recently diagnosed GBM patients from 2006 to 2014. In their study, long-period adjuvant chemotherapy group exhibited a higher median survival time than the standard-period adjuvant chemotherapy group (28.6 months and 25.2 months). However, following multivariate regression analysis, no significant differences between the two groups were determined (RR 0.77, P = 0.46).
Researchers have observed improvements in PFS from long-cycle chemotherapy on, as reported by multiple publications. Whether or not there is a statistically significant difference in OS, the long-cycle adjuvant TMZ chemotherapy group shows a higher 2-year survival rate[13–18]. In the present study, the 2-year survival rate of patients in the standard- and long-cycle adjuvant TMZ chemotherapy groups were 36% and 66%, respectively (P = 0.02). We believe that an increased 2-year survival rate in the long-term adjuvant chemotherapy group is associated with prolonged PFS from long-term chemotherapy. In a retrospective analysis of phase II clinical trials, 437 GBM patients included were divided into 9-week, 18-week, and 26-week groups according to post-operative PFS. The findings of this study show that patients with extended PFS also have higher survival rates after tumor recurrence. A retrospective analysis of 831 GBM patients included in trial RTOG 0525 showed that the risk of death after GBM progression was 6.6 times higher than in the group that did not exhibit cancer progression. There is a close correlation between PFS and OS. A longer PFS may improve the 2-year survival rate by decreasing the risk of death.
We observed that patients with tumors involving only a single lobe of the brain exhibited longer PFS than patients with multi-lobe involvement. A possible explanation is that GBM aggressively invades surrounding tissues, and invisible tumors can be more easily removed in the patients with tumors involving a single lobe of the brain. Similar to our study, Filippini, G. et al. conducted a survival analysis of 676 GBM patients and found that the prognosis of patients with single lobe involvement was significantly better than those with multiple lobe involvement (HR: 0.78, 95% CI (0.65–0.94), P = 0.008) . In a study by Kaisorn, L et al., RV was closely related to tumor recurrence. In addition to being negatively related to the degree of resection, RV was also affected by tumor location. When tumors involve multiple lobes and may not be fully removed by surgery, long-term adjuvant TMZ chemotherapy can be of benefit to these patients.
Despite our interesting results, our study has several limitations. First, the overall sample size of patients included in the study was small and they all came from the same clinical center. Second, this is a non-randomized retrospective study and that differences in treatment selection after tumor recurrence may affect OS. Therefore, a prospective multicenter clinical trial is necessary to evaluate the question of duration of TMZ therapy better.
In conclusion, long-term adjuvant TMZ chemotherapy is beneficial for PFS and 2-year survival rate in GBM patients. But OS was not significantly improved. Until the results of a large multicenter prospective trial are available, we do not support the extension of adjuvant TMZ chemotherapy cycles in patients with primary GBM.