In this study, younger age, right side, higher KPS, GTR, intraoperative MRI use for removal, p53 status, proton therapy, combination immunotherapy, and discharge to home were good prognostic factors in the univariate analysis. Among these, GTR, proton therapy, and immunotherapy were extracted as good prognostic factors, while the use of intraoperative MRI was closely related to EOR. In previous reports, intraoperative MRI was observed to improve the removal rate (19, 20) and our current study is consistent with these reports. As for the right side resulting in a good prognosis in the univariate analysis, the requirement of complex informed consent for advanced therapies, including proton therapy and immunotherapy, may be involved. Informed consent that contained explanations of possible complications tended to include more non-aphasic patients (the majority of whom had right-side lesions) in these advanced therapies. For instance, 20 (61%) out of 33 patients who underwent proton therapy had right-sided lesions as did 24 (61%) out of 39 patients who received immunotherapy (detailed data not-shown).
In the sub-analysis, immunotherapy was a good prognostic factor in the GTR group while GTR was also a good prognostic factor in the AFTV group that happens to represent the majority of immunotherapy given in our institution. Our previous, prospective clinical studies have also shown that high EOR prolongs PFS and OS, although significant differences were only obtained in univariate analyses using the small number of patients that were enrolled in the study (12, 18). In the present study, however, the significance of this result seems to be high because of the large, albeit retrospective, amount of patient data (277 cases). Moreover, sub-analysis using GTR patient data (Fig3) shows immunotherapy can produce long survival (for up to 5 years) in approximately 40% of patients if the tumor lesion is surgically removed without any residual bulk. To the best of our knowledge, no previous study has clarified this phenomenon. A recent meta-analysis using 9 total studies, representing 806 GBM patients, showed that half of GBM patients have PD-L1 overexpression and this expression in tumor tissues is significantly related to a poor OS (HR = 1.63, P = 0.003) with heterogeneity (I2 = 51%) (21). This result indicates that tumor bulk in most GBM cases engenders resistance to cytotoxic T cell lymphocytes (CTLs), an idea bolstered by our previous studies that showed immunosuppressive PD-1-positive cells and M2 macrophages colocalized to GBM tissue in early relapse cases after AFTV (22, 23). We therefore speculate that vaccine therapies, including AFTV combined with immune checkpoint inhibitors, M2 macrophage inhibitors, or local therapy that provokes a local immune response, will prolong OS for both GTR and non-GTR cases. Combinations of immunotherapy based on this concept are expected to become the next generation of immunotherapy. (18)
In this study, IDH status was not a statistically significant prognostic factor throughout the entire analysis (Table1) or in the 31 AFTV cases (detailed data not shown). The mOS values of IDH mutant GBM patients were fairly high (28.0 months in the entire analysis and 29.5 months in a sub-analysis using AFTV cases) and we speculate that this is due to the low number of IDH mutant cases. In a recent meta-analysis of GBM, 67 (36.61%) of 183 IDH1 wild-type GBM cases were PD-L1-positive, while only one (3.85%) of 26 IDH1 mutant GBM cases were PD-L1-positive. (21) The pooled OR indicates that PD-L1 positivity was closely related to IDH1 status (OR = 9.92, P = 0.007),(21) revealing that CTLs in the GBM microenvironment are more effective in IDH1 mutant GBM. Future studies will accumulate the data to confirm this theory. In our study, p53-negative/wild type was a good prognostic factor in the univariate analysis of the entire dataset as shown in Table1 (mOS values were 19.1, 16.4, and 15.7 months in p53 negative/wildtype, p53 positive/mutant, and unexamined cases, respectively, p=0.047 by the logrank test). In this regard, p53 status had no effect on prognosis in the univariate analysis of 238 cases (excluding immunotherapy cases; median OS values were 15.9, 13.7, and 14.7 months in p53 negative/wildtype, p53 positive/mutant, and unexamined cases, respectively, p=0.162 by the logrank test) and we assumed that the immunotherapies improved the prognoses of p53 negative/wildtype GBM patients. Our previous studies also suggest that this type is a good prognostic factor in GBM patients who receive AFTV but future prospective studies are needed to verify this.
Limitations of this study must be acknowledged and, to address them, a multicenter, randomized Phase III trial on AFTV was begun to clarify immunotherapy benefits in GTR patients. Detailed information about MRI data including existence of contrast enhancement (CE) in the lesion, volume of CE area and volume of fluid-attenuated inversion recovery high-intensity area were not included in the analysis. Heterogeneity in type of testing for IDH, p53, and MGMT statuses might make the results inaccurate and our insufficient analysis of molecular markers of intratumoral tissues related to prognosis in the immunotherapy group, outside of these 3 markers, should be rectified by additional studies. In addition, as only 3 patients received immunotherapy combined with proton therapy, the effect of this combination cannot be clearly stated in this study.
In conclusion, GTR, proton therapy, and immunotherapy were good prognostic factors in the multivariate analysis of single-center GBM cases. Notably, tumor vaccine therapy for GTR cases achieved high median survival times and long-term survival ratios, revealing that vaccine therapy should be performed for GTR cases.