The treatment of recurrent MG, especially in glioblastoma, after the first-line therapy is an ongoing challenge. Re-irradiation was considered a treatment option for recurrent MG. Clinical practice guidelines recommend re-irradiation to improve local tumor control, not accompanying survival benefits (class III evidence) . However, a recent systematic review of re-irradiation research yielded encouraging results in terms of both disease control and survival rates . With regard to radiation modality, SRS or fractionated SRT is usually utilized in the treatment of recurrent MG. In a recent meta-analysis of CyberKnife treatment for recurrent MG, the median OS values after CyberKnife were 11 and 8.4 months for grade 3 and grade 4 gliomas, respectively . A comparison between single-session SRS and fractionated SRS revealed no statistical differences between PFS and OS for MG (PFS, 4.5 and 4.6 months; OS, 12.7 and 12.6 months, respectively) .
Re-irradiation combined with chemotherapy, especially using bevacizumab, has been found to produce better outcomes than re-irradiation alone in patients with recurrent MG. In existing chemotherapies, a bevacizumab-based regimen improves PFS, but not OS in patients with recurrent glioblastoma . Linear-accelerator SRS with adjuvant bevacizumab results in significantly longer PFS and OS (5.2 and 11.2 months, respectively) than SRS alone (2.1 and 3.9 months, respectively) for recurrent glioblastoma . A systematic review of radiotherapies, including fully or hypo fractionated SRT and SRS with or without bevacizumab for recurrent MG also found that a combination of radiotherapy and bevacizumab results in longer PFS and OS (5.6 ± 1.0 and 11.2 ± 2.1 months, respectively) than radiotherapy alone (5.2 ± 1.6 and 9.9 ± 2.1 months, respectively), but the difference was not statistically significant . In a sub-analysis of radiation modalities, only fractionated SRT showed significantly longer OS in the bevacizumab group than in the non-bevacizumab group (11.3 ± 1.6 and 9.4 ± 1.6 months, respectively), but not PFS (6.4 ± 0.9 and 5.2 ± 1.4 months, respectively).
In addition to the antitumor effect, bevacizumab can control brain radiation necrosis, reducing perilesional edema, and contrast enhancement [11, 21]. Brain radiation necrosis, with or without symptomatic brain edema, occurred at a significantly lower rate in patients with recurrent MG treated with re-irradiation using intensity-modulated radiation therapy or volumetric-modulated arc therapy plus bevacizumab than in patients treated with re-irradiation alone (1-year risk rates of 23.9% and 54.1%, respectively) . SRS with bevacizumab also had a lower incidence of radionecrosis (5%) than SRS without bevacizumab (19%) . Therefore, the addition of bevacizumab to SRS permits an increase in the median prescription dose up to 22 Gy without significant adverse events associated with SRS alone in recurrent glioblastoma .
We have previously reported a retrospective study of BNCT for patients with recurrent MG using the same reactor used in the current study as the neutron source . The 1-year survival rate for glioblastoma was 26.3%. The median OS was 10.8 months for all cases and 9.6 months for recurrent glioblastoma cases. Our recent phase II trial of BNCT using a cyclotron-based neutron generator showed that the 1-year survival rate, and the median PFS and OS for recurrent glioblastoma were 79.2%, and 0.9 and 18.9 months, respectively . The acute tumor response to irradiation may explain the long median OS but short median PFS. This trial prohibited the use of bevacizumab until disease progression on MRI after BNCT. Pseudoprogression and radiation injuries, such as radiation necrosis and brain edema in the acute phase, were regarded as disease progression based on the RANO criteria . In this study, bevacizumab was initiated within 4 weeks of BNCT. Therefore, the median PFS of 8.3 months was longer than that for BNCT without bevacizumab. The early induction of bevacizumab treatment could suppress radiation toxicity after BNCT, as with other radiation therapies. Recently, a Taiwanese research group reported on BNCT of lower tumor dose (range, 8.51–25.09 Gy-equivalent) than other reports in treatment of recurrent MG with life-threatening, end-stage status . Their median PFS and OS were 4.18 and 7.25 months, respectively. They reported no adverse reactions, including no radiation necrosis. Although lower-dose BNCT prevented the occurrence of radiation injury, the dose reduction decreased the survival benefits provided by BNCT seen in the regimen of the Taiwanese study. Compared with other radiation therapies, BNCT can be applied to recurrent MG in larger volumes. The median gross tumor volume was 35.1 mL in this cohort. The median treated volume for SRS ranged from 2 to 20.1 mL in re-irradiation of glioblastoma . Even in this study, however, a small tumor volume (< 44.0 mL) was significantly associated with longer OS in patients treated with BNCT. Hence, small tumors respond better to re-irradiation than large tumors, even with BNCT.
There were several limitations to this study. Most of the patients were referred to our institute for BNCT from other provinces in Japan. Therefore, follow-up data were obtained mainly from the local physician’s reports. Under these circumstances, some data were missing, and follow-up periods were irregular. Although serious adverse events were reported properly, mild adverse events did not appear to be, based on their lower frequency than that seen in other clinical trials with bevacizumab. Most of the patients were diagnosed with MG histologically rather than molecularly. As IDH wild- and mutant-type tumors are biologically different, information on the molecular status of MG should be obtained to compare treatment effects to those seen with other recent therapies. This study included a small number of patients. The reactor required inspection for several months and its operation was suspended for earthquake-resistant renovation for 3 years. Therefore, it was not always possible to enroll candidates for this study. Finally, this study was discontinued midway through because the use of the Kyoto University research reactor for clinical irradiation was ended to launch clinical trials with accelerator-based BNCT. This study was designed with a single arm of BNCT and add-on bevacizumab. The efficacy of add-on bevacizumab to BNCT would have been demonstrated more clearly by a two-arm study comparing BNCT and add-on bevacizumab to treatment with bevacizumab alone.