Background
The prognosis of recurrent malignant gliomas (RMGs) is poor, and no standard treatment has been established[
1]. Since 2002 at our institute, we have been applying a form of tumor-selective particle radiation, boron neutron capture therapy (BNCT), for RMGs and observed favorable survival outcomes[
2,
3]. BNCT is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low-energy thermal neutrons to yield high-linear-energy transfer alpha particles and recoiling lithium-7 nuclei. These particles are released within a very short range such as 9 μm, and therefore the cytotoxic effects are confined within boron-10-containing cells[
4].
Boron-10-containing compounds can be accumulated selectively in tumor cells by several mechanisms. For example, boronophenylalanine (BPA) is selectively and preferentially accumulated in tumor cells via the augmented metabolism of amino acids compared to normal cells. Even with this novel and selective particle radiation technique, radiation damage — chiefly radiation necrosis (RN) and symptomatic pseudoprogression (psPD) — often occurs[
5,
6]. The radiation damage is especially likely in RMG cases, because full-dose X-ray treatment (XRT) is generally part of the treatment history in such cases.
Bevacizumab (BV), an anti-vascular endothelial growth factor (VEGF) antibody, has recently been used for the treatment of symptomatic RN[
7,
8]. Based on our analysis of human RN surgical specimens, we previously demonstrated that the edema in RN is caused by the overexpression of VEGF in reactive astrocytes[
9]. Following this determination, we used BV in an attempt to control the symptomatic RN and the symptomatic psPD encountered after BNCT for RMGs[
5,
7]. Here we present a case series report of our last four consecutive cases of RMG treated with BNCT and BV, with >18-month observation periods. All four patients had RMGs after primary treatment with XRT and chemotherapy consisting chiefly of temozolomide (TMZ). The patients’ profiles and survival data are listed in Table
1. Three of the patients were classified as recursive partitioning analysis (RPA) (advocated by Carson et al. in 2007[
1]) class 3 and one was classified as RPA class 4.
Table 1
The background of the four patients with recurrent malignant glioma (RMG)
1 | 43 | M | AA | 3 | 11.4 | 118 | 36.1 | 3 (11 M) | RN | 23 M, alive |
2 | 41 | M | GBM | 4 | 12.1 | 88.5 | 36.6 | 4 (14 M) | RN | 26 M, alive |
3 | 60 | M | AA | 3 | 10.8 | 110 | 82.3 | 6 (4 M) | PsPD | 16.5 M |
4 | 34 | F | AOA | 3 | 11.5 | 71.6 | 30.1 | 6 (2 M) | PsPD | 14 M |
Discussion
In comparison with many Phase I and II trials for RMG[
1], BNCT showed a marked survival benefit for RMG in our previous study, in which BV was not used[
3]. Briefly, BNCT resulted in median survival times (MSTs) (months and 95% confidence intervals) as follows: for all RPA classes (Classes 1–7), 10.8 (7.3–12.8) (n = 22), and in the poor-prognosis group (RPA class 3 + 7), 9.1(4.4–11.0) (n = 11). In a meta-analysis reported in the Journal of Clinical Oncology[
1], the MSTs in all RPA classes and in the poor-prognosis group (RPA class 3 + 7) were 7.0 (6.2–8.0) (n = 310) and 4.4 (3.6–5.4) (n = 129), respectively. These data showed the superiority of BNCT for RMGs, especially in poor-prognosis groups. In comparison, our previous data showed MSTs of RPA class 3 and 4 as 7.3 and 12.0 months, respectively, although the number of the patients was quite limited: 4 cases in class 3 and 3 cases in class 4[
3].
In our recent patients undergoing BNCT for RMGs, we have begun to treat RN or symptomatic psPD aggressively by administering BV. We applied intravenous BV treatment for four recent RMG patients treated with BNCT at our institute and in whom we encountered RN or symptomatic psPD; these cases are reported here. Three of these four patients were classified as RPA class 3 and one as class 4 (Table
1). The estimated survival time of class 3 patients is 3.8 months and that of class 4 patients is 10.8 months[
1]. Our three class 3 patients survived for 14, 16.5, and > 23 months, and the class 4 patient has survived for over 26 months.
At a glance, BNCT with BV seemed to prolong the survival of RMGs strikingly in comparison not only with Carson’s data set but also with our previous BNCT data. Although of course no definitive conclusion can be drawn from such a small number of cases.
In our limited experience, there is no obvious histological difference between RN and psPD[
6]. The center part of each pathology is characterized as histological necrosis, and marked angiogenesis is observed in the boundary of the necrotic core and normal brain tissue[
9]. Clinically, most psPD occurs at a relatively early stage after intensive treatments and is self-limiting without severe sequelae[
14]. In most cases, psPD improves over time without intensive treatments. On the other hand, RN often shows severe symptoms and occurs at least a half year after radiotherapy. Thereafter, symptomatic psPD is especially difficult to distinguish from RN. In Table
1, we distinguish them only from the duration of the symptomatic onset after BNCT.
We have described herein the use of BV for RN or psPD after BNCT. BV was approved for the treatment of RMGs as an anticancer agent[
15,
16], and several trials of re-irradiation using XRT or hypo-fractionated stereotactic radiotherapy in combination with BV just before radiotherapy for RMGs have recently been conducted, with favorable preliminary safety and response results[
17‐
19]. The authors of those reports described the role of BV not only as an anticancer agent but also for normalizing the perfusion pressure and oxygenation effects during irradiation. BV may also prevent RN and symptomatic psPD after re-irradiation.
We are now planning a prospective clinical trial of BNCT using BV immediately after neutron irradiation for RMG patients with poor prognosis (class 3 + 7). We are also conducting a clinical trial of BNCT for RMGs using a small accelerator in-hospital, instead of an atomic reactor. We hope to determine whether accelerator-based BNCT with BV could be used as a standard treatment for RMGs.
Acknowledgments
This work was supported in part by a Grant-in-Aid for Scientific Research (B) (19390385) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology to S-IM.
Competing interests
There is no conflict of interest to disclose for any of the authors.
Authors’ contributions
S-IM conceived of the study and participated in the follow-up of patients. SK, RH, and MS applied BNCT in the atomic reactor. MF followed the patients with bevacizumab. TK selected the patients for BNCT. All authors read and approved the final manuscript.