Current status of boron neutron capture therapy of high grade gliomas and recurrent head and neck cancer

Abstract

Boron neutron capture therapy (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. Clinical interest in BNCT has focused primarily on the treatment of high grade gliomas, recurrent cancers of the head and neck region and either primary or metastatic melanoma. Neutron sources for BNCT currently have been limited to specially modified nuclear reactors, which are or until the recent Japanese natural disaster, were available in Japan, United States, Finland and several other European countries, Argentina and Taiwan. Accelerators producing epithermal neutron beams also could be used for BNCT and these are being developed in several countries. It is anticipated that the first Japanese accelerator will be available for therapeutic use in 2013. The major hurdle for the design and synthesis of boron delivery agents has been the requirement for selective tumor targeting to achieve boron concentrations in the range of 20 μg/g. This would be sufficient to deliver therapeutic doses of radiation with minimal normal tissue toxicity. Two boron drugs have been used clinically, a dihydroxyboryl derivative of phenylalanine, referred to as boronophenylalanine or "BPA", and sodium borocaptate or "BSH" (Na2B12H11SH). In this report we will provide an overview of other boron delivery agents that currently are under evaluation, neutron sources in use or under development for BNCT, clinical dosimetry, treatment planning, and finally a summary of previous and on-going clinical studies for high grade gliomas and recurrent tumors of the head and neck region. Promising results have been obtained with both groups of patients but these outcomes must be more rigorously evaluated in larger, possibly randomized clinical trials. Finally, we will summarize the critical issues that must be addressed if BNCT is to become a more widely established clinical modality for the treatment of those malignancies for which there currently are no good treatment options.

Figure 1

Schematic diagram of the Massachusetts Institute of Technology Reactor (MITR). The fission converter based epithermal neutron irradiation (FCB) facility is housed in the experimental hall of the MITR and operates in parallel with other user applications. The FCB contains an array of 11 MITR-II fuel elements cooled by forced convection of heavy water coolant. The converter power is 120 kW at 6 MW reactor power. A shielded horizontal beam line contains an aluminum and Teflon® filter-moderator to tailor the neutron energy spectrum into the desired epithermal energy range. A patient collimator defines the beam aperture and extends into the shielded medical room to provide circular apertures ranging from 16 to 8 cm in diameter. The in-air epithermal flux is 6.2 × 10⁹ n/cm²s at the patient position with the 12 cm collimator. The measured specific absorbed doses are constant for all field sizes and are well below the inherent background of 2.8 × 10^-12 Gy_wcm²/n produced by epithermal neutrons in tissue. The dose distributions achieved with the FCB approach the theoretical optimum for BNCT. This facility is useful for clinical studies of superficial cancers and small animal studies.

Figure 2

A three-field treatment plan for a brain tumor (GBM) patient calculated using the MiMMC treatment planning system. The prescription is a mean brain dose of 7.7 Gy_w. Isodose contours calculated for tumor and normal brain are shown on axial and sagittal slices through the target volumes. The integral dose volume histograms (DVHs) summarize dosimetry for structures of interest including target volumes and organs at risk.

Figure 3

Contrast-enhanced T1-weighted MRI of representative glioblastoma patient and¹⁸ F-labeled BPA-PET image after initial debulking surgery. The patients received ¹⁸ F-BPA-PET to assess the distribution of BPA and to estimate the boron concentration in tumors before BNCT without direct determination of boron concentration in the tumor. The lesion to normal brain (L/N) ratio of the enhanced tumor was 7.8 in this case. Note that even the periphery of the main mass, i.e., the infiltrative portion of the tumor, showed BPA uptake. The L/N ratio of BPA uptake can be estimated from this study and dose planning was done according to this L/N ratio, and if the L/N ratio was more than 2.5, then BNCT was initiated. ¹⁸ F-BPA-PET accurate BPA provided an accurate estimate of the accumulation and distribution of BPA as previously reported [64,65].

Figure 4

¹⁸FDG-PET study prior and 6 months after BNCT of a 56 year-old male patient with recurrent squamous cell carcinoma of the maxilla.A: FDG accumulated in the left orbital region (arrows) and frontal lobe of brain (arrow heads). B: No accumulation of FDG-PET was detected 6 months after BNCT and the patient was disease free for 61 months at the time of the original report. Photographs are from Applied Radiation and Isotopes, 67:S37-S42, 2009.

Figure 5

Graphical representation of a parameterized model converting the maximum weighted dose, calculated Treatment Planning System (TPSs) from each center to an MIT calibrated dose as a function of boron uptake in tissue [69]. The plotted curves afford an easy and direct comparison of dose specification between participants of the International Dosimetry Exchange.

Figure 6

A. Kaplan-Meier estimates of overall survival for all newly diagnosed glioblastoma (WHO grade 4, n = 21). The median survival time of boron neutron capture therapy (BNCT) group (blue line) is 15.6 months. There is statistical significance between both group Log-rank test (p = 0.0035). B. Kaplan-Meier estimates of overall survival for all newly diagnosed glioblastoma (protocol 1 and 2). External beam X-ray irradiation (XRT) boost after boron neutron capture therapy (BNCT) was carried for the latter 11 cases. This improved the median survival time to 23.5 months (from 14.1 months for BNCT only, protocol 1, dotted line in blue).

Figure 7

Radiographic changes following BNCT in two representative patients with GBM. In both, there was a reduction in both mass and peritumoral edema without the administration of corticosteroids or mannitol within a few days. This is also shown in the FLAIR image of Case #12.

Figure 8

Before BNCT (left) and 22 months after the first BNCT (right) of a patient with a recurrent mucoepidermoid carcinoma of the parotid gland. Three treatments with BNCT produced a remarkable reduction in tumor size, but also resolution of a cutaneous ulcer and re-epithelization by normal skin. These results clearly demonstrate that BNCT is a highly tumor-selective treatment modality. She lived for 7 years following treatment (Applied Radiation and Isotopes, 61:1069–1073, 2004).

Figure 9

¹⁸FBPA-PET study prior to and 7 months following the first BNCT treatment.A. A 61 year-old female with residual maxillary adenoid cystic carcinoma (arrows) infiltrating into pterygopalatine fossa (T4N1M0) after maxillectomy, who was treated twice with BNCT using BPA followed by chemotherapy. B. Residual maxillary cancer and a regional lymph node metastasis were no longer evident at 42 months although bilateral multiple pulmonary metastases were detected at 18 months after the first BNCT treatment. The patient lived for 59 months following BNCT (Applied Radiation and Isotopes, 67:S37-S42, 2009).

Figure 10

Kaplan-Meier survival plots of patients with recurrent HNC treated by Kato et al. (6) with BNCT (26 cases, red line) and those who treated with other than BNCT (16 cases, blue line). The outcomes for the 26 patients: Mean survival time: 33.6 months, 4-year Overall survival (OS): 37.0%, 6-year OS: 31.7%. Most of the 26 patients had either recurrent or far advanced cancers of the head and neck region and 15 (58%) had regional lymph node metastases and 6 had developed distant metastases. Nineteen of the patients had squamous cell carcinomas, 4 salivary gland carcinomas and 3 had sarcomas. All but one had received standard therapy and developed recurrent tumors for which there were no other treatment options.

Figure 11

Kaplan-Meier survival plots of patients with either newly diagnosed or recurrent tumors of the head and neck region, treated by Suzuki et al. with BNCT. A total of 68 patients were treated. One and 2 year OS rates were 43.1% and 24.2% respectively. Thirty-three patients had squamous cell carcinomas (53%), 20 had adenocarcinomas (32%) and 11 (18%) had malignant melanomas.