Ruimei Ma

Boron Neutron Capture Therapy for Glioblastoma Multiforme: Interim Results from the Phase I/II Dose-Escalation Studies

OBJECTIVE: The primary objective of these Phase I/II dose-escalation studies is to evaluate the safety of boronophenylalanine (BPA)-fructose-mediated boron neutron capture therapy (BNCT) for patients with glioblastoma multiforme (GBM). A secondary purpose is to assess the palliation of GBM by BNCT, if possible. METHODS: Thirty-eight patients with GBM have been treated. Subtotal or gross total resection of GBM was performed for 38 patients (median age, 56 yr) before BNCT. BPA-fructose (250 or 290 mg BPA/kg body weight) was infused intravenously, in 2 hours, approximately 3 to 5 weeks after surgery. Neutron irradiation was begun between 34 and 82 minutes after the end of the BPA infusion and lasted 38 to 65 minutes. RESULTS: Toxicity related to BPA-fructose was not observed. The maximal radiation dose to normal brain varied from 8.9 to 14.8 Gy-Eq. The volume-weighted average radiation dose to normal brain tissues ranged from 1.9 to 6.0 Gy-Eq. No BNCT-related Grade 3 or 4 toxicity was observed, although milder toxicities were seen. Twenty-five of 37 assessable patients are dead, all as a result of progressive GBM. No radiation-induced damage to normal brain tissue was observed in postmortem examinations of seven brains. The minimal tumor volume doses ranged from 18 to 55 Gy-Eq. The median time to tumor progression and the median survival time from diagnosis (from Kaplan-Meier curves) were 31.6 weeks and 13.0 months, respectively. CONCLUSION: The BNCT procedure used has been safe for all patients treated to date. Our limited clinical evaluation suggests that the palliation offered by a single session of BNCT is comparable to that provided by fractionated photon therapy. Additional studies with further escalation of radiation doses are in progress.

Boron neutron capture therapy for malignant gliomas

Boron neutron capture therapy (BNCT) represents a promising modality for a relatively selective radiation dose delivery to the tumour tissue. Boron-10 nuclei capture slow ‘thermal’ neutrons preferentially and, upon capture, promptly undergo 10B(n,α)7Li reaction. The ionization tracks of energetic and heavy lithium and helium ions resulting from this reaction are only about one cell diameter in length (∼ 14 μm). Because of their high linear energy transfer (LET) these ions have a high relative biological effectiveness (RBE) for controlling tumour growth. The key to effective BNCT of tumours, such as glioblastoma multiforme (GBM), is the preferential accumulation of boron-10 in the tumour, including the infiltrating GBM cells, as compared with that in the vital structures of the normal brain. Provided that a sufficiently high tumour boron-10 concentration (∼109 boron-10 atoms/cell) and an adequate thermal neutron fluence (∼ 1012 neutrons/ cm2) are achieved, it is the ratio of the boron-10 concentration in tumour cells to that in the normal brain cells that will largely determine the therapeutic gain of BNCT.

Tolerance of the normal canine brain to epithermal neutron irradiation in the presence of p-boronophenylalanine

Twelve normal dogs underwent brain irradiation in a mixed-radiation, mainly epithermal neutron field at the Brookhaven Medical Research Reactor following intravenous infusion of 950 mg of 10B-enriched BPA/kg as its fructose complex. The 5 × 10 cm irradiation aperture was centered over the left hemisphere. For a subgroup of dogs reported previously, we now present more detailed analyses including dose–volume relationships, longer follow-ups, MRIs, and histopathological observations. Peak doses (delivered to 1 cm3 of brain at the depth of maximum thermal neutron flux) ranged from 7.6 Gy (photon-equivalent dose: 11.8 Gy-Eq) to 11.6 Gy (17.5 Gy-Eq). The average dose to the brain ranged from 3.0 Gy (4.5 Gy-Eq) to 8.1 Gy (11.9 Gy-Eq) and to the left hemisphere, 6.6 Gy (10.1 Gy-Eq) to 10.0 Gy (15.0 Gy-Eq). Maximum tolerated ‘threshold’ doses were 6.7 Gy (9.8 Gy-Eq) to the whole brain and 8.2 Gy (12.3 Gy-Eq) to one hemisphere. The threshold peak brain dose was 9.5 Gy (14.3 Gy-Eq). At doses below threshold, some dogs developed subclinical MRI changes. Above threshold, all dogs developed dose-dependent MRI changes, neurological deficits, and focal brain necrosis.

Cell Survival Following in Vitro Irradiation at Depth in a Lucite Phantom as a Measure of Epithermal Beam RBE

The radiation field produced in tissue during BNCT consists of a mixture of components with differing linear energy transfer (LET) characteristics. In addition to the high-LET products of the 10B(n,α)7Li reaction, the interaction of the neutron beam with the nuclei of elements in tissue will deliver an unavoidable, non-specific background dose, from a mixture of high- and low-LET radiation components, to both tumor and normal tissue. Thermal neutron capture by hydrogen releases a gamma ray through the 1H(n,γ)2H reaction. The capture of thermal neutrons by nitrogen in tissue, the 14N(n,p)14C reaction, releases a high-LET proton with an energy of 590 keV. Contaminating fast neutrons (those with kinetic energies >10keV) in the epithermal neutron beam produce high-LET recoil protons through collisions with hydrogen nuclei (1H(n,n′)p reaction) in tissue. Because the energies of the nitrogen capture proton and the fast neutron recoil proton tend to be in the same range, the biological effects of these high-LET components of the dose are most conveniently measured as a combined “proton dose”. This high-LET “proton dose” must be multiplied by an experimentally determined factor for relative biological effectiveness (RBE) in order to express the total BNCT dose in photon-equivalent units.

Upgrade of the Epithermal Neutron Beam Using 235U Fission Plates at Brookhaven Medical Research Reactor (BMRR)

Effective treatment of very deep intracranial tumors with BNCT requires a high intensity epithermal neutron beam and/or greater relative accumulation of boron in the tumor to deliver sufficient dose at depth. Since it is unlikely that a significantly improved boron delivery agent will become available for clinical use in the near future, the best approach for achieving an effective treatment of such tumors appears to be to improve the neutron beam. An upgraded epithermal beam facility, using 235U fission plates, has been designed for the BMRR and construction is now beginning.

Patterns of Tumor Progression Following BNCT of Glioblastoma Multiforme

The recurrence patterns after conventional adjuvant treatment of glioblastoma multiforme has been analyzed in the past. The most consistent pattern seen in these studies is the predominance of local recurrence.1,2,3 Hochberg and Pruitt were the first investigators to discover that the gross and microscopic tumors were within 2 cm of the contrast-enhancing tumor margin on pre-terminal CT scans in 83% of the patients.3 This became the basis for target volume definition in radiotherapy. In the first several BNCT protocols, this target definition was adopted. However, there has been considerable consternation over the significance of peritumoral edema when planning radiation fields. Biopsy and autopsy studies from the Mayo Clinic and Duke University have shown infiltrating cells in edematous regions.1,2 If so, peritumoral hypodense regions may be at risk for tumor recurrence and should be included in the treatment volume. However, this observation is still in dispute because the malignant nature of the infiltrating cells has not been proven. In the studies by Wallner et al. from Memorial Sloan Kettering Cancer Center, no tendency for tumor recurrence in edematous areas was shown.4 The present paper reports on the recurrence patterns seen on our BNCT trial, in particular, with relation to regions of peritumoral edema.

Nominal Effective Radiation Doses Delivered to the Tumor and Different Parts of the Normal Brain During BNCT for Glioblastoma Multiforme

The mixed radiation field produced during BNCT comprises radiations with different linear energy transfer (LET) characteristics and different efficacies in biological systems (relative biological effectiveness: RBE). The four major components of the BNCT radiation dose are: boron neutron capture (BNC) dose, gamma dose (originating primarily from neutron capture in hydrogen), fast neutron dose, and the nitrogen neutron capture (NNC) dose. Because of different attenuation of gamma rays and neutrons with various energies, the relative contributions of these components to the total dose vary with depth in tissues. In addition, the short range of BNC reaction products makes the 10B microdistribution particularly important and a compound biological effectiveness (CBE) factor must be used to express the BNC dose in photon gray-equivalent (Gy-Eq) units.1 Evaluation of the radiation doses delivered during BNCT combines data on spatial distribution of gamma and neutron fluxes, the 10B concentration and RBE/CBE factors. We report the radiation doses delivered to the tumors (post-operative contrast enhancing volumes), target volumes (tumor + a 2-cm margin), and different parts of the brains of 41 glioblastoma multiforme (GBM) patients treated with BNCT at the Brookhaven Medical Research Reactor (BMRR).2

Split-Dose BNCT Irradiations of Rat Oral Mucosa and Rat Brain Tumor Using BPA

Some BNCT patients irradiated with anterolateral beams have experienced mild, transient side effects in the oral mucosa, the ear mucosa and the parotid salivary gland. As the BPA-based BNCT clinical dose escalation trial continues, the possibility arises that oral mucosa or soft tissues in the head and neck, may become the critical dose-limiting tissue in some cases. The rapid turnover of mucosal epithelium suggests that a sparing effect could be achieved during fractionated BNCT through a repopulation mechanism. The effect of fractionated BNCT on the tumor must also be considered. Retargeting of boron to a different subset of tumor cells during the second fraction may make the two fraction treatment more effective than the single treatment. Tumor regrowth during the interfraction interval could make the two-fraction therapy less effective than the single treatment. Rat ventral tongue mucosa was chosen as a model system for oral mucosa radiobiology. Using the thermal neutron beam of the Brookhaven Medical Research Reactor, the single-fraction dose-response of the oral mucosa and the intracranial rat 9L gliosarcoma was compared to the same total dose given in two fractions separated by 3, 5, 7, or 9 days.

Radiation Risks from p-Boronophenylalanine-Mediated BNCT for Glioblastoma Multiforme

Boron neutron capture therapy (BNCT) is a binary treatment modality that requires selective delivery of a 10B-labeled compound to a tumor and slow neutron irradiation of the tumor-bearing tissues. The capture of thermalized neutrons by 10B releases high linear-energy-transfer (LET) alpha (α) and 7Li particles via the 10B(n,α)7Li reaction. These particles can kill or render non-clonogenic 10B-rich tumor cells while sparing boron-poor tissues. A phase I/II clinical trial of p-boronophenylalanine (≥95% 10B enriched)-mediated BNCT for GBM is being conducted using the Brookhaven Medical Research Reactor’s clinical epithermal neutron irradiation facility.

Efficacy of Boron Neutron-Capture Therapy Using a Carborane- Containing Tetraphenylporphyrin in Mice Bearing EMT-6 Tumors

Although numerous boron-containing compounds have been synthesized for boron neutron-capture therapy (BNCT), only a small fraction have been tested in vivo. Of this fraction, only a handful have shown biological properties favorable enough to warrant a therapeutic study. BNCT studies of tumors in rodent models have only been reported using BPA,1,2 BSH,3 and BSSB.4 Herein, we describe a study using porphyrin-mediated BNCT to palliate tumors in mice.