A. Z. Diaz

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.

Models for estimation of the 10B concentration after BPA-fructose complex infusion in patients during epithermal neutron irradiation in BNCT

PURPOSE To create simple and reliable models for clinical practice for estimating the blood (10)B time-concentration curve after p-boronophenylalanine fructose complex (BPA-F) infusion in patients during neutron irradiation in boron neutron capture therapy (BNCT). METHODS AND MATERIALS BPA-F (290 mg BPA/kg body weight) was infused i.v. during two hours to 10 glioblastoma multiforme patients. Blood samples were collected during and after the infusion. Compartmental models and bi-exponential function fit were constructed based on the (10)B blood time-concentration curve. The constructed models were tested with data from six additional patients who received various amounts of infused BPA-F and data from one patient who received a one-hour infusion of 170 mg BPA/kg body weight. RESULTS The resulting open two-compartment model and bi-exponential function estimate the clearance of (10)B after 290 mg BPA/kg body weight infusion from the blood with satisfactory accuracy during the first irradiation field (1 ppm, i.e., 7%). The accuracy of the two models in predicting the clearance of (10)B during the second irradiation field are for two-compartment model 1.0 ppm (8%) and 0.2 ppm (2%) for bi-exponential function. The models predict the average blood (10)B concentration with an increasing accuracy as more data points are available during the treatment. CONCLUSION By combining the two models, a robust and practical modeling tool is created for the estimation of the (10)B concentration in blood after BPA-F infusion.

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

Case Studies of Patients with Glioblastoma Multiforme Treated with Boron Neutron Capture Therapy at the Brookhaven Medical Research Reactor

Over the past decade, research at Brookhaven National Laboratory (BNL) and other places in the world has led to several significant advances in boron neutron capture therapy (BNCT) technology. These include the development of epithermal neutron beams1 as well as more tumor-specific boron compounds.2 In 1994, a Phase I/II clinical trial of BNCT using intravenous p-boronophenylalanine-fructose (BPA-F) and epithermal neutrons was initiated to determine both the safety and possible efficacy of BNCT for glioblastoma multiforme.3 As with any new therapy, a practical clinical experience with BNCT has been gained over time. Specific management issues seen in this trial have involved the use of steroid medication, early neurological deficits, seizure management, and BNCT-related necrosis.

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.