Jacek Capala

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 glioblastoma multiforme using p-boronophenylalanine and epithermal neutrons: trial design and early clinical results.

A Phase I/II clinical trial of boron neutroncapture therapy (BNCT) for glioblastoma multiforme is underwayusing the amino acid analog p-boronophenylalanine (BPA) andthe epithermal neutron beam at the Brookhaven MedicalResearch Reactor. Biodistribution studies were carried out in18 patients at the time of craniotomy usingan i.v. infusion of BPA, solubilized as afructose complex (BPA-F). There were no toxic effectsrelated to the BPA-F administration at doses of130, 170, 210, or 250 mg BPA/kg bodyweight. The tumor/blood, brain/blood and scalp/blood boron concentrationratios were approximately 3.5:1, 1:1 and 1.5:1, respectively.Ten patients have received BNCT following 2-hr infusionsof 250 mg BPA/kg body weight. The averageboron concentration in the blood during the irradiationwas 13.0 ± 1.5 μg 10B/g. The prescribedmaximum dose to normal brain (1 cm3 volume)was 10.5 photon-equivalent Gy (Gy-Eq). Estimated maximum andminimum doses (mean ± sd, n=10)to the tumor volume were 52.6 ± 4.9Gy-Eq (range: 64.4–47.6) and 25.2 ± 4.2 Gy-Eq(range: 32.3–20.0), respectively). The estimated minimum dose tothe target volume (tumor + 2 cm margin)was 12.3 ± 2.7 Gy-Eq (range: 16.2–7.8). Therewere no adverse effects on normal brain. Thescalp showed mild erythema, followed by epilation inthe 8 cm diameter field. Four patients developedrecurrent tumor, apparently in the lower dose (deeper)regions of the target volume, at post-BNCT intervalsof 7, 5, 3.5 and 3 months, respectively.The remaining patients have had less than 4months of post-BNCT follow-up. BNCT, at this startingdose level, appears safe. Plans are underway tobegin the dose escalation phase of this protocol.

Boron Neutron Capture Therapy for Glioblastoma Multiforme: Clinical Studies in Sweden.

A boron neutron capture therapy (BNCT) facility has been constructed at Studsvik, Sweden. It includes two filter/moderator configurations. One of the resulting neutron beams has been optimized for clinical irradiations with a filter/moderator system that allows easy variation of the neutron spectrum from the thermal to the epithermal energy range. The other beam has been designed to produce a large uniform field of thermal neutrons for radiobiological research. Scientific operations of the Studsvik BNCT project are overseen by the Scientific Advisory Board comprised of representatives of major universities in Sweden. Furthermore, special task groups for clinical and preclinical studies have been formed to facilitate collaboration with academia. The clinical Phase II trials for glioblastoma are sponsored by the Swedish National Neuro-Oncology Group and, presently, involve a protocol for BNCT treatment of glioblastoma patients who have not received any therapy other than surgery. In this protocol, p-boronophenylalanine (BPA), administered as a 6-h intravenous infusion, is used as the boron delivery agent. As of January 2002, 17 patients were treated. The 6-h infusion of 900 mg BPA/kg body weight was shown to be safe and resulted in the average blood–boron concentration of 24 μg/g (range: 15–32 μg/g) at the time of irradiation (approximately 2–3 h post-infusion). Peak and average weighted radiation doses to the brain were in the ranges of 8.0–15.5 Gy(W) and 3.3–6.1 Gy(W), respectively. So far, no severe BNCT-related acute toxicities have been observed. Due to the short follow-up time, it is too early to evaluate the efficacy of these studies.

Boron Neutron-Capture Therapy (BNCT) for Glioblastoma Multiforme (GBM) Using the Epithermal Neutron Beam at the Brookhaven National Laboratory

OBJECTIVE Boron neutron-capture therapy (BNCT) is a binary form of radiation therapy based on the nuclear reactions that occur when boron (10B) is exposed to thermal neutrons. Preclinical studies have demonstrated the therapeutic efficacy of p-boronophenylalanine (BPA)-based BNCT. The objectives of the Phase I/II trial were to study the feasibility and safety of single-fraction BNCT in patients with GBM. MATERIALS AND METHODS The trial design required (a) a BPA biodistribution study performed at the time of craniotomy; and (b) BNCT within approximately 4 weeks of the biodistribution study. From September 1994 to July 1995, 10 patients were treated. For biodistribution, patients received a 2-hour intravenous (i.v.) infusion of BPA-fructose complex (BPA-F). Blood samples, taken during and after infusion, and multiple tissue samples collected during surgical debulking were analyzed for 10B concentration. For BNCT, all patients received a dose of 250 mg BPA/kg administered by a 2-hour i.v. infusion of BPA-F, followed by neutron beam irradiation at the Brookhaven Medical Research Reactor (BMRR). The average blood 10B concentrations measured before and during treatment were used to calculate the time of reactor irradiation that would deliver the prescribed dose. RESULTS 10B concentrations in specimens of scalp and tumor were higher than in blood by factors of approximately 1.5 and approximately 3.5, respectively. The 10B concentration in the normal brain was < or = that in the blood; however, for purposes of estimating radiation doses to normal brain endothelium, it was always assumed to be equal to blood. BNCT doses are expressed as gray-equivalent (Gy-Eq), which is the sum of the various physical dose components multiplied to appropriate biologic effectiveness factors. The dose to a 1-cm3 volume where the thermal flux reached a maximum was 10.6 +/- 0.3 Gy-Eq in 9 patients and 13.8 Gy-Eq in 1 patient. The minimum dose in tumor ranged from 20 to 32.3 Gy-Eq. The minimum dose in the target volume (tumor plus 2 cm margin) ranged from 7.8 to 16.2 Gy-Eq. Dose to scalp ranged from 10 to 16 Gy-Eq. All patients experienced in-field alopecia. No CNS toxicity attributed to BNCT was observed. The median time to local disease progression following BNCT was 6 months (range 2.7 to 9.0). The median time to local disease progression was longer in patients who received a higher tumor dose. The median survival time from diagnosis was 13.5 months. CONCLUSION It is feasible to safely deliver a single fraction of BPA-based BNCT. At the dose prescribed, the patients did not experience any morbidity. To further evaluate the therapeutic efficacy of BNCT, a dose-escalation study delivering a minimum target volume dose of 17 Gy-Eq is in progress.

Boron neutron capture therapy (BNCT) for glioblastoma multiforme: A phase II study evaluating a prolonged high-dose of boronophenylalanine (BPA)

BACKGROUND AND PURPOSE To evaluate the efficacy and safety of boron neutron capture therapy (BNCT) for glioblastoma multiforme (GBM) using a novel protocol for the boronophenylalanine-fructose (BPA-F) infusion. PATIENT AND METHODS This phase II study included 30 patients, 26-69 years old, with a good performance status of which 27 have undergone debulking surgery. BPA-F (900 mg BPA/kg body weight) was given i.v. over 6h. Neutron irradiation started 2h after the completion of the infusion. Follow-up reports were monitored by an independent clinical research institute. RESULTS The boron-blood concentration during irradiation was 15.2-33.7 microg/g. The average weighted absorbed dose to normal brain was 3.2-6.1 Gy (W). The minimum dose to the tumour volume ranged from 15.4 to 54.3 Gy (W). Seven patients suffered from seizures, 8 from skin/mucous problem, 5 patients were stricken by thromboembolism and 4 from abdominal disturbances in close relation to BNCT. Four patients displayed 9 episodes of grade 3-4 events (WHO). At the time for follow-up, minimum ten months, 23 out of the 29 evaluable patients were dead. The median time from BNCT treatment to tumour progression was 5.8 months and the median survival time after BNCT was 14.2 months. Following progression, 13 patients were given temozolomide, two patients were re-irradiated, and two were re-operated. Patients treated with temozolomide lived considerably longer (17.7 vs. 11.6 months). The quality of life analysis demonstrated a progressive deterioration after BNCT. CONCLUSION Although, the efficacy of BNCT in the present protocol seems to be comparable with conventional radiotherapy and the treatment time is shorter, the observed side effects and the requirement of complex infrastructure and higher resources emphasize the need of further phase I and II studies, especially directed to improve the accumulation of (10)B in tumour cells.

Computational dosimetry and treatment planning for Boron Neutron Capture Therapy

The technology for computational dosimetry and treatment planning for Boron Neutron Capture Therapy (BNCT) has advanced significantly over the past few years. Because of the more complex nature of the problem, the computational methods that work well for treatment planning in photon radiotherapy are not applicable to BNCT. The necessary methods have, however, been developed and have been successfully employed both for research applications as well as human trials, although further improvements in speed are needed for routine clinical applications. Computational geometry for BNCT applications can be constructed directly from tomographic medical imagery and computed radiation dose distributions can be readily displayed in formats that are familiar to the radiotherapy community.

An improved neutron collimator for brain tumor irradiations in clinical boron neutron capture therapy

To improve beam penetration into a head allowing the treatment of deeper seated tumors, two neutron collimators were built sequentially and tested for use in the clinical boron neutron capture therapy (BNCT) program at the epithermal neutron irradiation facility of the Brookhaven Medical Research Reactor. The collimators were constructed from lithium-impregnated polyethylene, which comprises Li2CO3 powder (approximately 93% enriched isotopic 6Li) uniformly dispersed in polyethylene to a total 6Li content of 7.0 wt. %. The first collimator is 7.6 cm thick with a conical cavity 16 cm in diameter on the reactor core side tapering to 8 cm facing the patients head. The second collimator is 15.2 cm thick with a conical cavity 20 cm in diameter tapering to 12 cm. A clinical trial of BNCT for patients with malignant brain tumors is underway using the first collimator. Results of phantom dosimetry and Monte Carlo computations indicate that the new 15.2 cm thick collimator will improve the neutron beam penetration. Thus, the second collimator was made and will be used in an upcoming clinical trial. In-air and in-phantom mixed-field dosimetric measurements were compared to Monte Carlo computations for both collimators. The deeper penetration is achieved but at a sacrifice in beam intensity. In this report, a performance comparison of both collimators regarding various fluence rate and absorbed dose distributions in a head model is presented and discussed.

Distribution of BPA and metabolic assessment in glioblastoma patients during BNCT treatment: a microdialysis study

Boron neutron capture therapy (BNCT) is dependent on the selective accumulation of boron-10 in tumour cells. To maximise the radiation effect, the neutrons should be delivered when the ratio between the boron concentration in tumour cells to that in normal tissues reaches maximum. However, the pharmacokinetics of p-boronophenylalanine (BPA) and other boron delivery agents are only partly known. We used microdialysis to investigate the extracellular in vivo kinetics of boron in three intracerebral compartments -- solid tumour, brain adjacent to tumour (BAT), and the normal brain, as well as the subcutaneous tissue before, during, and after BNCT treatment. The findings were compared to the pharmacokinetics of BPA in the blood. We also measured the glucose metabolism and the levels of glutamate and glycerol in those compartments. Four patients were studied, two patients underwent surgical tumour resection and in two a stereotactic biopsy was performed. The patients were given BPA (900 mg/kg body weight) by a 6--h infusion. The infusion was completed approximately 2--3 h before neutron irradiation. In tumour tissue the extracellular concentration of BPA followed that of blood with a maximal concentration of 31.2 ppm and a maximal ratio vs. blood of 1.07. In BAT, the maximal concentration of BPA was 18.0 ppm with the peak level delayed for 4--6 h compared to the peak in blood with a maximal ratio of 1.2. Maximal blood concentration found was 41.0 ppm. The uptake of BPA in the normal brain was considerably lower than that in the blood and tumour tissue. No change in glucose metabolism was observed. The extracellular level of glycerol was increased after treatment in tumour tissue but not in normal brain suggesting a selective acute cytotoxic effect of BNCT on tumour cells.

Ligand liposomes and boron neutron capture therapy.

Boron neutron capture therapy (BNCT) has been used both experimentally and clinically for the treatment of gliomas and melanomas, with varying results. However, the therapeutic effects on micro-invasive tumor cells are not clear. The two drugs that have been used clinically, p-boronophenylalanine, (BPA), and the sulfhydryl borane, (BSH), seem to be taken up preferentially in solid tumor areas but it is uncertain whether enough boron is taken up by micro-invasive tumor cells. To increase the selective uptake of boron by such cells, would be to exploit tumor transformation related cellular changes such as over-expression of growth factor receptors. However, the number of receptors varies from small to large and the uptake of large amounts of boron for each receptor interaction is necessary in order to deliver sufficient amounts of boron. Therefore, each targeting moiety must deliver large number of boron atoms. One possible way to meet these requirements would be to use receptor-targeting ligand liposomes, containing large number of boron atoms. This will be the subject of this review and studies of boron containing liposomes, with or without ligand, will be discussed. Two recent examples from the literature are ligand liposomes targeting either folate or epidermal growth factor (EGF) receptors on tumor cells. Other potential receptors on gliomas include PDGFR and EGFRvIII. Besides the appropriate choice of target receptor, it is also important to consider delivery of the ligand liposomes, their pharmacodynamics and pharmacokinetics and cellular processing, subjects that also will be discussed in this review.

Boron neutron capture therapy (BNCT): Implications of neutron beam and boron compound characteristics

The potential efficacy of boron neutron capture therapy (BNCT) for malignant glioma is a significant function of epithermal-neutron beam biophysical characteristics as well as boron compound biodistribution characteristics. Monte Carlo analyses were performed to evaluate the relative significance of these factors on theoretical tumor control using a standard model. The existing, well-characterized epithermal-neutron sources at the Brookhaven Medical Research Reactor (BMRR), the Petten High Flux Reactor (HFR), and the Finnish Research Reactor (FiR-1) were compared. Results for a realistic accelerator design by the E. O. Lawrence Berkeley National Laboratory (LBL) are also compared. Also the characteristics of the compound p-Boronophenylaline Fructose (BPA-F) and a hypothetical next-generation compound were used in a comparison of the BMRR and a hypothetical improved reactor. All components of dose induced by an external epithermal-neutron beam fall off quite rapidly with depth in tissue. Delivery of dose to greater depths is limited by the healthy-tissue tolerance and a reduction in the hydrogen-recoil and incident gamma dose allow for longer irradiation and greater dose at a depth. Dose at depth can also be increased with a beam that has higher neutron energy (without too high a recoil dose) and a more forward peaked angular distribution. Of the existing facilities, the FiR-1 beam has the better quality (lower hydrogen-recoil and incident gamma dose) and a penetrating neutron spectrum and was found to deliver a higher value of Tumor Control Probability (TCP) than other existing beams at shallow depth. The greater forwardness and penetration of the HFR the FiR-1 at greater depths. The hypothetical reactor and accelerator beams outperform at both shallow and greater depths. In all cases, the hypothetical compound provides a significant improvement in efficacy but it is shown that the full benefit of improved compound is not realized until the neutron beam is fully optimized.