Robert G. Zamenhof

A Critical Examination of the Results from the Harvard-MIT NCT Program Phase I Clinical Trial of Neutron Capture Therapy for Intracranial Disease

SummaryA phase I trial was designed to evaluate normal tissue tolerance to neutron capture therapy (NCT); tumor response was also followed as a secondary endpoint. Between July 1996 and May 1999, 24 subjects were entered into a phase 1 trial evaluating cranial NCT in subjects with primary or metastatic brain tumors. Two subjects were excluded due to a decline in their performance status and 22 subjects were irradiated at the MIT Nuclear Reactor Laboratory. The median age was 56 years (range 24–78). All subjects had a pathologically confirmed diagnosis of either glioblastoma (20) or melanoma (2) and a Karnofsky of 70 or higher. Neutron irradiation was delivered with a 15 cm diameter epithermal beam. Treatment plans varied from 1 to 3 fields depending upon the size and location of the tumor. The10B carrier,l-p-boronophenylalanine-fructose (BPA-f), was infused through a central venous catheter at doses of 250 mg kg−1 over 1 h (10 subjects), 300 mg kg−1 over 1.5 h (two subjects), or 350 mg kg−1 over 1.5–2 h (10 subjects). The pharmacokinetic profile of10B in blood was very reproducible and permitted a predictive model to be developed. Cranial NCT can be delivered at doses high enough to exhibit a clinical response with an acceptable level of toxicity. Acute toxicity was primarily associated with increased intracranial pressure; late pulmonary effects were seen in two subjects. Factors such as average brain dose, tumor volume, and skin, mucosa, and lung dose may have a greater impact on tolerance than peak dose alone. Two subjects exhibited a complete radiographic response and 13 of 17 evaluable subjects had a measurable reduction in enhanced tumor volume following NCT.

A Pharmacokinetic Model for the Concentration of 10B in Blood after Boronophenylalanine-Fructose Administration in Humans

Abstract Kiger, W. S., III, Palmer, M. R., Riley, K. J., Zamenhof, R. G. and Busse, P. M. A Pharmacokinetic Model for the Concentration of 10B in Blood after Boronophenylalanine- Fructose Administration in Humans. An open two-compartment model has been developed for predicting 10B concentrations in blood after intravenous infusion of the l-p-boronophenylalanine-fructose complex (BPA-F) in humans and derived from studies of pharmacokinetics in 24 patients in the Harvard-MIT Phase I clinical trials of BNCT. The 10B concentration profile in blood exhibits a characteristic rise during the infusion to a peak of ∼32 μg/g (for infusion of 350 mg/kg over 90 min) followed by a biphasic exponential clearance profile with half-lives of 0.34 ± 0.12 and 9.0 ± 2.7 h, due to redistribution and primarily renal elimination, respectively. The model rate constants k1, k2 and k3 are 0.0227 ± 0.0064, 0.0099 ± 0.0027 and 0.0052 ± 0.0016 min–1, respectively, and the central compartment volume of distribution, V1, is 0.235 ± 0.042 kg/kg. The validity of this model was demonstrated by successfully predicting the average pharmacokinetic response for a cohort of patients who were administered BPA-F using an infusion schedule different from those used to derive the parameters of the model. Furthermore, the mean parameters of the model do not differ for cohorts of patients infused using different schedules.

Treatment planning and dosimetry for the Harvard-MIT Phase I clinical trial of cranial neutron capture therapy☆

PURPOSE A Phase I trial of cranial neutron capture therapy (NCT) was conducted at Harvard-MIT. The trial was designed to determine maximum tolerated NCT radiation dose to normal brain. METHODS AND MATERIALS Twenty-two patients with brain tumors were treated by infusion of boronophenylalanine-fructose (BPA-f) followed by exposure to epithermal neutrons. The study began with a prescribed biologically weighted dose of 8.8 RBE (relative biologic effectiveness) Gy, escalated in compounding 10% increments, and ended at 14.2 RBE Gy. BPA-f was infused at a dose 250-350 mg/kg body weight. Treatments were planned using MacNCTPlan and MCNP 4B. Irradiations were delivered as one, two, or three fields in one or two fractions. RESULTS Peak biologically weighted normal tissue dose ranged from 8.7 to 16.4 RBE Gy. The average dose to brain ranged from 2.7 to 7.4 RBE Gy. Average tumor dose was estimated to range from 14.5 to 43.9 RBE Gy, with a mean of 25.7 RBE Gy. CONCLUSIONS We have demonstrated that BPA-f-mediated NCT can be precisely planned and delivered in a carefully controlled manner. Subsequent clinical trials of boron neutron capture therapy at Harvard and MIT will be initiated with a new high-intensity, high-quality epithermal neutron beam.

Proton nuclear magnetic resonance measurement of p‐boronophenylalanine (BPA): A therapeutic agent for boron neutron capture therapy

Noninvasive in vivo quantitation of boron is necessary for obtaining pharmacokinetic data on candidate boronated delivery agents developed for boron neutron capture therapy (BNCT). Such data, in turn, would facilitate the optimization of the temporal sequence of boronated drug infusion and neutron irradiation. Current approaches to obtaining such pharmacokinetic data include: positron emission tomography employing F-18 labeled boronated delivery agents (e.g., p-boronophenylalanine), ex vivo neutron activation analysis of blood (and very occasionally tissue) samples, and nuclear magnetic resonance (NMR) techniques. In general, NMR approaches have been hindered by very poor signal to noise achieved due to the large quadrupole moments of B-10 and B-11 and (in the case of B-10) very low gyromagnetic ratio, combined with low physiological concentrations of these isotopes under clinical conditions. This preliminary study examines the feasibility of proton NMR spectroscopy for such applications. We have utilized proton NMR spectroscopy to investigate the detectability of p-boronophenylalanine fructose (BPA-f) at typical physiological concentrations encountered in BNCT. BPA-f is one of the two boron delivery agents currently undergoing clinical phase-I/II trials in the U.S., Japan, and Europe. This study includes high-resolution 1H spectroscopic characterization of BPA-f to identify useful spectral features for purposes of detection and quantification. The study examines potential interferences, demonstrates a linear NMR signal response with concentration, and presents BPA NMR spectra in ex vivo blood samples and in vivo brain tissues.

Pharamacokinetic Modeling for Boronophenylalanine-fructose Mediated Neutron Capture Therapy: 10B Concentration Predictions and Dosimetric Consequences

SummaryA two-compartment open model has been developed for predicting10B concentrations in blood following intravenous infusion of thel-p-boronophenylalanine-fructose complex in humans and derived from pharmacokinetic studies of 24 patients in Phase I clinical trials of boron neutron capture therapy. The10B concentration profile in blood exhibits a characteristic rise during the infusion to a peak of ∼32 µg/g (for infusion of 350 mg/kg over 90 min) followed by a biexponential disposition profile with harmonic mean half-lives of 0.32±0.08 and 8.2±2.7 h, most likely due to redistribution and primarily renal elimination, respectively. The mean model rate constantsk12,k21, andk10 are (mean ±SD) 0.0227±0.0064 min−1, 0.0099±0.0027 min−1, 0.0052±0.0016 min−1, respectively, and the central compartment volume of distributionV1 is 0.235 ± 0.042 L/kg. In anticipation of the initiation of clinical trials using an intense neutron beam with concomitantly short irradiations, the ability of this model to predict, in advance, the average blood10B concentration during brief irradiations was simulated in a retrospective analysis of the pharmacokinetic data from these patients. The prediction error for blood boron concentration and its effect on simulated dose delivered for each irradiation field are reported for three different prediction strategies. In this simulation, error in delivered dose (or, equivalently, neutron fluence) for a given single irradiation field resulting from error in predicted blood10B concentration was limited to less than 10%. In practice, lower dose errors can be achieved by delivering each field in two fractions (on two separate days) and by adjusting the second fraction’s dose to offset error in the first.

Microdosimetry for boron neutron capture therapy : A review

A review of the microdosimetry of boron neutroncapture therapy is presented focusing on the progressionof key scientific ideas and developments in thisfield rather than on a comprehensive and inclusivereview of the literature. The author concludes thatfrom a microdosimetry perspective the field is highlyadvanced, but what is lacking is the correlationof the proposed models and results with experimentalradiobiological data.

Boron neutron capture therapy and radiation synovectomy research at the Massachusetts Institute of Technology Research Reactor

In this paper, current research in boron neutron capture therapy (BNCT) and radiation synovectomy at the Massachusetts Institute of Technology Research Reactor is reviewed. In the last few years, major emphasis has been placed on the development of BNCT primarily for treatment of brain tumors. This has required a concerted effort in epithermal beam design and construction as well as the development of analytical capabilities for {sup 10}B analysis and patient treatment planning. Prompt gamma analysis and high-resolution track-etch autoradiography have been developed to meet the needs, respectively, for accurate bulk analysis and for quantitative imaging of {sup 10}B in tissue at subcellular resolutions. Monte Carlo-based treatment planning codes have been developed to ensure optimized and individualized patient treatments. In addition, the development of radiation synovectomy as an alternative therapy to surgical intervention is joints that are affected by rheumatoid arthritis is described.

The Microdosimetry of the 10B Reaction in Boron Neutron Capture Therapy: A New Generalized Theory

Abstract Santa Cruz, G. A. and Zamenhof, R. G. The Microdosimetry of the 10B Reaction in Boron Neutron Capture Therapy: A New Generalized Theory. Radiat. Res. 162, 702–710 (2004). The microdosimetry of 10B thermal neutron capture reactions should be considered as an essential step to be followed before studying the radiobiological aspects of boron neutron capture therapy. The boron dose itself is insufficient as the only quantity used to describe the biological effectiveness of the 10B reaction for two important reasons: the specific microdistribution that the 10B carrier compound exhibits at the cellular level and the primarily stochastic nature of the energy deposition process, which influences the biological response to the particulate radiation. In this work, these two aspects are analyzed in detail and an innovative rigorous analytical framework is developed in the microdosimetry domain. This formalism provides the necessary microdosimetric tools for more precisely describing the 10B dose distribution deposited in sensitive microscopic structures and offers improved approaches for analyzing the biological dose–effect relationship of 10B reactions.

Calculated DNA Damage from Gadolinium Auger Electrons and Relation to Dose Distributions in a Head Phantom

Purpose: To calculate the number of 157Gadolinium (157Gd) neutron capture induced DNA double strand breaks (DSB) in tumor cells resulting from epithermal neutron irradiation of a human head when the peak tissue dose is 10 Gy. To assess the lethality of these Gd induced DSB. Materials and Methods: DNA single and double strand breaks from Auger electrons emitted during 157Gd(n,gamma) events were calculated using an atomistic model of B‐DNA with higher‐order structure. When combined with gadolinium neutron capture reaction rates and neutron and photon physical dose rates calculated from the radiation transport through a model of the human head with explicit tumors, peak tissue dose can be related to the number of Auger electron induced DSB in tumor cell DNA. The lethality of these DNA DSB were assessed through a comparison with incorporated 125I decay cell survival curves and second comparison with the number of DSB resulting from neutron and photon interactions. Results: These calculations on a molecular scale (microscopic calculations) indicate that for incorporated 157Gd, each neutron capture reaction results in an average of 1.56±0.16 DNA single strand breaks (SSB) and 0.21±0.04 DBS in the immediate vicinity (∼40 nm) of the neutron capture. In an example case of Gd Neutron Capture Therapy (GdNCT), a 1 cm radius midline tumor, peak normal tissue dose of 10 Gy, and a tumor concentration of 1000 ppm Gd, result in a maximum of 140±27 DSBs per tumor cell. Conclusions: The number of DSB from the background radiation components is one order of magnitude lower than the Gd Auger electron induced DSB. The cell survival of mammalian cell lines with a similar amount of complex DSB induced from incorporated 125I decay yield one to two magnitudes of cell killing. These two points indicate that gadolinium auger electrons could significantly contribute to cell killing in GdNCT.

The Harvard-MIT BNCT Program

The clinical use of BNCT originated in Boston largely through the efforts of Dr. William Sweet at the Massachusetts General Hospital and his collaborators at the Brookhaven National Laboratory (BNL) and the Massachusetts Institute of Technology (MIT). The early clinical trials were for patients with primary brain tumors but were unsuccessful largely due to the poor biodistribution of 10B and thermal neutron beams that had limited penetration into tissue. Clinical and basic researchers recognized there would have to be a dramatic improvement in the amount of 10B delivered to a tumor as well as an improvement in the biodistribution, i.e., an increase in the tumor to normal tissue ratio, before clinical studies could be resumed. In addition, nuclear engineers and physicists realized epithermal beams needed to be developed that would obviate many of the physical limitations inherent in the thermal beams that had previously been used. The culmination of this multifaceted preclinical work in biology, physics, 10B quantification, treatment planning, and epithermal beam design was in September 1994 when the first human subject was irradiaied with epithcrmal nculton BNCT at the MIT Nuclear Reaclor Laboratory. This subject was irradiated to the plantar surface of the foot following the administration of oral p-boronophenylalanine (BPA); two weeks later another patient wiih glioblastoma received a single field of epithermal neutron irradiation al BNL, with iniravenously adminisiered BPA-fructose as a 10B carrier. Since then a number of clinical trials that are primarily phase I in natute have been conducted or are currently in progress at both insiitutions with epithermal neutton beams.1 Over 60 subjects have been irradiaied. the majority to the cranium for glioblasioma multiforme and in addition, 4 subjects have been irradiaied to 5 sites at MIT for melanoma of the extremity.