Reinhard A. Gahbauer

Boron neutron capture therapy of brain tumors: an emerging therapeutic modality.

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when boron-10, a stable isotope, is irradiated with low-energy thermal neutrons to yield alpha particles and recoiling lithium-7 nuclei. For BNCT to be successful, a large number of 10B atoms must be localized on or preferably within neoplastic cells, and a sufficient number of thermal neutrons must be absorbed by the 10B atoms to sustain a lethal 10B (n, alpha) lithium-7 reaction. There is a growing interest in using BNCT in combination with surgery to treat patients with high-grade gliomas and possibly metastatic brain tumors. The present review covers the biological and radiobiological considerations on which BNCT is based, boron-containing low- and high-molecular weight delivery agents, neutron sources, clinical studies, and future areas of research. Two boron compounds currently are being used clinically, sodium borocaptate and boronophenylalanine, and a number of new delivery agents are under investigation, including boronated porphyrins, nucleosides, amino acids, polyamines, monoclonal and bispecific antibodies, liposomes, and epidermal growth factor. These are discussed, as is optimization of their delivery. Nuclear reactors currently are the only source of neutrons for BNCT, and the fission reaction within the core produces a mixture of lower energy thermal and epithermal neutrons, fast or high-energy neutrons, and gamma-rays. Although thermal neutron beams have been used clinically in Japan to treat patients with brain tumors and cutaneous melanomas, epithermal neutron beams now are being used in the United States and Europe because of their superior tissue-penetrating properties. Currently, there are clinical trials in progress in the United States, Europe, and Japan using a combination of debulking surgery and then BNCT to treat patients with glioblastomas. The American and European studies are Phase I trials using boronophenylalanine and sodium borocaptate, respectively, as capture agents, and the Japanese trial is a Phase II study. Boron compound and neutron dose escalation studies are planned, and these could lead to Phase II and possibly to randomized Phase III clinical trials that should provide data regarding therapeutic efficacy.

A neutronic study of an accelerator-based neutron irradiation facility for boron neutron capture therapy

A neutronic study of an accelerator-based neutron irradiation facility (ANIF) for boron neutron capture therapy (BNCT) was performed using three-dimensional Monte Carlo transport calculations. The major components of the ANIF are a radio-frequency quadrupole proton accelerator, a /sup 7/Li target, and a moderator assembly. Neutrons are generated by bombarding the /sup 7/Li target with 2.5-MeV protons. The neutrons emerging from the /sup 7/Li target are too energetic to be used for BNCT and must therefore be moderated. Calculations show that, among all materials for the ANIF, beryllia (BeO) and heavy water (D/sub 2/O) are the best moderators. Between them, beryllia provides better neutron spectra, but D/sub 2/O gives higher neutron intensities. Adding alumina (Al/sub 2/O/sub 3/) to D/sub 2/O improves the neutron spectra, but it also increases gamma-ray contamination.

Determination of the Efficacy of Topical Oral Pilocarpine for Postirradiation Xerostomia in Patients With Head and Neck Carcinoma

Pilocarpine hydrochloride suspended in a candylike pastille was evaluated as a topical treatment for radiation‐induced xerostomia in head and neck cancer patients. This local delivery system, which differs from systemically administered pilocarpine preparations, was developed to hopefully maximize the local response and minimize the systemic side effects. A prospective, randomized, double‐blind, placebo‐controlled trial was undertaken to determine objective and subjective efficacy in reversing the decrease in salivation. Forty previously irradiated patients received increasingly higher pilocarpine dosages in pastilles for 5 successive weeks. At each successive dose of pilocarpine, no significant increased salivation was noted. However, 25 (74%) of 34 patients reported that pilocarpine alleviated their subjective xerostomia. Topical pilocarpine administration has shown similar results to previous systemic delivery methods for radiation‐induced xerostomia, but with improved patient tolerance.

Boron Neutron Capture Therapy of Brain Tumors: Biodistribution, Pharmacokinetics, and Radiation Dosimetry of Sodium Borocaptate in Patients with Gliomas

OBJECTIVEThe purpose of this study was to obtain tumor and normal brain tissue biodistribution data and pharmacokinetic profiles for sodium borocaptate (Na2B12H11SH) (BSH), a drug that has been used clinically in Europe and Japan for boron neutron capture therapy of brain tumors. The study was performed with a group of 25 patients who had preoperative diagnoses of either glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) and were candidates for debulking surgery. Nineteen of these patients were subsequently shown to have histopathologically confirmed diagnoses of GBM or AA, and they constituted the study population. METHODSBSH (non-10 B-enriched) was infused intravenously, in a 1-hour period, at doses of 15, 25, and 50 mg boron/kg body weight (corresponding to 26.5, 44.1, and 88.2 mg BSH/kg body weight, respectively) to groups of 3, 3, and 13 patients, respectively. Multiple samples of tumor tissue, brain tissue around the tumors, and normal brain tissue were obtained at either 3 to 7 or 13 to 15 hours after infusion. Blood samples for pharmacokinetic studies were obtained at times up to 120 hours after termination of the infusion. Sixteen of the patients underwent surgery at the Beijing Neurosurgical Institute and three at The Ohio State University, where all tissue samples were subsequently analyzed for boron content by direct current plasma-atomic emission spectroscopy. RESULTSBlood boron values peaked at the end of the infusion and then decreased triexponentially during the 120-hour sampling period. At 6 hours after termination of the infusion, these values had decreased to 20.8, 29.1, and 62.6 &mgr;g/ml for boron doses of 15, 25, and 50 mg/kg body weight, respectively. For a boron dose of 50 mg/kg body weight, the maximum (mean ± standard deviation) solid tumor boron values at 3 to 7 hours after infusion were 17.1 ± 5.8 and 17.3 ± 10.1 &mgr;g/g for GBMs and AAs, respectively, and the mean tumor value averaged across all samples was 11.9 &mgr;g/g for both GBMs and AAs. In contrast, the mean normal brain tissue values, averaged across all samples, were 4.6 ± 5.1 and 5.5 ± 3.9 &mgr;g/g and the tumor/normal brain tissue ratios were 3.8 and 3.2 for patients with GBMs and AAs, respectively. The large standard deviations indicated significant heterogeneity in uptake in both tumor and normal brain tissue. Regions histopathologically classified either as a mixture of tumor and normal brain tissue or as infiltrating tumor exhibited slightly lower boron concentrations than those designated as solid tumor. After a dose of 50 mg/kg body weight, boron concentrations in blood decreased from 104 &mgr;g/ml at 2 hours to 63 &mgr;g/ml at 6 hours and concentrations in skin and muscle were 43.1 and 39.2 &mgr;g/g, respectively, during the 3- to 7-hour sampling period. CONCLUSIONWhen tumor, blood, and normal tissue boron concentrations were taken into account, the most favorable tumor uptake data were obtained with a boron dose of 25 mg/kg body weight, 3 to 7 hours after termination of the infusion. Although blood boron levels were high, normal brain tissue boron levels were almost always lower than tumor levels. However, tumor boron concentrations were less than those necessary for boron neutron capture therapy, and there was significant intratumoral and interpatient variability in the uptake of BSH, which would make estimation of the radiation dose delivered to the tumor very difficult. It is unlikely that intravenous administration of a single dose of BSH would result in therapeutically useful levels of boron. However, combining BSH with boronophenylalanine, the other compound that has been used clinically, and optimizing their delivery could increase tumor boron uptake and potentially improve the efficacy of boron neutron capture therapy.

Gamma Knife radiosurgery for intracranial metastatic melanoma: an analysis of survival and prognostic factors

Objective of this study was to evaluate retrospectively the effectiveness of Gamma Knife radiosurgery for intracranial metastatic melanoma and to identify prognostic factors related to survival. Twenty-six patients with intracranial metastases (72 lesions) from melanoma underwent Gamma Knife radiosurgery. In 14 patients (54%) whole-brain radiotherapy (WBRT) was performed as part of the initial treatment, and in 12 patients (38%) immunotherapy and/or chemotherapy was given after Gamma Knife radiosurgery. The median tumor volume for Gamma Knife radiosurgery treated lesions was 1.72 cm3. The median prescribed radiation dose was 18 Gy (range 8–22 Gy) typically prescribed to the isodose at the tumor margin. Univariate and multivariate analyses were used to determine significant prognostic factors affecting survival. Overall median survival was 6 months after Gamma Knife radiosurgery, and 1-year survival was 25%. The median survival from the onset of brain metastases was 9 months and from the original diagnosis of melanoma was 50 months (range 4–160 months). There were no major acute or late GKS complications. In univariate testing, the Karnofsky score equal to or higher than 90% (P < 0.01, log-rank test), supratentorial localization (P < 0.001, log-rank test), intracranial tumor volume less than 1 cm3 (P < 0.02, log-rank test), and absence of neurological signs or symptoms before Gamma Knife radiosurgery (P < 0.003, log-rank test) were significant favorable factors for survival. In multivariate regression analyses, the most important predictors associated with increased survival were a KPS ≥ 90 (P < 0.023), female sex (P < 0.004), supratentorial localization (P < 0.01), and absence of neurological symptoms (P < 0.008). Radiosurgery is a noninvasive, safe, and effective treatment option for patients with single or multiple intracranial metastases from melanoma. Female sex, Karnofsky score ≥90, supratentorial localization and lack of symptoms before the Gamma Knife radiosurgery were good independent predictors of survival.

The rationale and requirements for the development of boron neutron capture therapy of brain tumors

The dismal clinical results in the treatment ofglioblastoma multiforme despite aggressive surgery, conventional radiotherapy, andchemotherapy, either alone or in combination has ledto the development of alternative therapeutic modalities. Amongthese is boron neutron capture therapy (BNCT). Thisbinary system is based upon two key requirements:(1) the development and use of neutron beamsfrom nuclear reactors or other sources with thecapability for delivering high fluxes of thermal neutronsat depths sufficient to reach all tumor foci,and (2) the development and synthesis of boroncompounds that can penetrate the normal blood-brain barrier,selectively target neoplastic cells, and persist therein forsuitable periods of time prior to irradiation. Theearlier clinical failures with BNCT related directly tothe lack of tissue penetration by neutron beamsand to boron compounds that showed little specificityfor and low retention by tumor cells, whileattaining high concentrations in blood. Progress has beenmade both in neutron beam and compound development,but it remains to be determined whether theseare sufficient to improve therapeutic outcomes by BNCTin comparison with current therapeutic regimens for thetreatment of malignant gliomas.

Pain in the foot: calcaneal metastasis as the presenting feature of endometrial cancer.

BACKGROUND Ninety percent of endometrial cancer cases present with abnormal bleeding. Bone metastasis as the presenting feature is extremely rare. CASE A 76-year-old woman presented with right heel pain. She had no vaginal bleeding or other symptoms suggestive of endometrial cancer. After failure of conservative therapy, imaging studies demonstrated a calcaneal metastasis. A biopsy showed adenocarcinoma. She received local radiation to her foot, with complete resolution of symptoms. Subsequent computed tomography scans showed multiple pulmonary nodules, pelvic and inguinal lymphadenopathy, and an enlarged uterus. Endometrial biopsy confirmed endometrial adenocarcinoma. She received palliative therapy and died 11 months after the diagnosis was made on the endometrial biopsy. CONCLUSION This case highlights the rare presentation of endometrial cancer with foot pain secondary to calcaneal metastasis. Aggressive treatment of bone metastases can provide effective palliation of symptoms.

Radiobiological rationale and patient selection for high-LET radiation in cancer therapy.

The rationale for introducing ion beams in cancer therapy is the high level of physical selectivity that can be achieved with ions, equal or even better than with proton beams or modern photon techniques, as well as the potential advantage of high-LET radiations for some tumour types and sites. The radiobiological arguments for high-LET radiation in cancer therapy are reviewed: reduction of OER in the case of hypoxic and poorly-reoxygenating tumours, and the lesser importance of repair phenomena which are a problem in controlling repair-proficient photon-resistant tumours. Fast neutrons were the first type of high-LET radiation used clinically, and were often applied under suboptimal technical conditions. Nevertheless, useful clinical information was derived from the neutron experience. A greater benefit from neutrons than from conventional radiotherapy was found for several tumour sites. The present discussion is limited to the results for salivary gland tumours and prostatic adenocarcinoma. Based on the fast neutron experience, radiobiological arguments, and the added benefit of excellent physical selectivity of ion beams, the potential clinical indications for high-LET ions are discussed: hypoxic, slowly growing and well-differentiated photon-resistant tumours. One of the main remaining issues is the selection of individual patients for high- or low-LET radiation. Since the physical selectivity of ions now matches that obtained with other techniques, the selection of patients will be based only on the radiobiological characteristics of the tumour.

Common challenges and problems in clinical trials of boron neutron capture therapy of brain tumors

SummaryClinical trials for binary therapies, like boron neutron capture therapy (BNCT), pose a number of unique problems and challenges in design, performance, and interpretation of results. In neutron beam development, different groups use different optimization parameters, resulting in beams being considerably different from each other. The design, development, testing, execution of patient pharmacokinetics and the evaluation of results from these studies differ widely. Finally, the clinical trials involving patient treatments vary in many aspects such as their dose escalation strategies, treatment planning methodologies, and the reporting of data. The implications of these differences in the data accrued from these trials are discussed. The BNCT community needs to standardize each aspect of the design, implementation, and reporting of clinical trials so that the data can be used meaningfully.

RBE in Normal Tissue Studies

Single dose RBEs for the radiations encountered in BNCT have been determined1 and can provide useful guidance for the tolerance to be expected. The difficulty of microdosimetric determination of dose2, the rapidly varying mix of constituent high and low LET radiations with depth, the possible synergistic interaction between high and low LET radiations3, and the strong dependence of biological efficacy on the distribution of boron within the cell are all factors limiting the usefulness of RBEs. Large animal studies arenecessary to determine late effect tolerance. To design, interpret, compare, and apply these studies to clinical use, it has been proposed to divide factors influencing “RBE” into two groups4; 1) estimated tolerance dose (ETD), which can be inferred from other experience reasonably well; and 2) compound factor (CF), which is much more variable as a function of microdosimetry and boron compound.