Dose prescription in boron neutron capture therapy.

PURPOSE: The purpose of this paper is to address some aspects of the many considerations that need to go into a dose prescription in boron neutron capture therapy (BNCT) for brain tumors; and to describe some methods to incorporate knowledge from animal studies and other experiments into the process of dose prescription. MATERIALS AND METHODS: Previously, an algorithm to estimate the normal tissue tolerance to mixed high and low linear energy transfer (LET) radiations in BNCT was proposed. We have developed mathematical formulations and computational methods to represent this algorithm. Generalized models to fit the central axis dose rate components for an epithermal neutron field were also developed. These formulations and beam fitting models were programmed into spreadsheets to simulate two treatment techniques which are expected to be used in BCNT: a two-field bilateral scheme and a single-field treatment scheme. Parameters in these spreadsheets can be varied to represent the fractionation scheme used, the 10B microdistribution in normal tissue, and the ratio of 10B in tumor to normal tissue. Most of these factors have to be determined for a given neutron field and 10B compound combination from large animal studies. The spreadsheets have been programmed to integrate all of the treatment-related information and calculate the location along the central axis where the normal tissue tolerance is exceeded first. This information is then used to compute the maximum treatment time allowable and the maximum tumor dose that may be delivered for a given BNCT treatment. RESULTS AND CONCLUSION: The effect of different treatment variables on the treatment time and tumor dose has been shown to be very significant. It has also been shown that the location of Dmax shifts significantly, depending on some of the treatment variables--mainly the fractionation scheme used. These results further emphasize the fact that dose prescription in BNCT is very complicated and nonintuitive. The physician prescribing the dose would need to rely on some method, like the one developed here, to come up with an appropriate dose prescription.

Is a surgical resection leaving positive margins of benefit to the patient with locally advanced squamous cell carcinoma of the head and neck: a comparative study using the intergroup study 0034 and the Radiation Therapy Oncology Group head and neck database.

PURPOSE: The purpose of this study was to determine whether or not for patients with squamous cell carcinomas of the head and neck, a surgical resection leaving positive margins followed by postoperative adjuvant therapy improves the outcome compared to a matched group of patients treated with definitive radiotherapy alone. METHODS AND MATERIALS: From January 1985 through January 1990 a consortium of national cooperative groups (Radiation Therapy Oncology Group, Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, Northern California Oncology Group, Southeast Group, and Southwest Oncology Group) conducted a phase III clinical trial testing the efficacy of adjuvant chemotherapy for patients with resectable, squamous cell carcinomas of the head and neck. One hundred and nine patients were excluded from this study due to positive surgical margins. These patients have been followed prospectively with regards to local/regional tumor control, development of distant metastases, and survival. The postoperative treatment of these patients was not specified by the protocol but the majority of patients received postoperative radiotherapy +/- chemotherapy. These patients were compared with a matched group of patients from the Radiation Therapy Oncology Group head and neck database of patients treated with definitive radiotherapy alone using a standard fractionation schema. Matching parameters included primary tumor site, T-stage, N-stage, Karnofsky performance status, and age. RESULTS: Actuarial curves are presented for local/regional control and survival. At 4 years the local/regional control rate is 44% for the positive margin patients compared to 24% for the patients from the data base (p = 0.007). However, there is no significant difference between the survival curves (p = 0.76) with respective median survivals being 18.1 months vs. 17.9 months and 4-year survivals being 29% vs. 25%. CONCLUSION: While an incomplete excision followed by postoperative therapy does not seem to improve survival compared to treatment with radiotherapy alone, it appears to yield significantly better local/regional control. This would argue for its applicability in selected palliative settings. A follow-up, Phase III trial for patients with advanced tumors may be warranted to test traditional resectability criteria.

Adjuvant chemotherapy for resectable squamous cell carcinomas of the head and neck: report on Intergroup Study 0034.

To test the efficacy of sequential chemotherapy as an adjuvant to surgery and postoperative radiotherapy for patients with locally-advanced but operable squamous cell cancers of the head and neck region, a randomized clinical trial was conducted under the auspices of the Head and Neck Intergroup (Radiation Therapy Oncology Group, Southwest Oncology Group, Eastern Oncology Group, Cancer and Leukemia Group B, Northern California Oncology Group, and Southeast Group). Eligible patients had completely resected tumors of the oral cavity, oropharynx, hypopharynx, or larynx. They were then randomized to receive either three cycles of cis-platinum and 5-FU chemotherapy followed by postoperative radiotherapy (CT/RT) or postoperative radiotherapy alone (RT). Patients were categorized as having either "low-risk" or "high-risk" treatment volumes depending on whether the surgical margin was greater than or equal to 5 mm, there was extracapsular nodal extension, and/or there was carcinoma-in-situ at the surgical margins. Radiation doses of 50-54 Gy were given to "low-risk" volumes and 60 Gy were given to "high-risk" volumes. A total of 442 analyzable patients were entered into this study with the mean-time-at-risk being 45.7 months at the time of the present analysis. The 4-year actuarial survival rate was 44% on the RT arm and 48% on the CT/RT arm (p = n.s.). Disease-free survival at 4 years was 38% on the RT arm compared to 46% on the CT/RT arm (p = n.s.). At 4 years the local/regional failure rate was 29% vs. 26% for the RT and CT/RT arms, respectively (p = n.s.). The incidence of first failure in the neck nodes was 10% on the RT arm compared to 5% on the CT/RT arm (p = 0.03 without adjusting for multiple testing) and the overall incidence of distant metastases was 23% on the RT arm compared to 15% on the CT/RT arm (p = 0.03). Treatment related toxicity is discussed in detail, but, in general, the chemotherapy was satisfactorily tolerated and did not affect the ability to deliver the subsequent radiotherapy. Implications for future clinical trials are discussed.

RTOG Phase I study on fast neutron teletherapy for squamous cell carcinoma of the esophagus.

From August, 1977, through January, 1981, the Radiation Therapy Oncology Group sponsored a Phase I study (RTOG 77-09) on the use of fast neutrons for treating inoperable squamous cell carcinomas of the esophagus. A total of 39 evaluable patients were treated with curative intent using either fast neutrons alone or in combination with low LET irradiation as part of a mixed beam fractionation scheme. Actuarial survival curves are presented for both the "neutrons alone" and the "mixed beam" treatment groups. There was no significant survival difference between these groups of patients. The projected survival at two years is less than 10%, which is comparable with megavoltage photon results for an unselected series of patients. The size of the primary lesion and the initial Karnofsky performance status were found to be the most important prognostic indications for prolonged survival. Sixteen of 39 patients were felt to have achieved local clearance of their tumor at some time during their follow-up with the median time until a local recurrence being 17 months. Treatment related complications and patterns of metastatic spread are discussed. In general, it appeared that the response of large tumors to neutron irradiation resulted in necrosis and fistula formation. In many cases this was accompanied by persistent/recurrent tumor within the high dose radiation volume.

A comparison of neutron beams for BNCT based on in-phantom neutron field assessment parameters.

In this paper our in-phantom neutron field assessment parameters, T and DTumor, were used to evaluate several neutron sources for use in BNCT. Specifically, neutron fields from The Ohio State University (OSU) Accelerator-Based Neutron Source (ABNS) design, two alternative ABNS designs from the literature (the Al/AIF3-Al2O3 ABNS and the 7LiF-AI2O3 ABNS), a fission-convertor plate concept based on the 500-kW OSU Research Reactor (OSURR), and the Brookhaven Medical Research Reactor (BMRR) facility were evaluated. In order to facilitate a comparison of the various neutron fields, values of T and DTumor were calculated in a 14 cm x 14 cm x 14 cm lucite cube phantom located in the treatment port of each neutron source. All of the other relevant factors, such as phantom materials, kerma factors, and treatment parameters, were kept the same. The treatment times for the OSURR, the 7LiF-Al2O3 ABNS operating at a beam current of 10 mA, and the BMRR were calculated to be comparable and acceptable, with a treatment time per fraction of approximately 25 min for a four fraction treatment scheme. The treatment time per fraction for the OSU ABNS and the Al/AlF3-Al2O3 ABNS can be reduced to below 30 min per fraction for four fractions, if the proton beam current is made greater than approximately 20 mA. DTumor was calculated along the bean centerline for tumor depths in the phantom ranging from 0 to 14 cm. For tumor depths ranging from 0 to approximately 1.5 cm, the value of DTumor for the OSURR is largest, while for tumor depths ranging from 1.5 to approximately 14 cm, the value of DTumor for the OSU-ABNS is the largest.

Ultrastructural microvascular response to boron neutron capture therapy in an experimental model.

A CD 344 rat glioma model currently used to investigate boron neutron capture therapy (BNCT) was used to demonstrate an increased survival rate after thermal neutron irradiation enhanced by administration of 10B-enriched polyhedral borane, Na2B12H11SH. To investigate the possible effects of BNCT on normal and tumor microvasculature, we subjected animals to sublethal neutron irradiation with and without intravenous injection of 50 mg/kg of enriched 10B and performed histological and ultrastructural analyses. In the rats that did not undergo tumor transplantation, minimal detectable morphological changes in the microvasculature of the central nervous system were observed after treatment, both in the immediate posttreatment phase and at 10 months. Light microscopy of cerebral cortex and caudate nucleus showed normal cytoarchitecture with no evidence of vessel occlusion, hyalinization, thickening, or reactive gliosis. Electron microscopy demonstrated that the junctional complexes of the endothelial cells, the basal lamina, and the perivascular glia were comparable in both treated and control animals. In those animals examined at 18 months, pathological membrane-bound clusters of electron-dense vesicles were seen in pericytes. In the rats implanted with gliomas, vascular proliferation with evidence of breakdown of the blood-brain barrier and vasogenic edema occurred. In the irradiated animals, we noted increased peritumoral edema 3 days after treatment. At seven days, both increased peritumoral edema and necrosis were noted in the rats treated with BNCT. These observations show that the normal microvasculature of the central nervous system tolerates BNCT at the treatment parameters used in our experimental model; the progressive edema and necrosis found in the peritumoral region after BNCT indicate a pathological endothelial response.

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.

Inhibition of tumor growth in a glioma model treated with boron neutron capture therapy.

This investigation attempts to determine whether increased survival time seen when the F98 glioma model is treated with boron neutron capture therapy (BNCT) is a result of inhibition of tumor growth caused by radiation-induced alterations in endothelial cells and normal tissue components. This indirect effect of radiation has been called the tumor bed effect. A series of tumor-bearing rats was studied, using a standardized investigational BNCT protocol consisting of 50 mg/kg of Na2B12H11SH injected intravenously 14 to 17 hours before neutron irradiation at 4 x 10(12) n/cm2. Ten rats, serving as controls, received no treatment either before or after tumor implantation. A second group of 10 rats was treated with BNCT 4 days before tumor implantation; these animals received no further treatment. The remaining group of 10 rats received no pretreatment but was treated with BNCT 10 days after implantation. Histological and ultrastructural analyses were performed in 2 animals from each group 17 days after implantation. Survival times of the untreated control animals (mean, 25.8 days) did not differ statistically from the survival times of the rats in the pretreated group (mean, 25.5 days). The rats treated with BNCT after implantation survived significantly longer (P less than 0.02; mean, 33.2 days) than the controls and the preirradiated animals. Tumor size indices calculated from measurements taken at the time of death were similar in all groups. These results indicate that, with this tumor model, BNCT does not cause a tumor bed effect in cerebral tissue. The therapeutic gains observed with BNCT result from direct effects on tumor cells or on the peritumoral neovascularity.

Boron neutron capture therapy of brain tumors: biodistribution, pharmacokinetics, and radiation dosimetry sodium borocaptate in patients with gliomas.

OBJECTIVE: The 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. METHODS: BSH (non-10B-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. RESULTS: Blood 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 microg/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 microg/g for GBMs and AAs, respectively, and the mean tumor value averaged across all samples was 11.9 microg/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 microg/g and the tumor/normal brain tissue ratios were3.8 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 microg/ml at 2 hours to 63 microg/ml at 6 hours and concentrations in skin and muscle were 43.1 and 39.2 microg/g, respectively, during the 3- to 7-hour sampling period. CONCLUSION: When 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.

Determination of the efficacy of topical oral pilocarpine for postirradiation xerostomia in patients with head and neck carcinoma.

Pilocarpine hydrochloride suspended in a candy-like 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.

Intensified regimen for advanced head and neck squamous cell carcinomas.

OBJECTIVE: To devise an intensified treatment regimen for patients with advanced, resectable head and neck squamous cell carcinomas. DESIGN: Phase I/II clinical trial consisting of perioperative cisplatin chemoradiotherapy, surgical resection, intraoperative radiotherapy, and postoperative cisplatin chemoradiotherapy. SETTING: The Ohio State University Comprehensive Cancer Center, Columbus. PATIENTS: Thirty-seven patients (median age, 63 years) with advanced oral cavity, oropharyngeal, or hypopharyngeal carcinomas. RESULTS: The range of time at risk was 1 to 30 months (median, 21 months). Thirty of the 37 registered patients were analyzable; 11 have died (5 with distant metastases; 1 of lung carcinoma; and 5 were cancer-free); 2 experienced second primary tumors in the oral cavity (out of or adjacent to the previous radiotherapy portals). Treatment compliance was excellent (92%), morbidity was low, and excellent locoregional control was achieved. CONCLUSIONS: The initial results are encouraging; the future strategy will intensify the systemic component of therapy based on results from concurrent laboratory studies.

Intensification regimen 2 for advanced head and neck squamous cell carcinomas.

OBJECTIVE: To determine the feasibility, toxicity, and compliance of an intense treatment regimen for patients with advanced, previously untreated, resectable head and neck squamous cell carcinomas. DESIGN: Prospective, nonrandomized, controlled (phase 1 or 2) clinical trial; median time at risk, 25 months (range, 7 days to 36 months). SETTING: Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus. PATIENTS: Forty-three patients (median age, 59 years; range, 32-76 years) with resectable, previously untreated stage III or IV squamous cell carcinomas of the oral cavity, oropharynx, or hypopharynx or stage II squamous cell carcinomas of the hypopharynx (referred sample of patients). INTERVENTIONS: Days 1 to 4, perioperative, slightly accelerated, hyperfractionated radiotherapy (9.1 Gy) to off cord fields; days 1 to 3, cisplatin, 30 mg/m2 per day; day 4, surgical resection and intraoperative radiotherapy boost (7.5 Gy); days 45 to 52, postoperative radiotherapy (40 Gy to the primary site and upper neck and 45 Gy to the supraclavicular areas); days 24, 45, and 66, paclitaxel, 135 mg/m2 per 24 hours, with routine granulocyte colony-stimulating factor support; and days 25 and 46, cisplatin, 100 mg/m2. MAIN OUTCOME MEASURES: Toxicity, compliance, local control, and distant metastatic rates. RESULTS: Patient compliance was 91% (39 of 43 patients), but protocol compliance was only 58% (25 of 43 patients), reflecting increased toxicity of the systemic regimen (2 [5%] of the 43 patients experienced grade 5 hematologic toxicity due to the regimen; 16 [37%], grade 4; and 10 [23%], grade 3). Local-regional control was 92% (23 of 25 patients), and the distant metastatic rate was 8% (2 of 25) in patients completing treatment per protocol. One patient had surgical salvage of a second primary tumor. CONCLUSIONS: Local control and patient compliance were encouraging, but systemic toxicity was unacceptable. Thus, the paclitaxel was changed to a weekly regimen.

Development and calculation of an energy dependent normal brain tissue neutron RBE for evaluating neutron fields for BNCT.

In Boron Neutron Capture Therapy (BNCT) of malignant brain tumors, the energy dependence of a clinically relevant Relative Biological Effectiveness (RBE) for epithermal neutrons, RBE(En), is important in neutron field design. In the first half of this paper, we present the development of an expression for the energy dependent normal-tissue RBE, RBE(En). We then calculate a reasonable estimate for RBE(En) for adult brain tissue. In the second half of the paper, two separate RBE expressions are developed, one for the RBE of the neutrons that interact in tissue via the 14N(n,p)14C reaction, denoted RBE(N), and one for the RBE of the neutrons which interact in tissue via the 1H(n,n')1H reaction, denoted RBE(H). The absorbed-dose-averaged values of these expressions are calculated for the neutron flux spectrum in phantom for the Brookhaven Medical Research Reactor (BMRR) epithermal neutron beam. The calculated values, [RBE(norm)N] = 3.4 and [RBE(norm)H] = 3.2, are within 6% of being equal, and support the use of equal values for RBEN and RBE(H) by researchers at Brookhaven National Laboratory (BNL). Finally, values of [RBE(norm)N] and [RBE(norm)H], along with the absorbed-dose-averaged RBE for brain, [RBE(norm)b], were calculated as a function of depth along the centerline of an ellipsoidal head phantom using flux spectra calculated for our Accelerator-Based Neutron Source (ABNS). These values remained essentially constant with depth, supporting the use of constant values for RBE, as is done at BNL.

Biological weighting of absorbed dose in radiation therapy.

Absorbed dose is a quantity which is scientifically rigorously defined and used to quantify the exposure of biological objects, including humans, to ionising radiation. There is, however, no unique relationship between absorbed dose and induced biological effects. The effects induced by a given absorbed dose to a given biological object depend also on radiation quality and temporal distribution of the irradiation. In radiation therapy, empirical approaches are still used today to account for these dependencies in practice. In hadron therapy (neutrons, protons, ions), radiation quality is accounted for with a diversity of (almost hospital specific) methods. The necessity to account for temporal aspects is well known in external beam therapy and in high dose rate brachytherapy. The paper reviews the approaches for weighting the absorbed dose in radiation therapy, and focusses on the clinical aspects of these approaches, in particular the accuracy requirements.

A challenge for high-precision radiation therapy: the case for photons.

The sophistication of Hadron facilities led to major technical and conceptual advances in the treatment immobilization, reproducibility, planning and execution. Some of these developments have had a pivotal impact on conventional treatments, which can now approach the dose localization advantage of protons in the majority of clinical situations. While the biological advantages of neutrons may finally be combined with excellent dose localization in Heavy Ion Facilities, modern surgical or systemic treatment methods may reduce high LET advantages. Clinical trials still need to define the relative merits of these approaches in their most modern implementation. The advantage gap has certainly been narrowed by recent developments in conventional therapy.

Alteration of the blood-brain barrier after irradiation: implication in boron neutron capture therapy.

The radiobiological and clinical data concerning the alteration of the blood-brain barrier (BBB) after cerebral irradiation are reviewed. Several boron neutron capture therapy (BNCT) programs are at present under study in Europe and in the USA. In these programs, irradiation is considered to be delivered in several fractions, and one could also imagine, in principle, delivering BNCT after a full course of external radiotherapy of the brain. These options raise the question of the alteration of the normal BBB by previous irradiation. Before starting clinical applications, it then becomes necessary to assess the integrity of the BBB after different dose ranges and fractionation schemes, and after different time intervals following irradiation. Extrapolation of the available radiobiological and clinical data suggests that for rather small hydrophilic compounds, such as BSH or L-BPA, an early increase in transport through the BBB may be foreseen after single photon dose larger than 10 Gy or after a full standard radiotherapy regimen. However, there is no evidence that the first fractions of a BNCT application (typically 2 to 4 Gy equivalent per fraction) would increase the permeability of the BBB sufficiently to permit transport of large boronated compounds such as porphyrins or antibodies, or even of smaller hydrophilic compounds such as BSH and L-BPA. It can be concluded that the dose selectivity of BNCT is unlikely to be compromised by early alteration of the BBB due to the first fractions of a typical BNCT fractionated regimen.

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

Clinical 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.

A challenge for high-precision radiation therapy: the case for hadrons.

Developments in Hadron therapy, i.e., fast neutrons, protons, pions, heavy ions and boron neutron capture therapy are reviewed. For each type of particle, operational and closed facilities are listed as well as planned new facilities. Improvements in clinical results have always been linked to technological developments and better physical selectivity of the irradiation. Exploring the benefit of further improvement in dose localization expected from protons and conformal therapy is the challenge for the coming years. The radiobiological rationale for high-LET radiation in cancer treatment, proposed in the fifties, is still valid and has not been contradicted by recent radiobiological findings. This justifies the planning of a therapy facility where protons and heavy ions (carbon ions) could be applied, under optimal physical and technical conditions. Appropriate selection between low- and high-LET radiation for a particular tumor is indeed a radiobiological problem, independent of technical development.

Biological considerations for treating alternate fields versus all fields daily with high and low LET radiation.

The rationale for treating all fields every day with photons was reviewed. Since the effects of neutron radiation are much less dependent on alterations of fractionation schedules, and since preferential sparing for late effects is not obtained by fractionation of neutron dose, less convincing reasons exist for treating all fields every day with neutrons. Treating one field/day would not alter the physical dose distribution or overall treatment time, yet still maintain biological homogeneity. Preliminary in vitro experiments support this conclusion.