Isoeffective dose: a concept for biological weighting of absorbed dose in proton and heavier-ion therapies.

When reporting radiation therapy procedures, International Commission on Radiation Units and Measurements (ICRU) recommends specifying absorbed dose at/in all clinically relevant points and/or volumes. In addition, treatment conditions should be reported as completely as possible in order to allow full understanding and interpretation of the treatment prescription. However, the clinical outcome does not only depend on absorbed dose but also on a number of other factors such as dose per fraction, overall treatment time and radiation quality radiation biology effectiveness (RBE). Therefore, weighting factors have to be applied when different types of treatments are to be compared or to be combined. This had led to the concept of 'isoeffective absorbed dose', introduced by ICRU and International Atomic Energy Agency (IAEA). The isoeffective dose D(IsoE) is the dose of a treatment carried out under reference conditions producing the same clinical effects on the target volume as those of the actual treatment. It is the product of the total absorbed dose (in gray) used and a weighting factor W(IsoE) (dimensionless): D(IsoE)=D×W(IsoE). In fractionated photon-beam therapy, the dose per fraction and the overall treatment time (in days) are the two main parameters that the radiation oncologist has the freedom to adjust. The weighting factor for an alteration of the dose per fraction is commonly evaluated using the linear-quadratic (α/ß) model. For therapy with protons and heavier ions, radiation quality has to be taken into account. A 'generic proton RBE' of 1.1 for clinical applications is recommended in a joint ICRU-IAEA Report [ICRU (International Commission on Radiation Units and Measurements) and IAEA (International Atomic Energy Agency). Prescribing, recording and reporting proton-beam therapy. ICRU Report 78, jointly with the IAEA, JICRU, 7(2) Oxford University Press (2007)]. For heavier ions (e.g. carbon ions), the situation is more complex as the RBE values vary markedly with particle type, energy and depth in tissue.

Aggressive papillary glioneuronal tumor: case report and literature review.

Papillary glioneuronal tumors (PGNT) are a rare, recently described form of mixed neoplasm composed of glial and neuronal components. PGNT usually occur in children and young adults, and typically demonstrate low-grade pathology, with a low proliferative index of 1-3%. Here we describe a newly diagnosed case of PGNT with a more aggressive phenotype that required irradiation and chemotherapy. The patient was a 19-year-old female who developed progressive headaches and visual seizures. An MRI revealed a heterogeneously enhancing solid mass in the left temporo-occipital region, with significant surrounding edema and mass effect. The mass was resected under stealth guidance without complication. Postoperative MRI scans showed patchy enhancement and residual T2 and FLAIR abnormality. Pathology revealed a highly cellular neoplasm with papillary-like structures, containing cells with glial and neuronal differentiation. Regions of mitoses and focal necrosis were noted, along with a Ki-67 labeling index of 26%. The diagnosis was aggressive PGNT, and treatment consisted of conformal irradiation and concomitant temozolomide over 6 weeks. Postirradiation follow-up MRI scans demonstrated a reduction of residual enhancement and FLAIR abnormality. The patient continues standard-dose adjuvant temozolomide on a monthly basis, with further improvement on subsequent MRI scans and a stable neurologic exam. This patient demonstrates that PGNT may, in rare cases, display an aggressive clinicopathologic phenotype that requires a therapeutic approach more consistent with a high-grade glioma.

The RBE issues in ion-beam therapy: conclusions of a joint IAEA/ICRU working group regarding quantities and units.

This paper summarises the conclusions of a working group established jointly by the International Atomic Energy Agency (IAEA) and the International Commission on Radiation Units and Measurements (ICRU) to address some of the relative biological effectiveness (RBE) issues encountered in ion-beam therapy. Special emphasis is put on the selection and definition of the involved quantities and units. The isoeffective dose, as introduced here for radiation therapy applications, is the dose that delivered under reference conditions would produce the same clinical effects as the actual treatment in a given system, all other conditions being identical. It is expressed in Gy. The reference treatment conditions are: photon irradiation, 2 Gy per fraction, 5 daily fractions a week. The isoeffective dose D(IsoE) is the product of the physical quantity absorbed dose D and a weighting factor W(IsoE). W(IsoE) is an inclusive weighting factor that takes into account all factors that could influence the clinical effects like dose per fraction, overall time, radiation quality (RQ), biological system and effects. The numerical value of W(IsoE) is selected by the radiation-oncology team for a given patient (or treatment protocol). It is part of the treatment prescription. Evaluation of the influence of RQ on W(IsoE) raises complex problems because of the clinically significant RBE variations with biological effect (late vs. early) and position in depth in the tissues which is a problem specific to ion-beam therapy. Comparison of the isoeffective dose with the equivalent dose frequently used in proton- and ion-beam therapy is discussed.

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.

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.

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.

Long-term follow-up on an intensified treatment regimen for advanced resectable head and neck squamous cell carcinomas.

From February 1993 through July 1994, 37 patients with stage III-IV squamous cell carcinomas of the oral cavity, oropharynx, or hypopharynx (stage II-IV) were registered to a treatment regimen consisting of preoperative continuous infusion cisplatin (80 mg/m2/80 hours) with hyperfractionated external beam radiotherapy (9.1 Gy/7 fractions of 1.3 Gy BID), surgical resection, intraoperative radiotherapy (7.5 Gy), and postoperative radiotherapy (40 Gy) with concurrent cisplatin (100 mg/m2 x 2 courses). The objectives of the regimen were to improve patient compliance while also increasing treatment intensity. The purpose of this article is to report the local, regional (nodal), and distant disease control of these patients after an extended time at risk (median 40 months). Overall compliance (73%), local control at primary site (97%), and regional nodal control (95%) were excellent. The rate of distant metastasis was 19%. Absolute survival at 48 months was 45.9%.

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.

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.

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.

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.

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.

Cross-sectional nodal atlas: a tool for the definition of clinical target volumes in three-dimensional radiation therapy planning.

Virtual three-dimensional clinical target volume definition requires the identification of areas suspected of containing microscopic disease (frequently related to nodal stations) on a set of computed tomographic (CT) images, rather than the traditional approach based on anatomic landmarks. This atlas displays the clinically relevant nodal stations and their correlation with normal lymphatic pathways on a set of CT images.

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.

Boron neutron capture therapy: principles and potential.

This book on the therapeutic applications of neutrons and high-LET radiations in cancer therapy would not have been complete without a review of the present situation of boron neutron capture therapy (BNCT) and a discussion of its future perspectives. BNCT is a special type of high-LET radiation therapy that attempts to achieve a selectivity at the cellular level. The rationale is to incorporate boron atoms selectively in the cancer cells and then bombard those atoms with thermal neutrons to produce a neutron capture reaction and subsequent decay that emits alpha and lithium particles. The efficiency of the technique depends upon achieving selective incorporation of the boron atoms in the cancer cells and not (or to a lesser extent) in the normal cells. The present status and future directions are described, with emphasis on boron carriers (drugs) and their delivery, as well as physical and treatment planning aspects.

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

The dismal clinical results in the treatment of glioblastoma multiforme despite aggressive surgery, conventional radiotherapy, and chemotherapy, either alone or in combination has led to the development of alternative therapeutic modalities. Among these is boron neutron capture therapy (BNCT). This binary system is based upon two key requirements: (1) the development and use of neutron beams from nuclear reactors or other sources with the capability for delivering high fluxes of thermal neutrons at depths sufficient to reach all tumor foci, and (2) the development and synthesis of boron compounds that can penetrate the normal bloodbrain barrier, selectively target neoplastic cells, and persist therein for suitable periods of time prior to irradiation. The earlier clinical failures with BNCT related directly to the lack of tissue penetration by neutron beams and to boron compounds that showed little specificity for and low retention by tumor cells, while attaining high concentrations in blood. Progress has been made both in neutron beam and compound development, but it remains to be determined whether these are sufficient to improve therapeutic outcomes by BNCT in comparison with current therapeutic regimens for the treatment of malignant gliomas.

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.

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.

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.