Spinal cord re-treatments using photon and proton based radiotherapy: LQ-derived tolerance doses.

Re-treatment, using megavoltage photon radiotherapy, can benefit carefully selected patients with new or recurrent tumours. Such re-treatments may involve the further exposure of tissues such as the brain or spinal cord. A time-dependent model has been developed, which incorporates data from all published radiobiological experiments concerned with the in vivo re-irradiation of the spinal cord using photons. It allows an estimation of the increasing recovery in tissue tolerance with elapsed time after the initial treatment course. In accordance with the experimental evidence, the recovery rate depends on the biological effective dose (BED) of the initial treatment. Various degrees of conservatism have been introduced in the model to allow for potential changes in CNS tissue tolerance due to patient age, chemotherapy, surgery etc. An estimation of the re-treatment dose-fractionation schedule is made easier by the use of a downloadable Graphical User Interface (GUI). Worked examples of its use are given forconventional photon (X-ray) based treatments, and also for protons, where relative biological effectiveness (RBE) considerations must be respected within the BED estimates. The model provides boundary conditions for clinical practice. The responsible clinician can choose to usemore 'forgiving' BED values and from this to calculate the re-irradiation dose-fractionation schedule. For protons, greater care is required sincethe inter-relationship between linear energy transfer (LET) and RBE can lead to significant over-dosage relative to accepted CNS tolerance doses, especially with the use of scanned proton beams. LET and RBE factors are important in order to deliver safe and effective re-treatment doses.

Radiological protection in ion beam radiotherapy: practical guidance for clinical use of new technology.

Recently introduced technologies in radiotherapy have significantly improved the clinical outcome for patients. Ion beam radiotherapy, involving proton and carbon ion beams, provides excellent dose distributions in targeted tumours, with reduced doses to the surrounding normal tissues. However, careful treatment planning is required in order to maximise the treatment efficiency and minimise the dose to normal tissues. Radiation exposure from secondary neutrons and photons, particle fragments, and photons from activated materials should also be considered for radiological protection of the patient and medical staff. Appropriate maintenance is needed for the equipment and air in the treatment room, which may be activated by the particle beam and its secondary radiation. This new treatment requires complex procedures and careful adjustment of parameters for each patient. Therefore, education and training for the personnel involved in the procedure are essential for both effective treatment and patient protection. The International Commission on Radiological Protection (ICRP) has provided recommendations for radiological protection in ion beam radiotherapy in Publication 127 Medical staff should be aware of the possible risks resulting from inappropriate use and control of the equipment. They should also consider the necessary procedures for patient protection when new technologies are introduced into clinical practice.

ICRP Publication 127: Radiological Protection in Ion Beam Radiotherapy.

Abstract ­: The goal of external-beam radiotherapy is to provide precise dose localisation in the treatment volume of the target with minimal damage to the surrounding normal tissue. Ion beams, such as protons and carbon ions, provide excellent dose distributions due primarily to their finite range, allowing a significant reduction of undesired exposure of normal tissue. Careful treatment planning is required for the given type and localisation of the tumour to be treated in order to maximise treatment efficiency and minimise the dose to normal tissue. Radiation exposure in out-of-field volumes arises from secondary neutrons and photons, particle fragments, and photons from activated materials. These unavoidable doses should be considered from the standpoint of radiological protection of the patient. Radiological protection of medical staff at ion beam radiotherapy facilities requires special attention. Appropriate management and control are required for the therapeutic equipment and the air in the treatment room that can be activated by the particle beam and its secondaries. Radiological protection and safety management should always conform with regulatory requirements. The current regulations for occupational exposures in photon radiotherapy are applicable to ion beam radiotherapy with protons or carbon ions. However, ion beam radiotherapy requires a more complex treatment system than conventional radiotherapy, and appropriate training of staff and suitable quality assurance programmes are recommended to avoid possible accidental exposure of patients, to minimise unnecessary doses to normal tissue, and to minimise radiation exposure of staff.

Enhancement of the radiation response of EMT-6 tumours by a copper octabromotetracarboranylphenylporphyrin.

OBJECTIVE: The carborane-containing porphyrin, copper (II) 2,3,7,8,12,13,17,18-octabromo-5,10,15,20-tetrakis(3-[1,2-dicarba-closo-dodecaboranyl]methoxyphenyl)-porphyrin (CuTCPBr), was investigated as a potential radiation enhancing agent for X-ray radiotherapy (XRT) in a subcutaneously implanted EMT-6 murine carcinoma. METHOD: The biodistribution and toxicological profile of this porphyrin has been shown to be favourable for another bimodal radiotherapy technique, boron neutron-capture therapy. For the XRT studies, CuTCPBr was formulated in either 9% Cremophor (BASF Corporation, Ludwigschafen, Germany) EL and 18% propylene glycol (9% CRM) or a revised formulation comprising 1% Cremophor ELP, 2% Tween 80 (JT Baker, Mansfield, MA), 5% ethanol and 2.2% PEG 400 (CTEP formulation), which would be more clinically acceptable than the original 9% CRM formulation. Using the 9% CRM formulation of CuTCPBr, doses of 100, 210 or 400 mg kg(-1) of body weight were used in combination with single doses of 25-35 Gy 100 kVp X-rays. RESULTS: While doses of 100 mg kg(-1) and 210 mg kg(-1) did not result in any significant enhancement of tumour response, the 400 mg kg(-1) dose did. A dose modification factor of 1.20±0.10 was obtained based on the comparison of doses that produced a 50% local tumour control probability. With the CTEP formulation of CuTCPBr, doses of 83 and 170 mg kg(-1) produced significant radiation enhancement, with dose modification factors based on the TCP(50) of 1.29±0.15 and 1.84±0.24, respectively. CONCLUSION: CuTCPBr significantly enhanced the efficacy of XRT in the treatment of EMT-6 carcinomas in mice. The CTEP formulation showed a marked improvement, with over 9% CRM being associated with higher dose modification factors. Moreover, the radiation response in the skin was not enhanced.

The radiobiological principles of boron neutron capture therapy: a critical review.

The radiobiology of the dose components in a BNCT exposure is examined. The effect of exposure time in determining the biological effectiveness of γ-rays, due to the repair of sublethal damage, has been largely overlooked in the application of BNCT. Recoil protons from fast neutrons vary in their relative biological effectiveness (RBE) as a function of energy and tissue endpoint. Thus the energy spectrum of a beam will influence the RBE of this dose component. Protons from the neutron capture reaction in nitrogen have not been studied but in practice protons from nitrogen capture have been combined with the recoil proton contribution into a total proton dose. The relative biological effectiveness of the products of the neutron capture reaction in boron is derived from two factors, the RBE of the short range particles and the bio-distribution of boron, referred to collectively as the compound biological effectiveness factor. Caution is needed in the application of these factors for different normal tissues and tumors.

Boron neutron capture therapy for newly diagnosed glioblastoma multiforme: an assessment of clinical potential.

The purpose of this analysis was to assess the potential of BNCT, with L-boronophenylalanine (L-BPA), as first line radiotherapy for glioblastoma multiforme (GBM). The survival of patients with newly diagnosed GBM from a phase II BNCT study was compared with those from the two arms of a phase III study with conventional radiotherapy (RT) vs. RT plus concomitant and adjuvant medication with temozolomide (TMZ). A small subgroup, for which the methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) DNA-repair gene was known, was also considered. The results indicated that the use of BNCT with BPA should be explored in a stratified randomized phase II trial in which patients with the unmethylated MGMT DNA-repair gene are offered BNCT vs. RT plus TMZ.

Fractionation effects in particle radiotherapy: implications for hypo-fractionation regimes.

The aim is to demonstrate the potential impact of changes in the value of the ß parameter in the linear quadratic (LQ) model on the calculation of clinical relative biological effectiveness (RBE) values used for high linear energy transfer (LET) radiotherapy. The parameter RBE(min) is introduced into the LQ formulation to account for possible changes in the ß radiosensitivity coefficient with changing LET. The model is used to fit fractionated data under two conditions, where RBE(min) = 1 and RBE(min) ≠ 1. Nonlinear regression and analysis of variance are used to test the hypothesis that the inclusion of a non-unity value of RBE(min) better predicts the total iso-effective dose required at low number of fractions for fast neutrons, carbon ions, π-meson and proton fractionation data obtained for various tissues from previous publications. For neutrons the assumption of RBE(min) ≠ 1 provided a better fit in 89% of the cases, whereas for carbon ions RBE(min) ≠ 1 provided a better fit only for normal tissue at the spread-out Bragg peak. The results provide evidence of the impact that variations in the ß parameter may have when calculating clinically relevant RBE values, especially when using high doses per fraction (i.e. hypofractionation) of high-LET radiations.

Boron neutron capture therapy for newly diagnosed glioblastoma multiforme: an assessment of clinical potential.

The purpose of this study was to assess the potential of boron neutron capture therapy (BNCT), with a 6-h infusion of the boron carrier l-boronophenylalanine as a fructose preparation (BPA-f), as first-line radiotherapy for newly diagnosed glioblastoma multiforme (GBM). Patient survival data from a Phase II study using BNCT were compared with retrospective data from the two arms of a Phase III study using conventional radiotherapy (RT) in the reference arm and using RT plus concomitant and adjuvant medication with temozolomide (TMZ) in the experimental arm, and were also compared with small subgroups of these patients for whom the methylation status of the MGMT (O(6)-methylguanine-DNA methyltransferase) DNA repair gene was known. Differences in the baseline characteristics, salvage therapy after recurrence and levels of severe adverse events were also considered. The results indicate that BNCT offers a treatment that is at least as effective as conventional RT alone. For patients with an unmethylated MGMT DNA repair gene, a possible clinical advantage of BNCT over RT/TMZ was suggested. BNCT is a single-day treatment, which is of convenience to patients, with mild side effects, which would offer an initial 6 weeks of good-quality life during the time when patients would otherwise be undergoing daily treatments with RT and TMZ. It is suggested that the use of BNCT with a 6-h infusion of BPA-f should be explored in a stratified randomised Phase II trial in which patients with the unmethylated MGMT DNA repair gene are offered BNCT in the experimental arm and RT plus TMZ in the reference arm.

Boron Neutron Capture Therapy for glioblastoma multiforme: advantage of prolonged infusion of BPA-f.

OBJECTIVES: To assess possible improved efficacy of Boron Neutron Capture Therapy (BNCT) for glioblastoma multiforme (GBM) using prolonged infusion and a correspondingly higher dose of l-boronophenylalanine, as the fructose complex (BPA-f). MATERIALS AND METHODS: The benefit of prolonged infusion was analyzed by comparing the results from a Phase II study using 6 h infusion of BPA-f with those obtained from a Phase I/II study using 2 h of infusion. Median survival time (MST) from diagnosis, patient baseline characteristics, salvage treatment and severe adverse events were considered in the comparison. RESULTS: MST increased significantly, from 12.8 (95% confidence interval or CI: 10.3-14.0) months with 2 h infusion to 17.7 (95% CI: 13.6-19.9) months with 6 h of infusion. The fraction of patients with WHO grade 3-4 adverse events was similar in the two studies at 13% and 14%, respectively. CONCLUSION: Prolonged infusion was found to be beneficial for the efficacy of BNCT and it is suggested that 6 h infusion of BPA-f should be used in future trials of BNCT for GBM. BNCT, which is a single-day treatment with mild side effects, should be assessed in a controlled trial, as an alternative to 30 daily fractions of conventional fractionated photon therapy over a period of 6 weeks.

Radiobiological compensation for unintended treatment interruptions during palliative radiotherapy.

Unlike radical treatment protocols, in which radiobiological methods have been used in an attempt to overcome the risk of reduced tumour control, the problem of compensation for unintended treatment interruptions during palliative radiotherapy has received little attention. For palliative radiotherapy, unnecessarily extended treatment times could theoretically reduce the duration of tumour regression and symptomatic relief. It can be shown, using a simple argument, that the overall extension of the treatment time is likely to be at least equal to the reduced duration of benefit. In most practical instances, this duration would amount to relatively few days, but it can sometimes be as long as 1-2 weeks. The mechanisms for gap compensations are the same as for radical radiotherapy, although there is greater scope for hypo-fractionated compensation provided that tissue tolerances are respected. It is debatable whether compensation should be applied in all patients, but there might be clinical situations where this would be indicated. Such decisions might influence waiting times for other patients requiring radical radiotherapy, and therefore must be balanced against the available resources.

Effects of very low dose-rate (90)Sr/(90)Y exposure on the acute moist desquamation response of pig skin.

BACKGROUND AND OBJECTIVES: Previous data, predominantly involving high dose-rate fractionated irradiation with incomplete repair intervals, had indicated that the kinetics of repair of sublethal damage for acute radiation reactions in pig skin could best be defined by a biphasic repair model with half-times for repair of 0.2 and 5.4 h, partition coefficient 0.5. To further test the validity of this finding and obtain a better estimate of the repair rate of the slow component of repair, the acute response of pig skin to very low dose-rates (VLDR), originally estimated to be 0.0067-0.0244 Gy/min, was investigated as part of a 4 fraction irradiation protocol involving an overall treatment time of <9 days to avoid confounding factors such as induced repopulation and enhanced radio-sensitivity in this animal tissue. MATERIALS AND METHODS: The flank skin of female Large White pigs, 3-4 months of age, was locally irradiated (8 sites/flank) with 22.5 mm diameter (90)Sr/(90)Y plaques. Irradiation with a 4 fraction protocol included 3 equal, high dose-rate, fractions with full repair, followed by a fourth VLDR fraction. The total doses administered were originally planned to represent the dose associated with the predicted ED(20), ED(50) and ED(80) (75% of total biological dose given at high dose-rate and 25% at VLDR) calculated on the basis of the repair kinetic parameters obtained from earlier studies. However, during the analysis a revision to the physical dosimetry was identified; this had been overlooked prior to the start of the study. Following completion of irradiation the irradiated sites were examined weekly and the presence or absence of moist desquamation recorded. RESULTS: The incidence of moist desquamation was slightly higher than expected on the basis of the parameters used to calculate iso-effective doses, at least in part as a consequence of the change to the dosimetry. Using likelihood methods and the original dose estimates, the best model based estimate of the dose-rate correction factor for the LDR and VLDR plaques was 1.29. This was comparable with the physical calibration factor, median value 1.23. The VLDR fraction associated with a 50% incidence of moist desquamation, based on experimental observation, was 23.2+/-0.84, 27+/-2.6 and 30.1+/-3.2 Gy, for corrected VLDRs of 0.0247, 0.0093 and 0.0068 Gy/min, respectively. A biphasic model, which incorporated a dose-rate correction factor, provided a better fit than a monophasic repair model to the total data set, which now included the new VLDR data. Moreover, the monophasic repair model suggested a dose-rate correction factor of 1.63, well outside the range derived from the re-evaluation of the physical dosimetry. CONCLUSION: Using the total data (with model based corrected dose-rates), the analysis revealed two components of repair with half-times of 0.103 (0.0594-0.177) and 2.97 (1.96-4.50) h; partition coefficient 0.375 (0.225-0.526). These are comparable with the estimates for other tissues (the CNS in particular) and suggest that the kinetics of repair may be relatively species and tissue independent with variation observed being more related to experimental design rather than any true differences.

The European Radiobiology Archives (ERA)--content, structure and use illustrated by an example.

The European Radiobiology Archives (ERA), supported by the European Commission and the European Late Effect Project Group (EULEP), together with the US National Radiobiology Archives (NRA) and the Japanese Radiobiology Archives (JRA) have collected all information still available on long-term animal experiments, including some selected human studies. The archives consist of a database in Microsoft Access, a website, databases of references and information on the use of the database. At present, the archives contain a description of the exposure conditions, animal strains, etc. from approximately 350,000 individuals; data on survival and pathology are available from approximately 200,000 individuals. Care has been taken to render pathological diagnoses compatible among different studies and to allow the lumping of pathological diagnoses into more general classes. 'Forms' in Access with an underlying computer code facilitate the use of the database. This paper describes the structure and content of the archives and illustrates an example for a possible analysis of such data.

Effects of dexpanthenol with or without Aloe vera extract on radiation-induced oral mucositis: preclinical studies.

PURPOSE: To define the effect of dexpanthenol with or without Aloe vera extract on radiation-induced oral mucositis. MATERIALS AND METHODS: Mouse tongue mucosal ulceration was analysed as the clinically relevant endpoint. Graded single or fractionated dose irradiation (10 x 3 Gy/2 weeks, graded test doses on day 14) were combined with topical administration of dexpanthenol or a base, with or without Aloe vera extract. The formulations were applied for 14 days (single dose) or 24 days after the first fraction. RESULTS: Single dose irradiation resulted in an ED50 (dose at which a positive mucosal response was expected in 50% of the animals irradiated) of 11.9+/-1.2 Gy. None of the formulations yielded a significant change in incidence or time course of ulceration. Test irradiation after 10 x 3 Gy gave an ED50 of 9.0+/-0.1 Gy. Base treatment increased the ED50-values to 10.5+/-0.8 Gy (p = 0.0095) and 9.9+/-0.7 Gy (p = 0.0445) without or with Aloe vera. Dexpanthenol resulted in ED50 values of 9.5+/-0.1 Gy without Aloe vera (p > 0.05), and of 10.9+/-0.9 Gy (p = 0.0035) with Aloe vera. The latent time to ulceration was prolonged, compared to the control (6.3 days) without Aloe vera (8.0-8.2 days, p < 0.001) and with dexpanthenol and Aloe vera (7.3 days, p = 0.0239). CONCLUSIONS: With single dose irradiation, neither dexpanthenol nor Aloe vera extract significantly changed the oral mucosal radiation response. With fractionated irradiation, drug administration significantly increased the isoeffective radiation doses, independent of dexpanthenol or Aloe vera content. Neither dexpanthenol nor Aloe vera display a prophylactic potential.

Porphyrin-mediated boron neutron capture therapy: a preclinical evaluation of the response of the oral mucosa.

Preclinical studies are in progress to determine the potential of boron neutron capture therapy (BNCT) for the treatment of carcinomas of the head and neck. Recently, it has been demonstrated that various boronated porphyrins can target a variety of tumor types. Of the porphyrins evaluated so far, copper tetracarboranylphenyl porphyrin (CuTCPH) is potentially a strong candidate for clinical use. In the present investigation, the response of the oral mucosa to CuTCPH-mediated boron neutron capture (BNC) irradiation was assessed using the ventral surface of the tongue of adult male Fischer 344 rats, a standard rodent model. CuTCPH was administered by intravenous infusion, at a dose of 200 mg/kg body weight, over a 48-h period. Three days after the end of the administration of CuTCPH, biodistribution studies indicated very low levels of boron (<2 microg/g) in the blood. Levels of boron in tongue tissue were 39.0 +/- 3.8 microg/g at this time. This was the time selected for irradiation with single doses of thermal neutrons from the Brookhaven Medical Research Reactor. The estimated level of boron-10 in the oral mucosa was used in the calculation of the physical radiation doses from the 10B(n,alpha)7Li reaction. This differs from the approach using the present generation of clinical boron carriers, where boron levels in blood at the time of irradiation are used for this calculation. Dose-response curves for the incidence of mucosal ulceration were fitted using probit analysis, and the doses required to produce a 50% incidence of the effect (ED50 +/- SE) were calculated. Analysis of the dose-effect data for CuTCPH-mediated BNC irradiation, compared with those for X rays and thermal neutrons alone, gave a compound biological effectiveness (CBE) factor of approximately 0.04. This very low CBE factor would suggest that there was relatively low accumulation of boron in the key target epithelial stem cells of the oral mucosa. As a consequence, with low levels of boron (<2 microg/g) in the blood, the response of the oral mucosa to CuTCPH-mediated BNCT will be governed primarily by the radiation effects of the thermal neutron beam and not from the boron neutron capture reaction [10B(n,alpha)7Li].

Effects of boron neutron capture irradiation on the normal lung of rats.

The whole lung of rats was irradiated with X-rays, thermal neutrons, or thermal neutrons in the presence of p-boronophenylalanine (BPA). A >/= 20% increase in breathing rate, in the period 40-80 days after irradiation, was indicative of radiation-induced pneumonitis. The ED(50) (+/-SE) for a >/= 20% increase in breathing rate, relative to age-matched controls, was 11.6 +/- 0.13 Gy for X-rays and 9.6 +/- 0.08 Gy for neutrons only. This indicated a thermal neutron beam RBE of 1.2 and an RBE of 2.2 for the high-LET components of the dose, assuming a dose reduction factor of 1.0 for gamma rays. Preliminary data indicate the compound biological effectiveness factor for BPA in the lung is approximately 1.5.

Tolerance of normal human brain to boron neutron capture therapy.

Data from the Harvard-MIT and the BNL Phase I and Phase I/II clinical trials, conducted between 1994 and 1999, have been analyzed and combined, providing the most complete data set yet available on the tolerance of the normal human brain to BPA-mediated boron neutron capture therapy. Both peak (1cm(3)) dose and average whole-brain dose show a steep dose-response relationship using somnolence syndrome as the clinical endpoint. Probit analysis indicates that the doses associated with a 50% incidence for somnolence (ED(50)+/-SE) were 6.2+/-1.0 Gy(w) for average whole-brain dose and 14.1+/-1.8 Gy(w) for peak brain dose.

Experimental evidence to support the hypothesis that damage to vascular endothelium plays the primary role in the development of late radiation-induced CNS injury.

Experimental evidence has been obtained to support the view that late necrosis in the brain, after irradiation, is a consequence of damage to the vascular system. Rats were locally irradiated to the brain with a single dose of 25 Gy of X-rays and their response was compared with rats given the same treatment after administration of the radioprotector, Gammaphos. Time-dependent changes in endothelial cell number were determined for up to 65 weeks after irradiation. The complex pattern of changes in endothelial cell number, seen after irradiation alone, was not found in animals receiving Gammaphos prior to irradiation. The initial marked loss of endothelial cells, seen after 24 h in unprotected animals, was effectively prevented by the pre-administration of Gammaphos. The subsequent slow decline in endothelial cell density in Gammaphos treated animals was insufficient to induce an abortive attempt at endothelial cell re-population. This occurred between 26 and 52 weeks after irradiation in unprotected animals. By 65 weeks after irradiation <10% of animals receiving Gammaphos showed necrosis on histological evaluation. This compared with approximately 50% of the animals showing necrosis that had not received the radioprotector. Since the radioprotector is restricted to the vasculature of the brain these data indicate that endothelium is the primary target cell population, damage to which leads to the development of late radiation-induced necrosis in the brain.

Time factor for acute tissue reactions following fractionated irradiation: a balance between repopulation and enhanced radiosensitivity.

Experimental data for acute radiation-induced skin reactions are reviewed. These show that for dose fractionation schedules with gaps, repopulation is initiated after a lag period. After this lag period, the isoeffective dose for a given level of skin reaction first increases rapidly, but then slows. The timing of the lag period is related to the total turnover time of the tissue under investigation and, for example, is shorter in rodent skin than in pig or human skin. At the point when accelerated repopulation is initiated, there is a major shortening of the turnover time of the target cell population. At this time, there is evidence, for a short period, for an increase in radiosensitivity of the surviving stem cells in a number of acutely responding normal tissues. This effect is clearly illustrated by the results of experiments using sequential dose fractionation schedules. Prolongation of the schedule from 'short' to schedules that include irradiation over the period when the cell turnover is accelerated is associated with a marked increase in tissue radiosensitivity. Clinically, this is best illustrated by a comparison of the effects of accelerated fractionation schedules, involving multiple fractions/day, with daily fractionation schedules. The increase in radiosensitivity produced by the prolongation of the treatment from 2 to 4-5 weeks was equivalent to > or =1 Gy day(-1). Comparable findings were obtained from animal studies. In the oral mucosa of mice, the initiation of accelerated cell proliferation in surviving cells is associated with the loss of dose sparing by subsequent dose fractionation due to the loss of the capacity to repair sublethal damage. Studies in pig and human skin have indicated that increased radiosensitivity is associated with a loss of cells in the G1 phase of the cell cycle. A collation of these two sets of findings suggests that the repair of sublethal damage takes place over this phase of the cell cycle. One clinical implication of these findings is that the alpha/beta ratio for acute skin reaction changes with the length of the overall treatment time; it is approximately 4.0 Gy for 'short' fractionation schedules that avoid any shortening of the cell cycle time. This increases to 11.2-13.3 Gy for schedules given in 3-4 weeks and to approximately 35 Gy for schedules given in 5-6 weeks. Results for pig skin were in total agreement with those for human skin.

Porphyrin-mediated boron neutron capture therapy: evaluation of the reactions of skin and central nervous system.

PURPOSE: Recently, various boronated porphyrins have been shown to preferentially target a variety of tumour types. Of the different porphyrins evaluated, copper tetra-phenyl-carboranyl porphyrin (CuTCPH) is a strong candidate for future preclinical evaluation. In the present study, the responses of two critical normal tissues, skin and central nervous system (CNS), to boron neutron capture (BNC) irradiation in the presence of this porphyrin were evaluated. MATERIALS AND METHODS: Standard models for the skin and spinal cord of adult male Fischer 344 rats were used. CuTCPH was administered by intravenous infusion at a dose of 200 mg x kg(-1) body weight, over 48 h. The thermal beam at the Brookhaven Medical Research Reactor was used for the BNC irradiations. The 20-mm diameter irradiation field, for both the skin and the spinal cord, was located on the mid-dorsal line of the neck. Dose-response data were fitted using probit analysis and the doses required to produce a 50% incidence rate of early and late skin changes or myeloparesis (ED(50) +/- SE) were calculated from these curves. RESULTS: Biodistribution studies indicated very low levels of boron (<3 microg x g(-1)) in the blood 3 days after the administration of CuTCPH. This was the time point selected for radiation exposure in the radiobiological studies. Levels of boron in the CNS were also low (2.8 +/- 0.6 microg x g(-1)) after 3 days. However, the concentration of boron in the skin was considerably higher at 22.7 +/- 2.6 microg x g(-1). Single radiation exposures were carried out using a thermal neutron beam. The impact of CuTCPH-mediated BNC irradiation on the normal skin and CNS at therapeutically effective exposure times was minimal. This was primarily due to the very low blood boron levels (from CuTCPH) at the time of irradiation. Analysis of the relevant dose-effect data gave compound biological effectiveness factors of about 1.8 for skin (moist desquamation) and about 4.4 for spinal cord (myeloparesis) for CuTCPH. These values were based on the BNC radiation doses to tissues calculated using the blood boron levels at the time of irradiation. CONCLUSIONS: CuTCPH-mediated BNC irradiation will not cause significant damage to skin and CNS at clinically relevant radiation doses provided that blood boron levels are low at the time of radiation exposure.

Evaluation of the relative biological effectiveness of a clinical epithermal neutron beam using dog brain.

This investigation was designed to determine the relative biological effectiveness (RBE) of an epithermal neutron beam (FiR 1 beam) using the brains of dogs. The FiR 1 beam was developed for the treatment of patients with glioma using boron neutron capture therapy. Comparisons were made between the effects of whole-brain irradiation with epithermal neutrons and 6 MV photons. For irradiations with epithermal neutrons, three dose groups were used, 9.4 +/- 0.1, 10.2 +/- 0.1 and 11.5 +/- 0.2 Gy. These physical doses were given as a single exposure and are quoted at the 90% isodose. Four groups of five dogs were irradiated with single doses of 10, 12, 14 or 16 Gy of 6 MV photons to the 100% isodose. Different reference isodoses were used to obtain the most comparable dose distribution in the brain for the two different irradiation modalities. Sequential magnetic resonance images (MRI) were taken for 77-115 weeks after irradiation to detect changes in the brain. Dose-effect relationships were established for changes in the brain as detected either by MRI or by subsequent gross morphology and histology. The doses that caused a specified response in 50% of the animals (ED(50)) were calculated from these dose-effect curves for each end point, and these values were used to calculate the RBE values for the different end points. The RBE values for the FiR 1 beam, based on changes observed on MRI, were in the range 1.2-1.3. For microscopic and gross pathological lesions, the values were in the range 1.2-1.4. The corresponding RBE values for the MRI and pathological end points for the high-LET components (protons from nitrogen capture and recoil protons from fast neutrons) were in the ranges 3.5-4.0 and 3.4-4.4, respectively. This assumed a dose-rate reduction factor of 0.6 for the low-dose-rate gamma-ray component of this beam. Finally, a comparison was made between experimentally derived photon doses, for a specified end point, with calculated photon equivalent doses, which were obtained using the weighting factors for clinical studies on the epithermal neutron beam on the Brookhaven Medical Research Reactor (BNL) in New York. This indicated that the radiation-induced lesions seen in the present study were, on average, detected at a 12% lower photon dose than predicted by the use of the BNL clinical weighting factors. This indicates the need for caution in the extrapolation of results from one reactor-based epithermal neutron beam to another.