BNCT for skin melanoma in extremities: updated Argentine clinical results.

As part of phase I/II melanoma BNCT clinical trial conducted in Argentina in a cooperative effort of the Argentine Atomic Energy Commission (CNEA) and the Oncology Institute Angel H. Roffo (IOAHR), 7 patients (6 female-1 male) received eight treatment sessions covering ten anatomical areas located in extremities. Mean age of the patients was 64 years (51-74). The treatments were performed between October 2003 and June 2007. All patients presented multiple subcutaneous skin metastases of melanoma and received an infusion containing approximately 14 gr/m(2) of (10)borophenyl-alanine (BPA) followed by the exposition of the area to a mixed thermal-epithermal neutron beam at the RA-6 reactor. The maximum prescribed dose to normal skin ranged from 16.5 to 24 Gy-Eq and normal tissue administered dose varied from 15.8 to 27.5 Gy-Eq. Considering evaluable nodules, 69.3% of overall response and 30.7% of no changes were seen. The toxicity was acceptable, with 3 out of 10 evaluable areas showing ulceration (30% toxicity grade 3).

Boron neutron capture therapy (BNCT) inhibits tumor development from precancerous tissue: an experimental study that supports a potential new application of BNCT.

We previously demonstrated the efficacy of boron neutron capture therapy (BNCT) mediated by boronophenylalanine (BPA), GB-10 (Na(2)(10)B(10)H(10)) and (GB-10+BPA) to control tumors, with no normal tissue radiotoxicity, in the hamster cheek pouch oral cancer model. Herein we developed a novel experimental model of field-cancerization and precancerous lesions (globally termed herein precancerous tissue) in the hamster cheek pouch to explore the long-term potential inhibitory effect of the same BNCT protocols on the development of second primary tumors from precancerous tissue. Clinically, second primary tumor recurrences occur in field-cancerized tissue, causing therapeutic failure. We performed boron biodistribution studies followed by in vivo BNCT studies, with 8 months follow-up. All 3 BNCT protocols induced a statistically significant reduction in tumor development from precancerous tissue, reaching a maximum inhibition of 77-100%. The inhibitory effect of BPA-BNCT and (GB-10+BPA)-BNCT persisted at 51% at the end of follow-up (8 months), whereas for GB-10-BNCT it faded after 2 months. Likewise, beam-only elicited a significant but transient reduction in tumor development. No normal tissue radiotoxicity was observed. At 8 months post-treatment with BPA-BNCT or (GB-10+BPA)-BNCT, the precancerous pouches that did not develop tumors had regained the macroscopic and histological appearance of normal (non-cancerized) pouches. A potential new clinical application of BNCT would lie in its capacity to inhibit local regional recurrences.

Tumor control and normal tissue complications in BNCT treatment of nodular melanoma: a search for predictive quantities.

A previous work concerning tumor control and skin damage in cutaneous melanoma treatments with BNCT has been extended to include doses, volumes and responses of 104 subcutaneous lesions from all patients treated in Argentina. Acute skin reactions were also scored for these patients, and cumulative dose-area histograms and dose-based figures of merit for skin were calculated. Broadening the tumor response analysis with the latest data showed that the (minimum or mean) tumor dose is not a good predictor of the observed clinical outcome by itself. However, when the tumor volume was included in the model as second explicative variable, the dose increases its significance and becomes a critical variable jointly with the volume (p-values<0.05). A preliminary analysis to estimate control doses for two groups of tumor sizes revealed that for small tumor volumes (< 0.1cm(3)) doses greater than 20 Gy-Eq produce a high tumor control (> 80%). However, when tumor volumes are larger than 0.1cm(3), control is moderate (< 40%) even for minimum doses up to 40 Gy-Eq. Some quantities based on skin doses, areas and complication probabilities were proposed as candidates for predicting the severity of the early skin reactions. With the current data, all the evaluated figures of merit derived similar results: ulceration is present among the cases for which these quantities take the highest values.

Unifying dose specification between clinical BNCT centers in the Americas.

A dosimetry intercomparison between the boron neutron capture therapy groups of the Massachusetts Institute of Technology (MIT) and the Comisión Nacional de Energía Atómica (CNEA), Argentina was performed to enable combined analyses of NCT patient data between the different centers. In-air and dose versus depth measurements in a rectangular water phantom were performed at the hyperthermal neutron beam facility of the RA-6 reactor, Bariloche. Calculated dose profiles from the CNEA treatment planning system NCTPlan that were calibrated against in-house measurements required normalizations of 1.0 (thermal neutrons), 1.13 (photons), and 0.74 (fast neutrons) to match the dosimetry of MIT.

Comparison of the performance of two NCT treatment planning systems using the therapeutic beam of the RA-6 reactor.

This work evaluates the performance of two NCT treatment planning systems: NCTPlan, developed by the CNEA and the Harvard-MIT group, and SERA, developed by the INEEL/Montana State University group. The study was performed in some simple geometries with the therapeutical hyperthermal beam of the RA-6 facility at Bariloche, Argentina. The first geometry was a rectangular phantom and calculations and measurements were made along the central beam axis and along a parellel axis, 4 cm apart from the central beam axis. Measurements and calculations were also performed in a cylindrical phantom, to explore the behavior of the treatment planning systems in a geometry simulating an extremity, in accordance with the CNEA clinical protocol. Comments on differences in source definitions and cross sections libraries are also included in the text. It can be seen that both codes give acceptable results on the central beam axis and on a lateral axis, showing good agreement with experimental results.

BNCT dose calculation in irregular fields using the sector integration method.

Irregular fields for boron neutron capture therapy (BNCT) have been already proposed to spare normal tissue in the treatment of superficial tumors. This added dependence would require custom measurements and/or to have a secondary calculation system. As a first step, we implemented the sector-integration method for irregular field calculation in a homogeneous medium and on the central beam axis. The dosimetric responses (fast neutron and photon dose and thermal neutron flux), are calculated by sector integrating the measured responses of circular fields over the field boundary. The measurements were carried out at our BNCT facility, the RA-6 reactor (Argentina). The input data were dosimetric responses for circular fields measured at different depths in a water phantom using ionisation and activation techniques. Circular fields were formed by shielding the beam with two plates: borated polyethilene plus lead. As a test, the dosimetric responses of a 7x4 cm(2) rectangular field, were measured and compared to calculations, yielding differences less than 3% in equivalent dose at any depth indicating that the tool is suitable for redundant calculations.

Boron neutron capture therapy for undifferentiated thyroid carcinoma: preliminary results with the combined use of BPA and BOPP.

We have shown the selective uptake of borophenylalanine (BPA) by undifferentiated human thyroid cancer (UTC) ARO cells both in vitro and in vivo. Moreover, a 50% histologic cure of mice bearing the tumor was observed when the complete boron neutron capture therapy was applied. More recently we have analyzed the biodistribution of BOPP (tetrakis-carborane carboxylate ester of 2,4-bis-(alpha,beta-dihydroxyethyl)-deutero-porphyrin IX) and showed that when BOPP was injected 5 days before BPA, and the animals were sacrificed 60 min after the i.p. injection of BPA, a significant increase in boron uptake by the tumor was found (38-45 ppm with both compounds vs. 20 ppm with BPA alone). Five days post the i.p BOPP injection and 1h after BPA the ratios were: tumor/blood 3.75; tumor/distal skin 2. Other important ratios were tumor/thyroid 6.65 and tumor/lung 3.8. The present studies were performed in mice transplanted with ARO cells and injected with BOPP and BPA. Only in mice treated with the neutron beam and injected with the boronated compounds we observed a 100% control of tumor growth. Two groups of mice received different total absorbed doses: 3.00 and 6.01 Gy, but no further improvement in the outcome was found compared to the previous results using BPA alone (4.3 Gy).

First BNCT treatment of a skin melanoma in Argentina: dosimetric analysis and clinical outcome.

A Phase I/II protocol for treating cutaneuos melanomas with BNCT was designed in Argentina by the Comisión Nacional de Energía Atómica and the medical center Instituto Roffo. The first of a cohort of thirty planned patients was treated on October 9, 2003. This article depicts the protocol-based procedure and describes the first clinical case, treatment regime and planning, patient irradiation, retrospective dosimetric analysis and clinical outcome. Considering the low acute skin toxicity and the complete response in 21 of the 25 subcutaneous melanoma nodules treated, a second irradiation was performed in a different location of the extremity of the same patient. The corresponding clinical outcome is still under evaluation.

Boron neutron capture therapy of skin melanomas at the RA-6 reactor: a procedural approach to beam set up and performance evaluation for upcoming clinical trials.

This article reports on the progress of the modeling and experimental characterization of the RA-6 reactor neutron beam, designed for the upcoming BNCT clinical trials of skin melanoma, and presents the first theoretical analysis of such beam performance. The aspects relating to surface source modeling and assessment, beam dosimetry, treatment planning system calibration, and treatment planning optimization are presented herein. Several methods and criteria were established in order to provide guidance for future clinical studies conducted in this facility. Following a realistic model, the theoretical analysis was based on a clinical case of malignant melanoma in extremities. Owing to the complex geometry of the tumor, this particular clinical case represents one of the most difficult lesions to be treated. This article discusses the thorough evaluation stage that has led to the optimization of the treatment planning procedure. Two candidate plans were proposed, and dose-volume distributions in the target volume were evaluated on the basis of the application of a series of criteria that define the critical normal structures which limit the dose delivered. In spite of the complexity of the clinical case under review, results showed that only 4% of the tumor volume is underdosed in cases of mean blood 10B concentration values, even in the most unfavorable analysis. The overall results suggest that this BNCT facility is prepared to rigorously explore the clinical efficacy of the RA-6 beam and the BNCT treatment modality for peripheral melanomas.

Boron neutron capture therapy for the treatment of oral cancer in the hamster cheek pouch model.

We have proposed and validated the hamster cheek pouch model of oral cancer for boron neutron capture therapy (BNCT) studies and shown that boronophenylalanine delivers potentially therapeutic 36.9 +/- 17.5 ppm boron to tumor tissue with tumor:normal tissue and tumor:blood ratios of 2.4:1 and 3.2:1, respectively. Here we report the first evidence of the usefulness of BNCT for the treatment of oral cancer in an experimental model. We assessed the response of hamster cheek pouch tumors, precancerous tissue, and normal oral tissue to boronophenylalanine-mediated BNCT using the thermalized epithermal beam of the RA-6 Reactor at the Bariloche Atomic Center. BNCT leads to complete remission by 15 days posttreatment in 78% of tumors and partial remission in an additional 13% of tumors with virtually no damage to normal tissue.