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.
The purpose of this study was to further evaluate the therapeutic efficacy of convection enhanced delivery (CED) of carboplatin in combination with radiotherapy for treatment of the F98 rat glioma. Tumor cells were implanted stereotactically into the brains of syngeneic Fischer rats, and 13 or 17 d. later carboplatin (20 μg/10 μL) was administered by either CED over 30 min or by Alzet osmotic pumps (0.5 μg/μL/h for 168 h.) beginning at 7 d after tumor implantation. Rats were irradiated with a 15 Gy fractionated dose (5 Gy × 3) of 6 MV photons to the whole brain beginning on the day after drug administration. Other groups of rats received either carboplatin or X-irradiation alone. The tumor carboplatin concentration following CED of 20 μg in 10 μL was 10.4 μg/g, which was equal to that observed following i.v. administration of 100 mg/kg b.w. Rats bearing small tumors, treated with carboplatin and X-irradiation, had a mean survival time (MST) of 83.4 d following CED and 111.8 d following pump delivery with 40% of the latter surviving >180 d (i.e. cured) compared to 55.2 d for CED and 77.2 d. for pump delivery of carboplatin alone and 31.8 d and 24.2 d, respectively, for X-irradiated and untreated controls. There was no microscopic evidence of residual tumor in the brains of all long-term survivors. Not surprisingly, rats with large tumors had much shorter MSTs. Only modest increases in MSTs were observed in animals that received either oral administration or CED of temozolomide plus X-irradiation (23.2 d and 29.3 d) compared to X-irradiation alone. The present survival data, and those previously reported by us, are among the best ever obtained with the F98 glioma model. Initially, they could provide a platform for a Phase I clinical trial to evaluate the safety and potential therapeutic efficacy of CED of carboplatin in patients with recurrent glioblastomas, and ultimately a Phase II trial of carboplatin in combination with radiation therapy.
Applications of mathematical modeling can improve outcome predictions of cancer therapy. Here we present a kinetic model incorporating effects of radiosensitivity, tumor repopulation, and dead-cell resolving on the analysis of tumor volume regression data of 80 cervical cancer patients (stages 1B2-IVA) who underwent radiation therapy. Regression rates and derived model parameters correlated significantly with clinical outcome (P < 0.001; median follow-up: 6.2 years). The 6-year local tumor control rate was 87% versus 54% using radiosensitivity (2-Gy surviving fraction S 2 < 0.70 vs. S 2 ≥ 0.70) as a predictor (P = 0.001) and 89% vs. 57% using dead-cell resolving time (T 1/2 < 22 days versus T 1/2 ≥ 22 days, P < 0.001). The 6-year disease-specific survival was 73% versus 41% with S 2 < 0.70 versus S 2 ≥ 0.70 (P = 0.025), and 87% vs. 52% with T 1/2 < 22 days versus T 1/2 ≥ 22 days (P = 0.002). Our approach illustrates the promise of volume-based tumor response modeling to improve early outcome predictions that can be used to enable personalized adaptive therapy. Cancer Res; 70(2); 463-70. ©2010 AACR.
We present commissioning and comprehensive evaluation for ArcCHECK as a QA equipment for volumetric‐modulated arc therapy (VMAT), using the 6 MV photon beam with and without the flattening filter, and the SNC patient software (version 6.2). In addition to commissioning involving absolute dose calibration, array calibration, and PMMA density verification, ArcCHECK was evaluated for its response dependency on linac dose rate, instantaneous dose rate, radiation field size, beam angle, and couch insertion. Scatter dose characterization, consistency and symmetry of response, and dosimetry accuracy evaluation for fixed aperture arcs and clinical VMAT patient plans were also investigated. All the evaluation tests were performed with the central plug inserted and the homogeneous PMMA density value. Results of gamma analysis demonstrated an overall agreement between ArcCHECK‐measured and TPS‐calculated reference doses. The diode based field size dependency was found to be within 0.5% of the reference. The dose rate‐based dependency was well within 1% of the TPS reference, and the angular dependency was found to be ± 3% of the reference, as tested for BEV angles, for both beams. Dosimetry of fixed arcs, using both narrow and wide field widths, resulted in clinically acceptable global gamma passing rates on the 3%/3 mm level and 10% threshold. Dosimetry of narrow arcs showed an improvement over published literature. The clinical VMAT cases demonstrated high level of dosimetry accuracy in gamma passing rates.PACS numbers: 87.56.Fc, 87.55.kh, 87.55.Qr
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