M. Ichihashi

Boron Neutron Capture Therapy of Malignant Melanoma Using 10B-Paraboronophenylalanine with Special Reference to Evaluation of Radiation Dose and Damage to the Normal Skin

A treatment regimen for boron neutron capture therapy of malignant melanomas is described using 10B-paraboronophenylalanine as the tumor-targeting compound. As a therapeutic dose, we adopted the maximum tolerable dose for the skin regardless of tumor 10B concentration. In practice, the maximum neutron fluence should be decided prior to starting irradiation. For this purpose, the kinetics of the concentration of 10B in the blood and skin and the skin-to-blood ratios were analyzed in the six patients who received 170 mg/kg of the compound intravenously, and skin concentrations during irradiation were predicted using a standard skin factor curve. This yields a skin concentration at time T based on the blood concentration at time 0. We calculated the maximum tolerable fluence yielding but not exceeding 18 RBE-Gy by assuming that the RBE of 14N(n,p)14C and 10B(n, alpha)7Li reaction for skin damage is 2.5. Actual skin reactions in three of five patients treated with the therapy were, as predicted, within tolerable limits, and we were able to obtain complete tumor regression in four cases. The results indicate that application of our logical approach will be useful for subsequent cases and further development of this therapy.

Advances in the Control of Human Cutaneous Primary and Metastatic Melanoma by Thermal Neutron Capture Therapy

Differing in principle from boron neutron capture therapy (NCT) of brain tumors using passive accumulation of 10B, since 1972 our ideal) has been to develop a new 10B delivery system actively targeting cancers by utilizing their enhanced specific metabolic activity. As a prototype, we have been working with melanoma using 10B1-p-boronophenylalanine (10B1-BPA), a 10B-dopaanalogue, melanogenesis-seeking melanin polymer substrate2).

Boron neutron capture therapy (BNCT) for malignant melanoma with special reference to absorbed doses to the normal skin and tumor

Twenty-two patients with malignant melanoma were treated with boron neutron capture therapy (BNCT) using10B-p-boronophenylalanine (BPA). The estimation of absorbed dose and optimization of treatment dose based on the pharmacokinetics of BPA in melanoma patients is described. The doses of γ-rays were measured using small TLDs of Mg2SiO4 (Tb) and thermal neutron fluence was measured using gold foil and wire. The total absorbed dose to the tissue from BNCT was obtained by summing the primary and capture γ-ray doses and the high LET radiation doses from10B(n,α)7Li and14N(n,p)14C reactions. The key point of the dose optimization is that the skin surrounding the tumour is always irradiated to 18 Gy−Eq, which is the maximum tolerable dose to the skin, regardless of the10B-concentration in the tumor. The neutron fluence was optimized as follows. (1) The10B concentration in the blood was measured 15−40 min after the start of neutron irradiation. (2) The10B-concentration in the skin was estimated by multiplying the blood10B value by a factor of 1.3. (3) The neutron fluence was calculated. Absorbed doses to the skin ranged from 15.7 to 37.1 Gy−Eq. Among the patients, 16 out of 22 patients exhibited tolerable skin damage. Although six patients showed skin damage that exceeded the tolerance level, three of them could be cured within a few months after BNCT and the remaining three developed severe skin damage requiring skin grafts. The absorbed doses to the tumor ranged from 15.7 to 68.5 Gy−Eq and the percentage of complete response was 73% (16/22). When BNCT is used in the treatment of malignant melanoma, based on the pharmacokinetics of BPA and radiobiological considerations, promising clinical results have been obtained, although many problems and issues remain to be solved.

Increased Selective 10B-Uptake by Malignant Melanoma Using Systemic Administration of 10B1-BPA·Fructose Complex

10B1-para-Boronophenylalanine(10B1-BPA) has selective affinity for malignant melanoma. In our first human case, we succeeded in obtaining complete regression of a metastatic subcutaneous melanoma lesion by neutron capture therapy (NCT) using distant perilesional injections of 10B1-BPA hydrochloride.

Selective Melanoma Thermal Neutron Capture Therapy for Lymph Node Metastases

The success of treatment of tumors with NCT lies primarily with the development of suitable vectors to optimally carry 10B to the tumor site, efficient methods of their administration, and effective neutron beam delivery.

Tolerance Limits of the Normal Skin Treated by a Single Thermal Neutron Capture Therapy

In the treatment of malignant melanoma by BNCT, it is very important to estimate the damage to the skin, because we must eradicate the tumour within the tolerance limits of the normal tissues. In this paper, early and late skin reactions were observed in 8 patients treated by BNCT using 10B-paraboronophenylalanine (10B-BPA) and maximum neutron fluences to the skin were estimated. The RBE for the skin damage of high LET capture reaction from nitrogen-14 and boron-10 was also approximated.

Rapid Spectrophotometric Determination of Boron in Biological Tissue with Alkali Fusion Decomposition

During our clinical applications of neutron capture therapy (NCT), after administration of 10B-p-Boronophenylalanine (BPA), 10B concentration in the melanoma and the skin near the melanoma are determined by the prompt γ method. From the data obtained, it is possible to calculate the boron concentration in melanoma during neutron irradiation, and irradiation time was determined. If the prompt γ method is not available, it is difficult to estimate the concentration in melanoma at the time of the irradiation.

In Vivo Cellular Pharmacology on the Selective Affinity of 10B1-BPA for Malignant Melanoma

We have previously shown that 10B1-paraboronophenylalanine (10B1-BPA) has selective affinity for both melanotic and amelanotic melanomas in vitro and in vivo1). We have also shown complete suppression of implanted melanoma in hamster by thermal neutron capture therapy (NCT) using 10B1- BPA1). Further, we have already treated succesfully six human melanoma cases by NCT using 10B1-BPA1,2).

In Vitro Evaluation of 10B-BPA for Melanoma at Moata - Joint Work between Japan and Australia BNCT Research Teams

A variety of conjugated compounk have been synthesized in Japan, the USA and Australia. Among these 10B-compounds, 10B1-paraboronophenylalanine (10B1-BPA) has been widely tested in vitro and in vivo for boron neutron capture therapy of melanoma. We have shown that 10B1-BPA is selectively incorporated into melanom cells in vitro1) and in vivo 2). Neutron capture therapy (NCT) using 10B1-BPA has been demonstrated not only to be highly lethal for melanoma cells in vitro3) but also to be effective for suppressing melanoma growth in vivo.

Boron Analytical Studies on 10B1-BPA Administration for Neutron Capture Therapy of Malignant Melanoma

Success of boron neutron capture therapy (NCT) for cancer depends mainly upon selective boron accumulation in the targeted tumor. Since 1987 we have succeeded in treating human melanoma lesions by NCT utilizing10B1-para-boronophenylalanine (10B1-BPA).1 At the same time we have investigated various methods of administering10B1-BPA for optimal NCT. The results of our analytical studies on boron kinetics in animals and humans by 10B1-BPA administration are described.