BNCT for skin melanoma in extremities: Updated Argentine clinical results
Introduction
Melanoma is an aggressive disease that frequently involves distant and locoregional spread, without, in many cases, a useful treatment approach. For initial stages disease prognostic is favorable; surgical treatment with wide excision offers good probability of cure. But for more advanced stages (despite aggressive surgery, radiotherapy or systemic treatments) prognosis is very poor. In certain advanced cases local or metastatic skin progression cannot be treated by surgery, and radiation therapy is the treatment of choice. Skin tolerance to radiation limits prescription dose. Levels greater than 45–50 Gy (fractionated) are avoided, to reduce incidence of late effects. Toxicities can vary from mild (erythema, dry desquamation, skin color changes) to severe (ulceration, atrophy, telangiectasia), producing cosmetic or functional sequelae (Archambeau et al., 1995). Overgaard and other authors (Overgaard, 1980; Hornsey, 1978; Habermalz and Fischer, 1976; Sause et al., 1991) used different dose fractionation schemes to treat cutaneous melanoma lesions, suggesting a correlation between increasing fraction size and improved radio-responsiveness of this tumor, but also an increased dose per fraction could decrease skin tolerance producing undesired side effects. In this context the binary characteristic of BNCT could be an attractive tool to improve response over the standard radiotherapy treatment delivering high dose to tumor while reducing normal tissue effect, due to the different boron uptake in normal and tumor cells. (Blaumann et al., 2004; Hiratsuka et al., 2000).
The initial human clinical BNCT experience in patients with melanoma was performed by Mishima after extensive studies in vitro and in vivo. He incorporated 10B into a precursor of melanina (BPA) to satisfy criteria for selective uptake (Mishima et al., 1989). The melanoma BNCT treatments in Japan by Mishima et al. were followed by Fukuda et al. (1999) and by Busse et al. (1997) in the USA. All of them showed encouraging tumor control rates.
BNCT project was started in Argentina during 1998. A few years later, in 2003, a clinical trial phase I/II protocol on cutaneous melanoma begun supported by the Argentine Atomic Energy Commission (CNEA) and the University of Buenos Aires Oncology Institute Angel H. Roffo. The protocol was designed to evaluate the efficacy and toxicity of BNCT for cutaneous skin melanomas in extremities (González et al., 2004a).
In the present work the primary end point in the trial described was to evaluate the tolerability of normal tissue to BNCT and also collecting information regarding tumor response.
Section snippets
Patients
Seven patients (eight irradiation procedures covering ten anatomical areas) having multiple subcutaneous skin metastases on extremities and progressed to initial surgical treatment were irradiated with the mixed neutron beam, named hyperthermal, of the RA-6 facility after ∼14 gm/m2 BPA-fructose infusion.
Six female and one male patients, mean age 64 years old (51–74 years old) having multiple subcutaneous skin metastasis on the right or left leg for all cases and progressed to previous treatment
Results and discussion
No adverse clinical events were observed during infusion or irradiation procedure and TLD gamma dose values determined were far below the tolerance values for normal tissues.
Only the first three patients performed tumor biopsy. The range of tumor/blood boron concentration ratios (T/B) were 1.7–2.5 at 2 h 45 min after infusion started for patient 1, 2.4–4.1 at 5 h for patient 2 and 2.7–3.2 at 10 h for patient 3. T/B for patient 1 was taken in a separate biodistribution study a few weeks before BNCT.
Conclusions
Although we continue to recruit patients for the protocol, data already obtained let us conclude that:
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Toxicity is acceptable for this treatment at the current prescribed dose level.
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Toxicity was found related to skin dose and the anatomic area.
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Clinical benefit was found in all the treated areas.
Acknowledgments
The authors acknowledge Tecnonuclear, for the kindly BPA solution preparation and Julieta Marrero and Paola Babay for the boron concentration measurements in blood samples. This trial is supported in part by the Agencia de Promoción Científica y Tecnológica.
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