BNCT for skin melanoma in extremities: Updated Argentine clinical results

https://doi.org/10.1016/j.apradiso.2009.03.020Get rights and content

Abstract

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 ∼14 gr/m2 of 10borophenyl-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).

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:

  • Toxicity is acceptable for this treatment at the current prescribed dose level.

  • Toxicity was found related to skin dose and the anatomic area.

  • 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.

References (16)

There are more references available in the full text version of this article.

Cited by (103)

  • Study of BNCT neutronics optimization for out-of-beam dosimetry based on radiobiological figures of merit

    2021, Nuclear Instruments and Methods in Physics Research, Section B: Beam Interactions with Materials and Atoms
View all citing articles on Scopus
View full text