ARTICLE IN PRESS

Applied Radiation and Isotopes 67 (2009) S50S53

Contents lists available at ScienceDirect

Applied Radiation and Isotopes

journal homepage: www.elsevier.com/locate/apradiso

BNCT for skin melanoma in extremities: Updated Argentine clinical results

P.R. Menendez a,, B.M.C. Roth a, M.D. Pereira a,b,c, M.R. Casal a, S.J. Gonzalez b,d, D.B. Feld b,
G.A. Santa Cruz b, J. Kessler b, J. Longhino b, H. Blaumann b, R. Jimenez Rebagliati b,
O.A. Calzetta Larrieu b, C. Fernandez b, S.I. Nievas b, S.J. Liberman b
a
Instituto de Oncologa Angel H. Roffo. Av. San Martn 5481, (1417) Cdad. de Buenos Aires, Argentina
b
Comisio n Nacional de Energa Ato
mica, Av. del Libertador 8250, (1429) Cdad. de Buenos Aires, Argentina
c
Agencia Nacional de Promocio n Cientca y Tecnolo
gica. PAV 22393, Cordoba 831, (1054) Cdad. de Buenos Aires, Argentina
d
CONICET, Avda. Rivadavia 1917, (1033) Cdad. de Buenos Aires, Argentina

a r t i c l e in f o a b s t r a c t

As part of phase I/II melanoma BNCT clinical trial conducted in Argentina in a cooperative effort of the
Keywords: Argentine Atomic Energy Commission (CNEA) and the Oncology Institute Angel H. Roffo (IOAHR),
BNCT 7 patients (6 female1 male) received eight treatment sessions covering ten anatomical areas located in
Skin melanomas extremities. Mean age of the patients was 64 years (5174). The treatments were performed between
BPA-F October 2003 and June 2007. All patients presented multiple subcutaneous skin metastases of
Clinical trials 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).
& 2009 Elsevier Ltd. All rights reserved.

1. 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) prog-
nosis 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 4550 Gy (fractio-
nated) 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
 Corresponding author. Tel./fax: +54 11 4580 2811.
E-mail address: pmenende@yahoo.com (P.R. Menendez).
increased dose per fraction could decrease skin tolerance produ-
cing undesired side effects. In this context the binary character-
istic 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
efcacy and toxicity of BNCT for cutaneous skin melanomas in
extremities (Gonzalez 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.

0969-8043/$ - see front matter & 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.apradiso.2009.03.020
 ARTICLE IN PRESS
P.R. Menendez et al. / Applied Radiation and Isotopes 67 (2009) S50S53 S51

2. Materials and methods
2.1. 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
(5174 years old) having multiple subcutaneous skin metastasis
on the right or left leg for all cases and progressed to previous
treatment were included in this study. The rst patient received
two irradiations of one fraction each for two different areas of the
leg (October and December 2003). The second patient received
one irradiation (one fraction) in June 2004. The third one was
irradiated with three consecutive elds at the level of the calf,
ankle and foot sole of the right leg on May 2005. Fourth to seventh
patients received one fraction covering one location (May and
December 2006, May and June 2007, respectively) as shown in
Table 1.
Atomic Center). The patient position was xed by means of
conventional positioning devices.
2.3. Dose prescription
The maximum tolerable dose (MTD) for skin was adopted as
the prescription dose, regardless of the boron concentration in the
tumor in order to keep skin toxicity at a safe level. A 20 Gy-Eq was
the dose assumed for 90% of tumor control probability in lesions
p1 cm. The feasibility of a treatment was decided if a therapeutic
dose could be administrated to the tumor, keeping the maximum
dose to the skin below the prescribed value. Another factor taken
into account was the treatment time, which has to be short
enough to avoid patient movement and/or discomfort.
To evaluate dose distribution in the skin a 5 mm thick layer of
tissue was considered. The MTD was scaled from 16.5 to 24
RBE Gy-Eq, as shown in Table 1. Median follow-up was 12 months
(436 Mon).
2.4. Dose calculation

CT scan of patients extremity, positioning coordinates and

2.2. Patient positioning
A simulation room (SR) for patient positioning procedures was
built at Constituyentes Atomic Center (Buenos Aires) with a
beams-eye view window in order to determine distances to the
patients skin reference marks. Templates were built for each eld,
based on two orthogonal images generated during the beam
assignment procedure accomplished with the treatment planning
system to reposition the limb at the irradiation room (Bariloche
typical values of 10B concentration in blood were the key data to
design a treatment plan using NCTPlan v. 1.3 treatment planning
system (Gonzalez et al., 2002a) and DVH Tool system (Gonzalez
et al., 2002b). Considering the above-mentioned dose prescription
limit, preliminary treatment time, skin and tumor doses were
calculated taking into account a boron tumor/blood concentration
ratio 3.5 (Liberman et al., 2004).
After the irradiation procedure has nished and all blood
samples have been collected, a retrospective patient dosimetry is

Table 1
Patient data, treatment dose and tumor response.

Patient Field CB Tum dose Clin.response TIFP. TOFP Normal tissue MTD/ Acute Status post BNCT (May/08) and time
(Gy-Eq) (Mon) (Mon) MDD (Gy-Eq) toxicity of follow-up

#1 Lower 11.4 13.431.4 21/25 CR 3 1 16.5/15.8 G1 Not alive

D.E. Leg 1/25 PR 18 Mon
3/25 NC MTS: lung
Upper 12.8 27.436.8 NA o1 0 2.0/18.5 G1
Leg

#2 Leg 14.7 21.751.5 1/11 CR 7 NA 22.0/22.6 G1 Not alive

M.A. 10/11 NC 11 Mon
MTS: inguinal, pelvic and liver

#3 Calf 15.3 4.157.2 4/4 CR 5 24.0/25.7 G1 Alive

L.G. Heel 14.0 43.548.2 3/3 CR 20.0/21.5 G3 36 Mon
Foot 13.0 51.051.5 4/4 CR 20.0/21.2 G3 MTS: inguinal
sole

#4 Leg 14.3 16.251.1 6/9 CR 7 22.0/21.2 G1 Alive

M.T.M. 1/9 PR 23 Mon
2/9 NC MTS: inguinal

#5 Heel 16.3 22.769.3 10/20 CR 2 24.0/27.5 G3 Not alive

M.C.G. 5/20 PR 4 Mon
5/20 NC MTS: CNS and skin

#6 Thigh 13.6 N1: 2/2 CR 6 24.0/20.8 G1 Alive

37.440.8
A.E.S. N2: 12 Mon
25.733.1
MTS: skin

#7 Ankle 14.8 36.455.7 1/10 CR 2 24.0/23.6 G3 Alive

A.P. 2/10 PR 11 Mon
7/10 NC MTS: skin

CB, average boron concentration during irradiation; NC, no change; MTD, maximum tolerable dose; PD, progressive disease; MDD, maximum delivered dose; TIFP, time to in
eld progression; NA, not available; TOFP, time outside eld progression; CR, complete response; Mon, months; PR, partial response; MTS, metastatic spread; CNS, central
nervous system.
 ARTICLE IN PRESS
S52 P.R. Menendez et al. / Applied Radiation and Isotopes 67 (2009) S50S53
calculated according to the described procedure (Gonzalez et al.,
2004a).
2.5. BPA-F infusion-patient irradiation
All patients received a 14g/m2 BPA-F IV infusion during
90 min. Blood samples were taken before and after the irradiation.
Vital signs (pulse oximetry, heart rate) were monitored during
infusion and irradiation. Tumor biopsy samples were ob-
tained after the irradiation for boron concentration analysis
in some patients. Irradiation times ranged from 50 min up to
85 min.
For estimation of gamma dose distribution, a set of TLDs 700
was put on different parts of the patients body, outside the
external beam port.
Patients follow-up consisted in monthly clinical exam, and
image procedures according to medical criteria.
Fig. 1. Patient ]3. Top: calf, middle: heel, bottom: foot sole. (a) before BNCT, (b) after 1 month, (c) after 6 months. Note the clinical response at these times and the G3
toxicity in heel and sole solved at 6 months evaluation.
3. 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 rst three patients performed tumor biopsy. The
range of tumor/blood boron concentration ratios (T/B) were
1.72.5 at 2 h 45 min after infusion started for patient 1, 2.44.1
at 5 h for patient 2 and 2.73.2 at 10 h for patient 3. T/B for patient
1 was taken in a separate biodistribution study a few weeks before
BNCT.
A T/B 3.5 was used to be consistent with mean values
reported in the literature (Busse et al., 1997; Liberman et al.,
2004). Nevertheless, these values show a signicant dispersion
probably caused by the inhomogeneity of boron uptake in the
tumor (Fukuda et al., 1999; Busse et al., 1997; Liberman et al.,
2004; Mallesh et al., 1994). Nodular melanoma might have a lower
T/B ratio, according to our results, but more experimental data
 ARTICLE IN PRESS
P.R. Menendez et al. / Applied Radiation and Isotopes 67 (2009) S50S53
would be needed (Liberman et al., 2004). A statistical analysis
carried out by Gonzalez et al. (2004b) in 39 nodules in one patient
with nodular melanoma resulted in a most probable T/B value of
3.0570.46 (95% condence interval). Further statistical studies
involving all patients in current protocol, as well as autoradio-
graphy measurements are in progress to improve the reliability of
the estimated T/B values and to compare them with the clinical
outcome. Table 1 summarizes patient characteristics and outcome
of the ten treated areas.
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. The calculated gamma dose rate was about 20%
of the total skin dose, while in the tumor represented 7% of the
total dose. This calculation was carried out using skin kerma-to-
dose factors and assuming charged particle equilibrium in the
5 mm layer of skin, thus the gamma dose is overestimated.
Nevertheless, it was considered to be a conservative approach to
the dose calculation in normal tissue, producing a negligible
difference in the calculated tumor doses. Mean difference
between maximum tolerable dose and maximum delivered dose
(MTD/MDD) was 0.13% (range 15.3% to +12.7%). The latter was
obtained from retrospective dose calculations based on the nal
blood 10B pharmacokinetic proles for every patient.
Overall response was observed in 69.3% of the nodules dened as a
target, with 30.7% of additional no-changed tumours. No progression
of disease was observed inside treatment elds along the follow-up.
Acute grade 3 toxicity (ulceration) was observed at heel, foot sole
and ankle in patients 3, 5 and 7. This could be explained in part by
the fact that in these areas skin received a higher mean dose than in
the other cases, and also by a different tolerance to radiotherapy for
these anatomical areas. Interestingly for patient ]3, just grade 1 skin
toxicity was observed at the level of the calf, where the maximum
normal tissue dose was 25.7 Gy-Eq, supporting the idea that not just
the dose level can explain the different pattern of toxicity (Fig. 1). Of
note is the fact that patient 3 suffered vitiligo, a disease that may
increase skin sensitivity to radiation therapy. Grade 3 toxicity solved
slowly, but all patients achieved a complete healing. As a result of
our clinical observations, 24 Gy-Eq was considered the prescription
dose to normal skin.
4. 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 benet 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
S53
boron concentration measurements in blood samples. This trial is
supported in part by the Agencia de Promocion Cientca y
Tecnologica.
References
Archambeau, J., Pezner, R., Wasserman, T., 1995. Pathophysiology of irradiated skin
and breast. Int. J. Radiat. Oncol. Biol. Phys. 31, 11711185.
Blaumann, H., Gonzalez, S., Longhino, J., Santa Cruz, G., Calzetta Larrieu, O.,
Bonomi, M., Roth, B., 2004. 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. Med. Phys. 31 (1), 7080.
Busse, P., Zamenhof, R., Madoc-Jones, H., Solares, G., Kiger, S., Riley, K., Chuang, C.,
Rogers, G., Harling, O., 1997. Clinical follow-up of patients with melanoma of
extremity treated in phase I boron neutron capture therapy protocol. In:
Larson, B., Crawford, J., Weinreich, R. (Eds.), Advances in Neutron Capture
Therapy, vol. I. Elsevier, pp. 6064.
Fukuda, H., Honda, C., Wadabayashi, N., Kobayashi, T., Yoshino, K., Hiratsuka, J.,
Takahashi, J., Akaizawa, T., Abe, Y., Ichihashi, M., Mishima, Y., 1999.
Pharmacokinetics of 10B-p-boronophenylalanine in tumors, skin and blood
of melanoma patients: a study of boron neutron capture therapy for malignant
melanoma. Melanoma. Res. 9, 7583.
Gonzalez, S.J., Santa Cruz, G.A., Kiger III, W.S., Goorley, J., Palmer, M., Buse, P.,
Zamenhof, R., 2002a. NCTPlan, the new PC version of MacNCTPlan: improve-
ments and verication of a BNCT treatment planning system. In: Proceedings
of the 10th International. Congress on Neutron Capture Therapy for Cancer,
Monduzzi Editore, Bologna, pp. 557561.
Gonzalez, S., Santa Cruz, G., Kiger III, W., Zamenhof, R., 2002b. A new
computational tool for constructing dosevolume histograms using combina-
torial techniques. In: Proceedings of the 10th ICNCT, Monduzzi Editore,
Bologna, pp. 629633.
Gonzalez, S., Bonomi, M., Santa Cruz, G., Blaumann, H., Calzetta Larrieu, O.,
Menendez, P., Jimenez Rebagliati, R., Longhino, J., Feld, D., Dagrosa, M.,
Argerich, C., Castiglia, S., Batistoni, D., Liberman, S., Roth, B., 2004. First BNCT
treatment of a skin melanoma in Argentina: dosimetric analysis and clinical
outcome. Appl. Radiat. Isot. 61, 11011105.
Gonzalez, S., Carando, D., Bonomi, M., 2004. A new approach to determine tumor-
to-blood 10B concentration ratios from clinical outcome of a BNCT treatment.
Appl. Radiat. Isot. 61, 923928.
Habermalz, H., Fischer, J., 1976. Radiation therapy of malignant melanoma:
experience with high individual treatment doses. Cancer 38, 2258.
Hiratsuka, J., Fukuda, H., Kobayashi, T., Yoshino, K., Honda, C., Ichihashi, M.,
Mishima, Y., 2000. Long term outcome of BNCT for malignant melanoma. In:
Proceedings of 9th International Symposium on Neutron Capture Therapy for
Cancer, Osaka, pp. 165166.
Hornsey, S., 1978. The relationship between total dose, number of fractions and
fraction size in the response of malignant melanoma in patients. Br. J. Radiol.
51, 905.
Liberman, S., Dagrosa, S., Jimenez Rebagliati, R., Bonomi, M., Roth, B., Turjanski, L.,
Castiglia, S., Gonzalez, S., Menendez, P., Cabrini, R., Roberti, M., Batistoni, D.,
2004. Biodistribution studies of boronophenylalanine-fructose in melanoma
and brain tumor patients in Argentina. Appl. Radiat. Isot. 61, 10951100.
Mallesh, J., Moore, D., Allen, B., McCarthy, W., Jones, R., Stening, W., 1994.
The pharmacokinetics of p-boronophenylalanine-fructose in human patients
with glioma and metastatic melanoma. Int. J. Radiat. Oncol. Biol. Phys. 28,
11831188.
Mishima, Y., Ichihashi, M., Hatta, S., Honda, C., Yamamura, K., Nakagawa, T., 1989.
New thermal neutron capture therapy for malignant melanoma: melanogen-
esisseeking 10B moleculemelanoma cell interaction from in vitro to rst
clinical trial. Pigment Cell. Res. 2, 226234.
Overgaard, J., 1980. Radiation treatment of malignant melanoma. Int. J. Radiat.
Oncol. Biol. Phys. 6, 41.
Sause, W.T., Cooper, J.S., Rush, S., Ago, C., Cosmatos, D., Coughlin, C., Janjan, N.,
Lipsett, J., 1991. Fraction size in external beam radiation therapy in the
treatment of melanoma. Int. J. Radiat. Oncol. Biol. Phys. 20, 429.