A case of radiation-induced osteosarcoma treated effectively by boron neutron capture therapy
© Futamura et al.; licensee BioMed Central Ltd. 2014
Received: 8 September 2014
Accepted: 14 October 2014
Published: 4 November 2014
We treated a 54-year-old Japanese female with a recurrent radiation-induced osteosarcoma arising from left occipital skull, by reactor-based boron neutron capture therapy (BNCT). Her tumor grew rapidly with subcutaneous and epidural extension. She eventually could not walk because of cerebellar ataxia. The tumor was inoperable and radioresistant. BNCT showed a marked initial therapeutic effect: the subcutaneous/epidural tumor reduced without radiation damage of the scalp except hair loss and the patient could walk again only 3 weeks after BNCT. BNCT seems to be a safe and very effective modality in the management of radiation-induced osteosarcomas that are not eligible for operation and other treatment modalities.
The incidence of radiation-induced sarcoma has been estimated to be between 0.03% and 0.3% of all patients who have received radiation therapy ,. Radiation-induced osteosarcomas are being encountered more frequently as the use of radiation therapy becomes more common, and the number of long-term cancer survivors has increased. The original diagnostic criteria for radiation-induced osteosarcomas were proposed in 1948 by Cahan et al. , and a short latency period was recently accepted for these tumors ,,. The diagnosis of radiation-induced osteosarcoma must fulfill the following four criteria: (1) the sarcoma must arise in a previously irradiated field, (2) the sarcoma must be histologically distinct from the original neoplasm, (3) there was no evidence of tumor in the involved bone at the time of initial irradiation, and (4) there must be a latency period between the irradiation and the development of the sarcoma at least 3 years.
Radiation-induced osteosarcoma of the head is a devastating complication of radiation therapy. It is very rare but aggressive, with high recurrence and a poor prognosis . The median overall survival time was reported to be 29 months . Osteosarcoma is thought to be radioresistant ,. Therefore, complete surgical resection has been described as the most important prognostic factor  and the first choice of treatment for radiation-induced osteosarcoma. However, if complete surgical resection is difficult (as it was in the present case), adjuvant chemotherapy and radiotherapy should be considered. These therapeutic effects have thus far been found to be insufficient, however. We report here the case of a patient with recurrent radiation-induced osteosarcoma who was treated effectively by boron neutron capture therapy (BNCT).
BNCT is based on the nuclear capture reactions that occur when non-radioactive boron-10 is irradiated with neutrons of the appropriate energy to yield high linear energy transfer (LET) alpha particles (4He) and recoiling lithium-7 (7Li) nuclei. Since these particles have short path-lengths of approximately one cell diameter, their lethality is primarily limited to boron-containing cells. Theoretically, high LET particles have the advantage to overcome radioresistance to photon radiotherapies (such as X-rays). BNCT can thus be regarded as tumor cell-selective and an intensive particle radiation modality with minimal damage to normal tissue, , even for X-ray-resistant tumors. Here we report a successfully treated a case of radiation-induced osteosarcoma by reactor-based BNCT.
Estimated dose distribution at the central axis of neutron-irradiation field
Total dose (tumor) (Gy-eq)
Total dose (skin) (Gy-eq)
Total dose (mucosa) (Gy-eq)
Total dose (brain) (Gy-eq)
Thermal neutron (Gy-eq)
Fast neutron (Gy-eq)
Boron dose (tumor) (Gy-eq)
5.28E + 01
1.24E + 01
2.08E + 01
8.37E + 00
2.13E + 00
1.00E + 00
4.92E + 01
6.79E + 01
2.61E + 01
9.90E + 00
1.87E + 00
1.22E + 00
6.41E + 01
8.06E + 01
3.06E + 01
1.12E + 01
1.64E + 00
1.43E + 00
7.67E + 01
8.47E + 01
3.20E + 01
1.16E + 01
1.35E + 00
1.63E + 00
8.09E + 01
9.00E + 01
3.39E + 01
1.21E + 01
1.17E + 00
1.80E + 00
8.62E + 01
9.38E + 01
3.53E + 01
1.26E + 01
1.11E + 00
1.92E + 00
8.98E + 01
9.55E + 01
3.58E + 01
1.27E + 01
2.02E + 00
9.16E + 01
9.53E + 01
3.57E + 01
1.27E + 01
2.09E + 00
9.14E + 01
9.18E + 01
3.44E + 01
1.22E + 01
2.11E + 00
8.80E + 01
8.62E + 01
3.24E + 01
1.16E + 01
2.10E + 00
8.26E + 01
7.97E + 01
3.00E + 01
1.08E + 01
2.08E + 00
7.62E + 01
7.15E + 01
2.70E + 01
9.79E + 00
1.99E + 00
6.82E + 01
6.77E + 01
2.56E + 01
9.31E + 00
1.95E + 00
6.45E + 01
RBE (relative biological effectiveness) factor
10B (n,α)7 Li: BPA
D: physical absorbed dose (Gy),
ΦThermal: fluence of theraml neutron (cm-2),
N: nitrogen concentration (2%, here)
C: B10 concentration (ppm).
For this patient, we estimated that the minimum tumor and maximum normal brain and skin doses were 67.7, 12.7 and 12.4 Gy-Eq, respectively in the BNCT, simulated from F-BPA-PET imaging and the blood BPA concentration (Table 1).
At one day after the BNCT, the patient's gait disturbance was aggravated. Computed tomography at that time showed aggravation of peri-lesional edema (data not shown). Remarkably, the MRI taken 4 days after the BNCT demonstrated the definitive shrinkage of the mass, but the left cerebellar edema was still there (Figure 2B and B'). We then treated the edema with dehydrators and steroids. The symptoms gradually improved.
At only 3 weeks after the BNCT, the patient was able to walk again stably without aid. The subcutaneous tumor was reduced dramatically without radiation injury of the scalp, with time after BNCT, as shown in Figure 1B and C. The only adverse effect was hair loss in neutron-irradiation field, as shown in Figure 1C. MRI showed the further reduction of tumor and the disappearance of the cerebellar edema (Figure 2C and C'), 3 months after BNCT. Also F-BPA-PET taken 2 months after BNCT showed faint tracer uptake, indicating some metabolic change at least by this treatment (Figure 3A' and B', L/N ratio as 1.2).
Radiation-induced osteosarcoma is not common. It has an aggressive nature, high recurrence rate, and poor prognosis. A standard therapy protocol has not yet been established for non-resectable tumors, but it was reported that particle radiotherapy (treatment with proton and carbon beams) had a therapeutic effect on these tumors ,.
In the present case, the tumor was chemo-resistant and difficult to totally resect because it invaded the left transverse and sigmoid venous sinuses. In addition, the subcutaneously extended tumor invaded the surface of the skin, and we thus suspected that a skin deficit due to surgery was inevitable and that particle radiotherapy for this tumor was likely to cause severe radiation-induced adverse effects on the scalp. The tumor was radiation-induced, and the cerebellum and overlying scalp had a history of X-ray treatment. Moreover, osteosarcomas have the characteristic of being radioresistant, i.e., X-ray-resistant. In light of these medical circumstances, we chose BNCT as the treatment modality for this patient. In the present case, the patient was successfully treated by BNCT without skin damage even though her tumor invaded the superficial scalp.
We recently reported the effectiveness of BNCT for radiation-refractory high-grade meningiomas . In that report, we speculated that the difference in tumor shrinkage between the alpha and lithium particles provided by BNCT and other particles such as carbon and protons may be ascribed to the difference in LET noted above and their fraction size .
Other types of particle radiotherapy and some stereotactic radiotherapies which have been tried recently for tumors were applied as multi-fraction. The reduction of the tumor mass was thus not very prominent, and it was difficult to improve the patients' symptoms by means other than BNCT. BNCT can deliver high dose particles in a tumor-selective fashion in a single session, and in some cases the resulting reduction of the tumor was fast; this rapid shrinkage might contribute to the prompt elimination of symptoms . Indeed, the present patient, within a very short time, exhibited improvement of her gait disturbance due to cerebellar ataxia.
Only a couple of articles were published with regard to pre-clinical study of BNCT for osteosarcoma in in vitro cell culture and animal experiments -. Among them, Russian research group reported successful treatment of dog osteosarcoma case by BNCT. Also only one preliminary report was published with regard to a BNCT-treated osteosarcoma case in head and neck region with limited description, so far . We are not sure of the compound biological effectiveness (CBE) of BPA for osteosarcomas, and we were only able to estimate CBE as being the same for glioblastoma (i.e., 3.8)  as we did for high-grade meningioma . For the estimation of the prescribed dose for this case, we adopted the reported value of CBE and relative biological effectiveness of neutron itself for tumors and normal tissues . Thereafter the estimated tumor dose was uncertain in this case. However, as a result of the BNCT, the tumor shrank rapidly, the patient's clinical symptoms improved, metabolically scarce uptake of the amino-acid tracer was observed in the follow-up PET imaging and no serious damage was observed in the scalp and brain, so far at 6 months after BNCT, although the observation period was short.
Based on this outcome, we found that BNCT was an effective treatment for our patient. However, careful follow-up or the use of bevacizumab may be necessary in some cases , because WBRT that has been already performed may cause brain radiation necrosis.
We experienced only a case of successful treatment of BNCT for radiation-induced osteosacoma. Hopefully these potential therapeutic effects will be applicable for non-radiation-induced osteosarcomas which are generally refractory for other treatment modalities.
BNCT is an effective treatment for non-resectable radiation-induced skull osteosarcoma. We suggest that BNCT is the only effective therapy for tumors that have invaded the skin. Further applications of BNCT for similar cases are expected.
S-IM conceived of the study and participated in the follow-up of the patient. GF, SK, NK, MS and KO applied BNCT in the atomic reactor. YS simulated BNCT dose. HS and TK participated in patient care in the hospital. MT and TT referred the patient for S-IM and also participated in the patient care and follow-up at the out-patient clinic. All authors read and approved the final manuscript.
We appreciate Dr. Silva Bortolussi, National Institute for Nuclear Physics (INFN) Section of Pavia, Italy for the critical reading of the manuscript and fruitful discussion.
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