Concurrent Hypofractionated Radiotherapy and 5-Fluorouracil for Advanced Sarcomas of the Bone

Purpose. 5-Fluorouracil (5-FU) has shown radiosensitizing properties in vitro. This paper reports the effects of radiotherapy and concomitant intravenous 5-FU radiosensitization in the treatment of advanced bone sarcomas. Subjects/methods. Four patients with large inoperable bone sarcomas (three chondrosarcomas and one fibrosarcoma) were treated with hypofractionated radiotherapy and concomitant 5-FU bolus injection (300 mg m−2) before each fraction of radiotherapy. A radiation fraction of 5 Gy was given twice a week to a normalized total dose (α/β=4 Gy) of 75 Gy. Results. The regimen was well tolerated, the main toxicity being grade I/II diarrhoea in two cases with pelvic irradiation. Treatment interruption for 1 week was necessary in two cases with pelvic disease but not in two patients treated for sarcoma of the extremities. A complete symptomatic relief was obtained in all cases immediately after the third to the fifth fraction and the median duration was 10 months. Computed tomography scan documented a partial response in 2/4 cases. Discussion. Hypofractionated radiotherapy combined with potential lethal damage inhibitors for bone sarcomas requires further investigation.


Introduction
Sarcom as of the bone are considered to be radioresistant tum ours. T he only curative therapy is surgical resection. 1,2 T he role of radical or pre-operative radiotherapy has been evaluated by several studies showing a 5-year disease-fre e survival of 20± 40% . 3,4 Post-operative chemotherapy has also been used in order to enhance local control and decrease the distant m etastases rate although there is no conclusive evidence of any bene® cial effect. 5 Good results have been reported for tumours in axial sites that are considered inoperable and are treated with radiotherapy or com bined radio-chemotherapy. 6,7 Although 5-¯uorouracil (5-F U) is not effective in bone sarcom as, 8 it has shown radiosensitizing properties in vitro, probably by inhibiting the radiation-induced D N A dam age repair. 9 Here, we report prelim inary results on four locally advanced bone sarcom as treated w ith high dose per fraction radiotherapy and concom itant intravenous 5-FU radiosensitization.

Subjects
Four patients with locally far advanced bone sarcom as were treated w ith high-dose hypofractionated radiotherapy and concom m itant 5-FU chem otherapy. All patients underw ent a detailed clinical and laboratory investigation (including chest and abdomen com puted tom ography (C T) scan). T he patient and tum our characteristics are reported in T able 1. T wo patients refused am putation, two had inoperable tum our (pelvic location). T hree out of four patients had tum our unresponsive to adriamycin/ifosfam ide chem otherapy. The age of the patients ranged from 31 to 58 years and the perform ance status ranged from 2 to 3.
T hree were histologically con® rmed as chondrosarcom as and one as ® brosarcom a, the grade being III for all cases.

Treatment
T he treatment characteristics are reported in T able 2. All cases w ere treated with a 6 M V X-ray linear accelerator and, where feasible, part of the dose was given w ith 15± 25 M eV electrons. A C T scan-base d radiotherapy treatm ent planning was considered for all cases; 5 Gy w ere given per fraction twice a w eek for a total num ber of 10 fractions. The norm alized total dose (NT D ) 10.11 to both the tum our and norm al tissue was calculated for a /b 5 4 G y, although higher values of a /b ratio (4± 10 Gy) have been reported from radioresponsiveness experiments in sarcom a cell lines. 12 The tum our N TD w as 75 G y. An intravenous bolus dose of 300 m g/m 2 of 5-FU w as given 1 h before each fraction of radiotherapy. M etoclopram ide 10 mg w as given intravenously before the injection of 5-FU.
Assessm ent of acute toxicity followed the W H O toxicity scale. 13 Full blood count and biochem ical tests were done weekly. Perform ance status was assessed every 2 weeks. Assessm ent of response was done clinically and with C T scan 4 w eeks after the com pletion of treatment and 4-m onthly thereafter. Patients were followed bim onthly with clinical exam ination, blood tests and chest X-ray.

Results
N o severe haem atological or organ-spe ci® c acute toxicity was observed. G rade I/II skin desquam ation w as also observed in all four patients. G rade I haem atological toxicity (neutropenia and/or anaem ia) was observed in 2/4 cases. D iarrh oea grade I appeared in two patients w ith pelvic disease and was well controlled with oral medication. In these tw o cases the treatment was interrupted for 1 week. N o ® brosis or late sequel has been observed (6± 18 m onths after radiotherapy. The m ain sym ptom atology of all four treated cases w as uncontrollable pain and three patients were under heavy analgesic m edication w ith m orphine. Substantial pain relief was obtained in all four patients im m ediately after the third to ® fth fraction and m orphine was discontinued. T he m edian duration of sym ptom atic control was 10 m onths. CT scan con® rm ed a partial response (50± 95% reduction in two-dim ensional m easurem ent) in 2/4 (50% ) cases. Figure 1(a) and 1(b) show s a case of chondrosarcoma of the iliac bone with partial response 6 m onths after treatment.

D iscussion
Bone sarcomas other than Ewing' s sarcoma are considered to be relatively radioresistant tum ours in which radical treatment is achieved only when surgery is app lied with or without adjuvant radiotherapy or chem otherapy. In a recent study from the N orwegian Radium Hospital, 14 com plete tum our rem oval w as a m ajor prognostic factor. U nfortunately, surgery cannot be applied in bone sarcom as of the axial skeleton, and pelvic tumour location requires extensive am putation w ith severe im pact on the quality of life. In these cases, curative radiotherapy should be tried as an alternative to surgery. A 40% 5-year actuarial survival has been reported by Krochak et al. 3 on 38 chondrosarcom as of bone, treated with conventionally fractionated radiother- apy. However, tum our size has not been analyzed and patients with high-grade tumour had a 5-year survival of 22% .
In the present study, we treated four patients with locally far advanced high-grade bone sarcomas with radical radiotherapy. In order to increase the results of radiotherapy, we used hypofractionation combined with 5-FU radiosensitization. T he N T D w as 75 Gy. Partial response was observed in 2/4 patients. Kinsella et al. 7 reported a study on 10 unresectable bone and soft tissue sarcom as treated with large fraction radiotherapy and m isonidasole radiosensitization. Although no com plete rem ission was observed, stabilization of the disease and com plete sym ptom atic relief w as achieved in 7/10 patients. This is in accordance w ith our results where a long lasting ( . 6 m onths) sym ptom atic relief was obtained in all four cases. In a recent study, Hug et al. 6 treated seven cases of bone tum ours of the axial skeleton with de® nitive radiotherapy using a com bination of protons and photons. Local failure was observed in 2/7 cases showing that a high radiation dose results in good local control. A high local control rate (7/9 patients) has also been reported by the Standford G roup 15 where intra-arterial 5-bro m odeoxyuridine w as given together with hypo fractionated radiotherapy for osteosarcom as. However, extensive local tissue toxicity was observed, including subcutaneous ® brosis, neuropathy and non-healing traum as.
The optimal w ay to treat inoperable sarcom as has not yet been de® ned. It seem s that high-dose radiotherapy offers excellent sym ptom atic relief and results in long-term progression-fre e survival in about 20% of cases. D istant m etastases rem ain a m ain cause of failure in high-grade bone sarcom as. O ur prelim inary experience shows that hypo fractionated radiotherapy for bone sarcom as com bined w ith potential lethal dam age inhibitors m ay have a role in the control of local disease.