Induction thermochemotherapy increases therapeutic gain factor for the fractionated radiotherapy given to a mouse fibrosarcoma

Purpose: It has been shown that thermochemotherapy (TC) given prior to radiation reduces the number of clonogens, with a resultant decrease in the tumor control radiation dose. The purpose of this article was to investigate using an animal tumor model how this clonogen reduction affects subsequent fractionated radiotherapy, including repopulation of surviving clonogens, and whether the induction TC can increase the therapeutic gain factor (TGF). Methods and Materials: The single-cell suspensions prepared from the fourth- generation isotransplants of a spontaneous fibrosarcoma, FSa-II, were transplanted into the C3Hf/Sed mouse foot. TC was given by heating tumors at 41.5°C for 30 min immediately after an intraperitoneal injection of cyclophosphamide (200 mg/kg) when tumors reached an average diameter of 4 min. Fractionated radiotherapy (R) with equally graded daily doses was initiated 24 h after TC either in air (A) or under hypoxic conditions (H). The 50% tumor control dose (TCD₅₀) and the radiation dose to induce a score 2.0 reaction (complete epilation with fibrosis) in one-half of irradiated animals, RD₅₀(2.0), were obtained, and the TGF was calculated. Our previous results on the fractionated radiotherapy using the same tumor system served as controls. Results: The TCD₅₀(A, single dose) and TCD₅₀(H, single dose) following TC+R were 52.2 and 57.3 Gy, respectively, which were 14.0 and 20.4 Gy lower than those following radiation alone. The TCD₅₀(A, TC+R) increased only slightly when the number of fractions was increased from one to 10 doses, and all TCD₅₀s were significantly lower than the TCD₅₀(A, R alone). Both TCDs0(H, TC+R) and TCD₅₀(H, R alone) increased consistently from a single close to 20 doses, but all TCD₅₀(H, TC+R) were significantly lower than the TCD₅₀(H, R alone). Regarding the normal tissue reaction, the RD₅₀ values both following TC+R and R alone increased consistently from a single dose to 20 daily doses. However, the RD₅₀(TC+R) and RD₅₀(R alone) for each corresponding number of fractions was not significantly different, resulting in the TGFs significantly > 1.0 for combined TC + R treatments, with the exception of 20 daily doses given in air. Conclusion: The induction TC decreased the TCD₅₀ values substantially without altering the RD₅₀ for a late reaction, resulting in an significant increase in the TGF. These results encourage the use of TC as an induction treatment prior to fractionated radiotherapy.