[CANCER RESEARCH 40, 2045-2050. June 1980] 0008-5472/80/0040-0000$02.00 MultifractionatedHyperthermiaTreatment of Malignant and Normal Tissue in Vivo1 Jens Overgaard,2 Herman D. Suit,3 and Alexander M. Walker Edwin L. Steele Laboratory of Radiation Biology, Department of Radiation Massachusetts 02114 ABSTRACT Recovery from thermal damage was studied in a methyl cholanthnene-induced fibrosarcoma (FSal) and the surrounding normal tissue. Tumors isotransplanted into the feet of C3H mice were treated in a water bath with two equal fractions of heat given at 2-, 6-, on 24-hr intervals and at 42.5—44.5°. The results were analyzed at 120 days as the 50% tumor control dose and as the dose required to achieve a specified level of normal tissue damage in one-half of the treated animals. The results show a slow and nearly parallel recovery in tumor and normal tissue for split treatments with intervals up to 24 hr. For an intertreatment interval of 6 hr, 50% tumor control dose and 50% response dose values were not different from those for single heat exposure. In fact, for a 2-hr interval, the 50% tumor control dose and 50% response dose values were lower than those for single treatments. This is probably due to short term physiological changes induced by the first heat exposure. For split time intervalsof 24 hn,a moderate degree of repair was notedwith recoveryratios between 1.27 and 1.56. Owing to parallel recovery found in tumors and normal tissue, no significant variations in the therapeutic ratio could be obtained by use of the two fraction schedules studied here. The time temperature relationship for fractionated thermal damage was not different from that seen after a single treatment. The effect of multifractionatedhyperthenmiawas studiedat a temperature of 43.5°. Daily treatments resulted in a pro nounced recovery, with recovery ratios for tumor and two different levels of normal tissue damage at 2.6 to 2.9 for heating in five fractions and 4.2 to 6.3 for heating in the ten fraction schedule. Although an increasing number of fractions tended to result in a greater recovery ratio for normal tissue damage than for tumor, this finding was not statistically signif icant. INTRODUCTION The increasing number of studies on the effect of hyperther mia on solid tumors have yielded new knowledge regarding the time-temperature relationship and the mechanisms of thermal destruction (1 , 16, 18, 19, 21 —23,26, 28). In most of those investigations, a single heat treatment has been used; the effect of fractionated hyperthermic treatment in animal tumors is only sparsely investigated. Consequently, little is known 1Supported in part by Department of Health, Education, and Welfare Grant CAl 331 1 and the Danish Cancer Society. 2 Present address: The Institute of Cancer Research, Radiumstationen, DK 8000 Aarhus C, Denmark. To whom requests for reprints should be addressed. 3 Andres Sorlano Director of Cancer Management, Massachusetts General Hospital. ReCeivedMay 7, 1979; accepted February 28, 1980. Medicine, Massachusetts General Hospital, Harvard Medical School, Boston. about the kinetics of recovery from hyperthermia damage by tumor or normal tissues in vivo. Thrall et a!. (29) observed in a C3H mouse mammary carci noma heated at 44.5° that a single treatment of 51 mm caused more reduction in tumor growth than did 4 daily fractions of 15 mm each. Ovengaand and Overgaard (22, 23) reported no significant difference in the response of diathermy-heated HB mammary carcinoma after a single treatment versus 2 equally large fractions given with a 24-hr interval. Other investigators have also demonstrated thermal tumor damage after use of more than one fraction, but without directly comparing the results with equivalent single-treatment doses (3, 15). In an investigation preliminary to the present study, the effect of fractionated treatment at 43.5° with different intervals was compared to that of a single heat treatment (26). This water bath-heated FSaI fibrosarcoma was evaluated by a TCD504 analysis and showed no recovery for intervals of 2 and 6 hr in a 2-fraction treatment schedule but a moderate recovery for a 24-hr interval. By comparison, recovery from thermal injury in several nor mal tissues was so effective that by 12 to 24 hr there was no residual injury detected by thermal challenge (4, 7). In cell culture, a similar recovery from thermal damage oc curs within a few hr. Furthermore, it has been shown in several in vitro cell lines that mammalian cells may be more resistant to a subsequent heat treatment if given within 24 hr (2, 5, 8—10, 13, 17, 24). This phenomenon is known as thermal tolerance and has recently been described for several normal tissues (4, 12).@ Information on the effect of more than 2 fractions is sparse. Although it has been shown that hyperthermic damage can accumulate when given in several daily fractions (20, 26, 29), both the observation by Thrall et a!. (29) and the preliminary data on the FSaI fibrosarcoma and the normal mouse foot (26) indicate a marked recovery from hyperthermic damage when applied in several daily fractions. Since, in clinical use, hyperthenmia is likely to be given in more than one fraction, knowledge of the recovery pattern in various tumors and normal tissues treated at different temper aturesisneeded. The aims of the present study were: (a) to evaluate the recovery from thermal damage at different temperatures in tumor and normal tissue using split doses at various time intervals; (b) to study the effect of multifractionated heat treat ment in tumor and normal tissue. The experiments were de signed to provide data for examination of therapeutic ratios. 4 The abbreviations used are: TCD@, time at hyperthermia that achieves control of one-half of the treated tumors; RD@,time at hyperthenmia that elicits a specific level of normal tissue reaction in one-half of the treated feet. 5 K. Henle, personal communication. JUNE 1980 2045 Research. on February 25, 2016. © 1980 American Association for Cancer cancerres.aacrjournals.org Downloaded from