With the rapid development of clinical hyperthermia for the treatment of cancer either alone or in conjunction with other modalities, a means of measuring a thermal dose in terms which are clinically relevant to the biological effect is needed. A comparison of published data empirically suggests a basic relationship that may be used to calculate a "thermal dose." From a knowledge of the temperature during treatment as a function of time combined with a mathematical description of the time-temperature relationship, an estimate of the actual treatment calculated as an exposure time at some reference temperature can be determined. This could be of great benefit in providing a real-time accumulated dose during actual patient treatment. For the purpose of this study, a reference temperature of 43 degrees C has been arbitrarily chosen to convert all thermal exposures to "equivalent-minutes" at this temperature. This dose calculation can be compared to an integrated calculation of the "degree-minutes" to determine its prognostic ability. The time-temperature relationship upon which this equivalent dose calculation is based does not predict, nor does it require, that different tissues have the same sensitivity to heat. A computer program written in FORTRAN is included for performing calculations of both equivalent-minutes (t43) and degree-minutes (tdm43). Means are provided to alter the reference temperature, the Arrhenius "break" temperature and the time-temperature relationship both above and below the "break" temperature. In addition, the effect of factors such as step-down heating, thermotolerance, and physiological conditions on thermal dose calculations are discussed. The equations and methods described in this report are not intended to represent the only approach for thermal dose estimation; instead, they are intended to provide a simple but effective means for such calculations for clinical use and to stimulate efforts to evaluate data in terms of therapeutically useful thermal units.

Thermal dose determination in cancer therapy

https://febs.onlinelibrary.wiley.com/doi/epdf/10.1016/j.febslet.2007.05.039

The heat shock protein 70 family: Highly homologous proteins with overlapping and distinct functions

https://repub.eur.nl/pub/9955/12181239.pdf

Heating the patient: a promising approach?

Physics of Radiology

There are great differences in heat sensitivity between different cell types and tissues. However, for an isoeffect induced in a specific cell type or tissue by heating for different durations at different temperatures varying from 43-44 degrees C up to about 57 degrees C, the duration of heating must be increased by a factor of about 2 (R value) when the temperature is decreased by 1 degrees C. This same time-temperature relationship has been observed for heat inactivation of proteins, and changing only one amino acid out of 253 can shift the temperature for a given amount of protein denaturation from 46 degrees C to either 43 or 49 degrees C. For cytotoxic temperatures <43-44 degrees C, R for mammalian cells and tissues is about 4-6. Many factors change the absolute heat sensitivity of mammalian cells by about 1 degrees C, but these factors have little effect on Rs, although the transition in R at 43-44 degrees C may be eliminated or shifted by about 1 degrees C. R for heat radiosensitization are similar to those above for heat cytotoxicity, but Rs for heat chemosensitization are much smaller (usually about 1.1-1.2). In practically all of the clinical trials that have been conducted, heat and radiation have been separated by 30-60 min, for which the primary effect should be heat cytotoxicity and not heat radiosensitization. Data are presented showing the clinical application of the thermal isoeffect dose (TID) concept in which different heating protocols for different times at different temperatures are converted into equivalent minutes (equiv) min at 43 degrees C (EM(43)). For several heat treatments in the clinic, the TIDs for each treatment can be added to give a cumulative equiv min at 43 degrees C, namely, CEM(43). This TID concept was applied by Oleson et al. in a retrospective analysis of clinical data, with the intent of using this approach prospectively to guide future clinical studies. Considerations of laboratory data and the large variations in temperature distributions observed in human tumors indicate that thermal tolerance, which has been observed for mammalian cells for both heat killing and heat radiosensitization, probably is not very important in the clinic. However, if thermal tolerance did occur in the clinical trials in which fractionation schemes were varied, it probably would not have been detected because with only the two-three-fold change in treatment time that occurs when comparing one versus two fractions per week, or three versus six total fractions, little difference would be expected in the response of the tumors since both thermal doses were extremely low on the dose-response curve. Data are shown which indicate that in order to test for thermal tolerance in the clinic and to have a successful phase III trial, the thermal dose should be increased about five-fold compared with what has been achieved in previous clinical trials. This increase in thermal dose could be achieved by increasing the temperature about 1.5 degrees C (from 39.5 to 41.0 degrees C in 90% of the tumor) or by increasing the total treatment time about five-fold. The estimate is that 90% of the tumor should receive a cumulative thermal dose (CEM(43)) of at least 25; this is abbreviated as a CEM(43) T(90) of 25. This value of 25 compares with 5 observed by Oleson et al. in their soft tissue sarcoma study. Arguments also are presented that thermal doses much higher than the CEM(43) T(90) induce the hyperthermic damage that causes the tumors to respond, and that the minimum CEM(43) T(90) of 25 only predicts which tumors that receive a certain minimal thermal dose in <90% of the regions of the tumors will respond. For example, in addition to a minimal CEM(43) T(90) of 25 a minimum CEM(43) T(50) of about 400 also may be required for a response. Finally, continuous heating for approximately 2 days at about 41 degrees C during either interstitial low dose-rate irradiation or fractionated high dose-rate irradiation, which we estimate could give a CEM(43) of 75, should be considered in order to enhance heat radiosensitization of the tumor as well as heat cytotoxicity. In order to exploit the use of hyperthermia in the clinic, we need a better understanding of the biology and physiology of heat effects in tumors and various normal tissues. As an example of an approach for mechanistic studies, one specific study is described which demonstrates that damage to the centrosome of CHO cells heated during G(1) causes irregular divisions that result in multinucleated cells that do not continue dividing to form colonies. This may or may not be relevant for heat damage in vivo. However, since normal tissues vary in thermal sensitivity by a factor of 10, similar approaches are needed to describe the fundamental lethal events that occur in the cells comprising the different tissues.

Arrhenius relationships from the molecule and cell to the clinic.

Forty-three patients with advanced, locally accessible neoplasms were treated in a Phase I clinical trial employing hyperthermia alone or hyperthermia combined with either high-dose-rate external beam or low-dose-rate interstitial radiotherapy (interstitial thermoradiography). All patients had failed previous conventional therapeutic attempts, including various combinations of surgery, chemotherapy and radiation therapy. Many had received tolerance or near tolerance levels of prior radiation that restricted dose prescriptions in this trial to subcurative values. A number of tumors with different histologies were treated, including squamous cell carcinoma (14), adenocarcinoma (14), melanoma (8), malignant fibrous histiocytoma (2), and sarcoma (5). The response evaluation criteria used included no response (NR--less than 50% decrease in tumor volume), partial response (PR--50% less than or equal to tumor volume reduction less than 100%) and complete response (CR--complete tumor disappearance). For all tumor types, hyperthermia therapy alone resulted in a total response rate of 45% (27% PR, 18% CR). Hyperthermia combined with high-dose-rate external beam radiotherapy yielded a total response rate of 80% (53% PR, 27% CR). Seventeen patients treated with interstitial thermoradiography displayed a 100% total response rate (29% PR, 71% CR). By tumor histologies for all treatment groups, total response rates have ranged from 50% to 79% for all types except melanoma, which has shown a 100% (8/8) response rate to date. Response durations have varied from one to 24 months. Twelve of the 43 patients remain alive; three have no evidence of disease (NED) while nine have either stable local disease or are NED in the treated volumes but have metastatic disease. Complications have been minimal and have included one third-degree burn and three second-degree burns from fringing RF fields, one vaginal-rectal fistula, a superficial focal soft tissue necrosis, and some minor blistering. The results of this Phase I trial demonstrate that hyperthermia alone or combined with radiation can be safely applied in the treatment of malignant disease. Most importantly, the data suggest that hyperthermia, especially when combined with interstitial thermoradiography, can yield remarkable results in the eradication of local cancers.

Clinical hyperthermia: results of a phase I trial employing hyperthermia alone or in combination with external beam or interstitial radiotherapy.

A total of 130 dogs and cats with squamous cell carcinomas, melanomas, fibrosarcomas, mammary adenocarcinomas, or mast cell sarcomas were randomized to receive radiation (XRT) or heat plus XRT Time-temperature data for each monitored tumor location were converted to degree-minutes or equivalent min at 43° (Eq43) Response rates and durations of response were compared for subgroups of histology, volume, site, and heat treatment method Thermal gradients existed in all heated tumors The influence of these gradients on tumor response was examined by correlation of response with degree-minutes and Eq43 minima, maxima, averages, and ranges A pattern emerged from these analyses linking dose minima, maxima, and ranges with prognostic subgroups as classified by volume, site, or treatment method The data indicated that the coolest part of the tumor governed the biological response to combined heat + XRT Tumors which received a minimum of 35 Eq43 had significantly longer durations of response than did those receiving XRT alone or

https://cancerres.aacrjournals.org/content/canres/44/1/43.full.pdf

Importance of Minimum Tumor Temperature in Determining Early and Long-Term Responses of Spontaneous Canine and Feline Tumors to Heat and Radiation

Continuous exposure of HeLa cells in culture to elevated temperatures (41-45 degrees) results in cell killing which increases exponentially as the time at the elevated temperature increases linearly When cells are returned to 37 degrees after an initial thermal dose, cellular sensitivity to subsequent hyperthermic doses is reduced Cell inactivation rates for cultures previously treated with 44 degrees for either 05 or 1 hr followed by incubation at 37 degrees for 2 hr, showed D0's of 11 and 15 hr, respectively, for subsequent thermal treatments at 44 degrees Cultures receiving no prior hyperthermic dose had a D0 of 05 hr for treatments at 44 degrees for up to 35 hr The viable progeny of cells treated with 44 degrees for 1 hr, however, had the same sensitivity to thermal doses at 44 degrees as did previously unheated cells These results and others demonstrate that (a) single thermal dose produce a state of thermotolerance in HeLa cells to subsequent hyperthermic doses; (b) the degree of thermotolerance produced is dependent on the magnitude (ie, temperature and time at the elevated temperature) of the first thermal dose; (cy thermotolerance does not develop at the elevated temperature but requires a return of culture temperatures to 37 degrees; (d) cellular acquisition of thermal tolerance is dependent on cell metabolism, as demonstrated by an inhibition of the effect at 0 degrees; and (e) this effect is a transient phenomenon which is lost as cells divide following the first thermal dose

https://cancerres.aacrjournals.org/content/canres/36/3/1035.full.pdf

A transient thermotolerant survival response produced by single thermal doses in HeLa cells.

Systemic hyperthermia in man may occur by accident, as in heat stroke or malignant hyperthermia during general anesthesia, or it may be therapeutically induced (fever therapy). The latter has been used infrequently since the advent of antibiotics, except recently for treatment of cancer. Local or regional heating combined with x irradiation for human cancer therapy has been sporadically reported for over 60 years, but has not found its place in clinical medicine possibly due to technical limitations in heat production and dosimetry. Preliminary results are reported for treatment of spontaneous animal tumors with radiofrequency current fields and x irradiation.

Prospects for hyperthermia in human cancer therapy. Part I: hyperthermic effects in man and spontaneous animal tumors.

Laboratory data from studies of hyperthermia as a potential antitumor agent indicate that: (a) tumor cells may be more sensitive to heat than normal tissue; (b) hyperthermia enhances response to irradiation and can increase the therapeutic ratio; (c) cells are most sensitive to hyperthermia during the S-phase, when they are resistant to ionizing radiations; (d) the oxygen effect is absent for hyperthermic cell killing, and radiation effects are less oxygen-dependent when potentiated by heat treatment; and (e) biological damage changes more rapidly at temperatures above 43 degrees C. Methods of heat production and dosimetry need to be refined further before these findings can be put to practical use in tumor therapy.

William G. Connor

Papers

Clinical hyperthermia: results of a phase I trial employing hyperthermia alone or in combination with external beam or interstitial radiotherapy.

Importance of Minimum Tumor Temperature in Determining Early and Long-Term Responses of Spontaneous Canine and Feline Tumors to Heat and Radiation

A transient thermotolerant survival response produced by single thermal doses in HeLa cells.

Prospects for hyperthermia in human cancer therapy. Part I: hyperthermic effects in man and spontaneous animal tumors.

Prospects for hyperthermia in human cancer therapy. Part II: implications of biological and physical data for applications of hyperthermia to man.