William G. Connor

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

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 thermoradiotherapy). 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% ≤ tumor volume reduction < 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 thermoradiotherapy 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 thermoradiotherapy, can yield remarkable results in the eradication of local cancers.

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

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.

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

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.

The Potential of Localized Heating as an Adjunct to Radiation Therapy1

Experimental studies have shown that (a) tumor cells may be more sensitive to heat than normal cells; (b) hyperthermia inactivates cellular repair mechanisms for radiation damage; and (c) heat may lower the OER for ionizing radiation (anoxic cells are at least as sensitive to hyperthermia as oxygenated cells). Localized hyperthemia produced by localized current fields in the range of 100 kHz-10 MHz by direct contact electrodes offers two major advantages: the eletrode configurations may be manipulated to obtain desired thermal dose distributions, and, since the mode of heating is essentially instantaneous, accurate temperature control can be maintained during treatment.

Thermometry considerations in localized hyperthermia.

The introduction of local hyperthermia as a method of cancer therapy implies the necessity of quantitative measurements of the thermal dose. Our intention is to describe the nature of the problem, both physically and physiologically, with illustrations drawn from thermographic measurements in phantoms and in animals. The characteristics of a thermometry calibration facility are described. Some measurement problems associated with conventional thermometer probes are mentioned and several new thermometers which were developed for use in the electromagnetic fields are reviewed. We present some of the concepts that will guide the development of noninvasive thermometry. Systemic hyperthermia is not considered. We recommend that other reviews specifically directed toward localized hyperthermia be prepared on the methods of heating and on thermal physiological problems.

PRELIMINARY RESULTS OF A PHASE III TRIAL OF SPONTANEOUS ANIMAL TUMORS TO HEAT AND/OR RADIATION: EARLY NORMAL TISSUE RESPONSE AND TUMOR VOLUME INFLUENCE ON INITIAL RESPONSE

A Phase III randomized trial was initiated to test the relative efficacies of heat alone, radiation alone and heat plus radiation using spontaneous malignancies in pet animals. Heat alone was inferior to the other two treatment arms as demonstrated by a significantly higher non-response rate and shorter response duration. The ratio of complete response rates (CR) for heat plus radiation to radiation alone or the thermal relative risk (TRR) was greater for tumors greater than 10 cm3 as compared to those less than 10 cm3 (TRR = 4.8 and 1.4, respectively). The overall TRR for complete responses was 2.3. The CR data for the combined therapy arm indicate at least an additive effect between heat and radiation for small tumors but most likely a synergistic effect in the larger tumor group. Based on the data currently available, no significant difference in response duration is observed between the two radiation arms, although a nonsignificant advantage to the combination therapy exists. Normal tissue effects were evaluated by incidence of full moist desquamation within the irradiated volume, late fibrosis and bone necrosis. Since the radiation skin dose depended upon the technique being used it was possible to estimate the dose to achieve moist desquamation in 50% of the animals (DD50) by a logistic regression model as being 3728 +/- 344 rad for radiation alone. Significant lowering of the DD50 was not observed for the addition of heat to radiation. Low patient numbers where intact skin was heated prevented an accurate analysis of the effect, however.

MONITORING OF TISSUE TEMPERATURE DURING HYPERTHERMIA THERAPY

If hyperthermic therapy is to progress beyond merely the recording of anecdotal case histories to a reliable means of treating cancer, it is essential that temperature distributions be determined as a function of time throughout the treated field of the patient. This is necessary for both localized and whole-body hyperthermia. The thermal dose, which is some sort of integrated function of the measured parameters, time and temperature, is not addressed here. Our problem of determining the temperature distribution is complicated by the fact that heterogeneous tissues have differing power absorption parameters, such as resistivity or ultrasonic attenuation, and differing rates of cooling depending upon the distribution of blood perfusion or the proximity of the tissue element to the surface. It is probable that the power absorption parameters are different for tumors than for surrounding normal tissue and that cooling rates due to heat exchange with the blood are less for tumors than for the surrounding normal tissue. Certainly, the latter is true for the necrotic core of large tumors and is plausible in the general case. Furthermore, neither the physiological response of tissue to heating, such as vasodilatation, nor the pathological effects of heating, such as possible destruction of blood vessels, are fully understood. Both affect the thermal distributions that result. Detailed mathematical models similar to those available for radiation dosimetry are plagued by both the complexity of the heterogeneity of the tissues and by the lack of data upon which to base the models. Thus, the temperature distribution as a function of time at every point within the field cannot be calculated because the parameters needed in mathematical interpolation functions are not known. Neither can the temperature the measured at a sufficient number of points because the clinical trauma would be too great and the perturbation of the field would be excessive. Our purpose here is to indicate the techniques that we use for estimating the temperature distributions. We do not attempt a comprehensive review. The first section of the paper deals with thermometer calibrations and quality assurance of these calibrations. The second section gives two clinical cases, which are used to demonstrate our approach to thermal dosimetry and to indicate its features and limitations. In the third section, thermal measurements required in certain biological experiments are illustrated. We conclude the paper by suggesting areas of research that should lead to improved thermal dosimetry in the near future.

Introduction to the use of protons and heavy ions in radiation therapy: Historical perspective

Abstract For over 20 years, medical irradiation using proton and subsequently helium ion beams has been utilized, principally for ablative therapy of the pituitary and most often with the plateau portion of the beam rather than the extended Bragg peak. More recently, cancer radiotherapy using proton beams has seen limited clinical trial in Sweden and more extensive ongoing trials in the Soviet Union.. Pilot studies of extended Bragg peak therapy of neoplastic disease using protons (Harvard cyclotron) and helium ions (184 in. Berkeley synchrocy-clotron) have been underway in this country for about one year. For ions heavier than helium, sufficiently penetrating beams for cancer radiotherapy became available August of 1974 with successful activation of the Bevalac at Berkeley. Extensive preclinical evaluation of the dosimetry and biological properties of these heavier ion beams are being directed toward an evaluation of their suitability for beginning clinical trials, with the latter planned for mid-1977 if results are favorable. Potential therapeutic advantages and the extent to which they are supported by present knowledge of the physical and biological characteristics of heavy charged particle beams will be discussed.

10 MV x-ray beam characteristics from a new 18 MeV linear accelerator.

Abstract The dosimetic properties of interest in a megavoltage therapy X-ray beam are per cent depth dose, skin sparing, penumbra, radiation field flatness and symmetry. The 10 MV X-ray beam from the Varian Associates Clinac 18 Linear Accelerator is studied with regard to these points. The primary points of interest are a 50% depth dose for a 10 × 10 cm 2 field at 18.0 cm in water and a depth of maximum dose of 2.4 ± 0.1 cm in water. Transmission measurements in aluminum and lead yielded 50% transmission thicknesses of 73.2 and 13.4 mm respectively. The flatness of the fields are parametrized as function of field size and depth. Decrement line plots are graphed and isodose curves for selected field sizes are presented.

Patient repositioning and motion detection using a video cancellation system

Abstract A video cancellation technique has been developed for patient repositioning and patient motion detection in radiation oncology departments. The system uses a closed circuit television (CCTV) camera and monitor plus a video disc recorder. The method utilizes the live image from the CCTV and a stored image of the desired treatment set up from the video disc. The images are processed in a video subtraction mode and viewed in cancellation. Repositioning errors of a millimeter are detectable and patient movements of the same magnitude are readily visualized.