Robert C. Miller

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.

Hyperthermic potentiation. Biological aspects and applications to radiation therapy

Experimental studies have provided evidence that hyperthermia may be an effective agent, either alone or in combination with ionizing radiation, in the treatment of cancer. Results have shown that temperatures in the range of 42° to 45°C: 1) are cytotoxic, with cell lethality showing little or no dependence on levels of oxygenation; 2) inhibit the recovery of cells from sub‐lethal and potentially lethal radiation damage while enhancing the levels of lethal damage; and 3) may be combined with x‐irradiation in a manner to improve therapeutic ratios. The observed interaction between hyperthermia and x‐rays may in part be due to differences in the Age Response Functions and reassortment of cycling cells to these two agents. Hyperthermia may also greatly change repopulation and re‐oxygenation parameters in irradiated tumor and normal tissue volumes. An overall consideration of these and other factors is essential in the design of optimal schedules of combined hyperthermia and x‐irradiation treatments in the management of malignant disease.

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.

Bilateral primary germ cell testicular tumors: report of four cases and review of the literature.

Bilateral primary germ cell tumors of the testicle are rare. The last comprehensive review of the literature (1955) revealed a 1.6% incidence. However, during the past twenty years, cases have been reported more often, raising the questions of increased frequency due to prolonged survival following surgery and/or roentgen therapy for unilateral tumors. A search of the medical journals during the past two decades fails to show any increased frequency of bilaterality (1.56%). All general combinations of cell types may occur and the tumors may appear simultaneously or sequentially. Successive seminomas are seen more often followed in frequency by concurrent seminomas. Although 50% of the second primaries were diagnosed within five years, 3% of the patients developed the second tumor after 20 years, stressing the need for extended follow‐up. Factors affecting the diagnosis, management and prognosis of bilateral testicular tumors are discussed. Four additional cases of bilateral germ cell tumors are described.

Adriamycin--irradiation cutaneous complications

Four cases of abnormally severe skin reactions including an instance of skin necrosis occurred in patients with breast cancer who were treated with cyclophosphamide, adriamycin and irradiation concurrently following mastectomy. These unusual skin reactions apparently resulted from the interaction of radiation with adriamycin and prompted us to modify both the radiation dose and the timing of administration of chemotherapy. To date, no unusual or severe skin reactions have been observed in 14 patients who have received chemotherapy with adriamycin plus radiation in accord with this modified treatment plan.

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.

p-Azidophenylglyoxal-Epidermal Growth Factor: A Photoactivatable Affinity Crosslinking Reagent

A photoaffinity derivative of highly purified 125I-labelled epidermal growth factor (125-I-EGF) has been synthesized. The heterobifunctional crosslinking reagent p-azidophenylglyoxal (PAPG) was bound to arginine residues in 125I-EGF. PAPG-125 I-EGF bound to EGF receptors on rat fibroblasts and human A431 epidermoid carcinoma cells in culture. An apparent decreased affinity of PAPG-125I-EGF for the EGF receptor is in accord with at least one arginine being at or near the EGF receptor binding site. The PAPG-125I-EGF:EGF receptor complexes on rat cells were internalized to the same extent as control EGF:receptor complexes. A431 cells treated with PAPG-125I-EGF were irradiated with ultraviolet light and the labelled proteins were analyzed by SDS-polyacrylamide gel electrophoresis. The 3 major labelled proteins had apparent molecular weights ranging from 75,000 to 200,000. Only the labelling of the 200,000-Mr protein was prevented by the addition of excess unlabelled EGF with the PAPG-125I-EGF. This molecular weight is in agreement with the reported size of the EGF receptor plus EGF. A protein with apparent molecular weight of 100,000 was labelled by 125I-EGF by an unknown mechanism which was dependent on the dose of UV light and blocked by the addition of excess unlabelled EGF.