Cynthia L. Schmitt

A new technological approach to radiant heat whole body hyperthermia.

A new methodology for administering radiant heat whole body hyperthermia (WBH) in humans is described. The technology utilized circulates hot water in a cylinder constructed from copper tubing; the design incorporates a counter current distribution system to maintain thermal constancy. The tubing is coated with a temperature resistant high emissivity finish. Other features include a humidification system to eliminate evaporative heat losses. Data accrued from initial evaluation of this apparatus with a canine model shows that there was no detectable WBH-related hematological, biochemical or physiological toxicity. The perceived advantages of this WBH-system are discussed.

Adjunctive therapy (whole body hyperthermia versus lonidamine) to total body irradiation for the treatment of favorable b-cell neoplasms: a report of two pilot clinical trials and laboratory investigations

Based on earlier clinical and preclinical investigations, we designed two different pilot trials for patients with nodular lymphoma or chronic lymphocytic leukemia. These studies evaluated the use of either 41.8 degrees C whole body hyperthermia (WBH), or the nonmyelosuppressive chemotherapeutic drug, lonidamine (LON), as an adjunct to total body irradiation (TBI) (12.5 cGy twice a week, every other week for a planned total dose of 150 cGy). Whole body hyperthermia was initiated approximately 10 min after total body irradiation; lonidamine was administered orally (420 mg/m2) on a daily basis. Although entry to the studies was nonrandomized, the two patient populations were accrued during the same time frame and were comparable in terms of histology, stage of disease, performance status, and prior therapy. Of 8 patients entered on the TBI/WBH study, we observed 3 complete responses (CR), 4 partial responses (PR), and 1 improvement (i.e., a 48% decrease in tumor burden). Of 10 patients entered in the TBI/LON study, there was 1 CR and 4 PR. For the TBI/WBH study, myelosuppression was not treatment-limiting; there were no instances of infection or bleeding and platelet support was never required. The median survival time for the TBI/WBH study is 52.5 months based on Kaplan Meir estimates. Two patients remain in a CR. The median time to treatment failure (MTTF) is 9.4 months (90% confidence interval = 7-15.4 months). In the TBI/LON study, 50% of patients receiving TBI required treatment modification due to platelet-count depression during therapy, but there were no instances of infection or bleeding. Frequently observed LON-related toxicities included myalgias, testicular pain, photophobia and ototoxicity. For the TBI/LON study, median survival is 7.6 months; MTTF was 2.4 months. In analyzing the results of these pilot studies, our subjective clinical impressions lead to the hypothesis that WBH protected against TBI-induced thrombocytopenia during therapy, whereas LON had no effect on TBI-induced myelosuppression. This speculation was tested and confirmed in a series of in vitro and in vivo experiments.

Tumoricidal interactions of hyperthermia with carboplatin, cisplatin and etoposide

Interactions of hyperthermia with carboplatin, cisplatin and etoposide were investigated in vitro in JM, a human, T cell, lymphoblastic cell line. Thermal enhancement ratios (TER) for carboplatin killing increased with temperature (2.3 at 40.5 degrees C, 3.2 at 41.8 degrees C) and were similar to those for cisplatin killing (2.6 at 40.5 degrees C, 3.6 at 41.8 degrees C). In a separate experiment, cytotoxicity was additive when carboplatin and cisplatin were given simultaneously at 37 degrees C and at 41.8 degrees C. Etoposide, which synergizes with platinum agents, did not have supra-additive cytotoxic interactions with hyperthermia. The data presented are relevant to the conduct of clinical hyperthermia trials.

Temperature distribution during radiant heat whole-body hyperthermia: experimental studies in the dog.

A radiant heat system for whole-body hyperthermia (WBH) has been safely and effectively used in mice, pigs and humans. This report details our adaptation of this methodology to dogs. Mongrel dogs were used to study different anaesthesia methods including spontaneous ventilation with or without intubation, as well as mechanical ventilation. Temperature distribution was studied during 42 degrees C WBH; intraabdominal, liver, bone marrow, brain, rectal, lung, oesophageal and skin temperatures were monitored. When a target temperature of 42 degrees C was achieved, temperature gradients between organs were minimal with the possible exception of bone marrow. Results obtained are consistent with the concept that the liver is a major source of metabolic heat production. The establishment of a dog model for WBH allows for physiological and pharmacological studies. The existence of spontaneous neoplasms should promote the use of this species for trials combining hyperthermia with other modalities.

Effect of hyperthermia in vitro and in vivo on adenine and pyridine nucleotide pools in human peripheral lymphocytes

Hyperthermia has been shown in vitro and in vivo to potentiate the effects of ionizing irradiation. Previous studies found that hyperthermia alters the metabolism of adenosine diphosphate (ADP)‐ribose polymers required for recovery from DNA damage and that poly(ADP‐ribose) polymerase activity is very sensitive to cellular nicotinamide‐adenine dinucleotide (NAD) levels. Thus, the effect of 41.8°C hyperthermia in vitro and in vivo on NAD and adenosine triphosphate (ATP) levels was studied in human peripheral lymphocytes. In vitro studies showed significant decreases in oxidized NAD (NAD+) and ATP levels after heating that simulated a clinical whole‐body hyperthermia (WBH) treatment. This nucleotide depletion could not be attributed to nucleotide leakage or increased enzymatic NAD+ consumption. As the reduction of NAD observed was sufficient to decrease poly(ADP‐ribose)polymerase activity by 50%, the studies were extended to clinical cases. Cellular NAD+ and ATP were measured in previously stored lymphocytes obtained from four patients before and after WBH; a statistically significant decrease in NAD+ was observed after WBH which quantitatively agreed with the in vitro results. Based on these results a prospective study was done in three patients; NAD+ was extracted immediately on sample collection, and the kinetics of WBH‐induced NAD depletion were studied. These data, which agree quantitatively with the laboratory results, are presented.

A hyperthermia study of differential sensitivity and thermotolerance in AKR murine leukemia and normal bone marrow cells

It has been previously demonstrated that AKR leukemia (lymphoma) cells are more sensitive than normal bone marrow cells to hyperthermic killing at 41.8 degrees C and 42.5 degrees C in vitro. This differential heat sensitivity might be explained by a greater ability to induce thermotolerance (TT) in normal versus neoplastic hematopoetic cells. We tested this hypothesis using the spleen colony methodology in the AKR murine model. A greater heat sensitivity of leukemia in comparison to normal bone marrow cells was observed at 42.5 degrees C; this observation agrees with previous reports. However, using a preincubation temperature of 40.0 degrees C for 120 min did not result in the induction of TT in either normal bone marrow (AKR) cells or AKR leukemia cells. The rationale for the choice of preincubation temperatures and times, as well as the clinical implications of these results are discussed.

Changes in mood state following whole-body hyperthermia

Mood states of cancer patients were assessed pre- and post-41.8 degrees C whole-body hyperthermia using the Profile of Mood States questionnaire. Results demonstrated a statistically significant increase in fatigue associated with decreased vigour which returned to baseline values by 72 h. In contrast, a significant improvement in depression was evident through 72 h following treatment. The relationship of this result to earlier studies of WBH-induced beta-endorphin is discussed.

Beta-blockade during whole-body hyperthermia: A toxicity study in the dog

A radiant heat device (RHD) for whole-body hyperthermia (WBH) has been safely and effectively used with a dog model. The cardiovascular changes which occur in the dog during WBH--including heart rate, blood pressure, cardiac output, stroke volume and ejection fraction--agree qualitatively and quantitatively with changes observed in previous WBH-RHD studies done in pigs and humans. We elected to study the effect of propanolol in dogs during WBH in order to evaluate this drugs potential use in human cancer patients who are ineligible for WBH because of coronary artery disease. This report details cardiovascular changes which occur with beta-blockade during 42 degrees C WBH in the dog. Our results show that the level of beta-blockade needed to control heart rate during WBH produces acute cardiovascular decompensation.