Justin D. Cohen

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.

Acute changes in glucose uptake after treatment: the effects of carmustine (BCNU) on human glioblastoma multiforme

SummarySequential positron emission tomographic scans with [18F]-2-fluorodeoxyglucose (PET-FDG) were performed on 6 patients with glioblastoma multiforme who were treated with adjuvant BCNU. Scans were acquired before and 24 hours after BCNU. All patients had prior brain irradiation. Ratios between the maximal tumor FDG uptake and the contralateral white matter FDG uptake, the glucose uptake ratio, were determined. Percent changes in the glucose uptake ratio between the baseline scan and the 24 hour post-treatment scan were of prognostic significance. Patients with the largest percent changes in FDG uptake had the shortest survival. In contrast, neither the baseline glucose uptake ratio nor the visual tumor grade accurately predicted length of survival.

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.

Cytotoxicity of diethyldithiocarbamate in human versus rodent cell lines

SummaryDiethyldithiocarbamate (DDTC) and other dithiocarbamates are currently receiving attention as potential adjuncts to traditional chemotherapy. In vitro studies with rodent cancer cell lines have consistently shown that DDTC concentrations of 0.1–1.0μ g/ml are highly cytotoxic. Paradoxically, however, concentrations of 10–100 μg/ml have been significantly less toxic.In the present study, such a ‘biphasic’ pattern was reproduced when 3 rodent cell lines were exposed for 1 hour to 0.001 to 1000 μg DDTC/ml. In contrast, in 7 human cell lines survival decreased steadily with increasing DDTC concentration (in the same dose range) without evidence of a biphasic pattern. These data might have implications for studies in which rodent cell lines are used to model the effects of dithiocarbamates in human tissues.

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.

Whole body hyperthermia and carboplatin: cytotoxicity for murine leukaemia and normal marrow.

Modern radiant heat whole body hyperthermia (WBH) safely permits core body temperatures up to 41.8°C in both animals and man (Robins et al., 1984; Robins et al., 1985). Temperature in this range potently sensitise neoplastic cells to cisplatin cytotoxicity in vitro and in vivo (Meyn et al., 1980; Barlogie et al., 1980). However, cisplatin nephrotoxicity is increased to a similar extent (Wondergem et al., 1988; Gerad et al., 1983) so that WBH offers no therapeutic gain for cisplatin. Temperatures compatible with WBH also markedly sensitise various neoplastic cells to carboplatin cytotoxicity in vitro producing 3 to 5-fold thermal dose modifying factors (Cohen & Robin, 1987; Cohen et al., 1989a; Cohen et al., 1990a). The degree of thermal sensitisation for carboplatin is equivalent to that for cisplatin (Cohen et al., 1989b). Carboplatin is also much less neurotoxic and emetogenic than cisplatin (Calvert et al., 1982; Koeller et al., 1986) an important consideration when using a WBH device which does not require endotracheal intubation or general anaesthesia (Robins et al., 1985). Most importantly, carboplatin produces little or no nephrotoxicity (Calvert et al., 1982; Koeller et al., 1986) even at doses used in autologous bone marrow transplantation (Nichols et al., 1988). Thus, carboplatin appears to be an ideal agent among the platinum analogues for use with WBH (Cohen & Robin, 1987). A key consideration, which has not been addressed previously, is how WBH affects carboplatins therapeutic index, i.e., the drugs relative toxicity for neoplastic vs normal cells. (Beginning with a report in this journal in 1982, only a few studies have ever addressed how WBH affects the therapeutic index of traditional chemotherapeutic agents (Honess & Bleehen, 1982, Honess & Bleehen, 1985a, Honess & Bleenhen, 1985b); none of these studies has involved radiant heat WBH.) Carboplatins dose limiting toxicity is myelosuppression (Calvert et al., 1982; Koeller et al., 1986). Therefore, in the present studies, we determined the effect of WBH and carboplatin, separately or in combination, on peripheral blood leukocyte and platelet counts as well as on the survival of leukaemic and normal bone marrow stem cells treated in vivo as measured by spleen colony formation. For the present studies, WBH was performed as we have previously described in detail (Robins et al., 1984; Steeves et al., 1987). In brief, groups of up to 12 6-8 week old, 20 g female AKR mice were heated simultaneously in a radiant heat device (Enthermics Medical Systems, Menomonee Falls, WI). The mice were not anesthetised or restrained. The mice

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.

Thymidine enhancement of carboplatin cytotoxicity: in vivo studies in normal B6D2 F1 mice

Our laboratory has previously demonstrated that 4-24-h thymidine exposures (50-1000 micrograms/ml) will enhance carboplatin cytotoxicity 2-3.3-fold in vitro. In order to show that these results are clinically applicable, we performed 24-h thymidine infusions with and without carboplatin in B6D2 F1 mice. The mice were evaluated for myelosuppression, weight loss and development of diarrhea. Results obtained demonstrated that thymidine did not enhance systemic carboplatin toxicity. The clinical relevance of these results is discussed.

Whole Body Hyperthermia and Intraperitoneal Carboplatin in Residual Ovarian Cancer

Intraperitoneal (IP) cisplatin-based chemotherapy provides prolonged disease-free survival in some women with residual peritoneal ovarian cancer following systemic chemotherapy. This review presents several considerations which support the combined use of IP carboplatin and whole body hyperthermia in this patient population. This novel treatment approach is predicated on projected advantages which relate to improved therapeutic index.