The importance of schedule in whole body thermochemotherapy.

PURPOSE: To determine an effective triple-agent schedule combining fever-range whole body thermal therapy (FR-WB-TT) with cisplatin and gemcitabine by optimizing the timing of drug with heat, and drug with drug. MATERIALS AND METHODS: Using an orthotopically implanted syngeneic breast adenocarcinoma in an immunologically normal female Fischer rat model, we investigated various schedules of a thermochemotherapy regimen combining FR-WB-TT with chemotherapy agents, cisplatin and gemcitabine. Differently timed combinations of a) cisplatin with FR-WB-TT, b) gemcitabine with FR-WB-TT, and c) cisplatin with gemcitabine were examined for anti-tumor efficacy and toxicity. A combination of the three agents based on the optimal two-agent schedules was then tested. RESULTS: The greatest primary tumor and axillary metastasis growth delay and lowest toxicity was induced with administration of cisplatin 24 h prior to gemcitabine and cisplatin 24 h prior to simultaneous gemcitabine and FR-WB-TT. Administering cisplatin 24 h prior to gemcitabine was more effective and less toxic than giving the two drugs simultaneously or gemcitabine prior to cisplatin. Survival was greatest when gemcitabine and FR-WB-TT were administered 24 h after cisplatin, even with reduced drug doses. One complete cure resulted from the triple agent treatment. CONCLUSIONS: The relative timing of agents in multiple modality treatments is critically important in achieving tumor control or cures, and in reducing toxicity. Optimizing the relative timing of multiple agents in thermochemotherapy allows use of lower drug doses to achieve maximal anti-tumor efficacy and minimal toxicity.

The effect of whole-body hyperthermia combined with 'metronomic' chemotherapy on rat mammary adenocarcinoma metastases.

Many women diagnosed with invasive breast cancer have undetected occult metastases at the time of their primary tumour diagnosis. The development and growth of these micro-metastases relies heavily on angiogenesis. Therefore, administering an angiogenesis-blocking treatment from the time of diagnosis could reduce the incidence of metastasis and, ultimately, increase patient survival. It is hypothesized that an antiangiogenesis strategy combining fever-range whole-body hyperthermia (FR-WBH) and metronomic chemotherapy could inhibit the development of metastatic disease with minimal toxicity. To test this theory, a low, daily dose of the topoisomerase-I inhibitor irinotecan hydrochloride (CPT-11) was administered over a prolonged period of time to rats bearing the highly metastatic MTLn3 mammary adenocarcinoma primary tumour surgically excised on day 12 after implantation. The metronomic CPT-11 was combined with long-duration, low-temperature, fever-range whole body hyperthermia (FR-WBH). This systemic hyperthermia enhances chemotherapy-induced cytotoxicity as well as immunological activity. Both the group treated with FR-WBH alone and the combined FR-WBH + CPT-11 group had delayed onset and reduced incidence of axillary lymph node metastases compared to control (p < 0.05). Combination therapy of FR-WBH + CPT-11 resulted in a significantly greater inhibition of axillary lymph node metastasis volume compared to both control and CPT-11 alone (p < 0.02) at day 16. Interestingly, none of the therapies significantly affected inguinal lymph node metastases. Lung metastases were decreased by 36% at the time of death in rats treated with FR-WBH + CPT-11, by 25% in the CPT-11 alone group and by 14% in the FR-WBH alone group. Rats treated with FR-WBH, + CPT-11 survived significantly longer (35%) than control animals (p < 0.04). Neither significant body weight loss nor gastrointestinal toxicity was observed in any group. These data suggest that, after excision of the primary tumour, FR-WBH and metronomic CPT-11 can be safely combined to reduce distant lymph node and lung metastases and, thus, to increase survival.

Effect of altered duration of 41.5 degrees C whole body hyperthermia in combination with cis-diamminedichloroplatinum (II) on tumor and normal tissue apoptosis and tumor response in rats.

We investigated the correlation between antitumor efficacy and kinetics of tumor and normal tissue apoptosis when cis-diamminedichloroplatinum (II) (CDDP) was combined with two different durations of whole body hyperthermia [SH-WBH, at 41.5 degrees C for 1 h (1 h WBH) or 2 h (2 h WBH)]. Rats bearing a mammary adenocarcinoma (MTLn3) were treated with 1 or 2 h WBH CDDP and then assessed for tumor growth delay (TGD). A separate study examined the amount of induced apoptosis in tumor and normal tissue (thymus and ileum) over 96 h following the same treatments. 1 h WBH + CDDP increased the TGD to 10.5+/-0.5 days, which was not statistically different from the TGD of 12.3+/-0.5 days obtained with 2 h WBH + CDDP. The area under the curve (AUC) of percentage tumor apoptosis for 1 h WBH + CDDP was 50% of that of 2 h WBH + CDDP. The AUC of percentage thymus apoptosis for 1 h WBH + CDDP was 25% of that of 2 h WBH + CDDP, and the AUC of the score of ileal apoptosis for 1 h WBH + CDDP was 81% of that of 2 h WBH + CDDP. These data indicate that while 1 h WBH + CDDP induced less tumor apoptosis than 2 h WBH + CDDP, antitumor activity was enhanced to a similar degree by both 1 h and 2 h WBH + CDDP, and since 1 h WBH + CDDP caused less normal tissue apoptosis than 2 h WBH + CDDP, a 1 h duration of WBH + CDDP may be a therapy that is both, as effective as, and safer than a 2 h duration of WBH + CDDP.

Therapeutic efficacy and apoptosis and necrosis kinetics of doxorubicin compared with cisplatin, combined with whole-body hyperthermia in a rat mammary adenocarcinoma.

We have compared the therapeutic efficacy as well as the kinetics of treatment-induced apoptosis and necrosis of the maximum tolerated dose (MTD) of doxorubicin (DOX) or cisplatin (CDDP) combined with long-duration, low-temperature whole-body hyperthermia (LL-WBH, at 40.0 degrees C for 6 hr), with the combination of the MTDs of either DOX or CDDP with short-duration, high-temperature WBH (SH-WBH, at 41.5 degrees C for 2 hr), in a rat mammary adenocarcinoma (MTLn3). The MTD of LL-WBH + DOX resulted in increased therapeutic efficacy, compared with the MTD of DOX alone and SH-WBH + DOX. The MTD of LL-WBH + CDDP, however, did not increase therapeutic efficacy, when compared with the MTD of CDDP alone or SH-WBH + CDDP. The MTD of LL-WBH + DOX caused a significant delay in the development of spontaneous axillary lymph node (ALN) metastasis and tended to cause longer mean survival, compared with SH-WBH + DOX. The peak of treatment-induced apoptosis was higher for the MTD of DOX + LL-WBH, compared with SH-WBH + DOX, whereas the apoptosis peak of the MTD of SH-WBH + CDDP was higher than that of LL-WBH + CDDP. The most extensive levels of tumor necrosis appeared to occur earlier with SH-WBH alone and the MTD of SH-WBH + DOX or CDDP than with other groups. Our results suggest that LL-WBH + DOX may be a promising therapy for breast cancer, and the extent of treatment-induced tumor apoptosis appears to correlate with antitumor response for MTDs of LL-WBH + DOX and SH-WBH + DOX, but not for the MTDs of CDDP with SH-WBH or LL-WBH.

Long-duration, mild whole body hyperthermia with cisplatin: tumour response and kinetics of apoptosis and necrosis in a metastatic rat mammary adenocarcinoma.

This study examines antitumour effect and induction of apoptosis and necrosis after treatment with long-duration, mild whole body hyperthermia (LL-WBH, 40.0 degrees C, for 6 h) in simultaneous combination with cisplatin (CDDP) on primary and metastatic tumour growth in a rat mammary adenocarcinoma. A significantly greater delay in primary mammary tumour growth was observed after treatment with LL-WBH + CDDP, compared to either modality alone (p < 0.05). LL-WBH alone caused a significant delay in spontaneous metastasis to the axillary lymph node (ALN) and LL-WBH + CDDP tended to further increase the delay in ALN metastasis. Survival was longest in rats receiving LL-WBH + CDDP, compared to other groups (p < 0.05). CDDP induced a peak of tumour apoptosis at 24 h after treatment beginning that was significantly greater than LL-WBH alone (p < 0.05). The peak of tumour apoptosis induced by LL-WBH + CDDP from 12 to 24 h was significantly greater than any other group (p < 0.01). These results suggest that the extent of treatment-induced apoptosis seems to correlate positively with antitumour response and the combination or LL-WBH with CDDP may lead to a promising adjuvant therapy for breast cancer.

Optimal duration of whole body hyperthermia when combined with cis-diaminne-1,1-cychlobutane dicarboxylate platinum (II) (carboplatin).

Minimizing normal tissue toxicity can enhance the therapeutic gain of thermochemotherapy. For this purpose, we investigated the optimal duration of whole body hyperthermia (WBH) (41.5 degrees C) when administered simultaneously with carboplatin (CBDCA). Using a transplantable fibrosarcoma in Fischer 344 rats, we measured tumor growth delay (TGD) as well as normal tissue toxicities (body weight loss, thrombocytopenia) induced by various durations of WBH (0.5, 1.0, 1.5, 2.0 or 2.5 hours) when combined with CBDCA (30 mg/kg, i.v.). When combined with CBDCA, 1.0 hour WBH increased the TGD compared to 0.5 hour of WBH, but with WBH durations greater than 1.0 hour, the TGD did not further significantly increase. Measuring CBDCA-induced myelosuppression, the platelet count on day 6 post-treatment decreased from a control mean of 6.8 x 10(8)/ml to 1.8 x 10(8)/ml after 2.5 hour WBH exposure in a duration-dependent manner (p < 0.001). To estimate the specific therapeutic efficacy (STE), we calculated a ratio of TGD to myelosuppression (thrombocytopenia). Compared to other WBH exposure times, 1.0 hour duration of WBH combined with CBDCA produced the highest STE (2.8) and over 1.5 hour duration of WBH did not result in any additional increase in STE. We conclude that 1.0 hour WBH exposure is optimal when combined with CBDCA in order to maximize the therapeutic gain.

The use of esmolol in whole-body hyperthermia: cardiovascular effects.

Whole-body hyperthermia (WBH) is a well-described investigational adjunct to systemic chemotherapy for the treatment of advanced malignancies. The hemodynamic consequences of this physiologic state may include tachycardia, which can produce acute myocardial ischemia in patients with coronary artery disease. Ischemic heart disease is currently considered a contraindication to WBH. We chose to investigate the consequences of using a new beta 1-adrenergic antagonist, esmolol, to attempt to control the tachycardia associated with WBH. After institutional approval and patient consent, nine consecutive patients with normal cardiac function presenting for WBH with carboplatin infusion were studied. Along with standard monitors, radial arterial and oximetric thermodilution pulmonary artery catheters were placed. Patients were sedated and heated in a radiant warmer (Enthermics). Spontaneous ventilation was maintained and hemodynamic data were gathered at 37 degrees C, and at 41.8 degrees C (before, during and after esmolol infusion). Heart rate and cardiac output increased (by 46% (p = 0.001) and 35% (p = 0.04) respectively) while mean arterial pressure and systemic vascular resistance fell (by 18% (p = 0.02) and 44% (p = 0.006) respectively) during hyperthermia. Heart rate was significantly reduced during esmolol administration (mean dose 180 micrograms/kg/min) in the absence of changes in cardiac index and calculated oxygen delivery. Ventricular filling pressures and stroke work were unchanged. No heart failure, pulmonary edema, or other adverse event was observed. Hemodynamic changes seen during esmolol administration were completely reversed 15 min after the infusion was stopped. We conclude that the administration of moderate doses of esmolol is safe for this population of patients undergoing WBH, and that this technique raises the question of whether patients with ischemic heart disease could safely undergo WBH.

Long duration-mild whole body hyperthermia of up to 12 hours in rats: feasibility, and efficacy on primary tumour and axillary lymph node metastases of a mammary adenocarcinoma: implications for adjuvant therapy.

The feasibility and efficacy of low temperature (40 degrees C) long duration whole body hyperthermia (LL-WBH) was investigated in rats bearing a highly metastatic mammary adenocarcinoma (MTLn3). We compared the treatment effects of various durations of LL-WBH (40 degrees C for 2-12 h) to that of conventional short duration-high temperature WBH (SH-WBH, 41.5 degrees C for 2 h). SH-WBH, 2 h LL-WBH, and 4 h LL-WBH resulted in only modest primary tumour growth delays (TGDs) of 0.9, 1.1 and 1.8 d (days) respectively. In contrast, significantly increased TGDs of 2.8, 3.2, 2.6, and 3.1 d were achieved with 6, 8, 10 and 12 h LL-WBH, respectively (p < 0.05 compared to SH-WBH, 2 h-LL-WBH, and 4 h-LL-WBH). Notably, LL-WBH reduced the incidence of axillary lymph node metastasis at 14 days post-treatment, from 100% in normothermic controls and 92% after SH-WBH, to 33, 40, 50, and 60% following 4, 6, 8 and 10 h LL-WBH respectively. When the duration of LL-WBH was extended to 12 h, no reduction in axillary lymph node metastasis was observed. Normal tissue toxicity of LL-WBH appeared to be minimal and LL-WBH durations of up to 12 h were well tolerated. These data show that LL-WBH for durations of from 4 to 10 h has greater antitumour activity than SH-WBH, against mammary adenocarcinoma, suggesting that LL-WBH may have therapeutic potential in the treatment of malignant disease.

Protective effect of NG-monomethyl-L-arginine against hypotension inducted by combined tumour necrosis factor-alpha and whole body hyperthermia in rats.

We studied: (a) the adverse effects of tumour necrosis factor-alpha (TNF) given during whole body hyperthermia (WBH) on mean arterial pressure (MAP) and gut mucosa in anaesthetized rats; (b) the potential protective effect of NG-monomethyl-L-arginine (L-NMA), an inhibitor of nitric oxide synthase; and (c) the influence of L-NMA on the antitumour effect of the trimodality therapy, WBH + TNF + Carboplatin (CBDCA). In normothermic rats, TNF alone (10(5) or 10(6) U/kg) did not cause hypotension, but increased MAP (p < 0.05). L-NMA alone (5, 10 and 20 mg/kg) increased MAP moderately and dose-dependently (p < 0.05). WBH (41.5 degrees C for 2 h) increased MAP markedly (from 103 +/- 4 to 161 +/- 4 mm Hg). This increase in MAP was sustained throughout the hyperthermia, but was followed by a transient relative hypotension (MAP = 80 +/- mm Hg) on cessation of WBH and an eventual return to near baseline at 30 min post-WBH (MAP = 94 +/- 5 mm Hg). WBH + TNF (10(5) or 10(6) U/kg) initially increased MAP similarly to WBH alone. During the second hour of WBH, however, MAP decreased towards pre-treatment levels, and cessation of WBH was followed by sustained hypotension. This late hypotensive state was associated with a mortality during the early (first 2 h) post-WBH period of 17 and 100% at TNF dose of 10(5) and 10(6) U/kg TNF, respectively. L-NMA given to rats receiving WBH + TNF (10(6) U/kg) maintained MAP at levels similar to WBH alone during WBH treatment. L-NMA prevented the post-WBH hypotension, and extended the survival beyond the early (first 2 h) post-WBH period. No rat, however, receiving high dose TNF (10(6) U/kg) survived more than 12 h even with L-NMA (totally 40 mg/kg). WBH + TNF (10(5) and 10(6) U/kg) also produced marked histopathological injury to the gut mucosa at 2 h post-treatment. L-NMA substantially protected the gut from this injury. In rats bearing a transplantable fibrosarcoma, L-NMA did not decrease the antitumour effect consisting of WBH + TNF (10(5) U/kg) + CBDCA, while it decreased (p < 0.05) the general toxicity (weight loss, diarrhea and foot oedema) of this combination. We conclude that L-NMA may prevent or ameliorate the early toxicity but not the late lethal effects of WBH + high dose TNF (10(6) U/kg). Additionally, L-NMA reduces some of the toxicity of WBH + TNF (10(5) U/kg) + CBDCA without decreasing the antitumour effect of this trimodality therapy. Inhibitors of nitric oxide synthase such as L-NMA may provide a novel approach to overcoming the toxicity of TNF in combination with WBH.

Apoptosis in tumors and normal tissues induced by whole body hyperthermia in rats.

Apoptosis in tumor and normal tissues was examined in rats treated with whole-body hyperthermia (WBH; 41.5 degrees C for 2 h). WBH alone produced 0.5 day of tumor growth delay (TGD) in a fibrosarcoma and 5.8 days of TGD in the Ward colon carcinoma. This difference in WBH-induced TGD indicates that the fibrosarcoma is relatively resistant to WBH, whereas the Ward colon carcinoma is relatively heat sensitive. A quantitative histological assay for apoptosis demonstrated that the extent of apoptosis in the fibrosarcoma reached a maximum level of 19% 4 h after WBH and returned to the control level by 24 h. In contrast, WBH induced apoptosis with a peak value of 43% at 8 h in the Ward colon carcinoma, and the apoptotic level remained elevated above the control level until 48 h after WBH. Within normal tissues, the spleen and the lymph nodes showed WBH-induced apoptosis; however, the highest level of WBH-induced apoptosis as well as the most prolonged increase in apoptotic levels occurred in the thymus. The WBH-induced apoptosis in the thymus remained elevated above the control level until 48 h after WBH. Within the entire gastrointestinal tract, the small intestine was the most sensitive to WBH. Apoptotic cells were observed in the small bowel mucosa following WBH exposure. We also noted a minor WBH-induced increase in the apoptotic level in the bone marrow. Except for the case of the thymus, increased apoptotic levels in the normal tissues declined after peak levels at 4 h, and apoptosis above control levels was not seen beyond 12 h following WBH. Thus, within the normal tissues, WBH-induced apoptosis declined to basal levels within 12-48 h. These data indicate that both the extent and the kinetics of WBH-induced apoptosis differ between the two tumors and, meaningfully, between tumor and normal tissues. The extent and duration of apoptosis seem to correlate with tumor response to WBH.

Chronic effect of whole-body hyperthermia combined simultaneously with cis-diamminedichloroplatinum (II) on normal tissue in rat.

Long-term effects of cisplatin (DDP) (6 mg/kg) alone at 37 degrees C and DDP (2 mg/kg) plus whole body hyperthermia 120 min at 41.5 degrees C) on DDP-mediated normal tissue toxicities were compared up to 12 months post-treatment using a F344 rat model. Acute renal damage, represented by an increase in blood urea nitrogen (BUN) at day 5 posttreatment, was significantly higher after DDP (6 mg/kg) alone at 37 degrees C than the increase in BUN after DDP (2 mg/kg) plus whole body hyperthermia. After recovery, BUN levels as a result of both treatments remained elevated. From 9 months onwards BUN levels as a result of the combined treatment gradually increased to values > 100 mg/dl. At 12 months, side toxicities as a result of the combined treatment were more severe than the side effects noted after DDP (6 mg/kg) alone at 37 degrees C. Red blood cell and hematocrit values were significantly reduced, whereas BUN was significantly increased. The results obtained with histological examination of the kidneys corresponded with the observed functional differences. Platinum levels in the kidney, however, were highest in the DDP (6 mg/kg) alone at 37 degrees C group. This observation does not explain why the chronic toxicity as a result of the combined modality treatment was more severe.

Therapeutic efficacy of long duration-low temperature whole body hyperthermia when combined with tumor necrosis factor and carboplatin in rats.

This study examines the effects of a combined modality regimen of long duration-low temperature whole body hyperthermia (6 h at 40.0 degrees C; LL-WBH), recombinant human tumor necrosis factor-alpha (TNF) and carboplatin (CBDCA) on a transplantable fibrosarcoma as well as normal tissue. We compare LL-WBH with short duration-high temperature whole body hyperthermia (2 h at 41.5 degrees; SH-WBH). LL-WBH alone had no significant effect on tumor growth. Tumor growth delay (TGD) with TNF alone (0.1 days) and that with CBDCA alone (1.3 days) were significantly increased to 2.6 days (P < 0.05) and 2.8 days (P < 0.05), respectively, when combined with LL-WBH. Although TNF+CBDCA produced minimally increased TGD of 1.9 days, the combination of LL-WBH+TNF+CBDCA produced a significantly greater TGD of 5.6 days, compared to the other dual combinations (P < 0.01). There was no difference between TGDs for SH-WBH and LL-WBH in combination with TNF+CBDCA. Trimodality treatment-induced normal tissue toxicities, characterized by body weight loss, diarrhea, foot edema, and myelosuppression, were significantly greater in rats treated with SH-WBH+TNF+CBDCA, compared to LL-WBH+TNF+CBDCA. Histopathological examination also demonstrated that SH-WBH+TNF+CBDCA caused severe damage to the lymphoid tissues, intestinal tract, and peripheral microvasulature. We observed minimal histopathological changes observed in rats treated with LL-WBH+TNF+CBDCA. These data suggest that LL-WBH in combination with TNF and CBDCA has a greater therapeutic efficacy than SH-WBH.

Haematological toxicity of carboplatin and cisplatin combined with whole body hyperthermia in rats.

Acute haematological toxicity induced by cis-diammine-1,1-cyclobutane dicarboxylate platinum (II) (carboplatin) and cis-diamminedichloroplatinum (II) (cisplatin) in combination with whole body hyperthermia (WBH) (2 h at 41.5 degrees C) was examined using a F344 rat model. The thermal enhancement ratios (TERs) of drug-mediated thrombocytopenia, anaemia and leukopenia were determined from the dose-response curves of the nadir values of the peripheral platelet, RBC and WBC counts. Carboplatin produced profound depression of platelet counts which was over three-fold greater than cisplatin (14% vs 51% of the control), while the decrease in WBC and RBC counts induced by carboplatin did not differ significantly from those observed with cisplatin. These carboplatin or cisplatin-mediated haematological toxicities were significantly enhanced by WBH. The depth of decrease in platelet, RBC and WBC counts induced by the maximum tolerated dose (MTD) of carboplatin (30 mg kg-1) combined with WBH was identical to that induced by the MTD of carboplatin (70 mg kg-1) alone. The TERs of carboplatin-mediated thrombocytopenia, anaemia and leukopenia were 2.0, 2.8 and 1.9, respectively. The thermal enhancement of cisplatin mediated haematological toxicity was similar to that of carboplatin, with TERs of 1.8 for thrombocytopenia, 2.4 for anaemia and 1.9 for leukopenia. These data, demonstrating thermal enhancement of cisplatin or carboplatin-mediated haematological toxicity, must be taken into account in the clinical application of the combination therapy of platinum and WBH.

Increased therapeutic efficacy induced by tumor necrosis factor alpha combined with platinum complexes and whole-body hyperthermia in rats.

This study examined the effect of a trimodality therapy of the combination of recombinant human tumor necrosis factor alpha (TNF), whole-body hypertheria (WBH), and cis-diamminedichloroplatinum(II) (CDDP) or cis-diammine-1,1-cyclobutane dicarboxylate platinum(II) (CBDCA) on a fibrosarcoma and normal tissue in F344 rats. TNF (1 x 10(5) units/kg) increased the antitumor effect of both CDDP (1.5 mg/kg) + WBH (2 h at 41.5 degrees C) and CBDCA (30 mg/kg) + WBH. Tumor growth delay, which was 1.9 days for CDDP + WBH and 2.7 days for CBDCA + WBH (P less than 0.01 compared to control), was significantly increased to 2.9 days with TNF + CDDP + WBH and 5.4 days with TNF + CBDCA + WBH (P less than 0.05). WBH, TNF, CDDP or CBDCA alone, TNF + CDDP, TNF + CBDCA, or TNF + WBH had no significant effect on tumor growth. In contrast, administration of TNF did not enhance the CDDP- or CBDCA-mediated dose limiting normal tissue toxicity. CDDP + WBH-mediated acute renal injury and CBDCA + WBH-mediated acute myelosuppression, as determined by blood urea nitrogen and peripheral blood cell counts, respectively, were not increased with the addition of TNF to either dual modality therapy. Histopathologically, addition of TNF produced no significant alterations in the kidney and the bone marrow as compared to CDDP + WBH or CBDCA + WBH. These data show that TNF enhanced the platinum + WBH-mediated antitumor effect without increasing normal tissue toxicity, suggesting that TNF may increase the therapeutic efficacy of CDDP or CBDCA combined with WBH.

Chemotherapy resistant sarcoma treated with whole body hyperthermia (WBH) combined with 1-3-bis(2-chloroethyl)-1-nitrosourea (BCNU).

Seventeen patients with chemotherapy-resistant metastatic sarcoma were treated with whole body hyperthermia (WBH) combined simultaneously with 1-3-Bis(2-chloroethyl)-1-nitrosourea (BCNU). All of the patients had chemotherapy resistant metastases to major organ sites. Patients were heated to 41.8-42.0 degrees C for 2 h using an insulated blanket heating technique. Two patients (12%) experienced partial responses (PR). In addition, four objective tumour responses (OR) lasting more than 4 months were documented. One patient with previously rapidly growing chondrosarcoma pulmonary metastases experienced stable disease (SD) for 38 months from the onset of treatment. Median survival of seven patients with responding tumours (PR, OR and SD) compared with 10 patients with progressive disease was 15 versus 2 months, respectively. Cumulative thrombocytopenia was a therapy-limiting toxicity of the combined treatment, and occurred in six of seven patients. Acute toxicities attributable to WBH alone included transient thrombocytopenia in all patients, non-cardiogenic pulmonary oedema in two patients, and mild hypotension in five patients. Acute granulocytosis was observed in all patients. No treatment related deaths occurred. These data suggest that WBH combined with chemotherapy is associated with disease response in patients with chemotherapy-resistant, widely disseminated sarcoma metastases.

Effect of whole-body hyperthermia on pharmacokinetics and tissue distribution of doxorubicin.

The effect of whole-body hyperthermia (41.5 degrees C, 2 h) on doxorubicin (DOX) tissue distribution and plasma pharmacokinetics was examined in rats bearing a subcutaneous fibrosarcoma. Tumour response to the hyperthermia regimen alone was minimal, but the combination of heat with DOX (5.0 mg/kg, i.v.) enhanced tumour growth delay. The combined therapy, however, showed increased toxicity to normal tissue (especially renal and cardiac). Although DOX levels in spleen tissue were higher in rats exposed to hyperthermia than in control normothermic rats, both groups had comparable levels of drug in tumour, heart, kidney, and small intestine tissue at all time-points examined. Compared with normothermic animals, hyperthermia-treated rats showed decreased DOX in the mean area under the concentration-time curve (AUC) and decreased plasma DOX t1/2 but increased plasma drug clearance. These heat-mediated alterations in DOX pharmacokinetic parameters, however, do not account for the significant increases in thermochemotherapy-mediated cytotoxicities observed in tumour, and in normal renal and cardiac tissues.

Protective effect of ICRF-187 against normal tissue injury induced by adriamycin in combination with whole body hyperthermia.

The use of [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)]propane (ICRF-187) as a protective agent against normal tissue toxicity caused by combined Adriamycin (ADR) and whole body hyperthermia (WBH; 2 h at 41.5 degrees C) was assessed in a rat model. The effect of ICRF-187 on the antitumor response induced by the combination of ADR and WBH was also investigated in order to assess alterations in the therapeutic index of this combined therapeutic modality treatment. ICRF-187 significantly reduced ADR-mediated body weight loss, renal toxicity, and cardiomyopathy under both normothermic and hyperthermic conditions as shown by morphological and functional assays. ADR-induced neuropathy (seen only in normothermic rats) was also ameliorated by ICRF-187. Although this study did not show a pronounced effect of ICRF-187 on ADR-induced acute myelosuppression, ADR-mediated chronic anemia, leukocytosis, and thrombocytosis were reduced by ICRF-187 in both normothermic and WBH-treated rats. The effect of ICRF-187 on antitumor response was evaluated with a tumor growth delay assay using an in vivo transplantable fibrosarcoma. ICRF-187 caused no significant change in tumor growth delay induced by either ADR alone or ADR combined with WBH. Indeed, the only complete tumor regression following treatment resulted from the combination of ICRF-187 plus ADR plus WBH. Thus, ICRF-187 significantly increases the therapeutic index of the combined modality treatment of ADR and WBH by selectively reducing normal tissue toxicity without interfering with antitumor efficacy.

Effect of adriamycin combined with whole body hyperthermia on tumor and normal tissues.

Thermal enhancement of Adriamycin-mediated antitumor activity and normal tissue toxicities by whole body hyperthermia were compared using a F344 rat model. Antitumor activity was studied using a tumor growth delay assay. Acute normal tissue toxicities (i.e., leukopenia and thrombocytopenia) and late normal tissue toxicities (i.e., myocardial and kidney injury) were evaluated by functional/physiological assays and by morphological techniques. Whole body hyperthermia (120 min at 41.5 degrees C) enhanced both Adriamycin-mediated antitumor activity and toxic side effects. The thermal enhancement ratio calculated for antitumor activity was 1.6. Thermal enhancement ratios estimated for "acute" hematological changes were 1.3, whereas those estimated for "late" damage (based on morphological cardiac and renal lesions) varied between 2.4 and 4.3. Thus, while whole body hyperthermia enhances Adriamycin-mediated antitumor effect, normal tissue toxicity is also increased, and the potential therapeutic gain of the combined modality treatment is eroded.

Effect of carboplatin combined with whole body hyperthermia on normal tissue and tumor in rats.

The antitumor activity and normal tissue toxicity of cis-diammine-1,1-cyclobutane dicarboxylate platinum (II) (carboplatin) in combination with whole body hyperthermia (WBH) (41.5 degrees C, 120 min.) were examined in an F344 rat model. Carboplatin data were compared with those of cis-diamminedichloroplatinum (II) (cisplatin). At 37 degrees C, carboplatin showed minimal activity against a rat fibrosarcoma, but when combined with WBH, the antitumor effect-of the drug was greatly enhanced. The major carboplatin-induced acute toxicity at both normothermic and hyperthermic temperatures was marked hypocellularity of the bone marrow. A significant decrease in peripheral blood platelet counts was caused by the maximum tolerated doses (MTD) of carboplatin alone and with WBH. While the lethal dose of carboplatin alone caused only minimal renal damage, mild acute tubular necrosis was observed at the MTD of carboplatin with WBH, although no significant increase in blood urea nitrogen occurred. Therapeutic ratios of the combined chemotherapy and WBH modalities were calculated by comparing tumor growth response at the MTD of drug alone and drug combined with WBH. The combination of the nephrotoxic cisplatin with WBH resulted in a therapeutic ratio of only 0.8, whereas when carboplatin was combined with WBH, a value of 3.0 was obtained, representing a 3- to 4-fold increase over cisplatin in the therapeutic ratio. These data indicate that the less nephrotoxic carboplatin in combination with WBH improves therapeutic gain and may provide a more promising clinical combination for cancer treatment than cisplatin combined with WBH.

Increased therapeutic gain of combined cis-diamminedichloroplatinum (II) and whole body hyperthermia therapy by optimal heat/drug scheduling.

To maximize therapeutic gain, the timing sequence of whole body hyperthermia (WBH) and cis-diamminedichloroplatinum (II) (DDP) was examined. Normal tissue injury as well as growth of a s.c. transplanted fibrosarcoma were measured in F344 rats treated with variable schedules of WBH and DDP. Simultaneous application of DDP (2 mg/kg i.v.) with WBH (120 min at 41.5 degrees C) resulted in severe renal injury, body weight loss, and mortality; while sequential use of the modalities caused minimal to no toxicity. DDP or WBH alone produced only minimal tumor growth delay, whereas supraadditive antitumor effects occurred with all tested schedules of DDP combined with WBH, regardless of sequence or interval between the two modalities. We designated the ratio of antitumor effect to nephrotoxicity as specific therapeutic efficacy (STE). DDP given simultaneously with WBH produced the lowest STE (0.6-1.2), which was less than or equal to either DDP (STE = 1.2) or WBH (STE = 1.5) alone. On the other hand, schedules of DDP prior to and after WBH resulted in a STE of 1.8-3.0, a supraadditive effect. These results indicate that an optimal scheduling of DDP with WBH significantly improves therapeutic gain by reducing normal tissue injury while maintaining enhanced antitumor activity.