Search

Purpose: Studies were conducted to test whether fever-range whole body thermal therapy would boost the efficacy of oxaliplatin chemotherapy without substantial toxicity., Materials and Methods: The effect of mild heat (40 degrees C) on oxaliplatin cytotoxicity, cellular uptake, and platinum-DNA adduct formation was studied in vitro using the MTLn3 tumour cell line. In vivo oxaliplatin was administered at various doses and times before, during and after fever-range thermal therapy (6 h at 40 degrees C) to rats bearing an MTLn3 mammary adenocarcinoma. Tumour growth, survival, and toxicity were measured to determine treatment outcome., Results: Heating halved the oxaliplatin IC-50 dose for MTLn3 cells. Cellular uptake of platinum and platinum adducts increased by 34% and 36%, respectively, with heat. In vivo, 50% of all rats given 10 mg/kg oxaliplatin 24 h before thermal therapy were completely immunologically cured, while a further 11% regressed their primary tumour but ultimately succumbed to metastases, and 17% experienced a limited response with increased survival. The curative response occurred only in a narrow range of doses, with most cures at 10 mg/kg. Thermochemotherapy-treated, but uncured, animals had delayed incidence and slowed growth of metastases. Anti-tumour efficacy was greatest, and toxicity was least, when oxaliplatin was administered 12 or 24 h before fever-range whole body thermal therapy., Conclusions: When properly dosed and scheduled, oxaliplatin thermochemotherapy achieved permanent eradication of all primary and metastatic tumours in 50% of animals, seemingly through an immune response. Successful clinical translation of this protocol would yield hitherto unseen cures and substantial improvement in quality of life.

Purpose: The purpose of the Phase I component of this study was to find the maximally tolerated dose (MTD) of cisplatin administered within a regimen of fever-range whole body thermal therapy (FR-WB-TT), cisplatin, gemcitabine, and low-dose interferon-alpha (IFN-alpha). The Phase II component aimed to assess which cancer diagnoses responded to the regimen, the response rate, and response duration., Materials and Methods: The protocol design derived from a schedule-optimized preclinical regimen. Drugs were administered together, and also with thermal therapy in a schedule that optimized the therapeutic index. Eligible patients were those with therapy-resistant, metastatic or advanced solid malignancies. Beginning at 40 mg/m(2), the cisplatin dose was escalated by 10 mg/m(2) to the maximally tolerated dose (MTD) in successive cohorts of 3 patients. A treatment cycle consisted of cisplatin on day one, followed by thermal therapy and simultaneous gemcitabine 36 hours later; then a second dose of gemcitabine one week later; and daily IFN- alpha., Results: Thirty-seven patients were treated on protocol. The MTD of cisplatin in the thermochemotherapy regimen was established to be 60 mg/m(2). The dose limiting toxicities (DLT) were peripheral neuropathy and ototoxicity. Complete and partial responses combined were 43%. The therapy improved the quality of life of responding patients., Conclusion: The protocol was well tolerated and was associated with antitumor activity in patients with a variety of advanced metastatic solid tumors. Tumor response occurred with the thermochemotherapy treatment despite treating malignancies that had progressed on the same chemotherapy drugs administered as standard treatment. Notably, good responses were observed in patients with high-grade neuroendocrine and pancreas cancers. This regimen will be tested in a phase II study.

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.

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.

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.

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.

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.

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.

The effects of various anaesthetics, including a balanced combination of different anaesthetics (consisting of ketamine, xylazine, and acepromazine), Nembutal, and halothane anaesthesia on DDP-induced renal and intestinal toxicities at 37 degrees C and at 41.5 degrees C were studied using a F344 rat model. The combination anaesthesia decreased the DDP-induced lethality (LD50) and toxic side-effects as evidenced by decreased in BUN and diarrhoea at day 5, whereas nembutal anaesthesia increased DDP-induced toxic side-effects at 37 degrees C. The inhalation anaesthetic halothane had only minor influence on these DDP-induced toxicities. Increasing the NaCl concentration of the DDP vehicle from 0.9 to 1.8 per cent decreased the DDP-induced toxicity both in non-anaesthetized and anaesthetized animals. When applied simultaneously with DDP administration, whole-body hyperthermia (WBH; 120 min at 41.5 degrees C) increased the DDP-induced toxicity as indicated by the thermal enhancement ratio of between 2.1 and 2.7 for the LD50 values. With combined WBH + DDP treatment the effect of anaesthetics on DDP-induced toxicities was generally similar to that observed at 37 degrees C. The protective effects of the high NaCl (1.8 vs 0.9 per cent) concentration of the DDP vehicle, however, were minimal under hyperthermic conditions. The data suggest the need for caution in the use of DDP in combination with WBH.