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.