Metastatic breast cancer is one of the leading causes of death from cancer in women. It has a dismal prognosis, that in most instances is only palliated by surgery, radiotherapy, and/or chemotherapy. We hypothesize that fever-range whole body hyperthermia (LL-WBH) combined with liposomal doxorubicin (Doxil) and prolonged intravenous infusion 5-fluorouracil (PIF 5-FU) will induce a significant antitumor effect in women with metastatic, therapy-resistant breast cancer and in other patients with advnaced metastatic cancers resistant to standard therapy, and will cause no more and possibly less toxicity than standard doxorubicin-based chemotherapy regimens. Preclinical studies in rats comparing whole-body hyperthermia (WBH) of maximally tolerated heat for a short duration to a long-duration lower-temperature heat demonstrated equivalent tumor cytotoxic effect, but LL-WBH induces significantly less normal tissue toxicity. We also have described a significantly increased tumor apoptosis/necrosis and tumor response when prolonged IV infusion of PIF 5-FU is administered 24 hours prior to WBH. A pegylated liposomal doxorubicin (Doxil) induces significantly enhanced antitumor effects compared to its parent compound, doxorubicin. Based on our preclinical data, and clinical data using Doxil and PIF 5-FU at normal body temperatures, we propose to use LL-WBH combined with PIF 5-FU and Doxil in this Phase I-II clinical protocol as a very promising combined modality therapy to test in the treatment of advanced breast cancer and other advanced or metastatic cancers. Subjects will be enrolled in the trial to evaluate toxicity, tolerance, and tumor response to a combined regimen of PIF 5-FU, followed by Doxil and then LL-WBH administered once per month in a 7-day cycle. LL-WBH will be performed using the Heckel HT2000 WBH Radiant Heat System and conscious sedation anesthesia procedures. The subjects' core body temperature will be raised to 40 C over 90 minutes, and maintained during the 6-hour study by manipulation of the tent canopy and radiant heat lamps. If the phase I trial data suggests a phase II trial, additional patients will be entered to treat women with metastatic, resistant breast cancer.
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