title: The effect of whole-body hyperthermia combined with 'metronomic' chemotherapy on rat mammary adenocarcinoma metastases.
abstract: 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.
authors.affiliation: The Division of Oncology, The Department of Internal Medicine, The University of Texas-Houston Medical School, 6431 Fannin Street, Houston, TX 77030, USA.
authors.forename: K
authors.initials: K
authors.lastname: Sumiyoshi
authors.forename: F R
authors.initials: FR
authors.lastname: Strebel
authors.forename: R W
authors.initials: RW
authors.lastname: Rowe
authors.forename: J M C
authors.initials: JM
authors.lastname: Bull
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002166:Camptothecin / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives*; D003131:Combined Modality Therapy; D005260:Female; D006979:Hyperthermia, Induced / Q000009:adverse effects; D000077146:Irinotecan; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000628:therapy*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D000970:Antineoplastic Agents; D000077146:Irinotecan; D002166:Camptothecin