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.