The effect of whole-body hyperthermia combined with 'metronomic' chemotherapy on rat mammary adenocarcinoma metastases.

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Int J Hyperthermia. 2003 Mar-Apr;19(2):103-18.
Sumiyoshi K, Strebel FR, Rowe RW, Bull JM.The
Division of Oncology, The Department of Internal Medicine, The
University of Texas-Houston Medical School, 6431 Fannin Street,
Houston, TX 77030, USA.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.
Materials and Methods
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.
Conclusion: 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