Phase I evaluation of mitoxantrone alone and combined with whole body hyperthermia in dogs with lymphoma

Abstract

The maximum tolerated dose of mitoxantrone (MX) administered alone or combined with whole body hyperthermia (WBH) was determined in this non-randomized, prospective study in dogs with lymphoma. MX was administered to 53 dogs every three weeks for a total of six treatments unless progressive disease or persistent, severe toxicity developed. Fifty dogs were evaluable (MX alone n = 30, MX/WBH n = 20). MX was administered as a 1 h infusion at the onset of the plateau phase of WBH in dogs treated with combined therapy. Dogs were evaluated weekly between treatments for the first four treatments with physical examination and complete blood counts to define acute and cumulative toxicity. Dogs were evaluated every three weeks for tumour response until relapse. The maximum tolerated dose (MTD) was defined as that dose in each group that resulted in a 50% incidence of moderate or severe toxicity as estimated from logistic regression analysis of the toxicity data. Myelosuppression was the only toxicity observed. Neutropenia was equal in frequency and severity between treatment groups. Thrombocytopenia was not observed in any dog receiving MX/WBH but occurred in 13% of dogs treated with MX alone. The MTD for MX ± WBH was 6·1 ± 0·6 and 6·5 ± 0·8mg/M² respectively. A steeper dose-response relationship was observed in dogs receiving combined therapy compared to dogs treated with MX alone suggesting WBH may improve the uniformity of patient response to chemotherapy. We concluded that MX may be administered without dose reduction to dogs undergoing WBH and that MX should be evaluated more thoroughly in future thermochemotherapy studies.

Key Words:

• Hyperthermia
• mitoxanthrone
• lymphoma
• canine