Mitoxantrone

Abstract

The antineoplastic agent mitoxantrone in combination with a corticosteroid (either prednisone or hydrocortisone) has shown clinical efficacy as palliative treatment for a proportion of patients (about 35 to 40%) with hormone-resistant advanced prostate cancer, a disease which predominantly affects elderly men and for which few systemic treatment options are available. Palliative end-points including pain relief decreased analgesic use and reduced prostate specific antigen levels (a marker of tumour response) are reached in a greater percentage of patients receiving combination therapy than corticosteroid alone. In addition, there are generally greater improvements in quality-of-life parameters in mitoxantrone recipients. However, combined treatment offers no survival advantage over cortico steroid monotherapy. Neutropenia is the most common toxicity associated with mitoxantrone therapy and may necessitate dosage reduction in some patients. Otherwise, mitoxantrone generally has a more favourable tolerability profile than has been established for other cytotoxic agents such as doxorubicin with regard to acute adverse events (e.g. nausea/vomiting, anorexia, constipation, alopecia, malaise/ fatigue, oedema) and cardiac toxicity. In conclusion, administration of mitoxantrone plus a corticosteroid can provide palliation for some elderly patients with hormone-resistant advanced prostate cancer, and is thus a valuable first-line treatment for this indication. Mitoxantrone is a synthetic anthracenedione derivative which has shown antitumour activity against a wide range of cancer cells in vitro and in vivo. Several mechanisms are thought to be responsible for its antitumour activity; these include stabilisation of the nuclear topoisomerase II-DNA intermediate complex (thereby preventing the ligation of DNA strand breaks), free radical generation, aggregation and compaction of DNA via electrostatic cross-linking, inhibition of microtubule assembly and inhibition of protein kinase C activity. Resistance to the antitumour activity of mitoxantrone has been seen both in vitro and in vivo and may occur by a number of mechanisms. In studies conducted in rats bearing prostate cancer tumours, those treated with mitoxantrone had significantly reduced tumour growth compared with controls. Inhibition of tumour growth was even greater in rats given mitoxantrone plus a luteinising hormone-releasing hormone agonist; however, this combination is not used in patients with advanced prostate cancer. Mitoxantrone is eliminated in a triphasic manner after intravenous administration. It has an initial distribution phase of 4 to 10 minutes, a distribution half-life of 0.3 to 3.1 hours and a terminal elimination half-life of up to 12 days. It is widely distributed into body tissues and has a very large volume of distribution (1000 to 4000L). Although no data are available on the distribution of mitoxantrone into prostate tissue, high concentrations of the drug are found in the liver, pancreas, thyroid, kidney, bone marrow, spleen and heart. Plasma protein binding has been estimated to be about 78%. Mitoxantrone is thought to be eliminated predominantly in the bile, with renal clearance accounting for about 10% of the total clearance of the drug. Hepatic impairment may prolong elimination of mitoxantrone. Combined therapy with intravenous mitoxantrone 12 to 14 mg/m² once every 3 weeks plus an oral corticosteroid (prednisone 10 mg/day or hydrocortisone 40 mg/day) has proven to be an effective palliative treatment for patients with advanced hormone-resistant prostate cancer. It reduces pain, analgesic use and prostate specific antigen (PSA) levels and improves patients’ quality of life. In a large phase III study, the primary response criteria (≥2-point decrease in pain intensity) was achieved in a significantly higher proportion of patients receiving combination therapy with mitoxantrone and prednisone than in patients receiving prednisone monotherapy (29 vs 12%; p=0.01). In addition, the mean duration of pain reduction was significantly longer in the combined treatment group (43 vs 18 weeks). The overall response rate including patients who met primary and/or secondary response criteria (reduced pain and/or ≥50% decrease in analgesic use) was 38 vs 21%. Quality-of-life analyses in all studies generally showed improvements in the domains related to pain, which tended to be greater in patients treated with both mitoxantrone plus corticosteroid than corticosteroid alone. Improvements in physical activity or function, constipation and mood have also been observed during treatment with mitoxantrone in some studies. Mitoxantrone reduces plasma levels of PS A by ≥50% in about 30% of patients with advanced prostate cancer. When mitoxantrone was combined with a corticosteroid, reductions in PSA levels were more frequent than with corticosteroids alone (≥50% reduction in 31 vs 17% of patients in one study). Despite favourable results with regard to palliative end-points, combined treatment with mitoxantrone plus either prednisone or hydrocortisone did not offer a survival advantage over corticosteroid monotherapy in either of the phase III studies (in which the median duration of survival was between 10 and 11.8 months). Phase II studies using the criteria of the National Prostatic Cancer Project (NPCP) found patients treated with mitoxantrone to have evidence of disease remission and stabilisation; however, these criteria are considered to be of little value as tumour responses are difficult to evaluate in this disease. The tolerability profile of mitoxantrone 10 to 14 mg/m² administered once every 3 weeks in patients with advanced prostate cancer is similar to that reported previously in patients receiving the drug for other malignancies. Haematological toxicity, particularly neutropenia, is the most common dose-limiting adverse event...