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Mitoxantrone

A Review of its Pharmacology and Clinical Efficacy in the Management of Hormone-Resistant Advanced Prostate Cancer

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Summary

Synopsis

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.

Overview of Pharmacological Properties

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.

Clinical Efficacy

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.

Tolerability

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 observed during mitoxantrone therapy. Thrombocytopenia and anaemia are less common and rarely severe.

Cardiac dysfunction, including a reduction in the left ventricular ejection fraction (LVEF) and congestive heart failure, has been observed in a proportion of patients with prostate cancer treated with mitoxantrone [16 of 119 patients (13%) in one study]. However, studies in patients with breast cancer indicated less cardiac toxicity with mitoxantrone than with doxorubicin therapy. The incidence of cardiac toxicity with mitoxantrone is estimated to be about 3% and is generally dose-dependent.

Other adverse events reported during mitoxantrone therapy include nausea/ vomiting, anorexia, constipation, alopecia, malaise/fatigue and oedema. These events were generally mild or moderate in severity (WHO grade 3 or 4 toxicity occurred in <5% of 119 patients in one study) and appeared to be less severe than those reported previously in patients with breast cancer treated with doxorubicin.

Dosage and Administration

The recommended dosage of mitoxantrone in combination with a corticosteroid for the treatment of advanced hormone-resistant prostate cancer is 12 to 14 mg/m2 administered by a short intravenous infusion once every 21 days. Treatment should be delayed in patients developing severe myelosuppression. Monitoring is recommended when administering the drug to patients with a history of cardiac dysfunction or hepatic impairment.

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Authors and Affiliations

  1. Adis International Limited, 41 Centorian Drive, Private Bag, Mairangi Bay, Auckland 10, 65901, New Zealand

    Lynda R. Wiseman & Caroline M. Spencer

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  1. Lynda R. Wiseman
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  2. Caroline M. Spencer
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Correspondence to Lynda R. Wiseman.

Additional information

Various sections of the manuscript reviewed by: M. Boyer, Department of Medical Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia; D. Cameron, ICRF Medical Oncology Unit, Western General Hospital, Edinburgh, Scotland; W. Kreis, Department of Medicine, Cornell University Medical College, Manhasset, New York, USA; M.J. Moore, Department of Medicine, Princess Margaret Hospital, Toronto, Ontario, Canada; G. Muzzonigro, Istituto di Patologia dell Apparato Urinario, Università Degli Studi di Ancona, Ancona, Italy; T. Otto, Urologische Klinik und Poliklinik, Medizinische Einrichtungen der Universität, Gesamthochschule, Essen, Germany; E. Schleyer, Department of Haematology/Oncology, University of Göttingen, Göttingen, Germany; I.F. Tannock, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada.

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Wiseman, L.R., Spencer, C.M. Mitoxantrone. Drugs & Aging 10, 473–485 (1997). https://doi.org/10.2165/00002512-199710060-00007

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