Mitoxantrone

Abstract

Mitoxantrone is a dihydroxyanthracenedione derivative which as intravenous mono- and combination therapy has demonstrated therapeutic efficacy similar to that of standard induction and salvage treatment regimens in advanced breast cancer, non- Hodgkin’s lymphoma, acute nonlymphoblastic leukaemia and chronic myelogenous leukaemia in blast crisis; it appears to be an effective alternative to the anthracycline component of standard treatment regimens in these indications. Mitoxantrone is also effective as a component of predominantly palliative treatment regimens for hepatic and advanced ovarian carcinoma. Limited studies suggest useful therapeutic activity in multiple myeloma and acute lymphoblastic leukaemia. Regional therapy of malignant effusions, hepatic and ovarian carcinomas has also been very effective, with a reduction in systemic adverse effects. Mitoxantrone inhibits DNA synthesis by intercalating DNA, inducing DNA strand breaks, and causing DNA aggregation and compaction, and delays cell cycle progression, particularly in late S phase In vitro antitumour activity is concentration- and exposure time- proportional, and synergy with other antineoplastic drugs has been demonstrated in murine tumour models Leucopenia may be dose- limiting in patients with solid tumours, whereas stomatitis may be dose- limiting in patients with leukaemia. Other adverse effects are usually of mild or moderate severity although cardiac effects, particularly congestive heart failure, may be of concern, especially in patients with a history of anthracycline therapy, mediastinal irradiation or cardiovascular disease. Mitoxantrone displays an improved tolerability profile compared with doxorubicin and other anthracyclines, although myelosuppression may occur more frequently Thus, mitoxantrone is an effective and better tolerated alternative to the anthracyclines in most haematological malignancies, in breast cancer and in advanced hepatic or ovarian carcinoma. Further studies may consolidate its role in the treatment of these and other malignancies Various human carcinoma cell lines are sensitive to mitoxantrone in vitro Synergism between mitoxantrone and cytarabine (cytosine arabinoside, ara-C), fluorouracil, vincristine, cisplatin, methotrexate, cyclophosphamide, thiotepa, dacarbazine (imidazole carboxamide), lucanthone and melphalan has been demonstrated in tumours in mice. Mitoxantrone produces concentration-and time-proportional delays in cell-cycle progression and although not considered cell-cycle specific, is most cytotoxic to cells in late S phase. It acts primarily on DNA, inducing DNA strand breaks by stabilising the topoisomerase-DNA cleavable complex and by free radical generation, and also induces DNA aggregation and compaction via electrostatic cross-linking. A cyclic derivative of mitoxantrone covalently binds DNA and may also be cytotoxic Tumour cell resistance to mitoxantrone may be a result of increased P-glycoprotein expression, alteration of the levels or activity of topoisomerase II, enhanced DNA repair mechanisms or a combination of these and other mechanisms. Incomplete cross-resistance with anthracyclines has been observed in vitro Mitoxantrone has also demonstrated immunosuppressive, antiviral and potential antiangiogenic activities in pharmacodynamic studies. Preclinical studies also indicated a potential for mitoxantrone to induce adverse effects in the heart, the gastrointestinal tract and on blood formation The pharmacokinetics of mitoxantrone have been extensively studied in cancer patients, but methodological difficulties have resulted in a wide range of reported pharmacokinetic values. Following intravenous administration, disappearance of the drug from plasma generally follows triphasic kinetics, with respective half-lives of 3 to 10 minutes, 0.3 to 3.1 hours, and up to 12 days. Mitoxantrone is extensively distributed to body tissues, binds to endothelial surfaces, and penetrates blood cells and tumour tissues. It has a volume of distribution of up to 2248 L/m². Plasma protein binding is approximately 78% Mitoxantrone persists for prolonged periods in the tissues and was detectable in autopsy tissue from patients who last received the drug up to 272 days before death. Mitoxantrone appears to be excreted mainly in the bile, with about 10% of an administered dose appearing in the urine (65% in unchanged form) within 24 to 120 hours. Thus, dosage reduction should not be necessary in patients with impaired renal function. However, in patients with hepatic impairment or third space abnormalities (e.g. ascites) mitoxantrone elimination may be considerably prolonged and dosage reduction may be required. Regional administration of mitoxantrone (e.g. into the peritoneal or pleural space) has resulted in high local drug concentrations, which are sustained for long periods because of the slow rate of clearance from these cavities Intravenous mitoxantrone monotherapy has demonstrated therapeutic efficacy similar to that of standard single-agent therapies in the treatment of advanced breast cancer, non-Hodgkin’s lymphoma, acute nonlymphoblastic leukaemia and chronic myelogenous leukaemia in blast crisis. Mitoxantrone substituted for the anthracycline component of standard combination salvage regimens produces similar efficacy, but often improves tolerability Mitoxantrone is a useful component of induction chemotherapy regimens, particularly in haematological malignancies in combination with cytarabine. It has also proved useful as a component of low toxicity regimens designed for use in patients who are elderly or have a poor performance status. Limited studies suggest mitoxantrone therapy may be of benefit in patients with multiple myeloma or acute lymphoblastic leukaemia. Mitoxantrone has also been used as palliative therapy in patients with hepatic or advanced ovarian carcinoma — mitoxantrone stabilises the disease in a significant proportion of patients with poor prognosis and may also result in objective responses. Following regional administration mitoxantrone seems particularly useful in the treatment of malignant effusions. Intra-arterial treatment of hepatic carcinoma and breast carcinoma, and intraperitoneal therapy of ovarian carcinoma, have also proved successful The role of consolidation and maintenance therapy in patients responding to mitoxantrone has not been investigated. Furthermore, additional studies are required to directly compare mitoxantrone with standard regimens in most treatment indications. The optimum combination of chemotherapy and surgery remains to be determined in advanced breast and ovarian carcinomas. Nonetheless, mitoxantrone is a generally effective alternative to the anthracycline component of treatment regimens for a number of malignant diseases and has also proved useful in various other combination chemotherapeutic regimens Administered as mono- or combination therapy, the tolerability of mitoxantrone is generally superior to that of the anthracyclines such as doxorubicin with regard to the severity of nausea, vomiting, stomatitis, alopecia and cardiotoxicity; myelosuppression, however, may occur more frequently with mitoxantrone. Leucopenia (especially granulocytopenia) may be dose-limiting in patients with solid tumours, particularly those with hepatic dysfunction and/or poor performance status. Leucocyte nadirs occur 10 to 14 days after a single dose, usually with recovery by 21 days. Thrombocytopenia and mild anaemia are rare. Stomatitis may limit dosage in patients with leukaemia. Nausea and vomiting can occur in up to 60% and alopecia in 30% of patients but these symptoms are rarely severe. Abdominal pain may follow intraperitoneal mitoxantrone administration Congestive heart failure, decreased left ventricular ejection fraction and arrhythmias have been reported in patients receiving mitoxantrone, particularly those with a history of anthracycline therapy, mediastinal irradiation or cardiovascular disease. The incidence of congestive heart failure appears to be dose-related but patients usually respond to cardiac glycoside and diuretic therapy The recommended intravenous dose of mitoxantrone is 14 mg/m² once every 3 weeks in patients with solid tumours, reduced by 2 to 4 mg/m² in patients with decreased marrow reserves, poor performance status or in those receiving combination chemotherapeutic regimens. If myelosuppression occurs, treatment should be withheld until haematological recovery with subsequent dosages titrated according to the severity and duration of this effect. In patients with leukaemia intravenous mitoxantrone 12 mg/m²/day for 5 days is recommended as monotherapy, or mitoxantrone 10 to 12 mg/m²/day for 3 days in combination with cytarabine. Mitoxantrone 8 mg/m²/day for 5 days has been used as monotherapy in paediatric leukaemia patients. Diluted mitoxantrone should be introduced slowly into the tube of a free-running intravenous solution. Cardiac monitoring is recommended in all patients, particularly those who have received large cumulative mitoxantrone dosages. Other administration methods and routes remain experimental and guidelines are not currently available