Ifosfamide/Mesna

Abstract

Ifosfamide is an oxazaphosphorine alkylating agent with a broad spectrum of antineoplastic activity. It is a prodrug metabolised in the liver by cytochrome P450 mixed-function oxidase enzymes to isofosforamide mustard, the active alkylating compound. Mesna, a uroprotective thiol agent, is routinely administered concomitantly with ifosfamide, and has almost eliminated ifosfamide-induced haemorrhagic cystitis and has reduced nephron toxicity. Therapeutic studies, mostly noncomparative in nature, have demonstrated the efficacy of ifosfamide/mesna alone, or more commonly as a component of combination regimens, in a variety of cancers. In patients with relapsed or refractory disseminated nonseminomatous testicular cancer, a salvage regimen of ifosfamide/mesna, cisplatin and either etoposide or vinblastine produced complete response in approximately one-quarter of patients. As a component of both induction and salvage chemotherapeutic regimens, ifosfamide/mesna has produced favourable response rates in small cell lung cancer, paediatric solid tumours, non-Hodgkin’s and Hodgkin’s lymphoma, and ovarian cancer. Induction therapy with ifosfamide/mesna-containing chemotherapeutic regimens has been encouraging in non-small cell lung cancer, adult soft-tissue sarcomas, and as neoadjuvant therapy in advanced cervical cancer. As salvage therapy, ifosfamide/mesna-containing combinations have a palliative role in advanced breast cancer and advanced cervical cancer. Ifosfamide/ mesna can elicit responses in patients refractory to numerous other antineoplastic drugs, including cyclophosphamide. With administration of concomitant mesna to protect against ifosfamide-induced urotoxicity, the principal dose-limiting toxicity of ifosfamide is myelosuppression; leucopenia is generally more severe than thrombocytopenia. Reversible CNS adverse effects ranging from mild somnolence and confusion to severe encephalopathy and coma can occur in approximately 10 to 20% of patients after intravenous infusion, and the incidence of neurotoxicity may be increased to 50% after oral administration because of differences in the preferential route of metabolism between the 2 routes of administration. Other adverse effects ofifosfamide include nephrotoxicity, alopecia, and nausea/ vomiting. In general, intravenously administered mesna is associated with a low incidence of adverse effects; however, gastrointestinal disturbances are common following oral administration. Thus, ifosfamide/mesna is an important and worthwhile addition to the currently available range of chemotherapeutic agents. It has a broad spectrum of antineoplastic activity and causes less marked myelosuppression than many other cytotoxic agents. At present, the role of ifosfamide/ mesna in refractory germ cell testicular cancer is clearly defined; however, its overall place in the treatment of other forms of cancer awaits delineation in future well-controlled comparative studies. Ifosfamide is an alkylating oxazaphosphorine agent closely related structurally to cyclophosphamide. Ifosfamide is a prodrug requiring enzymatic activation to form cytotoxic metabolites. Although the antitumour activity of this agent was recognised more than 2 decades ago, the haemorrhagic cystitis associated with its use proved dose-limiting and led to diminished interest in its clinical application. This changed following discovery of the thiol uroprotective compound, mesna. By combining with the toxic metabolites of ifosfamide, mesna prevents development of macroscopic haematuria. The addition of mesna to chemotherapeutic regimens has permitted investigation of ifosfamide in a variety of neoplastic diseases. Ifosfamide is thought to act in a similar manner to other alkylating drugs, interfering with normal DNA synthesis by producing irreparable cross-linking of DNA strands. Studies using experimental tumour systems showed ifosfamide to be more active than cyclophosphamide against early leukaemia L1210. Ifosfamide was also active against an Ehrlich-ascites tumour model resistant to anthracyclines and cyclophosphamide, indicating a degree of non-cross-resistance with other nitrogen mustard compounds. Fractionated administration of ifosfamide over several days resulted in an increased efficacy and therapeutic index relative to cyclophosphamide in the treatment of Yoshida ascites sarcoma in rats. Ifosfamide was also more active than cyclophosphamide against C3H mammary tumour, Ridgeway osteogenic sarcoma, and the naturally highly resistant DS-carcinosarcoma and TA-neuroblastoma of the rat. However, the antitumour effect of ifosfamide was less than that of cyclophosphamide against intraperitoneal B16 melanoma and subcutaneous CD8 f1 mammary cancer. In the advanced leukaemia L1210 model, ifosfamide demonstrated synergy with cisplatin, cytarabine and fluorouracil, but not with cyclophosphamide. Ifosfamide combined with vincristine was more effective than either drug alone in increasing survival time in animals with Yoshida ascites sarcoma. In nude mice, human breast, lung and testicular xenografts and sarcomas were most responsive to ifosfamide whereas ovarian, uterine, pancreatic and renal cancer xenografts failed to respond. Ifosfamide and cyclophosphamide each displayed a similar spectrum of antitumour activity in 30 selected human tumour models, but ifosfamide produced a higher response rate and lower toxicity. The pharmacokinetic properties of ifosfamide after intravenous and oral doses are independent of dose but not schedule. Peak plasma concentrations are attained within 1 hour after single oral doses, and the oral formulation is 100% bioavailable. The volume of distribution (Vd) of ifosfamide approximates total body water after intravenous administration, but is lower after oral administration. Vd appears to be increased in obese and elderly patients, perhaps because of increased distribution into body fat. Interpatient variations in steady-state plasma...