Summary
Synopsis
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.
Pharmacodynamic Properties
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.
Pharmacokinetic Properties
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 concentrations reflect differences in Vd rather than in drug clearance.
Ifosfamide, like cyclophosphamide, is a prodrug requiring in vivo activation by the cytochrome P-450 mixed-function oxidase system to exert cytotoxic activity. Hydroxylation produces 4-hydroxy-ifosfamide in spontaneous equilibrium with aldo-ifosfamide, which splits to yield isofosforamide mustard, the primary alkylating compound, and acrolein, a urotoxic agent. The slow rate of carbon ring hydroxylation leads to increased alternative pathway metabolism, resulting in the formation of the alkylating metabolites, dechloroethyl-cyclophosphamide and dechloroethyl-ifosfamide, as well as chloracetaldehyde, which may contribute to ifosfamide-induced neurotoxicity. There are differences in the preferential route of metabolism depending on route of administration (oral vs intravenous).
The terminal phase elimination half-life (t½β) of ifosfamide after single oral or intravenous doses is between 4 and 7 hours, and total clearance is approximately 3.6 L/h. Fractionation of the ifosfamide dose results in an enhanced rate of metabolism. There was a 36% reduction in median t½β from day 1 to day 5, and a corresponding 76% increase in total clearance without any change in the apparent Vd observed in 15 patients administered ifosfamide 1.5 g/m2/day (plus mesna) for 5 consecutive days.
Following administration, mesna is almost completely oxidised in the plasma to dimesna, which remains in the intravascular compartment where it is rapidly cleared by the kidneys. Glutathione reductase enzymes in the renal tubular epithelium convert approximately one-third of filtered dimesna back to mesna. The free sulfhydryl groups of mesna combine with urotoxic metabolites such as acrolein to form stable non-toxic compounds, which are excreted in the urine. Since urinary concentrations of mesna greatly exceed plasma concentrations, regional detoxification of ifosfamide occurs. Mesna does not reduce the cytotoxic effects of ifosfamide.
The mean tx00BD;β of mesna is 0.4 hours, and the t½β of dimesna is 1.2 hours. Urinary concentrations of mesna following oral administration are approximately half those observed after intravenous doses. Mesna excretion is nearly complete within 4 hours of an intravenous dose and within 8 hours of an oral dose.
Therapeutic Efficacy
In patients with relapsed or refractory disseminated nonseminomatous testicular cancer, combination chemotherapeutic regimens consisting of ifosfamide/mesna, cisplatin and either etopo-side or vinblastine have shown particular promise. Such salvage regimens have achieved complete response in 21 to 26% of patients, with up to 16% of remaining patients becoming disease free after subsequent surgical resection of viable tumour. Similarly, in patients with advanced bulky seminoma, salvage therapy consisting of ifosfamide/mesna combined with vinblastine and cisplatin has yielded encouraging results, although myelotoxicity was marked. Ongoing studies in the US are currently comparing the efficacy of cisplatin and etoposide with either bleomycin or ifosfamide as first-line therapy for patients with advanced stage testicular cancer.
Ifosfamide/mesna, used in conjunction with etoposide and other cytotoxic agents as induction therapy in small cell lung cancer (SCLC), has produced objective (complete plus partial) response rates of 75 to 95% in patients with limited disease and 44 to 100% in patients with extensive disease. Although a 90% objective response rate was achieved with oral ifosfamide/mesna and etoposide, this route of administration was accompanied by an unacceptably high incidence of CNS adverse effects. Overall, the duration of responses and survival times observed with ifosfamide/mesna-containing combinations were similar to those reported with standard chemotherapeutic regimens.
A few comparative studies in SCLC have also demonstrated a similar rate of efficacy between ifosfamide/mesna-containing combinations and standard chemotherapeutic regimens. Although limited, present data suggest that ifosfamide/mesna may be of some benefit as consolidation or late intensification therapy in patients with SCLC and as salvage chemotherapy in patients with primary recurrent or resistant disease.
In non-small cell lung cancer (NSCLC), combinations of ifosfamide/mesna plus cisplatin and either etoposide or mitomycin, have produced objective response rates of 26 to 70%, with generally better results occurring in patients with good pretreatment performance status and limited disease, and little association noted between response and histological type. However, median overall survival time has remained short/Objective response rates have been considerably lower (i.e. 20 to 40%) in patients treated with combinations of ifosfamide/mesna not containing cisplatin. Comparative studies in generally small groups of patients with NSCLC have failed to detect any marked differences between ifosfamide/mesna-containing combinations and various other chemotherapeutic combinations.
Ifosfamide/mesna- plus etoposide-based regimens have produced favourable rates of response in patients with recurrent non-Hodgkin’s lymphoma. In addition, complete response rates exceeding 80% and long term (i.e. 2 to 10 years) survival rates of greater than 60% have been documented with response-adapted protocols containing ifosfamide/mesna and etoposide in the first-line treatment of malignant lymphomas. Preliminary findings suggest a possible role for ifosfamide/mesna-based regimens alternating with conventional first-line therapy for Hodgkin’s disease, while ifosfamide/mesna, methotrexate, methyl-gag, and etoposide in combination have shown reasonable activity as salvage chemotherapy in recurrent Hodgkin’s disease.
Noncomparative studies of ifosfamide/mesna-containing chemotherapeutic combinations in induction therapy for adult patients with mainly soft tissue sarcomas have documented objective response rates most often around 40%. Although initial comparative studies indicate an efficacy advantage for ifosfamide/mesna — when used alone or in combination with dactinomycin (actinomycin D), doxorubicin (adriamycin) and vincristine — compared with cyclophosphamide, these results require confirmation in future prospective studies. In a comparative study in patients with soft tissue sarcoma, the Eastern Cooperative Oncology Group found that objective tumour regression occurred in 35% of patients treated with ifosfamide plus doxorubucin compared with only 19% of patients treated with doxorubicin alone.
In children with relapsed or refractory solid tumours and previous cyclophosphamide exposure, objective response rates were 24 to 32% for ifosfamide/mesna alone and 56% for combination regimens, with the highest level of response noted in Ewing’s sarcoma, Wilms’ tumour and rhabdomyosarcoma. Such results prompted investigation of ifosfamide/mesna-containing combination regimens as induction therapy in these tumours; at present, it is uncertain whether ifosfamide/mesna has any advantages over cyclophosphamide. Ifosfamide/mesna combination regimens appear to have limited value in the treatment of disseminated neuroblastoma.
In advanced metastatic breast cancer, ifosfamide/mesna-containing combinations have produced objective response rates of 17 to 79%, although as with other second-line treatments, this has comprised predominantly partial remission. Future comparative studies may determine whether ifosfamide/mesna has any advantages over cyclophosphamide in the treatment of this tumour.
Ifosfamide/mesna has shown considerable activity in the treatment of advanced cervical cancer refractory to surgery and/or radiotherapy. Preliminary data also suggest that ifosfamide/mesna in conjunction with cisplatin and bleomycin may be useful in reducing the size of bulky advanced cervical tumours prior to radiotherapy. In patients with advanced ovarian cancer resistant to or relapsing after first-line therapy, ifosfamide/mesna-containing regimens have produced moderate objective response rates of 18 to 45%. In induction therapy of advanced ovarian cancer, ifosfamide/mesna in combination with cisplatin has produced high objective response rates, including a complete response rate exceeding 40%. Conversely, ifosfamide/mesna has had limited success in the treatment of uterine cancer.
Similar to most other cytotoxic agents, single-agent ifosfamide/mesna has shown minimal activity in the treatment of advanced cancer of the oesophagus, stomach, colorectum, pancreas, or kidneys. However, it has shown promise in the treatment of patients with head and neck cancer who have not had previous exposure to chemotherapy.
Tolerability
Myelosuppression is the principle dose-limiting toxicity of ifosfamide when used with concomitant mesna. White blood cell nadirs occur most often between days 8 to 13 of the treatment cycle and are dose related. Thrombocytopenia is generally of mild to moderate severity and occurs less frequently than leucopenia. Haematological recovery is usually complete by day 17 or 18.
Whereas administration of ifosfamide alone is associated with dose-limiting haemorrhagic cystitis, routine concomitant mesna administration has greatly diminished urothelial toxicity; macrohaematuria is generally reported in fewer than 5% of patients. Despite concurrent mesna, however, nephrotoxicity evident as glomerular, or more often, tubular dysfunction, remains a potentially serious adverse effect. This occurs in a variable proportion of patients, and especially in paediatric patients, usually after several courses of therapy. The incidence of nephrotoxicity appears to be increased by prior administration of cisplatin, pre-existing renal impairment and concomitant administration of other potentially nephrotoxic treatments. Fanconi’s syndrome has been reported in small numbers of adults and children treated with ifosfamide/mesna.
CNS adverse effects ranging from somnolence to severe encephalopathy and coma can occur in about 10 to 20% of patients treated intravenously with ifosfamide, and this may increase to 50% following oral administration. The relative risk of CNS toxicity is related to previous cumulative dosages of cisplatin, as well as renal or hepatic dysfunction. Encephalopathy usually resolves spontaneously soon after stopping ifosfamide.
Alopecia is almost universal following administration of ifosfamide/mesna. Nausea and vomiting, although usually of moderate intensity, are quite common and are dose-related.
Orally administered mesna may be associated with adverse effects such as nausea, vomiting and abdominal cramps. Adverse effects occur less frequently with intravenous doses of mesna, although hypersensitivity reactions, diarrhoea, abdominal pain, headache, limb and joint pain, and transient changes in heart rate and blood pressure have been reported, particularly with bolus doses of 60 mg/kg or more. False-positive ketonuria is frequently detected in patients receiving mesna when a sodium nitroprusside-based testing strip is used.
Dosage and Administration
In the treatment of germ cell testicular cancer, the dose of ifosfamide (with concomitant mesna) approved in the US is 1.2 g/m2/day intravenously over 30 minutes for 5 consecutive days along with extensive hydration (minimum 2L fluid/day).
In clinical trials of various types of neoplastic disease, ifosfamide has most often been administered in fractionated dosages of 1.2 to 2.5 g/m2/day for 3 to 5 days, although single bolus doses of 5 to 8 g/m2 infused over 24 hours have also been investigated.
With fractionated doses of ifosfamide, mesna is commonly given as an intravenous bolus injection in a dose equal to 20% (w/w) that of ifosfamide, at 0, 4 and 8 hours after ifosfamide administration, and this is repeated each day ifosfamide is used. Mesna, in a dose equal to that of ifosfamide, may also be administered simultaneously with the alkylating agent as a continuous infusion. When used in this manner, mesna should be administered for an additional 12 to 24 hours after discontinuation of ifosfamide because of its comparatively short elimination half-life. When mesna is administered orally, the dosage is equal to 40% (w/w) that of ifosfamide.
Courses of chemotherapy are generally repeated every 21 or 28 days, but dosages and administration times may need to be adjusted on the basis of white blood cell and platelet counts.
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Various sections of the manuscript reviewed by: G. Blackledge, West Midlands Cancer Research, Campaign Clinical Trials Unit, Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Edgbaston, Birmingham, England; M. Boyer, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada; F. Cabanillas, Department of Hematology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA; T. Cerny, Inselspital Bern, Institut für Medizinische Onkologie der Universität, Bern, Switzerland; J. de Kraker, Werkgroep Kindertumoren, Emma Kinderziekenhuis, Children’s Academic Medical Centre, Amsterdam, The Netherlands; P. Drings, Thorax-Klinik Heidelberg-Rohrbach, Heidelberg, Federal Republic of Germany; C. Falkson, Department of Medical Oncology, Universiteit van Pretoria, Pretoria, South Africa; G. Falkson, Department of Medical Oncology, Universiteit van Pretoria, Pretoria, South Africa; C. Focan, Internal Medicine & Oncology Departments, Centre Hospitalier Saint-Joseph — Esperance, Clinique Sainte-Elisabeth, Liege, Belgium; N. Gad- El- Mawla, National Cancer Institute, Cairo, Egypt; L.D. Lewis, Johns Hopkins University, School of Medicine, Division of Clinical Pharmacology, Baltimore, Maryland, USA; P.J. Loehrer Sr, Section of Hematology/Oncology, Indiana University Medical Center, Indianapolis, Indiana, USA; C. Manegold, Thorax-Klinik Heidelberg-Rohrbach, Heidelberg, Federal Republic of Germany; M.J. Moore, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada; M. O’Brien, The Royal Marsden Hospital, London, England; M. Ogawa, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan; C.B. Pratt, Department of Hematology/ Oncology, St Jude’s Children’s Research Hospital, Memphis, Tennessee, USA; M.A. Rodriguez, Department of Hematology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA; G. Sutton, Department of Obstetrics and Gynecology, University Hospital, Indiana University Medical Center, Indianapolis, Indiana, USA; E. Wiltshaw, The Royal Marsden Hospital, London, England.
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Dechant, K.L., Brogden, R.N., Pilkington, T. et al. Ifosfamide/Mesna. Drugs 42, 428–467 (1991). https://doi.org/10.2165/00003495-199142030-00006
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DOI: https://doi.org/10.2165/00003495-199142030-00006