Ifosfamide encephalopathy: a reappraisal

Watkin, Simon; Husband, David; Green, John A.; Warenius, Hilmar M.

doi:10.1016/0277-5379(89)90077-1

Cited by 50 publications

(16 citation statements)

References 16 publications

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“…Pharmacokinet. 26 (6) 1994 1986; Kellie et al 1987;Lewis & Meanwell1990;Pratt et al 1986;Salloum et al 1987;Watkin et al 1989). This toxicity is plausibly related to chloroacetaldehyde because this metabolite is structurally related acetaldehyde, the metabolite of alcohol (ethanol), and the hypnotic chloral hydrate (Goren et al 1986;Kurowski et al 1991).…”

Section: Central Nervous System Toxicitymentioning

confidence: 98%

Ifosfamide Clinical Pharmacokinetics

Wagner

1994

Clinical Pharmacokinetics

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This article reviews the metabolism and pharmacokinetics of ifosfamide and their implications for the cytostatic efficacy and toxicity pattern of this alkylating agent. Ifosfamide is a prodrug that requires biotransformation to become cytotoxic. It is a structural isomer of cyclophosphamide from which it differs only in having the chlorethyl functions on different nitrogen atoms. This causes a considerable change in initial metabolism, although overall metabolism remains the same. Beside the formation of 4-hydroxy-ifosfamide ('activated ifosfamide'), a second pathway with liberation of chloroacetaldehyde exists. Therefore, less activated drug is formed than during cyclophosphamide metabolism. This fact may well explain why higher doses of ifosfamide are required during treatment. Chloroacetaldehyde may account for the adverse effects and therapeutic effects of the parent drug. This metabolite has been associated with central nervous system toxicity during ifosfamide treatment and was shown to deplete intracellular glutathione concentrations. Glutathione depletion may support the activity of alkylating metabolites in tumour cells, thus overcoming the relative resistance of the cells to alkylating agents. Possibly, this mechanism explains the lack of complete cross-resistance between ifosfamide and cyclophosphamide as well as the greater antitumour activity of ifosfamide in some tumours. Urotoxicity of ifosfamide, which was the dose-limiting adverse effect, can be successfully attenuated by the use of mesna. Distinct pharmacokinetic properties of mesna are responsible for the fact that in contrast to other sulphydryl compounds the uroprotective activity of mesna does not imply a loss of therapeutic efficacy.

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Section: Central Nervous System Toxicitymentioning

confidence: 98%

Ifosfamide Clinical Pharmacokinetics

Wagner

1994

Clinical Pharmacokinetics

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“…Fortunately, as in our series, all these clinical manifestations resolved within 3 days of stopping the infusion. 21 Watkin et al 22 reported CNS toxicity in 18 out of 82 (22%) patients treated with ifosfamide. In our study, we observed SNC disturbances in five out of 28 patients (18%), predominantly confusion and auditory or visual hallucinations.…”

Section: Discussionmentioning

confidence: 99%

Prospective randomized clinical trial comparing high-dose ifosfamide + GM-CSF vs high-dose cyclophosphamide + GM-CSF for blood progenitor cell mobilization

Vela‐Ojeda

Tripp-Villanueva

Montiel‐Cervantes

et al. 2000

Bone Marrow Transplant

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Summary:Between August 1994 and June 1999, 56 patients were prospectively randomized to receive ifosfamide 10 g/m 2 + GM-CSF 5 g/kg/day (IFO+GM-CSF n = 28) and cyclophosphamide 4 g/m 2 + GM-CSF 5 g/kg/day (CY+GM-CSF n = 28). Both groups were comparable for age, gender, diagnosis, disease stage and previous chemotherapy. The IFO+GM-CSF group demonstrated a shorter median interval between therapy and apheresis (10 days (8-14) vs 13 days (8-25) P = 0.002), median number of doses of GM-CSF (9 (7-13) vs 15 (9-31) P = 0.001), median of days with aplasia (0.5 (0-10) vs 6 (0-21) P = 0.001), median days with fever (0 (0-6) vs 3 (0-9) P = 0.006) and median of days using i.v. antibiotics (0 (0-11) vs 7.5 (0-19) P = 0.002). The median MNC yield was similar in both groups. The CD34 + cell yield was better in the CY+GM-CSF group (3.14 (0.9-11.8) vs 5.33 (0.08-32)) but not at significant levels (P = 0.1). White blood cell hematopoietic recovery was more rapid in the CY+GM-CSF group (16 (10-22) vs 13 (10-24) P = 0.02). Platelet engraftment was similar in both groups. Costs of mobilization and transplantation were almost the same: $28 570 ($18 527-$47 028) and $30 020 ($17 281-$67 591), respectively (P = 0.9). There were no differences in disease-free survival and overall survival between both groups. Mild and transient non-hematological toxicity (hemorrhagic cystitis, decrease in serum creatinine clearance and CNS dysfunction) was seen most frequently in the IFO+GM-CSF group. Bone Marrow Transplantation (2000) 25, 1141-1146.

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“…Watkin et al. also have shown, in a prospective assessment of 18 cases of ifosfamide encephalopathy, that the sensitivity of the Meanwell nomogram was only 18% ( 22 ) . We therefore believe that the use of the nomogram is limited in this group of patients.…”

Section: Discussionmentioning

confidence: 99%

Palliative chemotherapy in recurrent carcinoma of the cervix: an audit of the use of ifosfamide and review of the literature

Lodge

Blake

1999

Int J Gynecol Cancer

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A review was conducted on 34 patients treated with intravenous ifosfamide for relapsed, inoperable carcinoma of the cervix between 1988 and 1996. The median age of patients was 44 years. Thirty-two patients had squamous cell carcinoma and 2 had adenocarcinoma. Radiotherapy had been used in primary management in 33, neo-adjuvant platinum chemotherapy in 7, and previous palliative chemotherapy in 11. Symptomatic response was assessed with respect to the symptom requiring palliaton. 25 patients failed to complete 6 cycles of chemotherapy: due to progressive disease in 14, lack of symptom response in 2, and toxicity in 11 of whom 7 had encephalopathy sufficient to abandon treatment. 32 patients were evaluable for objective response. Pathologic complete response (CR) was achieved in 1 patient, and partial response (PR) was achieved in 3 patients. The objective response rate was 11.8%. Symptomatic response throughout treatment occurred in 8 patients (24%); objective response was seen in only 3 (1 CR, 2 PR) of them and progressive disease in the remaining 5. Response duration in the 4 objective responders was 25 months in the patient with CR and 4, 6 and 8 weeks in the 3 patients with PR. In conclusion, ifosfamide, as given, is associated with unacceptable toxicity and insufficient symptomatic efficacy for use as a palliative treatment in patients with relapsed carcinoma of the cervix.

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Ifosfamide encephalopathy: a reappraisal

Cited by 50 publications

References 16 publications

Ifosfamide Clinical Pharmacokinetics

Ifosfamide Clinical Pharmacokinetics

Prospective randomized clinical trial comparing high-dose ifosfamide + GM-CSF vs high-dose cyclophosphamide + GM-CSF for blood progenitor cell mobilization

Palliative chemotherapy in recurrent carcinoma of the cervix: an audit of the use of ifosfamide and review of the literature

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