Urothelial Toxicity Research Articles

A phase II study of ifosfamide in endometrial cancer

Around 32% of all patients with endometrial carcinoma relapse after primary therapy. The outlook for these patients is poor. Ifosfamide (IFX) has activity in a number of gynaecological malignancies and was selected for evaluation in this disease. The aims of this study were to assess the activity and toxicity of IFX in recurrent endometrial carcinoma no longer amenable to radical local treatment. In all, 16 evaluable patients with symptomatic advanced metastatic or recurrent disease entered a phase II study of this drug. Patients received IFX (5 g/m2) as a 24-h infusion, with mesna (8 g/m2) given during and for 12 h following IFX to prevent urothelial toxicity. Treatment was repeated every 21 days. Two patients showed evidence of response [one complete response (CR) of 3 months and one partial response (PR) lasting 5 months]. Most patients experienced nausea and vomiting, and WHO grade 3/4 alopecia invariably occurred after two or more cycles. Four patients developed severe (grade 3/4) IFX/mesna CNS toxicity, and four other patients had mild (grade 1/2) CNS toxicity. Significant myelosuppression was seen in 3/41 cycles. Haematuria was uncommon and invariably mild. There were two toxic deaths (one due to grade 4 CNS toxicity and one due to septicaemia). IFX has activity in endometrial carcinoma, but responses are of limited duration and toxicity is considerable.

Toxic and nontoxic changes induced in the urothelium by xenobiotics

Urothelial carcinogenesis progresses through several morphologically identifiable stages from simple hyperplasia, to nodular and papillary hyperplasia, to papilloma, and to noninvasive and invasive carcinoma. Unfortunately, no specific identifiable markers on any of the early lesions are available to distinguish those which will become neoplasms from those that are potentially reversible. Urothelial toxicity secondary to cyclophosphamide injection also progresses through several phases, beginning with vacuolization of the epithelium, to necrosis and ulceration, followed by an inflammatory infiltrate, granulation tissue formation, and marked regenerative hyperplasia of the epithelium, with ultimate repair and return to normal. Numerous changes related to toxicity are similar to those seen during carcinogenesis. In addition, several apparent morphologic “changes” occurring in the adult bladder can be mistaken for evidence of toxicity, and more importantly, many of the changes seen during regenerative repair and during carcinogenesis occur in the normal fetal urothelial development.

Ifosfamide and mesna in the treatment of malignant disease mesna as urothelial protector

One hundred and forty-six patients with advanced malignant disease were treated with 6 different dosage schedules of ifosfamide (IFX). Mesna was used as urothelial protector. With mesna, urothelial toxicity was moderate, and single doses of up to 7 g/m2 could be administered without intolerable urotoxicity. Leukopenia was the dose-limiting factor in this study. Unexpected pulmonary edema occurred in 3 patients. Therapeutic results were disappointing. A malignancy identified in this study that warrants further investigation with IFX and mesna, is malignant mesothelioma.

Ifosfamide by bolus as treatment for advanced non-small cell lung cancer.

Ifosfamide at 5 g/m2 was given as a bolus to 48 patients with advanced progressing non-small cell lung cancer. Mesna (5 g/m2) was also given with the ifosfamide, both over 30 min. Further mesna was then given p.o. (3 g/m2) at 4, 8, and 12 h. If oral mesna was not acceptable then one or, if necessary, two 4-h to 6-h infusions (3 g/m2) were administered. A maximum of six courses at 3-weekly intervals was prescribed. A total of 174 courses was administered, and oral mesna was given during 64 courses: discharge was considered possible within 8-10 h after 55% of courses. Haematological toxicity was mild and no renal dysfunction was noted. Two patients became drowsy shortly after ifosfamide, but recovered 24-36 h later. The objective response rate was 29%, with one complete responder. A further 31% of patients (symptomatic responders) with stable disease symptomatically improved after the chemotherapy, by 20 or more points on the Karnofsky scale. The median survival was 5 months for the whole group, and 8 months each for the objective and symptomatic responder groups. Most patients' Karnofsky and respiratory scores improved with the chemotherapy. Ifosfamide with mesna can be given by short infusions, and the mesna given p.o. prevents any urothelial toxicity. Further exploration of short-infusion ifosfamide and mesna therapy would reduce hospitalization and allow for day-case regimens.

Treatment of Ifosfamide-Induced Urothelial Toxicity by Oral Administration of Sodium 2-Mercaptoethane Sulphonate (MESNA) to Patients With Inoperable Lung Cancer

The protective effect of oral administration of the thiol compound sodium 2-mercaptoethane sulphonate (MESNA) against urothelial toxicity induced by ifosfamide (IF) was tested in a group of 45 patients with inoperable lung cancer under treatment with IF (2250 mg/m2 on days 2-5) as part of a polychemotherapy regimen repeated in a 4-week cycle. MESNA was given orally on the days of treatment with IF in 3 doses of 840 mg/m2, each administered at 0 hr (= injection of IF), 4 hr and 8 hr p.i. Out of a total of 88 courses of this treatment we observed 10 episodes of asymptomatic microscopic haematuria and no episodes of gross haematuria. In this group of 45 patients under protection with MESNA there were 5 complete remissions and 9 partial remissions (total 31%). A further group of 25 patients under polychemotherapy with IF were treated by conventional prophylactic measures (raised fluid intake and forced diuresis). In this group there were 1 complete and 5 partial remissions (total 24%), but nearly all patients developed either gross haematuria and/or symptoms of bladder irritation (cystitis and pollakisuria). There were no appreciable differences between the MESNA series and the conventional prophylaxis series with respect to either haematological or systemic toxicity of the cytostatic treatment. Our results support the view that MESNA, given orally in conjunction with combined cytostatic regimens which include IF, simplifies the treatment and provides optimum protection for the urinary epithelium. Protection with oral MESNA is particularly suitable for outpatients.

High-dose cyclophosphamide with autologous marrow transplantation for small cell carcinoma of the bronchus.

Twenty-five patients with previously untreated small cell carcinoma of the bronchus have been treated with cyclophosphamide 160-200 mg/kg and subsequent radiotherapy to the primary site. Eighty-four percent of patients responded to the single cycle of chemotherapy, with 56% attaining a complete response. Median duration of remission was 43 weeks and median survival 69 weeks. 2-Mercaptoethane sulphonate was given to prevent urothelial toxicity. Autologous bone marrow transplantation was used to mitigate bone marrow depression but sequential delay in reinfusing cryopreserved bone marrow did not alter the period of cytopenia. Other toxicities were mild. The procedure proved safe and manageable. High-dose chemotherapy may prove to be useful in the initial management of this tumour.

Treatment of ifosfamide-induced urothelial toxicity by oral administration of sodium 2-mercaptoethane sulphonate (MESNA) to patients with inoperable lung cancer

The protective effect of oral administration of the thiol compound sodium 2-mercaptoethane sulphonate (MESNA) against urothelial toxicity induced by ifosfamide (IF) was tested in a group of 45 patients with inoperable lung cancer under treatment with IF ( 2250 mg/m 2 on days 2–5) as part of a polychemotherapy regimen repeated in a 4-week cycle. MESNA was given orally on the days of treatment with IF in 3 doses of 840 mg/m 2 , each administered at 0 hr (= injection of IF), 4 hr and 8 hr p.i. Out of a total of 88 courses of this treatment we observed 10 episodes of asymptomatic microscopic haematuria and no episodes of gross haematuria. In this group of 45 patients under protection with MESNA there were 5 complete remissions and 9 partial remissions (total 31%). A further group of 25 patients under polychemotherapy with IF were treated by conventional prophylactic measures (raised fluid intake and forced diuresis). In this group there were 1 complete and 5 partial remissions (total 24%), but nearly all patients developed either gross haematuria and/or symptoms of bladder irritation (cystitis and pollakisuria). There were no appreciable differences between the MESNA series and the conventional prophylaxis series with respect to either haematological or systemic toxicity of the cytostatic treatment. Our results support the view that MESNA, given orally in conjunction with combined cytostatic regimens which include IF, simplifies the treatment and provides optimum protection for the urinary epithelium. Protection with oral MESNA is particularly suitable for outpatients.

High-dose cyclophosphamide with autologous marrow transplantation as initial treatment of small cell carcinoma of the bronchus.

Sixteen patients with untreated small cell carcinoma of the bronchus received cyclophosphamide in a total dose of 160-200 mg/kg. Autologous marrow transplantation was used to minimise the period of hypoplasia and 2-mercaptoethane sulphonate to prevent urothelial toxicity. The procedure was well tolerated, with predictable and manageable toxicity. Complete radiological and bronchoscopic response was achieved in seven patients and partial response in a further seven. High-dose cyclophosphamide may be a useful initial treatment for this disease.

PREVENTION OF ISOPHOSPHAMIDE-INDUCED UROTHELIAL TOXICITY WITH 2-MERCAPTOETHANE SULPHONATE SODIUM (MESNUM) IN PATIENTS WITH ADVANCED CARCINOMA

In 8 patients receiving intravenous isophosphamide 2 g/m2 at 2-week intervals for advanced bronchogenic carcinoma the protective effect of 2-mercaptoethane sulphonate sodium (mesnum) against isophosphamide-induced urothelial toxicity was tested in a single-blind crossover trial. With isophosphamide alone, 7 of the 8 patients developed either hæmaturia or symptoms of bladder irritation; when mesnum was given in addition, only 1 patient had microhæmaturia and frequency, and this was in association with a urinary-tract infection. 5 patients then received fifteen courses of isophosphamide in increasing doses of 4 to 8 g/m2 i.v. with mesnum. In contrast to previous experience with isophosphamide at this high dosage, frank hæmaturia was never seen, microhaematuria was seen after only three courses, and mild dysuria after only one course. Pharmacokinetic studies showed that mesnum did not interfere with the metabolism of isophosphamide or its active antitumour metabolite, isophosphoramide mustard. Mesnum therefore enhances the therapeutic ratio of isophosphamide and may thereby increase its clinical efficacy.