A phase II study of ifosfamide/mesna with doxorubicin for adult soft tissue sarcoma

Abstract

In a phase II study, 16 adult patients with locally advanced or metastatic soft tissue sarcomas were treated with i.v. infusions of ifosfamide/mesna 5 g/m2 plus i.v. doxorubicin 40 mg/m2. Courses were given every 3 weeks up to a maximum of six courses in responding patients. Six patients (37.5%) had either complete (1 patient) or partial responses (5 patients). Confidence limits for this response rate were 15.2%-64.5% (95% confidence level). There was one toxic death in association with encephalopathy, renal and bone marrow failure. Unilateral pneumothoraces occurred in 2 patients with large pulmonary metastases. Recurrent severe ifosfamide/mesna encephalopathy occurred in 2 patients at risk for this complication; patients who develop severe ifosfamide/mesna encephalopathy should not be retreated with this drug. Ifosfamide/mesna with doxorubicin is an active combination to treat adult soft tissue sarcoma but, despite the feasibility of the combination, sequential monotherapy with these drugs might provide similar or better clinical benefit.

Novel Approaches to Treatment of Leiomyosarcomas

“…The response rate for all STS in the doublet arm was 34% versus 20% in doxorubicin alone; however, the response rate for LMS, which made up 44% of the cases, was only 14% [12]. Several other studies have shown similar response rates in STS in general, varying from 22% to 37%, but no overall survival advantage [13][14][15][16]. A recent analysis of an EORTC trial showed a decrease in OS for patients with metastatic LMS treated with ifosfamide in the first-line setting [17], though it does have a role in the second-line after doxorubicin.…”

“…Many studies have looked at karyotyping for LMS with little consistency, in keeping with the expected heterogeneity and complexity [46]. The chromosomal changes described in LMS include imbalances or aberrations in the form of gains (chromosomes 1, 5, 6, 8, 15, 16, 17, 19, 20, 22, X), losses (chromosomes 1p, 2, 3, 4, 6q, 8, 9, 10p, 11p, 12q, 11q, 13, 16, 17p, 18, 19, 22q), and amplifications (chromosomes 1,5,8,12,13,17,19,20). Some gains and losses of chromosomal material are more frequently observed and tend to correlate with poor outcome, large tumor size, and metastatic disseminationeg, loss of 1p12-pter, 2p, 13q14-q21 (targeting the Rb pathway), 10q (targeting PTEN), and 16q; gains of 17p, 8q, and 5p14 pter [42].…”

Ifosfamide and mesna in combination with other cytostatic drugs in the treatment of patients with advanced cancer

“…Encouraging results have been reported with combinations of IFX and etoposide in patients with small cell lung cancer [10]. While doxorubicin has been used in combination with IFX, especially in the treatment of soft tissue sarcomas, response rates do not justify the added toxicity [11,12]. This is a report of our experience with IFX (plus mesna) in combination with other drugs in the treatment of patients with advanced malignant neoplasms.…”

Future directions in the management of soft tissue sarcomas

“…Ifosfamide and doxorubicin combinations with or without dacarbazine have been evaluated in a variety ofphase I1 and I11 studies (Kirchner et al, 1986;Wiltshaw et al, 1986;Schuette et al, 1987;Hartlapp et al, 1986;Bramwell et al, 1989;Cantwell et al, 1988;Elias et al, 1990;Edmonson et al, 1989;Mansi et al, 1988;Loehrer et al, 1989;Santoro et al, 1990). Response rates appear to be higher (50 per cent range) in those trials planning higher dose intensities of the two drugs, but drop to the 25-35 per cent range in cooperative group or lower dose intensity trials (Table 3).…”