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Phase III Trial of Two Investigational Schedules of Ifosfamide Compared With Standard-Dose Doxorubicin in Advanced or Metastatic Soft Tissue Sarcoma: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study

Paul Lorigan, Jaap Verweij, Zsuzsa Papai, Sjoerd Rodenhuis, Axel Le Cesne, Michael G. Leahy, John A. Radford, Martine M. Van Glabbeke, Anne Kirkpatrick, Pancras C.W. Hogendoorn, Jean-Yves Blay

From the Weston Park Hospital, Sheffield; Christie Hospital, Manchester; St James's University Hospital, Leeds, United Kingdom; Erasmus University Medical Center, Rotterdam; The Netherlands Cancer Institute, Amsterdam; University Medical Centre, Leiden, the Netherlands; National Institute of Oncology; National Medical Center, Budapest, Hungary; Institut Gustave Roussy, Villejuif; Centre Léon Bérard, Lyon, France; and the European Organisation for Research and Treatment of Cancer (EORTC) Data Center, Brussels, Belgium

Address reprint requests to Paul Lorigan, MB, FRCP, Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Rd, Manchester M20 4BX, United Kingdom; e-mail: Paul.Lorigan{at}christie-tr.nwest.nhs.uk

Purpose Single-agent doxorubicin remains the standard treatment for advanced soft tissue sarcomas. Combining doxorubicin with standard-dose ifosfamide has not been shown to improve survival and is associated with a significantly increased toxicity; it is not known whether higher dose single-agent ifosfamide is superior to doxorubicin.

Patients and Methods This randomized prospective multicenter phase III trial was designed to compare progression-free survival of patients with advanced soft tissue sarcoma receiving either regimen of standard doxorubicin 75 mg/m² every 21 days, ifosfamide 9 g/m² over 3 days continuous infusion, or ifosfamide 3 g/m² per day in 3 hours over 3 days. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, and toxicity.

Results The study included 326 patients. Grade 4 leukopenia, neutropenia, febrile neutropenia, and encephalopathy were more frequent in the ifosfamide arms. Progression-free survival, overall survival, and response rates were not significantly different between the three arms. An independent data monitoring committee reviewed the interim data and recommended early closure of the trial for futility (ie, no significant difference would be shown).

Conclusion Single-agent doxorubicin remains the treatment of choice for patients with advanced soft tissue sarcoma.

Supported by Grants No. 5U10-CA11488-27 through 2U10-CA11488-36 from the National Cancer Institute (Bethesda, MD); and by Cancer Research UK.

Presented at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002; Oral Presentation Connective Tissue Oncology Society, San Francisco, CA, October 2002.

This article's contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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