The Intergroup Rhabdomyosarcoma Study (IRS) is designed to answer important therapeutic, clinical, and laboratory research questions about rhabdomyosarcoma. The IRS has been in existence since 1972 and is a collaborative multidisciplinary study carried out by Childrens Cancer Group (CCG) and the Pediatric Oncology Group (POG). Eligible patients in CCG and POG institutions are registered on the IRS protocols. There have been four major protocol studies: IRS-I(1972- 78), IRS-II(1978-84), IRS-III(l984-l99l), and IRS-IV(199l-__), plus intervening pilot studyprotocols. The fourth protocol, IRS-IV, began in October 1991. Between 686 and 1062 eligible patients have been entered on each full study (IRS-I, -II, -III). Each protocol beginning with IRS-II, developed as an outgrowth of the preceding study. The results of IRS-I, -II, -III have shed light on various surgical, radiotherapeutic and chemotherapeutic aspects of treatment in relation to disease stage, primary tumor site, tumor histology and patterns of disease spread. Patient survival and complete remission (CR) duration have increased progressively and significantly from IRS-I to -II to - III with incremental intensification of therapy to defined risk groups. At 3 years, the overall survival rate of 73% in IRS-III is superior to IRS-II, 67% and IRS-I, 60% p<.OOl. The same relationship is true for CR duration (76% vs 69% vs 64%, p<.OOl). IRS-IV will accrue patients over a 5-year period. A new IRS-derived TNM pre-treatment staging classification determines treatment randomization. The main chemotherapy questions are (l) comparison of the efficacy of cyclophosphamide vs ifosfamide vs ifosfamide + VP-l6, and (2) rank ordering of induction drug doublets (vincristine/melphalan vs ifosfamide/etoposide vs ifosfamide doxorubicin) and their clinical cross-resistance to VAC therapy. A major radiotherapy question also is addressed: hyperfractionated vs conventional dose. Patient follow- up and data analysis will continue until all patients have been followed for a minimum of 5 years from the start of treatment. Late treatment effects are being monitored and identified in selected patient subgroups. IRS-V planning is well underway and will include DNA ploidy and cytogenetic staging, risk-directed treatment strategies to test therapeutic hypotheses, molecular genetics and other tumor biology studies, immunohistochemistry, and late effects. Pilot studies of new therapy for IRS-V have already been initiated. The IRS-V should begin in 1997.