title: Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial.
abstract: BACKGROUND
  Effective targeted treatment is unavailable for most sarcomas and doxorubicin and ifosfamide-which have been used to treat soft-tissue sarcoma for more than 30 years-still have an important role. Whether doxorubicin alone or the combination of doxorubicin and ifosfamide should be used routinely is still controversial. We assessed whether dose intensification of doxorubicin with ifosfamide improves survival of patients with advanced soft-tissue sarcoma compared with doxorubicin alone.
  
  
  METHODS
  We did this phase 3 randomised controlled trial (EORTC 62012) at 38 hospitals in ten countries. We included patients with locally advanced, unresectable, or metastatic high-grade soft-tissue sarcoma, age 18-60 years with a WHO performance status of 0 or 1. They were randomly assigned (1:1) by the minimisation method to either doxorubicin (75 mg/m(2) by intravenous bolus on day 1 or 72 h continuous intravenous infusion) or intensified doxorubicin (75 mg/m(2); 25 mg/m(2) per day, days 1-3) plus ifosfamide (10 g/m(2) over 4 days with mesna and pegfilgrastim) as first-line treatment. Randomisation was stratified by centre, performance status (0 vs 1), age (<50 vs ≥50 years), presence of liver metastases, and histopathological grade (2 vs 3). Patients were treated every 3 weeks till progression or unacceptable toxic effects for up to six cycles. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT00061984.
  
  
  RESULTS
  Between April 30, 2003, and May 25, 2010, 228 patients were randomly assigned to receive doxorubicin and 227 to receive doxorubicin and ifosfamide. Median follow-up was 56 months (IQR 31-77) in the doxorubicin only group and 59 months (36-72) in the combination group. There was no significant difference in overall survival between groups (median overall survival 12·8 months [95·5% CI 10·5-14·3] in the doxorubicin group vs 14·3 months [12·5-16·5] in the doxorubicin and ifosfamide group; hazard ratio [HR] 0·83 [95·5% CI 0·67-1·03]; stratified log-rank test p=0·076). Median progression-free survival was significantly higher for the doxorubicin and ifosfamide group (7·4 months [95% CI 6·6-8·3]) than for the doxorubicin group (4·6 months [2·9-5·6]; HR 0·74 [95% CI 0·60-0·90], stratified log-rank test p=0·003). More patients in the doxorubicin and ifosfamide group than in the doxorubicin group had an overall response (60 [26%] of 227 patients vs 31 [14%] of 228; p<0·0006). The most common grade 3 and 4 toxic effects-which were all more common with doxorubicin and ifosfamide than with doxorubicin alone-were leucopenia (97 [43%] of 224 patients vs 40 [18%] of 223 patients), neutropenia (93 [42%] vs 83 [37%]), febrile neutropenia (103 (46%) vs 30 [13%]), anaemia (78 [35%] vs 10 [5%]), and thrombocytopenia (75 [33%]) vs one [<1%]).
  
  
  CONCLUSIONS
  Our results do not support the use of intensified doxorubicin and ifosfamide for palliation of advanced soft-tissue sarcoma unless the specific goal is tumour shrinkage. These findings should help individualise the care of patients with this disease.
  
  
  BACKGROUND
  Cancer Research UK, EORTC Charitable Trust, UK NHS, Canadian Cancer Society Research Institute, Amgen.
authors.affiliation: Royal Marsden Hospital, London, UK. Electronic address: ian.judson@icr.ac.uk.
authors.forename: Ian
authors.initials: I
authors.lastname: Judson
authors.affiliation: Erasmus MC Cancer Institute, Rotterdam, Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.affiliation: Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
authors.affiliation: Eberhard Karls Universitaet Tübingen, Tübingen, Germany; Christian-Albrechts-University, Kiel, Germany; Catholic Hospital, Consortium, Bielefeld, Germany.
authors.forename: Jörg T
authors.initials: JT
authors.lastname: Hartmann
authors.affiliation: Department of General Medical Oncology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.affiliation: Department of Medicine, NetSARC and LYRIC, Centre Leon Berard, Lyon, France; University Centre Leon Berard, Lyon, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
authors.affiliation: Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: J Martijn
authors.initials: JM
authors.lastname: Kerst
authors.affiliation: National Cancer Institute, Bratislava, Slovakia.
authors.forename: Josef
authors.initials: J
authors.lastname: Sufliarsky
authors.affiliation: The London Sarcoma Service, University College Hospital, London, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Whelan
authors.affiliation: Mannheim University Medical Center, Mannheim, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Hohenberger
authors.affiliation: Department of Oncology, Herlev Hospital-University Copenhagen, Herlev, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Krarup-Hansen
authors.affiliation: Department of Oncology, McGill University Montreal, QC, Canada; Montreal General Hospital, Montreal, QC, Canada.
authors.forename: Thierry
authors.initials: T
authors.lastname: Alcindor
authors.affiliation: EORTC, Brussels, Belgium.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marreaud
authors.affiliation: EORTC, Brussels, Belgium.
authors.forename: Saskia
authors.initials: S
authors.lastname: Litière
authors.affiliation: EORTC, Brussels, Belgium.
authors.forename: Catherine
authors.initials: C
authors.lastname: Hermans
authors.affiliation: Royal Marsden Hospital, London, UK.
authors.forename: Cyril
authors.initials: C
authors.lastname: Fisher
authors.affiliation: Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Pancras C W
authors.initials: PC
authors.lastname: Hogendoorn
authors.affiliation: Azienda ULSS 9 Treviso, Treviso, Italy.
authors.forename: A Paolo
authors.initials: AP
authors.lastname: dei Tos
authors.affiliation: Department of Medical Oncology, Radboud University Medical Center Nijmegen, Netherlands.
authors.forename: Winette T A
authors.initials: WT
authors.lastname: van der Graaf
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005060:Europe; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010166:Palliative Care; D018579:Patient Selection; D012307:Risk Factors; D012509:Sarcoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary*; D012983:Soft Tissue Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D013997:Time Factors; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D055815:Young Adult
chemical_list: D004317:Doxorubicin; D007069:Ifosfamide