- 作者：Prof Ian Judson ; MDa ; ian.judson@icr.ac.uk" class="auth_mail ; Prof Jaap Verweij ; PhDb ; Prof Hans Gelderblom ; PhDc ; Prof Jö ; rg T Hartmann ; MDd ; e ; f ; Prof Patrick Schö ; ffski ; MPHg ; Prof Jean-Yves Blay ; PhDh ; i ; J Martijn Kerst ; PhDj ; Prof Josef Sufliarsky ; MDk ; Prof Jeremy Whelan ; MDl ; Prof Peter Hohenberger ; MDm ; Anders Krarup-Hansen ; MDn ; Prof Thierry Alcindor ; MDo ; p ; Sandrine Marreaud ; MDq ; Saskia Litiè ; re ; PhDq ; Catherine Hermansq ; Prof Cyril Fisher ; DSca ; Prof Pancras C W Hogendoorn ; PhDc ; Prof A Paolo dei Tos ; MDr ; Prof Winette T A van der Graaf ; PhDs ; for the European Organisation ; Treatment of Cancer Soft Tissue ; Bone Sarcoma Group &dagger
- 刊名：Lancet Oncology
- 出版年：April, 2014
- 年：2014
- 卷：15
- 期：4
- 页码：415-423
- 全文大小：320 K
Summary
Background
Effective targeted treatment is unavailable for most sarcomas and doxorubicin and ifosfamide鈥攚hich have been used to treat soft-tissue sarcoma for more than 30 years鈥攕till 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/m2 by intravenous bolus on day 1 or 72 h continuous intravenous infusion) or intensified doxorubicin (75 mg/m2; 25 mg/m2 per day, days 1-3) plus ifosfamide (10 g/m2 over 4 days with mesna and pegfilgrastim) as first-line treatment. Randomisation was stratified by centre, performance status (0 vs 1), age (<50 vs 鈮?0 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 , number .
Findings
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路8 months [95路5% CI 10路5-14路3] in the doxorubicin group vs 14路3 months [12路5-16路5] in the doxorubicin and ifosfamide group; hazard ratio [HR] 0路83 [95路5% CI 0路67-1路03]; stratified log-rank test p=0路076). Median progression-free survival was significantly higher for the doxorubicin and ifosfamide group (7路4 months [95% CI 6路6-8路3]) than for the doxorubicin group (4路6 months [2路9-5路6]; HR 0路74 [95% CI 0路60-0路90], stratified log-rank test p=0路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路0006). The most common grade 3 and 4 toxic effects鈥攚hich were all more common with doxorubicin and ifosfamide than with doxorubicin alone鈥攚ere 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%]).
Interpretation
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.
Funding
Cancer Research UK, EORTC Charitable Trust, UK NHS, Canadian Cancer Society Research Institute, Amgen.