(ChemotherapyAdvisor) – Single agent doxorubicin remains the gold standard in the first-line treatment of patients with advanced or metastatic soft tissue sarcoma, long-awaited results of a randomized phase 3 trial comparing the regimen to doxorubicin plus ifosfamide concluded during the European Society for Medical Oncology 2012 Congress.
“The study was initiated to address concerns that previous studies comparing these agents in soft tissue sarcomas had used suboptimal doses of ifosfamide,” noted Winette T.A. van der Graaf, MD, of Radboud University Medical Centre, Nijmegen, The Netherlands, adding that “nonrandomized data had suggested that a higher dose of this drug could increase response rate and progression-free survival [PFS].”
The EORTC Soft Tissue and Bone Sarcoma Group 38-center study randomly assigned 455 patients aged 18 to 60 years with locally advanced or metastatic grade 2 or 3 soft tissue sarcoma either to doxorubicin 75mg/m2 alone (n=228) or with iphosphamide 10g/m2 over 4 days with mesna and pegfilgrastim (n=227) every 3 weeks until disease progression for a maximum of 6 cycles.
Randomization was stratified by performance status 0 or 1, age ≤50 yrs, presence or absence of liver metastases, and histological grade 2 vs 3.
At a median follow-up of 56 months, overall survival (OS, the primary end point) was 14.3 months in the doxorubicin/iphosphamide arm and 12.8 months in the doxorubicin arm (HR 0.83; 95.5% CI, 0.67–1.03; P=0.076). OS at 1 year was 60% with doxorubicin/ifosfamide and 51% with doxorubicin alone, Prof. van der Graaf reported. The 2-year OS rate was 31% for doxorubicin/iphosphamide vs 28% for doxorubicin.
Doxorubicin/ifosfamide was associated with longer PFS, a median of 7.4 months vs 4.6 months for doxorubicin alone (HR 0.74; 95% CI: 0.60−0.90; P=0.003) and a higher overall response rate (26.5% vs 13.6%) vs doxorubicin alone; however, this was at the cost of increased toxicity. Febrile neutropenia was more common in the doxorubicin/iphosphamide arm (45.9% vs 13.6%), as was anaemia (35.3% vs 4.6%).
“The higher response rate suggests that doxorubicin/iphosphamide might be justified in selected patients age <60 if tumor shrinkage is critical, but it is significantly more toxic,” she concluded.