|Authors:||W.T.A. van der Graaf1, I. Judson2, J. Verweij3, H. Gelderblom4, J.T. Hartmann5, P. Schöffski6, J.-Y. Blay7, A.P. Dei Tos8, S. Marreaud9, S. Litiere9; 1Nijmegen/NL, 2London/UK, 3Rotterdam/NL, 4Leiden/NL, 5Tubingen/DE, 6Leuven/BE, 7Lyon Cedex/FR, 8Treviso/IT, 9Brussels/BE|
The EORTC 62012 trial was initiated to address concerns that previous studies comparing single agent doxorubicin (D) versus (vs) doxorubicin plus ifosfamide (I) in soft tissue sarcomas (STS) had used suboptimal doses of I. Non-randomised data suggested that a higher dose of I could increase response rate and progression free survival (PFS).
Methods: Patients (pts) with locally advanced or metastatic, grade 2 or 3 STS aged up to 60 yrs, were randomised to receive either single agent D (75 mg/m2) or D (75 mg/m2) with I (10 g/m2 over 4 days with mesna and pegfilgrastim) as first-line treatment. Randomisation was stratified by performance status (0 or 1), age (< / =50 yrs), presence or absence of liver metastases and histological grade (grade 2 vs 3). Pts were treated every 3 wks till progression or max. 6 cycles. The primary endpoint was overall survival (OS).
Results: 455 pts from 38 centres were randomised to D (n=228) or D-I (n=227). With median follow-up of 56 months, OS at 1 yr was slightly greater with D-I at 60% (95.5% CI 53 – 66) vs 51% (95.5% CI 44 – 58) with D alone, but the difference was not statistically significant (HR 0.82, 95.5% CI 0.66 – 1.01, stratified log rank test p = 0.061). No difference was seen in the 2-yr OS rate which was 31% (95.5%CI 25 – 38) for D-I vs 28% (95.5%CI 22 – 34) for D. Median PFS was significantly increased at 7.4 months (95% CI 6.6 – 8.3) for D-I vs 4.6 months (95% CI 2.9 – 5.6) for D (HR 0.72, 95% CI 0.59 – 0.88, stratified log rank test p = 0.002). Responses were CR: D = 1, D-I = 4; PR: D = 30 (13.2%), D-I = 56 (24.7%); SD: D = 105 (46.1%), D-I = 114 (50.2%). Febrile neutropenia was more common with D-I (45.9% vs 13.6%) as was anaemia (35.3% vs 4.6%).
Conclusions: The lack of a significant improvement in OS does not support the routine use of this intensive combination of D + I for STS in the palliative setting. The higher response rate suggests that D-I might be justified in selected pts age <60 if tumour shrinkage is critical, but it is significantly more toxic. D remains the gold standard for comparative studies of first line chemotherapy in metastatic STS.