Results of a randomised phase III trial (EORTC 62012) of single agent doxorubicin versus doxorubicin plus ifosfamide as first line chemotherapy for patients with advanced , soft tissue sarcoma: a survival study by the EORTC Soft Tissue and Bone Sarcoma Group.
Results of a randomised phase III trial (EORTC 62012) of single agent doxorubicin versus doxorubicin plus ifosfamide as first line chemotherapy for patients with advanced, soft tissue sarcoma: a survival study by the EORTC Soft Tissue and Bone Sarcoma Group.
Ian Judson, Jaap Verweij, Hans Gelderblom, Jorg- Thomas Hartmann, Patrick Schöffski, Jean-Yves Blay, Angelo Paolo dei Tos, Sandrine Marreaud, Saskia Litiere, Winette van der Graaf
single agent doxorubicin or a combination of doxorubicin and ifosfamide
Which situation justifies which treatment, especially the more toxic combination treatment?
And in designing studies with new drugs/treatments: what will be the standard treatment arm to compare with?
EORTC study: randomized phase III trial (all grades) 663 pts (Santoro, et al 1995)
A: doxorubicin 75 mg/m2
B: cyclophosphamide, vincristine, doxorubicin, and dacarbazine (CYVADIC)
C: doxorubicin 50 mg/m2 plus ifosfamide 5 g/m2
Overall Response rate: 24% median overall survival:
Arm A: Doxorubicine : 23.3% 52 weeks
Arm B: CYVADIC: 28.4% 51 weeks
Arm C: Dox-IFOS: 28.1% 55 weeks
Doxorubicin 75 mg/m2 d 1 or
as a 72 hour continousi.v. infusion
New Treatment: B
Doxorubicin 25 mg/m2 d 1-3
+ Ifosfamide2.5 g/m2 d 1-4
+ Neulasta 6mg s.c. d5
The primary end point:
The secondary end points:
toxicity (CTC 2.0)
treatment related mortality
Early stopping rule: as PFS was used as surrogate for OS a failure to produce a significant improvement in PFS (at least 50% increase) would predict a likely failure
1yr survival is at least 10% higher in the combination arm (60 versus 50%), corresponding with a HR of 0.737 or less. Two-sided logrank test (alpha=0.05, beta 0.2).
- malignant fibrous histiocytoma
- liposarcoma (Myxoid/round cell, pleomorphic or dediferentiated)
- synovial sarcoma
- malignant peripheral nerve sheath tumor
- epithelioid sarcoma
Total randomized, N=455
Doxorubicin + Ifosfamide, N=227
3 did not start treatment
2 started other arm
Ineligible, n = 7
Ineligible, n = 8
5 did not start treatment
1 started other arm
215 eligible patients started allocated treatment
217 eligible patients started allocated treatment
HR = 0.83 (95.5% CI 0.67 – 1.03)
Stratified logrank test, p = 0.076
Median overall survival: single agent doxorubicin versus doxorubicin plus
Doxorubicin: 12.8 months (95.5 CI 10.5-14.3)
Doxorubicin-ifosfamide: 14.3 months (95.5% CI 12.5-16.5).
Survival at 1-year:
Doxorubicin: 51% (95.5% CI 44-58)
Doxorubicin-ifosfamide: 60% (95.5% CI 53-66)
HR = 0.74 (95% CI 0.60 – 0.90)
Stratified logrank test, p = 0.003
Median PFS in the doxorubicin arm: 4.6 months (95% CI 2.9 – 5.6),
in the combination arm 7.4 months (95% CI 6.6 – 8.3).
Significant difference between the two arms: p < 0.001
In this group of patients all below 60,
median age 48 years
The combination of doxorubicin and ifosfamide:
and pro’s and cons should – as always- be discussed with the patient.