Adding Ifosfamide Fails to Improve Survival in Sarcoma

Combination treatment with ifosfamide and doxorubicin for advanced soft-tissue sarcoma did not improve overall survival compared with treatment with doxorubicin alone, despite improvements in both overall response and progression-free survival, according to the phase III results of the EORTC 62012 trial.

“If the goal is disease control (eg, for patients with asymptomatic lung metastases), sequential single-agent therapy is appropriate, but if tumor shrinkage is required (eg, prior to surgery, or for symptom control), then combination therapy is justified,” said study author Ian Judson, MD, head of the sarcoma unit at The Royal Marsden Hospital, London, and chairman of the EORTC Soft Tissue and Bone Sarcoma Group. 

According to Judson, in recent years there has been an increasing trend toward the use of combination ifosfamide plus doxorubicin for the treatment of advanced sarcoma, especially in North America, without any evidence that it provided an advantage, especially in relation to survival.

The phase III controlled EORTC 62012 trial was design to assess whether dose intensification of doxorubicin with ifosfamide improved survival compared with doxorubicin alone. The trial was conducted at 38 hospitals in 10 countries and randomly assigned 455 patients with advanced, unresectable, or metastatic high-grade soft-tissue sarcoma to one of two treatment arms: 1) doxorubicin alone-75 mg/m² by intravenous bolus on day 1 or 72 hour continuous intravenous infusion-or 2) intensified doxorubicin-75 mg/m²; 25 mg/m² per day for days 1 to 3-plus ifosfamide.

The primary endpoint of the study was overall survival. Results were published in the Lancet Oncology.

Median follow-up of patients in the doxorubicin group was 56 months (n = 228); it was 59 months for patients in the combination group (n = 227).

“The key finding of the study was that there was no statistically significant survival advantage to the use of the intensive combination regimen used in the trial, which was perhaps surprising, given that there was an advantage for objective response and progression-free survival,” Judson said.

The median overall survival was 12.8 months for the doxorubicin group compared with 14.3 months for the doxorubicin plus ifosfamide group (HR = 0.83; 95.5% CI, 0.67-1.03; P = .076). At 1 year, the overall survival was 51% for the doxorubicin group compared with 60% for the combination group.

Patients in the doxorubicin plus ifosfamide group did however have significantly longer progression-free survival compared with the doxorubicin alone group (7.4 months vs 4.6 months; P = .03). Additionally, 26% of patients in the combination group had an overall response compared with only 14% of patients in the doxorubicin alone group (P = .0006).

Commonly occurring grade 3 and 4 adverse effects were leucopenia, neutropenia, febrile neutropenia, anemia, and thrombocytopenia. All of these occurred more commonly in the combination treatment arm compared with doxorubicin alone.