No Overall Survival Benefit of First-Line Doxorubicin Plus Ifosfamide vs Doxorubicin Alone in Advanced Soft-Tissue Sarcoma


Key Points

  • Doxorubicin/ifosfamide did not increase overall survival compared with doxorubicin alone.
  • The combination may have a role in cases in which tumor shrinkage is the goal of treatment.

In the open-label, phase III EORTC 62012 trial reported in The Lancet Oncology, Judson et al found that doxorubicin plus ifosfamide was not associated with any overall survival advantage compared with doxorubicin alone in patients with advanced or metastatic soft-tissue sarcoma. Progression-free survival and objective response rate were improved with the intensified regimen, suggesting a role in cases where tumor shrinkage is the goal of treatment.

Study Details

In the trial, 455 patients with locally advanced unresectable or metastatic high-grade soft-tissue sarcoma aged 18 to 60 years with WHO performance status of 0 or 1 were randomly assigned between April 2003 and May 2010 to receive intensified doxorubicin (75 mg/m2 at 25 mg/m2 per day on days 1–3) plus ifosfamide (n = 227; 10 g/m2 over 4 days with mesna and pegfilgrastim [Neulasta]) or doxorubicin alone (n = 228; 75 mg/m2 by bolus on day 1 or 72-hour continuous infusion) every 3 weeks until disease progression or unacceptable toxicity for up to a maximum of six cycles. The primary endpoint was overall survival.

The doxorubicin/ifosfamide group and doxorubicin group were generally balanced for age (median, 47 and 48 years), sex (50% and 55% female), WHO performance status (0 in 54% and 57%, 1 in 45% and 43%), histology (liposarcoma in 14% and 11%, leiomyosarcoma in 26% and 24%, synovial sarcoma in 11% and 17%, other in 49% and 48%), and histologic grade (intermediate in 45% in both, high in 48% and 52%).

No Overall Survival Difference

Median follow-up was 59 months in the combination group and 56 months in the doxorubicin group. Median overall survival was 14.3 months in the doxorubicin/ifosfamide group vs 12.8 months in the doxorubicin group (hazard ratio [HR] = 0.83, P = .076). Median progression-free survival was significantly longer in the doxorubicin/ifosfamide group (7.4 vs 4.6 months, HR = 0.74, P = .003).

Subgroup analyses showed greater benefits with combination therapy in patients with high-grade tumors and worse performance status, but tests for heterogeneity were not significant. Objective response occurred in 26% vs 14% of patients (P < .0006), with stable disease occurring in 50% vs 46%, and progressive disease occurring in 13% vs 32%.

Postprotocol treatment consisted of surgery in 20% of patients in both groups and chemotherapy in 64% of the combination group and 63% of the doxorubicin group, with the most common treatments being gemcitabine (19%), trabectedin (18%), and docetaxel (16%) in the combination group and ifosfamide (46%), trabectedin (15%), and gemcitabine (15%) in the doxorubicin group.


Grade 3 or 4 adverse events were more common in the combination group and included leukopenia (43% vs 18%), neutropenia (42% vs 37%), febrile neutropenia (46% vs 13%), anemia (35% vs 5%), and thrombocytopenia (33% vs < 1%). Treatment was discontinued due to toxicity in 18% vs 3% (including toxic death in 1% vs 2%).

The investigators concluded, “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.”

Ian Judson, MD, of Royal Marsden Hospital, is the corresponding author for The Lancet Oncology article.

The study was funded by Cancer Research UK, EORTC Charitable Trust, UK NHS, Canadian Cancer Society Research Institute, and Amgen. The study authors reported no potential conflicts of interest.

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