No Survival Advantage for Ifosfamide Added to Doxorubicin in Advanced Soft Tissue Sarcoma

Winette van der Graaf, MD

The addition of ifosfamide to doxorubicin in the treatment of advanced soft tissue sarcomas delayed disease progression but did not improve survival in the EORTC 62012 trial, presented at the European Society for Medical Oncology (ESMO) 2012 Congress by Winette van der Graaf, MD, of Radboud University Nijmegen Medical Center in The Netherlands.

“The combination of doxorubicin and ifosfamide doubled the response rate and improved progression-free survival [PFS] significantly, but it did not significantly improve overall survival [OS] and it was considerably more toxic than doxorubicin alone,” van der Graaf reported.

The randomized phase III EORTC 62012 trial was initiated to address concerns that previous studies comparing single-agent doxorubicin versus doxorubicin plus ifosfamide in soft tissue sarcomas (STS) had used suboptimal doses of ifosfamide. Nonrandomized data suggested that a higher dose of the drug could increase response rate and PFS, van der Graaf said.

The study enrolled 455 patients with locally advanced or metastatic, grade 2 or 3 STS (age ≤ 60 years). The most common histological types were liposarcoma, leiomyosarcoma, and synovial sarcoma. More than two thirds of patients had lung metastases.

Patients were randomized to receive either single-agent doxorubicin (75 mg/m2) or doxorubicin (75 mg/m2) with ifosfamide (10 g/m2 over 4 days with growth factor support) as first-line treatment. Patients were treated every three weeks until progression or for a maximum of six cycles. The primary endpoint was OS.

At a median follow-up of 56 months, OS at 1 yr was numerically a little greater with doxorubicin/ifosfamide (60% vs 51%) but the difference was not statistically significant (hazard ratio [HR] = 0.83; P = .076). Median OS was 14.3 months with the combination and 12.8 months with doxorubicin alone.

Median PFS, however, was 7.4 months with the combination and 4.6 months with doxorubicin alone, for a 26% reduction in risk that was statistically significant (HR = 0.74; P = .003).

The objective response rate was 26.5% with the combination and 13.6% with doxorubicin. Progressive disease was noted for 13.2% and 32.5%, respectively.

Hematologic toxicity ≥ grade 3 was more common with the combination, including febrile neutropenia (45.9% vs 13.5%), anemia (34.9% vs 4.6%) and thrombocytopenia (33.5% vs 0.4%). Although more patients discontinued treatment due to progression with doxorubicin (41.7% vs 20.7%), more discontinued due to toxicity with the combination (17.6% vs 2.6%).

The investigators concluded that the lack of a significant improvement in OS does not support the routine use of the intensive combination of doxorubicin plus ifosfamide in the palliative setting. The higher response rate suggests that doxorubicin/ifosfamide might be justified in selected patients aged 60 years and under if tumor shrinkage is critical, but it is significantly more toxic.

van der Graaf suggested that the results can help guide treatment decisions. “The advantage of having these results is that now it is easier to have discussions with patients as to which treatment is optimal in which situation,” she said.

George Demetri, MD, director of the Ludwig Center and Sarcoma Center at Dana-Farber Cancer Institute and Harvard Medical School in Boston, Massachusetts, agreed and suggested that the question should not be which is the best first-line therapy for metastatic STS, but what is the best first-line therapy for a specific patient. The trial results can be used “to make informed choices based on solid data,” he said.

Demetri further noted that the average patient with metastatic STS lives 13 months. “The results mean that sarcoma is controlled for approximately 20% longer with combination chemotherapy,” and this is meaningful to the patient, he said.

van der Graaf WTA, Judson I, Verweij J, et al. 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 or metastatic soft tissue sarcoma: a survival study by the EORTC Soft Tissue and Bone Sarcoma Group. Paper presented at: 37th European Society for Medical Oncology Congress; September 28-October 2, 2012; Vienna, Austria. Abstract LBA7.

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