The addition of aggressively dosed ifosfamide to doxorubicin in the treatment of advanced soft-tissue sarcomas significantly delayed disease progression but did not improve survival in the randomized phase III EORTC 62012 trial conducted by the Soft Tissue and Bone Sarcoma Group of the European Organisation for Research and Treatment of Cancer. The study was presented at the 2012 European Society for Medical Oncology (ESMO) Congress.¹

“The combination of doxorubicin and ifosfamide doubled the response rate and significantly improved progression-free survival, but it did not significantly improve overall survival and it was considerably more toxic than doxorubicin alone,” reported Winette van der Graaf, MD, of Radboud University Nijmegen Medical Center in The Netherlands.

Study Rationale

EORTC 62012 was initiated to address concerns that previous studies comparing single-agent doxorubicin vs doxorubicin/ifosfamide had used suboptimal doses of ifosfamide. Nonrandomized data had suggested that higher doses could increase responses and might impact survival, Dr. van der Graaf explained, but randomized data are necessary for proof.

The 455 patients (all age ≤ 60) had locally advanced or metastatic grade 2 or 3 soft-tissue sarcomas; in total, half of them were liposarcoma, leiomyosarcoma, and synovial sarcoma.

They were randomly assigned 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 3 weeks for a maximum of six cycles or until progression.

Major Findings

At a median follow-up of 56 months, the primary endpoint—overall survival—was numerically greater at 1 year with doxorubicin/ifosfamide (60% vs 51%), but the difference did not achieve statistical significance. Median overall survival was 14.3 months with the combination and 12.8 months with doxorubicin alone (HR = 0.83; P = .076). Virtually all of the patients who received doxorubicin alone subsequently received ifosfamide as second-line therapy, which could impact the overall survival results.

Median progression-free survival, 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), she reported.

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.

Despite colony-stimulating factor support, the combination regimen produced more severe (> grade 3) hematologic toxicity, including febrile neutropenia (45.9% vs 13.5%), anemia (34.9% vs 4.6%), and thrombocytopenia (33.5% vs 0.4%). While more patients discontinued treatment due to progression with doxorubicin (41.7% vs 20.7%), more discontinued the combination regimen due to toxicity (17.6% vs 2.6%).

According to the investigators, the findings do not support the routine use of the intensive combination of doxorubicin plus ifosfamide in the setting of advanced incurable disease. They added, however, that the higher response rate suggests this regimen might be justified in select patients aged ≤ 60 if tumor shrinkage is critical, with the caveat that it is significantly more toxic than doxorubicin alone.

While the regimen should not be universally applied, Dr. van der Graaf said the study’s results “make it is easier to have discussions with patients, as to which treatment is optimal in which situation.” ■

Disclosure:Dr. van der Graaf reported no potential conflicts of interest.

Reference

1. van der Graaf WTA, Judson I, Verweij J, et al: Results of a randomized 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.2012 ESMO Congress. Abstract LBA7. Presented October 1, 2012.