Neoadjuvant chemotherapy with an anthracycline and ifosfamide is better than histology-driven chemotherapy in patients with high-risk soft tissue sarcoma

Neoadjuvant chemotherapy with an anthracycline plus ifosfamide was associated with significant survival gains in patients with soft tissue sarcoma of the trunk or extremities who are at high-risk of recurrence. The study compared this type of chemotherapy with chemotherapy regimens tailored to histology sub-types and was designed to show a benefit in the relapse risk of the histology-driven therapy. However, this trial showed that neoadjuvant anthracycline plus ifosfamide was better than the histology-driven regimens. The statistically significant and clinically relevant benefit in recurrence-free (RFS) and overall survival (OS) in favor of standard chemotherapy does provide evidence in support of its efficacy, which is currently still debated

The presented multi-center study included 287 patients with high-risk soft tissue sarcoma from five histological subtypes (representing approximately 80% of all soft tissue sarcomas) arising in an extremity or the trunk wall. Patients were randomized 1:1 to receive either three cycles of epirubicin (120 mg/sqm) plus ifosfamide (9 g/sqm), or three cycles of one of the following five histologically-tailored regimens: gemcitabine plus docetaxel for undifferentiated pleomorphic sarcoma; trabectedin for patients with high-grade myxoid liposarcoma; high-dose prolonged-infusion ifosfamide in synovial sarcoma; etoposide plus ifosfamide for patients with malignant peripheral nerve sheath tumors; or gemcitabine plus dacarbazine in case of leiomyosarcoma. All chemotherapy regimens were administered in the neo-adjuvant setting.

After a median follow-up of 12.3 months, patients randomized to epirubicin plus ifosfamide had a significantly higher probability of being relapse-free at 46 months than patients who were treated with a histology-driven regiment (0.62 vs. 0.38, p=0.004; cox univariate HR[95%CI]: 1.955[1.119-3.190]; p=0.007). Also the OS was significantly better with anthracycline-ifosfamide strategy (probability of being alive after 46 months: 0.89 vs. 0.64, p=0.033; cox univariate HR[95%CI]: 2.687[1.104-6.937]; p=0.034).

Formally, this trial was negative as it failed to show an advantage of histology-driven neoadjuvant chemotherapy over standard neoadjuvant chemotherapy with an anthracycline and ifosfamide in resectable high-risk soft tissue sarcoma of the extremities or trunk wall. However, the observation of a statistically significant and clinically relevant difference in RFS and OS in favor of standard chemotherapy provides evidence in support of its efficacy, a fact that is currently debated. However, the question remains whether this approach is better than giving no treatment. Nevertheless, this trial including patients with soft tissue sarcoma selected by a risk of relapse averaging 60 to 70%, demonstrates that a short full-dose course of neoadjuvant anthracycline plus ifosfamide increases the RFS by 20% and the OS by 10% at 46 months. Of note, while the study failed to show any benefit from histologically-tailored regimens, a subgroup analysis did suggest that patients with high-grade myxoid liposarcoma who were treated with trabectedin had a similar RFS and OS than those treated with epirubicin plus ifosfamide. As trabectedin is far less toxic than conventional chemotherapy, this subgroup will be expanded to assess if there is no difference between the two in terms of outcomes.

Reference

Gronchi A, Ferrari S, Quagliuolo V, et al. Full-dose neoadjuvant anthracycline + ifosfamide chemotherapy is associated with a relapse free survival (RFS) and overall survival (OS) benefit in localized high-risk adult soft tissue sarcomas (STS) of the extremities and trunk wall: Interim analysis of a prospective randomized trial. Presented at ESMO 2016; Abstract LBA6_PR.