Neoadjuvant Therapy Shows Unexpected Benefit for High-Risk Soft Tissue Sarcoma

Despite the technically negative results, a recent trial in high-risk adult soft tissue sarcoma still showed a significant survival benefit for anthracycline-based neoadjuvant chemotherapy, according to a study reported at the 2016 European Society for Medical Oncology (ESMO) Congress.

After follow-up for up to five years, patients who received full-dose anthracycline-ifosfamide chemotherapy had a relapse-free survival (RFS) probability of 62 percent versus 38 percent for patients who preoperative therapy tailored to individual tumor histology. Overall survival (OS) was 89 percent with chemotherapy and 64 percent without.

Despite the survival advantage for anthracycline-based chemotherapy, the trial failed to achieve its primary objective: demonstrate a benefit from tailoring chemotherapy to tumor histology.

“In a population of soft tissue sarcoma patients selected by a risk of relapse averaging 60 percent to 70 percent, the neoadjuvant administration of a short, full-dose anthracycline-plus-ifosfamide chemotherapy increases relapse-free survival by more than 20 percent and overall survival by at least 10 percent at more than three years,” said Alessandro Gronchi, M.D., chair of Sarcoma Surgery at the National Cancer Institute in Milan, Italy. “The final analysis will be performed when the follow-up is mature, but we believe that clinical practice guidelines and future studies will have to accommodate this new evidence.”

Studies of adjuvant chemotherapy in soft tissue sarcoma have yielded conflicting results, making the role of such therapy in clinical practice unclear. A randomized trial conducted by the Italian Sarcoma Group (ISG) provided evidence of a survival benefit in high-risk soft tissue sarcoma in adults treated with anthracycline-ifosfamide adjuvant chemotherapy. However, a subsequent randomized trial showed no evidence of benefit with the same regimen administered as neoadjuvant therapy.

To emphasize the uncertainty surrounding systemic therapy for high-risk STS, Gronchi cited the ESMO/European Sarcoma Network Working Group guideline on soft tissue sarcoma.

“Adjuvant chemotherapy is not standard treatment in adult-type STS. It can be proposed as an option to the high-risk individual patient (high-grade, deep, greater than 5 cm tumors) for a shared decision making with the patient or within clinical trials.”

In an effort to bring some clarity to the controversy, the ISG conducted another randomized trial to compare neoadjuvant epirubicin-ifosfamide with histology-tailored neoadjuvant therapy. The tailored therapy options were: gemcitabine-docetaxel for undifferentiated pleomorphic sarcoma; trabectedin for high-grade myxoid liposarcoma; high-dose, prolonged-infusion ifosfamide for synovial sarcoma; etoposide-ifosfamide for malignant peripheral nerve sheath tumors; and gemcitabine-dacarbazine in leiomyosarcoma.

Eligible patients had high-risk soft tissue sarcoma of the extremities or trunk wall (grade 3, at least 5 cm, deep site). The trial had a primary endpoint of RFS, and OS was a secondary endpoint. Investigators hypothesized that histology-tailored therapy would improve RFS by 33 percent compared with the epirubicin-ifosfamide regimen.

Investigators randomized 287 patients from 2011 to 2016. The study population had a median follow-up of 12.34 months.

Patients had a median age of 50 and a median tumor size of 10 cm. Preoperative chemotherapy was completed in 85 percent of patients in each treatment arm. Gronchi said 240 patients were evaluable for response.

Data analysis showed a 14 percent absolute difference in RFS probability at 46 months in favor of the epirubicin-ifosfamide arm. The difference translated into a hazard ratio of 1.955 for the comparison of the tailored therapy versus standard therapy. The 25 percent absolute difference in the probability of survival at 46 months also achieved statistical significance in favor of standard therapy, translating into a hazard ratio of 2.687 for the comparison of the tailored to standard therapy.

“Formally, this is a negative trial, as it ails to show any advantage of histology-tailored chemotherapy over standard chemotherapy in resectable high-risk soft tissue sarcoma of the extremities or trunk wall,” said Gronchi. “However, the presence of a statistically significant and clinically relevant difference in relapse-free survival and overall survival at more than three years in favor of standard chemotherapy provides strong, randomized evidence in support of its efficacy.”