Standard neoadjuvant chemotherapy improves OS, RFS in soft tissue sarcoma

COPENHAGEN, Denmark — Neoadjuvant chemotherapy with three full-dose courses of an anthracycline plus ifosfamide improved OS and RFS compared with histology-tailored regimens in patients with localized soft tissue sarcoma at high risk for relapse, according to interim results of a randomized trial presented at the European Society for Medical Oncology Congress.

“Adjuvant chemotherapy has been debated over the years; its benefit is not uniformly accepted because the largest studies were negative, while the smallest were positive,” Alessandro Gronchi, MD, chair of sarcoma surgery at National Cancer Institute in Milan, Italy, said during a press conference. “[The Italian Sarcoma Group] was the first to show a benefit with adjuvant chemotherapy in a small population of patients with a very high risk for disease relapse. Based on this study, which was carried out in the 90s, we later developed a regimen using conventional drugs used at full doses proven to be effective.”

Alessandro Gronchi

Gronchi and colleagues compared these conventional drugs — 120 mg/m² epirubicin plus 9 g/m² ifosfamide — with histology-driven regimens that have demonstrated selective activity in specific subgroups of patients treated on trials for metastatic sarcoma. The histology-drive regimens included:

gemcitabine plus docetaxel for undifferentiated pleomorphic sarcoma;
trabectedin (Yondelis, Janssen) for high-grade myxoid liposarcoma;
high-dose prolonged-infusion ifosfamide for synovial sarcoma;
etoposide plus ifosfamide for malignant peripheral nerve sheath tumors; and
gemcitabine plus dacarbazine for leiomyosarcoma.

These five histologies represent 80% of soft tissue sarcomas at high risk for relapse.

“Soft tissue sarcomas are rare, and they are also heterogeneous,” Gronchi said. “They are made up of different diseases. We wanted to see if conventional chemotherapy given to everybody, independently of histology type, was as good or worse compared with giving histology-tailored chemotherapy regimens.”

The analysis included data from 287 patients (median age, 50 years, range, 19-75) with localized high-risk soft tissue sarcoma of extremities or trunk wall. Patients had grade 3 disease and a tumor size larger than 5 cm (median, 10 cm).

Ninety-seven patients had undifferentiated pleomorphic sarcoma, 65 had myxoid liposarcoma, 70 had synovial sarcoma, 27 had malignant peripheral nerve sheath tumors and 28 had leiomyosarcoma.

Researchers randomly assigned patients to three cycles of standard chemotherapy or their appropriate histology-driven regimen. RFS served as the study’s primary endpoint.

Median follow-up was 12.34 months. Two hundred forty patients were evaluable for response.

Patients in the conventional chemotherapy arm demonstrated a significantly higher Kaplan Meier probability of 46-month RFS (0.62 vs. 0.38; P = .004) and 46-month OS (0.89 vs. 0.65; P = .033). The histology-driven regimens were associated with an increased risk for relapse (HR = 1.95; 95% CI, 1.11-3.19) and death (HR = 2.68; 95% CI, 1.1-5.93).

“Formally, this is a negative trial because it was designed to test superiority of the histology-driven chemotherapy over the conventional chemotherapy,” Gronchi said. “However, the presence of this statistically significant and clinically relevant improvement in OS and RFS at 3 years in favor of standard chemotherapy provides for the first time, strong and randomized evidence in support of its efficacy that had been, up to now, questioned.”

Based on recommendations from the Independent Reviewing Committee, the study was closed early, but additional subgroup analyses are ongoing.

“We believe that future practice guidelines and trials will have to accommodate this evidence,” Gronchi said.

Despite these findings, questions remain regarding neoadjuvant chemotherapy, Thomas Brodowicz, MD, program director of the bone and soft tissue sarcoma unit at Medical University Vienna in Austria, said in a press release.

“What we can conclude out of this is that the neoadjuvant anthracycline plus ifosfamide is better than the histology-driven regimens, but the question still is, is it better in comparison to no treatment?” he said. “Furthermore, are three cycles of histology-driven therapy enough, and is the neoadjuvant approach the right approach for all high-risk patients?”

Further, these findings cannot be extended to patients with metastatic disease, Brodowicz said.

More follow-up is needed, Gronchi said.

“As it was not apparent that the histology-driven therapy could have been associated with any detrimental effect per se, the main interest of these findings — if confirmed by a longer follow-up — is proof that using a neoadjuvant therapy in patients affected by high-risk soft tissue sarcoma of the extremities or trunk wall, is associated with a clear-cut OS and RFS advantage, as compared with any other available strategy, including no treatment,” Gronchi said in a press release. – by Alexandra Todak

Reference:

Gronchi A, et al. Abstract LBA6_PR. Presented at: European Society for Medical Oncology Congress; Oct. 7-11, 2016; Copenhagen, Denmark.

Disclosure: The researchers report no relevant financial disclosures.