Neoadjuvant Chemotherapy Causes Significant Survival Gains in Soft Tissue Sarcoma

Patients with high-risk soft tissue sarcoma who received neoadjuvant chemotherapy with an anthracycline plus ifosfamide achieved significant survival gains, an interim analysis found.

For the multi-center study, researcher enrolled 287 patients with high-risk soft tissue sarcoma of the trunk of extremities from 5 histological subtypes.

Patients were randomized 1:1 to receive either 3 cycles of 120-mg/sqm epirubicin plus 9 g/sqm ifosfamide, or 3 cycles of 1 of 5 histological-tailored regimes: gemcitabine plus docetaxel (undifferentiated pleomorphic sarcoma); trabectedin (high-grade myxoid liposarcoma); high-dose prolonged-infusion ifosfamide (synovial sarcoma); etoposide plus ifosfamide (malignant peripheral nerve sheath tumors; or gemcitabine plus dacarbazine (leiomyosarcoma); all of which were given pre-operatively.

The results of the analysis showed that after a median follow-up of 12.3 months, patients who received epirubicin plus ifosfamide showed significantly higher probability of relapse-free survival at 46 months, compared with patients given a histology-driven regiment (0.62 vs 0.38, respectively, p=0.004). Overall survival was 0.89 versus 0.64 respectively (p=0.033).

“In this 80% of patients who have a high-risk of soft tissue sarcoma of the trunk or extremities, it is worthwhile considering chemotherapy with epirubicin plus ifosfamide because their prognosis is improved by 20%,” said principal study investigator Alessandro Gronchi. “We look forward to further follow-up of this trial to provide confirmation of this interim analysis as this is the first time that convincing evidence favoring the use of neoadjuvant chemotherapy is provided.”

Although the study did not produce any benefit from histologically-tailored regiments, the sub-group analysis did suggest that patients with high-grade myxoid liposarcoma treated with trabectedin had similar progression-free and overall survival to those treated with epirubicin plus ifosfamide.

“Trabectedin is far less toxic than conventional chemotherapy, so we will now expand this sub-group to assess if there is no difference between the 2 in terms of outcomes,” Gronchi said.

Professor Thomas Brodowicz commented on the study stated that there has been increased interest in histology-driven regimens for metastatic disease. Although the results of the current study in localized disease were negative, the conclusions could not be extended to metastatic disease, he said.

“Investigators wanted to show a one-third reduction in the relapse risk in favor of histology-driven therapy, so that means the trial did not meet the primary objective,” Brodowicz said. “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? Furthermore, are 3 cycles of histology-driven therapy enough and is the neoadjuvant approach the right approach for all high risk patients?”

The authors noted that more research needs to be done, as well as a longer follow-up.

“As it was not apparent that the histology-driven therapy could have been associated with detrimental effect per se, the main interest of these findings (if confirmed by a longer follow-up) is proof that using a neo-adjuvant therapy in patients affected by high risk soft tissue sarcoma of the extremities or trunk wall, is associated with a clear-cut overall and relapse-free survival advantage, as compared with any other available strategy, including no treatment,” Gronchi said.