ASO Author Reflections: Moving the Needle in Extremity and Trunk Soft Tissue Sarcoma

PAST

Data from seminal randomized trials over the last several decades has resulted in local control rates of 80–95% of patients with localized extremity and trunk sarcoma (ETSTS) undergoing limb-sparing surgery with pre- or postoperative radiation therapy (RT) and anthracycline-based chemotherapy;¹ however, up to 50% of patients with localized disease will develop distant metastases. Although doxorubicin (± ifosfamide) has remained the backbone of systemic chemotherapy for ETSTS over the last 40 years, it benefits only a subset of patients with sometimes significant toxicity, highlighting the need for novel therapies in this rare disease.

PRESENT

The observed long-term toxicity from high-dose RT has led to the identification of populations of ETSTS patients who may benefit from RT at lower doses (i.e. myxoid liposarcoma)² or are able to omit RT altogether (tumors resected with widely negative margins)¹ while maintaining excellent local control rates. On the other hand, the concurrent administration of neoadjuvant chemoradiation is being increasingly considered for tumors of borderline resectability or when function preservation is the goal.¹ In addition, the development of widely validated nomograms has improved the survival risk calculation of a single patient, helping select those who can benefit the most from the available systemic chemotherapy.³ Finally, a better understanding of the diverse behavior of the various histopathologic subtypes of soft tissue sarcoma has led to approval of multiple systemic agents in patients with recurrent and/or metastatic STS, such as eribulin (microtubule inhibitor) for adipocytic sarcomas, trabectedin (alkylating agent) for liposarcoma and leiomyosarcoma, and pazopanib (multiple kinase inhibitor including vascular endothelial growth factor receptor, platelet-derived growth factor receptor, c-KIT, and fibroblast growth factor receptor) for STS.⁴ However, whether these agents reduce the likelihood of developing metastases in patients with localized disease remains unanswered.

FUTURE

Currently, there are approximately 500 active clinical trials evaluating novel combinatorial strategies for patients with sarcoma,⁵ including combinations of RT with cytotoxic agents (trabectedin and RT in myxoid liposarcoma), molecular target therapy (pazopanib and RT), devices (nanoparticles and RT), and immunotherapy trials. With the emergence of novel combinations of systemic therapy demonstrating response rates equal to (or better) than doxorubicin in patients with advanced disease, the incorporation of patients with localized disease in clinical trials is paramount to improving the long-term outcomes of our patients. Indeed, splitting patients by histologic subtype and individual risk of death using nomograms will be critical to maximize the chance to understand the benefit of these new agents/modalities. This is why in a disease as rare and variegated as sarcoma, moving the needle is particularly challenging, but the community of researchers and clinicians involved in the care of patients with STS has demonstrated the ability to collaborate and recruit patients in a rapid manner and this collaboration should be fostered with all means. Finally, increased use of alternative design strategies, including Bayesian adaptive trials, biomarker-driven designs, and surrogate endpoints such as pathologic response, are necessary to ensure that patients enrolled in the available trials are most likely to benefit.