Neoadjuvant Therapy for Primary Resectable Retroperitoneal Sarcomas—Looking Forward

SIMPLE SUMMARY: This review summarizes the current evidence around neoadjuvant radiotherapy and systemic therapy for retroperitoneal sarcoma (RPS). While surgery is the cornerstone of treatment for these tumors, data from prospective studies, retrospective studies, early phase trials, and—most recently—our first phase III randomized trial for RPS suggest there are clinical scenarios in which neoadjuvant therapy may provide benefit. This review evaluates the STRASS results in the setting of other recent studies, identifies active trials of interest, and suggests future directions of study in this field. The intersection of STRASS and STRASS2 is considered and a summary of current acceptable approaches to neoadjuvant therapy for RPS is provided. ABSTRACT: The cornerstone of therapy for primary retroperitoneal sarcomas (RPS) is complete surgical resection, best achieved by resecting the tumor en bloc with adherent structures even if not overtly infiltrated. Until recently, trials designed to elucidate the role of neoadjuvant radiation or chemotherapy for RPS have been unable to achieve sufficient enrollment. The completion of the STRASS trial, which explored neoadjuvant radiotherapy for primary resectable RPS, is a major milestone in RPS research, but has prompted further questions about histology-driven treatment paradigms for RPS. Though it was ultimately a negative trial with respect to its primary endpoint of abdominal recurrence-free survival, STRASS produced a signal that suggested improved abdominal recurrence-free survival with neoadjuvant radiotherapy (RT) for patients with liposarcoma (LPS). No effect was seen for leiomyosarcoma (LMS) or high-grade dedifferentiated (DD) LPS, consistent with recent literature suggesting LMS and high-grade DD-LPS have a predominant pattern of distant rather than local failure. These results, along with those from other recent studies conducted at the bench and the bedside, emphasize the importance of a histology-specific approach to RPS research. Recent evidence for patterns of distant failure in LMS and high-grade DD-LPS has prompted the initiation of STRASS2, a study of neoadjuvant chemotherapy for these histologies. As this study unfolds, evidence may emerge for novel systemic therapy options in specific sarcoma histotypes given the explosion in targeted and immunotherapeutic applications over the last decade. This article reviews current and recent evidence around neoadjuvant radiation and chemotherapy as well as avenues for future study to optimize these treatment approaches.