Chemotherapy is associated with improved survival in adult patients with primary extremity synovial sarcoma.

Synovial sarcoma comprises 10% to 15% of adult soft tissue sarcomas (STSs) with the extremity being the most common site of primary disease.1–8 This unique spindle cell tumor occurs predominately in young adults, is by definition histologically high grade and has been considered to present a poor prognosis compared with other STS histologies.9–13 Synovial sarcoma is divided into 2 histologic subtypes, biphasic and monophasic. Biphasic synovial sarcomas are composed of both spindle cell and epithelial components, whereas monophasic subtypes are entirely composed of spindle cells, with no epithelial component. In virtually all cases, synovial sarcomas contain a characteristic translocation (X;18;p11;q11) representing the fusion of SYT (18q11) with either SSX1 or SSX2 (both at Xp11).14,15 The resulting 2 gene fusions, SYT-SSX1 or SYT-SSX2, appear to be mutually exclusive and concordant in primary and metastatic tumors.16 Multiple studies have identified a number of prognostic factors associated with disease specific survival such as age, size, margin, mitotic activity, bone or neurovascular invasion, histologic subtype, p53 overexpression, Ki-67 proliferative index, and SYT-SSX fusion type.9–13,16,17 The relative predictive value of each of these prognostic factors remains controversial; however, large tumor size has consistently proven to be associated with the development of distant metastasis and decreased disease-specific survival.9–13,16,17 In patients with primary extremity synovial sarcoma that are ≥5 cm in size, distant metastasis occur in up to 53% of the patients with a resultant 5-year tumor-related mortality of 37%.11 Although surgery and radiation therapy have achieved excellent local control, distant metastasis remains the primary problem limiting survival. During the last several decades, neoadjuvant/adjuvant chemotherapy has been used to improve the outcome of patients with high-risk extremity STS as they have a significant risk of harboring subclinical micrometastasis at presentation. Because of the toxicity of these treatments and limited impact on survival, their use in patients with primary disease has been controversial.18,19 Ifosfamide-based chemotherapy (IF) was introduced as a promising treatment of patients with primary STS in the early 1990s. The few randomized controlled clinical trials performed using ifosfamide have conflicting results and are limited in their impact due to the inclusion of multiple, nonextremity tumor sites, heterogeneity of histologic types, and small sample sizes.20–22 Although several studies have suggested that IF offers a survival benefit to some high-risk patients with primary extremity STSs, these studies were designed to examine the impact of chemotherapy on a collection of many different histologies, making it difficult to assess the potential benefit to a specific histology.22–25 While IF has been shown to generate impressive responses in the treatment of metastatic synovial sarcoma, its effect on the survival of adult patients with primary disease remains unclear.26–30 The objective of this study is to determine if IF offers a survival benefit to adult patients with high-risk extremity synovial sarcoma.