Systemic Anti-Cancer Therapy in Synovial Sarcoma: A Systematic Review

Synovial sarcoma (SS) is an aggressive malignancy which accounts for approximately 5–10% of all soft-tissue sarcomas. SS has pathologic and genomic characteristics that define it as a distinct subtype of soft tissue sarcoma (STS). STS subtypes continue to be recognized as distinct entities with specific characteristics, including differential chemo-sensitivity. The objective of this study was to conduct a descriptive review of current data on survival outcomes of systemic anti-cancer therapy specific to SS. A systematic literature review was conducted, using a custom search strategy to search EMBASE, Medline and CENTRAL for clinical trials and observational studies reporting overall survival (OS), progression-free survival (PFS) and/or response for cohorts of at least 50 SS patients. We identified 28 studies meeting these criteria, 25 of which were retrospective studies. Only three prospective studies were identified. Survival reports varied widely between studies based on the population, in particular on the disease stage, and reporting was heterogeneous in terms of the time points reported on. For patients with localized disease, reports of five-year PFS ranged from 26% to 80.7% and five-year OS from 40% to 90.7%, whereas five-year OS for patients with metastatic disease was very low at around 10%; and in one case, 0% was reported. Only four of the included publications reported outcomes by type of systemic anti-cancer therapy received. Our study draws attention to the fact that additional prospective studies to better define the most appropriate treatment for SS in all stages and lines of therapy are still needed.

To study the association of clinicopathologic variables with recurrence, metastases, and tumor-related death in patients with synovial sarcoma who did not have metastases at presentation.
Scheer, 2016 [2] Assess the outcomes, identify prognostic factors, and to analyse treatment strategies in synovial sarcoma patients with metastases at diagnosis. Krieg, 2011 [3] To investigate the extent to which individual clinical tumor-specific factors as well as surgical approach affect the outcome of patients with synovial sarcoma with at least 10-year followup.
Beaino, 2016 [4] To determine the local recurrence-free survival and distant recurrence-free survival in patients with T1 (<5 cm) localized synovial sarcoma; To identify what determines local recurrence and metastasis; To assess if radiation and chemotherapy affect local recurrence and metastasis in early stage disease.
Orbach, 2011 [5] To determine if the modified indications for radiotherapy or radical surgery, according to the quality of initial resection and response to initial chemotherapy, had an impact on survival.
Shi, 2013 [6] To review the outcomes of a cohort of synovial sarcoma patients at single institution, identify prognostic factors impacting both local and distant disease control, and document acute and late toxicity related to treatment.

Eilber, 2007 [7]
To determine if ifosfamide-based chemotherapy offers a survival benefit to adult patients with primary extremity synovial sarcoma.
Al-Hussaini, 2011 [8] To investigate the impact of chemotherapy on survival in both paediatric and adult patients with localized synovial sarcoma treated at two specialized sarcoma centres.

Trassard, 2001 [9]
To identify most significant and therapeutically relevant prognostic factors in adults with localized primary synovial sarcomas and to confirm the usefulness of the French Federation of Cancer Centers (FNCLCC) grading system.

Ferrari, 2015 [10]
To assess survival rates and treatment failure patterns; the role of ifosfamide-doxorubicin chemotherapy in improving response rates in patients with unresectable synovial sarcoma; and to determine the impact of omitting adjuvant chemotherapy in patients with low-risk synovial sarcoma. Brecht, 2006 [11] To identify risk and treatment factors which influence survival rates in patients with synovial sarcoma.

Italiano, 2009 [12]
To clarify the prognosis factors and the impact of neo-adjuvant/adjuvant chemotherapy for adult patients with localized synovial sarcoma.
Canter, 2008 [13] To analyse the clinicopathologic predictors of distant recurrence and sarcoma-specific death.
Vlenterie, 2015 [14] To explore age as a prognostic factor in synovial sarcoma patients.
Vining, 2017 [15] To study the effect of adjuvant chemotherapy on OS among a large cohort of patients undergoing curative-intent resection of synovial sarcoma.
Gronchi, 2017 [16] Show the superiority of the neoadjuvant administration of histotype-tailored regimen to standard chemotherapy.

Locally advanced or metastatic
Takenaka, 2008 [17] To clarify the prognostic impact of SYTY-SSX fusion type, in association with other clinical factors, in patients with synovial sarcoma in Japan.

Setsu, 2013 [18]
To investigate the phosphorylation status of Akt (protein kinase B), mTOR, 4E-BP1, and S6 in a large series of synovial sarcoma and evaluated the relation between Akt/mTOR pathway activation and clinical and histopathologic features. Deshmukh, 2004 [19] To determine whether distal or truncal location of synovial sarcoma is of prognostic significance for survival when corrected for tumor size. Guillou, 2004 [20] To assess the prognostic value of SYT-SSX fusion type, in comparison with other factors, in patients with synovial sarcoma. Palmerini, 2009 [21] To retrospectively examine all synovial sarcoma patients treated at our institution to identify tumor-related and treatment-related factors influencing survival. Ferrari, 2004 [22] To retrospectively analyse a large series of synovial sarcoma patients of all ages who were treated at a single centre.
Vlenterie, 2016 [23] Compared the demographics and outcome of a large subset of advanced synovial sarcoma patients treated in first-line palliative chemotherapy studies between 1976 and 2012 and compared these results with other advanced STS patients treated in these studies.
Brennan, 2016 [24] To assess the role of age, socioeconomic status and other prognostic factors on outcome for synovial sarcoma.
Corey, 2014 [25] To determine demographic and survivorship of 34 soft tissue sarcomas. Spurrell, 2005 [26] To look specifically at a cohort of patients with advanced synovial sarcoma and to identify potential prognostic factors.

Metastatic disease
Sanfilippo, 2015 [27] To review all patients with advanced synovial sarcoma treated with trabectedin at four European sarcoma reference centers and within the Italian Rare Cancer Network.
Savina, 2017 [28] To utilized a unique set of data to assess the modalities of treatment of patients with metastatic STS in a real-life setting, to evaluate their impact on the outcome according to the histological subtype.