Synovial sarcoma: characteristics, challenges, and evolving therapeutic strategies

Abstract

Synovial sarcoma (SS) is a rare and aggressive disease that accounts for 5%-10% of all soft tissue sarcomas. Although it can occur at any age, it typically affects younger adults and children, with a peak incidence in the fourth decade of life. In >95% of cases, the oncogenic driver is a translocation between chromosomes X and 18 that leads to the formation of the SS18::SSX fusion oncogenes. Early and accurate diagnosis is often a challenge; optimal outcomes are achieved by referral to a specialist center for diagnosis and management by a multidisciplinary team as soon as SS is suspected. Surgery with or without radiotherapy and/or chemotherapy can be effective in localized disease, especially in children. However, the prognosis in the advanced stages is poor, with treatment strategies that have relied heavily on traditional cytotoxic chemotherapies. Therefore, there is an unmet need for novel effective management strategies for advanced disease. An improved understanding of disease pathology and its molecular basis has paved the way for novel targeted agents and immunotherapies that are being investigated in clinical trials. This review provides an overview of the epidemiology and characteristics of SS in children and adults, as well as the patient journey from diagnosis to treatment. Current and future management strategies, focusing particularly on the potential of immunotherapies to improve clinical outcomes, are also summarized.

Highlights

• •Synovial sarcoma is a rare sarcoma with an incidence of 3/10e6/yr affecting all ages.
• •Synovial sarcomas present with translocations affecting SS18 and SSX1, SSX2, SSX4 genes, whose protein products affects the transcriptional program of the cancer cell.
• •Treatment of synovial sarcoma in localized phase follows the usual rules of sarcoma treatment, with uncertainties on the value of systemic treatment.
• •In advanced phase, the disease is rarely curable, with current systemic treatments.
• •Immunotherapy with autologous modified T cell recognizing MAGE-A4 or NY-ESO-1 have provided high response rates in recent reports.

Introduction

Synovial sarcoma (SS) is a rare and malignant tumor of the connective tissues that presents challenges in diagnosis and treatment.^1,2 This article describes the epidemiology, clinical and genomic characteristics of SS, and the patient pathway from diagnosis to treatment. Current and future management strategies will also be described, focusing particularly on the potential of immunotherapies to improve clinical outcomes.

Synovial sarcoma epidemiology, demographics, and clinical characteristics

Epidemiology

SS accounts for ∼5%-10% of all soft tissue sarcomas (STSs).^1,2 In children, SS is the most common nonrhabdomyosarcoma STS, accounting for 26%-36% of these cancers.³ STSs are a diverse group of rare tumors that arise from pathological changes in the mesenchyme, the mesodermal part of the embryo that develops into connective and skeletal tissues.^1,2 The reference to ‘synovial’ in SS is a misnomer as the cell of origin is uncertain and tumor cells do not originate from the synovium. An estimated 800-1000 new SS cases per year occur in both the United States and the European Union.^4,5 In a recent nationwide database study in France (2013-2016), SS had a yearly incidence of 1.67 cases per million.⁶ Similarly, in the United States, an estimated one to two people per million are diagnosed with SS annually.⁷

Patient demographics

As STS is a heterogenous grouping, with >100 histological types classified to date, the availability of SS-specific demographic data is limited.^1,8 Furthermore, most clinical studies include patients with various histologies.^1,9, 10, 11 SS can occur at any age, although it characteristically affects younger adults, with a peak incidence in the fourth decade of life and a median age at diagnosis of ∼30 years.12, 13, 14 A study on patients registered in the Surveillance, Epidemiology, and End Results (SEER) database determined that the age-adjusted incidence of SS was greater in adults than in children (1.42 versus 0.81 per million individuals, respectively).

Natural history of synovial sarcoma

SS occurs primarily in the soft tissue of the extremities (e.g. in the foot, knee, or ankle joints), often in proximity to joint capsules and tendon sheaths; however, it can also occur in other areas of the body, including the trunk, head and neck, abdomen, pelvis, mediastinum, pleura, lungs, and rarely, bone.^13,15,16 As with other STS types, patients with SS often present with nonspecific symptoms such as swelling or pain caused by compression of adjacent tissue.¹⁶ Symptoms of patients with SS are not specific and can overlap with benign conditions including trauma, myositis, bursitis, or tendonitis, leading to a risk of misdiagnosis early in the disease course.¹⁶ Patients with SS may also report long-standing pain at the site of the tumor before swelling becomes apparent.¹⁷

Most patients are diagnosed with localized disease; however, ∼6%-18% present with metastatic disease at diagnosis.^15,18 A SEER database study identified a similar frequency of distant SS metastases at diagnosis in adults compared with children: 13% versus 11%, respectively.¹⁹ The metastatic potential of SS is high in adults, as ∼50% of adult patients with SS develop metastatic disease; individuals ≤24 years of age have reported less frequent metastatic relapses with 5-year metastatic-free survival at 85.3% [95% confidence interval (CI) 75.9% to 94.7%].^12,20 The incidence of metastatic SS is slightly higher in men compared with women, and more common in white patients than in black or Hispanic patients.^11,21

Typically, the main sites of metastasis are the lungs, lymph nodes, and bone (in ∼80%, 7%-20%, and 2%-5% of patients, respectively).^18,22 Depending on the primary and distant tumor sites, symptoms of metastatic SS may include pain, fatigue, respiratory problems, reduced mobility, and gastrointestinal symptoms such as constipation, diarrhea, and vomiting.²

The 5-year cancer-specific survival (CSS) rates are ∼60% in adults and 80% in younger patients.¹⁹ Compared with those presenting with localized disease, patients with advanced SS at initial diagnosis have a poor prognosis.²³ Adults with metastatic SS at diagnosis have a 5-year overall survival (OS) rate of 10% versus 76% for those with localized disease at diagnosis.¹⁸ Across all adult patients with advanced SS (both de novo and after recurrence from limited disease), a median survival of 16.2 months (95% CI 12.6-23.2 months) has been reported.²⁴

As recorded by clinical and retrospective studies, survival rates and prognoses among children with localized SS at diagnosis are better than in adults, with a 5-year event-free survival (EFS) of 80.7% (95% CI 72.5% to 86.7%).^14,19,25,26 A US-based analysis of adults and children with any grade SS, included in the SEER public access database between 1983 and 2005, associated older age with a worse prognosis and reduced 5- and 10-year CSS rates.¹⁹ Similarly, a single-site retrospective analysis observed reduced CSS and OS rates with older patient age (P = 0.0240), irrespective of tumor location and site, in patients with grades 1-3 SS.²⁵ A retrospective study recorded greater 5- and 10-year OS rates for patients <18 years of age when compared with those aged 35-64 years;¹⁴ these rates were impacted by prognostic factors including older age, larger tumor size, and primary tumor localization in the trunk.¹⁴ However, survival outcomes for metastatic tumors are poor in children, with 5-year EFS and OS of 26% and 30%, respectively, among patients <21 years of age with primary distant metastases.²⁷ A risk-based prospective trial in children and young adults <30 years of age with SS recorded greater 5-year EFS and OS rates in the low-risk (localized disease) treatment arm when compared with the high-risk (metastatic disease) arm (82% and 98% versus 8% and 13%, respectively).²⁸

Several patient characteristics were found to be associated with longer survival in the real-life nationwide METAstatic SYNovial sarcoma (METASYN) study of 417 adult and pediatric patients with metastatic SS. These included younger age, lung being the primary metastatic site, fewer metastases, and metachronous metastases.²⁹ This study recorded a 5-year OS rate of 14.8% (95% CI 11.1% to 18.9%) and a median OS of 22.3 months (95% CI 19.7-24.1 months) in adults and children (9-87 years of age) diagnosed with metastatic SS.²⁹

Pathology and biology of synovial sarcoma

Morphologically, SS can present as one of three distinct histologic variants: monophasic, biphasic, and poorly differentiated.⁵ Monophasic SS is the most frequent histologic variant, as observed by a prospective study assessing patients with locally advanced SS (N = 171); 59% (n = 78) of these were monophasic, 33% (n = 44) were biphasic, and 8% (n = 11) were poorly differentiated.³⁰ Monophasic SS is most often composed of monomorphous spindle cells with moderate cytologic atypia organized in fascicles.^5,31,32 Biphasic tumors, in addition to a fascicular spindle cell component, feature a variably abundant epithelial component sometimes forming true glandular-like structures.^5,32,33 Poorly differentiated tumors contain areas of high cellularity and the tumor cells most often have a rounded morphology.^5,32,34 The prognostic role of histological variants is yet to be fully elucidated.^5,31, 32, 33, 34 A multicenter, retrospective analysis showed high histologic grade [Fédération Nationale des Centres de Lutte Contre Le Cancer (FNCLCC) grade 3], high mitotic count (≥10 mitoses/10 high-power field), large tumor size (>7 cm), International Union Against Cancer (Union Internationale Contre le Cancer)(UICC)/tumour–node–metastasis (TNM) stage III disease, tumor necrosis, and the presence of poorly differentiated morphology as poor prognostic indicators in adults with SS.³⁵ Similarly, a single-center, retrospective case study of 196 patients found that OS was significantly worse in patients with either monophasic SS or grade 3 tumors.³⁶ However, in children and young adults, a multivariate analysis by the EpSSG identified genomic index, tumor site, and tumor size as prognostic for EFS, instead of morphology and grade.^20,24 Furthermore, an analysis of pediatric patients enrolled in one of the four consecutive Cooperative Weichteilsarkom Studie (CWS) trials found that large tumor size (>5 cm) was a poor prognostic factor for OS and EFS outcomes, as opposed to histological grade or age.³⁷

Genomic complexity is present in both adult and pediatric SS and is associated with greater metastatic risk, although the adult genome is more frequently rearranged in SS.^20,38 In >95% of cases, SS is characterized by a pathognomonic translocation between chromosomes X and 18 [t(X;18)(p11.2;q11.2)], which fuses the SYT gene from chromosome 18 to chromosome X; the fusion partner is the SSX1 gene in approximately two-thirds of patients, the SSX2 gene in approximately one-third of patients, and the SSX4 gene in rare cases.^5,39 The SS18::SSX fusion oncogene is likely to be the driving oncogenic event in SS.^5,40 The resulting SS18:SSX fusion protein, while not containing any DNA-binding motifs, binds to the SWI/SNF (BAF) complex, a known epigenetic regulator.^5,40 This complex also includes the chromatin-binding regulatory protein BRD9, which is required for maintaining SS cell viability and maintaining SS18:SSX fusion protein-mediated gene expression.⁴¹ Binding of the fusion protein to the SWI/SNF (BAF) complex displaces the full-length SS18 and the tumor suppressor protein, SMARCB1/INI1, from the complex. This change enables the modified BAF complex to bind to the sex-determining region Y-box 2 (Sox2) locus, which, in turn, prevents polycomb-mediated inhibition, thereby activating Sox2, which is uniformly expressed in SS and plays an essential role in proliferation.^5,10,40 The SS18::SSX gene fusion has also been linked to aberrant E-cadherin repression, overexpression of B-cell lymphoma 1-2 (Bcl1-2), and downregulation of myeloid cell leukemia-1 (Mcl1) in SS. Finally, the downstream effects of the SS18:SSX fusion protein may also include increased expression of several cancer testis antigens (CTAs) of interest, including melanoma-associated antigen-4 (MAGE-A4), New York esophageal squamous cell carcinoma-1 (NY-ESO-1), and preferentially expressed antigen in melanoma (PRAME).^5,42, 43, 44

A recent comprehensive transcriptomic analysis of SS tissue demonstrated that differentially expressed genes were upregulated in cell cycle pathways and downregulated in metabolic-related biological processes compared with tumor-adjacent tissue.⁴⁵ SS18::SSX1/SSX2 and novel gene fusions were identified in SS tissue, in addition to abnormal alternative splicing of genes and circular RNAs. All these transcriptomic aberrations may contribute to SS progression. Although the SS18::SSX2 translocation is considered to be more oncogenic than SS18::SSX1, fusion protein type does not appear to be a prognostic factor in SS.^35,46

Diagnostic pathway and challenges

Early and accurate differential diagnosis is important to define the most appropriate treatment strategy for SS because of its established chemosensitivity relative to other sarcomas, the effectiveness of resection, and the availability of targeted therapies. Patients should be referred to a sarcoma specialist when there is a first suspicion of STS (e.g. when there is an unexplained deep mass of soft tissue or a superficial lesion with a diameter ≥5 cm), before any biopsy is carried out (Figure 1).⁴⁷ International clinical practice guidelines recommend referral to a sarcoma center before any treatment; early referral can improve prognosis, specifically via the use of specialized surgical interventions that are available at these centers (Figure 1).^48,49 Patients should be managed from the outset by a multidisciplinary team involving medical/pediatric, surgical orthopedic and radiation oncologists, as well as pathologists, radiologists, nuclear medicine specialists, and organ-based specialists, as applicable.^47,49 Despite these guidelines, initial sarcoma management is often carried out in a community (primary care) oncology hospital or clinic, without specific guidance from a sarcoma multidisciplinary team. In reality, although the European Society for Medical Oncology (ESMO), the EpSSG, guidelines recommend optimal strategies for the treatment of SS, their implementation varies greatly between countries, with differential utilization of inpatient, outpatient, and primary care settings for the management of the disease.^47,50, 51, 52 This increases the likelihood of secondary or even tertiary interventions being required, adding to patient burden, potentially worsening outcomes, and incurring additional health care resource use and costs.⁴⁹ The health care setting in which surgery is carried out has been shown to be a prognostic factor for treatment outcome, with surgery conducted in expert sarcoma centers associated with better disease outcomes.^29,48,53 In a registry study of ∼35 000 patients with a range of localized sarcomas, including SS, who presented to a NETSARC multidisciplinary specialist center, OS was lower when surgery was subsequently carried out at a nonspecialist center.⁴⁸ Similarly, for adult and pediatric patients with metachronous metastatic SS in the METASYN study, primary surgery at an expert French Sarcoma Group (FSG) center, versus another facility, was an independent favorable prognostic factor.²⁹

Figure 1.

Initial patient pathway from presentation to diagnosis and early disease management in adult and pediatric patients with SS^a,47. Adj, adjuvant; CT, computerized tomography; FNCLCC, Fédération Nationale des Centres de Lutte Contre Le Cancer; RT, radiotherapy; STS, soft tissue sarcoma. ^aAccording to tumor size. ^bSubject to histology and site. ^cAdapted from Figures 1, 2, 3, and 4 of ‘Soft tissue and visceral sarcomas: ESMO–EURACAN–GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up’ published by Gronchi et al, in Annals of Oncology (2017). ^dAccording to recent reports, there is an ongoing debate on whether patients with SS can be grade 1.⁹³ According to the FNCLCC grading system, synovial differentiation should be scored at 3, with a mitotic HMF score of >1 and a necrosis of >0, corresponding to grade 2 disease.⁹⁴

The significant morphological heterogeneity of SS and overlap with other neoplasms present additional diagnostic challenges. With >100 STS histological types currently identified, accurate diagnosis can be difficult for pathologists who lack sufficient sarcoma experience.^1,54 Accurate diagnosis requires highly specialized expertise, as highlighted by the lack of concordance observed between the first assessment and a second expert opinion in a population-based study in France and Italy, in which almost 42% of first diagnoses were found to be inaccurate when reviewed by a centralized expert panel.⁵⁴

In many cases, the pathological diagnosis of SS relies not only on morphology but also needs to be complemented by immunohistochemistry (IHC) and molecular pathology.⁴⁷ Molecular ancillary tests form the basis of diagnosis in many cases of SS. The lack of sensitivity and specificity of available IHC markers has, however, contributed to diagnostic uncertainty.⁵⁵ In an early diagnostic marker study, the vast majority of cases express epithelial differentiation markers such as pan-cytokeratin and epithelial membrane antigen, and up to 40% of monophasic fibrous SS showed a diffused or focal IHC staining for S100 protein.⁵⁶ Further, although the majority of SS tumors express CD99, a similar membranous pattern with anti-CD99 IHC is seen in Ewing sarcoma, potentially delaying accurate diagnosis of SS.⁵⁷ As a result of these challenges, the interval between initial investigations for SS and a definitive diagnosis can be long. The introduction of better diagnostic IHC markers and the use of molecular assays for gene translocation, such as FISH, may help diagnose SS more rapidly. Recently, SS fusion protein-specific IHC has shown promise as a diagnostic tool. The SS18:SSX fusion-specific antibody, E9X9V, was designed to bind to the fusion protein at the fusion junction and demonstrated high sensitivity and specificity for SS.³³ A second antibody, E5A2C, which is targeted to the SSX C-terminus, showed high sensitivity, but was slightly less specific than E9X9V for SS.³³ Diagnostic IHC E9X9V thus has the potential to replace molecular genetic or cytogenetic testing for diagnostic purposes and could be a valuable tool for future biochemical and genomic investigations of the SS18:SSX fusion protein.³³

Current treatment landscape in synovial sarcoma

Adult population

Five-year survival rates in adults with SS have plateaued since the 1980s with no advances in treatment efficacy. For localized STS, treatment guidelines recommend surgical resection with wide excision with negative margins where possible, combined with radiotherapy (neoadjuvant or adjuvant) for intermediate-high-grade (grades 2-3), deep, >5 cm lesions.^47,58 Currently, the optimal use of neoadjuvant chemotherapy in patients with SS remains uncertain, particularly in terms of identifying patients who may derive benefits and determining the appropriate number of treatment cycles. While the ESMO guidelines recommend three cycles of neoadjuvant full-dose anthracycline plus ifosfamide chemotherapy, due to noninferior OS compared with five cycles,^47,59 treatment recommendations should be made on an individual basis in patients affected by more rare STS histological types.⁶⁰ In recent years, validated nomograms, which include histological type as well as tumor size, grading, and location, have been developed as an aid for personalized risk assessment and clinical decision making regarding the individual benefits of perioperative adjuvant/neoadjuvant treatments. In the literature, the SARCULATOR prediction of OS can aid decision making regarding neoadjuvant chemotherapy; this was demonstrated in a post hoc observational cohort study that compared three cycles of perioperative anthracycline plus ifosfamide treatment with histology-tailored chemotherapy in adult patients with STS. A SARCULATOR-predicted 5-year OS of 0.71% (95% CI 0.68% to 0.73%) and 0.72% (95% CI 0.69% to 0.74%), respectively, was observed.⁶¹

In advanced/metastatic STS, metachronous (disease-free interval ≥1 year), resectable lung metastases without extrapulmonary disease can be managed with pulmonary surgery alone if complete excision of all lesions is feasible.⁴⁷ It is important to note that determining the number of lesions and the time of metastasectomy are important factors for identifying which patients are suitable for surgery. If suitable, a minimally invasive thoracoscopic approach is recommended. Otherwise, employing techniques such as thermal ablation or stereotactic-guided radiotherapy is also appropriate.^47,52 Surgery or radiotherapy for the metastatic site(s) without chemotherapy can be considered for fit patients with single organ, limited, and completely resectable/treatable extrapulmonary metastatic disease, while systemic therapy is the preferable option for patients with pulmonary nonresectable disease or extrapulmonary metastatic disease, or short disease-free intervals.^47,59

In advanced/metastatic STS, including SS, anthracycline-based chemotherapy is the standard first-line treatment.^5,62 Table 1 provides an outline of studies assessing treatment in patients with STS. In adult patients with advanced/metastatic STS, first-line anthracycline-based chemotherapy is associated with an overall response rate (ORR) of ∼22% [complete response (CR), 0.8%; partial response, 20.7%]; 46% and 27% of patients treated with anthracyclines had stable disease and progressive disease, respectively.¹¹ Doxorubicin is the standard first-line treatment, and is often administered alongside ifosfamide; this combination has achieved a response rate of ∼60% compared with 25% when each is used as a monotherapy in SS.⁶³ While this approach is associated with a higher response rate and longer progression-free survival (PFS) in chemotherapy-sensitive histological types including SS, compared with doxorubicin monotherapy, no significant differences in OS have been recorded for such treatment approaches.^12,47,64

Table 1.

Summary of data for systemic treatment for patients with STS and advanced SS

Study type	Disease setting and prior treatment	Population (N)	Age group (years)	Treatment regimen	Line of therapy	Endpoint(s)	Reference
Adult population
Phase III RCT	STS (grades 2-3)	455	18-60	Doxorubicin versus doxorubicin and ifosfamide	1L treatment Doxorubicin Doxorubicin and ifosfamide	Doxorubicin versus combination: OS (months): 12.8 versus 14.3 PFS (months): 4.6 versus 7.4 Best overall response (n): 31 versus 60	64
Phase II	Advanced STS Patients completed >1 anthracycline-based chemotherapy regimen	40	22-71	Ifosfamide	NA	OS (months): 12 Duration of response (months): 8 Partial response (%): 33	65
Phase III study	Metastatic STS Patients had at least one regimen containing anthracycline and a maximum of four previous lines of systemic therapy for metastatic disease	372	≥18	Pazopanib	3L treatment Pazopanib	OS (months): 12.5 Duration of treatment (weeks): 16.4	71
Meta-analysis	Locally advanced and metastatic SS	3711	<35-≥65	Anthracyclines Doxorubicin and ifosfamide CYVADIC Ifosfamide	1L treatment Anthracyclines Doxorubicin and ifosfamide CYVADIC	SS patients versus other STS patients PFS (months): 6.3 versus 3.7 OS (months): 15.0 versus 11.7 Response to chemotherapy (%): 27.8 versus 18.8	11
Database analysis	Locally advanced and metastatic SS	104	<20->50	Ifosfamide/doxorubicin Ifosfamide Doxorubicin Ifosfamide/doxorubicin/vincristine CYVADIC Isolated limb perfusion 5-FU/doxorubicin/cyclophosphamide Caelyx VAC Docetaxel Epirubicin MAID VAI Vincristine/epirubicin/carboplatin/etoposide/cyclophosphamide/actinomycin D High dose + PBSCT Interferon	1L treatment Ifosfamide/doxorubicin Ifosfamide Doxorubicin Ifosfamide/doxorubicin/vincristine CYVADIC Isolated limb perfusion 5-FU/doxorubicin/cyclophosphamide Caelyx VAC Docetaxel Epirubicin MAID VAI Vincristine/epirubicin/carboplatin/etoposide/cyclophosphamide/actinomycin D High dose + PBSCT Interferon	Median diagnosis of survival of advanced disease: 22 months 1L chemotherapy Response rates (%) Ifosfamide/doxorubicin: 58.6 Ifosfamide: 25 Doxorubicin: 25	63
Retrospective	SS, liposarcoma, leiomyosarcoma, high-grade sarcoma not otherwise specified Prior therapy with an adjuvant combination of doxorubicin and ifosfamide, or 1L palliative ifosfamide-containing therapy	67	18-71	Doxorubicin and ifosfamide Ifosfamide-containing therapy	2L treatment Rechallenged ifosfamide	Adjuvant versus palliative patients, (%) Partial remission: 28.6 versus 20.8 SD: 21.4 versus 13.2 PFS (months): 11.5 versus 1.4 PD: 50 versus 54.2	60
Retrospective	STS	140	17-77	Intravenous trabectedin	0-3L treatment Intravenous trabectedin	PFS (months): 3.7 OS (months): 14.3	66
Retrospective	Advanced and metastatic SS	21	20-61	Gemcitabine/docetaxel	2L and 3L treatment Gemcitabine/docetaxel	Gemcitabine/docetaxel (months) PFS: 2.0 OS: 8.4	67
Retrospective	Refractory STS	40	24-73	Dacarbazine	2L treatment Dacarbazine	PR (n): 3 CR (n): 0 PFS (months): 2 DOR (months): 9	68
Pediatric population
Prospective	Nonmetastatic SS	138	<21	Ifosfamide Doxorubicin plus ifosfamide	1L treatment Ifosfamide Doxorubicin plus ifosfamide	5-year EFS (%): 80.7 OS (%): 97.2	26
Prospective	Localized SS	60	<21	Surgical resection	NA	3-year EFS (%): 90 OS (%): 100	72
Nationwide cohort	Metastatic SS	417	<26	Ifosfamide Ifosfamide plus doxorubicin Trabectedin	1L treatment Ifosfamide Ifosfamide plus doxorubicin	Ifosfamide versus combination: OS (%): 22 versus 14.8 PFS (months): 7.7. versus 8.5	29

1L, first line; 2L, second line; 5-FU, 5-fluorouracil; CR, complete response; CYVADIC, cyclophosphamide/doxorubicin/vincristine/DTIC; DOR, duration of response; EFS, event-free survival; MAID, ifosfamide/doxorubicin/DTIC; NA, not available; OS, overall survival; PBSCT, peripheral blood stem cell transplant; PD, progressive disease; PFS, progression-free survival; PR, partial response; RCT, randomized controlled trial; SD, stable disease; SS, synovial sarcoma; STS, soft tissue sarcoma; VAI, vincristine, actinomycine ifosfamide; VAC, vincristine/actinomycin D/cyclophosphamide.

Second-line treatment options for advanced/metastatic STS typically include chemotherapy-based regimens. For example, in patients treated with ifosfamide combination therapy, high-dose single-agent ifosfamide infusions over 4-5 or 14 days can be administered.⁴⁷ With high-dose ifosfamide as a 14-day infusion, the median response duration was 8 months and the median OS was 12 months in patients with advanced STS.⁶⁵ Rechallenge with ifosfamide was studied in adults with STS, including SS, who had previously received first-line ifosfamide-containing combination therapy as either adjuvant or palliative treatment.⁶⁰ In the adjuvant group, the median PFS and OS were 11.5 months and 4 years, respectively, whereas in the palliative group of patients, the median PFS and OS were 6.9 months and 2.6 years, respectively.⁶⁰ Rechallenge was mostly active in patients with SS, with 49% attaining partial remission or stable disease.⁶⁰ In advanced SS treated with trabectedin, median PFS and OS were 5.6 and 14.3 months, respectively.⁶⁶ In a retrospective study in adults with advanced and metastatic SS, gemcitabine plus docetaxel showed little efficacy as second- or third-line chemotherapy and should therefore not be offered to these patients.⁶⁷ Another retrospective study assessing adult patients ≥24 years of age with refractory STS showed that dacarbazine as a second-line treatment achieved no CRs and a median PFS of 2 months.⁶⁸ Pazopanib is also approved for the treatment of adult advanced STS from the second line.^69,70 Median PFS and OS in patients with metastatic STS treated with pazopanib were reported to be 4.6 and 12.5 months, respectively.⁷¹

Pediatric population

The optimal approach to the treatment of SS in pediatric patients is now better defined. The disease is rare in the pediatric population, making it difficult to conduct randomized pediatric SS-specific clinical trials.¹⁹ Historically, SS was considered chemosensitive and treated according to rhabdomyosarcoma treatment protocols.²⁶ However, the treatment approach has evolved to resemble that used in adults with SS.^26,62 In localized SS, this typically involves initial first-line resection, where feasible, plus adjuvant or second-line treatments, including a combination of full-dose doxorubicin and ifosfamide chemotherapy, depending on an individual risk stratification that takes account of tumor stage, site, and size. Table 1 outlines studies assessing such treatments. A prospective trial by the EpSSG in patients <21 years of age with nonmetastatic SS showed that with multimodal treatment, which included radiotherapy and a combination of doxorubicin and ifosfamide chemotherapy according to tumor stage, site, and size, 5-year EFS was 80.7% and OS was 90.7%. Among 67 patients with high-risk disease in this study who had unresected tumors, the overall response to neoadjuvant chemotherapy was 55.2%, with 22.4% CR and 32.8% minor remissions.²⁶ A joint analysis by the EpSSG and the Children’s Oncology Group (COG), however, found that pediatric patients with a localized nonmetastatic SS tumor of grade 2 of any size or grades 3 and ≤5 cm that had been fully resected could be treated effectively with surgery alone.⁷²

Approaches to relapsing SS in children have included additional surgery, second-line chemotherapy (e.g. with ifosfamide combinations), and radiotherapy.⁷³ In a retrospective study of 37 patients in France who had initially been diagnosed at <18 years of age, but had experienced ≥1 relapse, treatment comprised combinations of further surgery (75.7%), second-line chemotherapy (73.0%), and radiotherapy (48.6%). Overall, 70.3% of patients attained a second complete remission, with a 5-year median EFS of 32.8% and OS of 42.1%. Factors significantly associated with better survival in this population were not only age at diagnosis, primary tumor location, and localized relapse, but also lack of chemotherapy and radiotherapy as part of their initial treatment.⁷³ A retrospective Italian study of 44 children and young adults <21 years of age with nonmetastatic SS at diagnosis who then experienced a localized, metastatic, or combined relapse showed a poor 5-year OS of 29.7%. The key factors associated with poor survival were relapse <18 months after the first diagnosis and the presence of multiple metastases, whereas complete resection of local relapse and metastases were linked to a better outcome. The authors commented that an aggressive surgical approach is warranted at relapse and that more effective chemotherapy options are required for these patients.⁷⁴

The METASYN study: real-world outcomes in adult and pediatric patients

The recent retrospective nationwide METASYN study from the FSG reported real-world treatment outcomes for metastatic SS in 417 patients [n = 64 (≤25 years of age); n = 353 (>25 years of age)].²⁹

In the metastatic setting, 75.3% of patients received first-line systemic chemotherapy and a median of three lines of treatment. Ifosfamide was the most frequently used in 68.8% of patients.²⁹ The ORR with first-line chemotherapy was 39.2%, with a median PFS of 6 months (95% CI 5.26-7.36 months). Further lines of treatment involved local treatment of second and third metastatic relapses for 21.1% and 10.1% of patients, respectively. Second-line treatments were polychemotherapy, including anthracycline and/or ifosfamide or another combination, and monotherapy with doxorubicin, ifosfamide, trabectedin, a tyrosine kinase (TK) inhibitor, or other systemic therapy.²⁹ The ORR was 22.4%, 20.8%, 13.9%, and 13.2% for second-, third-, fourth-, and fifth-line of chemotherapy, respectively. Median PFS for the second, third, and further lines of treatment was 4.1 months (95% CI 3.45-4.70 months), 2.8 months (95% CI 2.27-3.12 months), and 2 months (95% CI 1.81-2.29 months), respectively.

As well as systemic therapy, at their first metastatic relapse, 48.4% of patients received local treatment of their metastases with surgery, radiotherapy, or thermal ablation as part of their first-line treatment. The findings of METASYN emphasized the importance of this local treatment; even in advanced disease, when employed alongside second- or third-line chemotherapy, local treatment improved survival. Median PFS was 24.3 months with local treatment versus 8.9 months (P < 0.001) without local treatment in the second-line setting and 19.5 months versus 7.7 months (P = 0.003), respectively, in the third-line setting. In addition to local treatment, other parameters identified as contributing to longer survival included younger age, surgery of the primary tumor, and surgery in a specialist center.²⁹

Future perspectives on synovial sarcoma treatment

The poor prognosis of patients with advanced SS with currently available treatment options highlights the unmet clinical need for novel treatments. Tables 2 and 3 provides an overview of ongoing clinical studies of investigational targeted agents and immunotherapies that were enrolling patients with SS as of June 2023. Agents directed at the following targets are under investigation: vascular endothelial growth factor receptors, platelet-derived growth factor receptors, mitogen-activated protein kinases, the receptor TK c-Kit, the enhancer of zeste homolog 2 (EZH2), the raptor-mammalian target of rapamycin (mTOR) complex 1/rictor-mTOR complex (mTORC1/2), the chromatin-binding regulatory protein BRD9, and neural cell adhesion molecule CD56. Among agents directed against these targets, a phase II study showed that tazemetostat, an oral selective EZH2 inhibitor, was well tolerated but showed marginal clinical activity in patients with SS.⁷⁵ The investigative agent, regorafenib, was studied in a prospective randomized study versus placebo, and improved median PFS (5.6 versus 1 month; P < 0.0001) but not median OS (13.4 versus 6.7 months; P = 0.79).⁷⁶ In patients with STS who were 18-70 years of age, administration of the novel TK inhibitor, anlotinib, achieved an ORR of 18.75%, a disease control rate of 56.25%, and a median PFS of 6.27 months (95% CI 1.89-10.65 months).⁷⁷ In addition, a phase III study in patients aged ≥18-70 years determined a greater PFS for anlotinib than dacarbazine [2.89 months (95% CI 2.73-6.87 months) and 1.64 months (95% CI 1.45-2.70 months), respectively].⁷⁸

Table 2.

Ongoing clinical trials of targeted agents and immunotherapies for patients with SS

NCT number (name)	Phase	Therapy class	Treatment regimen(s)	Population (N)	Endpoints
Targeted agents
NCT03016819 (APROMISS)79	III	Anti-VEGFR, FGFR, PDGFR, and c-kit	Anlotinib (versus dacarbazine)	Adults with previously treated SS, advanced alveolar soft part sarcoma, or leiomyosarcoma (N = 325)	Primary (SS): PFS Secondary (SS): ORR, CR
NCT02601950	II	EZH2 inhibitor	Tazemetostat	Adults with relapsed/refractory SS with SS18::SSX rearrangement; INI1-negative tumors (N = 250)	Primary: ORR, PFS, safety Secondary: DOR, DCR, ORR, PFS, OS, AEs
NCT04965753	I	BRD9 degrader	FHD-609	Adolescents and adults (aged ≥16 years) with advanced SS or advanced SMARCB1-loss tumors (N = 104)	Primary: Incidence of TEAEs, AEs, SAEs, and DLTs, with dose escalation and expansion Secondary: ORR, DOR, PFS, TTR, OS, PK
NCT05355753	I/II	BRD9 degrader	CFT8634	Adolescents and adults (aged ≥12 years) with locally advanced or metastatic SMARCB1-perturbed cancers, including SS with unresectable or metastatic disease (N = 110)	Primary: AEs, SAEs, laboratory parameters, dose interruptions or reductions, DLTs, ORR, dose proportionality assessment Secondary: PK, PD, ORR, DOR, PFS, OS, time to next treatment

Immunotherapies
NCT03063632	II	Anti-PD-1	Pembrolizumab + IFN-gamma-1b	Adolescents (age ≥12 years) and adults with advanced/metastatic SS, myxoid/round cell liposarcoma, mycosis fungoides, and Sézary syndrome (N = 28)	Primary: ORR Secondary: AEs, TTR, DOR, PFS, EFS, ORR ≥12 months
NCT02815995	II	Anti-PD-L1, anti-CTLA-4	Durvalumab + tremelimumab	Adults with advanced/metastatic STS including SS (N = 56)	Primary: PFS Secondary: tumor response, OS, CRR, PRR
NCT04356872	II	Anti-PD-1	Sintilimab (+ doxorubicin/ifosfamide)	Adults (age 18-75 years) with previously untreated metastatic/unresectable STS, including SS (N = 45)	Primary: ORR Secondary: PFS, OS, AEs
NCT03967223 (IGNYTE-ESO)	II	TCR T-cell therapy	Letetresgene autoleucel (+ fludarabine/cyclophosphamide)	Children (age ≥10 years) and adults with previously untreated or chemotherapy-treated advanced, metastatic, or unresectable SS or myxoid/round cell liposarcoma, HLA-A2+ with NY-ESO-1, and/or LAGE-1a (N = 103)	Primary: ORR Secondary: TTR, DOR, DCR, PFS, AEs, patients with replication competent lentivirus or insertional oncogenesis, laboratory parameters, PK, OS, ADAs
NCT04044768 (Spearhead 1)	II	TCR T-cell therapy	Afamitresgene autoleucel	Adolescents and adults (aged 16-75 years) with advanced SS or myxoid/round cell liposarcoma (N = 90)	Primary: ORR Secondary: safety, T-cell clonality, BOR, TTR, DOR, PFS, OS, genetically engineered T cells in PBMCs
NCT02650986	I/II	TCR T-cell therapy	TGFβDNRII-transduced autologous tumor infiltrating lymphocytes (± decitabine)	Adolescents (aged ≥12 years) and adults with previously treated metastatic or unresectable NY-ESO-1+ SS or other solid tumors (N = 15)	Primary: DLT, feasibility Secondary: NY-ESO-1 T-cell receptor transgenic protein expression in PBMCs, patients with replication competent lentivirus, tumor response

The table includes data from ClinicalTrials.gov as of June 2023. All trials have a target enrollment of ≥10 patients.

ADA, antidrug antibody; AE, adverse event; BOR, best overall response; CR, complete response; CRR, complete response rate; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DCR, disease control rate; DLT, dose-limiting toxicity; DOR, duration of response; EFS, event-free survival; EZH2, enhancer of zeste homolog 2; FGFR, fibroblast growth factor receptor; HLA, human leukocyte antigen; mTOR, mammalian target of rapamycin; mTORC1/2, raptor-mTOR complex 1/rictor-mTOR complex 2; NY-ESO-1, New York-esophageal squamous cell carcinoma-1; ORR, overall response rate; OS, overall survival; PBMC, peripheral blood mononuclear cell; PD, pharmacodynamics; PD-1, programmed cell death protein 1; PDGFR, platelet-derived growth factor receptor; PD-L1, programmed death-ligand 1; PFS, progression-free survival; PK, pharmacokinetics; PRR, pattern recognition receptor response SAE, serious AE; SS, synovial sarcoma; STS, soft tissue sarcoma; TCR, T-cell receptor; TEAE, treatment-emergent AE; TGF, transforming growth factor; TTR, time to response; VEGFR, vascular endothelial growth factor receptor.

Table 3.

Summary of clinical trial data for immunotherapies in patients with SS

CTA	NCT number (name)	Phase	Therapy class	Treatment regimen(s)	Population (N)	Results	References
MAGE-A4	NCT03132922	I	TCR T-cell therapy	Afami-cel + fludarabine + cyclophosphamide	Patients (aged 18-75 years) who are HLA-A∗02 positive and have one of the indicated tumor types that has MAGE-A4 RNA or protein expression (N = 52)	•Initial analysis found detectable transduced T cells in the peripheral blood •AEs for the first two patients reported at grade ≥3 included blood-related disordersa • Serious AEs included: – Grade 4 hyponatremia, grade 3 atrial fibrillation, grade 3 syncope (each unrelated to treatment) – Grade 1 CRS and grade 2 encephalopathy syndrome (both treatment related) – Grade 2 generalized muscle weakness (possibly treatment related)	95
MAGE-A4	NCT04044768	II	TCR T-cell therapy	Afami-cel + anthracycline- or ifosfamide-containing regimen	Patients aged ≥16 (10 years at selected sites) to ≤75 years who are HLA-A∗02 positive and have SS or MRCLS that has MAGE-A4-expressing tumors (N = 45)	• Interim analysis of the 25 evaluable patients with SS/MRCLS: – Two had a complete response – Eight had a partial response – Eleven had stable disease – Four had progressive disease •The most common AEs of any grade (>30% patients) were neutropenia, lymphopenia, nausea, CRS, leukopenia, fatigue, pyrexia, and anemia •CRS of any grade occurred in 19/32 patients (95% of those events were ≤grade 2) •No report of ICANS •Cytopenia (≥G3) at 4 weeks after infusion was observed in six patients	96
NY-ESO-1	NCT01343043	I	TCR T-cell therapy	Lete-cel + fludarabine/cyclophosphamide	Patients (aged ≥4 years) with unresectable, metastatic, or recurrent SS intolerant/nonresponsive to standard first-line chemotherapy, NY-ESO-1+, and HLA-A∗02+ (N = 45)	Cohort 1/2/3/4b • ORR (%): 50/31/20/27 – Median DOR (weeks): 31.0/8.6/32.1/16.4 – Median PFS (weeks): 15.4/13.1/8.6/22.4 – Median OS (months): 24.3/9.9/19.9/not available (immature) AEs of special interest included: •CRS in 44% of patients (n = 20); maximum grade 1/2/3/4 in 9/7/3/1 patients, respectively; five patients had CRS that were SAEs (grade ≥3 in two patients); all AEs/SAEs resolved •Guillain–Barré syndrome in two patients (grade 3 SAEs; resolved with sequelae) •Multilineage cytopenias in 96% of patients (n = 43); maximum grade 5 in one patient, grade 3/4 in others	97,98
PRAME	NCT03686124	I	TCR T-cell therapy	IMA203 + IMADetect + atezolizumab	Patients (aged ≥18 years) who are HLA-A∗02 positive and with an advanced and/or metastatic solid tumor that shows PRAME expression (N = 102)	•In 12 evaluable patients: Disease control: 100%; PR: 50%. • Treatment-emergent AEs were transient and manageable, including: – Cytopenias (grades 1-4) – CRS and ICANS (both grades 1 and 2)	99

AE, adverse event; afami-cel, afamitresgene autoleucel; CRS, cytokine release syndrome; CTA, cancer testis antigen; DOR, duration of response; HLA, human leukocyte antigen; ICANS, immune effector cell-associated neurotoxicity syndrome; IHC, immunohistochemistry; lete-cel, letetresgene-autoleucel; MAGE-A4, melanoma-associated antigen-4; MRCLS, myxoid round cell liposarcoma; NY-ESO-1, New York-esophageal squamous cell carcinoma-1; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; PRAME, preferentially expressed antigen in melanoma; SAE, serious adverse event; SS, synovial sarcoma; TCR, T-cell receptor.

^aBlood-related disorders include anemia, hypoglycemia, hyponatremia, lymphopenia, neutropenia, and thrombocytopenia.

^bNY-ESO-1 expression/lymphodepletion regimen varied between cohorts: Cohort 1 (n = 12): high (IHC score 2+ or 3+ in ≥50% of tumor cells)/high doses of fludarabine/cyclophosphamide; Cohort 2 (n = 13): low (IHC score ≥1+ in ≥1% cells but not exceeding 2+ or 3+ in ≥50% cells)/high doses of fludarabine/cyclophosphamide; Cohort 3 (n = 5), high (IHC score 2+ or 3+ in ≥50% of tumor cells)/high dose of cyclophosphamide only; Cohort 4 (n = 15), high (IHC score 2+ or 3+ in ≥50% of tumor cells)/low doses of fludarabine/cyclophosphamide.

Immune checkpoint inhibitors including programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors have shown little activity in SS. An open-label phase II study of patients with advanced SS treated with ipilimumab demonstrated disease progression after three or fewer treatment cycles and a response rate of 0% according to RECIST.⁷⁹ Another phase II finding determined that a subset of STS with associated tertiary lymphoid structures and a high density of B cells may respond to PD-1 blockade with pembrolizumab;⁸⁰ however this population does not often include patients with SS. Cellular immunotherapies, and engineered T-cell therapies involving modified T-cell receptors (TCRs), show promising clinical responses in STS and advanced metastatic SS. Clinical trial data for immunotherapies in patients with SS are summarized in Table 3. Unlike chimeric antigen receptor T cells, which are genetically engineered to express personalized receptors that bind a specific tumor cell surface antigen, these modified TCRs can recognize so-called CTAs, which are antigenic epitopes of intracellular proteins processed and presented by human leukocyte antigens (HLAs) on the surface of cancer cells.81, 82, 83 CTAs are highly immunogenic and expressed in multiple tumor types; other than in the testis and placenta, they show limited expression in healthy tissue. CTA-directed TCRs are generally considered tumor specific.^81,84 Off-target effects on the testes and germ cells are limited as germ cells lack expression of the HLA molecules required to present the CTAs of interest on the cell surface.^81,84, 85, 86, 87 However, the use of CTAs as a target is limited as they only present a therapeutic opportunity for subsets of patients depending on HLA status and NY-ESO-1, MAGE-A4, and PRAME target expression; such targets are present in 61% (66/108), 82% (89/108), and 71% of patients with SS, respectively.^88,89 A preclinical study showed that ∼39% of patients with metastatic SS tested positive for HLA-A∗02 and other subtypes.⁹⁰ These CTAs are currently under evaluation as targets for TCR T-cell-based therapies, further highlighted in Table 4.

Table 4.

CTA expression of interest in SS and associated TCR T-cell therapies under investigation

CTA	Expression in SS	CTA detection method	CTA-targeted TCR T-cell therapy	References
MAGE-A4	53%-82%	IHC	Afami-cel	9,42,100,101
NY-ESO-1	70%-80%	IHC	Lete-cel	84,91,97,102
PRAME	100%	IHC or PCR	IMA203	43,100,103

Afami-cel, afamitresgene autoleucel; CTA, cancer testis antigen; IHC, immunohistochemistry; lete-cel, letetresgene-autoleucel; NY-ESO-1, New York esophageal squamous cell carcinoma-1; MAGE-A4, melanoma-associated antigen-4; PRAME, preferentially expressed antigen in melanoma; SS, synovial sarcoma; TCR, T-cell receptor.

Afamitresgene autoleucel (afami-cel; Adaptimmune Therapeutics Inc., Philadelphia) T-cell therapy comprises genetically engineered autologous T cells that target MAGE-A4 peptide when expressed on tumors in the context of HLA-A∗02. In a phase I study (NCT03132922) in patients screened for MAGE-A4 tumor expression HLA-A∗02-positive alleles (excluding HLA-A∗02:05 and ∗02:07), initial safety assessments found no evidence of on-target or off-target toxicity with afami-cel. Preliminary phase II (NCT04044768) results have shown efficacy and tolerability in patients with SS (Table 4, N = 45). Of the 25 evaluable patients with SS, 2 (8%) had CRs, 8 (32%) had partial responses, 11 (44%) had stable disease, and 4 (16%) had progressive disease. The TCR T-cell therapy letetresgene autoleucel (lete-cel; GSK PLC, Brentford, UK) comprises genetically engineered autologous CD4+ and CD8+ T cells, transduced with a self-inactivating lentiviral vector encoding a TCR that recognizes NY-ESO-1, expressed by 70%-80% of SS. A phase I study (NCT01343043) in patients with SS screened for HLA-A∗02:01, HLA-A∗02:05, and/or HLA-A∗02:06-positive alleles and NY-ESO-1 tumor expression was conducted across four cohorts with low or high tumor NY-ESO-1 expression and a low or high lymphodepletion regimen (Table 4; N = 45). A RECIST ORR across the cohorts of 20%-50% and a median duration of response of 8.6-32.1 weeks were observed. The median PFS ranged from 8.6 to 22.4 weeks and the median OS from 9.9 to 24.3 months.⁹¹ Another TCR T-cell therapy targeting NY-ESO-1 is TAEST16001; results from a phase I dose-escalation and expansion study in patients with advanced STS (N = 12) treated with the investigational TA-EST16001 T-cell therapy recorded an ORR of 41.7%.⁹² PRAME is expressed by a number of solid tumors, including SS, in a complex with HLA-A∗02 and is the target of IMA203 (Immatics NV, Tübingen, Germany), which consists of genetically modified autologous T cells encoding a TCR directed against this complex. An interim analysis of an ongoing phase I trial of IMA203 (NCT03686124) showed a manageable adverse event profile and stable disease or partial response in 16 patients with advanced solid tumors screened for HLA-A∗02:01 and PRAME expression (Table 4).

Summary

SS presents challenges in diagnosis and treatment, and there is a need for novel effective therapy for advanced and metastatic disease. Despite international guidelines for the diagnosis and management of SS, there is a risk of diagnostic delay and misdiagnosis following the initial presentation. Early referral of suspected STS to a specialist sarcoma center for biopsy and expert pathology evaluation are recommended by guidelines, such as those published by the ESMO. Surgery at specialist centers is a key pillar of effective management of localized, resectable disease in adults and children with SS, and with the addition of radiotherapy and chemotherapy as indicated by risk assessment tools. In the event of disease progression/metastases, local techniques, such as surgery, radiotherapy (including stereotactic techniques), and thermal ablation for managing individual metastases, as well as novel systemic therapies may also help to extend survival and improve outcomes. The combination of diagnosis, disease evaluation, and multidisciplinary treatment approaches at specialist sarcoma centers can help achieve optimal outcomes for disease management in this patient population.

Current treatment strategies for advanced or metastatic SS rely on cytotoxic chemotherapies, with PFS and OS often measured in months rather than years. However, recent progress in understanding the histopathology and molecular basis of oncogenesis in SS has identified several targets for novel therapeutic agents, currently being investigated in clinical trials. Advances in immunotherapy, such as engineered T-cell therapies involving modified TCRs, are being explored; early trial results for CTA TCR therapies suggest clinical benefits that require further confirmation and long-term follow-up in additional studies.

There are several limitations concerning available data on SS treatments and avenues for future research. As STS is a heterogenous grouping, with >100 histological types classified, the availability of SS-specific studies is limited, especially for classic chemotherapeutic agents, as the information available from these agents comes from retrospective analysis or small prospective series (including subgroup analysis). Currently, there are several clinical trials assessing the efficacy of targeted therapies or immunotherapies in SS, thus the quality of the evidence for these drugs will be higher. Furthermore, due to the rare occurrence of SS, the risk of diagnostic delay and misdiagnosis associated with SS may contribute to the small number of participants in clinical trials. However, with international collaboration between clinicians and pediatricians, and patient representatives it has been possible to carry out histology-specific trials in a well-defined group of patients with SS. Because of the rarity of SS, these collaborations are needed to acquire efficacy data for treatments under investigation in a larger population of patients with SS. Overall, it is hoped that novel, effective therapies will improve the outcome of patients with SS.