Skip to main content

Advertisement

Log in

Relapsed Synovial Sarcoma: Treatment Options

  • Sarcoma (SH Okuno, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Synovial sarcoma (SS) is a fusion-driven subtype of sarcoma that is a more chemo-sensitive subtype of soft tissue sarcoma. While chemotherapy options are currently standard of care, our fundamental understanding of the biology of SS is driving new therapies. We will review the current standard of care, as well as the current therapies showing promise in a clinical trial. It is our hope that by encouraging participation in clinical trials, the fundamental therapies available for SS will change the current treatment paradigm.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Thway K, Fisher C. Synovial sarcoma: defining features and diagnostic evolution. Ann Diagn Pathol. 2014;18:369–80.

    Article  PubMed  Google Scholar 

  2. Corey RM, Swett K, Ward WG. Epidemiology and survivorship of soft tissue sarcomas in adults: a national cancer database report. Cancer Med. 2014;3:1404–15.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Vodanovich DA. PF MC Soft-tissue sarcomas. Indian J Orthop. 2018;52:35–44.

    Article  PubMed  PubMed Central  Google Scholar 

  4. von Mehren M, Randall RL, Benjamin RS, et al. Soft tissue sarcoma, Version 2.2018, NCCN Clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2018;16:536–63.

    Article  Google Scholar 

  5. Krieg AH, Hefti F, Speth BM, et al. Synovial sarcomas usually metastasize after >5 years: a multicenter retrospective analysis with minimum follow-up of 10 years for survivors. Ann Oncol. 2011;22:458–67.

    Article  CAS  PubMed  Google Scholar 

  6. Riedel RF, Jones RL, Italiano A, et al. Systemic anti -cancer therapy in synovial sarcoma: a systematic review. Cancers (Basel). 2018;10(11):417.

    Article  PubMed  Google Scholar 

  7. Vlenterie M, Litière S, Rizzo E, et al. Outcome of chemotherapy in advanced synovial sarcoma patients: review of 15 clinical trials from the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group; setting a new landmark for studies in this entity. Eur J Cancer. 2016;58:62–72.

    Article  PubMed  Google Scholar 

  8. Spurrell EL, Fisher C, Thomas JM, Judson IR. Prognostic factors in advanced synovial sarcoma: an analysis of 104 patients treated at the Royal Marsden Hospital. Ann Oncol. 2005;16:437–44.

    Article  CAS  PubMed  Google Scholar 

  9. Cesne AL, Cresta S, Maki RG, et al. A retrospective analysis of antitumour activity with trabectedin in translocation-related sarcomas. Eur J Cancer. 2012;48:3036–44.

    Article  PubMed  Google Scholar 

  10. Sanfilippo R, Dileo P, Blay JY, et al. Trabectedin in advanced synovial sarcomas: a multicenter retrospective study from four European institutions and the Italian Rare Cancer Network. Anticancer Drugs. 2015;26:678–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kawai A, Araki N, Sugiura H, et al. Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study. Lancet Oncol. 2015;16:406–16.

    Article  CAS  PubMed  Google Scholar 

  12. Schöffski P, Ray-Coquard IL, Cioffi A, et al. Activity of eribulin mesylate in patients with soft-tissue sarcoma: a phase 2 study in four independent histological subtypes. Lancet Oncol. 2011;12:1045–52.

    Article  PubMed  Google Scholar 

  13. van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379:1879–86.

    Article  PubMed  Google Scholar 

  14. Kasper B, Sleijfer S, Litière S, et al. Long-term responders and survivors on pazopanib for advanced soft tissue sarcomas: subanalysis of two European Organisation for Research and Treatment of Cancer (EORTC) clinical trials 62043 and 62072. Ann Oncol. 2014;25:719–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nakamura T, Matsumine A, Kawai A, et al. The clinical outcome of pazopanib treatment in Japanese patients with relapsed soft tissue sarcoma: a Japanese musculoskeletal oncology group (JMOG) study. Cancer. 2016;122:1408–16.

    Article  CAS  PubMed  Google Scholar 

  16. Gelderblom H, Judson IR, Benson C, et al. Treatment patterns and clinical outcomes with pazopanib in patients with advanced soft tissue sarcomas in a compassionate use setting: results of the SPIRE study(). Acta Oncol. 2017;56:1769–75.

    Article  CAS  PubMed  Google Scholar 

  17. Mir O, Brodowicz T, Italiano A, et al. Safety and efficacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2016;17:1732–42.

    Article  CAS  PubMed  Google Scholar 

  18. Brodowicz T, Mir O, Wallet J, et al. Efficacy and safety of regorafenib compared to placebo and to post-cross-over regorafenib in advanced non-adipocytic soft tissue sarcoma. Eur J Cancer. 2018;99:28–36.

    Article  CAS  PubMed  Google Scholar 

  19. Le Deley M-C, Blay J-Y, Wallet J, et al. Activity of regorafenib in patients with non-adipocytic soft tissue sarcoma (NASTS): evaluation of heterogeneity of treatment effect on the updated analysis of pooled cohorts. J Clin Oncol. 2022;40:11555–11555.

    Article  Google Scholar 

  20. Chi Y, Sun Y, Cai J, et al. Phase II study of anlotinib for treatment of advanced soft tissues sarcomas. Journal of Clinical Oncology. 2016;34:11005–11005.

    Article  Google Scholar 

  21. Van Tine BA, Chawla SP, Trent JC et al. A phase III study (APROMISS) of AL3818 (Catequentinib, Anlotinib) hydrochloride monotherapy in subjects with metastatic or advanced synovial sarcoma. J Clin Oncol 2021; 39: 11505-11505. This reference is of importance because it is the initial data was presented as an oral abstract at ASCO 2021 demonstrating efficacy of catequentinib as compared to standard of care dacarbazine in synovial sarcoma. In addition to efficacy the drug was shown to be well safe and well tolerated.

  22. Schoffski P, Agulnik M, Stacchiotti S, et al. Phase 2 multicenter study of the EZH2 inhibitor tazemetostat in adults with synovial sarcoma (NCT02601950). J Clin Oncol. 2017;35:11057–11057.

    Article  Google Scholar 

  23. Schmitt T, Mayer-Steinacker R, Mayer F, et al. Vorinostat in refractory soft tissue sarcomas - results of a multi-centre phase II trial of the German soft tissue sarcoma and bone tumour working group (AIO). Eur J Cancer. 2016;64:74–82.

    Article  CAS  PubMed  Google Scholar 

  24. Cassier PA, Lefranc A, Amela EY, et al. A phase II trial of panobinostat in patients with advanced pretreated soft tissue sarcoma A study from the French Sarcoma Group. Br J Cancer. 2013;109:909–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Brashears CB, Prudner BC, Rathore R, et al. Malic enzyme 1 absence in synovial sarcoma shifts antioxidant system dependence and increases sensitivity to ferroptosis induction with ACXT-3102. Clin Cancer Res. 2022;28(16):3573–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dixon SJ, Patel DN, Welsch M, et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife. 2014;3: e02523.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Bean GR, Kremer JC, Prudner BC, et al. A metabolic synthetic lethal strategy with arginine deprivation and chloroquine leads to cell death in ASS1-deficient sarcomas. Cell Death Dis. 2016;7: e2406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. D’Angelo S, Demetri G, Van Tine B, et al. Final analysis of the phase 1 trial of NY-ESO-1–specific T-cell receptor (TCR) T-cell therapy (letetresgene autoleucel; GSK3377794) in patients with advanced synovial sarcoma (SS). J Immunother Cancer. 2020;8(Suppl 3):A325–A325.

    Google Scholar 

  30. Iura K, Maekawa A, Kohashi K, et al. Cancer-testis antigen expression in synovial sarcoma: NY-ESO-1, PRAME, MAGEA4, and MAGEA1. Hum Pathol. 2017;61:130–9.

    Article  CAS  PubMed  Google Scholar 

  31. Van Tine BA AD, Blay J, Le Cesne A, Ganjoo K, Valverde Morales CM, Albiruni Ryan Abdul Razak, Scott Schuetze, Michael J. Wagner, Erin Van Winkle,Cheryl McAlpine, Jean-Marc Navenot, Martin Isabelle, Robyn Broad, Revashnee Naidoo, Ruoxi Wang, Dzmitry Batrakou, Thejo Annareddy, Swethajit Biswas, Dennis Williams, Elliot Norry, Sandra P. D'Angelo. Final analysis from SPEARHEAD-1 cohort 1 of Afamitresgene Autoleucel (“Afami-cel” [formerly ADP-A2M4]) in Advanced synovial sarcoma and myxoid/round cell liposarcoma. In CTOS. Vancouver, British Columbia: 2022. This reference is of importance because it is the first to show efficacy and safety in synovial sarcoma utilizing adoptive T cell therapies against MAGE-A4, a cancer testis antigen unique to SS.

  32. Sleijfer S, Ouali M, van Glabbeke M, et al. Prognostic and predictive factors for outcome to first-line ifosfamide-containing chemotherapy for adult patients with advanced soft tissue sarcomas: an exploratory, retrospective analysis on large series from the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG). Eur J Cancer. 2010;46:72–83.

    Article  CAS  PubMed  Google Scholar 

  33. Venkatramani R, Xue W, Randall RL, et al. Synovial sarcoma in children, adolescents, and young adults: a report from the children’s oncology group ARST0332 study. J Clin Oncol. 2021;39:3927–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Palmerini E, Sanfilippo R, Grignani G, et al. Trabectedin for patients with advanced soft tissue sarcoma: a non-interventional, retrospective, multicenter study of the Italian sarcoma group. Cancers. 2021;13:1053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Le Cesne A, Blay JY, Judson I, et al. Phase II study of ET-743 in advanced soft tissue sarcomas: a European Organisation for the Research and Treatment of Cancer (EORTC) soft tissue and bone sarcoma group trial. J Clin Oncol. 2005;23:576–84.

    Article  PubMed  Google Scholar 

  36. Garcia-Carbonero R, Supko JG, Maki RG, et al. Ecteinascidin-743 (ET-743) for chemotherapy-naive patients with advanced soft tissue sarcomas: multicenter phase II and pharmacokinetic study. J Clin Oncol. 2005;23:5484–92.

    Article  CAS  PubMed  Google Scholar 

  37. Xie C, Wan X, Quan H, et al. Preclinical characterization of anlotinib, a highly potent and selective vascular endothelial growth factor receptor-2 inhibitor. Cancer Sci. 2018;109:1207–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kadoch C, Crabtree GR. Reversible disruption of mSWI/SNF (BAF) complexes by the SS18-SSX oncogenic fusion in synovial sarcoma. Cell. 2013;153:71–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kohashi K, Oda Y. Oncogenic roles of SMARCB1/INI1 and its deficient tumors. Cancer Sci. 2017;108:547–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Brien GL, Remillard D, Shi J, Hemming ML et al. Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma. Elife. 2018;7:e41305.

  41. Su L, Sampaio AV, Jones KB, et al. Deconstruction of the SS18-SSX fusion oncoprotein complex: insights into disease etiology and therapeutics. Cancer Cell. 2012;21:333–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Laporte AN, Ji JX, Ma L, et al. Identification of cytotoxic agents disrupting synovial sarcoma oncoprotein interactions by proximity ligation assay. Oncotarget. 2016;7:34384–94.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Laporte AN, Poulin NM, Barrott JJ, et al. Death by HDAC inhibition in synovial sarcoma cells. Mol Cancer Ther. 2017;16:2656–67.

    Article  CAS  PubMed  Google Scholar 

  44. Ito T, Ouchida M, Morimoto Y, et al. Significant growth suppression of synovial sarcomas by the histone deacetylase inhibitor FK228 in vitro and in vivo. Cancer Lett. 2005;224:311–9.

    Article  CAS  PubMed  Google Scholar 

  45. Vlenterie M, Hillebrandt-Roeffen MH, Flucke UE, et al. Next generation sequencing in synovial sarcoma reveals novel gene mutations. Oncotarget. 2015;6:34680–90.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Vlenterie M, Hillebrandt-Roeffen MH, Schaars EW, et al. Targeting cyclin-dependent kinases in synovial sarcoma: palbociclib as a potential treatment for synovial sarcoma patients. Ann Surg Oncol. 2016;23:2745–52.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Li X, Seebacher NA, Garbutt C, et al. Inhibition of cyclin-dependent kinase 4 as a potential therapeutic strategy for treatment of synovial sarcoma. Cell Death Dis. 2018;9:446.

    Article  PubMed  PubMed Central  Google Scholar 

  48. El Beaino M, Araujo DM, Lazar AJ, Lin PP. Synovial sarcoma: advances in diagnosis and treatment identification of new biologic targets to improve multimodal therapy. Ann Surg Oncol. 2017;24:2145–54.

    Article  PubMed  Google Scholar 

  49. Hsu RY. Pigeon liver malic enzyme. Mol Cell Biochem. 1982;43:3–26.

    Article  CAS  PubMed  Google Scholar 

  50. Frenkel R. Regulation and physiological functions of malic enzymes. Curr Top Cell Regul. 1975;9:157–81.

    Article  CAS  PubMed  Google Scholar 

  51. Edens WA, Urbauer JL, Cleland WW. Determination of the chemical mechanism of malic enzyme by isotope effects. Biochemistry. 1997;36:1141–7.

    Article  CAS  PubMed  Google Scholar 

  52. DeBerardinis RJ, Mancuso A, Daikhin E, et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A. 2007;104:19345–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kranich O, Dringen R, Sandberg M, Hamprecht B. Utilization of cysteine and cysteine precursors for the synthesis of glutathione in astroglial cultures: preference for cystine. Glia. 1998;22:11–8.

    Article  CAS  PubMed  Google Scholar 

  54. Ohman KA, Hashim YM, Vangveravong S, et al. Conjugation to the sigma-2 ligand SV119 overcomes uptake blockade and converts dm-Erastin into a potent pancreatic cancer therapeutic. Oncotarget. 2016;7:33529–41.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Prudner BC, Sun F, Kremer JC, et al. Amino acid uptake measured by [(18)F]AFETP increases in response to arginine starvation in ASS1-deficient sarcomas. Theranostics. 2018;8:2107–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kremer JC, Prudner BC, Lange SES, et al. Arginine deprivation inhibits the Warburg effect and upregulates glutamine anaplerosis and serine biosynthesis in ASS1-deficient cancers. Cell Rep. 2017;18:991–1004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Bowles TL, Kim R, Galante J, et al. Pancreatic cancer cell lines deficient in argininosuccinate synthetase are sensitive to arginine deprivation by arginine deiminase. Int J Cancer. 2008;123:1950–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kim JE, Kim SY, Lee KW, Lee HJ. Arginine deiminase originating from Lactococcus lactis ssp. lactis American Type Culture Collection (ATCC) 7962 induces G1-phase cell-cycle arrest and apoptosis in SNU-1 stomach adenocarcinoma cells. Br J Nutr. 2009;102:1469–76.

    Article  CAS  PubMed  Google Scholar 

  59. Feun L, You M, Wu CJ, et al. Arginine deprivation as a targeted therapy for cancer. Curr Pharm Des. 2008;14:1049–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Tawbi HA, Burgess M, Bolejack V, et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol. 2017;18:1493–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. D’Angelo SP, Mahoney MR, Van Tine BA, et al. Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. Lancet Oncol. 2018;19:416–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Dallos M, Tap WD, D’Angelo SP. Current status of engineered T-cell therapy for synovial sarcoma. Immunotherapy. 2016;8:1073–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Mia C. Weiss MD or Brian A. Van Tine MD, PhD.

Ethics declarations

Conflict of Interest

Mia C. Weiss declares that she has no conflict of interest. Brian A. Van Tine reports personal fees from Polaris and personal fees from Adaptimmune, outside the submitted work; in addition, Dr. Van Tine has a patent Sigma-2 Receptor Ligands and Therapeutic uses therefor (006766) licensed to Accuronix Therapeutics, a patent Modular Platform for Targeted Therapeutic Delivery (006755) licensed to Accuronix Therapeutics, and a patent Sigma-2 Receptor Ligand Drug Conjugates as Antitumor Compounds, Methods of synthesis and Uses Thereof (014229) pending to Accuronix Therapeutics.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Sarcoma

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Weiss, M.C., Van Tine, B.A. Relapsed Synovial Sarcoma: Treatment Options. Curr. Treat. Options in Oncol. 24, 229–239 (2023). https://doi.org/10.1007/s11864-023-01056-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11864-023-01056-5

Navigation