Skip to main content

Advertisement

Log in

Dedifferentiated Liposarcoma: Systemic Therapy Options

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

Opinion statement

Over the last several years, the systemic treatment landscape for dedifferentiated liposarcoma (DDLPS) has notably expanded. Historically, systemic therapy options have been limited to cytotoxic chemotherapy agents, including doxorubicin, ifosfamide, gemcitabine, and docetaxel, that were shown to have efficacy in unselected populations of patients with soft tissue sarcomas. More recently, however, there have been phase II and III trials establishing clinical benefit of the cytotoxic agents trabectedin and eribulin along with the tyrosine kinase inhibitor pazopanib in patients with advanced liposarcoma and DDLPS. Additionally, there are several investigational targeted therapies that have incorporated advances in the understanding of DDLPS disease biology, exploiting the fact that nearly all such tumors include highly amplified expression of MDM2 and CDK4. Recent clinical trials have supported the benefit of the CDK4 inhibitor abemaciclib and the nuclear export inhibitor selinexor and support continued development of anti-MDM2 therapies, with particular attention to the bone marrow toxicity and resultant thrombocytopenia that has thus far limited their use. In contrast, the checkpoint inhibitors pembrolizumab and nivolumab remain of questionable benefit, although these immunotherapy drugs may have a role when combined with other therapeutic agents. Ongoing phase III trials will clarify the role of these novel agents. Future directions include directly comparing current standard-of-care options and newer therapies, developing synergistic combinations of novel agents, and evaluating their role in patients with localized DDLPS.

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 importance

  1. • Thway K. Well-differentiated liposarcoma and dedifferentiated liposarcoma: an updated review. Semin Diagn Pathol. 2019;36(2):112–21 This review provides a current overview of the clinical, pathologic, and genetic features of DDLPS.

    PubMed  Google Scholar 

  2. Lee ATJ, Thway K, Huang PH, Jones RL. Clinical and molecular spectrum of liposarcoma. J Clin Oncol. 2018;36(2):151–9.

    CAS  PubMed  Google Scholar 

  3. Crago AM, Dickson MA. Liposarcoma: multimodality management and future targeted therapies. Surg Oncol Clin N Am. 2016;25(4):761–73.

    PubMed  PubMed Central  Google Scholar 

  4. Gootee J, Aurit S, Curtin C, Silberstein P. Primary anatomical site, adjuvant therapy, and other prognostic variables for dedifferentiated liposarcoma. J Cancer Res Clin Oncol. 2019;145(1):181–92.

    CAS  PubMed  Google Scholar 

  5. Henricks WH, Chu YC, Goldblum JR, Weiss SW. Dedifferentiated liposarcoma: a clinicopathological analysis of 155 cases with a proposal for an expanded definition of dedifferentiation. Am J Surg Pathol. 1997;21(3):271–81.

    CAS  PubMed  Google Scholar 

  6. Weiss SW, Rao VK. Well-differentiated liposarcoma (atypical lipoma) of deep soft tissue of the extremities, retroperitoneum, and miscellaneous sites. A follow-up study of 92 cases with analysis of the incidence of "dedifferentiation". Am J Surg Pathol. 1992;16(11):1051–8.

    CAS  PubMed  Google Scholar 

  7. McCormick D, Mentzel T, Beham A, Fletcher CD. Dedifferentiated liposarcoma. Clinicopathologic analysis of 32 cases suggesting a better prognostic subgroup among pleomorphic sarcomas. Am J Surg Pathol. 1994;18(12):1213–23.

    CAS  PubMed  Google Scholar 

  8. Lucas DR, Nascimento AG, Sanjay BK, Rock MG. Well-differentiated liposarcoma. The Mayo Clinic experience with 58 cases. Am J Clin Pathol. 1994;102(5):677–83.

    CAS  PubMed  Google Scholar 

  9. Montgomery E, Fisher C. Paratesticular liposarcoma: a clinicopathologic study. Am J Surg Pathol. 2003;27(1):40–7.

    PubMed  Google Scholar 

  10. Boland JM, Colby TV, Folpe AL. Liposarcomas of the mediastinum and thorax: a clinicopathologic and molecular cytogenetic study of 24 cases, emphasizing unusual and diverse histologic features. Am J Surg Pathol. 2012;36(9):1395–403.

    PubMed  Google Scholar 

  11. Dei Tos A, Marino-Enriquez A, Pedeutour F, Rossi S. Dedifferentiated liposarcoma. In: Fletcher C, Bridge J, Hogendoorn P, Mertens F, editors. WHO classification of tumours of soft tissue and bone. 4th ed. Lyon: IARC Press; 2013. p. 37–8.

    Google Scholar 

  12. Keung EZ, Hornick JL, Bertagnolli MM, Baldini EH, Raut CP. Predictors of outcomes in patients with primary retroperitoneal dedifferentiated liposarcoma undergoing surgery. J Am Coll Surg. 2014;218(2):206–17.

    PubMed  Google Scholar 

  13. Ikoma N, Torres KE, Somaiah N, Hunt KK, Cormier JN, Tseng W, et al. Accuracy of preoperative percutaneous biopsy for the diagnosis of retroperitoneal liposarcoma subtypes. Ann Surg Oncol. 2015;22(4):1068–72.

    PubMed  Google Scholar 

  14. Somaiah N, Gilbert E, Conley A, Zarzour A, Patel S, Benjamin R et al. PET/CT imaging might be superior to percutaneous biopsy in identifying dedifferentiation in patients with well-differentiated (WDLS)/ dedifferentiated liposarcoma (DDLS). CTOS; November 4–November 7; Salt Lake City2015.

  15. Singer S, Socci ND, Ambrosini G, Sambol E, Decarolis P, Wu Y, et al. Gene expression profiling of liposarcoma identifies distinct biological types/subtypes and potential therapeutic targets in well-differentiated and dedifferentiated liposarcoma. Cancer Res. 2007;67(14):6626–36.

    CAS  PubMed  Google Scholar 

  16. Network TCGAR. Comprehensive and integrated genomic characterization of adult soft tissue sarcomas. Cell. 2017;171(4):950–65.

    Google Scholar 

  17. Italiano A, Bianchini L, Keslair F, Bonnafous S, Cardot-Leccia N, Coindre JM, et al. HMGA2 is the partner of MDM2 in well-differentiated and dedifferentiated liposarcomas whereas CDK4 belongs to a distinct inconsistent amplicon. Int J Cancer. 2008;122(10):2233–41.

    CAS  PubMed  Google Scholar 

  18. Neuhaus SJ, Barry P, Clark MA, Hayes AJ, Fisher C, Thomas JM. Surgical management of primary and recurrent retroperitoneal liposarcoma. Br J Surg. 2005;92(2):246–52.

    CAS  PubMed  Google Scholar 

  19. Bill KLJ, Seligson ND, Hays JL, Awasthi A, Demoret B, Stets CW, et al. Degree of MDM2 amplification affects clinical outcomes in dedifferentiated Liposarcoma. Oncologist. 2019;24(7):989–96.

    CAS  PubMed  Google Scholar 

  20. Ricciotti RW, Baraff AJ, Jour G, Kyriss M, Wu Y, Liu Y, et al. High amplification levels of MDM2 and CDK4 correlate with poor outcome in patients with dedifferentiated liposarcoma: a cytogenomic microarray analysis of 47 cases. Cancer Genet. 2017;218-219:69–80.

    CAS  PubMed  Google Scholar 

  21. Crago AM, Singer S. Clinical and molecular approaches to well differentiated and dedifferentiated liposarcoma. Curr Opin Oncol. 2011;23(4):373–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Gronchi A, De Paoli A, Dani C, Merlo DF, Quagliuolo V, Grignani G, et al. Preoperative chemo-radiation therapy for localised retroperitoneal sarcoma: a phase I-II study from the Italian sarcoma group. Eur J Cancer. 2014;50(4):784–92.

    CAS  PubMed  Google Scholar 

  23. Bonvalot S, Gronchi A, Pechoux CL, Swallow CJ, Strauss DC, Meeus P, et al. STRASS (EORTC 62092): a phase III randomized study of preoperative radiotherapy plus surgery versus surgery alone for patients with retroperitoneal sarcoma. J Clin Oncol. 2019;37(15_suppl):11001.

    Google Scholar 

  24. Livingston JA, Bugano D, Barbo A, Lin H, Madewell JE, Wang WL, et al. Role of chemotherapy in dedifferentiated liposarcoma of the retroperitoneum: defining the benefit and challenges of the standard. Sci Rep. 2017;7(1):11836.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Gootee JM, Curtin CE, Aurit SJ, Randhawa SE, Kang BY, Silberstein PT. Treatment facility: an important prognostic factor for dedifferentiated Liposarcoma survival. Fed Pract. 2019;36(Suppl 5):S34–41.

    PubMed  PubMed Central  Google Scholar 

  26. Murphy JD, Padwal J, Guss ZD, Okamoto K, Sarkar R. Impact of hospital volume on patterns of care and outcomes in soft tissue sarcoma. J Clin Oncol. 2018;36(15_suppl):e23550-e.

    Google Scholar 

  27. Judson I, Verweij J, Gelderblom H, Hartmann JT, Schoffski P, Blay JY, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol. 2014;15(4):415–23.

    CAS  PubMed  Google Scholar 

  28. Seddon B, Strauss SJ, Whelan J, Leahy M, Woll PJ, Cowie F, et al. Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial. Lancet Oncol. 2017;18(10):1397–410.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. • Schoffski P, Chawla S, Maki RG, Italiano A, Gelderblom H, Choy E, et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet. 2016;387(10028):1629–37 This randomized phase III trial demonstrated an OS benefit of eribulin in LPS and DDLPS patients.

    CAS  PubMed  Google Scholar 

  30. • Demetri GD, von Mehren M, Jones RL, Hensley ML, Schuetze SM, Staddon A, et al. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial. J Clin Oncol. 2016;34(8):786–93 This randomized phase III trial showed a PFS benefit of trabectedin in LPS and DDLPS patients.

    CAS  PubMed  Google Scholar 

  31. van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379(9829):1879–86.

    PubMed  Google Scholar 

  32. • Samuels BL, Chawla SP, Somaiah N, Staddon AP, Skubitz KM, Milhem MM, et al. Results of a prospective phase 2 study of pazopanib in patients with advanced intermediate-grade or high-grade liposarcoma. Cancer. 2017;123(23):4640–7 Report from a single arm trial supporting a clinical benefit of pazopanib in DDLPS patients.

    CAS  PubMed  Google Scholar 

  33. Copur M, Harrold L, Ramaekers R, Tiedemann D. In: Chu E, DeVita VT, editors. Physicians' cancer chemotherapy drug manual. Burlington: Jones and Bartlett Learning; 2015.

  34. Ryan CW, Merimsky O, Agulnik M, Blay JY, Schuetze SM, Van Tine BA, et al. PICASSO III: a phase III, placebo-controlled study of doxorubicin with or without palifosfamide in patients with metastatic soft tissue sarcoma. J Clin Oncol. 2016;34(32):3898–905.

    CAS  PubMed  Google Scholar 

  35. Tap WD, Papai Z, Van Tine BA, Attia S, Ganjoo KN, Jones RL, et al. Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2017;18(8):1089–103.

    CAS  PubMed  Google Scholar 

  36. Young RJ, Litiere S, Lia M, Hogendoorn PCW, Fisher C, Mechtersheimer G, et al. Predictive and prognostic factors associated with soft tissue sarcoma response to chemotherapy: a subgroup analysis of the European organisation for research and treatment of cancer 62012 study. Acta Oncol. 2017;56(7):1013–20.

    PubMed  Google Scholar 

  37. Italiano A, Toulmonde M, Cioffi A, Penel N, Isambert N, Bompas E, et al. Advanced well-differentiated/dedifferentiated liposarcomas: role of chemotherapy and survival. Ann Oncol. 2012;23(6):1601–7.

    CAS  PubMed  Google Scholar 

  38. Tap WD, Jones RL, Van Tine BA, Chmielowski B, Elias AD, Adkins D, et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. 2016;388(10043):488–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Tap WD, Wagner AJ, Papai Z, Ganjoo KN, Yen C-C, Schoffski P, et al. ANNOUNCE: A randomized, placebo (PBO)-controlled, double-blind, phase (Ph) III trial of doxorubicin (dox) + olaratumab versus dox + PBO in patients (pts) with advanced soft tissue sarcomas (STS). J Clin Oncol. 2019;37(18_suppl):LBA3–LBA.

    Google Scholar 

  40. Maki RG, Wathen JK, Patel SR, Priebat DA, Okuno SH, Samuels B, et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected]. J Clin Oncol. 2007;25(19):2755–63.

    CAS  PubMed  Google Scholar 

  41. Demetri GD, Schoffski P, Grignani G, Blay JY, Maki RG, Van Tine BA, et al. Activity of eribulin in patients with advanced liposarcoma demonstrated in a subgroup analysis from a randomized phase III study of eribulin versus dacarbazine. J Clin Oncol. 2017;35(30):3433–9.

    CAS  PubMed  Google Scholar 

  42. Tawbi HA, Burgess M, Bolejack V, Van Tine BA, Schuetze SM, Hu J, 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(11):1493–501.

    CAS  PubMed  Google Scholar 

  43. Burgess MA, Bolejack V, Schuetze S, Tine BAV, Attia S, Riedel RF, et al. Clinical activity of pembrolizumab (P) in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated/pleomorphic liposarcoma (LPS): final results of SARC028 expansion cohorts. Journal of Clinical Oncology. 2019;37(15_suppl):11015.

    Google Scholar 

  44. Wilky BA, Trucco MM, Subhawong TK, Florou V, Park W, Kwon D, et al. Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft-part sarcoma: a single-centre, single-arm, phase 2 trial. Lancet Oncol. 2019;20(6):837–48.

    CAS  PubMed  Google Scholar 

  45. Fessas P, Lee H, Ikemizu S, Janowitz T. A molecular and preclinical comparison of the PD-1-targeted T-cell checkpoint inhibitors nivolumab and pembrolizumab. Semin Oncol. 2017;44(2):136–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. D'Angelo SP, Mahoney MR, Van Tine BA, Atkins J, Milhem MM, Jahagirdar BN, 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(3):416–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Bentebibel SE, Hurwitz ME, Bernatchez C, Haymaker C, Hudgens CW, Kluger HM, et al. A first-in-human study and biomarker analysis of NKTR-214, a novel IL2Rbetagamma-biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discov. 2019;9(6):711–21.

    PubMed  Google Scholar 

  48. D'Angelo SP, Conley AP, Kelly CM, Dickson MA, Gounder MM, Chi P, et al. Pilot study of NKTR214 and nivolumab in patients with sarcomas. J Clin Oncol. 2019;37(15_suppl):11010.

    Google Scholar 

  49. Moll UM, Petrenko O. The MDM2-p53 interaction. Mol Cancer Res. 2003;1(14):1001–8.

    CAS  PubMed  Google Scholar 

  50. Nie L, Sasaki M, Maki CG. Regulation of p53 nuclear export through sequential changes in conformation and ubiquitination. J Biol Chem. 2007;282(19):14616–25.

    CAS  PubMed  Google Scholar 

  51. Nakayama R, Zhang YX, Czaplinski JT, Anatone AJ, Sicinska ET, Fletcher JA, et al. Preclinical activity of selinexor, an inhibitor of XPO1, in sarcoma. Oncotarget. 2016;7(13):16581–92.

    PubMed  PubMed Central  Google Scholar 

  52. Garg M, Kanojia D, Mayakonda A, Said JW, Doan NB, Chien W, et al. Molecular mechanism and therapeutic implications of selinexor (KPT-330) in liposarcoma. Oncotarget. 2017;8(5):7521–32.

    PubMed  Google Scholar 

  53. Harper JW, Elledge SJ, Keyomarsi K, Dynlacht B, Tsai LH, Zhang P, et al. Inhibition of cyclin-dependent kinases by p21. Mol Biol Cell. 1995;6(4):387–400.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Gounder MM, Zer A, Tap WD, Salah S, Dickson MA, Gupta AA, et al. Phase IB study of selinexor, a first-in-class inhibitor of nuclear export, in patients with advanced refractory bone or soft tissue sarcoma. J Clin Oncol. 2016;34(26):3166–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Gounder MM, Somaiah N, Attia S, Chawla SP, Villalobos VM, Chmielowski B, et al. Phase 2 results of selinexor in advanced de-differentiated (DDLS) liposarcoma (SEAL) study: a phase 2/3, randomized, double blind, placebo controlled cross-over study. J Clin Oncol. 2018;36(15_suppl):11512.

    Google Scholar 

  56. de Jonge M, de Weger VA, Dickson MA, Langenberg M, Le Cesne A, Wagner AJ, et al. A phase I study of SAR405838, a novel human double minute 2 (HDM2) antagonist, in patients with solid tumours. Eur J Cancer. 2017;76:144–51.

    PubMed  Google Scholar 

  57. Jung J, Lee JS, Dickson MA, Schwartz GK, Le Cesne A, Varga A, et al. TP53 mutations emerge with HDM2 inhibitor SAR405838 treatment in de-differentiated liposarcoma. Nat Commun. 2016;7:12609.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Iancu-Rubin C, Mosoyan G, Glenn K, Gordon RE, Nichols GL, Hoffman R. Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis. Exp Hematol. 2014;42(2):137–45 e5.

    CAS  PubMed  Google Scholar 

  59. Mahfoudhi E, Lordier L, Marty C, Pan J, Roy A, Roy L, et al. P53 activation inhibits all types of hematopoietic progenitors and all stages of megakaryopoiesis. Oncotarget. 2016;7(22):31980–92.

    PubMed  PubMed Central  Google Scholar 

  60. Bauer TM, Gounder MM, Weise AM, Schwartz GK, Carvajal RD, Kumar P, et al. A phase 1 study of MDM2 inhibitor DS-3032b in patients with well/de-differentiated liposarcoma (WD/DD LPS), solid tumors (ST) and lymphomas (L). J Clin Oncol. 2018;36(15_suppl):11514.

    Google Scholar 

  61. Dickson MA, Schwartz GK, Keohan ML, D'Angelo SP, Gounder MM, Chi P, et al. Progression-free survival among patients with well-differentiated or dedifferentiated liposarcoma treated with CDK4 inhibitor Palbociclib: a phase 2 clinical trial. JAMA Oncol. 2016;2(7):937–40.

    PubMed  PubMed Central  Google Scholar 

  62. Klein ME, Kovatcheva M, Davis LE, Tap WD, Koff A. CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought. Cancer Cell. 2018;34(1):9–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Dickson MA, Koff A, D'Angelo SP, Gounder MM, Keohan ML, Kelly CM, et al. Phase 2 study of the CDK4 inhibitor abemaciclib in dedifferentiated liposarcoma. J Clin Oncol. 2019;37(15_suppl):11004.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Amanda Parkes MD.

Ethics declarations

Conflict of Interest

Zhubin Gahvari and Amanda Parkes declare they have no conflict of interest.

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gahvari, Z., Parkes, A. Dedifferentiated Liposarcoma: Systemic Therapy Options. Curr. Treat. Options in Oncol. 21, 15 (2020). https://doi.org/10.1007/s11864-020-0705-7

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11864-020-0705-7

Keywords

Navigation