First-Line Therapy for Metastatic Soft Tissue Sarcoma

  • Megan Meyer
  • Mahesh SeetharamEmail author
Sarcoma (SH Okuno, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Sarcoma

Opinion statement

Soft tissue sarcomas are rare cancers with an expected incidence of about 14,000 new cases in 2018, and account for less than 1% of all cancers. It includes in excess of 75 heterogeneous subtypes with varying biology, molecular aberrations, and variable response to treatment. Because of the rarity of these tumors and the many different subtypes, there is no large-scale data to guide treatment, and hence the need for a multidisciplinary individualized approach to treatment, preferably at a high-volume tertiary referral center. For localized disease, surgery with or without radiation is the preferred treatment. In metastatic disease, the longest track record is with use of anthracyclines, either alone or in combination with ifosfamide, but the median overall survival even with combination was just over a year. There have been recent advances in understanding the heterogeneity of these tumors and the need for an individualized approach. With that new knowledge, recent approvals of trabectedin, eribulin, and pazopanib have been limited to some select histologic subtypes with improved outcomes. More recently, immunotherapy has been tested in select histotypes of sarcoma with encouraging activity and has led to further evaluation in combination with immunotherapeutic agents, as well as with chemotherapy and radiation treatments. Here, in this article, we summarize the data of the currently approved therapies in metastatic soft tissue sarcoma, with the principal focus on first-line therapies. We also review the recent encouraging data with PDGFR-targeted antibody (olaratumab) with doxorubicin which showed an impressive improvement in overall survival in phase II study. Molecular characterization of sarcoma subtypes will likely improve understanding of these very diverse tumors and improve target characterization. The ongoing efforts in better understanding these rare tumors hold the key to make a difference in the outcome of these patients.


Metastatic soft tissue sarcoma First line treatment Targeted therapies 


Compliance with Ethical Standards

Conflict of Interest

Megan Meyer and Mahesh Seetharam declare that 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.

References and Recommended Reading

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

  1. 1.
    Vezeridis MP, Moore R, Karakousis CP. Metastatic patterns in soft-tissue sarcomas. Arch Surg. 1983;118(8):915–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Billingsley KG, et al. Pulmonary metastases from soft tissue sarcoma: analysis of patterns of diseases and postmetastasis survival. Ann Surg. 1999;229(5):602–10 discussion 610–2.Google Scholar
  3. 3.
    Ryan CW, 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.PubMedCrossRefGoogle Scholar
  4. 4.
    Van Glabbeke M, et al. Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: an analysis of 2185 patients treated with anthracycline-containing first-line regimens--a European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol. 1999;17(1):150–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Borden EC, et al. Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas. J Clin Oncol. 1987;5(6):840–50.PubMedCrossRefGoogle Scholar
  6. 6.
    Benjamin RS, Wiernik PH, Bachur NR. Adriamycin: a new effective agent in the therapy of disseminated sarcomas. Med Pediatr Oncol. 1975;1(1):63–76.PubMedCrossRefGoogle Scholar
  7. 7.
    Mertens F, et al. Translocation-related sarcomas. Semin Oncol. 2009;36(4):312–23.PubMedCrossRefGoogle Scholar
  8. 8.
    Judson I, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomized controlled phase 3 trial. Lancet Oncol. 2014;15(4):415–23.PubMedCrossRefGoogle Scholar
  9. 9.
    Judson I, et al. Randomized phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2001;37(7):870–7.PubMedCrossRefGoogle Scholar
  10. 10.
    •• Tap WD, et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomized phase 2 trial. Lancet. 2016;388(10043):488–97 This phase II study showed significant overall survival improvement in metastatic soft tissue sarcoma with addition of olaratumab to doxorubicin.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Hensley ML, et al. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol. 2002;20(12):2824–31.PubMedCrossRefGoogle Scholar
  12. 12.
    Maki RG, 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.PubMedCrossRefGoogle Scholar
  13. 13.
    •• Pautier P, et al. Trabectedin in combination with doxorubicin for first-line treatment of advanced uterine or soft-tissue leiomyosarcoma (LMS-02): a non-randomized, multicentre, phase 2 trial. Lancet Oncol. 2015;16(4):457–64 The phase II study with combination of trabectedin and doxorubicin showed higher partial responses and disease control rate but with higher but manageable toxicity.PubMedCrossRefGoogle Scholar
  14. 14.
    Demetri GD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347(7):472–80.PubMedCrossRefGoogle Scholar
  15. 15.
    Penel N, et al. Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX Study. J Clin Oncol. 2008;26(32):5269–74.PubMedCrossRefGoogle Scholar
  16. 16.
    Rutkowski P, et al. Imatinib mesylate in advanced dermatofibrosarcoma protuberans: pooled analysis of two phase II clinical trials. J Clin Oncol. 2010;28(10):1772–9.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Jacob SV, et al. An unusual case of systemic inflammatory myofibroblastic tumor with successful treatment with ALK-inhibitor. Case Rep Pathol. 2014;2014:470340.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Patel SR, et al. High-dose ifosfamide in bone and soft tissue sarcomas: results of phase II and pilot studies--dose-response and schedule dependence. J Clin Oncol. 1997;15(6):2378–84.PubMedCrossRefGoogle Scholar
  19. 19.
    Grenader T, et al. Long-term response to pegylated liposomal doxorubicin in patients with metastatic soft tissue sarcomas. Anti-Cancer Drugs. 2009;20(1):15–20.PubMedCrossRefGoogle Scholar
  20. 20.
    Kaya AO, et al. Efficacy and toxicity of gemcitabine plus docetaxel combination as a second line therapy for patients with advanced stage soft tissue sarcoma. Asian Pac J Cancer Prev. 2012;13(2):463–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Schmitt T, et al. Gemcitabine and docetaxel for metastatic soft tissue sarcoma - a single center experience. Onkologie. 2013;36(7–8):415–20.PubMedGoogle Scholar
  22. 22.
    •• Seddon B, et al. Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomized controlled phase 3 trial. Lancet Oncol. 2017;18(10):1397–410 The study shows noninferiority of gemcitabine/docetaxel compared to doxorubicin, and hence an option in patients ineligible for anthracyclines.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Choong PF, et al. Survival after pulmonary metastasectomy in soft tissue sarcoma. Prognostic factors in 214 patients. Acta Orthop Scand. 1995;66(6):561–8.PubMedCrossRefGoogle Scholar
  24. 24.
    • Chudgar NP, et al. Pulmonary metastasectomy with therapeutic intent for soft-tissue sarcoma. J Thorac Cardiovasc Surg. 2017;154(1):319–330.e1 In this single center trial, careful selection of patients for metastectomy showed improved overall survival.Google Scholar
  25. 25.
    van Geel AN, et al. Surgical treatment of lung metastases: the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group study of 255 patients. Cancer. 1996;77(4):675–82.PubMedCrossRefGoogle Scholar
  26. 26.
    Pawlik TM, et al. Results of a single-center experience with resection and ablation for sarcoma metastatic to the liver. Arch Surg. 2006;141(6):537–43 discussion 543–4.Google Scholar
  27. 27.
    Faraj W, et al. Liver resection for metastatic colorectal leiomyosarcoma: a single center experience. J Gastrointest Oncol. 2015;6(5):E70–6.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Leitao MM, et al. Surgical resection of pulmonary and extrapulmonary recurrences of uterine leiomyosarcoma. Gynecol Oncol. 2002;87(3):287–94.PubMedCrossRefGoogle Scholar
  29. 29.
    • Schoffski P, et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomized, open-label, multicentre, phase 3 trial. Lancet. 2016;387(10028):1629–37 This phase III study showed improved overall survival with Eribulin compared to dacarbazine in patients with advanced liposarcoma.PubMedCrossRefGoogle Scholar
  30. 30.
    Jones RL, et al. Efficacy and tolerability of trabectedin in elderly patients with sarcoma: subgroup analysis from a phase 3, randomized controlled study of trabectedin or dacarbazine in patients with advanced liposarcoma or leiomyosarcoma. Ann Oncol. 2018;29(9):1995–2002.Google Scholar
  31. 31.
    • Demetri GD, et al. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma sfter failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial. J Clin Oncol. 2016;34(8):786–93 This phase III study showed favorable improvement in progression free survival with Trabectedin compared to dacarbazine.PubMedCrossRefGoogle Scholar
  32. 32.
    Dickson MA, et al. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol. 2013;31(16):2024–8.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Seddon B, et al. A phase II trial to assess the activity of gemcitabine and docetaxel as first line chemotherapy treatment in patients with unresectable leiomyosarcoma. Clin Sarcoma Res. 2015;5:13.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Hamed MO, et al. Contemporary management and classification of hepatic leiomyosarcoma. HPB (Oxford). 2015;17(4):362–7.CrossRefGoogle Scholar
  35. 35.
    Giuntoli RL 2nd, et al. Retrospective review of 208 patients with leiomyosarcoma of the uterus: prognostic indicators, surgical management, and adjuvant therapy. Gynecol Oncol. 2003;89(3):460–9.CrossRefGoogle Scholar
  36. 36.
    Nishida T, et al. Efficacy and safety profile of imatinib mesylate (ST1571) in Japanese patients with advanced gastrointestinal stromal tumors: a phase II study (STI571B1202). Int J Clin Oncol. 2008;13(3):244–51.PubMedCrossRefGoogle Scholar
  37. 37.
    Verweij J, et al. Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumors, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study. Eur J Cancer. 2003;39(14):2006–11.PubMedCrossRefGoogle Scholar
  38. 38.
    Demetri GD, et al. NCCN task force report: management of patients with gastrointestinal stromal tumor (GIST)--update of the NCCN clinical practice guidelines. J Natl Compr Cancer Netw. 2007;5(Suppl 2):S1–29 quiz S30.Google Scholar
  39. 39.
    Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1640 patients. J Clin Oncol. 2010;28(7):1247–53.Google Scholar
  40. 40.
    • Huss S, et al. Classification of KIT/PDGFRA wild-type gastrointestinal stromal tumors: implications for therapy. Expert Rev Anticancer Ther. 2015;15(6):623–8 This paper outlines the prognostic importance of mutation type in GIST tumors to help select appropriate treatment.PubMedCrossRefGoogle Scholar
  41. 41.
    Lee JH, et al. Correlation of imatinib resistance with the mutational status of KIT and PDGFRA genes in gastrointestinal stromal tumors: a meta-analysis. J Gastrointestin Liver Dis. 2013;22(4):413–8.PubMedGoogle Scholar
  42. 42.
    Nagano T, et al. Docetaxel: a therapeutic option in the treatment of cutaneous angiosarcoma: report of 9 patients. Cancer. 2007;110(3):648–51.PubMedCrossRefGoogle Scholar
  43. 43.
    Agulnik M, et al. An open-label, multicenter, phase II study of bevacizumab for the treatment of angiosarcoma and epithelioid hemangioendotheliomas. Ann Oncol. 2013;24(1):257–63.PubMedCrossRefGoogle Scholar
  44. 44.
    Bui N, et al. A multicenter phase II study of Q3 week or weekly paclitaxel in combination with bevacizumab for the treatment of metastatic or unresectable angiosarcoma. Rare Tumors. 2018;10:2036361318771771.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    De Yao JT, et al. Scalp angiosarcoma remission with bevacizumab and radiotherapy without surgery: a case report and review of the literature. Sarcoma. 2011;2011:160369.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Ray-Coquard IL, et al. Paclitaxel given once per week with or without bevacizumab in patients with advanced angiosarcoma: a randomized phase II trial. J Clin Oncol. 2015;33(25):2797–802.PubMedCrossRefGoogle Scholar
  47. 47.
    Wang C, et al. Target therapy of unresectable or metastatic dermatofibrosarcoma protuberans with imatinib mesylate: an analysis on 22 Chinese patients. Medicine (Baltimore). 2015;94(17):e773.CrossRefGoogle Scholar
  48. 48.
    Heery CR. Chordoma: the quest for better treatment options. Oncol Ther. 2016;4(1):35–51.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Jagodzinska-Mucha P, et al. Long-term results of therapy with sunitinib in metastatic alveolar soft part sarcoma. Tumori. 2017;103(3):231–5.PubMedCrossRefGoogle Scholar
  50. 50.
    Li T, et al. A retrospective analysis of 14 consecutive Chinese patients with unresectable or metastatic alveolar soft part sarcoma treated with sunitinib. Investig New Drugs. 2016;34(6):701–6.CrossRefGoogle Scholar
  51. 51.
    Kummar S, et al. Cediranib for metastatic alveolar soft part sarcoma. J Clin Oncol. 2013;31(18):2296–302.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Stacchiotti S, et al. Sunitinib malate in solitary fibrous tumor (SFT). Ann Oncol. 2012;23(12):3171–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Park MS, et al. Activity of temozolomide and bevacizumab in the treatment of locally advanced, recurrent, and metastatic hemangiopericytoma and malignant solitary fibrous tumor. Cancer. 2011;117(21):4939–47.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    • Ebata T, et al. Efficacy and safety of pazopanib for recurrent or metastatic solitary fibrous tumor. Oncology. 2018;94(6):340–4 This study shows pazopanib to be an effective agent in solitary fibrous tumor with high response rate based on choi criteria, with manageable toxicity.PubMedCrossRefGoogle Scholar
  55. 55.
    Gelderblom H, et al. Nilotinib in locally advanced pigmented villonodular synovitis: a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2018;19(5):639–48.PubMedCrossRefGoogle Scholar
  56. 56.
    Blay JY, et al. Complete response to imatinib in relapsing pigmented villonodular synovitis/tenosynovial giant cell tumor (PVNS/TGCT). Ann Oncol. 2008;19(4):821–2.PubMedCrossRefGoogle Scholar
  57. 57.
    Stacchiotti S, et al. Response to imatinib in villonodular pigmented synovitis (PVNS) resistant to nilotinib. Clin Sarcoma Res. 2013;3(1):8.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Butrynski JE, et al. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N Engl J Med. 2010;363(18):1727–33.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Kimbara S, et al. A case report of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion gene treated with the ALK inhibitor, crizotinib. Jpn J Clin Oncol. 2014;44(9):868–71.PubMedCrossRefGoogle Scholar
  60. 60.
    Benson C, et al. A retrospective study of patients with malignant PEComa receiving treatment with sirolimus or temsirolimus: the Royal Marsden Hospital experience. Anticancer Res. 2014;34(7):3663–8.PubMedGoogle Scholar
  61. 61.
    Dickson MA, et al. Extrarenal perivascular epithelioid cell tumors (PEComas) respond to mTOR inhibition: clinical and molecular correlates. Int J Cancer. 2013;132(7):1711–7.PubMedCrossRefGoogle Scholar
  62. 62.
    Shitara K, et al. Dramatic tumor response to everolimus for malignant epithelioid angiomyolipoma. Jpn J Clin Oncol. 2011;41(6):814–6.PubMedCrossRefGoogle Scholar
  63. 63.
    Starbuck KD, et al. Treatment of advanced malignant uterine perivascular epithelioid cell tumor with mTOR inhibitors: single-institution experience and review of the literature. Anticancer Res. 2016;36(11):6161–4.PubMedCrossRefGoogle Scholar
  64. 64.
    • Tawbi HA, 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 This phase II study showed efficacy of pembrolizumab in undifferentiated pleomorphic and liposarcoma.PubMedCrossRefGoogle Scholar
  65. 65.
    Agulnik M, et al. A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas. Ann Oncol. 2017;28(1):121–7.PubMedGoogle Scholar
  66. 66.
    Ray-Coquard I, et al. Sarcoma: concordance between initial diagnosis and centralized expert review in a population-based study within three European regions. Ann Oncol. 2012;23(9):2442–9.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Qureshi YA, et al. Unplanned excision of soft tissue sarcoma results in increased rates of local recurrence despite full further oncological treatment. Ann Surg Oncol. 2012;19(3):871–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Choi H, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol. 2007;25(13):1753–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Benjamin RS, et al. We should desist using RECIST, at least in GIST. J Clin Oncol. 2007;25(13):1760–4.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Internal MedicineMayo ClinicPhoenixUSA
  2. 2.Hematology and OncologyMayo ClinicPhoenixUSA

Personalised recommendations