Selection of Patients With Localized Extremity Soft Tissue Sarcoma for Treatment With Perioperative Chemotherapy

  • John Charlson
Sarcoma (SH Okuno, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Sarcoma

Opinion statement

Soft tissue sarcoma (STS) is a heterogeneous disease, in terms of histologic subtype, body site of presentation, and behavior. Localized soft tissue sarcoma may be cured with complete tumor excision, but overall, outcomes are sub-optimal. Metastatic disease is associated with shortened survival. Systemic therapy has been studied for several decades as adjunctive therapy, but the use of adjuvant and neo-adjuvant chemotherapy remains controversial. The heterogeneity of patients included in clinical trials, and of sarcoma in general, has made it difficult to draw conclusions about which patients with localized STS should be treated with chemotherapy. Over time, published outcomes for STS of the extremities have improved, and one of the factors that contributes to this improvement may be selection of patients most likely to benefit from the prescribed treatment. Recent studies of neo-adjuvant and adjuvant chemotherapy have recruited patients with the highest recurrence risk—those with large, high-grade, deep tumors. It is reasonable, in practice, to apply similar criteria in deciding whether to recommend treatment. Looking ahead, it will be important to refine our ability to identify patients at highest risk of recurrence, and to develop tools to predict which patients and tumors will respond to chemotherapy.


Soft tissue sarcoma Neo-adjuvant chemotherapy Adjuvant chemotherapy 


Compliance with Ethical Standards

Conflict of Interest

John Charlson has received clinical trial support from Lilly and has received compensation from Immune Design for participating in an advisory meeting.

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.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30.CrossRefGoogle Scholar
  2. 2.
    Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. WHO classification of tumours of soft tissue and bone. Volume 5, 4th edition. 2013.Google Scholar
  3. 3.
    Lawrence W Jr, Donegan WL, Natarajan N, Mettlin C, Beart R, Winchester D. Adult soft tissue sarcomas. A pattern of care survey of the American College of Surgeons. Ann Surg. 1987;205(4):349–59.CrossRefGoogle Scholar
  4. 4.
    Brennan MF, Antonescu CR, Moraco N, Singer S. Lessons learned from the study of 10,000 patients with soft tissue sarcoma. Ann Surg. 2014;260(3):416–22.CrossRefGoogle Scholar
  5. 5.
    Zagars GK, Ballo MT, Pisters PWT, Pollock RE, Patel SR, Benjamin RS, et al. Prognostic factors for patients with localized soft-tissue sarcoma treated with conservation surgery and radiation therapy. Cancer. 2003;97(10):2530–43.CrossRefGoogle Scholar
  6. 6.
    Bedi M, King DM, Shivakoti M, Wang T, Zambrano EV, Charlson J, et al. Prognostic variables in patients with primary soft tissue sarcoma of the extremity and trunk treated with neoadjuvant radiotherapy or neoadjuvant sequential chemoradiotherapy. Radiat Oncol. 2013;8(1):60.CrossRefGoogle Scholar
  7. 7.
    Kolovich GG, Wooldridge AN, Christy JM. A retrospective statistical analysis of high-grade soft tissue sarcomas. Med Oncol. 2012;29(2):1335–44.Google Scholar
  8. 8.
    Stefanovski PD, Bidoli E, De Paoli A. Prognostic factors in soft tissue sarcomas: a study of 395 patients. Eur J Surg Oncol. 2002;28(2):153–64.Google Scholar
  9. 9.
    Biermann JS, Chow W, Reed DR, Lucas D, Adkins DR, Agulnik M, et al. NCCN Guidelines Insights: Bone Cancer, Version 2.2017. J Natl Compr Cancer Netw. 2017;15(2):155–67.CrossRefGoogle Scholar
  10. 10.
    von Mehren M, Randall RL, Benjamin RS, Boles S, Bui MM, Ganjoo KN, et al. Soft Tissue Sarcoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Cancer Netw. 2018;16(5):536–63.CrossRefGoogle Scholar
  11. 11.
    ESMO/European Sarcoma Network Working Group. Soft tissue and visceral sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014;25 Suppl 3:iii102–12.Google Scholar
  12. 12.
    Borden EC, Amato DA, Rosenbaum C, Enterline HT, Shiraki MJ, Creech RH, et al. Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas. J Clin Oncol. 1987;5(6):840–50.CrossRefGoogle Scholar
  13. 13.
    Santoro A, Tursz T, Mouridsen H, Verweij J, Steward W, Somers R, et al. Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol. 1995;13(7):1537–45.CrossRefGoogle Scholar
  14. 14.
    Borden EC, Amato DA, Edmonson JH, Ritch PS, Shiraki M. Randomized comparison of doxorubicin and vindesine to doxorubicin for patients with metastatic soft-tissue sarcomas. Cancer. 1990;66(5):862–7.CrossRefGoogle Scholar
  15. 15.
    Edmonson JH, Ryan LM, Blum RH, Brooks JS, Shiraki M, Frytak S, et al. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol. 1993;11(7):1269–75.CrossRefGoogle Scholar
  16. 16.
    Schoenfeld DA, Rosenbaum C, Horton J, Wolter JM, Falkson G, DeConti RC. A comparison of adriamycin versus vincristine and adriamycin, and cyclophosphamide versus vincristine, actinomycin-D, and cyclophosphamide for advanced sarcoma. Cancer. 1982;50(12):2757–62.CrossRefGoogle Scholar
  17. 17.
    Judson I, Verweij J, Gelderblom H, Hartmann JT, Schöffski P, Blay J-Y, 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.CrossRefGoogle Scholar
  18. 18.
    Mouridsen HT, Bastholt L, Somers R, Santoro A, Bramwell V, Mulder JH, et al. Adriamycin versus epirubicin in advanced soft tissue sarcomas. A randomized phase II/phase III study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer Clin Oncol. 1987;23(10):1477–83.CrossRefGoogle Scholar
  19. 19.
    Bramwell VH, Mouridsen HT, Santoro A, Blackledge G, Somers R, Verweij J, et al. Cyclophosphamide versus ifosfamide: a randomized phase II trial in adult soft-tissue sarcomas. The European Organization for Research and Treatment of Cancer [EORTC], Soft Tissue and Bone Sarcoma Group. Cancer Chemother Pharmacol. 1993;31(Suppl 2):S180–4.PubMedGoogle Scholar
  20. 20.
    van Oosterom AT, Mouridsen HT, Nielsen OS, Dombernowsky P, Krzemieniecki K, Judson I, et al. Results of randomised studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) with two different ifosfamide regimens in first- and second-line chemotherapy in advanced soft tissue sarcoma patients. Eur J Cancer. 2002;38(18):2397–406.CrossRefGoogle Scholar
  21. 21.
    Lee SH, Chang MH, Baek KK, Han B, Lim T, Lee J, et al. High-dose ifosfamide as second- or third-line chemotherapy in refractory bone and soft tissue sarcoma patients. Oncology. 2011;80(3–4):257–61.CrossRefGoogle Scholar
  22. 22.
    Patel SR, Vadhan-Raj S, Papadopolous N, Plager C, Burgess MA, Hays C, 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.CrossRefGoogle Scholar
  23. 23.
    Benjamin RS, Legha SS, Patel SR, Nicaise C. Single-agent ifosfamide studies in sarcomas of soft tissue and bone: the M.D. Anderson experience. Cancer Chemother Pharmacol. 1993;31(Suppl 2):S174–9.PubMedGoogle Scholar
  24. 24.
    Lorigan P, Verweij J, Papai Z, Rodenhuis S, Cesne AL, Leahy MG, et al. Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol. 2007;25(21):3144–50.CrossRefGoogle Scholar
  25. 25.
    Sarcoma Meta-analysis Collaboration. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Sarcoma Meta-analysis Collaboration. Lancet 1997;350(9092):1647–54.Google Scholar
  26. 26.
    Datta J, Ecker BL, Neuwirth MG, Geha RC, Fraker DL, Roses RE, et al. Contemporary reappraisal of the efficacy of adjuvant chemotherapy in resected retroperitoneal sarcoma: evidence from a nationwide clinical oncology database and review of the literature. Surg Oncol. 2017;26(2):117–24.CrossRefGoogle Scholar
  27. 27.
    • Frustaci S, Gherlinzoni F, De Paoli A, Bonetti M, Azzarelli A, Comandone A, et al. Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. J Clin Oncol. 2001;19(5):1238–47. Randomized, placebo-controlled trial demonstrated efficacy of high (current standard)-dose epirubicin and ifosfamide in extremity and trunk wall STS patients identified as high risk.CrossRefGoogle Scholar
  28. 28.
    Frustaci S, De Paoli A, Bidoli E, La Mura N, Berretta M, Buonadonna A, et al. Ifosfamide in the adjuvant therapy of soft tissue sarcomas. Oncology. 2003;65(Suppl. 2):80–4.CrossRefGoogle Scholar
  29. 29.
    Petrioli R, Coratti A, Correale P, D’Aniello C, Grimaldi L, Tanzini G, et al. Adjuvant epirubicin with or without ifosfamide for adult soft-tissue sarcoma. Am J Clin Oncol. 2002;25(5):468–73.CrossRefGoogle Scholar
  30. 30.
    Gortzak E, Azzarelli A, Buesa J. A randomised phase II study on neo-adjuvant chemotherapy for ‘high-risk’ adult soft-tissue sarcoma. Eur J Cancer. 2001;37(9):1096–103.Google Scholar
  31. 31.
    • Woll PJ, Reichardt P, Le Cesne A, Bonvalot S, Azzarelli A, Hoekstra HJ, et al. Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial. Lancet Oncol. 2012;13(10):1045–54. Randomized, placebo-controlled trial in STS patients that showed no significant survival benefit for adjuvant chemotherapy. This negative study is a key part of the reason chemotherapy is controversial in this setting. It was not included in the Sarcoma Meta-analysis.CrossRefGoogle Scholar
  32. 32.
    •• Pervaiz N, Colterjohn N, Farrokhyar F, Tozer R, Figueredo A, Ghert M. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer. 2008;113(3):573–81. This updated meta-analysis provides evidence of significant improvement in RFS and OS, in particular in the subset of patients treated with anthracycline and ifosfamide combination therapy.CrossRefGoogle Scholar
  33. 33.
    Sundby Hall K, Bruland ØS, Bjerkehagen B, Zaikova O, Engellau J, Hagberg O, et al. Adjuvant chemotherapy and postoperative radiotherapy in high-risk soft tissue sarcoma patients defined by biological risk factors—a Scandinavian Sarcoma Group study (SSG XX). Eur J Cancer. 2018;99:78–85.CrossRefGoogle Scholar
  34. 34.
    Grobmyer SR, Maki RG, Demetri GD, Mazumdar M, Riedel E, Brennan MF, et al. Neo-adjuvant chemotherapy for primary high-grade extremity soft tissue sarcoma. Ann Oncol. 2004;15(11):1667–72.CrossRefGoogle Scholar
  35. 35.
    Palassini E, Ferrari S, Verderio P, De Paoli A, Martin Broto J, Quagliuolo V, et al. Feasibility of preoperative chemotherapy with or without radiation therapy in localized soft tissue sarcomas of limbs and superficial trunk in the Italian Sarcoma Group/Grupo Espanol de Investigacion en Sarcomas Randomized Clinical Trial: three versus five cycles of full-dose epirubicin plus ifosfamide. J Clin Oncol. 2015;33(31):3628–34.CrossRefGoogle Scholar
  36. 36.
    Davis EJ, Chugh R, Zhao L, Lucas DR, Biermann JS, Zalupski MM, et al. A randomised, open-label, phase II study of neo/adjuvant doxorubicin and ifosfamide versus gemcitabine and docetaxel in patients with localised, high-risk, soft tissue sarcoma. Eur J Cancer. 2015;51(13):1794–802.CrossRefGoogle Scholar
  37. 37.••
    Gronchi A, Ferrari S, Quagliuolo V, Martin Broto J, López-Pousa A, Grignani G, et al. Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trial. Lancet Oncol. 2017;18:812–22. This randomized trial, comparing three cycles of epirubicin and ifosfamide to chemotherapy regimens hypothesized to have enhanced activity for specific subtypes of STS, showed that standard therapy with epirubicin/ifosfamide was superior in terms of DFS and OS, and so the trial was terminated early. Another possible conclusion is that since standard chemotherapy improved outcomes compared to alternate chemotherapy, it is also superior to not doing treatment, providing support for use of neo-adjuvant chemotherapy.Google Scholar
  38. 38.
    Kattan M, Leung D, Brennan M. Post-operative nomogram for 12-year sarcoma specific survival. J Clin Oncol. 2002;20(3):791–6.Google Scholar
  39. 39.
    • Callegaro D, Miceli R, Bonvalot S, Ferguson P, Strauss DC, Levy A, et al. Development and external validation of two nomograms to predict overall survival and occurrence of distant metastases in adults after surgical resection of localised soft-tissue sarcomas of the extremities: a retrospective analysis. Lancet Oncol. 2016;17(5):671–80. These nomograms are the basis for the Sarculator app, which is useful in estimating recurrence and mortality risk for STS cases.CrossRefGoogle Scholar
  40. 40.
    Pasquali S, Colombo C, Pizzamiglio S, Verderio P, Callegaro D, Stacchiotti S, et al. High-risk soft tissue sarcomas treated with perioperative chemotherapy: improving prognostic classification in a randomised clinical trial. Eur J Cancer. 2018;93:28–36.CrossRefGoogle Scholar
  41. 41.
    Schenone AD, Luo J, Montgomery L, Morgensztern D, Adkins DR, Van Tine BA. Risk-stratified patients with resectable soft tissue sarcoma benefit from epirubicin-based adjuvant chemotherapy. Cancer Med. 2014;3(3):603–12.CrossRefGoogle Scholar
  42. 42.
    Chibon F, Lagarde P, Salas S, Pérot G, Brouste V, Tirode F, et al. Validated prediction of clinical outcome in sarcomas and multiple types of cancer on the basis of a gene expression signature related to genome complexity. Nat Med. 2010;16:781.CrossRefGoogle Scholar
  43. 43.
    Bertucci F, De Nonneville A, Finetti P, Perrot D, Nilbert M, Italiano A, et al. The Genomic Grade Index predicts postoperative clinical outcome in patients with soft-tissue sarcoma. Ann Oncol. 2018;29(2):459–65.CrossRefGoogle Scholar
  44. 44.
    Eriksson M. Histology-driven chemotherapy of soft-tissue sarcoma. Ann Oncol. 2010;21(suppl_7):vii270–vii6.PubMedGoogle Scholar
  45. 45.
    Van Glabbeke M, Van Oosterom AT, Oosterhuis JW, Mouridsen H, Crowther D, Somers R, 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.CrossRefGoogle Scholar
  46. 46.
    Young RJ, Litière 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.CrossRefGoogle Scholar
  47. 47.
    Jones RL, Fisher C, Al-Muderis O, Judson IR. Differential sensitivity of liposarcoma subtypes to chemotherapy. Eur J Cancer. 2005;41(18):2853–60.CrossRefGoogle Scholar
  48. 48.
    Ferrari A, Gronchi A, Casanova M, Meazza C, Gandola L, Collini P, et al. Synovial sarcoma: a retrospective analysis of 271 patients of all ages treated at a single institution. Cancer. 2004;101(3):627–34.CrossRefGoogle Scholar
  49. 49.
    Kraybill WG, Harris J, Spiro IJ. Phase II study of neoadjuvant chemotherapy and radiation therapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514. J Clin Oncol. 2006;24(4):619–25.Google Scholar
  50. 50.
    Ryan CW, Montag AG, Hosenpud JR, Samuels B, Hayden JB, Hung AY, et al. Histologic response of dose-intense chemotherapy with preoperative hypofractionated radiotherapy for patients with high-risk soft tissue sarcomas. Cancer. 2008;112(11):2432–9.CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Hematology/OncologyMedical College of WisconsinMilwaukeeUSA

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