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Adjuvant Therapy for High-Risk Soft Tissue Sarcoma in the Adult

  • Sarcoma (SH Okuno, Section Editor)
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Opinion statement

Adult-type soft tissue sarcomas (STS) are curable in roughly one half of cases. Surgery is the treatment mainstay in patients with localized STS and should be performed in centers that have specific expertise with the disease. Radiation therapy complements surgery in several cases, improving the local control. The value of adjuvant chemotherapy is still debated. There is some evidence, however, backing the notion that adjuvant chemotherapy may add to the systemic control of the disease, and thereby overall survival, in the subgroup of patients with high-risk STS. These patients are those with a high-grade, large, and deep tumor. Unfortunately, benefit is apparent when merging all data generated by several trials performed throughout decades, but it was not confirmed by the largest trials, including one that was recently reported. A confounding factor for large clinical trials is that STS are a family of 50-plus different histological subtypes. It is difficult to perform studies that focus on each of them separately, and subgroup analyses suffer from many limitations. Indeed, some histological types are more sensitive to standard chemotherapy and other are less. Furthermore, some histologies are specifically sensitive to some agents that may be completely inactive in others. A prospective, randomized trial is underway to compare standard neoadjuvant chemotherapy in high-risk STS versus a neoadjuvant regimen that is tailored to different histologies. Some rare histological subtypes (alveolar soft part sarcoma, clear cell sarcoma, extraskeletal myxoid chondrosarcoma, solitary fibrous tumor) have shown promising sensitivity to molecular target agents in the metastatic setting, but the value of these therapies in the adjuvant one has not been studied yet. It is probable that in the future the biological background of the different soft tissue sarcoma subtypes will guide the selection of therapies as well as the setting to deliver them.

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References and Recommended Reading

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  1. Gatta G, van der Zwan JM, Casali PG, et al. Rare cancers are not so rare: the rare cancer burden in Europe. Eur J Cancer. 2011;47:2493–511.

    Article  PubMed  Google Scholar 

  2. Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. WHO Classification of tumours of Soft Tissue and Bone. Lyon: IARC; 2013.

    Google Scholar 

  3. Keng VW, Rahrmann EP, Watson AL, et al. PTEN and NF1 inactivation in Schwann cells produces a severe phenotype in the peripheral nervous system that promotes the development and malignant progression of peripheral nerve sheath tumors. Cancer Res. 2012;72(13):3405–13.

    Article  PubMed  CAS  Google Scholar 

  4. Sorrell AD, Espenschied CR, Culver JO, et al. Tumor protein p53 (TP53) testing and Li-Fraumeni syndrome: current status of clinical applications and future directions. Mol Diagn Ther. 2013;17(1):31–47.

    Article  PubMed  Google Scholar 

  5. Woods JS, Polissar L, Severson RK, et al. Soft tissue sarcoma and non-Hodgkin's lymphoma in relation to phenoxyherbicide and chlorinated phenol exposure in western Washington. J Natl Cancer Inst. 1987;78(5):899–910.

    PubMed  CAS  Google Scholar 

  6. Hardell L, Eriksson M. The association between soft tissue sarcomas and exposure to phenoxyacetic acids, A new case-referent study. Cancer. 1988;62(3):652–6.

    Article  PubMed  CAS  Google Scholar 

  7. Wingren G, Fredrikson M, Brage HN, et al. Soft tissue sarcoma and occupational exposures. Cancer. 1990;66(4):806–11.

    Article  PubMed  CAS  Google Scholar 

  8. Smith JG, Christophers AJ. Phenoxy herbicides and chlorophenols: a case control study on soft tissue sarcoma and malignant lymphoma. Br J Cancer. 1992;65(3):442–8.

    Article  PubMed  CAS  Google Scholar 

  9. Hoar SK, Blair A, Holmes FF, et al. Agricultural herbicide use and risk of lymphoma and soft-tissue sarcoma. JAMA 1986, 256(9):1141–7. Erratum in: JAMA 1986; 256(24):3351

    Google Scholar 

  10. Hoppin JA, Tolbert PE, Herrick RF, et al. Occupational chlorophenol exposure and soft tissue sarcoma risk among men aged 30–60 years. Am J Epidemiol. 1998;148(7):693–703.

    Article  PubMed  CAS  Google Scholar 

  11. Sharma A, Schwartz RA. Stewart-Treves syndrome: pathogenesis and management. J Am Acad Dermatol. 2012;67(6):1342–8.

    Article  PubMed  Google Scholar 

  12. Trojani M, Contesso G, Coindre JM, et al. Soft-tissue sarcomas of adults; study of pathological prognostic variables and definition of a histopathological grading system. Int J Cancer. 1984;33:37–42.

    Article  PubMed  CAS  Google Scholar 

  13. Coindre JM, Terrier P, Bui NB, et al. Prognostic factors in adult patients with locally controlled soft tissue sarcoma. A study of 546 patients from the French Federation of Cancer Centers Sarcoma Group. J Clin Oncol. 1996;14:869–77.

    PubMed  CAS  Google Scholar 

  14. Gronchi A, Casali PG, Mariani L, et al. Status of surgical margins and prognosis in adult soft tissue sarcomas of the extremities: a series of patients treated at a single institution. J Clin Oncol. 2005;23:96–104.

    Article  PubMed  CAS  Google Scholar 

  15. Trovik CS, Bauer HCF, Alvegard TA, et al. Surgical margins, local recurrence and metastasis in soft tissue sarcomas: 599 surgically-treated patients from the Scandinavian Sarcoma Group register. Eur J Cancer. 2000;36:710–6.

    Article  PubMed  CAS  Google Scholar 

  16. Zagars GK, Ballo MT, Pisters PWT, et al. Surgical margins and re-excision in the management of patients with soft tissue sarcoma using conservative surgery and radiation therapy. Cancer. 2003;97:2530–43.

    Article  PubMed  Google Scholar 

  17. Stojadinovic A, Leung DHY, Hoos A, et al. Analysis of the prognostic significance of microscopic margins in 2084 localized primary adult soft tissue sarcomas. Ann Surg. 2002;235:424–34.

    Article  PubMed  Google Scholar 

  18. Colombo C, Randall RL, Andtbacka RH, et al. A new surgical perspective in soft tissue sarcoma (STS) management: more conservative in ESTS (Extremity Soft Tissue Sarcoma), more extended in RSTS (Retroperitoneal Soft Tissue Sarcoma). Expert Rev Anticancer Ther. 2012;12(8):1079–87.

    Article  PubMed  CAS  Google Scholar 

  19. Kawaguchi N, Ahmed AR, Matsumoto S, et al. The concept of curative margin in surgery for bone and soft tissue sarcoma. Clin Orthop Relat Res. 2004;419:165–72.

    Article  PubMed  Google Scholar 

  20. Bonvalot S, Raut CP, Pollock RE, et al. Technical Considerations in Surgery for Retroperitoneal Sarcomas: Position Paper from E-Surge, a Master Class in Sarcoma Surgery, and EORTC–STBSG. Ann Surg Oncol. 2012;19:2981–91.

    Article  PubMed  Google Scholar 

  21. Stojadinovic A, Leung DH, Allen P, et al. Primary adult soft tissue sarcoma: time-dependent influence of prognostic variables. J Clin Oncol. 2002;20(21):4344–52.

    Article  PubMed  Google Scholar 

  22. Gronchi A, Miceli R, Colombo C, et al. Primary Extremity Soft Tissue Sarcoma: outcome improvement over time at a single institution. Ann Oncol. 2011;22(7):1675–81.

    Article  PubMed  CAS  Google Scholar 

  23. Gronchi A, Lo Vullo S, Colombo C, et al. Extremity soft tissue sarcoma in a series of patients treated at a single institution: the local control directly impacts survival. Ann Surg. 2010;251:512–7.

    Article  Google Scholar 

  24. Pisters PWT, Harrison LB, Leung DHY, et al. Long-Term Results of a Prospective Randomized Trial of Adjuvant Brachytherapy in Soft Tissue Sarcoma. J Clin Oncol. 1996;14:859–68.

    PubMed  CAS  Google Scholar 

  25. Yang JC, Chang AE, Sindelar WF, et al. Randomized Prospective Study of the Benefit of Adjuvant Radiation Therapy in the Treatment of Soft Tissue Sarcomas of the Extremity. J Clin Oncol. 1998;16:197–203.

    PubMed  CAS  Google Scholar 

  26. O'Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet. 2002;359:2235–41.

    Article  PubMed  Google Scholar 

  27. Delaney TF. Radiation therapy: neoadjuvant, adjuvant, or not at all. Surg Oncol Clin N Am. 2012;21(2):215–41.

    Article  PubMed  Google Scholar 

  28. Gerrand CH, Wunder JS, Kandel RA, et al. Classification of positive margins after resection of soft-tissue sarcoma of the limb predicts the risk of local recurrence. J Bone Joint Surg Br. 2001;83(8):1149–55.

    Article  PubMed  CAS  Google Scholar 

  29. Dagan R, Indelicato DJ, McGee L, et al. The significance of a marginal excision after preoperative radiation therapy for soft tissue sarcoma of the extremity. Cancer. 2012;118(12):3199–207.

    Article  PubMed  Google Scholar 

  30. Al Yami A, Griffin AM, Ferguson PC, et al. Positive surgical margins in soft tissue sarcoma treated with preoperative radiation: is a postoperative boost necessary? Int J Radiat Oncol Biol Phys. 2010;77(4):1191–7.

    Article  PubMed  Google Scholar 

  31. Chung PW, Deheshi BM, Ferguson PC, et al. Radiosensitivity translates into excellent local control in extremity myxoid liposarcoma: a comparison with other soft tissue sarcomas. Cancer. 2009;115(14):3254–61.

    Article  PubMed  Google Scholar 

  32. http://clinicaltrials.gov/NCT01344018

  33. Le Péchoux C, Musat E, Baey C, et al. Should adjuvant radiotherapy be administered in addition to front-line aggressive surgery (FAS) in patients with primary retroperitoneal sarcoma? Ann Oncol. 2013;24(3):832–7.

    Article  PubMed  Google Scholar 

  34. Elias A, Ryan L, Sulkes A, et al. Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy. J Clin Oncol. 1989;7:1208–16.

    PubMed  CAS  Google Scholar 

  35. van der Graaf WTA, Judson I, Verweij J, et al. Results of a randomised phase III trial (EORTC 62012) of single agent doxorubicin versus doxorubicin plus ifosfamide as first line chemotherapy for patients with advanced or metastatic soft tissue sarcoma: a survival study by the EORTC Soft Tissue and Bone Sarcoma Group. Paper presented at: 37th European Society for Medical Oncology Congress; September 28-October 2, 2012; Vienna, Austria. Abstract LBA7

  36. Pervaiz N, Colterjohn N, Farrokhyar F, et al. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer. 2008;113:573–81.

    Article  PubMed  Google Scholar 

  37. Woll PJ, Reichardt P, Le Cesne A, et al.; EORTC Soft Tissue and Bone Sarcoma Group and the NCIC Clinical Trials Group Sarcoma Disease Site Committee. Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial. Lancet Oncol 2012; 13: 1045-105. The largest single trial on adjuvant chemotherapy in soft tissue sarcoma, showing no benefit in overall survival

  38. Frustaci S, Gherlinzoni F, De Paoli 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;19:1238–47.

    PubMed  CAS  Google Scholar 

  39. Gronchi A, Frustaci S, Mercuri M, et al. Short, full-dose adjuvant chemotherapy in high-risk adult soft tissue sarcomas: a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. J Clin Oncol. 2012;30:850–6. @A neoadjuvant trial on chemotherapy in high risk soft tissue sarcoma of the extremities showing that the limited benefit on overall survival can be obtained with a short full dose regimen.

    Article  PubMed  CAS  Google Scholar 

  40. ESMO / European Sarcoma Network Working Group. Soft tissue and visceral sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23 Suppl 7:vii92–99.

    Article  Google Scholar 

  41. Gronchi A, Verderio P, De Paoli A, et al. Quality of surgery and neoadjuvant combined therapy in the ISG-GEIS trial on soft tissue sarcomas of limbs and trunk wall. Ann Oncol. 2013;24(3):817–23. An unplanned analysis generating the hypothesis that chemo-radiation therapy, given in the neoadjuvant setting, can benefit patients affected by high risk tumors of borderline resectability.

    Article  PubMed  CAS  Google Scholar 

  42. Hensley ML, Ishill N, Soslow R, et al. Adjuvant gemcitabine plus docetaxel for completely resected stages I-IV high grade uterine leiomyosarcoma: Results of a prospective study. Gynecol Oncol. 2009;112(3):563–7.

    Article  PubMed  CAS  Google Scholar 

  43. Hensley ML, Wathen JK, Maki RG, et al. Adjuvant therapy for high-grade, uterus-limited leiomyosarcoma: Results of a phase 2 trial (SARC 005). Cancer. 2013;119(8):1555–61.

    Article  PubMed  CAS  Google Scholar 

  44. Pautier P, Floquet A, Penel N, et al. Randomized multicenter and stratified phase II study of gemcitabine alone versus gemcitabine and docetaxel in patients with metastatic or relapsed leiomyosarcomas: a Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) French Sarcoma Group Study (TAXOGEM study). Oncologist. 2012;17(9):1213–20.

    Article  PubMed  CAS  Google Scholar 

  45. Stacchiotti S, Palassini E, Sanfilippo R, et al. Gemcitabine in advanced angiosarcoma: a retrospective case series analysis from the Italian Rare Cancer Network. Ann Oncol. 2012;23:501–8.

    Article  PubMed  CAS  Google Scholar 

  46. Penel N, Bui BN, Bay JO, Cupissol D, et al. Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX Study. J Clin Oncol. 2008;26:5269–74.

    Article  PubMed  CAS  Google Scholar 

  47. Demetri GD, Chawla SP, von Mehren M, Ritch P, Baker LH, Blay JY, et al. Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules. J Clin Oncol. 2009;27:4188–96.

    Article  PubMed  CAS  Google Scholar 

  48. Grosso F, Sanfilippo R, Virdis E, Piovesan C, Collini P, Dileo P, et al. Trabectedin in myxoid liposarcomas (MLS): a long-term analysis of a single-institution series. Ann Oncol. 2009;20:1439–44.

    Article  PubMed  CAS  Google Scholar 

  49. Grosso F, Jones RL, Demetri GD, et al. Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study. Lancet Oncol. 2007;8:595–602.

    Article  PubMed  CAS  Google Scholar 

  50. Gronchi A, Bui BN, Bonvalot S, et al. Phase II Clinical Trial of Neoadjuvant Trabectedine in patients with advanced localized myxoid liposarcoma. Ann Oncol. 2012;23(3):771–6.

    Article  PubMed  CAS  Google Scholar 

  51. Canter RJ, Qin LX, Maki RG, et al. A synovial sarcoma-specific preoperative nomogram supports a survival benefit to ifosfamide-based chemotherapy and improves risk stratification for patients. Clin Cancer Res. 2008;14(24):8191–7.

    Article  PubMed  CAS  Google Scholar 

  52. Lorigan P, Verweij J, Papai Z, 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;25:3144–50.

    Article  PubMed  CAS  Google Scholar 

  53. Garcia del Muro X, Lopez-Pousa A, Martin J, et al. A phase II trial of temozolomide as a 6-week, continuous, oral schedule in patients with advanced soft tissue sarcoma: a study by the Spanish Group for Research on Sarcomas. Cancer. 2005;104:1706–12.

    Article  PubMed  CAS  Google Scholar 

  54. http://clinicaltrials.gov/ct2/show/NCT01710176 last accessed April 15th 2013

  55. Rutkowski P, Van Glabbeke M, Rankin CJ, et al. Imatinib mesylate in advanced dermatofibrosarcoma protuberans: pooled analysis of two phase II clinical trials. J Clin Oncol. 2010;28:1772–9.

    Article  PubMed  CAS  Google Scholar 

  56. Stacchiotti S, Pedeutour F, Negri T, Conca E, Marrari A, Palassini E, et al. Dermatofibrosarcoma protuberans-derived fibrosarcoma: Clinical history, biological profile and sensitivity to imatinib. Int J Cancer. 2011;129:1761–72.

    Article  PubMed  CAS  Google Scholar 

  57. Stacchiotti S, Longhi A, Ferraresi V, Grignani G, Comandone A, Stupp R, et al. Phase II study of imatinib in advanced chordoma. J Clin Oncol. 2012;30:914–20.

    Article  PubMed  CAS  Google Scholar 

  58. Cassier PA, Gelderblom H, Stacchiotti S, et al. Efficacy of imatinib mesylate for the treatment of locally advanced and/or metastatic tenosynovial giant cell tumor/pigmented villonodular synovitis. Cancer. 2012;118(6):1649–55.

    Article  PubMed  CAS  Google Scholar 

  59. van der Graaf WT, Blay JY, Chawla SP, et al. EORTC Soft Tissue and Bone Sarcoma Group; PALETTE study group. 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 

  60. Stacchiotti S, Negri T, Zaffaroni N, et al. Sunitinib in advanced alveolar soft part sarcoma: evidence of a direct antitumor effect. Ann Oncol. 2011;22:1682–90.

    Article  PubMed  CAS  Google Scholar 

  61. Stacchiotti S, Negri T, Palassini E, et al. Sunitinib malate and figitumumab in solitary fibrous tumor: patterns and molecular bases of tumor response. Mol Cancer Ther. 2010;9:1286–97.

    Article  PubMed  CAS  Google Scholar 

  62. MacKenzie AR, von Mehren M. Mechanisms of mammalian target of rapamycin inhibition in sarcoma: present and future. Expert Rev Anticancer Ther. 2007;7:1145–54.

    Article  PubMed  CAS  Google Scholar 

  63. Wan X, Helman LJ. The biology behind mTOR inhibition in sarcoma. Oncologist. 2007;12:1007–18.

    Article  PubMed  Google Scholar 

  64. Wagner AJ, Malinowska-Kolodziej I, Morgan JA, et al. Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors. J Clin Oncol. 2010;28:835–40.

    Article  PubMed  CAS  Google Scholar 

  65. DeMatteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373:1097–104.

    Article  PubMed  CAS  Google Scholar 

  66. Joensuu H, Eriksson M, Sundby HK, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA. 2012;307:1265–72.

    Article  PubMed  CAS  Google Scholar 

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Conflict of Interest

Alessandro Gronchi received honoraria from Novartis Pharma and received payment for the development of educational presentations from Novartis Pharma and PharmaMar.

Paolo G. Casali has been a consultant to Glaxo, Merck SD, PharmaMar, Sanofi Aventis, Novartis, and Pfizer, received payment for the development of educational presentations from PharmaMar and Janssen Cilag, and has had travel/accommodations expenses covered or reimbursed by PharmaMar, Novartis, and Pfizer.

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Gronchi, A., Casali, P.G. Adjuvant Therapy for High-Risk Soft Tissue Sarcoma in the Adult. Curr. Treat. Options in Oncol. 14, 415–424 (2013). https://doi.org/10.1007/s11864-013-0243-7

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