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Treating soft tissue sarcomas with adjuvant chemotherapy

  • Soft Tissue Sarcomas
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Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Surgery remains the cornerstone of treatment and the only curative loco-regional approach of localized resectable soft tissue sarcoma (STS) in 2011: the usual first-line treatment is wide margin surgery plus radiotherapy, especially in the case of primary tumors arising in the limbs. An optimal initial R0 resection is one of the most reproducible and reliable prognostic factors for survival in resectable STS. Nevertheless, despite improved local control rates, more than half of the patients still develop and die from unresectable, locally advanced, and/or metastatic disease. Unfortunately, very few cytotoxic drugs have shown activity in this clinical setting with the exception of doxorubicin, ifosfamide, and to a lesser extent, dacarbazine. A conventional-dose, single-agent chemotherapy is still considered to be the standard treatment for metastatic disease. The impact of adjuvant chemotherapy after resection of a high-grade STS remains controversial due to the lack of reproducible impact on survival. Because STS is a rare disease, most trials have involved a relatively small number of patients, with heterogeneous groups of histological/molecular subtypes of sarcomas, initial sites of the disease, and patient’s characteristics. In a few trials, a lower risk for local recurrence was observed among patients receiving adjuvant chemotherapy but without any significant gain in overall survival. A meta-analysis based on individual data of these randomized studies has confirmed a significant impact of adjuvant chemotherapy on relapse, either local or metastatic, but without any significant benefit on survival. It should be of importance to include the last recent large trials in a new meta-analysis of source data in order to more carefully analyze a possible benefit of systemic adjuvant chemotherapy in localized sarcoma. Until this study is performed, it is an obvious conclusion that adjuvant chemotherapy has not reproducibly demonstrated its capacity to improve overall survival and relapse-free survival in an unselected population of patients. In 2011, there is therefore an urgent need to determine whether or not there are small subpopulations of patients truly benefiting from adjuvant chemotherapy (with conventional agents), and to identify prospectively these populations. With the exception of male, older than 40 years, with a non-optimal resection of their primary (R1 resection) or in the subgroup of grade 3 STS, no other relevant clinical prognostic/predictive factors have been highlighted. The take home messages in 2011 could be as follows: (1) adjuvant chemotherapy is not recommended routinely in high-grade STS; (2) adjuvant chemotherapy is recommended in patients underwent a R1 resection and with a grade 3 STS; (3) adjuvant chemotherapy cannot rescue an inadequate initial surgery; (4) if selected, chemotherapy has to be contain anthracycline and fractionated adequate dose of ifosfamide (around 9 g/m2 per cycle); (5) the era of adjuvant chemotherapy trials with the same chemotherapy regimen in all histological subtype of sarcoma is ended; and (6) prognosis of patients with a localized STS starts at diagnosis. The dramatic activity of imatinib in GIST, the heterogeneous outcome of each histological subtype of sarcomas akin to being different diseases, and the high sensitivity of some histological subtypes of sarcoma to specific agents clearly open a new era in the management and the evaluation of new agents in the field of STS. The design of the future adjuvant trials has to incorporate these new findings and new prognostic/predictive biomarkers in order to improve the as yet dismal prognosis of patients developing high-grade localized STS.

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References and Recommended Reading

  1. Delaney TF, Yang JC, Glatstein E. Adjuvant therapy for adult patients with soft tissue sarcomas. Oncology. 1991;5:105–18.

    CAS  PubMed  Google Scholar 

  2. Brennan MF, Singer S, Maki R, et al. Sarcomas of the Soft Tissue and Bone. In: Devita VT, Lawrence TS, Rosenberg SA, editors. Cancer Principles and Practice of Oncology. 8th ed. Philadelphia: Lippincott Williams and Wilkins; 2008. p. 1741–94.

    Google Scholar 

  3. Bramwell V, Rouesse J, Steward W. Adjuvant CYVADIC Chemotherapy for Adult Soft Tissue Sarcoma-Reduced Local Recurrence but No Improvement in Survival: A Study of the European Organization for Research and Treatment of Cancer. Soft Tissue and Bone Sarcoma Group. J Clin Oncol. 1994;12:1137–49.

    CAS  PubMed  Google Scholar 

  4. Sarcoma Meta-analysis Collaboration. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Lancet. 1997;350:1647–54.

    Article  Google Scholar 

  5. Jones GW, Chouinard M, Patel M. A systematic overview and quantitative meta-analysis. Clin Invest Med. 1991;14 suppl 19:A772.

    Google Scholar 

  6. Zalupski MM, Ryan JR, Hussein ME, et al. Defining the role of adjuvant chemotherapy for patients with soft tissue sarcoma of the extremities. In: Salmon SE, editor. Adjuvant therapy of cancer VII. Philadelphia: JB Lippincott; 1993. p. 385–92.

    Google Scholar 

  7. Tierney JF, Mosseri V, Stewart LA, et al. Adjuvant chemotherapy for soft-tissue sarcoma: review and metaanalysis of the published results of randomised clinical trials. Br J Cancer. 1995;72:469–75.

    Article  CAS  PubMed  Google Scholar 

  8. Brodowicz T, Schwameis E, Widder J, et al. Intensified adjuvant IFADIC chemotherapy for adult soft tissue sarcoma: a prospective randomized feasibility trial. Sarcoma. 2000;4:151–60.

    Article  CAS  PubMed  Google Scholar 

  9. Petrioli R, Coratti A, Correale P, et al. Adjuvant epirubicin with or without ifosfamide for adult soft-tissue sarcoma. Am J Clin Oncol. 2002;25(5):468–73.

    Article  PubMed  Google Scholar 

  10. Frustachi S, Gherlinzoni F, De Paoli A, et al. Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian Randomised Cooperative Trial. J Clin Oncol. 2001;19:1238–47.

    Google Scholar 

  11. Cormier JN, Huang X, Xing Y, et al. Cohort analysis of patients with localized, high-risk, extremity soft-tissue sarcoma treated at two cancer centers: chemotherapy-associated outcomes. J Clin Oncol. 2004;22:4567–74.

    Article  PubMed  Google Scholar 

  12. Woll PJ, van Glabbeke M, Hohenberger A, et al.: Adjuvant chemotherapy (CT) with doxorubicin and ifosfamide in resected soft tissue sarcoma (STS): interim analysis of a randomized phase III trial. J Clin Oncol 2007, ASCO Annual Meeting Proceedings Part I. 25 (18S):10008.

  13. Le Cesne A, van Glabbeke M, Woll PJ, et al.: The end of adjuvant chemotherapy (adCT) era with doxorubicin-based regimen in resected high-grade soft-tissue sarcoma (STS): pooled analysis of the two STBSG-EORTC phase III clinical trials. J Clin Oncol 2008, 26: (May 20 suppl; abstr 10525).

  14. 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 

  15. Gortzak E, Azzarelli A, Buesa J, et al. A randomized phase II study on neo-adjuvant chemotherapy for ‘high-risk’ adult soft-tissue sarcoma. Eur J Cancer. 2001;37:1096–103.

    Article  CAS  PubMed  Google Scholar 

  16. O’Connor JM, Chacón, Petracci FE, et al.: Adjuvant chemotherapy in soft tissue sarcoma (STS): a meta-analysis of published data. J Clin Oncol 2008, 26: (May 20 suppl; abstr 10526).

  17. Italiano A, Delva F, Mathoulin-Pelissier S, et al. Effect of adjuvant chemotherapy on survival in FNCLCC grade 3 soft tissue sarcomas: a multivariate analysis of the French Sarcoma Group Database. Ann Oncol. 2010;21(12):2436–41.

    Article  CAS  PubMed  Google Scholar 

  18. Sleijifer 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(1):72–83.

    Article  Google Scholar 

  19. Penel N, Bul BN, Bay JO, et al. Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX study. J Clin Oncol. 2008;26(32):5269–74.

    Article  CAS  PubMed  Google Scholar 

  20. 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(3):576–84.

    Article  PubMed  Google Scholar 

  21. Demetri GD, Chawla SP, von Mehren M, 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. 2010;27(25):4188–96.

    Article  Google Scholar 

  22. Judson IR, Blay J, Chawla SP, et al.: Trabectedin (Tr) in the treatment of advanced uterine leiomyosarcomas (U-LMS): Results of a pooled analysis of five single-agent phase II studies using the recommended dose. J Clin Oncol 2010, 28:15s (suppl; abstr 10028).

  23. 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;112:563–7.

    Article  CAS  PubMed  Google Scholar 

  24. Garcia Del Muro X, Fra J, Lopez Pousa A, et al.: Randomized phase II study of dacarbazine plus gemcitabine versus DTIC alone in patients with advanced soft tissue sarcoma: A Spanish Group for Research on Sarcomas (GEIS) study. J Clin Oncol 2009, 27:15s (suppl; abstr 10529).

  25. Maki RG, Wathen JK, Patel SR, 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. J Clin Oncol. 2007;25(19):2755–63.

    Article  CAS  PubMed  Google Scholar 

  26. Pautier P, Bui Nguyen B, Penel S, et al.: Final results of a FNCLCC French Sarcoma Group multicenter randomized phase II study of gemcitabine (G) versus gemcitabine and docetaxel (G+D) in patients with metastatic or relapsed leiomyosarcoma (LMS). J Clin Oncol 2009, 27:15s (suppl; abstr 10527).

  27. Pautier P, Duffaud F, Bui Nguyen ML, et al.: A pooled analysis of the final results of the two randomized phase II studies comparing Gemcitabine (G) vs Gemcitabine + Docetaxel (G+D) in patients (pts) with metastatic/relapsed leiomyosarcoma (LMS). Abstract presented at the 35 th Congress of the European Society of Medical Oncology. Milan; October 8–12, 2010. Abstract 13450.

  28. Hensley ML, Wathen RG, Maki D, et al.: Adjuvant treatment of high-risk primary uterine leiomyosarcoma with gemcitabine/docetaxel (GT), followed by doxorubicin (D): Results of phase II multicenter trial SARC005. J Cin Oncol 2010, 28:15s)suppl; abstr 10021).

  29. Chibon F, Lagarde P, Salas S, 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(7):781–8.

    Article  CAS  PubMed  Google Scholar 

  30. Schöffski P. DNA repair functionality modulates the clinical outcome of patients with advanced sarcoma treated with trabectedin (ET-743). J Clin Oncol 2006, ASCO Annual Meeting Proceedings Part I Vol 24, No 18S (June 20 Supplement), 2006:9522.

  31. Ruiz-Soto R., Auger N., Tournay E. et al. Topoisomerase II-alpha protein expression and histological response following doxorubicin-based induction chemotherapy predict survival of locally advanced soft tissue sarcoma. EJC 2011, in press

  32. De Matteo 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(9669):1097–104.

    Article  Google Scholar 

  33. Schuetze S, Rutkowski P, Van Glabbeke MM, et al.: Combined analysis of two phase II trials of imatinib in advanced dermatofibrosarcoma protuberans (DFSP). J Clin Oncol 2009, 27:15s (suppl; abstr 10520).

  34. Rutkowski P, Van Glabbeke M, Rankin CJ, et al. Imatinib mesylate in advanced dermatofibrosarcoma protuberans: polled analysis of two phase II clinical trials. J Clin Oncol. 2010;28(10):1772–8.

    Article  CAS  PubMed  Google Scholar 

  35. Thomas D. M, S. Chawla, Skubitz K, et al. Denosumab for the treatment of giant cell tumor (GCT) of bone: Final results from a proof-of-concept, phase II study. J Clin Oncol. 2009, 27:15S (suppl; abstr 10510).

  36. 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(7):595–602.

    Article  CAS  PubMed  Google Scholar 

  37. Gronchi A, Le Cesne A, Bui NB, et al.: A phase II clinical trial of neo-adjuvant trabectedin in patients with nonmetastatic advanced myxoid/round cell liposarcoma (MRCL). J Clin Oncol 2009, 27:15s (suppl; abstr 10520).

  38. Gardner K, Judson I, Leahy M, et al.: Activity of cediranib, a highly potent and selective VEGF signaling inhibitor, in alveolar soft part sarcoma. J Clin Oncol 2009, 27(15s) (suppl; abstr 10523).

  39. Stacchiotti S, Tamborini E, Marrari A, et al. Response to sunitinib malate in advanced alveolar soft part sarcoma. Cancer Res. 2009;15(3):1096–10104.

    Article  CAS  Google Scholar 

  40. Maki RG, Keohan ML, Undevia SD, et al.: Updated results of a phase II study of oral multi-kinase inhibitor sorafenib in sarcomas, CTEP study 7060. J Clin Oncol 2008, 26(15s) (suppl; abstr 10531).

    Google Scholar 

  41. Maki RG, D’Adamo DR, Keohan ML, et al. Phase II study of sorafenib in patients with metastatic or recurrent sarcomas. J Clin Oncol. 2009;27(19):3133–40.

    Article  CAS  PubMed  Google Scholar 

  42. Vigil CE, Chiaporri AA, Williams CA et al. Phase II of sunitinib malate (SM) in patients with metastatic soft tissue sarcomas (STS) other than GIST: Results of a phase II study. J Clin Oncol 2008, 26 (suppl; abstract 10535).

    Google Scholar 

  43. Sleijfer S, Ray-Coquard I, Papai Z, et al. Pazopanib (GW786034) in patients (pts) with relapsed or refractory soft tissue sarcoma (STS); a phase II study from the EORTC STBSG (EORTC 62043). J Clin Oncol 2007, 25 (suppl; abstract 10031).

    Google Scholar 

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Correspondence to Axel Le Cesne MD.

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Patrikidou, A., Domont, J., Cioffi, A. et al. Treating soft tissue sarcomas with adjuvant chemotherapy. Curr. Treat. Options in Oncol. 12, 21–31 (2011). https://doi.org/10.1007/s11864-011-0145-5

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