Treatment of Advanced Soft Tissue Sarcoma: Conventional Agents and Promising New Drugs

Author:
Andrew Wagner From Harvard Medical School, Department of Medical Oncology and Ludwig Center for Cancer Research, Dana-Farber Cancer Institute, Boston, Massachusetts.

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 MD, PhD
Volume/Issue:
Volume 5: Issue 4
Online Publication Date:
Apr 2007
DOI:
https://doi.org/10.6004/jnccn.2007.0035
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Effective treatment of advanced soft tissue sarcomas remains challenging, despite more than 30 years of clinical trials with conventional chemotherapy. Although some agents display modest efficacy against soft tissue sarcomas, modifications in the doses and combinations of therapies have not consistently led to significant improvements in response rates or concomitant increase in overall survival. Novel therapies designed to inhibit defined molecular alterations, as exemplified by the use of imatinib in gastrointestinal stromal tumors, have revolutionized the approach to the treatment of sarcomas. As more underlying genetic mechanisms are uncovered, new agents designed to target these lesions will lead to more specific, less toxic, and more effective therapies.

Correspondence: Andrew J. Wagner, MD, PhD, Harvard Medical School, Department of Medical Oncology and Ludwig Center for Cancer Research, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. E-mail: awagner@partners.org
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  • 1.

    Gottlieb JA, Baker LH, Quagliana JM et al.. Chemotherapy of sarcomas with a combination of adriamycin and dimethyl triazeno imidazole carboxamide. Cancer 1972;30;1632–1638.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Santoro A, Tursz T, Mouridsen H 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 1995,13:1537–1545.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Verweij J, Lee SM, Ruka W et al.. Randomized phase II study of docetaxel versus doxorubicin in first- and second-line chemotherapy for locally advanced or metastatic soft tissue sarcomas in adults: a study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 2000,18:2081–2086.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Borden EC, Amato DA, Rosenbaum C et al.. Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas. J Clin Oncol 1987,5:840–850.

  • 5.

    Le Cesne A, Judson I, Crowther D et al.. Randomized phase III study comparing conventional-dose doxorubicin plus ifosfamide versus high-dose doxorubicin plus ifosfamide plus recombinant human granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: a trial of the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group. J Clin Oncol 2000,18:2676–2684.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Patel SR, Vadhan-Raj S, Papadopolous N 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;15:2378–2384.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Judson I, Radford JA, Harris M et al.. Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL(R)/CAELYX(R)) 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;37:870–877.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Skubitz KM. Phase II trial of pegylated-liposomal doxorubicin (Doxil) in sarcoma. Cancer Investigations 2003;21:167–176.

  • 9.

    Chidiac T, Budd GT, Pelley R et al.. Phase II trial of liposomal doxorubicin (Doxil) in advanced soft tissue sarcomas. Invest New Drugs 2000;18:253–259.

  • 10.

    Luce JK, Thurman WG, Isaacs BL, Talley RW. Clinical trials with the antitumor agent 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide(NSC-45388). Cancer Chemother Rep 1970;54:119–124.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Gottlieb JA, Benjamin RS, Baker LH et al.. Role of DTIC (NSC-45388) in the chemotherapy of sarcomas. Cancer Treat Rep 1976;60:199–203.

  • 12.

    Woll PJ, Judson I, Lee SM et al.. Temozolomide in adult patients with advanced soft tissue sarcoma: a phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 1999;35:410–412.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Talbot SM, Keohan ML, Hesdorffer M et al.. A phase II trial of temozolomide in patients with unresectable or metastatic soft tissue sarcoma. Cancer 2003;98:1942–1946.

  • 14.

    Trent JC, Beach J, Burgess MA et al.. A two-arm phase II study of temozolomide in patients with advanced gastrointestinal stromal tumors and other soft tissue sarcomas. Cancer 2003;98:2693–2699.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    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;104:1706–1712.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Stuart-Harris RC, Harper PG, Parsons CA et al.. High-dose alkylation therapy using ifosfamide infusion with mesna in the treatment of adult advanced soft-tissue sarcoma. Cancer Chemother Pharmacol 1983;11:69–72.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Antman KH, Montella D, Rosenbaum C, Schwen M. Phase II trial of ifosfamide with mesna in previously treated metastatic sarcoma. Cancer Treat Rep 1985;69:499–504.

  • 18.

    Bramwell VH, Mouridsen HT, Santoro A 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–S184.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    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–S179.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    van Oosterom AT, Mouridsen HT, Nielsen OS 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;38:2397–2406.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Worden FP, Taylor JMG, Biermann JS et al.. Randomized phase II evaluation of 6 g/m2 of ifosfamide plus doxorubicin and granulocyte colony-stimulating factor (G-CSF) compared with 12 g/m2 of ifosfamide plus doxorubicin and G-CSF in the treatment of poor-prognosis soft tissue sarcoma. J Clin Oncol 2005,23:105–112. Erratum in J Clin Oncol 2006;24:4223.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Merimsky O, Meller I, Flusser G et al.. Gemcitabine in soft tissue or bone sarcoma resistant to standard chemotherapy: a phase II study. Cancer Chemother Pharmacol 2000;45:177–181.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Okuno S, Ryan LM, Edmonson JH et al.. Phase II trial of gemcitabine in patients with advanced sarcomas (E1797): a trial of the Eastern Cooperative Oncology Group. Cancer 2003;97:1969–1973.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Patel SR, Gandhi V, Jenkins J et al.. Phase II clinical investigation of gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation. J Clin Oncol 2001;19:3483–3489.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Spath-Schwalbe E, Genvresse I, Koschuth A et al.. Phase II trial of gemcitabine in patients with pretreated advanced soft tissue sarcomas. Anticancer Drugs 2000,11:325–329.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    van Hoesel QG, Verweij J, Catimel G et al.. Phase II study with docetaxel (Taxotere) in advanced soft tissue sarcomas of the adult. EORTC Soft Tissue and Bone Sarcoma Group. Ann Oncol 1994;5:539–542.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Edmonson J, Ebbert L, Nascimento A et al.. Phase II study of docetaxel in advanced soft tissue sarcomas. Am J Clin Oncol 1996;19:574–576.

  • 28.

    Kostler WJ, Brodowicz T, Attems Y et al.. Docetaxel as rescue medication in anthracycline- and ifosfamide-resistant locally advanced or metastatic soft tissue sarcoma: results of a phase II trial. Ann Oncol 2001;12:1281–1288.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Omura GA, Major FJ, Blessing JA et al.. A randomized study of adriamycin with and without dimethyl triazenoimidazole carboxamide in advanced uterine sarcomas. Cancer 1983;52:626–632.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    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 1989,7:1208–1216.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Antman K, Crowley J, Balcerzak SP et al.. An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol 1993;11:1276–1285.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Loehrer PJ Sr, Sledge GW Jr, Nicaise C et al.. Ifosfamide plus doxorubicin in metastatic adult sarcomas: a multi-institutional phase II trial. J Clin Oncol 1989;7:1655–1659.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Patel SR, Vadhan-Raj S, Burgess MA et al.. Results of two consecutive trials of dose-intensive chemotherapy with doxorubicin and ifosfamide in patients with sarcomas. Am J Clin Oncol 1998;21:317–321.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Hensley ML, Maki R, Venkatraman E et al.. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol 2002;20:2824–2831.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Maki RG, Hensley ML, Wathen JK et al.. A SARC multicenter phase III study of gemcitabine (G) vs. gemcitabine and docetaxel (G+D) in patients (pts) with metastatic soft tissue sarcomas (STS) [abstract]. J Clin Oncol 2006;24(suppl 1): Abstract 9514.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Bay JO, Ray-Coquard I, Fayette J et al.. Docetaxel and gemcitabine combination in 133 advanced soft-tissue sarcomas: a retrospective analysis. Int J Cancer 2006,119:706–711.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Heinrich MC, Corless CL, Blanke CD et al.. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 2006;24:4764–4774.

  • 38.

    Buchdunger E, Cioffi CL, Law N et al.. Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 2000;295:139–145.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Corless CL, Schroeder A, Griffith D et al.. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 2005;23:5357–5364.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Druker BJ, Tamura S, Buchdunger E et al.. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996;2:561–566.

  • 41.

    Heinrich MC, Griffith DJ, Druker BJ et al.. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 2000;96:925–932.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    Tuveson DA, Willis NA, Jacks T et al.. STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene 2001;20:5054–5058.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Abrams TJ, Lee LB, Murray LJ et al.. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther 2003;2:471–478.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Mendel DB, Laird AD, Xin X et al.. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003;9:327–337.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.

    Demetri GD, von Mehren M, Blanke CD et al.. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472–480.

  • 46.

    Heinrich MC, Corless CL, Demetri GD et al.. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 2003;21:4342–4349.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47.

    Verweij J, Casali PG, Zalcberg J et al.. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 2004;364:1127–1134.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48.

    Rankin C, Mehren MV, Blanke C et al.. Dose effect of imatinib (IM) in patients (pts) with metastatic GIST—phase III Sarcoma Group Study S0033 [abstract]. J Clin Oncol 2004;22(suppl): Abstract 9005.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49.

    Wardelmann E, Merkelbach-Bruse S, Pauls K et al.. Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res 2006;12:1743–1749.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50.

    Morgan JA, Demetri GD, Fletcher JA et al.. Patients with imatinib mesylate-resistant GIST exhibit durable responses to sunitinib malate (SU11248). Eur J Cancer 2005;3(suppl):421.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51.

    Demetri GD, van Oosterom AT, Garrett CR et al.. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006;368:1329–1338.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52.

    Heinrich MC, McArthur GA, Demetri GD et al.. Clinical and molecular studies of the effect of imatinib on advanced aggressive fibromatosis (desmoid tumor). J Clin Oncol 2006;24:1195–1203.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53.

    Mace J, Biermann SJ, Sondak V et al.. Response of extraabdominal desmoid tumors to therapy with imatinib mesylate. Cancer 2002;95:2373–2379.

  • 54.

    Maki RG, Awan RA, Dixon RH et al.. Differential sensitivity to imatinib of 2 patients with metastatic sarcoma arising from dermatofibrosarcoma protuberans. Int J Cancer 2002;100:623–626.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 55.

    Sjoblom T, Shimizu A, O'Brien KP et al.. Growth inhibition of dermatofibrosarcoma protuberans tumors by the platelet-derived growth factor receptor antagonist STI571 through induction of apoptosis. Cancer Res 2001;61:5778–5783.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56.

    Reichardt P, Casali PG, Blay M et al.. A phase I study of AMN107 alone and in combination with imatinib in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST) [abstract]. J Clin Oncol 2006;24(suppl): Abstract 9545.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 57.

    Morgan J, Demetri G, Wang D et al.. A phase I study of dasatinib, a Src and multi-kinase inhibitor, in patients (pts) with GIST and other solid tumors 18th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics 2006: Poster 383.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58.

    Benjamin R, Schoffski P, Hartmann J et al.. Initial results of a multicenter single arm phase 2 study of AMG 706, an oral multikinase inhibitor, for the treatment of advanced imatinib-resistant gastrointestinal stromal tumors (GIST). Presented at the 12th Annual Connective Tissue Oncology Society Meeting. Venice, Italy, November 2–4, 2006.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59.

    van Oosterom A, Reichardt P, Blay J et al.. A phase I/II trial of the oral mTOR-inhibitor everolimus (E) and imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM: study update [abstract]. J Clin Oncol 2005;23(suppl): Abstract 9033.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60.

    Okuno SH, Mahoney MR, Bailey HH et al.. A multicenter phase 2 consortium (P2C) study of the mTOR inhibitor CCI-779 in advanced soft tissue sarcomas (STS) [abstract]. J Clin Oncol 2006;24(suppl): Abstract 9504.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 61.

    Mita MM, Rowinsky EK, Goldston ML et al.. Phase I, pharmacokinetic (PK), and pharmacodynamic (PD) study of AP23573, an mTOR inhibitor, administered IV daily X 5 every other week in patients (pts) with refractory or advanced malignancies [abstract]. J Clin Oncol 2004;22(suppl): Abstract 3076b.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 62.

    Chawla SP, Tolcher AW, Staddon AP et al.. Updated results of a phase II trial of AP23573, a novel mTOR inhibitor, in patients (pts) with advanced soft tissue or bone sarcomas [abstract]. J Clin Oncol 2006;24(suppl): Abstract 9505.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 63.

    Blay JY, Le Cesne A, Verweij J et al.. A phase II study of ET-743/trabectedin (`Yondelis') for patients with advanced gastrointestinal stromal tumours. Eur J Cancer 2004;40:1327–1331.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 64.

    Garcia-Carbonero R, Supko JG, Manola J et al.. Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy. J Clin Oncol 2004;22:1480–1490.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 65.

    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;23:576–584.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 66.

    Terry J, Lubieniecka JM, Kwan W et al.. Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin prevents synovial sarcoma proliferation via apoptosis in in vitro models. Clin Cancer Res 2005;11:5631–5638.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 67.

    Demetri GD, George S, Morgan JA et al.. Overcoming resistance to tyrosine kinase inhibitors (TKIs) through inhibition of heat shock protein 90 (Hsp90) chaperone function in patients with metastatic GIST: results of a phase I trial of IPI504, a water-soluble Hsp90 inhibitor. Eur J Cancer Suppl 2006;4:173.

    • PubMed
    • Search Google Scholar
    • Export Citation
Copyright:
Copyright © 2007 by the National Comprehensive Cancer Network
Page Numbers:
10
Article Category:
Research Article
Received:
16 Oct 2006
Accepted:
28 Oct 2006
Print Publication Date:
01 Apr 2007
Online Publication Date:
Apr 2007
Keywords:
Sarcoma; chemotherapy; targeted therapies; GIST
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