, Volume 65, Issue 2, pp 167–178

Recent Developments in Salvage Chemotherapy for Patients with Metastatic Soft Tissue Sarcoma

Leading Article


The number of effective cytotoxic agents for the treatment of patients with metastatic adult soft tissue sarcoma is limited, especially when patients have failed anthracycline- and ifosfamide-based chemotherapy. For the subgroup of patients with inoperable gastrointestinal stromal tumour (GIST), progress has been made via the rapid development and approval of the targeted therapy imatinib. Small round cell tumours (SRCTs), such as Ewing’s sarcoma/primitive neuroectodermal tumour, desmoplastic SRCT and rhabdomyosarcoma, are chemotherapy-sensitive and potentially curable malignancies, which are treated with multimodality, dose-intensive, neoadjuvant protocols regardless of size or overt metastatic disease. Most other high-grade (grading >I), so-called ‘adult type’, soft tissue sarcomas such as fibrosarcoma, liposarcoma, pleomorphic and synovial sarcomas are treated with an anthracycline-based regimen with or without ifosfamide as front-line therapy. In relapsed ‘adult type’ soft tissue sarcomas, trofosfamide, gemcitabine and trabectedin (ecteinascidin 743) appear to be drugs associated with some activity and an acceptable toxicity profile. A high activity has been reported for the taxanes, in particular for paclitaxel, in vascular sarcomas located in the scalp or face and in Kaposi’s sarcoma. It is interesting to note that the different drugs have particular effects in distinct subtypes of soft tissue sarcoma; however, it should be taken into account that the number of patients included in the phase II trials is limited. The role of the newer agents (e.g. epothilones, brostallicin) is currently undefinable. Targeted therapy inhibiting vascular endothelial growth factor receptor, epidermal growth factor receptor, RAF kinase, c-KIT or platelet-derived growth factor receptors will continue to be tested in GIST patients refractory to imatinib and in other sarcoma histologies.


  1. 1.
    Patel SR. New agents in the treatment of soft-tissue sarcomas. Expert Opin Investig Drugs 2000; 9: 1545–51PubMedCrossRefGoogle Scholar
  2. 2.
    Patel SR, Chu P, Vadhan-Raj S. Differential responsiveness of leiomyosarcoma (leio) arising at different sites to doxorubicin-based chemotherapy [abstract]. Proc Am Assoc Cancer Res 1997; 38: 7Google Scholar
  3. 3.
    Bertuzzi A, Castagna L, Nozza A, et al. High-dose chemotherapy in poor-prognosis adult small round-cell tumors: clinical and molecular results from a prospective study. J Clin Oncol 2002; 20: 2181–8PubMedCrossRefGoogle Scholar
  4. 4.
    Kushner BH, LaQuaglia MP, Wollner N, et al. Desmoplastic small round-cell tumor: prolonged progression-free survival with aggressive multimodality therapy. J Clin Oncol 1996; 14: 1526–31PubMedGoogle Scholar
  5. 5.
    Borden EC, Amato DA, Rosenbaum C, et al. Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas. J Clin Oncol 1987; 5: 840–50PubMedGoogle Scholar
  6. 6.
    Lopez M, Vici P, Di Lauro L, et al. Increasing single epirubicin doses in advanced soft tissue sarcomas. J Clin Oncol 2002; 20: 1329–34PubMedCrossRefGoogle Scholar
  7. 7.
    Cure H, Krakowski I, Adenis A, et al. Results of a phase II trial with second-line cystemustine at 60 mg/m2 in advanced soft tissue sarcoma: a trial of the EORTC Early Clinical Studies Group. Eur J Cancer 1998; 34: 422–3PubMedCrossRefGoogle Scholar
  8. 8.
    Bramwell VH, Anderson D, Charette ML. Doxorubicin-based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatic soft tissue sarcoma. Cochrane Database Syst Rev 2003; (3): CD003293Google Scholar
  9. 9.
    Bokemeyer C, Franzke A, Hartmann JT, et al. A phase I/II study of sequential, dose-escalated, high dose ifosfamide plus doxorubicin with peripheral blood stem cell support for the treatment of patients with advanced soft tissue sarcomas. Cancer 1997; 80: 1221–7PubMedCrossRefGoogle Scholar
  10. 10.
    Frustaci S, Buonadonna A, Galligioni E, et al. Increasing 4′-epidoxorubicin and fixed ifosfamide doses plus granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: a pilot study. J Clin Oncol 1997; 15: 1418–26PubMedGoogle Scholar
  11. 11.
    Reichardt P, Tilgner J, Hohenberger P, et al. Dose-intensive chemotherapy with ifosfamide, epirubicin, and filgrastim for adult patients with metastatic or locally advanced soft tissue sarcoma: a phase II study. J Clin Oncol 1998; 16: 1438–43PubMedGoogle Scholar
  12. 12.
    Steward WP, Verweij J, Somers R, et al. Granulocyte-macrophage colony-stimulating factor allows safe escalation of dose-intensity of chemotherapy in metastatic adult soft tissue sarcomas: a study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 1993; 11: 15–21PubMedGoogle Scholar
  13. 13.
    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: 317–21PubMedCrossRefGoogle Scholar
  14. 14.
    Benjamin RS, Legha SS, Patel SR, et al. Single-agent ifosfamide studies in sarcomas of soft tissue and bone: the MD Anderson experience. Cancer Chemother Pharmacol 1993; 31 Suppl. 2: S174–9PubMedGoogle Scholar
  15. 15.
    Gottlieb JA, Benjamin RS, Baker LH, et al. Role of DTIC (NSC-45388) in the chemotherapy of sarcomas. Cancer Treat Rep 1976; 60: 199–203PubMedGoogle Scholar
  16. 16.
    Balcerzak SP, Benedetti J, Weiss GR, et al. A phase II trial of paclitaxel in patients with advanced soft tissue sarcomas: a Southwest Oncology Group study. Cancer 1995; 76: 2248–52PubMedCrossRefGoogle Scholar
  17. 17.
    Gallup DG, Blessing JA, Andersen W, et al. Evaluation of paclitaxel in previously treated leiomyosarcoma of the uterus: a gynecologic oncology group study. Gynecol Oncol 2003; 89: 48–51PubMedCrossRefGoogle Scholar
  18. 18.
    Fata F, O’Reilly E, Ilson D, et al. Paclitaxel in the treatment of patients with angiosarcoma of the scalp or face. Cancer 1999; 86: 2034–7PubMedCrossRefGoogle Scholar
  19. 19.
    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: 539–42PubMedGoogle Scholar
  20. 20.
    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: 1281–8PubMedCrossRefGoogle Scholar
  21. 21.
    Edmonson JH, Ebbert LP, Nascimento AG, et al. Phase II study of docetaxel in advanced soft tissue sarcomas. Am J Clin Oncol 1996; 19: 574–6PubMedCrossRefGoogle Scholar
  22. 22.
    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: 2081–6PubMedGoogle Scholar
  23. 23.
    Okuno S, Geyer SM, Maples WJ, et al. Phase 2 study of epothilone B analog (BMS-247550) in soft tissue sarcomas: an interim report [abstract no. 1645]. Proc Am Soc Clin Oncol 2002; 21: 412aGoogle Scholar
  24. 24.
    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: 325–9PubMedCrossRefGoogle Scholar
  25. 25.
    Svancarova L, Blay JY, Judson IR, et al. Gemcitabine in advanced adult soft-tissue sarcomas: a phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2002; 38: 556–9PubMedCrossRefGoogle Scholar
  26. 26.
    Okuno S, Edmonson J, Mahoney M, et al. Phase II trial of gemcitabine in advanced sarcomas. Cancer 2002; 94: 3225–9PubMedCrossRefGoogle Scholar
  27. 27.
    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: 1969–73PubMedCrossRefGoogle Scholar
  28. 28.
    Hartmann JT, Oechsle K, Huober J, et al. An open label, non-comparative phase II study of gemcitabine as salvage treatment for patients with pretreated advanced soft tissue sarcoma [abstract no. PO878]. J Cancer Res Clin Oncol 2004; 130: S192CrossRefGoogle Scholar
  29. 29.
    Amodio A, Carpano S, Manfredi C, et al. Gemcitabine in advanced stage soft tissue sarcoma: a phase II study [in Italian]. Clin Ter 1999; 150: 17–20PubMedGoogle Scholar
  30. 30.
    Yovine A, Riofrio M, Blay JY, et al. Phase II study of ecteinascidin-743 in advanced pretreated soft tissue sarcoma patients. J Clin Oncol 2004; 22: 890–9PubMedCrossRefGoogle Scholar
  31. 31.
    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: 1480–90PubMedCrossRefGoogle Scholar
  32. 32.
    Hartmann JT, Oechsle K, Mayer F, et al. Phase II trial of trofosfamide in patients with advanced pretreated soft tissue sarcomas. Anticancer Res 2003; 23(2C): 1899–901PubMedGoogle Scholar
  33. 33.
    Kollmannsberger C, Brugger W, Hartmann JT, et al. Phase II study of oral trofosfamide as palliative therapy in pretreated patients with metastatic soft-tissue sarcoma. Anticancer Drugs 1999; 10: 453–6PubMedCrossRefGoogle Scholar
  34. 34.
    Blomqvist C, Wiklund T, Pajunen M, et al. Oral trofosfamide: an active drug in the treatment of soft-tissue sarcoma. Cancer Chemother Pharmacol 1995; 36: 263–5PubMedCrossRefGoogle Scholar
  35. 35.
    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: 410–2PubMedCrossRefGoogle Scholar
  36. 36.
    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: 2693–9PubMedCrossRefGoogle Scholar
  37. 37.
    Budd GT, Rankin C, Hutchins LF, et al. Phase II trial of topotecan by continuous infusion in patients with advanced soft tissue sarcomas, a SWOG study: Southwest Oncology Group. Invest New Drugs 2002; 20: 129–32PubMedCrossRefGoogle Scholar
  38. 38.
    Reichardt P, Oechsle K, Pink D, et al. An open label, non-comparative phase II study of topotecan as salvage treatment for patients with soft tissue sarcoma. Invest New Drugs 2003; 21: 481–6PubMedCrossRefGoogle Scholar
  39. 39.
    Saylors III RL, Stine KC, Sullivan J, et al. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 2001; 19: 3463–9PubMedGoogle Scholar
  40. 40.
    Hosono A, Makimoto A, Kawamoto H, et al. A retrospective analysis in safety and efficacy of protracted administration of irinotecan for patients with small round cell sarcomas relapsed after stem cell transplantation (SCT) [abstract no. 3269]. Proc Am Soc Clin Oncol 2003; 22: 813Google Scholar
  41. 41.
    Pappo AS, Lyden E, Breitfeld PP, et al. Irinotecan (CPT-11) is active against pediatric rhabdomyosarcoma (RMS): a phase II window trial from the Soft Tissue Sarcoma Committee (STS) of the Children’s Oncology Group (COG) [abstract no. 1570]. Proc Am Soc Clin Oncol 2002; 21: 393Google Scholar
  42. 42.
    De Angelo D, Naujoks R, Manola J, et al. Phase II study of irinotecan (CPT-11) in relapsed or refractory soft tissue sarcoma (STS) [abstract no. 2186]. Proc Am Soc Clin Oncol 2000; 19: 555aGoogle Scholar
  43. 43.
    Patel SR, Beach J, Papadopoulos N, et al. Results of a 2-arm phase II study of 9-nitrocamptothecin in patients with advanced soft-tissue sarcomas. Cancer 2003; 97: 2848–52PubMedCrossRefGoogle Scholar
  44. 44.
    Fidias P, Demetri GD, Harmon D. Navelbine shows activity in previously treated sarcoma patients: phase II results from MGH/Dana Farber/Partner’s Cancercare Study [abstract no. 1977]. Proc Am Soc Clin Oncol 1998; 17: 513aGoogle Scholar
  45. 45.
    Blay JY, Judson I, Rodenhuis S, et al. Phase II study of raltitrexed (‘Tomudex’) for patients with advanced soft tissue sarcomas refractory to doxorubicin-containing regimens. Anticancer Drugs 1999; 10: 873–7PubMedCrossRefGoogle Scholar
  46. 46.
    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: 2824–31PubMedCrossRefGoogle Scholar
  47. 47.
    Pivot X, Chevreau C, Cupissol D, et al. Phase II trial of paclitaxel-epirubicin in patients with recurrent soft-tissue sarcoma. Am J Clin Oncol 2002; 25: 561–4PubMedCrossRefGoogle Scholar
  48. 48.
    Casanova M, Ferrari A, Spreafico F, et al. Vinorelbine in previously treated advanced childhood sarcomas: evidence of activity in rhabdomyosarcoma. Cancer 2002; 94: 3263–8PubMedCrossRefGoogle Scholar
  49. 49.
    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: 3483–9PubMedGoogle Scholar
  50. 50.
    Van Glabbeke M, Verweij J, Judson I, et al. Progression-free rate as the principal end-point for phase II trials in soft-tissue sarcomas. Eur J Cancer 2002; 38: 543–9PubMedCrossRefGoogle Scholar
  51. 51.
    Delaloge S, Yovine A, Taamma A, et al. Ecteinascidin-743: a marine-derived compound in advanced, pretreated sarcoma patients: preliminary evidence of activity. J Clin Oncol 2001; 19: 1248–55PubMedGoogle Scholar
  52. 52.
    Demetri GD. ET-743: the US experience in sarcomas of soft tissues. Anticancer Drugs 2002; 13 Suppl. 1: S7–9PubMedGoogle Scholar
  53. 53.
    Puchalski TA, Ryan DP, Garcia-Carbonero R, et al. Pharmacokinetics of ecteinascidin 743 administered as a 24-h continuous intravenous infusion to adult patients with soft tissue sarcomas: associations with clinical characteristics, pathophysiological variables and toxicity. Cancer Chemother Pharmacol 2002; 50: 309–19PubMedCrossRefGoogle Scholar
  54. 54.
    Takahashi N, Li WW, Banerjee D, et al. Sequence-dependent enhancement of cytotoxicity produced by ecteinascidin 743 (ET-743) with doxorubicin or paclitaxel in soft tissue sarcoma cells. Clin Cancer Res 2001; 7: 3251–7PubMedGoogle Scholar
  55. 55.
    Leahy MG, Blay JY, le Cesne A, et al. EORTC 62011: phase II trial of brostallicin for soft tissue sarcoma [abstract no. 694]. Eur J Cancer Suppl 2003; 1(5): S209CrossRefGoogle Scholar
  56. 56.
    Stevens MF, Hickman JA, Stone R, et al. Antitumor imidazotetrazines. 1: synthesis and chemistry of 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4 (3 H)-one, a novel broad-spectrum antitumor agent. J Med Chem 1984; 27: 196–201PubMedCrossRefGoogle Scholar
  57. 57.
    Tsang LL, Quarterman CP, Gescher A, et al. Comparison of the cytotoxicity in vitro of temozolomide and dacarbazine, prodrugs of 3-methyl-(triazen-1-yl)imidazole-4-carboxamide. Cancer Chemother Pharmacol 1991; 27: 342–6PubMedCrossRefGoogle Scholar
  58. 58.
    Stevens MF, Hickman JA, Langdon SP, et al. Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Res 1987; 47: 5846–52PubMedGoogle Scholar
  59. 59.
    Muro XD, Pousa AL, Buesa JM, et al. Temozolomide as a 6-week continuous oral schedule in advanced soft tissue sarcoma (STS): a phase II trial of the Spanish Group for Research on Sarcomas (GEIS) [abstract no. 1412]. Proc Am Soc Clin Oncol 2001; 20: 873Google Scholar
  60. 60.
    O’Reilly S, Rowinsky EK, Slichenmyer W, et al. Phase I and pharmacologic study of topotecan in patients with impaired renal function. J Clin Oncol 1996; 14: 3062–73PubMedGoogle Scholar
  61. 61.
    Bramwell VH, Eisenhauer EA, Blackstein M, et al. Phase II study of topotecan (NSC 609 699) in patients with recurrent or metastatic soft tissue sarcoma. Ann Oncol 1995; 6: 847–9PubMedGoogle Scholar
  62. 62.
    Wall ME, Wani MC, Natschke SM, et al. Plant antitumor agents: 22. Isolation of 11-hydroxycamptothecin from Camptotheca acuminata Decne: total synthesis and biological activity. J Med Chem 1986; 29(8): 1553–5Google Scholar
  63. 63.
    Kharbanda S, Rubin E, Gunji H, et al. Camptothecin and its derivatives induce expression of the c-jun protooncogene in human myeloid leukemia cells. Cancer Res 1991; 51: 6636–42PubMedGoogle Scholar
  64. 64.
    Natelson EA, Giovanella BC, Verschraegen CF, et al. Phase I clinical and pharmacological studies of 20-(S)-camptothecin and 20-(S)-9-nitrocamptothecin as anticancer agents. Ann N Y Acad Sci 1996; 803: 224–30PubMedCrossRefGoogle Scholar
  65. 65.
    Raney RB, Anderson JR, Barr FG, et al. Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life: a selective review of intergroup rhabdomyosarcoma study group experience and rationale for Intergroup Rhabdomyosarcoma Study V. J Pediatr Hematol Oncol 2001; 23: 215–20PubMedCrossRefGoogle Scholar
  66. 66.
    Tolcher AW, Eckhardt SG, Kuhn J, et al. Phase I and pharmacokinetic study of NSC 655649, a rebeccamycin analog with topoisomerase inhibitory properties. J Clin Oncol 2001; 19: 2937–47PubMedGoogle Scholar
  67. 67.
    Bramwell VH, Morris D, Ernst DS, et al. Safety and efficacy of the multidrug-resistance inhibitor biricodar (VX-710) with concurrent doxorabicin in patients with anthracycline-resistant advanced soft tissue sarcoma. Clin Cancer Res 2002; 8: 383–93PubMedGoogle Scholar
  68. 68.
    Maki R, Kraft A, Demetri GD, et al. A phase II multicenter study of proteasome inhibitor PS-341 (LDP-341, bortezomib) for untreated recurrent or metastatic soft tissue sarcoma (STS); CTEP study 1757 [abstract no. 3291]. Proc Am Soc Clin Oncol 2003; 22: 819Google Scholar
  69. 69.
    Schoffski P, Thate B, Beutel G, et al. Phase I and pharmacokinetic study of TZT-1027, a novel synthetic dolastatin 10 derivative, administered as a 1-hour intravenous infusion every 3 weeks in patients with advanced refractory cancer. Ann Oncol 2004 Apr; 15(4): 671–9PubMedCrossRefGoogle Scholar
  70. 70.
    Debrock G, Vanhentenrijk V, Sciot R, et al. A phase II trial with rosiglitazone in liposarcoma patients. Br J Cancer 2003; 89: 1409–12PubMedCrossRefGoogle Scholar
  71. 71.
    Li W, Fan J, Bertino JR. Selective sensitization of retinoblastoma protein-deficient sarcoma cells to doxorabicin by flavopiridol-mediated inhibition of cyclin-dependent kinase 2 kinase activity. Cancer Res 2001; 61: 2579–82PubMedGoogle Scholar
  72. 72.
    Tomek S, Koestler W, Horak P, et al. Trail-induced apoptosis and interaction with cytotoxic agents in soft tissue sarcoma cell lines. Eur J Cancer 2003; 39: 1318–29PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  1. 1.Medizinische Klinik II and Interdisciplinary Sarcoma CenterUniversitätsklinikum, Eberhard-Karls-UniversityTuebingenGermany
  2. 2.Department of Sarcoma Medical OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  3. 3.Department of Hematology/Oncology/Immunology/Rheumatology, UKT-Medical Center IIEberhard-Karls-University TuebingenTuebingenGermany

Personalised recommendations