Abstract
In the present paper the treatment of advanced and metastatic soft tissue sarcoma is reviewed with the primary emphasis on chemotherapy. One of the major advances in the treatment of soft tissue sarcomas is their treatment by multidisciplinary teams in specialized centers. Despite optimal local treatment of the primary tumor, disseminated disease will develop in many patients. Consequently, chemotherapy has been extensively studied but, unfortunately, the responsiveness of these tumors to chemotherapy has been disappointingly low. Doxorubicin and ifosfamide appear to be the most effective drugs — the latter with a somewhat higher toxicity at effective dosages. Other drugs with some first line activity are dacarbazine, liposomal doxorubicin and possibly trabectedin (ET-743). Imatinib is very effective in gastrointestinal stromal tumors (GIST) where it is now the treatment of choice. The combination of doxorubicin and ifosfamide increases the response rate without affecting overall survival. For these reasons, single agent doxorubicin is, in many centers, considered the standard treatment for advanced soft tissue sarcoma, and combination chemotherapy should be reserved for special subgroups of patients such as young patients with chemosensitive tumors. Chemotherapy for patients with advanced and metastatic soft tissue sarcoma is inadequate at present and new drugs are desperately needed. Fortunately, exciting new drugs are under development and hopefully they will improve the treatment of patients with this disease.
Similar content being viewed by others
References
Brennan MF, Alektiar KM, Maki RG. Soft tissue sarcoma. In: De Vita VT, Hellman S, Rosenberg SA, editors. Cancer principles & practice of oncology. 6th ed. Philadelphia (PA): Lippincott Williams & Wilkins, 2001: 1841–90
Dirix LY, van Oosterom AT. Soft tissue sarcoma in adults. Curr Opin Oncol 1999; 11: 285–95
Storm HH. Survival of adult patients with cancer of soft tissues or bone in Europe. Eur J Cancer 1998; 34: 2212–7
Flugstad DL, Wilke CP, McNutt MA,. Importance of surgical resection in the successful management of soft tissue sarcoma. Arch Surg 1999; 134: 856–61
Siebenrock KA, Hertel R, Ganz R. Unexpected resection of soft-tissue sarcoma. More mutilating surgery, higher local recurrence rates, and obscure prognosis as consequences of improper surgery. Arch Orthop Trauma Surg 2000; 120: 65–9
O’Sullivan B, Wylie J, Catton C, et al. The local management of soft tissue sarcoma. Semin Radiat Oncol 1999; 9: 328–48
Lewis JJ, Leung D, Espat J, et al. Effect of re-resection in extremity soft tissue sarcoma. Ann Surg 2000; 231: 655–63
O’Byrne K, Steward WP. The role of chemotherapy in the treatment of adult soft tissue sarcomas. Oncology 1999; 56: 13–23
Verweij J, Mouridsen HT, Nielsen OS, et al. The present state of the art in chemotherapy for soft tissue sarcomas in adults: the EORTC point of view. Crit Rev Oncol Hematol 1995, 201
Adjuvant chemotherapy for localized resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Sarcoma Meta-analysis Collaboration. Lancet 1997; 350: 1647–54
Adjuvant chemotherapy for localized resectable soft tissue sarcoma in adults. Available in the Cochrane Library [database on disk and CD ROM]. Updated quarterly. The Cochrane Collaboration; issue 4. Oxford: Update Software, 2000: CD001419
Nielsen OS, Dombernowsky P, Mouridsen H, et al. Epirubicin is not superior to doxorubicin in the treatment of advanced soft tissue sarcomas: the experience of the EORTC soft tissue and bone sarcoma group. Sarcoma 2000; 4: 31–5
van Geel AN, Pastorino U, Jauch KW, et al. Surgical treatment of lung metastases: the European Organization for Research and Treatment of Cancer - Soft Tissue and Bone Sarcoma Group study of 255 patients. Cancer 1996; 77: 675–82
Pastorino U. Metastasectomy for soft tissue sarcomas. Cancer Treat Res 1997; 91: 65–75
Launchbury AP, Habboubit N. Epirubicin and doxorubicin: a comparison of their characteristics, therapeutic activity and toxicity. Cancer Treat Rev 1993; 19: 197–228
Bramwell VHC, Mouridsen HT, Mulder JH, et al. Carminomycin vs. adriamycin in advanced soft tissue sarcomas: an EORTC randomized phase II study. Eur J Cancer Clin Oncol 1983; 19: 1097–104
Bull FE, von Hoff DD, Balcerak SP, et al. Phase II trial of mitoxantrone in advanced sarcomas: a Southwest Oncology Group study. Cancer Treat Rep 1985; 69: 231–3
Mouridsen HT, Bastholt L, Somers R, et al. Adria-mycin 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: 1477–83
Nielsen OS, Dombernowsky P, Mouridsen H, et al. High-dose epirubicin is not an alternative to standard-dose doxorubicin in the treatment of advanced soft tissue sarcomas: a study of the EORTC soft tissue and bone sarcoma group. Br J Cancer 1998; 78: 1634–9
Toma S, Tucci A, Villani G, et al. Liposomal doxorubicin (Caelyx) in advanced pretreated soft tissue sarcomas: a phase II study of the Italian Sarcoma Group (ISG). Anticancer Res 2000; 20(1B): 485–91
Judson I, Radford JA, Harris M, et al. Randomized phase II trial of pegylated liposomal doxorubicin (Doxil®/Caelyx®) 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: 870–7
Hoefer-Janker H, Scheef U, Gunther U, et al. Erfahrungen mit der franctionierten ifosfamide-stosstherapie bei generalisierten malignant tumoren. Med Welt 1975; 26: 972–9
Bruhl P, Gunther U, Hoefer-Janker H, et al. Results obtained with fractionated ifosfamide massive dose treatment in generalized malignant tumors. Int J Clin Pharmacol 1976, 39
Zalupski M, Baker LH. Ifosfamide. J Natl Cancer Inst 1988; 80: 556–66
Dirix LY, van Oosterom AT. The role of if osfamide in the treatment of adult soft tissue sarcomas, Ewing’s sarcoma, and osteosarcoma: a review. Sem Oncol 1990; 17Suppl. 4: 55–7
Stuart-Harris RC, Harper PG, Parsons CA, et al. High dose alkylation therapy using ifosfamide infusion with mesna in the treatment of adult advanced softtissue sarcoma. Cancer Chemother Pharmacol 1983; 11: 69–72
Bramwell VHC, Mouridsen HT, Santoro A, et al. Cyclophosphamide vs ifosfamide: a randomized phase II trial in adult soft tissue and bone sarcoma. Preliminary report of EORTC Soft Tissue and Bone Sarcoma Group [abstract]. Proc Am Soc Clin Oncol 1985; 4: 143
Antman KH, Ryan L, Elias A, et al. Response to ifosfamide and mesna: 124 previously treated patients with metastatic or unresectable sarcoma. J Clin Oncol 1989; 1: 126–31
van Oosterom AT, Krzemienlecki K, Nielsen OS, et al. Randomized phase II study of the EORTC Soft Tissue and Bone Sarcoma Group comparing two different ifosfamide regimens in chemotherapy untreated advanced soft tissue sarcoma patients. Eur J Cancer. In press.
Nielsen OS, Judson I, van Hoesel Q, et al. Effect of high-dose ifosfamide in advanced soft tissue sarcomas: a multicentre phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2000; 36: 61–7
Le Cesne A, Antoine E, Spielman M, et al. High-dose ifosfamide: circumvention of resistance to standard-dose ifosfamide in advanced soft tissue sarcomas. J Clin Oncol 1995; 13: 1600–8
Patel SR, Vadham-Raj S, Papadopolous N, et al. High-dose ifosfamide in body and soft tissue sarcomas: results of phase II and pilot studies: dose response and schedule dependence. J Clin Oncol 1997; 15: 2378–84
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: 1248–55
Demetri GD, Seiden M, Garcia-Carbonero R, et al. ET743 shows promising activity in distinct populations of sarcoma patients: summary of 3 phase II trials [abstract]. Proc Am Soc Clin Oncol 2000; 19: 553a (2177)
Le Cesne A. Phase II study of ET743 in advanced soft tissue sarcomas (ASTS) in adults. A STBSG EORTC Trial [abstract]. Proc Am Soc Clin Oncol 2000; 19: 554a (2182)
Amodio A, Carpano S, Manfredi C, et al. Gemcitabine in advanced soft tissue sarcoma: a phase II study. Clin Ter 1999; 150: 17–20
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(4): 556–9
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: 453–6
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(10): 2081–6
Sutton G, Blessing JA, Ball H. Phase II trial of paclitaxel in leiomyosarcoma of the uterus: a gynecologic oncology group study. Gynecol Oncol 1999; 74: 346–9
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: 2034–7
Patel S, 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: 317–21
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: 1438–43
Leyvraz S, Bacchi M, Cerny T, et al. Phase I multicenter study of combined high-dose ifosfamide and doxorubicin in the treatment of advanced sarcomas, Swiss Group for Clinical Research (SAKK). Ann Oncol 1998; 9: 877–84
Santoro A, Tursz T, Mouridsen H, et al. Doxorubicin versus CyVADIC versus ifosfamide plus doxorubicin in first line treatment of advanced soft tissue sarcomas: a randomized study of the EORTC Soft tissue and bone sarcoma group. J Clin Oncol 1995; 13: 1537–45
Steward WP, Verweij J, Somers R, et al. Granulocyte-macrophage colonystimulating 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(1): 15–21
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 colonystimulating 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(14): 2676–84
Schoenfeld DA, Rosenbaum C, Horton J, et al. 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
Borden EC, Amato DA, Rosenbaum C, et al. Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas. J Clin Oncol 1987; 5(6): 840–50
Edmonson JH, Ryan LM, Blum RG, et al. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin and cis-platin against advanced soft tissue sarcomas. J Clin Oncol 1993; 11: 1269–75
O’Bryan RM, Baker LH, Gottlieb JB, et al. Dose response evaluation of adriamycin in neoplasm. Cancer 1977; 39: 1940–8
Elias AD, Eder JP, Skea T, et al. High dose ifosfamide with mesna uroprotection: a phase I study. J Clin Oncol 1990; 8: 170–8
Cerny T, Leyvraz S, Daggi H, et al. Phase II trials of ifosfamide and mesna in advanced soft tissue sarcoma patients: a definite dose-response relationship [abstract]. Proc Am Soc Clin Oncol 1992; 11: 416
Rosen G, Forscher C, Lowenbraun S, et al. Synovial sarcoma. Uniform response of metastases to high dose ifosfamide. Cancer 1994; 73: 2506–11
Saeter G, Alvegaard TA, Monge OR, et al. Ifosfamide and continuous infusion etoposide in advanced adult soft tissue sarcoma: a Scandinavian Sarcoma Group Phase II Study. Eur J Cancer 1997; 33: 1551–8
Jelic S, Kovcin V, Milanovic N, et al. Randomized study of high-dose epirubicin versus high-dose epirubicin-cisplatin chemotherapy for advanced soft tissue sarcoma. Eur J Cancer 1997; 33: 220–5
Antman KH, Crowley J, Balcerzak SP, et al. An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide an Mesna in advanced soft tissue and bone sarcomas. J Clin Oncol 1993; 11: 1276–85
Horowitz ME, Kinsella TJ, Wexler LH, et al. Total-body irradiation and autologous bone marrow transplant in the treatment of high-risk Ewing’s sarcoma and rhabdomyosarcoma. J Clin Oncol 1993; 11: 1911–8
Koscielniak E, Klingebiel TH, Peters C, et al. Do patients with metastatic and recurrent rhabdomyosarcoma benefit from high-dose therapy with hematopoietic rescue?. Report of the German/Austrian Pediatric Bone Marrow Transplantation Group. Bone Marrow Transplant 1997; 19: 227–31
Burdach S, Jurgens H, Peters C, et al. Myeloablative radiochemotherapy and hematopoietic stem cell rescue in poor-prognosis Ewing’s sarcoma. J Clin Oncol 1993; 11: 1482–8
Boulad F, Kernan NA, LaQuaglia MP, et al. High-dose induction chemoradiotherapy followed by autologous bone marrow transplantation as consolidation therapy in rhabdomyosarcoma, extraosseous Ewing’s sarcoma, and undifferentiated sarcoma. J Clin Oncol 1998; 16: 1697–706
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: 1221–7
Samuels B, Elias A, Vogelzang N, et al. High dose chemotherapy with ABMT for refractory sarcoma [abstract]. Proc Am Soc Clin Oncol 1989; 8: 1068
Elias AD, Ayash LJ, Wheeler C, et al. Phase I study of high-dose ifosfamide, carboplatin and etoposide with autologous hematopoietic stem cell support. Bone Marrow Transplant 1995; 15: 373–9
Dumontet C, Biron P, Bouffet E, et al. High dose chemotherapy with ABMT in soft tissue sarcomas: a report of 22 cases. Bone Marrow Transplant 1992; 10: 405–8
Kessinger A, Petersen K, Bishop M, et al. High dose therapy with autologous hematopoietic stem cell rescue for patients with metastatic sarcoma [abstract]. Proc Am Soc Clin Oncol 1994; 13: 1674
Mesia R, Sola C, Lopez Pousa A, et al. High-dose chemotherapy and autologous bone marrow transplantation in high-grade metastatic sarcomas. Rev Clin Esp 1994; 194: 960–5
Blay J-Y, Bouhour D, Ray-Coquard I, et al. High-dose chemotherapy with autologous hematopoietic stem-cell transplantation for advanced soft tissue sarcoma in adults. J Clin Oncol 2000; 18: 3643–50
Rosti G, Philip T, Chauvin F, et al. European Group for Blood and Bone Marrow Transplantation (EBMT) registry in solid tumors: a 12 years experience [abstract]. Bone Marrow Transplant 1997; 17: 469
Blay JY, van Glabbeke M, Nielsen OS, et al. Five-year survivors in patients (pts) with advanced soft tissue sarcoma (ASTS) treated with doxorubicin: a study on 1742 patients (STBSG) [abstract]. Proc Am Soc Clin Oncol 1998; 17: 512a
Yap BS, Sincovics JG, Burgess MA, et al. The curability of advanced soft tissue sarcomas in adult with chemotherapy [abstract]. Proc Am Soc Clin Oncol 1983; 1: 239
Wiklund T, Saeter G, Strander H, et al. The outcome of advanced soft tissue sarcoma patients with complete tumor regression after either chemotherapy alone or chemotherapy plus surgery. Eur J Cancer 1997; 33(3): 357–61
Antman KH, Elias A. Dana-Farber Cancer Institute studies in advanced sarcoma. Semin Oncol 1990; 17Suppl. 2: 7–15
Pastorino U. Metastasectomy for soft tissue sarcomas. In: Verweij J, Pinedo HM, Suit H, editors. Soft tissue sarcomas: present achievements and future prospects. Boston (MA): Kluwer Academic Publishers, 1997: 65–75
Miller DS, Blessing JA, Kilgore LC, et al. Phase II trial of topotecan in patients with advanced, persistent, or recurrent uterine leiomyosarcomas: a Gynecologic Oncology Group Study. Am J Clin Oncol 2000; 23(4): 355–7
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(2): 177–81
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: 873–7
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: 410–2
Kindblom L-G, Remotti HE, Aldenborg F, et al. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol 1998; 152: 1259–69
Sircar K, Hewlett BR, Huizinga JD, et al. Interstitial cells of Cajal as precursors of gastrointestinal stromal tumors. Am J Surg Pathol 1999; 23: 377–89
Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998; 279: 577–80
VanGlabbeke M, van Oosterom AT, Oosterhuis JW, et al. Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcomas: an analysis of 2,185 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 Oncology 1999; 17: 150–7
Platt BE, Hollema H. Molenaar WM, et al. Soft tissue leiomyosarcomas and malignant gastrointestinal stromal tumors: differences in clinical outcome and expression of multidrug resistance proteins. J Clin Oncol 2000; 18: 3211–20
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
Van Oosterom AT, Judson I, Verweij J, et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumors: a phase I study. Lancet 2001; 358: 1421–3
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: 93–8
Billingsley KG, Lewis JJ, Leung DH, et al. Multifactorial analysis of the survival f patients with distant metastases arising from primary extremity sarcoma. Cancer 1999; 85(2): 389–95
van Geel AN, van Coevorden F, Blankensteijn JD, et al. Surgical treatment of pulmonary metastases from soft tissue sarcomas: a retrospective study in the Netherlands. J Surg Oncol 1994; 56: 172–7
Ueda T, Uchida A, Kodama K, et al. Aggressive pulmonary metastasectomy for soft tissue sarcomas. Cancer 1993; 72: 1919–25
Temeck BK, Wewter LH, Streinberg SM, et al. Metastasectomy for sarcomatous pediatric histologies: results and prognostic factors. Ann Thorac Surg 1995; 59(6): 1386–9
Verazin GT, Warneke JA, Driscoll DL, et al. Resection of lung metastases from soft-tissue sarcomas: a multivariate analysis. Arch Surg 1992; 127: 1407–11
Billingsley KG, Burt ME, Jara E, et al. Pulmonary metastases from soft tissue sarcoma: analysis of patterns of disease and postmetastasis survival. Ann Surg 1999; 229(5): 610–2
Choong PF, Pritchard DJ, Rock MG, et al. Survival after pulmonary metastasectomy in soft tissue sarcoma. Prognostic factors in 214 patients. Acta Orthop Scand 1995; 66(6): 561–8
Weiser MR, Downey RJ, Leung DH, et al. Repeat resection of pulmonary metastases in patients with soft-tissue sarcoma. J Am Coll Surg 2000; 191(2): 184–90
VanGlabbeke M, Donate Di Paola E, Mouridsen H, et al. Response to anthracycline based chemotherapy (ABC) and overall survival in patients (PTS) with lung metastases from tissues sarcoma (STS): a retrospective study of the EORTC soft tissue and bone sarcoma group (STBSG) [abstract]. J Clin Oncol 1999; 18: 542a(2093)
Putnam JB, Roth JA. Surgical management for pulmonary metastases from sarcomas. Hematol Oncol Clin North Am 1995; 9: 869–86
Acknowledgements
The authors have provided no information on sources of funding or on conflicts of interest directly relevant to the content of this review.
Author information
Authors and Affiliations
Consortia
Corresponding author
Rights and permissions
About this article
Cite this article
Nielsen, O.S., Blay, JY., Judson, I.R. et al. Metastatic Soft Tissue Sarcoma in Adults. Am J Cancer 2, 211–221 (2003). https://doi.org/10.2165/00024669-200302030-00005
Published:
Issue Date:
DOI: https://doi.org/10.2165/00024669-200302030-00005