What is the role for systemic therapy in advanced soft-tissue sarcoma?

From Cancer Guidelines Wiki


Soft-tissue sarcomas comprise over fifty histologically distinct subtypes, with corresponding differences in molecular aetiology and biological behaviour.[1] The first presentation with advanced (metastatic or unresectable) disease raises the issue of the timing and types of therapeutic options.

There are three therapeutic options that may be considered. The first is watchful waiting, which may be suitable particularly for indolent and asymptomatic sarcoma subtypes, especially in an elderly or frail population. The second is consideration of local therapies, particularly radiotherapy, for symptomatic or rapidly progressive single or oligometastatic disease. Objective local control rates for radiotherapy approach 80%. Finally, consideration may be given to systemic therapy. Most (but not all) types of soft-tissue sarcoma tend to be relatively resistant to systemic therapies, with objective response rates ranging from 0-50%, depending on subtype. In no circumstance is systematic therapy for advanced or unresectable soft-tissue sarcoma considered curative, although a subset of patients may have substantial, long-term survival in this situation.[2]

Systemic therapy for advanced soft tissue sarcoma may be divided into aggressive and gentle palliation. The therapeutic decision between these two approaches usually depends on the need for rapid disease control, the state of fitness of the patient, the type of sarcoma, and the therapeutic philosophy of the patient and treating clinician. The need for rapid disease control is determined by the symptoms of the patient, and the rate and sites of progression of the tumours. Recent data suggest little difference on overall survival between doxorubicin alone or when administered with ifosfamide, when administered in first line for advanced disease.[3]

For the most common subtypes of soft-tissue sarcomas (pleomorphic high-grade undifferentiated sarcoma, leiomyosarcoma, well- or de-differentiated liposarcoma, pleomorphic liposarcoma and myxoid liposarcoma, and synovial cell sarcoma), the major therapeutic options with Australian regulatory approval for soft-tissue sarcoma are based on anthracycline and alkylating agents, gemcitabine with taxanes or dacarbazine, or dacarbazine alone. Gemcitabine and docetaxel may be superior to single agent doxorubicin for uterine leiomyosarcoma.[4] It is notable that doxorubicin and alkylators appear to have significant dose-response relationships, which may influence the choice of agent depending on the need for disease control.

Newer agents are emerging with clinical activity in advanced soft-tissue sarcomas, such as trabectedin and pazopanib. Trabectedin is not approved by the Therapeutic Goods Administration for this indication. Pazopanib has recently been recommended for listing by the Pharmaceutical Benefits Advisory Committee onto the Pharmaceutical Benefits Scheme.

For a specific subset of sarcomas, including dermatofibrosarcoma protuberans, alveolar soft-part sarcoma, perivascular epithelioid cell tumor (PEComa), and to a lesser extent for angiosarcoma and desmoid tumours, evidence for the selective activity of various targeted and non-targeted therapies may be considered.

Given the difficulties in making clear pathologic diagnoses, the absence of level I or II evidence for most therapeutic recommendations, and the complexities of expert multidisciplinary care, patients with soft-tissue sarcoma should be referred to a multidisciplinary service with dedicated interests in the management of sarcomas.

Where there is no high level evidence for standard practice, then entering patients into clinical trials should be considered.

Specific soft-tissue sarcoma subtypes

The development of kinase inhibitor therapy (KIT) and other kinase-directed inhibitors for gastrointestinal stromal tumours (GIST) have sparked a strong effort to identify similar specific molecular drivers for other sarcoma subtypes. GISTs will not be discussed as part of these guidelines, but it is important to note that the differential diagnosis of GIST should be considered carefully in any patient with an intra-abdominal soft tissue sarcomas (STS) given the treatment implications.

Apart from GIST, there have been other noted examples of molecularly-targeted therapies that should be considered for selected subtypes. Dermatofibrosarcoma protuberans (DFSP) have a characteristic translocation (t17:22) that results in the creation of a fusion oncogene between COL1A1 and PDGFB, which results in constitutively activated PDGF. These tumours are highly sensitive to PDGF inhibition with imatinib, which is registered/reimbursed for inoperable DFSP in Australia.[5]

Activity has also been noted in the following sarcoma subtypes with molecularly-targeted therapies. Malignant perivascular epithelioid cell tumors (PEComas) are often associated with the loss of tuberous sclerosis complex (TSC1/TSC2 tumour supressors), with clear activity noted with mammalian target of rapamycin (mTOR) inhibitors.[6]

Inflammatory myofibroblastic tumours are associated with transolcations of anaplastic lymphoma kinase (ALK) in approximately 50% of cases; activity has been reported with the ALK inhibitor crizotinib.[7]

Alveolar soft-part sarcoma (ASPS) are highly vascular tumours that typically affect adolescents and young adults.Clear activity has been noted in patients treated with VEGF-directed tyrosine kinase inhibitors including sunitinib and cediranib. Of note, in a recent large phase II trial with cediranib, 15 of 43 patients achieved a partial response (35%) with a disease control rate at 24 weeks of 84%.[8]

Desmoid tumours (also known as aggressive fibromatosis or desmoid type fibromatosis) have a highly variable natural history, with some patients having prolonged stable disease or even spontaneous regressions. Although they are not at risk of metastasising, local invasion into vital structures can cause significant morbidity and may be fatal. Intra-abdominal desmoids tumours in particular, are invariably infiltrative into surrounding mesenteric structures, making R0 surgery very difficult to achieve. The clinical algorithm for patient management is therefore complex, and should be individualised after taking into account the above factors. As a general principle, a watchful waiting approach is preferred. Systemic therapies should be reserved for patients with clear disease progression on serial assessments, or in patients with clear symptoms from their disease and for whom localised measures such as radiotherapy or surgery have also been considered. Systemic therapy options include cytotoxic and non-cytotoxic agents, with a general approach to consider a stepwise progression from less toxic non-cytotoxic agents to cytotoxics.[9][10][11][12][13][14][15]

Angiosarcomas, although not characterised molecularly, need to be considered as a distinctive soft tissue subtype, and treated accordingly.

Back to top

Evidence summary and recommendations

Systemic approaches to common soft-tissue sarcomas


Evidence summary Level References
Doxorubicin, alone or in combination with ifosfamide is standard first-line treatment.

Although the response rate to doxorubicin as a single agent is lower than to the combination, the toxicity of the combination is greater and there is to date no evidence of a difference in overall survival for patients treated with the combination.

I, II, IV [16], [17], [18], [19], [3]
For patients in whom doxorubicin is considered inappropriate (for example, for patients who have received doxorubicin as part of adjuvant or neoadjuvant therapy, or for patients who have cardiac dysfunction, or who have glucose-6-phosphate dehydrogenase deficiency), ifosfamide as a single agent has the second highest objective response rate. II, IV [20], [21]
For patients with uterine leiomyosarcoma, the combination of docetaxel and gemcitabine may be considered in first-line. III-1, IV [22], [23], [4]
Evidence-based recommendationQuestion mark transparent.png Grade
There is no evidence to support combination chemotherapy regimens over sequential single agent regimens in the first-line treatment of advanced soft-tissue sarcomas.

Second-line and third-line

Evidence summary Level References
For patients who have not received ifosfamide as first-line, single agent ifosfamide may be considered. I, II [21], [24]
For patients with myxoid liposarcoma or leiomyosarcoma, consideration may be given to trabectedin.* II, III-2, IV [25], [26], [27], [28]
For patients who have been exposed to both doxorubicin and ifosfamide, dacarbazine is considered the next most active approved agent. If aggressive combination therapy is indicated, the combination of dacarbazine and gemcitabine has demonstrated a survival benefit compared to dacarbazine alone. II [29]
The antiangiogenic agent, pazopanib, was superior to placebo in progression-free but not overall survival, in patients with advanced soft tissue sarcomas (excluding GIST and adipocytic tumours) who have received prior chemotherapy. II [30]

*Trabectedin is not approved in Australia for soft-tissue sarcoma.

Evidence-based recommendationQuestion mark transparent.png Grade
Single agent ifosfamide can be considered as second-line treatment for patients who have not received ifosfamide as first-line.
Evidence-based recommendationQuestion mark transparent.png Grade
Dacarbazine with or without gemcitabine is reasonable third-line therapy after exposure to doxorubicin and ifosfamide in advanced soft tissue sarcoma.

Systemic approaches to other selected soft-tissue sarcomas

Evidence summary Level References
Hormonal agents (anti-oestrogens such as tamoxifen), alone or in combination with nonsteroidal anti-inflammatory drugs (sulindac) have shown some activity in treating Desmoid tumours.

Molecularly-targeted agents including imatinib* and sorafenib* have been assessed in single-arm, non-randomised phase II trials, with some level of activity.

If other options have failed or are there is a need for a more aggressive approach, cytotoxic options include those that are less toxic (combination of methotrexate and vinblastine or vinorelbine) or more toxic (doxorubicin by prolonged intravenous infusion, or ideally delivered in its liposomal formulation) have shown some levels of activity. However, all of these results must be taken in context, given the highly variable natural history of disease and lack of control arm comparisons with any of these studies

III-2, IV [9], [10], [11], [12], [13], [14], [15]
Paclitaxel (administered weekly) and liposomal doxorubicin both have activity in angiosarcomas. Although primary angiosarcomas, which often arise in the head and neck, are more chemo-sensitive than those that are radiation-associated, systemic therapy should be considered in all of these patients given the palliation that can be offered by these agents. IV [31]

*Imatinib and sorafenib are not approved or reimbursed for this indication in Australia.

Evidence-based recommendationQuestion mark transparent.png Grade
Systemic therapy with paclitaxel is reasonable in all patients with angiosarcoma, given the palliation that can be offered by these agents.

Practice pointQuestion mark transparent.png

Clinical trial participation should be considered for patients with soft tissue sarcomas.

Back to top


  1. Fletcher C DM, Bridge JA, Hogendoorn P, Mertens F. WHO Classification of Tumours of Soft Tissue and Bone. Fourth Edition. WHO 2013;IARC WHO Classification of Tumours, No 5. ISBN-13 9789283224341 Abstract available at http://apps.who.int/bookorders/anglais/detart1.jsp?codlan=1&codcol=70&codcch=4005.
  2. Blay JY, van Glabbeke M, Verweij J, van Oosterom AT, Le Cesne A, Oosterhuis JW, et al. Advanced soft-tissue sarcoma: a disease that is potentially curable for a subset of patients treated with chemotherapy. Eur J Cancer 2003 Jan;39(1):64-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12504660.
  3. 3.0 3.1 Judson I, Verweij J, Gelderblom H, Hartmann JT, Schöffski P, Blay JY, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol 2014 Apr;15(4):415-23 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24618336.
  4. 4.0 4.1 Gupta AA, Yao X, Verma S, Mackay H, Hopkins L, the Sarcoma Disease Site Group and the Gynecology Cancer Disease Site Group. Systematic Chemotherapy for Inoperable, Locally Advanced, Recurrent, or Metastatic Uterine Leiomyosarcoma: A Systematic Review. Clin Oncol (R Coll Radiol) 2013 Jan 5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23295078.
  5. McArthur GA, Demetri GD, van Oosterom A, Heinrich MC, Debiec-Rychter M, Corless CL, et al. Molecular and clinical analysis of locally advanced dermatofibrosarcoma protuberans treated with imatinib: Imatinib Target Exploration Consortium Study B2225. J Clin Oncol 2005 Feb 1;23(4):866-73 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15681532.
  6. Wagner AJ, Malinowska-Kolodziej I, Morgan JA, Qin W, Fletcher CD, Vena N, 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 Feb 10;28(5):835-40 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20048174.
  7. Butrynski JE, D'Adamo DR, Hornick JL, Dal Cin P, Antonescu CR, Jhanwar SC, et al. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. NEJM 2010 Oct;28;363(18):1727-33. doi: 10.1056/NEJMoa1007056. Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20979472.
  8. Kummar S, Allen D, Monks A, Polley EC, Hose CD, Ivy SP, et al. Cediranib for metastatic alveolar soft part sarcoma. J Clin Oncol 2013 Jun 20;31(18):2296-302 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23630200.
  9. 9.0 9.1 Hansmann A, Adolph C, Vogel T, Unger A, Moeslein G. High-dose tamoxifen and sulindac as first-line treatment for desmoid tumors. Cancer 2004 Feb 1;100(3):612-20 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14745880.
  10. 10.0 10.1 Chugh R, Wathen JK, Patel SR, Maki RG, Meyers PA, Schuetze SM, et al. Efficacy of imatinib in aggressive fibromatosis: Results of a phase II multicenter Sarcoma Alliance for Research through Collaboration (SARC) trial. Clin Cancer Res 2010 Oct 1;16(19):4884-91 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20724445.
  11. 11.0 11.1 Heinrich MC, McArthur GA, Demetri GD, Joensuu H, Bono P, Herrmann R, et al. Clinical and molecular studies of the effect of imatinib on advanced aggressive fibromatosis (desmoid tumor). J Clin Oncol 2006 Mar 1;24(7):1195-203 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16505440.
  12. 12.0 12.1 Garbay D, Le Cesne A, Penel N, Chevreau C, Marec-Berard P, Blay JY, et al. Chemotherapy in patients with desmoid tumors: a study from the French Sarcoma Group (FSG). Ann Oncol 2012 Jan;23(1):182-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21444357.
  13. 13.0 13.1 de Camargo VP, Keohan ML, D'Adamo DR, Antonescu CR, Brennan MF, Singer S, et al. Clinical outcomes of systemic therapy for patients with deep fibromatosis (desmoid tumor). Cancer 2010 May 1;116(9):2258-65 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20187095.
  14. 14.0 14.1 Gega M, Yanagi H, Yoshikawa R, Noda M, Ikeuchi H, Tsukamoto K, et al. Successful chemotherapeutic modality of doxorubicin plus dacarbazine for the treatment of desmoid tumors in association with familial adenomatous polyposis. J Clin Oncol 2006 Jan 1;24(1):102-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16382119.
  15. 15.0 15.1 Constantinidou A, Jones RL, Scurr M, Al-Muderis O, Judson I. Pegylated liposomal doxorubicin, an effective, well-tolerated treatment for refractory aggressive fibromatosis. Eur J Cancer 2009 Nov;45(17):2930-4 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19767198.
  16. Edmonson JH, Ryan LM, Blum RH, Brooks JS, Shiraki M, Frytak S, et al. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol 1993 Jul;11(7):1269-75 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8315424.
  17. Bramwell VH, Anderson D, Charette ML. Doxorubicin-based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatic soft-tissue sarcoma: a meta-analysis and clinical practice guideline. Sarcoma 2000;4(3):103-12 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18521288.
  18. Santoro A, Tursz T, Mouridsen H, Verweij J, Steward W, Somers R, 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 Jul;13(7):1537-45 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7602342.
  19. Leyvraz S, Herrmann R, Guillou L, Honegger HP, Christinat A, Fey MF, et al. Treatment of advanced soft-tissue sarcomas using a combined strategy of high-dose ifosfamide, high-dose doxorubicin and salvage therapies. Br J Cancer 2006 Nov 20;95(10):1342-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17031396.
  20. Nielsen OS, Judson I, van Hoesel Q, le Cesne A, Keizer HJ, Blay JY, 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 Jan;36(1):61-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10741296.
  21. 21.0 21.1 Bramwell VH, Mouridsen HT, Santoro A, Blackledge G, Somers R, Verweij J, 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:S180-4 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8453694.
  22. Maki RG, Wathen JK, Patel SR, Priebat DA, Okuno SH, Samuels B, 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 [corrected]. J Clin Oncol 2007 Jul 1;25(19):2755-63 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17602081.
  23. Hensley ML, Blessing JA, Degeest K, Abulafia O, Rose PG, Homesley HD. Fixed-dose rate gemcitabine plus docetaxel as second-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II study. Gynecol Oncol 2008 Jun;109(3):323-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18394689.
  24. Verma S, Younus J, Stys-Norman D, Haynes AE, Blackstein M, Members of the Sarcoma Disease Site Group of Cancer Care Ontario's Program in Evidence-Based Care. Meta-analysis of ifosfamide-based combination chemotherapy in advanced soft tissue sarcoma. Cancer Treat Rev 2008 Jun;34(4):339-47 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18313854.
  25. 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 Sep 1;27(25):4188-96 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19652065.
  26. Le Cesne A, Blay JY, Judson I, Van Oosterom A, Verweij J, Radford J, 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 Jan 20;23(3):576-84 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15659504.
  27. Yovine A, Riofrio M, Blay JY, Brain E, Alexandre J, Kahatt C, et al. Phase II study of ecteinascidin-743 in advanced pretreated soft tissue sarcoma patients. J Clin Oncol 2004 Mar 1;22(5):890-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14990645.
  28. Monk BJ, Blessing JA, Street DG, Muller CY, Burke JJ, Hensley ML. A phase II evaluation of trabectedin in the treatment of advanced, persistent, or recurrent uterine leiomyosarcoma: a gynecologic oncology group study. Gynecol Oncol 2012 Jan;124(1):48-52 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21996263.
  29. García-Del-Muro X, López-Pousa A, Maurel J, Martín J, Martínez-Trufero J, Casado A, et al. Randomized phase II study comparing gemcitabine plus dacarbazine versus dacarbazine alone in patients with previously treated soft tissue sarcoma: a Spanish Group for Research on Sarcomas study. J Clin Oncol 2011 Jun 20;29(18):2528-33 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21606430.
  30. van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2012 May;19;379(9829):1879-86. doi: 10.1016/S0140-6736(12)60651-5. Epub 2012 May 16. Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22595799.
  31. Penel N, Bui BN, Bay JO, Cupissol D, Ray-Coquard I, Piperno-Neumann S, et al. Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX Study. J Clin Oncol 2008 Nov 10;26(32):5269-74 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18809609.

Back to top


Further resources