Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Nodal Disease

Stage IV sarcomas are tumors that have metastatic involvement of regional lymph nodes or have spread to distant organs. Soft tissue sarcomas that more commonly spread to lymph nodes include synovial cell sarcomas, epithelioid sarcomas, and rhabdomyosarcomas. For stage IV sarcomas, local control of the primary tumor is probably best obtained by resection with negative margins, lymphadenectomy when appropriate, and postoperative external-beam radiation therapy.[1] For gastrointestinal stromal tumors (GISTs), preliminary evidence indicates that imatinib mesylate, a tyrosine kinase inhibitor, induced sustained tumor response in patients with unresectable or metastatic tumors.[2,3,4,5][Level of evidence: 3iiiDiii]

STANDARD TREATMENT OPTIONS:

1. Surgical resection and lymphadenectomy for patients with clinically positive lymph nodes with or without postoperative radiation to the primary site may be used.
2. In some centers, radiation therapy may be used prior to and following surgical extirpation.[6]
3. Adjuvant chemotherapy may be considered for patients eligible for clinical trials.[7,8,9,10]

Visceral Disease

With distant metastases, surgery with curative intent is possible for patients with limited pulmonary metastases who are also undergoing or have undergone complete resection of the primary tumor.[11,12,13] The role of adjuvant therapy for pulmonary nodules is under clinical evaluation.[14] The value of resection of hepatic metastases is unclear. Doxorubicin alone or with dacarbazine is considered one of the most frequently used chemotherapeutic regimens for advanced sarcoma.[15,16,17] When used as single agents, only doxorubicin and ifosfamide show >20% response rates; less active drugs include dacarbazine, cisplatin, methotrexate, and vinorelbine.[18] A randomized trial of 340 patients with advanced sarcoma showed a higher response rate (32% vs. 17%, P < .002) and longer time-to-progression (6 vs. 4 months, P < .02) for doxorubicin, dacarbazine, ifosfamide, and mesna versus doxorubicin and dacarbazine alone.[19][Level of evidence: 1iiDii] For older patients, sequential use of single agents with each recurrence is a better strategy for palliation. High-dose chemotherapy (with or without transplantation) has not influenced disease-free survival or overall survival in published studies so far, but it remains under clinical evaluation for patients with metastatic disease in first complete remission, after resection of pulmonary nodules, or for inoperable large primaries.[20]For GISTs, preliminary evidence indicates that imatinib mesylate, a tyrosine kinase inhibitor, induced sustained tumor response in patients with unresectable or metastatic tumors.[2,3,4][Level of evidence: 3iiiDiii]

STANDARD TREATMENT OPTIONS:

1. Surgical resection of the primary tumor with radiation therapy. Resection of pulmonary lesions may be performed following definitive therapy of the primary tumor.[11,12,13]
   • Surgical excision with negative tissue margins may be used.
   • If the tumor is resectable but wide margins cannot be obtained, radiation therapy may be added.
   • If the tumor is unresectable, high-dose radiation therapy may be used, often with chemotherapy.
   • For tumors of the retroperitoneum, trunk, and head and neck, surgical resection with preoperative and/or postoperative radiation therapy, and sometimes chemotherapy, may be used.
2. For palliation of patients with unresectable visceral disease, chemotherapy with the following agents may be used:
   • Doxorubicin.[15]
   • Doxorubicin + dacarbazine.[15,16]
   • Doxorubicin + ifosfamide.[21]
   • Doxorubicin + dacarbazine + ifosfamide + mesna.[19,22]
   • High-dose ifosfamide regimens.[23,24,25]

References:

1. Eilber FR, Eckhardt J, Morton DL: Advances in the treatment of sarcomas of the extremity. Current status of limb salvage. Cancer 54 (11 Suppl): 2695-701, 1984.
2. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al.: Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344 (14): 1052-6, 2001.
3. Blanke CD, von Mehren M, Joensuu H, et al.: Evaluation of the safety and efficacy of an oral molecularly-targeted therapy, STI157, in patients (pts) with unresectable or metastatic gastrointestinal stromal tumors (GISTs) expressing c-kit (CD117). [Abstract] Proceedings of the American Society of Clinical Oncology 20: A-1, 1a, 2001.
4. Van Oosterom AT, Judson I, Verweij J, et al.: STI 571, an active drug in metastatic gastro intestinal stromal tumors (GIST), an EORTC phase I study. [Abstract] Proceedings of the American Society of Clinical Oncology 20: A-2, 1a, 2001.
5. Debiec-Rychter M, Sciot R, Le Cesne A, et al.: KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42 (8): 1093-103, 2006.
6. Schwartz DL, Einck J, Bellon J, et al.: Fast neutron radiotherapy for soft tissue and cartilaginous sarcomas at high risk for local recurrence. Int J Radiat Oncol Biol Phys 50 (2): 449-56, 2001 Jun 1.
7. Antman KH: Adjuvant therapy of sarcomas of soft tissue. Semin Oncol 24 (5): 556-60, 1997.
8. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Sarcoma Meta-analysis Collaboration. Lancet 350 (9092): 1647-54, 1997.
9. Buesa JM, López-Pousa A, Martín J, et al.: Phase II trial of first-line high-dose ifosfamide in advanced soft tissue sarcomas of the adult: a study of the Spanish Group for Research on Sarcomas (GEIS) Ann Oncol 9 (8): 871-6, 1998.
10. 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 21 (3): 317-21, 1998.
11. 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 77 (4): 675-82, 1996.
12. Casson AG, Putnam JB, Natarajan G, et al.: Five-year survival after pulmonary metastasectomy for adult soft tissue sarcoma. Cancer 69 (3): 662-8, 1992.
13. Putnam JB Jr, Roth JA: Surgical treatment for pulmonary metastases from sarcoma. Hematol Oncol Clin North Am 9 (4): 869-87, 1995.
14. Van Geel A, European Organization for Research and Treatment of Cancer: Phase III Randomized Study of High-Dose Doxorubicin and Ifosfamide With or Without Filgrastim (G-CSF) Before and After Metastasectomy Versus Metastasectomy Alone in Patients With Lung Metastases Secondary to Soft Tissue Sarcoma (Summary Last Modified 07/2001), EORTC-62933, Clinical trial, Closed.
15. 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 13 (7): 1537-45, 1995.
16. Zalupski M, Metch B, Balcerzak S, et al.: Phase III comparison of doxorubicin and dacarbazine given by bolus versus infusion in patients with soft-tissue sarcomas: a Southwest Oncology Group study. J Natl Cancer Inst 83 (13): 926-32, 1991.
17. Borden EC, Amato DA, Rosenbaum C, et al.: Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas. J Clin Oncol 5 (6): 840-50, 1987.
18. Demetri GD, Elias AD: Results of single-agent and combination chemotherapy for advanced soft tissue sarcomas. Implications for decision making in the clinic. Hematol Oncol Clin North Am 9 (4): 765-85, 1995.
19. 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 11 (7): 1276-85, 1993.
20. Elias AD: High-dose therapy for adult soft tissue sarcoma: dose response and survival. Semin Oncol 25 (2 Suppl 4): 19-23; discussion 45-8, 1998.
21. Edmonson JH, Ryan LM, Blum RH, et al.: Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol 11 (7): 1269-75, 1993.
22. 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 7 (9): 1208-16, 1989.
23. 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 15 (6): 2378-84, 1997.
24. 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 16 (4): 1438-43, 1998.
25. 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 38 (18): 2397-406, 2002.