Adult Soft Tissue Sarcoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]

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Adult Soft Tissue Sarcoma Treatment

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult soft tissue sarcoma. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

  • Prognostic factors.
  • Cellular classification.
  • Staging.
  • Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

General Information

Note: Separate PDQ summaries on Childhood Soft Tissue Sarcoma Treatment and Uterine Sarcoma Treatment are also available.

Note: Estimated new cases and deaths from soft tissue sarcoma in the United States in 2009: [1]

  • New cases: 10,660.
  • Deaths: 3,820.

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.)

Soft tissue sarcomas are malignant tumors that may arise in any of the mesodermal tissues of the extremities (50%), trunk and retroperitoneum (40%), or head and neck (10%). Rarely, these tumors arise in the gastrointestinal tract or gastrointestinal stroma, and a small percentage of these are called gastrointestinal stromal tumors (GISTs). Malignant GISTs can occur from the esophagus to the rectum but occur most commonly in the stomach and small intestine. Soft tissue sarcomas occur with greater frequency in patients with:[2]

  • von Recklinghausen disease (neurofibromatosis).
  • Gardner syndrome.
  • Werner syndrome.
  • Tuberous sclerosis.
  • Basal cell nevus syndrome.
  • Li-Fraumeni syndrome (p53 mutations).

Soft tissue sarcomas may be heterogeneous, so adequate tissue should be obtained via either core-needle or incisional biopsy for microscopic examination to determine histologic type and tumor grade. Careful planning of the initial biopsy is important to avoid compromising subsequent curative resection. Since the selection of treatment is determined by the grade of the tumor, it is essential to have a careful review of the biopsy tissue by a pathologist who is experienced in diagnosing sarcomas. Complete staging and treatment planning by a multidisciplinary team of cancer specialists is required to determine the optimal treatment for patients with this disease. In most cases, a combined modality approach of preoperative or postoperative radiation therapy is used, rather than the radical surgical procedures that were used in the past. The role of chemotherapy is less well defined. Because of the evolving nature of the state of the art in the treatment of this disease, all patients with such lesions should be included in a clinical trial whenever possible.

The prognosis for patients with adult soft tissue sarcomas depends on several factors, including the patient's age and the size, histologic grade, and stage of the tumor.[3,4,5] Factors associated with a poorer prognosis include age older than 60 years, tumors larger than 5 cm, or high-grade histology.[6]

While low-grade tumors are usually curable by surgery alone, higher-grade sarcomas (as determined by the mitotic index and by the presence of hemorrhage and necrosis) are associated with higher local treatment failure rates and increased metastatic potential.[7] When feasible, wide margin function-sparing surgical excision is the cornerstone of effective treatment, with the goal of preservation of a functional extremity.[8,9] This may be facilitated by soft tissue reconstructive surgery.[10] Mohs surgical technique may be considered as an alternative to wide surgical excision for small, well-differentiated sarcomas when cosmetic results are considered to be very important, as margins can be assured with minimal normal tissue removal.[2,11] High-grade soft tissue sarcomas of the extremities can often be effectively treated while preserving the limb with combined-modality treatment consisting of preoperative or postoperative radiation therapy to reduce local recurrence. A phase II trial (SWOG-9119) was conducted of neoadjuvant therapy with DOX/DTIC/IFF for poor prognosis soft tissue sarcoma.[8,12,13,14,15,16,17,18,19] In adults, local control of high-grade soft tissue sarcomas of the trunk and the head and neck can be achieved with surgery, often in combination with radiation therapy with or without chemotherapy.[20]

Effective treatment of retroperitoneal sarcomas requires removal of all gross disease while sparing adjacent viscera not invaded by tumor. The prognosis for patients with high-grade retroperitoneal sarcomas is less favorable than for patients with tumors at other sites, partly because of the difficulty in completely resecting these tumors and the limitations placed on high-dose radiation therapy.[2,21] Surgical resection is the most effective treatment modality for GISTs.[22] Evidence indicates that imatinib mesylate, a tyrosine kinase inhibitor, induced sustained tumor response in patients with unresectable or metastatic GIST tumors.[23,24,25][Level of evidence: 3iiiDiv][26,27]

Several prospective randomized trials have been unable to confirm conclusively whether doxorubicin-based adjuvant chemotherapy benefits adults with resectable soft tissue sarcomas. The majority of these studies accrued small numbers of patients and did not demonstrate a metastasis-free survival or an overall survival (OS) benefit for adjuvant chemotherapy.[20] A small study of adjuvant chemotherapy showed a positive impact in disease-free survival and OS in patients treated with postoperative chemotherapy.[28] There was wide interstudy variability among the numerous trials, including differences in therapeutic regimens, drug doses, sample size, tumor site, and histologic grade. A quantitative meta-analysis of updated data from 1,568 individual patients from 14 trials of doxorubicin-based adjuvant therapy showed an absolute benefit from adjuvant therapy of 6% for local relapse-free interval (95% confidence interval [CI], 1–10), 10% for distant relapse-free interval (95% CI, 5–15), and 10% for recurrence-free survival (95% CI, 5–15); however, there was no OS benefit at 10 years.[29][Level of evidence: 1iiDii] Patients with high-grade tumors (grades 3 or 4) larger than 5 cm in diameter have the greatest tendency for disease to metastasize and are eligible for prospective clinical trials of adjuvant chemotherapy.

With distant metastases (stage IV), surgery with curative intent is possible for patients selected for optimal underlying biologic behavior (i.e., patients with a limited number of metastases, with a long disease-free interval, and with slow clinical growth) with pulmonary metastases who have undergone or are undergoing complete resection of the primary tumor.[30,31,32] Doxorubicin alone or with dacarbazine is considered the best chemotherapeutic regimen for advanced sarcoma.[33,34,35] 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 (MAID) versus doxorubicin and dacarbazine alone.[36][Level of evidence: 1iiDiii] The increased response rate of the MAID regimen may be justified in preoperative management of younger patients with borderline resectability, but the increased toxic effects argue against its use in older patients.[36]

Complete surgical resection is often difficult for sarcomas of the retroperitoneum because of their large size before detection and anatomic location.[37,38] Prospective randomized trials have not shown improved survival with preoperative or postoperative adjuvant chemotherapy for this subgroup.[29]

References:

1. American Cancer Society.: Cancer Facts and Figures 2009. Atlanta, Ga: American Cancer Society, 2009. Also available online. Last accessed January 6, 2010.
2. Brennan M, Singer S, Maki R, et al.: Sarcomas of the soft tissues and bone. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 1581-1631.
3. Le Doussal V, Coindre JM, Leroux A, et al.: Prognostic factors for patients with localized primary malignant fibrous histiocytoma: a multicenter study of 216 patients with multivariate analysis. Cancer 77 (9): 1823-30, 1996.
4. Le QT, Fu KK, Kroll S, et al.: Prognostic factors in adult soft-tissue sarcomas of the head and neck. Int J Radiat Oncol Biol Phys 37 (5): 975-84, 1997.
5. Coindre JM, Terrier P, Guillou L, et al.: Predictive value of grade for metastasis development in the main histologic types of adult soft tissue sarcomas: a study of 1240 patients from the French Federation of Cancer Centers Sarcoma Group. Cancer 91 (10): 1914-26, 2001.
6. Vraa S, Keller J, Nielsen OS, et al.: Prognostic factors in soft tissue sarcomas: the Aarhus experience. Eur J Cancer 34 (12): 1876-82, 1998.
7. Collin CF, Friedrich C, Godbold J, et al.: Prognostic factors for local recurrence and survival in patients with localized extremity soft-tissue sarcoma. Semin Surg Oncol 4 (1): 30-7, 1988.
8. Watson DI, Coventry BJ, Langlois SL, et al.: Soft-tissue sarcoma of the extremity. Experience with limb-sparing surgery. Med J Aust 160 (7): 412-6, 1994.
9. Geer RJ, Woodruff J, Casper ES, et al.: Management of small soft-tissue sarcoma of the extremity in adults. Arch Surg 127 (11): 1285-9, 1992.
10. Lohman RF, Nabawi AS, Reece GP, et al.: Soft tissue sarcoma of the upper extremity: a 5-year experience at two institutions emphasizing the role of soft tissue flap reconstruction. Cancer 94 (8): 2256-64, 2002.
11. Fish FS: Soft tissue sarcomas in dermatology. Dermatol Surg 22 (3): 268-73, 1996.
12. Marcove RC, Sheth DS, Healey J, et al.: Limb-sparing surgery for extremity sarcoma. Cancer Invest 12 (5): 497-504, 1994.
13. Williard WC, Collin C, Casper ES, et al.: The changing role of amputation for soft tissue sarcoma of the extremity in adults. Surg Gynecol Obstet 175 (5): 389-96, 1992.
14. Yang JC, Chang AE, Baker AR, et al.: Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 16 (1): 197-203, 1998.
15. Schmidt RA, Conrad EU 3rd, Collins C, et al.: Measurement and prediction of the short-term response of soft tissue sarcomas to chemotherapy. Cancer 72 (9): 2593-601, 1993.
16. Temple WJ, Temple CL, Arthur K, et al.: Prospective cohort study of neoadjuvant treatment in conservative surgery of soft tissue sarcomas. Ann Surg Oncol 4 (7): 586-90, 1997 Oct-Nov.
17. Valle AA, Kraybill WG: Management of soft tissue sarcomas of the extremity in adults. J Surg Oncol 63 (4): 271-9, 1996.
18. Pollack A, Zagars GK, Goswitz MS, et al.: Preoperative vs. postoperative radiotherapy in the treatment of soft tissue sarcomas: a matter of presentation. Int J Radiat Oncol Biol Phys 42 (3): 563-72, 1998.
19. Schoenfeld GS, Morris CG, Scarborough MT, et al.: Adjuvant radiotherapy in the management of soft tissue sarcoma involving the distal extremities. Am J Clin Oncol 29 (1): 62-5, 2006.
20. O'Byrne K, Steward WP: The role of adjuvant chemotherapy in the treatment of adult soft tissue sarcomas. Crit Rev Oncol Hematol 27 (3): 221-7, 1998.
21. Lewis JJ, Leung D, Woodruff JM, et al.: Retroperitoneal soft-tissue sarcoma: analysis of 500 patients treated and followed at a single institution. Ann Surg 228 (3): 355-65, 1998.
22. Pidhorecky I, Cheney RT, Kraybill WG, et al.: Gastrointestinal stromal tumors: current diagnosis, biologic behavior, and management. Ann Surg Oncol 7 (9): 705-12, 2000.
23. 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.
24. 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.
25. 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.
26. Demetri GD, von Mehren M, Blanke CD, et al.: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347 (7): 472-80, 2002.
27. Bümming P, Andersson J, Meis-Kindblom JM, et al.: Neoadjuvant, adjuvant and palliative treatment of gastrointestinal stromal tumours (GIST) with imatinib: a centre-based study of 17 patients. Br J Cancer 89 (3): 460-4, 2003.
28. Frustaci S, Gherlinzoni F, De Paoli A, et al.: Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. J Clin Oncol 19 (5): 1238-47, 2001.
29. 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.
30. 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.
31. 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.
32. Putnam JB Jr, Roth JA: Surgical treatment for pulmonary metastases from sarcoma. Hematol Oncol Clin North Am 9 (4): 869-87, 1995.
33. 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.
34. 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.
35. 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.
36. 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.
37. Heslin MJ, Lewis JJ, Nadler E, et al.: Prognostic factors associated with long-term survival for retroperitoneal sarcoma: implications for management. J Clin Oncol 15 (8): 2832-9, 1997.
38. Jaques DP, Coit DG, Hajdu SI, et al.: Management of primary and recurrent soft-tissue sarcoma of the retroperitoneum. Ann Surg 212 (1): 51-9, 1990.

Cellular Classification

Soft tissue sarcomas are classified histologically according to the soft tissue cell of origin, though the cell type is not part of the prognostic staging system. Additional studies, including electron microscopy, histochemistry, flow cytometry, cytogenetics, and tissue culture studies may allow identification of particular subtypes within the major histologic categories. The histologic grade reflects the metastatic potential of these tumors more accurately than the classic cellular classification listed below.[1,2,3] Overall, malignant fibrous histiocytoma is the most common histologic type (40% of the total) followed by liposarcoma (25%); however, frequency of histologic type is site-dependent. Pathologists assign grade based on the number of mitoses per high-powered field, presence of necrosis, cellular and nuclear morphology, and the degree of cellularity; discordance among expert pathologists can reach 40% on prospective review.[3,4]

Soft tissue sarcomas include the following tumors:

  • Alveolar soft-part sarcoma.[5]
  • Angiosarcoma.[6,7,8]
  • Dermatofibrosarcoma protuberans.[9]
  • Epithelioid sarcoma.
  • Extraskeletal chondrosarcoma.
  • Extraskeletal osteosarcoma.
  • Fibrosarcoma.
  • Gastrointestinal stromal tumor (GIST).
  • Leiomyosarcoma.
  • Liposarcoma.
  • Malignant fibrous histiocytoma.
  • Malignant hemangiopericytoma.
  • Malignant mesenchymoma.
  • Malignant schwannoma.
  • Malignant peripheral nerve sheath tumor.
  • Peripheral neuroectodermal tumors.
  • Rhabdomyosarcoma.
  • Synovial sarcoma.
  • Sarcoma, NOS (not otherwise specified).

GISTs are mesenchymal in origin and are immunohistochemically distinct from leiomyosarcomas, schwannomas, and fibrosarcomas with which they are often classified. They can be distinguished by being CD34 positive and CD117 positive. These tumors express a growth factor receptor with tyrosine kinase activity called c-kit (CD117). GISTs of the stomach wall are considered malignant when they exceed 5 to 10 cm, have a high mitotic index, or have metastasized. GISTs of the small bowel are considered malignant if they have any mitoses or are larger than 2 cm. Current evidence suggests that c-kit mutations are more commonly identified in malignant GISTs than in benign GISTs. Malignant GISTs are also usually CD34 positive.[10,11,12,13]

References:

1. Marcus SG, Merino MJ, Glatstein E, et al.: Long-term outcome in 87 patients with low-grade soft-tissue sarcoma. Arch Surg 128 (12): 1336-43, 1993.
2. Soft tissue sarcoma. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 193-7.
3. Gaynor JJ, Tan CC, Casper ES, et al.: Refinement of clinicopathologic staging for localized soft tissue sarcoma of the extremity: a study of 423 adults. J Clin Oncol 10 (8): 1317-29, 1992.
4. Alvegård TA, Berg NO: Histopathology peer review of high-grade soft tissue sarcoma: the Scandinavian Sarcoma Group experience. J Clin Oncol 7 (12): 1845-51, 1989.
5. van Ruth S, van Coevorden F, Peterse JL, et al.: Alveolar soft part sarcoma. a report of 15 cases. Eur J Cancer 38 (10): 1324-8, 2002.
6. Fury MG, Antonescu CR, Van Zee KJ, et al.: A 14-year retrospective review of angiosarcoma: clinical characteristics, prognostic factors, and treatment outcomes with surgery and chemotherapy. Cancer J 11 (3): 241-7, 2005 May-Jun.
7. Abraham JA, Hornicek FJ, Kaufman AM, et al.: Treatment and outcome of 82 patients with angiosarcoma. Ann Surg Oncol 14 (6): 1953-67, 2007.
8. Fayette J, Martin E, Piperno-Neumann S, et al.: Angiosarcomas, a heterogeneous group of sarcomas with specific behavior depending on primary site: a retrospective study of 161 cases. Ann Oncol 18 (12): 2030-6, 2007.
9. Mendenhall WM, Zlotecki RA, Scarborough MT: Dermatofibrosarcoma protuberans. Cancer 101 (11): 2503-8, 2004.
10. Pidhorecky I, Cheney RT, Kraybill WG, et al.: Gastrointestinal stromal tumors: current diagnosis, biologic behavior, and management. Ann Surg Oncol 7 (9): 705-12, 2000.
11. Wang L, Vargas H, French SW: Cellular origin of gastrointestinal stromal tumors: a study of 27 cases. Arch Pathol Lab Med 124 (10): 1471-5, 2000.
12. Nishida T, Hirota S: Biological and clinical review of stromal tumors in the gastrointestinal tract. Histol Histopathol 15 (4): 1293-301, 2000.
13. Miettinen M, Sarlomo-Rikala M, Lasota J: Gastrointestinal stromal tumors: recent advances in understanding of their biology. Hum Pathol 30 (10): 1213-20, 1999.

Stage Information

Staging has an important role in determining the most effective treatment of soft tissue sarcomas. The stage is determined by the size of the tumor, the histologic grade, and whether it has spread to lymph nodes or distant sites. Intracompartmental or extracompartmental extension of extremity sarcomas is also important for surgical decision making. For complete staging, a thorough physical examination, x-rays, laboratory studies, and careful review of all biopsy specimens (including those from the primary tumor, lymph nodes, or other suspicious lesions) are essential. Computed tomographic scan of the chest is recommended for sarcomas larger than 5 cm (T2) or with moderate to poor differentiation (grades 2–4). Nodal involvement is rare, occurring in less than 3% of patients with sarcoma.[1]

The American Joint Committee on Cancer (AJCC) has designated staging by the four criteria of tumor size, nodal status, grade, and metastasis (TNGM).[2]

Grade and TNM Definitions

Tumor grade (G)

  • GX: Grade cannot be assessed
  • G1: Well differentiated
  • G2: Moderately differentiated
  • G3: Poorly differentiated
  • G4: Poorly differentiated or undifferentiated

Primary tumor (T)

  • TX: Primary tumor cannot be assessed
  • T0: No evidence of primary tumor
  • T1: Tumor 5 cm or less in greatest dimension
    • T1a: Superficial tumor
    • T1b: Deep tumor
  • T2: Tumor 5 cm or larger in greatest dimension
    • T2a: Superficial tumor
    • T2b: Deep tumor

Superficial tumor is located exclusively above the superficial fascia without invasion of the fascia; deep tumor is located either exclusively beneath the superficial fascia, or superficial to the fascia with invasion of or through the fascia, or both superficial yet beneath the fascia. Retroperitoneal, mediastinal, and pelvic sarcomas are classified as deep tumors.

Regional lymph nodes (N)

  • NX: Regional lymph nodes cannot be assessed
  • N0: No regional lymph node metastasis
  • N1: Regional lymph node metastasis Presence of positive nodes (N1) is considered stage IV.

Distant metastasis (M)

  • MX: Distant metastasis cannot be assessed
  • M0: No distant metastasis
  • M1: Distant metastasis

AJCC Stage Groupings

STAGE I

Stage I tumor is defined as low-grade, superficial, and deep.

  • G1, T1a, N0, M0
  • G1, T1b, N0, M0
  • G1, T2a, N0, M0
  • G1, T2b, N0, M0
  • G2, T1a, N0, M0
  • G2, T1b, N0, M0
  • G2, T2a, N0, M0
  • G2, T2b, N0, M0

STAGE II

Stage II tumor is defined as high-grade, superficial, and deep.

  • G3, T1a, N0, M0
  • G3, T1b, N0, M0
  • G3, T2a, N0, M0
  • G4, T1a, N0, M0
  • G4, T1b, N0, M0
  • G4, T2a, N0, M0

STAGE III

Stage III tumor is defined as high-grade, large, and deep.

  • G3, T2b, N0, M0
  • G4, T2b, N0, M0

STAGE IV

Stage IV is defined as any metastasis to lymph nodes or distant sites.

  • Any G, any T, N1, M0
  • Any G, any T, N0, M1

References:

1. Fong Y, Coit DG, Woodruff JM, et al.: Lymph node metastasis from soft tissue sarcoma in adults. Analysis of data from a prospective database of 1772 sarcoma patients. Ann Surg 217 (1): 72-7, 1993.
2. Soft tissue sarcoma. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 193-7.

Stage I Adult Soft Tissue Sarcoma

Low-grade soft tissue sarcomas (grade 1 or 2) have little metastatic potential, but they may recur locally if they are inadequately treated. Accordingly, surgical excision with negative tissue margins of 2 cm or larger in all directions is the treatment of choice for patients with these early-stage sarcomas.[1] Mohs surgical technique may be considered as an alternative to wide surgical excision for small, well-differentiated sarcomas when cosmetic results are considered to be very important, as margins can be assured with minimal normal tissue removal.[2,3]

Carefully executed high-dose radiation therapy using a shrinking field technique may be beneficial for unresectable tumors or for resectable tumors in which a high likelihood of residual disease is thought to be present, when margins are known to be smaller than 2 cm, and when wider resection would require either an amputation or the removal of a vital organ.[4] Because of the low metastatic potential of these tumors, chemotherapy is usually not given.[5]

STANDARD TREATMENT OPTIONS:

1. Surgical excision with negative tissue margins of several centimeters in all directions.
2. Conservative surgical excision with preoperative or postoperative radiation therapy.[6,7,8]
3. If the tumor is unresectable, high-dose preoperative radiation therapy may be used, followed by surgical resection and postoperative radiation therapy.[4,9]
4. For tumors of the retroperitoneum, trunk, and head and neck:
  • Surgical resection with the option of postoperative radiation therapy if negative margins cannot be obtained. Wide margins are unusual in these sites, and radiation therapy is usually advocated for trunk and head and neck primary sites.[3]
  • Preoperative radiation therapy followed by maximal surgical resection. Radiation therapy is usually used to maximize local control because of the inability to obtain wide surgical margins.
  • Fast neutron therapy.[10]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage I adult soft tissue sarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Pearlstone DB, Pisters PW, Bold RJ, et al.: Patterns of recurrence in extremity liposarcoma: implications for staging and follow-up. Cancer 85 (1): 85-92, 1999.
2. Fish FS: Soft tissue sarcomas in dermatology. Dermatol Surg 22 (3): 268-73, 1996.
3. Brennan M, Singer S, Maki R, et al.: Sarcomas of the soft tissues and bone. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 1581-1631.
4. Temple WJ, Temple CL, Arthur K, et al.: Prospective cohort study of neoadjuvant treatment in conservative surgery of soft tissue sarcomas. Ann Surg Oncol 4 (7): 586-90, 1997 Oct-Nov.
5. Geer RJ, Woodruff J, Casper ES, et al.: Management of small soft-tissue sarcoma of the extremity in adults. Arch Surg 127 (11): 1285-9, 1992.
6. Tepper JE, Suit HD: Radiation therapy of soft tissue sarcomas. Cancer 55 (9 Suppl): 2273-7, 1985.
7. Yang JC, Chang AE, Baker AR, et al.: Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 16 (1): 197-203, 1998.
8. Pisters PW, Pollock RE, Lewis VO, et al.: Long-term results of prospective trial of surgery alone with selective use of radiation for patients with T1 extremity and trunk soft tissue sarcomas. Ann Surg 246 (4): 675-81; discussion 681-2, 2007.
9. Schmidt RA, Conrad EU 3rd, Collins C, et al.: Measurement and prediction of the short-term response of soft tissue sarcomas to chemotherapy. Cancer 72 (9): 2593-601, 1993.
10. 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.

Stage II and III Adult Soft Tissue Sarcoma

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.)

High-grade localized soft tissue sarcomas have an increased potential for metastatic spread. For sarcomas of the extremities, local control comparable to that obtained with amputation may be achieved with limb-sparing surgery that involves wide local excision in combination with preoperative or postoperative radiation therapy and in some instances, chemotherapy.[1,2,3,4]

Several prospective randomized trials have been unable to confirm conclusively whether doxorubicin-based adjuvant chemotherapy benefits adults with resectable soft tissue sarcomas. The majority of these studies accrued small numbers of patients and did not demonstrate a metastasis-free survival or an overall survival (OS) benefit for adjuvant chemotherapy.[5] Interstudy variability was wide among the numerous trials, including differences in therapeutic regimens, drug doses, sample size, tumor site, and histologic grade. A quantitative meta-analysis of updated data from 1,568 individual patients from 14 trials of doxorubicin-based adjuvant therapy showed an absolute benefit from adjuvant therapy of 6% for local relapse-free interval (95% confidence interval [CI], 1–10), 10% for distant relapse-free interval (95% CI, 5–15), and 10% for recurrence-free survival (95% CI, 5–15); however, there was no OS benefit at 10 years.[6][Level of evidence: 1iiDii] Patients with high-grade tumors (grades 3 or 4) larger than 5 cm in diameter have the greatest tendency for disease to metastasize and are eligible for prospective clinical trials of adjuvant chemotherapy.

Complete surgical resection is often difficult for sarcomas of the retroperitoneum because of their large size before detection and anatomical location.[7,8] As opposed to soft tissue sarcomas of the extremities, local recurrence is the most common cause of death in patients with retroperitoneal soft tissue sarcomas. Complete surgical resection (i.e., removal of all gross tumor) is the most important factor in preventing local recurrence and, in many instances, requires resection of adjacent viscera. The role of adjuvant radiation therapy in the treatment of patients with retroperitoneal sarcoma has not been clearly defined. Prospective randomized trials have not shown improved survival with preoperative or adjuvant chemotherapy for this subgroup.[6,9]

STANDARD TREATMENT OPTIONS:

1. Surgical excision with negative tissue margins of several centimeters in all directions may be used.
2. If the tumor is greater than 5 cm in diameter, surgical excision with negative tissue margins of several centimeters in all directions followed by radiation therapy may be used.
3. If the tumor is unresectable, high-dose radiation therapy may be used, but poor local control is likely to result.
4. In some situations, radiation therapy or chemotherapy may be used prior to surgery to convert a marginally resectable tumor to one that can be adequately resected with limb preservation; this treatment may be followed by postoperative radiation therapy.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage II adult soft tissue sarcoma and stage III adult soft tissue sarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Schmidt RA, Conrad EU 3rd, Collins C, et al.: Measurement and prediction of the short-term response of soft tissue sarcomas to chemotherapy. Cancer 72 (9): 2593-601, 1993.
2. Temple WJ, Temple CL, Arthur K, et al.: Prospective cohort study of neoadjuvant treatment in conservative surgery of soft tissue sarcomas. Ann Surg Oncol 4 (7): 586-90, 1997 Oct-Nov.
3. Watson DI, Coventry BJ, Langlois SL, et al.: Soft-tissue sarcoma of the extremity. Experience with limb-sparing surgery. Med J Aust 160 (7): 412-6, 1994.
4. Cormier JN, Huang X, Xing Y, et al.: Cohort analysis of patients with localized, high-risk, extremity soft tissue sarcoma treated at two cancer centers: chemotherapy-associated outcomes. J Clin Oncol 22 (22): 4567-74, 2004.
5. O'Byrne K, Steward WP: The role of adjuvant chemotherapy in the treatment of adult soft tissue sarcomas. Crit Rev Oncol Hematol 27 (3): 221-7, 1998.
6. 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.
7. Heslin MJ, Lewis JJ, Nadler E, et al.: Prognostic factors associated with long-term survival for retroperitoneal sarcoma: implications for management. J Clin Oncol 15 (8): 2832-9, 1997.
8. Jaques DP, Coit DG, Hajdu SI, et al.: Management of primary and recurrent soft-tissue sarcoma of the retroperitoneum. Ann Surg 212 (1): 51-9, 1990.
9. Eilber FC, Eilber FR, Eckardt J, et al.: The impact of chemotherapy on the survival of patients with high-grade primary extremity liposarcoma. Ann Surg 240 (4): 686-95; discussion 695-7, 2004.

Stage IV Adult Soft Tissue Sarcoma

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.[2,3,4,5,6][Level of evidence: 3iiiDiv]

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.[7]
3. Adjuvant chemotherapy may be considered for patients eligible for clinical trials.[8,9,10,11]

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.[12,13,14] The role of adjuvant therapy for pulmonary nodules is under clinical evaluation in trials such as the EORTC-62933 trial.

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 greater than 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 months vs. 4 months, P < .02) for doxorubicin, dacarbazine, ifosfamide, and mesna versus doxorubicin and dacarbazine alone.[19][Level of evidence: 1iiDiii] 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][Level of evidence: 3iiiDiv]

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: 3iiiDiv]

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.[12,13,14]
  • 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]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage IV adult soft tissue sarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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. Blanke CD, Rankin C, Demetri GD, et al.: Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 26 (4): 626-32, 2008.
7. 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.
8. Antman KH: Adjuvant therapy of sarcomas of soft tissue. Semin Oncol 24 (5): 556-60, 1997.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. Putnam JB Jr, Roth JA: Surgical treatment for pulmonary metastases from sarcoma. Hematol Oncol Clin North Am 9 (4): 869-87, 1995.
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.

Recurrent Adult Soft Tissue Sarcoma

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.)

Treatment of recurrent soft tissue sarcomas depends on the type of initial presentation and treatment. Patients who develop a local recurrence often can only be salvaged by aggressive local therapy: local excision plus radiation therapy after previous minimal therapy or amputation after previous aggressive treatment.[1,2] For selected patients who received radiation therapy, preoperative radiation therapy and wide local excision may avoid the need for amputation.[3,4,5] Metastases to the lung as first recurrence usually occur within 2 to 3 years of initial diagnosis and should be treated as described under treatment for stage IV disease.[6,7,8] A 30% survival rate at 3 years is noted if limited pulmonary metastases are resectable.

Doxorubicin alone or with dacarbazine is one of the most frequently used chemotherapeutic regimens for advanced sarcoma.[9,10,11] When used as single agents, only doxorubicin and ifosfamide show response rates greater than 20%; less active drugs include dacarbazine, cisplatin, methotrexate, and vinorelbine.[12] In a small study, pegylated liposomal doxorubicin has shown similar activity to doxorubicin, with fewer toxic effects.[13][Level of evidence: 3iiiDiv] 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.[14][Level of evidence: 1iiDiii] Sequential use of doxorubicin followed by ifosfamide or other drugs with each subsequent recurrence is frequently preferred. Clinical trials of phase I and II agents should be considered for subsequent recurrences. High-dose chemotherapy (with or without transplantation) has not influenced disease-free survival or overall survival in published studies, but it remains under clinical evaluation for patients with metastatic disease in first complete remission, after resection of pulmonary metastases, or for inoperable large primaries.[15,16,17]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent adult soft tissue sarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Brennan M, Singer S, Maki R, et al.: Sarcomas of the soft tissues and bone. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 1581-1631.
2. Midis GP, Pollock RE, Chen NP, et al.: Locally recurrent soft tissue sarcoma of the extremities. Surgery 123 (6): 666-71, 1998.
3. Essner R, Selch M, Eilber FR: Reirradiation for extremity soft tissue sarcomas. Local control and complications. Cancer 67 (11): 2813-7, 1991.
4. Singer S, Antman K, Corson JM, et al.: Long-term salvageability for patients with locally recurrent soft-tissue sarcomas. Arch Surg 127 (5): 548-53; discussion 553-4, 1992.
5. Lewis JJ, Leung D, Heslin M, et al.: Association of local recurrence with subsequent survival in extremity soft tissue sarcoma. J Clin Oncol 15 (2): 646-52, 1997.
6. 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.
7. 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.
8. Putnam JB Jr, Roth JA: Surgical treatment for pulmonary metastases from sarcoma. Hematol Oncol Clin North Am 9 (4): 869-87, 1995.
9. 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.
10. 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.
11. 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.
12. 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.
13. Judson I, Radford JA, Harris M, et al.: Randomised 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 37 (7): 870-7, 2001.
14. 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.
15. 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.
16. 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.
17. 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.

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