Adult soft tissue sarcoma

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Adult soft tissue sarcoma

GENERAL INFORMATION
CELLULAR CLASSIFICATION
STAGE INFORMATION Grade and TNM definitions Stage IA Stage IB Stage IIA Stage IIB Stage IIC Stage III Stage IV
TREATMENT OPTION OVERVIEW
STAGE IA, IB, AND IIA ADULT SOFT TISSUE SARCOMA Low-grade
STAGE IIB, IIC, AND III ADULT SOFT TISSUE SARCOMA High-grade, no lymph node or distant metastases
STAGE IV ADULT SOFT TISSUE SARCOMA Nodal disease Visceral disease
RECURRENT ADULT SOFT TISSUE SARCOMA

GENERAL INFORMATION

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 levels of evidence summary 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 the head and neck (10%). Soft tissue sarcomas occur with greater frequency in patients with von Recklinghausen's disease (neurofibromatosis), Gardner's syndrome, Werner's syndrome, tuberous sclerosis, basal cell nevus syndrome, and among Li-Fraumeni kindreds (p53 mutations).[1] These tumors may be heterogeneous, thus 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 optimal treatment of patients with this disease. In most cases, the radical surgical procedures of the past have given way to a combined modality approach: pre- or postoperative radiation therapy. 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.[2,3] Older than 60 years of age, tumors larger than 5 centimeters, or high-grade histology are associated with a poorer prognosis.[4] While low-grade tumors are usually curable by surgery alone, higher grade sarcomas (as determined by the mitotic index and the presence of hemorrhage and necrosis) are associated with higher local treatment failure rates and increased metastatic potential.[5] When feasible, wide margin function-sparing surgical excision is the cornerstone of effective treatment.[6,7] 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.[1,8] 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.[6,9-16] 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.[17] Effective treatment of retroperitoneal sarcomas requires removal of all gross disease while sparing adjacent viscera not invaded by tumor. The prognosis for high-grade retroperitoneal sarcomas is less favorable than for other sites, partly because of the difficulty in completely resecting these tumors and the limitations placed on high-dose radiation therapy.[1,18]

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 or an overall survival benefit for adjuvant chemotherapy.[17] 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 1568 individual patients from 14 trials of doxorubicin-based adjuvant therapy showed an absolute benefit from adjuvant therapy of 6% (95% confidence interval (CI) 1-10) for local relapse-free interval, 10% (95% CI 5-15) for distant relapse-free interval, and 10% (95% CI 5-15) for recurrence-free survival. However, there was no overall survival benefit at 10 years.[19][Level of evidence: 1iiiDi] Patients with high-grade tumors (grades 3 or 4) greater than 5 centimeters 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.[20-22] Doxorubicin alone or with dacarbazine is considered the best chemotherapeutic regimen for advanced sarcoma.[23-25] A randomized trial of 340 patients with advanced sarcoma showed a higher response rate (32% versus 17%, p<.002) and longer time-to-progression (6 versus 4 months, p<.02) for doxorubicin, dacarbazine, ifosfamide, and mesna (MAID) versus doxorubicin and dacarbazine alone.[26][Level of evidence: 1iiDii] 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.[26]

Complete surgical resection is often difficult for sarcomas of the retroperitoneum due to large size before detection and anatomic location.[27,28] Prospective randomized trials have not shown improved survival with preoperative or postoperative adjuvant chemotherapy for this subgroup.[19]

References:

Brennan MF, Casper ES, Harrison LB: Soft tissue sarcoma. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 1738-1788.
Le Doussal V, Coindre JM, Leroux A, et al.: Prognostic factors for patients with localized primary malignant fibrous histiocytoma. Cancer 77(9): 1823-1830, 1996.
Le QT, Fu KK, Kroll S, et al.: Prognostic factors in adult soft-tissue sarcomas of the head and neck. International Journal of Radiation Oncology, Biology, Physics 37(5): 975-984, 1997.
Vraa S, Keller J, Nielsen OS, et al.: Prognostic factors in soft tissue sarcomas: the Aarhus experience. European Journal of Cancer 34(12): 1876-1882, 1998.
Collin CF, Friedrich C, Godbold J, et al.: Prognostic factors for local recurrence and survival in patients with localized extremity soft-tissue sarcoma. Seminars in Surgical Oncology 4(1): 30-37, 1988.
Watson DI, Coventry BJ, Langlois SL, et al.: Soft-tissue sarcoma of the extremity: experience with limb-sparing surgery. Medical Journal of Australia 160(7): 412-416, 1994.
Geer RJ, Woodruff J, Casper ES, et al.: Management of small soft-tissue sarcoma of the extremity in adults. Archives of Surgery 127(11): 1285-1289, 1992.
Fish FS: Soft tissue sarcomas in dermatology. Dermatologic Surgery 22(3): 268-273, 1996.
Marcove RC, Sheth DS, Healey J, et al.: Limb-sparing surgery for extremity sarcoma. Cancer Investigation 12(5): 497-504, 1994.
Williard WC, Collin C, Casper ES, et al.: The changing role of amputation for soft tissue sarcoma of the extremity in adults. Surgery, Gynecology and Obstetrics 175(5): 389-396, 1992.
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. Journal of Clinical Oncology 16(1): 197-203, 1998.
Zalupski MM, Southwest Oncology Group: Phase II Pilot Study of Neoadjuvant Therapy with DOX/DTIC/IFF for Poor-Prognosis Soft Tissue Sarcoma (Summary Last Modified 08/98), SWOG-9119, clinical trial, closed, 06/15/1998.
Schmidt RA, Conrad EU III, Collins C, et al.: Measurement and prediction of the short-term response of soft tissue sarcomas to chemotherapy. Cancer 72(9): 2593-2601, 1993.
Temple WJ, Temple CL, Arthur K, et al.: Prospective cohort study of neoadjuvant treatment in conservative surgery of soft tissue sarcomas. Annals of Surgical Oncology 4(7): 586-590, 1997.
Valle AA, Kraybill WG: Management of soft tissue sarcomas of the extremity in adults. Journal of Surgical Oncology 63(4): 271-279, 1996.
Pollack A, Zagars GK, Goswitz MS, et al.: Preoperative vs. postoperative radiotherapy in the treatment of soft tissue sarcomas: a matter of presentation. International Journal of Radiation Oncology, Biology, Physics 42(3): 563-572, 1998.
O'Byrne K, Steward WP: The role of adjuvant chemotherapy in the treatment of adult soft tissue sarcomas. Critical Reviews in Oncology/Hematology 27(3): 221-227, 1998.
Lewis JJ, Leung D, Woodruff JM, et al.: Retroperitoneal soft-tissue sarcoma: analysis of 500 patients treated and followed at a single institution. Annals of Surgery 228(3): 355-365, 1998.
Sarcoma Meta-analysis Collaboration: Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Lancet 350(9092): 1647-1654, 1997.
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): 675-682, 1996.
Casson AG, Putman JB, Natarajan G, et al.: Five-year survival after pulmonary metastasectomy for adult soft tissue sarcoma. Cancer 69(3): 662-668, 1992.
Putnam JB Jr, Roth JA: Surgical treatment for pulmonary metastases from sarcoma. Hematology Oncology Clinics of North America 9(4): 869-887, 1995.
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. Journal of Clinical Oncology 13(7): 1537-1545, 1995.
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. Journal of the National Cancer Institute 83(13): 920-926, 1991.
Borden EC, Amato DA, Rosenbaum C, et al.: Randomized comparison of three Adriamycin regimens for metastatic soft tissue sarcomas. Journal of Clinical Oncology 5(6): 840-850, 1987.
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. Journal of Clinical Oncology 11(7): 1276-1285, 1993.
Heslin MJ, Lewis JJ, Nadler E, et al.: Prognostic factors associated with long-term survival for retroperitoneal sarcoma: implications for management. Journal of Clinical Oncology 15(8): 2832-2839, 1997.
Jaques DP, Coit DG, Hajdu SI, et al.: Management of primary and recurrent soft-tissue sarcoma of the retroperitoneum. Annals of Surgery 212(1): 51-59, 1990.

CELLULAR CLASSIFICATION

Soft tissue sarcomas are classified histologically according to the soft tissue cell of origin, although 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.[1-3] 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]

alveolar soft-part sarcoma
angiosarcoma
dermatofibrosarcoma protuberans
epithelioid sarcoma
extraskeletal chondrosarcoma
extraskeletal osteosarcoma
fibrosarcoma
leiomyosarcoma
liposarcoma
malignant fibrous histiocytoma
malignant hemangiopericytoma
malignant mesenchymoma
malignant schwannoma
malignant peripheral nerve sheath tumor
peripheral neuroectodermal tumors
rhabdomyosarcoma
synovial sarcoma
sarcoma, NOS

References:

Marcus SG, Merino MJ, Glastein E, et al.: Long-term outcome in 87 patients with low-grade soft-tissue sarcoma. Archives of Surgery 128(12): 1336-1343, 1993.
Soft tissue sarcoma. In: American Joint Committee on Cancer: AJCC Cancer Staging Manual. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 149-156.
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. Journal of Clinical Oncology 10(8): 1317-1329, 1992.
Alvegard TA, Berg NO, for the Scandinavian Sarcoma Group: Histopathology peer review of high-grade soft tissue sarcoma: the Scandinavian Sarcoma Group experience. Journal of Clinical Oncology 7(12): 1845-1851, 1989.

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 greater than 5 centimeters (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: 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 more than 5 cm in greatest dimension

T2a: Superficial tumor
T2b: Deep tumor

Note: 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 superficial and 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

Distant metastasis (M)

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

Stage IA

Stage IA tumor is defined as low grade, small, superficial, and deep.

G1, T1a, N0, M0
G1, T1b, N0, M0
G2, T1a, N0, M0
G2, T1b, N0, M0

Stage IB

Stage IB tumor is defined as low grade, large, and superficial.

G1, T2a, N0, M0
G2, T2a, N0, M0

Stage IIA

Stage IIA tumor is defined as low grade, large, and deep.

G1, T2b, N0, M0
G2, T2b, N0, M0

Stage IIB

Stage IIB tumor is defined as high grade, small, superficial, and deep.

G3, T1a, N0, M0
G3, T1b, N0, M0
G4, T1a, N0, M0
G4, T1b, N0, M0

Stage IIC

Stage IIC tumor is defined as high grade, large, and superficial.

G3, T2a, 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:

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. Annals of Surgery 217(1): 72-77, 1993.
Soft tissue sarcoma. In: American Joint Committee on Cancer: AJCC Cancer Staging Manual. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 149-156.

TREATMENT OPTION OVERVIEW

The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.

STAGE IA, IB, AND IIA ADULT SOFT TISSUE SARCOMA

Low-grade

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 at least 2 centimeters or more in all directions is the treatment of choice for these early stage sarcomas.[1] 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 less than 2 centimeters, and when wider resection would require either an amputation or the removal of a vital organ.[2] Because of the low metastatic potential of these tumors, chemotherapy is usually not given.[3] 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.[4,5]

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]

3. If the tumor is unresectable, high-dose preoperative radiation therapy may be used, followed by surgical resection and postoperative radiation therapy.[2,8]

4. For tumors of the retroperitoneum, trunk, and head and neck:

a. 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.[5]

b. 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.

References:

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.
Temple WJ, Temple CL, Arthur K, et al.: Prospective cohort study of neoadjuvant treatment in conservative surgery of soft tissue sarcomas. Annals of Surgical Oncology 4(7): 586-590, 1997.
Geer RJ, Woodruff J, Casper ES, et al.: Management of small soft-tissue sarcoma of the extremity in adults. Archives of Surgery 127(11): 1285-1289, 1992.
Fish FS: Soft tissue sarcomas in dermatology. Dermatologic Surgery 22(3): 268-273, 1996.
Brennan MF, Casper ES, Harrison LB: Soft tissue sarcoma. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 1738-1788.
Tepper JE, Suit HD: Radiation therapy of soft tissue sarcomas. Cancer 55(9, Suppl): 2273-2277, 1985.
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. Journal of Clinical Oncology 16(1): 197-203, 1998.
Schmidt RA, Conrad EU III, Collins C, et al.: Measurement and prediction of the short-term response of soft tissue sarcomas to chemotherapy. Cancer 72(9): 2593-2601, 1993.

STAGE IIB, IIC, AND III ADULT SOFT TISSUE SARCOMA

High-grade, no lymph node or distant metastases

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.[1-3]

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 or an overall survival benefit for adjuvant chemotherapy.[4] 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 1568 individual patients from 14 trials of doxorubicin-based adjuvant therapy showed an absolute benefit from adjuvant therapy of 6% (95% confidence interval (CI) 1-10) for local relapse-free interval, 10% (95% CI 5-15) for distant relapse-free interval, 10% (95% CI 5-15) for recurrence-free survival. However, there was no overall survival benefit at 10 years.[5][Level of evidence: 1iiiDi] Patients with high-grade tumors (grades 3 or 4) greater than 5 centimeters 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 due to large size before detection and anatomical location.[6,7] 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 (removal of all gross tumor) is the most important factor in preventing local recurrence and, in many instances, requires resection of adjacent viscera. Prospective randomized trials have not shown improved survival with preoperative or adjuvant chemotherapy for this subgroup.[5]

Treatment options:

1. Surgical excision with negative tissue margins of several centimeters in all directions.

2. If the tumor is greater than 5 centimeters in diameter, radiation therapy is added.

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 and in some instances, 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.

References:

Schmidt RA, Conrad EU III, Collins C, et al.: Measurement and prediction of the short-term response of soft tissue sarcomas to chemotherapy. Cancer 72(9): 2593-2601, 1993.
Temple WJ, Temple CL, Arthur K, et al.: Prospective cohort study of neoadjuvant treatment in conservative surgery of soft tissue sarcomas. Annals of Surgical Oncology 4(7): 586-590, 1997.
Watson DI, Coventry BJ, Langlois SL, et al.: Soft-tissue sarcoma of the extremity: experience with limb-sparing surgery. Medical Journal of Australia 160(7): 412-416, 1994.
O'Byrne K, Steward WP: The role of adjuvant chemotherapy in the treatment of adult soft tissue sarcomas. Critical Reviews in Oncology/Hematology 27(3): 221-227, 1998.
Sarcoma Meta-analysis Collaboration: Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Lancet 350(9092): 1647-1654, 1997.
Heslin MJ, Lewis JJ, Nadler E, et al.: Prognostic factors associated with long-term survival for retroperitoneal sarcoma: implications for management. Journal of Clinical Oncology 15(8): 2832-2839, 1997.
Jaques DP, Coit DG, Hajdu SI, et al.: Management of primary and recurrent soft-tissue sarcoma of the retroperitoneum. Annals of Surgery 212(1): 51-59, 1990.

STAGE IV ADULT SOFT TISSUE SARCOMA

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]

Treatment options:

1. Surgical resection and lymphadenectomy for patients with clinically positive lymph nodes, with or without postoperative radiation to the primary site.

2. In some centers, radiation therapy may be used prior to and following surgical extirpation.

3. Adjuvant chemotherapy may be considered for patients eligible for clinical trials.[2-5]

Visceral disease

With distant metastases (stage IV), 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.[6-8] The role of adjuvant therapy for pulmonary nodules is under clinical evaluation.[9] 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.[10-12] When used as single agents, only doxorubicin and ifosfamide show greater than 20% response rates; less active drugs include dacarbazine, cisplatin, methotrexate, and vinorelbine.[13] A randomized trial of 340 patients with advanced sarcoma showed a higher response rate (32% versus 17%, p<.002) and longer time-to-progression (6 versus 4 months, p<.02) for doxorubicin, dacarbazine, ifosfamide, and mesna (MAID) verus doxorubicin and dacarbazine alone.[14][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 or overall survival in published studies so far, but remains under clinical evaluation for patients with metastatic disease in first complete remission, after resection of pulmonary nodules, or for inoperable large primaries.[15]

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.[6-8]

a. Surgical excision with negative tissue margins.

b. If the tumor is resectable but wide margins cannot be obtained, radiation therapy may be added.

c. If the tumor is unresectable, high-dose radiation therapy may be used, often with chemotherapy.

d. 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:

doxorubicin [10]
doxorubicin + dacarbazine [10,11]
doxorubicin + ifosfamide [16]
doxorubicin + dacarbazine + ifosfamide + mesna [14,17]
high-dose ifosfamide regimens [18,19]

References:

Eilber FR, Eckhardt J, Morton DL: Advances in the treatment of sarcomas of the extremity: current status of limb salvage. Cancer 54(11): 2695-2701, 1984.
Antman KH: Adjuvant therapy of sarcomas of soft tissue. Seminars in Oncology 24(5): 556-560, 1997.
Sarcoma Meta-analysis Collaboration: Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Lancet 350(9092): 1647-1654, 1997.
Buesa JM, Lopez-Pousa A, et al, for the Grupo Espanol de Investigacion en Sarcomas (GEIS): 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). Annals of Oncology 9(8): 871-876, 1998.
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. American Journal of Clinical Oncology 21(3): 317-321, 1998.
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): 675-682, 1996.
Casson AG, Putman JB, Natarajan G, et al.: Five-year survival after pulmonary metastasectomy for adult soft tissue sarcoma. Cancer 69(3): 662-668, 1992.
Putnam JB Jr, Roth JA: Surgical treatment for pulmonary metastases from sarcoma. Hematology Oncology Clinics of North America 9(4): 869-887, 1995.
Van Geel AN, EORTC Soft Tissue and Bone Sarcoma Cooperative Group: Phase III Randomized Study of Neoadjuvant High-Dose DOX/IFF with or without G-CSF Followed by Metastasectomy vs Metastasectomy Alone for Lung Metastases in Patients with Soft Tissue Sarcoma (Summary Last Modified 05/1998), EORTC-62933, clinical trial, active, 04/15/1996.
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. Journal of Clinical Oncology 13(7): 1537-1545, 1995.
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. Journal of the National Cancer Institute 83(13): 920-926, 1991.
Borden EC, Amato DA, Rosenbaum C, et al.: Randomized comparison of three Adriamycin regimens for metastatic soft tissue sarcomas. Journal of Clinical Oncology 5(6): 840-850, 1987.
Demetri GD, Elias AD: Results of single-agent and combination chemotherapy for advanced soft tissue sarcomas. Implications for decision making in the clinic. Hematology Oncology Clinics of North America 9(4): 765-785, 1995.
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. Journal of Clinical Oncology 11(7): 1276-1285, 1993.
Elias AD: High-dose therapy for adult soft tissue sarcoma: dose response and survival. Seminars in Oncology 25(2, suppl 4): 19-23, 1998.
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. Journal of Clinical Oncology 11(7): 1269-1275, 1993.
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. Journal of Clinical Oncology 7(9): 1208-1216, 1989.
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. Journal of Clinical Oncology 15(6): 2378-2384, 1997.
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. Journal of Clinical Oncology 16(4): 1438-1443, 1998.

RECURRENT ADULT SOFT TISSUE SARCOMA

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.[3-5] 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.[6-8] 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.[9-11] 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] A randomized trial of 340 patients with advanced sarcoma showed a higher response rate(32% versus 17%, p<.002) and longer time-to-progression (6 versus 4 months, p<.02) for doxorubicin, dacarbazine, ifosfamide, and mesna (MAID) versus doxorubicin and dacarbazine alone.[13][Level of evidence: 1iiDii] 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 or overall survival in published studies so far, but remains under clinical evaluation for patients with metastatic disease in first complete remission, after resection of pulmonary metastases, or for inoperable large primaries.[14-16]

References:

Brennan MF, Casper ES, Harrison LB: Soft tissue sarcoma. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 1738-1788.
Midis GP, Pollock RE, Chen NP, et al.: Locally recurrent soft tissue sarcoma of the extremities. Surgery 123(6): 666-671, 1998.
Essner R, Selch M, Eilber FR: Reirradiation for extremity soft tissue sarcomas: local control and complications. Cancer 67(11): 2813-2817, 1991.
Singer S, Antman K, Corson JM, et al.: Long-term salvageability for patients with locally recurrent soft-tissue sarcomas. Archives of Surgery 127(5): 548-554, 1992.
Lewis JJ, Leung D, Heslin M, et al.: Association of local recurrence with subsequent survival in extremity soft tissue sarcoma. Journal of Clinical Oncology 15(2): 646-652, 1997.
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): 675-682, 1996.
Casson AG, Putman JB, Natarajan G, et al.: Five-year survival after pulmonary metastasectomy for adult soft tissue sarcoma. Cancer 69(3): 662-668, 1992.
Putnam JB Jr, Roth JA: Surgical treatment for pulmonary metastases from sarcoma. Hematology Oncology Clinics of North America 9(4): 869-887, 1995.
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. Journal of Clinical Oncology 13(7): 1537-1545, 1995.
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. Journal of the National Cancer Institute 83(13): 920-926, 1991.
Borden EC, Amato DA, Rosenbaum C, et al.: Randomized comparison of three Adriamycin regimens for metastatic soft tissue sarcomas. Journal of Clinical Oncology 5(6): 840-850, 1987.
Demetri GD, Elias AD: Results of single-agent and combination chemotherapy for advanced soft tissue sarcomas. Implications for decision making in the clinic. Hematology Oncology Clinics of North America 9(4): 765-785, 1995.
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. Journal of Clinical Oncology 11(7): 1276-1285, 1993.
Buesa JM, Lopez-Pousa A, et al, for the Grupo Espanol de Investigacion en Sarcomas (GEIS): 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). Annals of Oncology 9(8): 871-876, 1998.
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. American Journal of Clinical Oncology 21(3): 317-321, 1998.
Elias AD: High-dose therapy for adult soft tissue sarcoma: dose response and survival. Seminars in Oncology 25(2, suppl 4): 19-23, 1998.

Date Last Modified: 09/1999

PDQ® Treatment Health Professionals

Adult soft tissue sarcoma

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