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

General Information About Soft Tissue Sarcoma

Incidence and Mortality

Estimated new cases and deaths from soft tissue sarcoma in the United States in 2023:[1]

• New cases: 13,400.
• Deaths: 5,140.

The reported international incidence of soft tissue sarcoma ranges from 1.8 to 5 cases per 100,000 individuals per year.[2] The rate of new cases of soft tissue cancer in the United States was 3.4 per 100,000 people per year. The death rate was 1.3 per 100,000 people per year. These rates are age-adjusted and based on cases from 2015 through 2019 and deaths from 2016 through 2020.[3]

Risk Factors

Most soft tissue sarcomas are sporadic. Risk factors include the following:[4,5,6]

• Previous radiation therapy.
• Chronic lymphedema (risk factor for lymphangiosarcoma).
• Exposure to the chemicals thorium dioxide (Thorotrast), vinyl chloride, or arsenic. These are established carcinogens for hepatic angiosarcomas.
• HIV and human herpesvirus 8 infection. These viruses have been implicated in the pathogenesis of Kaposi sarcoma. For more information, see Kaposi Sarcoma Treatment.

Soft tissue sarcomas occur more frequently in patients with the following inherited syndromes:[4,5,6]

• Li-Fraumeni syndrome (TP53 mutation).
• von Recklinghausen disease (neurofibromatosis type 1; NF1 mutation).
• Gardner syndrome (APC mutation).
• Nevoid basal cell carcinoma syndrome (Gorlin syndrome; PTCH1 mutation).
• Tuberous sclerosis (Bourneville disease; TSC1 or TSC2 mutation).
• Werner syndrome (adult progeria; WRN mutation).

Clinical Features

Soft tissue sarcomas are a heterogenous family of malignant tumors that may arise in nearly any organ system. The anatomical distribution in adults is as follows:[5]

• Extremities (45%).
• Intra-abdominal organs (38%).
• Trunk (10%).
• Head and neck (5%).

Diagnostic Evaluation

Adequate tissue should be obtained via either image-guided core-needle biopsy or planned incisional biopsy (for select cases). The samples should be reviewed by a pathologist who is experienced in diagnosing sarcomas. Careful planning of the initial biopsy, with consultation among the surgeon, radiation oncologist, and interventional radiologist, is important to avoid compromising subsequent curative resection. In general, incisional biopsies are reserved for patients whose prior core-needle biopsies were nondiagnostic or when a core-needle biopsy cannot be safely performed because of anatomical constraints.

Before any intervention is initiated, imaging is performed to evaluate the sarcoma and determine if there are metastases. The following modalities may be used as clinically indicated:

• Plain radiography.
• Computed tomography (CT).
• Magnetic resonance imaging (MRI).
• Positron emission tomography (PET) scan and bone scan. May be used along with CT. PET imaging is particularly useful for sarcoma subtypes with a propensity for lymph node metastases (e.g., synovial sarcoma, clear cell sarcoma, angiosarcoma, rhabdomyosarcoma, and epithelioid sarcoma).

Prognostic Factors

Factors for a poor prognosis in adults with soft tissue sarcomas include the following:[4,5,6,7,8,9,10,11,12,13,14,15]

• Age older than 60 years.
• Tumor size (e.g., larger than 5 cm in greatest dimension, variable impact depending on sarcoma subtype).
• High histological grade of the tumor (incorporating histology-specific differentiation, mitotic rate, and extent of tumor necrosis).
• Advanced pathological stage of the tumor at the time of diagnosis.
• Positive tumor margins after surgery.[10]

Small low-grade tumors, particularly in the trunk or extremities, are frequently curable by surgery alone. Higher-grade sarcomas are associated with higher local-treatment failure rates and increased metastatic potential.[16]

Prognostic nomograms (incorporating specific variables) have been developed for soft tissue sarcomas of the retroperitoneum and the extremities.[11,12,13,14]

Follow-up Testing

PET and CT imaging may have higher sensitivity than contrast-enhanced CT imaging when recurrent sarcoma is suspected. Late recurrences (more than 5 years from initial diagnosis) are seen with some histologies, such as synovial sarcoma or alveolar soft-part sarcoma.[17,18]

Evidence (posttreatment imaging surveillance):

1. A retrospective review included 174 consecutive patients with soft tissue sarcoma of the limb who underwent follow-up by oncologists at a single center from 2003 to 2009.[19][Level of evidence C2] The rate and site of recurrence and mode of detection were analyzed. The following results were reported:
   1. Eighty-two patients (47%) experienced relapse.
   2. Isolated local recurrences occurred in 26 patients, and local relapse with synchronous pulmonary metastases occurred in 5 patients.
      • Local recurrences were detected clinically in 30 of the 31 patients.
      • MRI identified only one local recurrence.
   3. Twenty-eight patients (16%) developed isolated lung metastases.
      • The lung metastases were amenable to resections in nine patients, seven of whom were free of disease after treatment.
      • Lung metastases were detected by chest x-ray in 19 patients, by CT scan in 3 patients, and clinically in 11 patients.
   4. Twenty-three patients developed nonpulmonary metastases.
   5. More than 80% of the relapses occurred in the first 2 years of follow-up. Later recurrences were also observed.

This study supports imaging surveillance for detection of lung metastases. Local recurrences at the primary site were usually detected by clinical examination. The impact of metastases detection on overall survival or quality of life is unknown.[19]

References:

1. American Cancer Society: Cancer Facts and Figures 2023. American Cancer Society, 2023. Available online. Last accessed January 13, 2023.
2. Wibmer C, Leithner A, Zielonke N, et al.: Increasing incidence rates of soft tissue sarcomas? A population-based epidemiologic study and literature review. Ann Oncol 21 (5): 1106-11, 2010.
3. National Cancer Institute: SEER Cancer Stat Facts: Soft Tissue including Heart Cancer. Bethesda, Md: National Cancer Institute. Available online. Last accessed December 13, 2022.
4. Singer S, Antonescu CR: Molecular biology of sarcomas. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1384-99.
5. Singer S, Tap WD, Kirsch DG: Soft tissue sarcoma. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1400-49.
6. O'Donnell RJ, DuBois SG, Haas-Kogan DA: Sarcomas of bone. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1450-74.
7. 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.
8. Kasper B, Ouali M, van Glabbeke M, et al.: Prognostic factors in adolescents and young adults (AYA) with high risk soft tissue sarcoma (STS) treated by adjuvant chemotherapy: a study based on pooled European Organisation for Research and Treatment of Cancer (EORTC) clinical trials 62771 and 62931. Eur J Cancer 49 (2): 449-56, 2013.
9. Zagars GK, Ballo MT, Pisters PW, et al.: Prognostic factors for patients with localized soft-tissue sarcoma treated with conservation surgery and radiation therapy: an analysis of 1225 patients. Cancer 97 (10): 2530-43, 2003.
10. Trovik LH, Ovrebo K, Almquist M, et al.: Adjuvant radiotherapy in retroperitoneal sarcomas. A Scandinavian Sarcoma Group study of 97 patients. Acta Oncol 53 (9): 1165-72, 2014.
11. Gronchi A, Miceli R, Shurell E, et al.: Outcome prediction in primary resected retroperitoneal soft tissue sarcoma: histology-specific overall survival and disease-free survival nomograms built on major sarcoma center data sets. J Clin Oncol 31 (13): 1649-55, 2013.
12. Callegaro D, Miceli R, Bonvalot S, et al.: Development and external validation of two nomograms to predict overall survival and occurrence of distant metastases in adults after surgical resection of localised soft-tissue sarcomas of the extremities: a retrospective analysis. Lancet Oncol 17 (5): 671-80, 2016.
13. Raut CP, Callegaro D, Miceli R, et al.: Predicting Survival in Patients Undergoing Resection for Locally Recurrent Retroperitoneal Sarcoma: A Study and Novel Nomogram from TARPSWG. Clin Cancer Res 25 (8): 2664-2671, 2019.
14. Callegaro D, Miceli R, Bonvalot S, et al.: Development and external validation of a dynamic prognostic nomogram for primary extremity soft tissue sarcoma survivors. EClinicalMedicine 17: 100215, 2019.
15. 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.
16. 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.
17. Krieg AH, Hefti F, Speth BM, et al.: Synovial sarcomas usually metastasize after >5 years: a multicenter retrospective analysis with minimum follow-up of 10 years for survivors. Ann Oncol 22 (2): 458-67, 2011.
18. Guadagnolo BA, Zagars GK, Ballo MT, et al.: Long-term outcomes for synovial sarcoma treated with conservation surgery and radiotherapy. Int J Radiat Oncol Biol Phys 69 (4): 1173-80, 2007.
19. Rothermundt C, Whelan JS, Dileo P, et al.: What is the role of routine follow-up for localised limb soft tissue sarcomas? A retrospective analysis of 174 patients. Br J Cancer 110 (10): 2420-6, 2014.

Cellular Classification of Soft Tissue Sarcoma

Soft tissue sarcomas are heterogeneous, with more than 100 different entities described in the World Health Organization (WHO) 2020 classification.[1]

Soft tissue sarcomas are classified histologically according to the presumed tissue of origin. Immunohistochemistry, flow cytometry, molecular profiling, and, rarely, electron microscopy may identify particular subtypes within the major histological categories. Some subtypes of sarcomas are characterized by genetic events such as chromosomal translocations (e.g., translocation t(X;18)(p11;q11) in synovial sarcomas and translocation t(12;16)(q13;p11) in myxoid liposarcomas).[2,3,4]

References:

1. WHO Classification of Tumours Editorial Board, eds: Soft Tissue and Bone Tumours. IARC Press; 2020. WHO Classification of Tumours. 5th ed; Vol 3.
2. Singer S, Antonescu CR: Molecular biology of sarcomas. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1384-99.
3. Singer S, Tap WD, Kirsch DG: Soft tissue sarcoma. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1400-49.
4. O'Donnell RJ, DuBois SG, Haas-Kogan DA: Sarcomas of bone. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1450-74.

Stage Information for Soft Tissue Sarcoma

Staging Evaluation

In addition to histology, identifying the location and extent of disease (e.g., localized, locally advanced, metastatic) is important in determining the most effective initial treatment for patients with soft tissue sarcoma.[1]

Imaging tests used in the staging evaluation may include the following:[1,2,3,4,5]

• Magnetic resonance imaging (MRI) and/or computed tomography (CT) scan of the primary tumor area.
• Chest CT scan for high-grade sarcomas to look for metastasis to the lung (the most common site of distant spread).
• Abdominal/pelvic CT scan.
• Positron emission tomography (PET) scan.

Some staging evaluation procedures depend on the tumor histology and site, including the following:

• CT scan of the abdomen and pelvis and whole spine MRI for round cell and myxoid liposarcomas, as these histologies can have extrapulmonary spread to unusual sites.[6]
• Brain imaging for subtypes that have a higher propensity for central nervous system involvement, such as angiosarcoma, epithelioid sarcoma, or alveolar soft-part sarcoma.

Knowledge of intracompartmental or extracompartmental extension of extremity sarcomas is important for surgical decision making. For complete staging, a thorough review of all biopsy specimens, including those from the primary tumor, lymph nodes, or other suspicious lesions, is essential. Nodal involvement is rare, occurring in less than 3% of patients with sarcoma, but it occurs more often in certain subtypes, such as rhabdomyosarcoma, angiosarcoma, synovial sarcoma, clear cell sarcoma, and epithelioid sarcoma.[7,8]

American Joint Committee on Cancer (AJCC) Staging System

The 2017 AJCC/Union for International Cancer Control (UICC) cancer staging classification system recommends the use of the three-tiered French Federation of Comprehensive Cancer Centers (Fédération Nationale des Centres de Lutte Contre Le Cancer [FNCLCC]) Sarcoma Group grading schema. Prognostic factors required for stage grouping are from FNCLCC. The definitions of grade are provided in Table 6. Of note, staging is primarily used as a research tool and does not routinely impact decision making outside of the factors listed above (sarcoma subtype and grade, primary location, extent of disease [localized, locally advanced, distant metastases]).

The AJCC staging system has designated stage by the following criteria:[1,2,3,4,5]

• Tumor size, nodal status, metastasis, histological grade (TNMG).
• Anatomical primary tumor site (head and neck, trunk and extremities, abdomen and thoracic visceral organs, retroperitoneum, and unusual histologies and sites).

For information on unusual histologies and sites, see the eighth edition of the AJCC Cancer Staging Manual,[1] which indicates that the TNMG staging classification has different T staging criteria and prognostic groups based on the primary tumor site (see Table 1). The characteristic molecular markers of some sarcomas are not formally incorporated in the staging system pending further evaluation of their impact on prognosis.[2,3,4,5]

Recurrent sarcomas are restaged using the same system that is used for primary tumors, with the notation that the tumor is recurrent.

TNM definitions

FNCLCC histological grade

The histological grade of the sarcoma is an important factor in staging all soft tissue sarcomas. It is determined by the following three parameters:

• Histology-specific tumor differentiation (see Table 4).
• Mitotic activity.
• Extent of tumor necrosis.

The purpose of the grading system is to predict which patients will develop metastasis and therefore benefit from postoperative chemotherapy.[9,10] Each parameter is scored, and the scores are then added to determine the FNCLCC histological grade (see Table 5 and Table 6).

Prognostic stage groups

There is no recommended prognostic stage grouping for soft tissue sarcoma of the abdomen, thoracic visceral organs, and head and neck.

References:

1. Maki RG, Folpe AL, Guadagnolo BA, et al.: Soft tissue sarcoma - unusual histologies and sites. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 539-45.
2. O'Sullivan B, Maki RG, Agulnik M, et al.: Soft tissue sarcoma of the head and neck. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 499-505.
3. Yoon SS, Maki RG, Asare EA, et al.: Soft tissue sarcoma of the trunk and extremities. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 507-15.
4. Raut CP, Maki RG, Baldini EH, et al.: Soft tissue sarcoma of the abdomen and thoracic visceral organs. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 517-21.
5. Pollock RE, Maki RG, Baldini EH, et al.: Soft tissue sarcoma of the retroperitoneum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 531-7.
6. Schwab JH, Boland P, Guo T, et al.: Skeletal metastases in myxoid liposarcoma: an unusual pattern of distant spread. Ann Surg Oncol 14 (4): 1507-14, 2007.
7. 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.
8. Mazeron JJ, Suit HD: Lymph nodes as sites of metastases from sarcomas of soft tissue. Cancer 60 (8): 1800-8, 1987.
9. 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.
10. Guillou L, Coindre JM, Bonichon F, et al.: Comparative study of the National Cancer Institute and French Federation of Cancer Centers Sarcoma Group grading systems in a population of 410 adult patients with soft tissue sarcoma. J Clin Oncol 15 (1): 350-62, 1997.
11. Pollock RE, Maki RG: Introduction to soft tissue sarcoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 489-97.

Treatment Option Overview for Soft Tissue Sarcoma

Planning Therapy

Complete staging and treatment planning by a multidisciplinary team of cancer specialists is required to determine the optimal treatment for patients with soft tissue sarcoma. In most cases, a combined modality approach of preoperative radiation therapy (preRT) or postoperative radiation therapy (PORT) is used for treatment, rather than a radical surgical procedure such as amputation. Surgery without PORT may be possible in selected cases. The role of chemotherapy is not well defined.

Specialized centers

There is evidence that favorable clinical outcomes may be associated with referral to a specialized sarcoma treatment center.

Evidence (referral to a specialized sarcoma treatment center):

1. An analysis of a population-based consecutive series of 375 patients with soft tissue sarcoma in Sweden reported the following:[1][Level of evidence C2]
   • The local recurrence rate was 45% (35 of 78 patients) in patients who were not referred.
   • The local recurrence rate was 24% (24 of 102 patients) in patients who were referred after initial surgery or incisional biopsy.
   • The local recurrence rate was 18% (36 of 195 patients) in patients who were referred before any surgical procedure.
   • Local recurrence rates in patients with resected tumors were higher in those who were not referred (for the primary tumor) to the specialized center (P = .0001 for the difference between those not referred vs. those referred before any surgical procedure).
   • There were no statistically significant differences in death from sarcoma among the groups.
2. A British study of 260 patients with soft tissue sarcoma diagnosed within a 3-year period reported the following:[2]
   • Thirty-seven percent of the patients had most of their treatment at a specialized center.
   • The remaining 63% were treated at 38 different hospitals.
   • The rate of local recurrence was 19% for patients treated at the specialized center.
   • The rate of local recurrence was 39% for patients treated at the district general hospitals, even though the tumors in these patients were smaller and of lower grade.
   • The most significant factors affecting survival were tumor grade (high grade vs. low grade) and the depth of the tumor.
   • Patients treated at the specialized center had a small survival advantage after multivariate analysis.

Treatment Options for Soft Tissue Sarcoma

Surgery

Surgical resection is the mainstay of therapy for soft tissue sarcomas.

In some small low-grade tumors of the extremities or trunk, surgery alone can be performed without the use of radiation. Evidence for this approach is limited to single-institution, relatively small case series [3,4,5] or analysis of outcomes in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program tumor registry.[6] These comparisons suffer from low statistical power and differential evaluability rates that could have introduced bias.[3]

Patient selection factors may vary among surgeons. In general, surgery alone is considered in patients with low-grade tumors of the extremity or superficial trunk that are 5 cm or smaller in diameter (T1) and have microscopically negative surgical margins. In these patients, long-term local tumor control is about 90%.[7]

Extremity tumors

When feasible, wide-margin function-sparing surgical excision is the cornerstone of effective treatment for extremity tumors. This may be facilitated by soft tissue reconstructive surgery, which generally permits wider margins than those obtained when the surgical plan involves direct closure of the excision site.[8] Cutting into the tumor mass or shelling out the gross tumor is associated with an elevated risk of local recurrence. Even for high-grade disease, soft tissue sarcomas of the extremities can usually be effectively treated while preserving the limb with combined-modality treatment consisting of preRT or PORT to reduce local recurrence.[9] For more information, see the Radiation Therapy section.

Evidence (amputation vs. limb-sparing surgery):

1. A retrospective study analyzed a prospective sarcoma database of 649 patients with extremity soft tissue sarcoma. Ninety-two patients underwent amputation, and 557 patients had a limb-sparing procedure. Patients who underwent amputation had large (≥5 cm) high-grade tumors that invaded major vascular or nervous structures.[10]
   • The patients who underwent amputation achieved significantly better local control than the patients who had a limb-sparing procedure (P = .007).
   • However, no survival benefit was demonstrated in the patients selected for amputation (i.e., patients with large high-grade tumors) when compared with patients undergoing a limb-sparing procedure with similar tumors.
   • Prevention of local recurrence by amputation did not improve survival in this group compared with similar patients undergoing limb-sparing surgery who did develop a local recurrence.
2. A retrospective study included 769 patients with a high-grade sarcoma of the extremities who underwent a limb-sparing surgery. Eighty-nine patients were treated with neoadjuvant radiation therapy, 315 patients were treated with adjuvant irradiation, and 365 patients were treated with surgery alone.[11]
   • After a mean follow-up of 45 months, 95 local recurrences occurred, resulting in a local recurrence-free survival rate of 83.2% after 5 years and 75.9% after 10 years.
   • Neoadjuvant radiation therapy provided the best local recurrence-free rate for 5 years (90.0%), but after 10 years (78.3%) adjuvant irradiation resulted in better local control.
   • Patients treated with neoadjuvant radiation therapy had the highest rate of revision surgery (9.0%), followed by patients who were treated with surgery alone (5.5%) and patients who received adjuvant irradiation (4.4%) (P = .085).

Trunk and head/neck tumors

Local control of high-grade soft tissue sarcomas of the trunk and the head and neck can be achieved with surgery in combination with radiation therapy.[12] Surgery without PORT may be possible in selected patients. A case series was reported from a specialized sarcoma treatment referral center, in which 74 selected patients with primary extremity and trunk tumors 5 cm or smaller were found to have no histological involvement of the surgical margins.[3] These patients were observed without radiation therapy, and the estimated local recurrence rate after 10 years was 11%.[3][Level of evidence C3]

Retroperitoneal tumors

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 dose-limiting toxicity of high-dose radiation therapy on visceral organs.[13,14,15,16]

Local disease control is crucial in patients with retroperitoneal sarcomas. Disease-specific mortality caused by local recurrence (without synchronous metastasis) was reported in up to 77% of patients with retroperitoneal sarcomas compared with 9% of patients with extremity or trunk sarcomas.[17] An additional consideration in retroperitoneal sarcomas is the extent of surgery.

Evidence (extended surgical resection):

1. A series of 382 patients with retroperitoneal sarcoma in a multivariate analysis showed the following results:[18]
   • Patients treated with extended surgical resection had a 3.3-fold lower rate of local recurrence compared with patients who underwent simple complete resection.
   • Extended surgical resection was not associated with improved survival.
   • In a follow-up analysis, a 66% overall survival (OS) rate was observed in the extended surgical resection cohort compared with a 48% OS rate in historic controls.[19]

An extended surgical approach has to be weighed against an increase in morbidity (resulting from surgical complications) and mortality.[20,21,22,23]

Metastatic disease

In the setting of distant metastasis, surgery may be associated with long-term disease-free survival (DFS) in patients with pulmonary metastasis and optimal underlying disease biology. This includes patients with a limited number of metastases and slow nodule growth who have undergone or are undergoing complete resection of the primary tumor.[24,25,26] It is not clear to what degree the favorable outcomes are attributable to the efficacy of surgery or the careful selection of patients based on factors that are associated with less-aggressive disease.

Radiation Therapy

A patterns-of-care study using SEER data was queried to identify patients undergoing surgery for trunk and extremity soft tissue sarcomas from 2004 to 2009.[27] Of 5,075 patients, 50% received radiation therapy. Radiation therapy was not given as recommended in a significant portion of patients undergoing treatment for soft tissue sarcoma in the United States. Although routine radiation therapy is not recommended for patients with stage I disease, 25% of them still underwent radiation. Even though routine radiation therapy is recommended for patients with stage II and III tumors, only 60% of them underwent radiation. Predictors of radiation therapy efficacy from the multivariate analysis included the following:[27][Level of evidence C2]

• Age younger than 50 years (odds ratio [OR], 1.57; 95% confidence interval [CI], 1.28–1.91).
• Malignant fibrous histiocytoma histology (OR, 1.47; 95% CI, 1.3–1.92).
• T2 disease (OR, 1.88; 95% CI, 1.60–2.20).
• High tumor grade (G3) (OR, 6.27; 95% CI, 5.10–7.72).

Patients with stage III soft tissue sarcoma who received radiation therapy showed improved disease-specific survival at 5 years, compared with those who did not receive radiation therapy (68% vs. 46%, P < .001).

On occasion, surgical excision cannot be performed in the initial management of soft tissue sarcomas because the morbidity would be unacceptable or nearby critical organs make complete resection impossible. In such circumstances, radiation has been used as the primary therapy;[28] however, this must be considered a treatment of last resort. Experience of radiation as the primary therapy is limited to retrospective case series from single centers.[28][Level of evidence C3]

Extremity and trunk tumors

Radiation plays an important role in limb-sparing therapy. Pre- and postoperative radiation therapy has been shown to decrease the risk of local recurrence. These techniques have not demonstrated increased OS in prospective trials, but they are used to avoid amputation for all but the most locally advanced tumors or in limbs seriously compromised by vascular disease, where acceptable functional preservation is not possible. In the case of external-bean radiation therapy (EBRT), irradiation of the entire limb circumference is avoided to preserve vascular and nerve structures that are critical to retain the function of the limb.

Evidence (PORT):

1. PORT has been tested in a single-institution randomized trial of 141 patients with extremity sarcomas who were treated with limb-sparing surgery. Patients with high-grade tumors (n = 91) also received adjuvant chemotherapy (five 28-day cycles of doxorubicin and cyclophosphamide). Patients were randomly assigned to receive either radiation therapy (45 Gy to a wide field, plus a tumor-bed boost of 18 Gy over 6–7 weeks) concurrently with chemotherapy (in the case of high-grade tumors) or no radiation.[29][Level of evidence B1]
   • At up to 12 years of follow-up, there was one local recurrence in the 70 patients randomly assigned to receive radiation therapy versus 17 recurrences in the 71 control patients (P = .0001). There was a similar reduction in risk of local recurrence for both high- and low-grade tumors.
   • There was no difference in OS between the radiation therapy group and the control group.
   • Global quality of life was similar in the two groups, but the radiation therapy group had substantially worse functional deficits resulting from reduced strength, reduced joint motion, and increased edema.

To limit acute toxicity, smaller fields and lower doses of radiation are generally given with preRT than with PORT. PreRT has been directly compared with PORT for extremity soft tissue sarcomas in a multicenter randomized trial, and no significant difference in local control or OS rates was found.[30,31,32]

Evidence (preRT vs. PORT):

1. Though designed to include 266 patients, a trial was stopped after 190 patients were accrued because wound complications in the preRT group had increased. In the first phase of the trial, patients in the preRT group received wide-field radiation therapy of 50 Gy (in 2-Gy fractions). In the second phase of the trial, patients received an additional 16 Gy to 20 Gy to the tumor bed and a 2-cm margin (only if tumor cells were found at the surgical margins). Patients in the PORT group received radiation therapy during both phases of the trial.[30,31,32]
   • The wound complication rates were 35% in the preRT group and 17% in the PORT group (P = .01). In addition, limb function at 6 weeks after surgery was worse in the preRT group (P = .01).[30]
   • At 5 years, the two groups had similar local control rates (93% for the preRT group vs. 92% for the PORT group) and OS rates (73% for the preRT group vs. 67% for the PORT group; P = .48).[31]
   • Of the 129 patients evaluated for limb function at 21 to 27 months after surgery (n = 73 for preRT and n = 56 for PORT), limb function was similar in both groups, but there was a statistical trend for less fibrosis in the preRT group (P = .07).[32]

Brachytherapy has also been investigated as an adjuvant therapy for soft tissue sarcomas. Although brachytherapy has the possible advantages of convenience and giving less radiation to normal surrounding tissue relative to EBRT, the two treatment strategies have not been directly compared in terms of efficacy or morbidity. However, adjuvant brachytherapy has been compared with surgery without radiation.

Evidence (surgery followed by brachytherapy vs. surgery alone):

1. In a single-institution trial, 164 patients with sarcomas of the extremity or superficial trunk were randomly assigned during surgery (if all gross tumor could be excised) to receive an iridium Ir 192 implant delivering 42 Gy to 45 Gy over 4 to 6 days (78 patients) or to a control arm of no radiation (86 patients).[33,34] Thirty-four patients in each study arm with high-grade tumors who were believed to be at risk for metastasis received adjuvant doxorubicin-based chemotherapy.[33][Level of evidence B1]
   • With a median follow-up of 76 months, the 5-year actuarial local recurrence rates were 18% in the brachytherapy arm and 31% in the control arm (P = .04). This difference was limited to patients with high-grade tumors.
   • There was no discernible difference in sarcoma-specific survival rates between the brachytherapy arm (84%) and control arm (81%) (P = .65), and there was no difference in patients with high-grade tumors.
   • The rates of clinically important wound complications (e.g., the need for operative revision or repeated seroma drainage, wound separation, large hematomas, or purulent infection) were 24% in the brachytherapy arm and 14% in the control arm (P = .13). The wound reoperation rates were 10% in the brachytherapy arm and 0% in the control arm (P = .006).[34]

Intensity-modulated radiation therapy (IMRT) has been used to deliver preRT or PORT to patients with extremity soft tissue sarcomas to spare the femur, joints, and selected other normal tissues from the full prescription dose, and thus maintain local control while potentially reducing radiation therapy–related morbidity. Initial single-institution reports suggest that high rates of local control with some reduction in morbidity are possible with IMRT.[35,36]

Retrospective comparison of IMRT and 3-dimensional, conformal radiation therapy demonstrated that local recurrence for primary soft tissue sarcomas of the extremity was worse in the non-IMRT group.[37][Level of evidence C3]

Retroperitoneal tumors

Retrospective data support the use of preRT or PORT versus surgery alone to treat retroperitoneal sarcomas.

Evidence (preRT or PORT vs. surgery alone):

1. Outcomes from a total of 9,068 patients in two case-control studies conducted between 2003 and 2011 were analyzed.[38]

   The 2,196 patients who received PORT were compared with 2,196 matched controls.

   • The median OS was 89 months for the patients in the PORT group versus 64 months for the patients who did not receive radiation therapy.
   • The 5-year survival rate was 60% for the patients in the PORT group and 52% for the patients who did not receive radiation therapy.

   The 563 patients who received preRT were compared with 1,126 matched controls.[38]

   • The median OS was 110 months for the patients who received preRT versus 66 months for the patients who did not receive radiation therapy.
   • The 5-year survival rate was 62% for the patients who received preRT versus 54% for the patients who did not receive radiation therapy.
2. Two small prospective studies explored the role of neoadjuvant radiation therapy in patients with intermediate- or high-grade retroperitoneal sarcomas. In a combined analysis of the 54 patients who underwent R0 resection (resection for cure or complete remission) or R1 resection (resection to microscopic residual tumor) after preRT, the following results were reported:[39]
   • The 5-year local relapse-free survival (RFS) rate was 60%.
   • The 5-year DFS rate was 60%.
   • The 5-year OS rate was 61%. The median OS had not been reached (>60 months) at the time of the report.

Chemotherapy

Adjuvant chemotherapy for clinically localized tumors

The role of adjuvant chemotherapy remains controversial. Any potential benefits should be considered in the context of the short- and long-term toxicities of the chemotherapy regimen.

Several prospective, randomized trials were unable to determine conclusively whether doxorubicin-based adjuvant chemotherapy benefits adults with resectable soft tissue sarcomas. Most of these studies accrued small numbers of patients and did not demonstrate a metastasis-free survival or an OS benefit from adjuvant chemotherapy.[12] There was wide interstudy variability among the reported trials, including differences in therapeutic regimens, drug doses, sample sizes, tumor sites, and tumor histological grades.

Evidence (doxorubicin-based adjuvant chemotherapy):

1. A quantitative meta-analysis of updated data from 1,568 individual patients in 14 trials of doxorubicin-based adjuvant chemotherapy was reported. Only a small proportion of patients in this meta-analysis were treated with ifosfamide, an agent with demonstrated activity against soft tissue sarcoma.[40,41][Level of evidence B1] The following results were reported:
   • An absolute benefit from adjuvant chemotherapy of 6% for local relapse-free interval (95% CI, 1%–10%), 10% for distant relapse-free interval (95% CI, 5%–15%), and 10% for RFS (95% CI, 5%–15%).
   • No statistically significant OS benefit at 10 years was detected; the absolute difference was 4% (95% CI, -1% to +9%).
   • A subset analysis suggested that patients with sarcomas of the extremities may have benefited from adjuvant chemotherapy, with a reported 7% absolute OS improvement at 10 years (hazard ratio [HR]_death, 0.8; P = .029).[41]

Subsequent chemotherapy trials were performed using anthracycline and ifosfamide combinations in patients who primarily had extremity or trunk soft tissue sarcomas. The data are conflicting.

Evidence (anthracycline and ifosfamide or cyclophosphamide combinations):

1. In a small feasibility study, 59 patients with high-risk soft tissue sarcomas (58 of whom had an extremity or the trunk as the primary site) underwent primary resection plus PORT. They were then randomly assigned to observation versus a dose-dense regimen of six 14-day cycles of ifosfamide, dacarbazine (DTIC), and doxorubicin (IFADIC regimen) with granulocyte colony-stimulating factor (G-CSF) bone marrow support.[42]
   • There were no statistically significant differences in OS or RFS; however, the study was severely underpowered.
2. In a second trial performed by the Italian National Council for Research, high-risk patients were treated with local therapy (wide resection plus preRT or PORT, or amputation as clinically necessary) and were then randomly assigned to observation versus five 21-day cycles of 4-epidoxorubicin (epirubicin) plus ifosfamide (with mesna and G-CSF).[43,44]
   • Based on power calculations, the planned study size was 190 patients, but the trial was stopped after 104 patients had been entered because an interim analysis revealed a statistically significant (P = .001) difference in DFS favoring the chemotherapy arm. By the time of the initial peer-reviewed report of the study, the DFS still favored the chemotherapy arm (median DFS of 48 months vs. 16 months), but the P value had risen to .04.[43]
   • Although there was no difference in metastasis-free survival at the time of the report, there was an improvement in median OS (75 months for the chemotherapy arm vs. 46 months for the observation arm; P = .03).
   • At the follow-up report (median follow-up of 89.6 months in a range of 56–119 months), OS differences were no longer statistically significant (58.5% in the chemotherapy arm vs. 43.1% in the observation arm; P = .07).[44]
   • The DFS difference had also lost statistical significance (47.2% in the chemotherapy arm vs. 16.0% in the observation arm; P = .09).[44]

   In summary, the trial was underpowered because it was stopped early, and the promising early results that led to stopping the trial diminished as the trial matured.

3. In a third, underpowered, single-center trial, 88 patients with high-risk soft tissue sarcomas (64 with extremity or trunk primary tumors) underwent surgery (with or without radiation) and were then randomly assigned to receive four 21-day cycles of chemotherapy, epirubicin (n = 26) or epirubicin plus ifosfamide (n = 19), versus no adjuvant chemotherapy (n = 43).[45] The trial was closed prematurely because of a slow accrual rate.
   • After a median follow-up of 94 months, the 5-year DFS rates were 69% in the chemotherapy arm and 44% in the control arm (P = .01).
   • The 5-year OS rates were 72% in the chemotherapy arm and 47% in the control arm (P = .06).
   • All the benefit associated with chemotherapy appeared restricted to the 19 patients who received epirubicin plus ifosfamide.
4. In another underpowered trial, 134 patients with high-risk soft tissue sarcomas (93% with extremity or trunk primary tumors) were randomly assigned to undergo surgical resection (with or without radiation) or to receive three preoperative 21-day cycles of doxorubicin plus ifosfamide.[46] This multicenter trial from the European Organisation for Research and Treatment of Cancer (EORTC) (EORTC-62874) was closed because of slow accrual and results that were not promising enough to warrant continuation of the trial.
   • With a median follow-up of 7.3 years, the 5-year DFS rates were 52% in the surgery-alone arm and 56% in the chemotherapy-plus-surgery arm (P = .35).
   • The 5-year OS rates were 64% in the surgery-alone arm and 65% in the chemotherapy-plus-surgery arm (P = .22).
5. The previous four trials have been combined with the 14 first-generation trials in a trial-level meta-analysis.[47] Of the 18 randomized trials of patients with resectable soft tissue sarcomas, 5 trials used a combination of doxorubicin (50–90 mg/m² per cycle) plus ifosfamide (1,500–5,000 mg/m² per cycle). The remaining 13 trials used doxorubicin (50–70 mg/m² per cycle) alone or with other drugs.[47][Level of evidence A1]
   • The absolute risk reduction in local recurrence rates associated with any chemotherapy added to local therapy was 4% (95% CI, 0%–7%), and it was 5% (95% CI, 1%–12%) when ifosfamide was combined with doxorubicin.
   • The absolute reduction in overall mortality was 6% with any chemotherapy (95% CI, 2%–11%; this was a reduction from 46% to 40%), 11% for doxorubicin plus ifosfamide (95% CI, 3%–19%; this was a reduction from 41% to 30%), and 5% for doxorubicin without ifosfamide.
6. An additional multicenter randomized trial (EORTC-62931 [NCT00002641]) that used adjuvant doxorubicin (75 mg/m²) plus ifosfamide (5,000 mg/m²) was not included in the previous meta-analysis.[48] After local therapy, 351 patients were randomly assigned to five 21-day cycles of adjuvant therapy versus observation. The results of EORTC-62931 differed from those reported in the previous meta-analysis.[47]
   • The OS rate did not differ significantly between groups (HR, 0.94; 95% CI, 0.68–1.31; P = .72); neither did the RFS rate (HR, 0.91, 0.67–1.22; P = .51).
   • The 5-year OS rates were 66.5% (95% CI, 58.8%–73%) in the chemotherapy group and 67.8% (95% CI, 60.3%–74.2%) in the control group.
7. In a subsequent analysis of pooled individual patient data, the EORTC investigators combined data from this trial (EORTC-62931) with data from their previous trial (EORTC-62771) [49] of adjuvant cyclophosphamide plus doxorubicin plus dacarbazine (CYVADIC), representing the two largest trials of adjuvant therapy for adults with soft tissue sarcoma in the literature (N = 819 patients).[50] [Level of evidence A1];[51]
   • Large tumor size, high histological grade, and R1 resection emerged as independent adverse prognostic factors for RFS and OS.
   • Adjuvant chemotherapy was an independent favorable prognostic factor for RFS but not for OS.
   • Males and patients older than 40 years had a significantly better RFS in the treatment arms, while adjuvant chemotherapy was associated with a marginally worse OS in females and patients younger than 40 years.
   • The combined analysis showed no improvement in either RFS or OS associated with adjuvant chemotherapy.

In summary, the impact of adjuvant chemotherapy on survival is still controversial but is likely to be small in absolute magnitude.

Neoadjuvant chemotherapy

In prospective studies, neoadjuvant chemotherapy with or without radiation therapy has shown response rates of 17% to 32%, 10-year RFS rates of up to 58%, and 10-year OS rates of up to 64%.[46,52,53,54,55,56]

In retrospective studies, neoadjuvant chemotherapy with or without radiation therapy has resulted in DFS rates of 80% to 90% compared with about 60% in historical controls.[57,58,59]

A combined analysis of the RTOG-9514 study (NCT00002791) of neoadjuvant chemoradiation and the RTOG-0630 study (NCT00589121) of neoadjuvant radiation therapy showed rates of pathological complete response of 27.5% in patients on neoadjuvant chemoradiation and 19.4% in patients on neoadjuvant radiation therapy in 123 evaluable patients. At a median follow-up of more than 5 years, the OS rate was 100% in patients with pathological complete responses; 5-year survival rates were 76.5% (RTOG-9514) and 56.4% (RTOG-0630) for patients who did not achieve pathological complete responses.[60]

Evidence (neoadjuvant histotype-tailored chemotherapy vs. standard chemotherapy):

1. The phase III ISG-STS1001 study (NCT01710176) enrolled 164 patients with high-risk features (grade 3 tumor or grade 2 tumor with more than 50% necrosis, size ≥5 cm, deep location).[56] Patients were randomly assigned to receive either standard chemotherapy or histotype-tailored chemotherapy for three cycles as listed below:
   1. Standard chemotherapy (every 21 days):
      • Epirubicin, 60 mg/m², on days 1 and 2 plus ifosfamide, 3 g/m², on days 1, 2, and 3.
   2. Histotype-tailored chemotherapy:
      • Undifferentiated pleomorphic sarcoma: docetaxel, 75 mg/m², on day 8 plus gemcitabine, 900 mg/m², on days 1 and 8 (every 21 days).
      • Myxoid liposarcoma: trabectedin, 1.3 mg/m², continuous infusion (every 21 days).
      • Synovial sarcoma: ifosfamide, 14 g/m², 14 days of continuous infusion (every 28 days).
      • Malignant peripheral nerve sheath tumor: ifosfamide, 3 g/m², on days 1, 2, and 3 plus etoposide, 150 mg/m², on days 1, 2, and 3 (every 21 days).
      • Leiomyosarcoma: gemcitabine, 1,800 mg/m², on day 1 plus dacarbazine, 500 mg/m², on day 1 (every 14 days).

   The following results were reported:

   • With a median follow-up of 12.3 months, the projected RFS rate at 46 months was 62% (95% CI, 48%–77%) for patients who received standard chemotherapy versus 38% (95% CI, 22%–P = .004).
   • The OS rate was 89% (95% CI, 78%–99%) in the standard chemotherapy group versus 64% (95% CI, 27%–100%) in the histotype-tailored chemotherapy group (P = .034).
   • Trabectedin for myxoid liposarcoma had outcomes similar to those for the standard chemotherapy group.[56]

Chemotherapy for advanced disease

Anthracyclines remain the first-line class of systemic therapy in managing most locally advanced and metastatic soft tissue sarcoma.[61]

Other regimens, approved for use as second-line therapy and beyond, include:

• Gemcitabine/docetaxel.[62]
• Ifosfamide.
• Trabectedin (liposarcoma and leiomyosarcoma).[63]
• Eribulin (liposarcoma).[64]
• Pazopanib.[65]
• Dacarbazine.
• Pegylated liposomal (encapsulated) doxorubicin.[66]

Taxanes or taxane combinations are used for patients with angiosarcomas.

The clinical benefit of adding other drugs to the single-agent doxorubicin regimen is controversial.

In randomized studies, the combination of doxorubicin with ifosfamide has not demonstrated superiority over doxorubicin alone in terms of OS, but adding ifosfamide to doxorubicin may be considered in cases where reaching a better response to treatment, despite more toxicity, is the main treatment goal.[52,67]

References:

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29. 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.
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32. Davis AM, O'Sullivan B, Turcotte R, et al.: Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol 75 (1): 48-53, 2005.
33. Pisters PW, Harrison LB, Leung DH, et al.: Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 14 (3): 859-68, 1996.
34. Alektiar KM, Zelefsky MJ, Brennan MF: Morbidity of adjuvant brachytherapy in soft tissue sarcoma of the extremity and superficial trunk. Int J Radiat Oncol Biol Phys 47 (5): 1273-9, 2000.
35. Alektiar KM, Brennan MF, Healey JH, et al.: Impact of intensity-modulated radiation therapy on local control in primary soft-tissue sarcoma of the extremity. J Clin Oncol 26 (20): 3440-4, 2008.
36. Alektiar KM, Brennan MF, Singer S: Local control comparison of adjuvant brachytherapy to intensity-modulated radiotherapy in primary high-grade sarcoma of the extremity. Cancer 117 (14): 3229-34, 2011.
37. Folkert MR, Singer S, Brennan MF, et al.: Comparison of local recurrence with conventional and intensity-modulated radiation therapy for primary soft-tissue sarcomas of the extremity. J Clin Oncol 32 (29): 3236-41, 2014.
38. Nussbaum DP, Rushing CN, Lane WO, et al.: Preoperative or postoperative radiotherapy versus surgery alone for retroperitoneal sarcoma: a case-control, propensity score-matched analysis of a nationwide clinical oncology database. Lancet Oncol 17 (7): 966-975, 2016.
39. Pawlik TM, Pisters PW, Mikula L, et al.: Long-term results of two prospective trials of preoperative external beam radiotherapy for localized intermediate- or high-grade retroperitoneal soft tissue sarcoma. Ann Surg Oncol 13 (4): 508-17, 2006.
40. 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.
41. Sarcoma Meta-analysis Collaboration (SMAC): Adjuvant chemotherapy for localised resectable soft tissue sarcoma in adults. Cochrane Database Syst Rev (4): CD001419, 2000.
42. Brodowicz T, Schwameis E, Widder J, et al.: Intensified Adjuvant IFADIC Chemotherapy for Adult Soft Tissue Sarcoma: A Prospective Randomized Feasibility Trial. Sarcoma 4 (4): 151-60, 2000.
43. 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.
44. Frustaci S, De Paoli A, Bidoli E, et al.: Ifosfamide in the adjuvant therapy of soft tissue sarcomas. Oncology 65 (Suppl 2): 80-4, 2003.
45. Petrioli R, Coratti A, Correale P, et al.: Adjuvant epirubicin with or without Ifosfamide for adult soft-tissue sarcoma. Am J Clin Oncol 25 (5): 468-73, 2002.
46. Gortzak E, Azzarelli A, Buesa J, et al.: A randomised phase II study on neo-adjuvant chemotherapy for 'high-risk' adult soft-tissue sarcoma. Eur J Cancer 37 (9): 1096-103, 2001.
47. Pervaiz N, Colterjohn N, Farrokhyar F, et al.: A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer 113 (3): 573-81, 2008.
48. Woll PJ, Reichardt P, Le Cesne A, et al.: Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial. Lancet Oncol 13 (10): 1045-54, 2012.
49. Bramwell V, Rouesse J, Steward W, et al.: Adjuvant CYVADIC chemotherapy for adult soft tissue sarcoma--reduced local recurrence but no improvement in survival: a study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 12 (6): 1137-49, 1994.
50. Le Cesne A, Van Glabbeke M, Woll PJ, et al.: The end of adjuvant chemotherapy (adCT) era with doxorubicin-based regimen in resected high-grade soft tissue sarcoma (STS): pooled analysis of the two STBSG-EORTC phase III clinical trials. [Abstract] J Clin Oncol 26 (Suppl 15): A-10525, 2008.
51. Le Cesne A, Ouali M, Leahy MG, et al.: Doxorubicin-based adjuvant chemotherapy in soft tissue sarcoma: pooled analysis of two STBSG-EORTC phase III clinical trials. Ann Oncol 25 (12): 2425-32, 2014.
52. 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.
53. DeLaney TF, Spiro IJ, Suit HD, et al.: Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 56 (4): 1117-27, 2003.
54. Kraybill WG, Harris J, Spiro IJ, et al.: Phase II study of neoadjuvant chemotherapy and radiation therapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514. J Clin Oncol 24 (4): 619-25, 2006.
55. Gronchi A, Stacchiotti S, Verderio P, et al.: Short, full-dose adjuvant chemotherapy (CT) in high-risk adult soft tissue sarcomas (STS): long-term follow-up of a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. Ann Oncol 27 (12): 2283-2288, 2016.
56. Gronchi A, Ferrari S, Quagliuolo V, et al.: Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trial. Lancet Oncol 18 (6): 812-822, 2017.
57. Pezzi CM, Pollock RE, Evans HL, et al.: Preoperative chemotherapy for soft-tissue sarcomas of the extremities. Ann Surg 211 (4): 476-81, 1990.
58. Spiro IJ, Rosenberg AE, Springfield D, et al.: Combined surgery and radiation therapy for limb preservation in soft tissue sarcoma of the extremity: the Massachusetts General Hospital experience. Cancer Invest 13 (1): 86-95, 1995.
59. Grobmyer SR, Maki RG, Demetri GD, et al.: Neo-adjuvant chemotherapy for primary high-grade extremity soft tissue sarcoma. Ann Oncol 15 (11): 1667-72, 2004.
60. Wang D, Harris J, Kraybill WG, et al.: Pathologic complete response and survival outcomes in patients with localized soft tissue sarcoma treated with neoadjuvant chemoradiotherapy or radiotherapy: Long-term update of NRG Oncology RTOG 9514 and 0630. [Abstract] J Clin Oncol 35 (Suppl 15): A-11012, 2017. Also available online. Last accessed December 13, 2022.
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66. 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.
67. 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.

Treatment of Stage I Soft Tissue Sarcoma

Treatment Options for Stage I Soft Tissue Sarcoma

Treatment options for stage I soft tissue sarcoma include the following:

1. Surgery.
2. Surgery with radiation therapy.
3. High-dose radiation therapy.

For more information on surgery and radiation therapy, see the Treatment Option Overview for Soft Tissue Sarcoma section.

Because of the low metastatic potential of these tumors, chemotherapy is usually not administered to patients with stage I soft tissue sarcoma.[1,2]

Surgery

Low-grade soft tissue sarcomas have little metastatic potential, but they have a tendency to recur locally. The treatment of choice for patients with early-stage sarcomas (tumors ≤5 cm in diameters) is surgical excision with negative tissue margins (of 1 cm to 2 cm or larger) in all directions.[3,4,5,6,7,8,9,10]

The Mohs surgical technique may be considered as an alternative to wide surgical excision for very rare, small, well-differentiated primary sarcomas of the skin when cosmetic results are important, as margins can be assured with minimal normal tissue removal.[11]

Surgery with radiation therapy

Surgical excision with preoperative radiation therapy (preRT) or postoperative radiation therapy (PORT) may be indicated. Radiation therapy decreases the risk of local recurrence but has not been shown to increase overall survival.[12,13,14]

For tumors of the retroperitoneum, trunk, and head and neck, the following are options:

• Surgical resection with the option of PORT 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 tumor sites.[15]
• PreRT followed by maximal surgical resection. Radiation therapy may be used in sarcomas of the trunk and head and neck to maximize local control when wide surgical margins cannot be obtained.[16]

High-dose radiation therapy

For unresectable tumors, higher doses of radiation therapy with curative intent may be used.[17] Carefully executed high-dose radiation therapy using a shrinking-field technique may be beneficial in the following cases:[18]

• Unresectable tumors.
• Resectable tumors with inadequate margins and a high likelihood of residual disease.
• A wide resection requires an amputation or the removal of a vital organ.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Sarcoma Meta-analysis Collaboration (SMAC): Adjuvant chemotherapy for localised resectable soft tissue sarcoma in adults. Cochrane Database Syst Rev (4): CD001419, 2000.
2. Pervaiz N, Colterjohn N, Farrokhyar F, et al.: A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer 113 (3): 573-81, 2008.
3. Singer S, Antonescu CR: Molecular biology of sarcomas. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1384-99.
4. Singer S, Tap WD, Kirsch DG: Soft tissue sarcoma. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1400-49.
5. O'Donnell RJ, DuBois SG, Haas-Kogan DA: Sarcomas of bone. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1450-74.
6. Al-Refaie WB, Habermann EB, Jensen EH, et al.: Surgery alone is adequate treatment for early stage soft tissue sarcoma of the extremity. Br J Surg 97 (5): 707-13, 2010.
7. 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.
8. Fabrizio PL, Stafford SL, Pritchard DJ: Extremity soft-tissue sarcomas selectively treated with surgery alone. Int J Radiat Oncol Biol Phys 48 (1): 227-32, 2000.
9. Rydholm A, Gustafson P, Rööser B, et al.: Limb-sparing surgery without radiotherapy based on anatomic location of soft tissue sarcoma. J Clin Oncol 9 (10): 1757-65, 1991.
10. Rydholm A: Surgery without radiotherapy in soft tissue sarcoma. Acta Orthop Scand Suppl 273: 117-9, 1997.
11. Fish FS: Soft tissue sarcomas in dermatology. Dermatol Surg 22 (3): 268-73, 1996.
12. 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.
13. O'Sullivan B, Davis AM, Turcotte R, et al.: Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 359 (9325): 2235-41, 2002.
14. Davis AM, O'Sullivan B, Turcotte R, et al.: Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol 75 (1): 48-53, 2005.
15. Singer S, Maki RG, O'Sullivan B: Soft tissue sarcoma. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 1533-77.
16. Baldini EH, Wang D, Haas RL, et al.: Treatment Guidelines for Preoperative Radiation Therapy for Retroperitoneal Sarcoma: Preliminary Consensus of an International Expert Panel. Int J Radiat Oncol Biol Phys 92 (3): 602-12, 2015.
17. Kepka L, DeLaney TF, Suit HD, et al.: Results of radiation therapy for unresected soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 63 (3): 852-9, 2005.
18. 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.

Treatment of Stage II and Node-Negative Stage III Soft Tissue Sarcoma

Treatment Options for Stage II and Node-Negative Stage III Soft Tissue Sarcoma

Treatment options for stage II and node-negative stage III soft tissue sarcoma include the following:

1. Surgery.
2. Surgery with radiation therapy.
3. Radiation therapy and/or chemotherapy followed by surgery.
4. High-dose radiation therapy.

For more information on surgery, radiation therapy, and chemotherapy, see the Treatment Option Overview for Soft Tissue Sarcoma section.

Surgery

Complete surgical resection (removal of the entire gross tumor) is the most important factor in preventing local recurrence and, in many instances, requires resection of adjacent viscera. Surgical excision with negative tissue margins in all directions is generally restricted to low-grade tumors of the extremities (≤5 cm in diameter) or superficial trunk tumors with microscopically negative surgical margins.[1,2,3,4,5]

Complete surgical resection of retroperitoneal sarcomas is often difficult because of their large size at detection and anatomical location.[6,7] Local recurrence is the most common cause of death in these patients.

Surgery with radiation therapy

High-grade localized soft tissue sarcomas have an increased potential for local recurrence and metastasis. 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 radiation therapy (preRT) or postoperative radiation therapy (PORT). Radiation decreases the risk of local recurrence but has not been shown to increase overall survival.[8,9,10,11]

A retrospective review that compared surgery with or without preRT for retroperitoneal sarcomas suggested that the addition of preRT was associated with improved local recurrence-free survival, but not disease-free survival.[12]

Radiation therapy and/or chemotherapy followed by surgery

In some situations, radiation therapy and/or chemotherapy may be used before surgery to convert a marginally resectable tumor to one that can be adequately resected with limb preservation. This treatment may be followed by PORT.

High-dose radiation therapy

For unresectable tumors, high-dose radiation therapy may be used, but poor local control is likely to result.[13]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Al-Refaie WB, Habermann EB, Jensen EH, et al.: Surgery alone is adequate treatment for early stage soft tissue sarcoma of the extremity. Br J Surg 97 (5): 707-13, 2010.
2. 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.
3. Fabrizio PL, Stafford SL, Pritchard DJ: Extremity soft-tissue sarcomas selectively treated with surgery alone. Int J Radiat Oncol Biol Phys 48 (1): 227-32, 2000.
4. Rydholm A, Gustafson P, Rööser B, et al.: Limb-sparing surgery without radiotherapy based on anatomic location of soft tissue sarcoma. J Clin Oncol 9 (10): 1757-65, 1991.
5. Rydholm A: Surgery without radiotherapy in soft tissue sarcoma. Acta Orthop Scand Suppl 273: 117-9, 1997.
6. 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.
7. 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.
8. 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.
9. Rosenberg SA, Tepper J, Glatstein E, et al.: The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 196 (3): 305-15, 1982.
10. O'Sullivan B, Davis AM, Turcotte R, et al.: Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 359 (9325): 2235-41, 2002.
11. Davis AM, O'Sullivan B, Turcotte R, et al.: Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol 75 (1): 48-53, 2005.
12. Kelly KJ, Yoon SS, Kuk D, et al.: Comparison of Perioperative Radiation Therapy and Surgery Versus Surgery Alone in 204 Patients With Primary Retroperitoneal Sarcoma: A Retrospective 2-Institution Study. Ann Surg 262 (1): 156-62, 2015.
13. Kepka L, DeLaney TF, Suit HD, et al.: Results of radiation therapy for unresected soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 63 (3): 852-9, 2005.

Treatment of Advanced Stage III (N1) Soft Tissue Sarcoma

Treatment Options for Advanced Stage III (N1) Soft Tissue Sarcoma

Treatment options for advanced stage III (N1) soft tissue sarcoma include the following:

1. Surgery and lymphadenectomy.
2. Surgery with neoadjuvant or adjuvant therapy.

For more information on surgery, radiation therapy, and chemotherapy, see the Treatment Option Overview for Soft Tissue Sarcoma section.

Surgery and lymphadenectomy

Regional lymph node involvement by soft tissue sarcomas in adults is rare but may occur in some sarcoma types. The sarcoma types that more commonly spread to lymph nodes include the following:[1]

• High-grade rhabdomyosarcoma.
• Vascular sarcomas.
• Synovial sarcoma.
• High-grade fibrosarcoma.
• Clear cell sarcoma.
• Epithelioid sarcomas.

Surgical resection and lymphadenectomy with or without postoperative radiation therapy may be indicated for patients with clinically positive lymph nodes.[1]

Surgery with neoadjuvant or adjuvant therapy

Neoadjuvant chemotherapy with or without radiation therapy or radiation therapy alone may be considered in selected cases where a limb-sparing surgery is advisable and/or there is a high probability of surgical resection with positive margins.[2,3,4,5,6,7]

Adjuvant chemotherapy may be considered but is not known to improve overall survival.[1,8,9,10,11] Clinical trials should be considered when available.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Mazeron JJ, Suit HD: Lymph nodes as sites of metastases from sarcomas of soft tissue. Cancer 60 (8): 1800-8, 1987.
2. 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.
3. Gortzak E, Azzarelli A, Buesa J, et al.: A randomised phase II study on neo-adjuvant chemotherapy for 'high-risk' adult soft-tissue sarcoma. Eur J Cancer 37 (9): 1096-103, 2001.
4. DeLaney TF, Spiro IJ, Suit HD, et al.: Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 56 (4): 1117-27, 2003.
5. Kraybill WG, Harris J, Spiro IJ, et al.: Phase II study of neoadjuvant chemotherapy and radiation therapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514. J Clin Oncol 24 (4): 619-25, 2006.
6. Gronchi A, Stacchiotti S, Verderio P, et al.: Short, full-dose adjuvant chemotherapy (CT) in high-risk adult soft tissue sarcomas (STS): long-term follow-up of a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. Ann Oncol 27 (12): 2283-2288, 2016.
7. Gronchi A, Ferrari S, Quagliuolo V, et al.: Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trial. Lancet Oncol 18 (6): 812-822, 2017.
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. 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.
10. 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.
11. 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.

Treatment of Stage IV Soft Tissue Sarcoma

Treatment Options for Stage IV Soft Tissue Sarcoma

Treatment options for stage IV soft tissue sarcoma include the following:

1. Chemotherapy.
2. Other agents after first-line chemotherapy.
3. Surgery.

For more information on surgery and chemotherapy, see the Treatment Option Overview for Soft Tissue Sarcoma section.

Chemotherapy

Doxorubicin has been the standard systemic therapy in managing metastatic soft tissue sarcoma for several decades.[1,2,3,4,5,6] Other drugs that may have clinical activity as single agents or in combination with doxorubicin are ifosfamide, other anthracyclines (epirubicin, pegylated liposomal doxorubicin), gemcitabine, trabectedin, eribulin, pazopanib, dacarbazine, and taxanes.[4,5,6,7,8,9,10] Despite improved response rates with anthracycline combinations, toxicity is markedly higher without an improvement in overall survival (OS) for patients with soft tissue sarcoma, with the exception of some specific subtypes.[11] Thus, sequential use of single agents is the preferred strategy in most clinical settings.

A variety of other regimens have been used, but none have increased OS when compared with doxorubicin alone.[1,2]

There is some evidence that the addition of ifosfamide increases response rates, but not survival.

Evidence (doxorubicin and ifosfamide vs. doxorubicin alone):

1. A randomized study (NCT00061984) assessed whether dose intensification of doxorubicin and ifosfamide improved the survival of patients with advanced soft tissue sarcoma compared with doxorubicin alone.[11][Level of evidence A1] In this study, 228 patients were randomly assigned to receive doxorubicin, and 227 patients were randomly assigned to receive doxorubicin and ifosfamide. The median follow-up was 56 months (interquartile range [IQR], 31–77 months) in the doxorubicin-only group and 59 months (IQR, 36–72 months) in the combination group.
   1. There was no significant difference in OS between groups: median OS was 12.8 months (95.5% confidence interval [CI], 10.5–14.3) in the doxorubicin-alone group versus 14.3 months (range, 12.5–16.5) in the doxorubicin and ifosfamide group (hazard ratio [HR], 0.83; 95.5% CI, 0.67–1.03; stratified log-rank test P = .076).
   2. Median progression-free survival (PFS) was significantly higher for the doxorubicin and ifosfamide group (7.4 months; 95% CI, 6.6–8.3) than for the doxorubicin-alone group (4.6 months; range, 2.9–5.6 ) (HR, 0.74; 95% CI, 0.60–0.90; stratified log-rank test P = .003).
   3. More patients in the doxorubicin and ifosfamide group had an overall response (60 of 227 patients [26%]) than did patients in the doxorubicin-alone group (31 of 228 patients [14%]) (P < .0006).
   4. The most common grade 3 and 4 toxic effects were all more common with doxorubicin and ifosfamide (n = 224) than with doxorubicin alone (n = 223), as follows:
      • Leukopenia: 97 patients (43%) in the doxorubicin and ifosfamide group versus 40 patients (18%) in the doxorubicin-alone group.
      • Neutropenia: 93 patients (42%) in the doxorubicin and ifosfamide group versus 83 patients (37%) in the doxorubicin-alone group.
      • Febrile neutropenia: 103 patients (46%) in the doxorubicin and ifosfamide group versus 30 patients (13%) in the doxorubicin-alone group.
      • Anemia: 78 patients (35%) in the doxorubicin and ifosfamide group versus 10 patients (5%) in the doxorubicin-alone group.
      • Thrombocytopenia: 75 patients (33%) in the doxorubicin and ifosfamide group versus 1 patient (<1%) in the doxorubicin-alone group.

   Based on these data, treatment intensification with doxorubicin and ifosfamide for palliation of advanced soft tissue sarcoma should not be considered outside of selected clinical settings.

The combination of gemcitabine and docetaxel is used as second-line therapy in treating patients with soft tissue sarcoma. In selected cases, this combination may also be considered as first-line therapy.[5,12] Toxicity is increased with the use of combination chemotherapy. However, no quality-of-life studies have compared the use of single-agent therapy with combination therapy.

Evidence (gemcitabine and docetaxel vs. gemcitabine alone):

1. A randomized phase II study of 122 patients with soft tissue sarcoma reported the following:[5][Level of evidence B3]
   • The objective response rate was 16% in the gemcitabine and docetaxel group versus 8% in the gemcitabine-alone group.
   • Median PFS was 6.2 months in the gemcitabine and docetaxel group versus 3.0 months in the gemcitabine-alone group.
   • Median OS was 17.9 months in the gemcitabine and docetaxel group versus 11.5 months in the gemcitabine-alone group.
2. In a retrospective series of 133 patients, gemcitabine and docetaxel showed activity in patients with leiomyosarcoma as well as other histologies with an overall response rate of 18.4%.[13]

Evidence (gemcitabine and docetaxel vs. doxorubicin alone):

1. The GeDDis trial (ISRCTN07742377) randomly assigned 257 previously untreated patients to receive either gemcitabine and docetaxel or doxorubicin alone.[12]
   • The PFS rate at 24 weeks (46% in both groups) and the primary end point (median PFS, 23.3 weeks vs. 23.7 weeks) were identical in both groups.
   • This study may have been limited by the relatively low dose of gemcitabine used (675 mg/m² on days 1 and 8 instead of 900 mg/m² as in previous trials).

Although doxorubicin alone has traditionally been considered the standard when comparing new drugs or regimens in the context of phase III clinical trials, some sarcoma subtypes have shown higher sensitivity to specific agents. Some sarcoma subtypes are intrinsically resistant to traditional chemotherapy and referral for clinical trials or treatment with kinase inhibitors may be preferred. For examples of sarcoma subtypes with higher sensitivity to specific agents, see Table 9.

Other agents after first-line chemotherapy

After first-line chemotherapy, the following agents are standard options for patients with metastatic disease:

• Gemcitabine combinations (gemcitabine plus docetaxel, gemcitabine plus vinorelbine, gemcitabine plus dacarbazine).
• Trabectedin for leiomyosarcoma and liposarcoma after anthracycline-based chemotherapy.[9]
• Eribulin for liposarcoma after anthracycline-based chemotherapy.[10]
• Pazopanib.[8]
• Ifosfamide or ifosfamide with etoposide.
• Dacarbazine.
• Pegylated liposomal doxorubicin.
• Temozolomide.
• Vinorelbine.
• Regorafenib.

Surgery

If the primary tumor is under control, resection of metastatic lung tumors may be associated with long-term disease-free survival in patients with optimal underlying disease biology, such as a limited number of metastases and slow tumor growth.[20,21,22] It is not clear whether favorable outcomes are attributable to the efficacy of surgery or to patient selection bias.[20,21,22]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Bramwell VH, Anderson D, Charette ML, et al.: Doxorubicin-based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatic soft tissue sarcoma. Cochrane Database Syst Rev (3): CD003293, 2003.
2. Verma S, Younus J, Stys-Norman D, et al.: Meta-analysis of ifosfamide-based combination chemotherapy in advanced soft tissue sarcoma. Cancer Treat Rev 34 (4): 339-47, 2008.
3. Grenader T, Goldberg A, Hadas-Halperin I, et al.: Long-term response to pegylated liposomal doxorubicin in patients with metastatic soft tissue sarcomas. Anticancer Drugs 20 (1): 15-20, 2009.
4. Lorigan P, Verweij J, Papai Z, et al.: Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol 25 (21): 3144-50, 2007.
5. Maki RG, Wathen JK, Patel SR, et al.: Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected]. J Clin Oncol 25 (19): 2755-63, 2007.
6. Okuno S, Ryan LM, Edmonson JH, et al.: Phase II trial of gemcitabine in patients with advanced sarcomas (E1797): a trial of the Eastern Cooperative Oncology Group. Cancer 97 (8): 1969-73, 2003.
7. Nielsen OS, Dombernowsky P, Mouridsen H, et al.: High-dose epirubicin is not an alternative to standard-dose doxorubicin in the treatment of advanced soft tissue sarcomas. A study of the EORTC soft tissue and bone sarcoma group. Br J Cancer 78 (12): 1634-9, 1998.
8. van der Graaf WT, Blay JY, Chawla SP, et al.: Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 379 (9829): 1879-86, 2012.
9. Demetri GD, von Mehren M, Jones RL, et al.: Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial. J Clin Oncol 34 (8): 786-93, 2016.
10. Schöffski P, Chawla S, Maki RG, et al.: Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet 387 (10028): 1629-37, 2016.
11. Judson I, Verweij J, Gelderblom H, et al.: Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol 15 (4): 415-23, 2014.
12. Seddon B, Strauss SJ, Whelan J, et al.: Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial. Lancet Oncol 18 (10): 1397-1410, 2017.
13. Bay JO, Ray-Coquard I, Fayette J, et al.: Docetaxel and gemcitabine combination in 133 advanced soft-tissue sarcomas: a retrospective analysis. Int J Cancer 119 (3): 706-11, 2006.
14. Rutkowski P, Klimczak A, Ługowska I, et al.: Long-term results of treatment of advanced dermatofibrosarcoma protuberans (DFSP) with imatinib mesylate - The impact of fibrosarcomatous transformation. Eur J Surg Oncol 43 (6): 1134-1141, 2017.
15. Stacchiotti S, Pantaleo MA, Negri T, et al.: Efficacy and Biological Activity of Imatinib in Metastatic Dermatofibrosarcoma Protuberans (DFSP). Clin Cancer Res 22 (4): 837-46, 2016.
16. Butrynski JE, D'Adamo DR, Hornick JL, et al.: Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N Engl J Med 363 (18): 1727-33, 2010.
17. Wagner AJ, Malinowska-Kolodziej I, Morgan JA, et al.: Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors. J Clin Oncol 28 (5): 835-40, 2010.
18. Laetsch TW, DuBois SG, Mascarenhas L, et al.: Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol 19 (5): 705-714, 2018.
19. Gounder M, Schöffski P, Jones RL, et al.: Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study. Lancet Oncol 21 (11): 1423-1432, 2020.
20. 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.
21. 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.
22. Putnam JB, Roth JA: Surgical treatment for pulmonary metastases from sarcoma. Hematol Oncol Clin North Am 9 (4): 869-87, 1995.

Treatment of Recurrent Soft Tissue Sarcoma

Treatment of patients with recurrent soft tissue sarcoma depends on the clinical presentation of the disease and previous treatment.

Treatment Options for Recurrent Soft Tissue Sarcoma

Treatment options for recurrent soft tissue sarcoma include the following:

1. Surgery with or without radiation therapy.
2. Chemotherapy and targeted therapy.
3. Immune checkpoint inhibitor therapy.

For more information on surgery, radiation therapy, and chemotherapy, see the Treatment Option Overview for Soft Tissue Sarcoma section.

Surgery with or without radiation therapy

Patients who develop a local recurrence can often be treated with local therapy, such as surgical excision plus radiation therapy (after previous minimal therapy) or amputation (after previous aggressive treatment).[1,2,3,4,5,6,7] Resection of limited pulmonary metastases may be associated with favorable disease-free survival.[8,9,10][Level of evidence C3] However, the contribution of selection factors, such as low tumor burden, slow tumor growth, and long disease-free interval, to these favorable outcomes is not known.

Chemotherapy and targeted therapy

Single-agent chemotherapy may be used with other single agents for disease recurrence.[11,12,13,14,15,16] Agents such as ifosfamide or gemcitabine may be used sequentially at the time of recurrence or progression.[13,14,15,17][Level of evidence C3] However, none of these agents has been shown to increase overall survival (OS) in this setting; therefore, clinical trials are an appropriate option.

Since 2012, the U.S. Food and Drug Administration (FDA) has approved three drugs for the treatment of soft tissue sarcomas after failure of a first-line chemotherapy regimen:

• Eribulin for liposarcoma.[18]
• Trabectedin for leiomyosarcoma and liposarcoma.[19]
• Pazopanib for all soft tissue sarcomas except adipocytic subtypes.[20]

Eribulin

Eribulin is a microtubule inhibitor that the FDA approved in 2016 to treat patients with unresectable or metastatic liposarcoma, who previously received anthracycline-containing chemotherapy.

Evidence (eribulin):

1. The approval of eribulin was based on a phase III, multicenter, randomized study (NCT01327885) of 452 patients with advanced leiomyosarcoma or adipocytic sarcoma who received eribulin (1.4 mg/m² intravenously [IV] on days 1 and 8 every 3 weeks) versus dacarbazine (850–1,200 mg/m² IV on day 1 every 3 weeks).[18]
   • Although the median OS was 13.5 months for patients who received eribulin versus 11.5 months for patients who received dacarbazine (hazard ratio [HR]_death, 0.77; 95% confidence interval [CI], 0.62–0.95), a preplanned subset analysis revealed a median survival of 15.6 months for eribulin versus 8.4 months for dacarbazine in patients with liposarcoma.
   • Median progression-free survival (PFS) was the same in both groups (2.6 months).

Trabectedin

Trabectedin is an FDA-approved option for second-line treatment of patients with advanced liposarcoma and leiomyosarcoma.

Evidence (trabectedin):

1. The approval of trabectedin was based on a phase III randomized study (NCT01343277) of 518 patients who received trabectedin (1.5 mg/m² over 24 hours on day 1 every 21 days) or dacarbazine (1,000 mg/m² on day 1 every 21 days).[19]
   • Treatment with trabectedin significantly improved median PFS (4.2 months for patients who received trabectedin vs. 1.5 months for patients who received dacarbazine).
   • OS, the primary end point, was not statistically different (12.4 months for patients who received trabectedin vs. 12.9 months for patients who received dacarbazine).
   • Response rates were low in both arms (10% for patients who received trabectedin vs. 7% for patients who received dacarbazine), but clinical benefit (that included both response rates and stable disease) was higher for the trabectedin group (34%) than for the dacarbazine group (19%).
   • The most common grade 3 and 4 adverse events in the trabectedin group were myelosuppression and transient elevation of liver function test results.

Phase II studies have shown a particularly high response rate to trabectedin in patients with myxoid/round cell liposarcoma, with overall response rates up to 51%, and a 6-month PFS rate of 88%.[21]

Pazopanib

Pazopanib is a multitargeted, oral, small molecule inhibitor of several tyrosine kinases, including vascular endothelial growth factor receptor-1, -2, and -3; platelet-derived growth factor receptor alpha and beta; and fibroblast growth factor receptor-1, and -3.

Evidence (pazopanib):

1. The phase III, randomized, double-blind PALETTE study (NCT00753688) from the European Organisation for Research and Treatment of Cancer compared pazopanib (800 mg daily) with placebo in 369 patients with different soft tissue sarcoma subtypes, excluding adipocytic sarcomas and gastrointestinal stromal tumors. Patients were enrolled after disease progression on a first-line anthracycline-based regimen.[20]
   • The median PFS was 4.6 months for patients who received pazopanib versus 1.6 months for patients who received placebo.
   • The OS difference was not statistically significant. OS was 12.5 months for patients who received pazopanib versus 10.7 months for patients who received placebo (HR, 0.86; 95% CI, 0.67–1.1).
   • Overall response rate was 6% for patients who received pazopanib versus 0% for patients who received placebo.
   • The stability of disease rate was 67% for patients who received pazopanib versus 38% for patients who received placebo.
   • The most common grade 3 or 4 toxicities in the pazopanib arm were fatigue, hypertension, diarrhea, anorexia, and transient elevation of liver function test results.

On the basis of the above data, pazopanib was approved by the FDA in 2012 for the treatment of patients with soft tissue sarcomas (except the adipocytic subtypes) who have received previous chemotherapy.

Immune checkpoint inhibitor therapy

Two trials have explored the immune checkpoint inhibitors pembrolizumab, nivolumab, and ipilimumab. Although some activity has been shown in selected soft tissue sarcoma subtypes, the factors that may predict activity to treatment with immune checkpoint inhibitors remain unknown, and their use cannot be routinely recommended.

Evidence (immune checkpoint inhibitors):

1. The phase II Sarcoma Alliance for Research through Collaboration trial (SARC028 [NCT02301039]) studied treatment with pembrolizumab alone in patients with four soft tissue sarcoma subtypes: undifferentiated pleomorphic sarcoma, synovial sarcoma, leiomyosarcoma, and poorly differentiated or dedifferentiated liposarcoma.[22] Eighty patients were evaluable for response, with half of the patients in the soft tissue sarcoma group and half in the bone sarcoma cohort.

   Responses were noted in the following subtypes:

   • Four of 10 patients with undifferentiated pleomorphic sarcoma.
   • Two of 10 patients with poorly differentiated or dedifferentiated liposarcoma.
   • One of 10 patients with synovial sarcoma.
   • Zero of 10 patients with leiomyosarcoma.
   • The overall response rate was 18%.
2. The phase II Alliance A091401 study (NCT02500797) randomly assigned patients to receive nivolumab (n = 43) versus nivolumab and ipilimumab (n = 42) for the treatment of different soft tissue sarcomas.[23]
   • Two patients in the nivolumab group had an objective response (5%; one patient with alveolar soft-part sarcoma and one patient with leiomyosarcoma). Six patients in the combination group had an objective response (16%; two patients with leiomyosarcoma, one patient with myxofibrosarcoma, two patients with undifferentiated pleomorphic sarcoma, and one patient with angiosarcoma).

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Singer S, Antonescu CR: Molecular biology of sarcomas. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1384-99.
2. Singer S, Tap WD, Kirsch DG: Soft tissue sarcoma. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1400-49.
3. O'Donnell RJ, DuBois SG, Haas-Kogan DA: Sarcomas of bone. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1450-74.
4. Midis GP, Pollock RE, Chen NP, et al.: Locally recurrent soft tissue sarcoma of the extremities. Surgery 123 (6): 666-71, 1998.
5. Essner R, Selch M, Eilber FR: Reirradiation for extremity soft tissue sarcomas. Local control and complications. Cancer 67 (11): 2813-7, 1991.
6. 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.
7. 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.
8. 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.
9. 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.
10. Putnam JB, Roth JA: Surgical treatment for pulmonary metastases from sarcoma. Hematol Oncol Clin North Am 9 (4): 869-87, 1995.
11. Bramwell VH, Anderson D, Charette ML, et al.: Doxorubicin-based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatic soft tissue sarcoma. Cochrane Database Syst Rev (3): CD003293, 2003.
12. Grenader T, Goldberg A, Hadas-Halperin I, et al.: Long-term response to pegylated liposomal doxorubicin in patients with metastatic soft tissue sarcomas. Anticancer Drugs 20 (1): 15-20, 2009.
13. Lorigan P, Verweij J, Papai Z, et al.: Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol 25 (21): 3144-50, 2007.
14. Maki RG, Wathen JK, Patel SR, et al.: Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected]. J Clin Oncol 25 (19): 2755-63, 2007.
15. Okuno S, Ryan LM, Edmonson JH, et al.: Phase II trial of gemcitabine in patients with advanced sarcomas (E1797): a trial of the Eastern Cooperative Oncology Group. Cancer 97 (8): 1969-73, 2003.
16. Verma S, Younus J, Stys-Norman D, et al.: Meta-analysis of ifosfamide-based combination chemotherapy in advanced soft tissue sarcoma. Cancer Treat Rev 34 (4): 339-47, 2008.
17. Nielsen OS, Dombernowsky P, Mouridsen H, et al.: High-dose epirubicin is not an alternative to standard-dose doxorubicin in the treatment of advanced soft tissue sarcomas. A study of the EORTC soft tissue and bone sarcoma group. Br J Cancer 78 (12): 1634-9, 1998.
18. Schöffski P, Chawla S, Maki RG, et al.: Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet 387 (10028): 1629-37, 2016.
19. Demetri GD, von Mehren M, Jones RL, et al.: Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial. J Clin Oncol 34 (8): 786-93, 2016.
20. van der Graaf WT, Blay JY, Chawla SP, et al.: Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 379 (9829): 1879-86, 2012.
21. Grosso F, Jones RL, Demetri GD, et al.: Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study. Lancet Oncol 8 (7): 595-602, 2007.
22. Tawbi HA, Burgess M, Bolejack V, et al.: Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol 18 (11): 1493-1501, 2017.
23. D'Angelo SP, Mahoney MR, Van Tine BA, et al.: Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. Lancet Oncol 19 (3): 416-426, 2018.

Changes to This Summary (03 / 03 / 2023)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information About Soft Tissue Sarcoma

Updated statistics with estimated new cases and deaths for 2023 (cited American Cancer Society as reference 1).

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of soft tissue sarcoma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Soft Tissue Sarcoma Treatment are:

• Russell S. Berman, MD (New York University School of Medicine)
• Minh Tam Truong, MD (Boston University Medical Center)
• Vinayak Venkataraman, MD

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this 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.

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The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Soft Tissue Sarcoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/soft-tissue-sarcoma/hp/adult-soft-tissue-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389481]

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Last Revised: 2023-03-03