Estimated new cases and deaths from soft tissue sarcoma in the United States in 2024:[1]
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 and deaths from 2016 through 2020.[3]
Most soft tissue sarcomas are sporadic. Risk factors include the following:[4-6]
Soft tissue sarcomas occur more frequently in patients with the following inherited syndromes:[4-6]
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]
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:
Factors for a poor prognosis in adults with soft tissue sarcomas include the following:[4-15]
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.[11-14]
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):
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]
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).[2-4]
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:[1-5]
Some staging evaluation procedures depend on the tumor histology and site, including the following:
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]
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:[1-5]
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.[2-5]
Recurrent sarcomas are restaged using the same system that is used for primary tumors, with the notation that the tumor is recurrent.
| T Category | Soft Tissue Sarcoma of the Trunk, Extremities, and Retroperitoneum | Soft Tissue Sarcoma of the Head and Neck | Soft Tissue Sarcoma of the Abdomen and Thoracic Visceral Organs |
|---|---|---|---|
| aAdapted from O'Sullivan et al.,[2] Yoon et al.,[3] Raut et al.,[4] and Pollock et al.[5] | |||
| TX | Primary tumor cannot be assessed. | Primary tumor cannot be assessed. | Primary tumor cannot be assessed. |
| T0 | No evidence of primary tumor. | ||
| T1 | Tumor ≤5 cm in greatest dimension. | Tumor ≤2 cm. | Organ confined. |
| T2 | Tumor >5 cm and ≤10 cm in greatest dimension. | Tumor >2 to ≤4 cm. | Tumor extension into tissue beyond organ. |
| –T2a | Invades serosa or visceral peritoneum. | ||
| –T2b | Extension beyond serosa (mesentery). | ||
| T3 | Tumor >10 cm and ≤15 cm in greatest dimension. | Tumor >4 cm. | Invades another organ. |
| T4 | Tumor >15 cm in greatest dimension. | Tumor with invasion of adjoining structures. | Multifocal involvement. |
| –T4a | Tumor with orbital invasion, skull base/dural invasion, invasion of central compartment viscera, involvement of facial skeleton, or invasion of pterygoid muscles. | Multifocal (2 sites). | |
| –T4b | Tumor with brain parenchymal invasion, carotid artery encasement, prevertebral muscle invasion, or central nervous system involvement via perineural spread. | Multifocal (3–5 sites). | |
| –T4c | Multifocal (>5 sites). | ||
| N Category | Soft Tissue Sarcoma of the Trunk, Extremities, and Retroperitoneum | Soft Tissue Sarcoma of the Head and Neck | Soft Tissue Sarcoma of the Abdomen and Thoracic Visceral Organs |
|---|---|---|---|
| aAdapted from O'Sullivan et al.,[2] Yoon et al.,[3] Raut et al.,[4] and Pollock et al.[5] | |||
| N0 | No regional lymph node metastasis or unknown lymph node status. | No regional lymph node metastasis or unknown lymph node status. | No lymph node involvement or unknown lymph node status. |
| N1 | Regional lymph node metastasis. | Regional lymph node metastasis. | Lymph node involvement present. |
| M Category | Soft Tissue Sarcoma of the Trunk, Extremities, and Retroperitoneum | Soft Tissue Sarcoma of the Head and Neck | Soft Tissue Sarcoma of the Abdomen and Thoracic Visceral Organs |
|---|---|---|---|
| aAdapted from O'Sullivan et al.,[2] Yoon et al.,[3] Raut et al.,[4] and Pollock et al.[5] | |||
| M0 | No distant metastasis. | No distant metastasis. | No metastasis. |
| M1 | Distant metastasis. | Distant metastasis. | Metastasis present. |
The histological grade of the sarcoma is an important factor in staging all soft tissue sarcomas. It is determined by the following three parameters:
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).
| Histology Type | Score |
|---|---|
| aReprinted with permission from AJCC: Introduction to Soft Tissue Sarcoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 489–496. | |
| Atypical lipomatous tumor/well-differentiated liposarcoma | 1 |
| Myxoid liposarcoma | 2 |
| Round cell liposarcoma | 3 |
| Pleomorphic liposarcoma | 3 |
| Dedifferentiated liposarcoma | 3 |
| Fibrosarcoma | 2 |
| Myxofibrosarcoma | 2 |
| Undifferentiated pleomorphic sarcoma (formerly termed malignant fibrous histiocytoma, pleomorphic type) | 3 |
| Well-differentiated leiomyosarcoma | 1 |
| Conventional leiomyosarcoma | 2 |
| Poorly differentiated/pleomorphic/epithelioid leiomyosarcoma | 3 |
| Biphasic/monophasic synovial sarcoma | 3 |
| Poorly differentiated synovial sarcoma | 3 |
| Pleomorphic rhabdomyosarcoma | 3 |
| Mesenchymal chondrosarcoma | 3 |
| Extraskeletal osteosarcoma | 3 |
| Ewing sarcoma/primitive neuroectodermal tumor (PNET) | 3 |
| Malignant rhabdoid tumor | 3 |
| Undifferentiated sarcoma, not otherwise specified | 3 |
| Determinants and Scores | Description |
|---|---|
| FNCLCC = Fédération Nationale des Centres de Lutte Contre Le Cancer; HPF = high-power field. | |
| aAdapted from Pollock et al.[11] | |
| Tumor Differentiation | |
| Score 1 | Sarcoma closely resembling normal adult mesenchymal tissue (e.g., low-grade liposarcoma) |
| Score 2 | Sarcomas for which histological typing is certain (e.g., myxoid/round cell liposarcoma) |
| Score 3 | Embryonal and undifferentiated sarcomas, sarcomas of doubtful type, synovial sarcomas, soft tissue osteosarcoma, Ewing sarcoma/primitive neuroectodermal tumor (PNET) of soft tissue |
| Mitotic Count | |
| Score 1 | 0–9 mitoses per 10 HPF |
| Score 2 | 10–19 mitoses per 10 HPF |
| Score 3 | ≥20 mitoses per 10 HPF |
| Tumor Necrosis | |
| Score 0 | No necrosis |
| Score 1 | <50% tumor necrosis |
| Score 2 | ≥50% tumor necrosis |
| G | G Definition |
|---|---|
| FNCLCC = Fédération Nationale des Centres de Lutte Contre Le Cancer. | |
| aReprinted with permission from AJCC: Soft tissue sarcoma of the head and neck. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 499–505. | |
| GX | Grade cannot be assessed. |
| G1 | Total tumor differentiation, mitotic count, and necrosis score of 2 or 3. |
| G2 | Total tumor differentiation, mitotic count, and necrosis score of 4 or 5. |
| G3 | Total tumor differentiation, mitotic count, and necrosis score of 6, 7, or 8. |
There is no recommended prognostic stage grouping for soft tissue sarcoma of the abdomen, thoracic visceral organs, and head and neck.
| Stage | Tumor | Node | Metastasis | Grade |
|---|---|---|---|---|
| T = primary tumor; N = regional lymph node; M = distant metastasis; G = grade. | ||||
| aAdapted from Yoon et al.[3] and Pollock et al.[5] | ||||
| bStage IIIB for soft tissue sarcoma of the retroperitoneum; stage IV for soft tissue sarcoma of the trunk and extremities. | ||||
| IA | T1 | N0 | M0 | GX, G1 |
| IB | T2, T3, T4 | N0 | M0 | GX, G1 |
| II | T1 | N0 | M0 | G2, G3 |
| IIIA | T2 | N0 | M0 | G2, G3 |
| IIIB | T3, T4 | N0 | M0 | G2, G3 |
| IIIBb/IVb | Any T | N1 | M0 | Any G |
| IV | Any T | Any N | M1 | Any G |
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.
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):
| Stage (TNMG Staging Criteria) | Treatment Options | |
|---|---|---|
| T = primary tumor; N = regional lymph node; M = distant metastasis; G = grade. | ||
| Stage I soft tissue sarcoma | Surgery | |
| Surgery with radiation therapy | ||
| High-dose radiation therapy | ||
| Stage II and node-negative stage III soft tissue sarcoma | Surgery | |
| Surgery with radiation therapy | ||
| Radiation therapy and/or chemotherapy followed by surgery | ||
| High-dose radiation therapy | ||
| Advanced stage III (N1) soft tissue sarcoma | Surgery and lymphadenectomy | |
| Surgery with neoadjuvant or adjuvant therapy | ||
| Stage IV soft tissue sarcoma | Chemotherapy | |
| Histology-specific targeted or immunotherapy treatment | ||
| Surgery | ||
| Recurrent soft tissue sarcoma | Surgery with or without radiation therapy | |
| Chemotherapy and targeted therapy | ||
| Immune checkpoint inhibitor therapy (under clinical evaluation) | ||
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 [3-5] 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]
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):
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]
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.[13-16]
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):
An extended surgical approach has to be weighed against an increase in morbidity (resulting from surgical complications) and mortality.[20-23]
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.[24-26] 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.
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]
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]
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):
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.[30-32]
Evidence (preRT vs. PORT):
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):
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]
Retrospective data support the use of preRT or PORT versus surgery alone to treat retroperitoneal sarcomas.
Evidence (preRT or PORT vs. surgery alone):
The 2,196 patients who received PORT were compared with 2,196 matched controls.
The 563 patients who received preRT were compared with 1,126 matched controls.[38]
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):
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):
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.
In summary, the impact of adjuvant chemotherapy on survival is still controversial but is likely to be small in absolute magnitude.
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%.[46,52-56]
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.[57-59]
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):
The following results were reported:
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:
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]
Treatment options for stage I soft tissue sarcoma include the following:
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]
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.[3-10]
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]
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.[12-14]
For tumors of the retroperitoneum, trunk, and head and neck, the following are options:
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]
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.
Treatment options for stage II and node-negative stage III soft tissue sarcoma include the following:
For more information on surgery, radiation therapy, and chemotherapy, see the Treatment Option Overview for Soft Tissue Sarcoma section.
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.[1-5]
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.
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.[8-11]
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]
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.
For unresectable tumors, high-dose radiation therapy may be used, but poor local control is likely to result.[13]
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.
Treatment options for advanced stage III (N1) soft tissue sarcoma include the following:
For more information on surgery, radiation therapy, and chemotherapy, see the Treatment Option Overview for Soft Tissue Sarcoma section.
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]
Surgical resection and lymphadenectomy with or without postoperative radiation therapy may be indicated for patients with clinically positive lymph nodes.[1]
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.[2-7]
Adjuvant chemotherapy may be considered but is not known to improve overall survival.[1,8-11] Clinical trials should be considered when available.
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.
Treatment options for stage IV soft tissue sarcoma include the following:
For more information on surgery and chemotherapy, see the Treatment Option Overview for Soft Tissue Sarcoma section.
Doxorubicin has been the standard systemic therapy in managing metastatic soft tissue sarcoma for several decades.[1-6] 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.[4-10] 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 (with mesna) to doxorubicin increases response rates and progression-free survival (PFS), but it has not been shown to improve OS.[11] There is some evidence that the addition of trabectedin to doxorubicin improves PFS in patients with metastatic or unresectable leiomyosarcoma.[12]
Evidence (doxorubicin and ifosfamide vs. doxorubicin alone):
Evidence (doxorubicin and trabectedin vs. doxorubicin alone in leiomyosarcoma):
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.[5,14] 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):
Evidence (gemcitabine and docetaxel vs. doxorubicin alone):
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. Table 9 provides examples of specific agents that can be used as frontline treatment for specific subtypes.
| Sarcoma Subtype | Specific Agent |
|---|---|
| ALK = anaplastic lymphoma kinase; mTOR = mammalian target of rapamycin; PEComa = perivascular epithelioid cell tumor; TKI = tyrosine kinase inhibitor. | |
| Alveolar soft-part sarcoma | TKIs, including sunitinib [16] and pazopanib [17] |
| Immunotherapy, including atezolizumab [18] and pembrolizumab [19] | |
| Angiosarcoma | Taxanes [20] |
| Dermatofibrosarcoma protuberans | Imatinib [21,22] |
| Inflammatory myofibroblastic tumor | ALK inhibitors [23] |
| PEComa | mTOR inhibitors [24], including nab-sirolimus [25] |
| NTRK-fusion-associated sarcomas | Larotrectinib [26] |
| Epithelioid sarcoma | Tazemetostat [27] |
| Desmoid tumors | Gamma secretase inhibitors, including nirogacestat [28] |
| TKIs, including sorafenib [29] | |
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.[30-32] It is not clear whether favorable outcomes are attributable to the efficacy of surgery or to patient selection bias.[30-32]
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.
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 include the following:
For more information on surgery, radiation therapy, and chemotherapy, see the Treatment Option Overview for Soft Tissue Sarcoma section.
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).[1-7] Resection of limited pulmonary metastases may be associated with favorable disease-free survival.[8-10][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.
Single-agent chemotherapy may be used with other single agents for disease recurrence.[11-16] Agents such as ifosfamide or gemcitabine may be used sequentially at the time of recurrence or progression.[13-15,17][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.
The U.S. Food and Drug Administration (FDA) has approved eribulin, trabectedin, and pazopanib for the treatment of soft tissue sarcomas after failure of a first-line chemotherapy regimen.
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):
Trabectedin is an FDA-approved option for second-line treatment of patients with advanced liposarcoma and leiomyosarcoma.
Evidence (trabectedin):
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%.[20]
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):
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.
After first-line chemotherapy, other agents can be considered, including the following:
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):
Responses were noted in the following subtypes:
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.
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.
Treatment of Stage IV Soft Tissue Sarcoma
Revised text to state that there is evidence that the addition of ifosfamide (with mesna) to doxorubicin increases response rates and progression-free survival (PFS), but it has not been shown to improve overall survival. There is some evidence that the addition of trabectedin to doxorubicin improves PFS in patients with metastatic or unresectable leiomyosarcoma (cited 2022 Pautier et al. as reference 12).
Added text about the results of a randomized, open-label, phase III trial that evaluated the combination of trabectedin and doxorubicin compared with doxorubicin alone for the treatment of metastatic and unresectable leiomyosarcoma. Also added text about the final analysis of the trial that was presented at the European Society of Medical Oncology Congress in 2023 (cited 2023 Pautier et al. as reference 13).
Added Histology-specific targeted or immunotherapy treatment as a new subsection.
Treatment of Recurrent Soft Tissue Sarcoma
Added text to state that after first-line chemotherapy, other agents can be considered, including ifosfamide with or without etoposide, dacarbazine, temozolomide, vinorelbine, and regorafenib.
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.
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.
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:
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:
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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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