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Incidence and Mortality
Estimated new cases and deaths from soft tissue sarcoma in the United States in 2019:
Soft tissue sarcomas are malignant tumors that arise in any of the mesodermal tissues of the extremities (50%), trunk and retroperitoneum (40%), or head and neck (10%). The reported international incidence rates range from 1.8 to 5 cases per 100,000 individuals per year.
Risk Factors and Genetic Factors
The risk of sporadic soft tissue sarcomas is increased by previous radiation therapy and, in the case of lymphangiosarcoma, by chronic lymphedema. The chemicals Thorotrast (thorium dioxide), vinyl chloride, and arsenic are established carcinogens for hepatic angiosarcomas.[3,4,5] The HIV and human herpes 8 have been implicated in the pathogenesis of Kaposi sarcoma.
Soft tissue sarcomas occur with greater frequency in patients with the following inherited syndromes:[3,4,5]
Soft tissue sarcomas may be heterogeneous, with more than 100 different entities described in the World Health Organization 2013 classification. Adequate tissue should be obtained via either core-needle or incisional biopsy for microscopic examination, with a careful review by a pathologist who is experienced in diagnosing sarcomas. Careful planning of the initial biopsy is important to avoid compromising subsequent curative resection. Complete staging and treatment planning by a multidisciplinary team of cancer specialists is required to determine the optimal treatment for patients with this disease.
There is evidence that at least some favorable clinical outcomes may be associated with referral to a specialized sarcoma treatment center. In a population-based consecutive series of 375 soft tissue sarcoma patients in Sweden, local recurrence rates of resected tumors were higher in patients who were not referred to the specialized center: in 35 of 78 (45%) patients not referred; in 24 of 102 (24%) patients referred after initial surgery or incisional biopsy; and in 36 of 195 (18%) patients referred before any surgical procedure (P = .0001 for the difference between those never referred vs. those referred before any surgical procedure).[Level of evidence: 3iDii] However, there were no statistically significant differences in death from sarcoma between the groups of patients.
In a British study of 260 patients with soft tissue sarcoma diagnosed within a 3-year period, 37% of the patients had most of their treatment at a specialist center, and the remaining 63% of the patients were treated at 38 different hospitals. The rate of local recurrence was 39% for patients treated at the district general hospitals compared with 19% for patients treated at the specialist center, even though the tumors in patients treated at the district hospitals 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 specialist center had a small survival advantage after multivariate analysis.
The prognosis for patients with adult soft tissue sarcomas depends on several factors including:[3,4,5,9,10,11,12,13]
Factors associated with a poorer prognosis include the following:
Although patients with low-grade tumors are frequently curable by surgery alone, higher-grade sarcomas are associated with higher local-treatment failure rates and increased metastatic potential.
Prognostic nomograms incorporating specific variables have been developed for soft tissue sarcomas of the retroperitoneum and the extremities.
Surveillance for Relapse
A retrospective review included 174 consecutive patients with a soft tissue sarcoma of the limb who underwent follow-up by oncologists at a single center from 2003 to 2009. The rate and site of recurrence and mode of detection were analyzed. Eighty-two patients (47%) experienced relapse. 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; magnetic resonance imaging identified only one local recurrence. Twenty-eight patients developed isolated lung metastases; in 9 patients, the lung metastases were amenable to resections, 7 of whom were free of disease after treatment. Lung metastases were detected by chest x-ray in 19 patients, by computed tomography (CT) scanning in 3 patients, and clinically in 11 patients. Twenty-three patients developed nonpulmonary metastases. More than 80% of the relapses occurred in the first 2 years of follow-up; however, later recurrences were also observed.[Level of evidence: 3iiDi] This study supports imaging surveillance for detection of lung metastases, whereas local recurrences at the primary site were usually detected by clinical examination. The impact of picking up metastases on overall survival or quality-of-life data is unknown.
Positron emission tomography and CT imaging may have higher sensitivity than contrast-enhanced CT imaging in the setting of clinical suspicion of recurrent sarcoma. Late recurrences (more than 5 years from diagnosis) are seen with some histologies, such as synovial sarcoma or alveolar soft part sarcoma.
Other PDQ summaries containing information about soft tissue sarcoma include:
Soft tissue sarcomas are classified histologically according to the presumed tissue of origin. Electron microscopy, specialized immunohistochemistry, flow cytometry, cytogenetics, and tissue culture studies may allow identification of particular subtypes within the major histologic categories. For example, S100 antigen suggests neural sheath origin, cytokeratin suggests epithelioid or synovial cell origin, and factor VIII–related antigen suggests endothelial origin. Likewise, some subtypes of sarcomas have characteristic genetic markers—chromosomal translocation translated into fusion proteins—but these markers are not generally used in the routine clinical setting (e.g., translocation t(X;18)(p11;q11) in synovial sarcomas and translocation t(12;16)(q13;p11) in myxoid liposarcomas).[1,2,3]
The histologic grade reflects the metastatic potential of these tumors more accurately than the classic cellular classification listed below. Disagreement among expert pathologists regarding tumor grade, and even histologic subtype, can be substantial.
The World Health Organization lists the following cell types in its classification of soft tissue sarcomas:[5,6]
Staging has an important role in determining the most effective treatment for soft tissue sarcoma. Clinical staging involves magnetic resonance imaging (MRI) and/or computed tomography (CT) of the primary tumor area and a chest CT scan to look for metastasis to the lung (the most common site of distant spread). A CT scan of the abdomen and pelvis should be considered in case of round cell and myxoid liposarcomas because there is a tendency for extrapulmonary spread. Brain imaging should also be a consideration for subtypes that have a higher propensity for central nervous system involvement such as angiosarcoma or alveolar soft part sarcoma.
Fluorodeoxyglucose (FDG)-positron emission tomography (PET) (FDG-PET) may be useful to predict outcomes of patients with high-grade extremity soft tissue sarcomas who were initially treated with chemotherapy.
Intracompartmental or extracompartmental extension of extremity sarcomas is also 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. A CT scan of the chest is recommended for sarcomas larger than 5 cm or with moderate to poor differentiation. Nodal involvement is rare, occurring in fewer than 3% of patients with sarcoma, but it varies depending on the specific subtypes, such as rhabdomyosarcoma, vascular sarcomas, synovial sarcomas, clear cell sarcomas, and epithelioid sarcomas.[2,3] Stage is based on the resected tumor or pretreatment biopsy and considered together with the appropriate imaging.[4,5,6,7,8] Grade, which is based on tumor differentiation, mitotic count, tumor necrosis, and histology, should be recorded for all soft tissue sarcomas. (See Table 5 below.) The 2017 AJCC/Union for International Cancer Control (UICC) cancer staging classification system recommends the use of the three-tiered French Federation of Cancer Centers Sarcoma Group (FNCLCC) grading schema.
The American Joint Committee on Cancer (AJCC) staging system has designated stage by the criteria of tumor size, nodal status, metastasis, histologic grade (TNMG), and whether there is spread to lymph nodes or distant sites.[4,5,6,7,8] The eighth edition of the AJCC Cancer Staging Manual indicates that the TNMG staging classification has different T staging criteria and prognostic groups depending on the location of the sarcoma. The characteristic molecular markers of some sarcomas are not formally incorporated in the staging system pending further evaluation of their impact on prognosis. Recurrent sarcomas are restaged using the same system as for primary tumors with the specification that the tumor is recurrent.
TNM Staging System
The eighth edition of the AJCC Cancer Staging Manual has designated staging by the following criteria: tumor size, nodal status, histologic grade, metastasis, and anatomic primary tumor site (head and neck; trunk and extremities; abdomen and thoracic visceral organs; retroperitoneum; and unusual histologies and sites).[4,5,6,7,8] For information on unusual histologies and sites, refer to the AJCC Cancer Staging Manual.
Soft tissue sarcoma of the head and neck is a new classification that needs data collected before a stage grouping for head and neck sarcomas is defined. Prognostic factors required for stage grouping are from FNCLCC and the definition of grade is in Table 5 below.
AJCC Stage Groupings, TNM Definitions, and FNCLCC Histologic Grades
For soft tissue sarcoma of the abdomen and thoracic visceral organs, there is no recommended prognostic stage grouping at this time.
For soft tissue sarcomas with unusual histologies and sites, the FNCLCC grading system is used at this time.
In most cases, a combined modality approach of preoperative radiation therapy (preRT) or postoperative radiation therapy (PORT) is used, rather than the radical surgical procedures, such as amputation, that were used in the past. It may even be possible to use surgery without PORT in selected cases. The role of chemotherapy is not as well defined as is the role of radiation therapy. Because of the evolving nature of the treatment options for this disease, patients should be considered for clinical trials when available. Information about ongoing clinical trials is available from the NCI website.
Role of Surgery
Surgical resection is the mainstay of therapy for soft tissue sarcomas. 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. Cutting into the tumor mass or shelling out the gross tumor along the plane of the pseudocapsule of compressed tumor cells and reactive tissue that often surrounds soft tissue sarcomas are 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. (Refer to the Role of Radiation Therapy section of this summary for more information.)
Only one small, single-institution, randomized trial has directly compared amputation with limb-sparing surgery for soft tissue sarcomas of the extremities. In a 2:1 randomization ratio, 27 patients with high-grade extremity sarcomas were assigned to wide excision plus PORT (45 Gy–50 Gy to the wide local excision area, and a total of 60 Gy–70 Gy to the tumor bed over 6–7 weeks), and 16 were assigned to amputation (at or above the joint proximal to the tumor). Both groups received adjuvant chemotherapy (i.e., doxorubicin, cyclophosphamide, and high-dose methotrexate). At 63 months, with a median follow-up of 56 months, there were four local recurrences in the 27 patients who underwent limb-sparing surgery and no recurrences in the 16 patients who underwent amputation (P = .12). Overall survival (OS) rates were not statistically significantly different (actuarial 5-year survival rate, 83% vs. 88%, P2 = .99).[Level of evidence: 1iiA]
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. It may be possible to use surgery without PORT in selected cases. For example, 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 histologic involvement of the surgical margins. They were observed without radiation therapy, and the estimated local recurrence rate after 10 years was 11%.[Level of evidence: 3iiiDiv] The role of chemotherapy is not as well defined as is the role of radiation therapy. Because of the evolving nature of the treatment options for this disease, patients should be offered the option of clinical trials when available.
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.[5,6,7,8] 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 only 9% of patients with extremity or trunk sarcomas.
An additional consideration is the extent of surgery in retroperitoneal sarcomas. In a series of 382 patients with retroperitoneal sarcoma, extended surgical resection showed a 3.3-fold lower rate of local recurrence compared with simple complete resection in the multivariate analysis; however, it was not associated with improved survival. In a follow-up analysis, a 66% OS rate was observed in the extended surgical resection cohort compared with a 48% OS rate in historic controls. An extended surgical approach has to be weighed against an increase in morbidity resulting from surgical complications and mortality.[11,12,13,14,15]
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 (i.e., patients with a limited number of metastases and slow nodule growth) who have undergone or are undergoing complete resection of the primary tumor.[16,17,18] 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.
Role of Radiation Therapy
Radiation plays an important role in limb-sparing therapy. Pre- and postoperative external-beam radiation therapies (EBRT), as well as brachytherapy, have been shown to decrease the risk of local recurrence. They have not been shown to increase OS in prospective trials but are used to avoid amputation for all but the most locally advanced tumors or for limbs seriously compromised by vascular disease, where acceptable functional preservation is not possible. In the case of EBRT, irradiation of the entire limb circumference is avoided to preserve vascular and nerve structures that are critical to function and preservation of the limb.
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 (i.e., five 28-day cycles of doxorubicin and cyclophosphamide). All patients were randomly assigned to receive radiation (45 Gy to a wide field, plus a tumor-bed boost of 18 Gy over 6–7 weeks), concurrent with chemotherapy in the case of high-grade tumors versus no radiation. At up to 12 years of follow-up, there was one local recurrence in the 70 patients randomly assigned to receive radiation versus 17 recurrences in the 71 control patients (P = .0001), with similar reduction in risk of local recurrence for both high- and low-grade tumors. However, there was no difference in OS between the radiation and control groups.[Level of evidence: 1iiDiii] Global quality of life was similar in the two groups, but the radiation therapy group had substantially worse functional deficits resulting from reduced strength and joint motion as well as increased edema.
To limit acute toxicity with preRT, smaller fields and lower doses are generally given than is the case with PORT. PreRT has been directly compared with PORT for extremity soft tissue sarcomas in a multicenter randomized trial.[20,21,22] Designed to include 266 patients, the trial was stopped early after 190 patients had been accrued because of an increase in wound complications in the preRT group. The scheduled radiation in the preRT group was a wide field of 50 Gy in 2-Gy fractions (first phase of the trial) with an additional 16 Gy to 20 Gy to the tumor bed and a 2-cm margin (second phase of the trial) only if tumor cells were found at the surgical margins.
Patients in the PORT group were scheduled to receive radiation during both phases of the trial. The wound complication rates were 35% versus 17% in the preRT and PORT groups, respectively (P = .01). In addition, limb function at 6 weeks after surgery was worse in the preRT group (P = .01). At 5 years, the two groups had similar local control rates (93% vs. 92%) and OS (73% vs. 67%, P = .48). 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).
Brachytherapy has also been investigated as an adjuvant therapy for soft tissue sarcomas. Although it has possible advantages of convenience and 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.
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–45 Gy over 4–6 days; 78 patients) or to a control arm of no radiation (86 patients).[23,24] Some of the patients with high-grade tumors received adjuvant doxorubicin-based chemotherapy if they were thought to be at a high risk for metastasis (34 patients in each study arm). With a median follow-up of 76 months, the 5-year actuarial local recurrence rates were 18% and 31% in the brachytherapy and control arms, respectively (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 (84%) and control (81%) arms (P = .65), and there was no difference in the high tumor-grade group.[Level of evidence: 1iiDiii] The rates of clinically important wound complications (e.g., need for operative revision or repeated seroma drainage, wound separation, large hematomas, or purulent infection) were 24% in the radiation arm and 14% in the control arm (P = .13); the wound reoperation rate was 10% in the radiation arm and 0% in the control arm (P = .006).
Intensity-modulated radiation therapy (IMRT)
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 to 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 this technique.[25,26] Retrospective comparison of IMRT and 3-dimensional, conformal radiation therapy demonstrates that local recurrence for primary soft tissue sarcomas of the extremity was worse in the non-IMRT group.[Level of evidence: 3iiiDiv]
Surgery and radiation therapy
In some 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 [4,28,29] or analysis of outcomes in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) tumor registry. However, these comparisons suffer from low statistical power and differential evaluability rates that could have introduced bias. Patient selection factors may vary among surgeons. In general, this approach 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; long-term local tumor control is about 90% in such patients.
A patterns-of-care study using SEER data was queried to identify patients undergoing surgery for truncal and extremity soft tissue sarcomas from 2004 to 2009. Of 5,075 patients, 50% received radiation therapy. Radiation was underused in a significant portion of patients undergoing treatment for soft tissue sarcoma in the United States. Although routine radiation therapy is not recommended for stage I patients, 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. On multivariate analysis, predictors of radiation therapy efficacy included 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), and 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 (68% vs. 46%, P < .001).[Level of evidence: 3iDii]
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. However, this must be considered a treatment of last resort. Experience is limited to retrospective case series from single centers.[Level of evidence: 3iiiDiv]
In retroperitoneal sarcomas, retrospective data support the use of preRT or PORT versus surgery alone.
Outcomes from a total of 9,068 patients in two case control studies between 2003 and 2011 were analyzed. The 2,196 patients who received PORT were compared with 2,196 matched controls. Median OS was 89 months for patients in the PORT group versus 64 months for patients in the no-radiation-therapy group. The 5-year survival rate was 60% for patients in the PORT group and 52% for patients in the no-radiation-therapy group.
The 563 patients who received preRT were compared with 1,126 matched controls. Median OS was 110 months for the patients who received preRT versus 66 months for the patients in the no-radiation-therapy group. Five-year survival was 62% for the patients who received preRT versus 54% for the patients in the no-radiation-therapy group.
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 for cure or complete remission) or R1 (resection to microscopic residual tumor) resection after preRT, the 5-year local RFS rate was 60%, the 5-year DFS rate was 60%, and the 5-year OS rate was 61%. Median OS had not been reached (>60 months).
Role of Adjuvant or Neoadjuvant Chemotherapy for Clinically Localized Tumors
The role of adjuvant chemotherapy is not completely clear. In discussions with a patient, any potential benefits should be considered in the context of the short- and long-term toxicities of the chemotherapy.
Several prospective, randomized trials were unable to determine conclusively whether doxorubicin-based adjuvant chemotherapy benefits adults with resectable soft tissue sarcomas. The majority of these studies accrued small numbers of patients and did not demonstrate a metastasis-free survival or an OS benefit for adjuvant chemotherapy. There was wide interstudy variability among the reported trials, including differences in therapeutic regimens, drug doses, sample size, tumor site, and histologic grade.
A quantitative meta-analysis of updated data from 1,568 individual patients in 14 trials of doxorubicin-based adjuvant therapy showed an absolute benefit from adjuvant therapy of 6% for a local relapse-free interval (95% CI, 1%–10%), 10% for a distant relapse-free interval (95% CI, 5%–15%), and 10% for relapse-free survival (RFS) (95% CI, 5%–15%). A statistically significant OS benefit at 10 years was not detected: absolute difference 4% (95% CI, -1%–+9%).[36,37][Level of evidence: 1iiDii] However, only a small proportion of patients in this meta-analysis were treated with ifosfamide, an agent with demonstrated activity against soft tissue sarcoma. In addition, 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).
Subsequent chemotherapy trials were performed using anthracycline and ifosfamide combinations in patients who primarily had extremity or truncal soft tissue sarcomas. The data are conflicting, and the issue is still not settled. 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 and were randomly assigned to observation versus a dose-dense regimen of six 14-day courses of ifosfamide, dacarbazine (DTIC), and doxorubicin (IFADIC regimen) with granulocyte colony-stimulating factor (G-CSF) bone marrow support. There were no statistically significant differences in OS or RFS, but the study was severely underpowered.
In a second trial performed by the Italian National Council for Research, high-risk patients were treated with local therapy (i.e., 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).[39,40] 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 group (median DFS of 48 months vs. 16 months), but the P value had risen to .04.
Although there was no difference in metastasis-free survival at the time of the report, there was an improvement in median OS (75 months vs. 46 months, P = .03). However, at the follow-up report (at a median of 89.6 months in a range of 56–119 months), OS differences were no longer statistically significant (58.5% vs. 43.1% [P = .07]). The DFS difference had also lost statistical significance (47.2% vs. 16.0% [P = .09]). In summary, the trial was underpowered because it was stopped early, and the early promising results that led to stopping the trial diminished as the trial matured.
In a third, underpowered, single-center trial, 88 patients with high-risk, soft tissue sarcomas (64 of whom had extremity or truncal 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). 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.
In yet another underpowered trial, 137 patients with high-risk, soft tissue sarcomas (93% with extremity or truncal 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. This multicenter European Organization for Research and Treatment of Cancer trial (EORTC-62874) was closed because of slow accrual and results that were not promising enough to continue. 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); and OS rates were 64% in the surgery-alone arm and 65% in the chemotherapy-plus-surgery arm (P = .22).
These last four trials have been combined with the 14 first-generation trials in a trial-level meta-analysis. Of the 18 randomized trials of patients with resectable soft tissue sarcomas, five 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. The absolute risk reduction in local recurrence rates associated with any chemotherapy added to local therapy was 4 percentage points (95% CI, 0%–7%), and it was 5 percentage points (95% CI, 1%–12%) when ifosfamide was combined with doxorubicin. The absolute reduction in overall mortality was 6 percentage points with any chemotherapy (95% CI, 2%–11%; [i.e., a reduction from 46% to 40%]), 11 percentage points for doxorubicin plus ifosfamide (95% CI, 3%–19%; [i.e., a reduction from 41% to 30%]), and 5 percentage points for doxorubicin without ifosfamide.[Level of evidence: 1iiA]
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 above meta-analysis. The results differed from those reported in the meta-analysis. After local therapy, 351 patients were randomly assigned to five 21-day cycles of adjuvant therapy versus observation. OS did not differ significantly between the groups (HR, 0.94 [95% CI, 0.68–1.31]; P = .72) nor did RFS (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.
In a subsequent analysis of pooled individual patient data, the EORTC investigators combined data of this trial with their previous trial (EORTC-62771)  of adjuvant cyclophosphamide plus doxorubicin plus DTIC (CYVADIC), representing the two largest trials of adjuvant therapy for adult soft tissue sarcoma in the literature (N = 819 patients). Tumor size, high histologic 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. Patients with R1 resection had a significantly better RFS and OS favoring the adjuvant chemotherapy arms. The combined analysis showed no improvement in either RFS or OS associated with adjuvant chemotherapy.[Level of evidence: 1iiA]
In summary, the impact of adjuvant chemotherapy on survival is still controversial but is likely to be small in absolute magnitude. Therefore, in discussions with a patient, any potential benefits should be considered in the context of the short- and long-term toxicities of the chemotherapy.
Neoadjuvant chemotherapy with or without radiation therapy
In retrospective studies, preoperative chemotherapy with or without radiation therapy has resulted in DFS rates of 80% to 90% compared with about 60% in historical controls.[48,49,50]
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%.[42,51,52,53,54,55] A combined analysis of the RTOG-9514 study (NCT00002791) on neoadjuvant chemoradiation and the RTOG-0630 study (NCT00589121) on neoadjuvant radiation therapy showed rates of pathologic 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, OS was 100% in patients with pathologic complete responses and 5-year survival rates were 76.5% (RTOG-9514) and 56.4% (RTOG-0630) for patients who did not achieve pathologic complete responses.
The phase III ISG-STS1001 study (NCT01710176) enrolled 164 patients with high-risk features (grade 3 or grade 2, if more than 50% necrosis, size ≥5 cm, deep location). Patients were randomly assigned to receive either of the following for three cycles:
With a median follow-up of 12.3 months, the projected RFS at 46 months was 62% (95% CI, 48%–77%) for patients who received epirubicin and ifosfamide versus 38% (95% CI, 22%–55%) for patients who received histotype-tailored treatment (P = .004). OS was 89% (95% CI, 78%–99%) in the epirubicin and ifosfamide group versus 64% (95% CI, 27%–100%) for the histotype-tailored chemotherapy group (P = .034). Trabectedin for myxoid liposarcoma had similar outcomes compared with the standard chemotherapy group.
Role of regional hyperthermia
The use of regional hyperthermia to enhance the local effects of systemic chemotherapy in the neoadjuvant and adjuvant setting is under investigation. In a multicenter phase III trial (NCT00003052), 341 patients with high-risk (tumor ≥5 cm, grade 2–3, and deep to fascia) soft tissue sarcomas (149 extremity tumors and 192 nonextremity tumors) were randomly allocated to receive four 21-day cycles of chemotherapy (etoposide 125 mg/m2 on days 1 and 4; ifosfamide 1,500 mg/m2 on days 1–4; doxorubicin 50 mg/m2 on day 1) with or without regional hyperthermia both before and after local therapy. Approximately 11% of the patients were being treated for recurrent tumors. The regional hyperthermia was designed to produce tumor temperatures of 42°C for 60 minutes and was given on days 1 and 4 of each chemotherapy cycle. After the first four cycles of chemotherapy, definitive surgical excision of the tumor was performed, if possible, followed by radiation therapy, if indicated (i.e., a 52.7 Gy median dose delivered), and then the last four cycles of chemotherapy plus or minus hyperthermia. Three of the nine treatment centers with particular expertise in hyperthermia treated 91% of the patients in the trial.
The median duration of follow-up was 34 months. Local progression occurred in 56 patients in the hyperthermia group and 76 patients in the control group. The relative HR for local progression or death was 0.58 (95% CI, 0.41–0.84), with an absolute difference at 2 years of 15% (76% vs. 61%; 95% CI of the difference, 6–26). The decreased risk of local progression or death was seen in both extremity and nonextremity tumors. However, hyperthermia had no effect on distant failure rates nor was there a statistically significant effect on OS (HR, 0.88, 95% CI, 0.64–1.21; P = .43).[Level of evidence: 1iiDiii] There was a higher rate of grade 3 to 4 leucopenia in the hyperthermia group: 77.6% versus 63.5% (P = .005). Since a large proportion of the patients were treated at centers with special expertise, there is no certainty that the finding can be generalized to apply to other settings.
The final long-term results of this trial have been published. At a median follow-up of 11.3 years, adding regional hyperthermia improved local progression-free survival (HR, 0.65; 95% CI, 0.49–0.86; P = .002) compared with neoadjuvant chemotherapy alone. Additionally, patients randomly assigned to the combination group had prolonged survival rates compared with those randomly assigned to neoadjuvant chemotherapy alone (HR, 0.73; 95% CI, 0.54–0.98; P = .04). The 5-year survival rates were 62.7% for patients in the combination group (95% CI, 55.2%–70.1%) versus 51.3% for patients in the neoadjuvant chemotherapy alone group (95% CI, 43.7%–59%), and 10-year survival rates were 52.6% for patients in the combination group (95% CI, 44.7%–60.6%) versus 42.7% for patients in the neoadjuvant chemotherapy alone group (95% CI, 35%–50.4%). The authors concluded that for patients who are candidates for neoadjuvant treatment, the addition of regional hyperthermia may be warranted.
Role of isolated limb perfusion
Isolated limb perfusion is under investigation as a means to deliver high doses of chemotherapy and permit limb salvage in unresectable primary or recurrent extremity soft tissue sarcomas that would otherwise require amputation, in the opinion of the surgeon.[59,60] Common drugs used in the procedure are tumor necrosis factor (TNF)-alpha, melphalan, and interferon-gamma. Experience is limited to case series with response rates and reported avoidance of amputation as the outcome.[59,60][Level of evidence: 3iiiDiv] The technique requires specialized expertise to avoid severe local and systemic toxicity including systemic effects of TNF-alpha. The technique has not been directly compared with standard approaches using combined systemic and local therapy.
A systematic review of 518 patients in 12 studies reported a tumor response in 408 patients, and 428 patients had the affected limbs spared. However, no trial fulfilled essential quality criteria, and 7 of them did not include statistical methodology.
Another review of 18 studies provided outcomes for 1,030 patients. TNF-alpha with melphalan was the most common regimen in use. Twenty-two percent of patients achieved a complete response with an overall response rate of 72% and a limb salvage rate of 81%; however, 27% of patients experienced local recurrence, and 40% experienced distant failure. Evidence was insufficient to determine any impact on survival.
A systematic review and meta-analysis of 19 studies with a total of 1,288 patients confirmed the significant response rates: the overall response rate was 73.3%, with 25.8% achieving a complete response, and the limb salvage rate was 73.8% with limb perfusion or infusion. However, optimal treatment regimens still need to be defined.
Role of chemotherapy for advanced disease
Doxorubicin is a mainstay of systemic therapy in the management of locally advanced and metastatic soft tissue sarcoma. In randomized studies, the combination of doxorubicin with ifosfamide has never been shown to be superior to doxorubicin alone in terms of OS, but it may be considered in selected cases where reaching a better response to treatment, despite more toxicity, is the main treatment goal.
Pegylated liposomal encapsulated doxorubicin is a formulation of doxorubicin designed to prolong the half-life of circulating doxorubicin and slow the release of active drugs. The changed pharmacokinetics result in less myelosuppression and possibly less cardiotoxic effects, but there is a substantial incidence of hypersensitivity-like reactions and hand-foot syndrome. Its clinical activity relative to unencapsulated doxorubicin is not completely clear.[Level of evidence: 3iiiDiv] In a phase II randomized study from the EORTC group, a similar response rate of only about 10% was seen with either doxorubicin or pegylated liposomal doxorubicin, with less toxicity for the second regimen.[Level of evidence: 3iiiDiv] Other drugs that are thought to have clinical activity as a single agent are ifosfamide, epirubicin, gemcitabine, and paclitaxel in angiosarcoma.[66,67,68,69][Level of Evidence: 3iiiDiv] Their clinical activity relative to single-agent doxorubicin is not clear, and they are not known to have superior activity.
There is controversy about the clinical benefit of adding other drugs to the single-agent doxorubicin regimen. A systematic evidence review and meta-analysis conducted by the Cochrane Collaboration summarized the eight randomized trials reported from 1976 to 1995. Single-agent doxorubicin had been compared with a variety of doxorubicin-containing combinations that included vincristine, vindesine, cyclophosphamide, streptozotocin, mitomycin-C, cisplatin, and/or ifosfamide. Combination regimens consistently caused more nausea and hematologic toxicity. However, the better response rates associated with combination therapy were marginal and depended on the statistical model used (fixed effects model ORresponse = 1.29; 95% CI, 1.03–1.60, P = .03; random effects model ORresponse = 1.26; 95% CI, 0.96–1.67, P = .10) There was no statistically significant difference in the 1- (ORmortality = 0.87; 95% CI, 0.73–1.05, P = .14) or 2-year mortality rates (ORmortality = 0.84; 95% CI, 0.67–1.06, P = .13).
These results were very similar even when the analyses were restricted to the four trials that used DTIC and/or ifosfamide as part of the combination regimen with doxorubicin that were postulated to have greater activity than the others tested. A subsequent meta-analysis of all three published randomized trials of chemotherapy regimens that contained ifosfamide versus those that did not came to similar conclusions: tumor response rates were better when the regimen included ifosfamide (tumor response rate [RR],1.52; 95% CI, 1.11–2.08), but mortality at 1 year was not (RRmortality = 0.98; 95% CI, 0.85–1.13).[Level of evidence: 1iiDiv]. Therefore, response rate was a poor surrogate for OS. Quality-of-life outcomes were not reported in any of the above-mentioned randomized trials, but toxicity was worse when agents were added to doxorubicin.
Refer to the Treatment Option Overview section of this summary for a more detailed discussion of the roles of surgery and radiation therapy.
Low-grade soft tissue sarcomas have little metastatic potential, but they have a propensity to recur locally. Accordingly, surgical excision with negative tissue margins of 1 cm to 2 cm or larger in all directions is the treatment of choice for patients with these early-stage sarcomas.[1,2,3] The Mohs surgical technique may be considered as an alternative to wide surgical excision for the very rare, small, well-differentiated primary sarcomas of the skin when cosmetic results are considered to be important, as margins can be assured with minimal normal tissue removal.
Carefully executed high-dose radiation therapy using a shrinking-field technique may be beneficial for unresectable tumors or for resectable tumors in which a high likelihood of residual disease is thought to be present when margins are judged to be inadequate, and when wider resection would require either an amputation or the removal of a vital organ. Because of the low metastatic potential of these tumors, chemotherapy is usually not administered to these patients.[6,7]
Standard treatment options:
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.
Refer to the Treatment Option Overview section of this summary for a more detailed discussion of the roles of surgery, radiation therapy, and chemotherapy.
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).
Complete surgical resection of retroperitoneal sarcomas is often difficult because of their large size before detection and anatomical location.[1,2] As opposed to soft tissue sarcomas of the extremities, local recurrence is the most common cause of death in patients with retroperitoneal soft tissue sarcomas. Complete surgical resection (i.e., removal of the entire gross tumor) is the most important factor in preventing local recurrence and, in many instances, requires resection of adjacent viscera. For retroperitoneal sarcomas, a retrospective review that compared surgery alone with preRT review suggested that preRT was associated with improved local recurrence-free survival, but not disease-free survival.
Regional lymph node involvement by soft tissue sarcomas in adults is very infrequent. However, sarcoma types that more commonly spread to lymph nodes include high-grade rhabdomyosarcoma, vascular sarcomas, synovial sarcoma, high-grade fibrosarcoma, clear cell sarcoma, and epithelioid sarcomas.
Refer to the Treatment Option Overview section of this summary for a more detailed discussion of the roles of surgery, radiation therapy, and chemotherapy.
In the setting of lung metastasis, resection of metastatic tumors may be associated with long-term disease-free survival in patients selected for optimal underlying disease biology (i.e., patients with a limited number of metastases and slow tumor growth).[1,2,3] It is not clear to what degree the favorable outcomes are attributable to the efficacy of surgery or to careful selection of patients on the basis of factors that are associated with less aggressive disease.[1,2,3] The value of resection of hepatic metastases is unclear.
Doxorubicin has been considered the standard systemic therapy in the management of metastatic sarcomas for several years.[4,5] Other drugs that may have clinical activity as single agents are ifosfamide, epirubicin, gemcitabine, and paclitaxel.[6,7,8,9] Their clinical activity relative to single-agent doxorubicin is not clear, and they are not known to have superior activity. There is controversy about whether adding drugs to doxorubicin offers clinical benefit beyond what is achieved by doxorubicin as a single agent. To avoid severe toxicity in older patients, sequential use of single agents may be the preferred strategy for palliation.
A randomized study (NCT00061984) assessed whether dose intensification of doxorubicin with ifosfamide improved the survival of patients with advanced soft tissue sarcoma compared with doxorubicin alone. 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) in the doxorubicin-only group and 59 months (IQR, 36–72) in the combination group.
There was no significant difference in overall survival (OS) between groups (median OS, 12.8 months; 95.5% confidence interval [CI], 10.5–14.3 in the doxorubicin-alone group vs. 14.3 months; range, 12.5–16.5 months in the doxorubicin and ifosfamide group; hazard ratio [HR], 0.83; 95.5% CI, 0.67–1.03; stratified log-rank test P = .076). 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 months; HR, 0.74; 95% CI, 0.60–0.90; stratified log-rank test P = .003). 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 (31of 228 patients [14%]; P < .0006). The most common grade 3 and 4 toxic effects, which were all more common with doxorubicin and ifosfamide than with doxorubicin alone, were leucopenia (97 of 224 patients [43%] vs. 40 of 223 patients [18%]), neutropenia (93 [42%] vs. 83 [37%]), febrile neutropenia (103 (46%) vs. 30 [13%]), anemia (78 [35%] vs. 10 [5%]), and thrombocytopenia (75 [33%]) vs. 1 [<1%]).[Level of evidence: 1iiA] Treatment intensification with doxorubicin and ifosfamide for palliation of advanced soft tissue sarcoma is not indicated.
In 2016, the U.S. Food and Drug Administration (FDA) approved the use of olaratumab in combination with doxorubicin for the first-line treatment of patients with metastatic soft tissue sarcoma, on the basis of the results of a phase II randomized study (NCT01185964). Olaratumab is a human immunoglobulin G1 monoclonal antibody against the platelet-derived growth factor receptor alpha that has been shown to block platelet-derived growth factor ligands from binding. The combination of doxorubicin administered at 75mg/m2 intravenously (IV) on day 1 with or without olaratumab administered at 15mg/kg IV on days 1 and 8 of a 21-day cycle was explored.
Median OS was 26.5 months for the combination regimen and 14.7 months for doxorubicin alone (HR, 0.46; 95% CI, 0.30–0.71, P = .0003). The PFS difference was not statistically significant (6.6 months for the combination and 4.1 months for doxorubicin). The objective response rate was 18.2% for the combination and 11.9% for the single-agent doxorubicin (P = .3421). Adverse events were more common in the combination arm and included neutropenia (58% vs. 35% but the rate of febrile neutropenia was similar), mucositis (53% vs. 35%), vomiting (45% vs. 18%), and diarrhea (34% vs. 23%).
The combination of gemcitabine and docetaxel originally showed promising activity in patients with leiomyosarcoma but has also shown activity in other histologies, with an overall response rate of 18.4% in a retrospective series of 133 patients.
The GeDDis trial (ISRCTN07742377) randomly assigned 257 previously untreated patients to either receive gemcitabine and docetaxel or doxorubicin alone. The PFS rate at 24 weeks (46% in both groups) and the primary endpoint (median PFS, 23.3 vs. 23.7 weeks) were identical in both groups. This study has been criticized because of the relatively low dose of gemcitabine used (675 mg/m2 on days 1 and 8 instead of 900 mg/m2 as in previous trials) and because of the relatively low representation of patients with undifferentiated pleomorphic sarcoma, an area in which previous studies showed a signal of activity. Although the authors of the paper claimed that doxorubicin alone should remain the standard of care as first-line treatment in the metastatic setting, other experts may advocate for equal acceptance of the two regimens; however, each regimen provides a different spectrum of side effects.
Although doxorubicin alone has traditionally been considered the standard arm for comparing new drugs or regimens in the context of phase III clinical trials, some sarcoma subtypes have shown higher sensitivity to specific agents. Examples of the relationship between some subtypes and specific agents include the following:
Some subtypes such as clear cell sarcoma and epithelioid sarcoma are intrinsically resistant to traditional chemotherapy. Leiomyosarcoma is quite resistant to ifosfamide (about 5% response rate) as is synovial sarcoma, which is generally considered one of the most chemosensitive subtypes. Round cell/myxoid liposarcoma is intensely sensitive to ifosfamide.
Standard treatment options
Treatment of patients with recurrent soft tissue sarcoma depends on the type of initial presentation and treatment. Patients who develop a local recurrence often can be treated with local therapy: 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: 3iiiDiv] 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.
Since 2012, three drugs have been approved for the treatment of soft tissue sarcomas after failure of a first-line chemotherapy regimen: the tyrosine kinase inhibitor pazopanib for all soft tissue sarcomas except adipocytic subtypes, eribulin for liposarcoma, and trabectedin for leiomyosarcoma and liposarcoma. Other agents such as ifosfamide or gemcitabine may be used sequentially at the time of further recurrence or progression.[11,12,13,14][Level of Evidence: 3iiiDiv] However, none of these agents has been shown to increase overall survival (OS) in this setting; therefore, clinical trials are an appropriate option.
Pazopanib is a multitargeted, oral, small molecule inhibitor of several tyrosine kinases including vascular endothelial growth factor receptors-1, -2, and -3; platelet-derived growth factor receptor alpha and beta; and fibroblast growth factor receptor-1, and -3. The phase III randomized, double-blind PALETTE study (NCT00753688) from the European Organization for Research and Treatment of Cancer compared pazopanib (800 mg q d) with placebo in 369 patients with different subtypes, excluding adipocytic sarcomas and gastrointestinal stromal tumors, after progression on a first-line anthracycline-based regimen. The median progression-free survival (PFS) was 4.6 months for patients who received pazopanib versus 1.6 months for patients who received placebo. OS difference was not statistically significant at 12.5 months for patients who received pazopanib versus 10.7 months for patients who received placebo (hazard ratio [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. Stability of disease 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 liver function tests elevations. Based on the above data, pazopanib was approved by the U.S. Food and Drug Administration (FDA) in 2012 for the treatment of patients with soft tissue sarcomas, excluding adipocytic subtypes, who have received previous chemotherapy.
Eribulin is a microtubule inhibitor that was approved in 2016 by the FDA for the treatment of patients with unresectable or metastatic liposarcoma, who previously received anthracycline-containing chemotherapy. The approval was based on a phase III multicenter randomized trial of eribulin (1.4mg/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) in 452 patients with advanced leiomyosarcoma or adipocytic sarcoma. Although median OS in the overall group was 13.5 months for patients who received eribulin versus 11.5 months for patients who received dacarbazine (HRdeath, 0.77; 95% CI, 0.62–0.95), a preplanned subset analysis revealed a striking median survival of 15.6 months for eribulin versus 8.4 months for dacarbazine in patients with liposarcoma. Median PFS was the same in both groups (2.6 months).
Trabectedin is an FDA-approved option for second-line treatment of patients with advanced liposarcoma and leiomyosarcoma. The approval was based on a phase III randomized study 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). Treatment with trabectedin resulted in a significant improvement in median PFS (4.2 months for patients who received trabectedin vs. 1.5 months for patients who received dacarbazine). OS, the primary endpoint, 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 liver function tests elevations. 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 PFS at 6 months was found in 88% of the patients.
Checkpoint inhibitors have been explored in two trials. The phase II Sarcoma Alliance for Research through Collaboration trial (SARC028 [NCT02301039]) studied treatment with pembrolizumab alone in four subtypes (undifferentiated pleomorphic sarcoma [UPS], synovial sarcoma [SS], leiomyosarcoma [LMS], and poorly differentiated or dedifferentiated liposarcoma). A different phase II randomized study examined nivolumab versus nivolumab plus ipilimumab for the treatment of different soft tissue sarcomas. In the pembrolizumab study, 80 patients were evaluable for response, with half of the patients in the soft tissue group and half in the bone sarcoma cohort. Responses were noted in 4 of 10 patients with UPS, 2 of 10 patients with LPS, 1 of 10 patients with SS, and 0 of 10 patients with LMS, for an overall response rate of 18%. In the Alliance A091401 study (NCT02500797), patients were randomly assigned to receive either nivolumab (n = 43 patients) or nivolumab plus ipilimumab (n = 42 patients). The number of objective responses was 2 in the nivolumab group (5%; 1 alveolar soft part sarcoma and 1 LMS) and 6 in the combination group (16%; 2 LMS, 1 myxofibrosarcoma, 2 UPS, and 1 angiosarcoma). Although some activity has been shown in selected subtypes, the factors that may predict activity to treatment with checkpoint inhibitors remain unknown, and their use cannot be routinely recommended.
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.
Editorial changes were made to this summary.
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Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult soft tissue sarcoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
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).
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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.
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Levels of Evidence
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PDQ® Adult Treatment Editorial Board. PDQ Adult 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: 2019-05-15
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