Soft tissue sarcomas (STS) are rare solid tumors of mesenchymal cell origin that display a heterogenous mix of clinical and pathologic characteristics. STS can develop from fat, muscle, nerves, blood vessels, and other connective tissues. The evaluation and treatment of patients with STS requires a multidisciplinary team with demonstrated expertise in the management of these tumors. The complete NCCN Guidelines for Soft Tissue Sarcoma (available at NCCN.org) provide recommendations for the diagnosis, evaluation, and treatment of extremity/superficial trunk/head and neck STS, as well as intra-abdominal/retroperitoneal STS, gastrointestinal stromal tumor, desmoid tumors, and rhabdomyosarcoma. This manuscript discusses guiding principles for the diagnosis and staging of STS and evidence for treatment modalities that include surgery, radiation, chemoradiation, chemotherapy, and targeted therapy.

Abstract

Soft tissue sarcomas (STS) are rare solid tumors of mesenchymal cell origin that display a heterogenous mix of clinical and pathologic characteristics. STS can develop from fat, muscle, nerves, blood vessels, and other connective tissues. The evaluation and treatment of patients with STS requires a multidisciplinary team with demonstrated expertise in the management of these tumors. The complete NCCN Guidelines for Soft Tissue Sarcoma (available at NCCN.org) provide recommendations for the diagnosis, evaluation, and treatment of extremity/superficial trunk/head and neck STS, as well as intra-abdominal/retroperitoneal STS, gastrointestinal stromal tumor, desmoid tumors, and rhabdomyosarcoma. This manuscript discusses guiding principles for the diagnosis and staging of STS and evidence for treatment modalities that include surgery, radiation, chemoradiation, chemotherapy, and targeted therapy.

NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Overview

Sarcomas constitute a heterogeneous group of rare solid tumors of mesenchymal cell origin with distinct clinical and pathologic features; they are usually divided into 2 broad categories:

  • Sarcomas of soft tissues (including fat, muscle, nerve and nerve sheath, blood vessels, and other connective tissues); and

  • Sarcomas of bone.

Sarcomas collectively account for approximately 1% of all adult malignancies and 15% of pediatric malignancies. In 2016, an estimated 12,310 people will be diagnosed with soft tissue sarcoma (STS) in the United States, and approximately 4,990 people will die of the disease.1 The true incidence of STS is underestimated, especially because a large proportion of patients with gastrointestinal stromal tumors (GISTs) may not have been included in tumor registry databases before 2001. In the United States, the incidence of GISTs is expected to be at least 5,000 new cases per year.2,3 Prior radiation therapy (RT) to the affected area is a risk factor for the development of STS.46 More than 50 different histologic subtypes of STS have been identified. The most common subtypes of STS are undifferentiated pleomorphic sarcoma, GIST, liposarcoma, leiomyosarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumors.7 The anatomic site of the primary disease represents an important variable that influences treatment and outcome. Extremities (43%), the trunk (10%), visceral (19%), retroperitoneum (15%), and head and neck (9%) are the most common primary sites.8 STS most commonly metastasizes to the lungs; tumors arising in the abdominal cavity more commonly metastasize to the liver and peritoneum. Rhabdomyosarcoma (RMS) is the most common STS among children and adolescents and is less common in adults.

NCCN encompasses institutions with extensive experience in managing sarcomas using multidisciplinary care, and they function as referral centers of consultative support for community-based practitioners. The expertise of these institutions lends their extensive experience in defining the consensus

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NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma, Version 2.2016

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NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma, Version 2.2016

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NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma, Version 2.2016

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NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma, Version 2.2016

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Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 14, 6; 10.6004/jnccn.2016.0078

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NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma, Version 2.2016

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NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma, Version 2.2016

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NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma, Version 2.2016

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Soft Tissue Sarcoma, Version 2.2016

Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are category 2A unless otherwise indicated.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 14, 6; 10.6004/jnccn.2016.0078

guidelines for the management of patients with sarcomas.

The complete NCCN Guidelines for STS (available at NCCN.org) address the management of STS in adult patients from the perspective of the following disease subtypes:

  • STS of extremity, superficial/trunk, and head and neck

  • Retroperitoneal or intra-abdominal STS

  • GISTs

  • Desmoid tumors (aggressive fibromatoses)

  • RMS

Before the start of treatment, all patients should be evaluated and managed by a multidisciplinary team with extensive expertise and experience in the treatment of STS.9

NOTE: This manuscript highlights only a portion of the NCCN Guidelines on STS. The guidelines in this issue discuss important general principles and evidence for diagnosis, staging, and treatment of STS in adult patients. For treatment recommendations specific to tumor location, stage, and subtype, please refer to the complete guidelines at NCCN.org.

Genetic Cancer Syndromes With Predisposition to STS

Genetic cancer syndromes caused by germline mutations in a number of different genes are also associated with an inherited predisposition for the development of STS.5,1014 Li-Fraumeni syndrome (resulting from germline mutations in the TP53 tumor suppressor gene) is characterized by an increased risk of developing multiple primary malignancies, predominantly STS, osteosarcomas, breast cancer, leukemia, brain tumors, and adrenocortical carcinoma, before 45 years of age.10,1517 The incidence of STS ranges from 12% to 21% in individuals with TP53 germline mutations.1820 In general, STS associated with Li-Fraumeni syndrome is diagnosed at significantly younger ages than sporadic STS. The mean age at diagnosis, however, varies with the histologic subtype. In an analysis of 475 tumors in 91 families with TP53 germline mutations, Kleihues et al18 reported RMS, fibrosarcomas, and undifferentiated pleomorphic sarcomas as the most frequent histologic subtypes, identified in 55%,13%, and 10% of patients, respectively. The mean age at diagnosis for RMS was younger than 6 years, and the mean age at diagnosis for undifferentiated pleomorphic sarcomas was older than 50 years.

Familial adenomatous polyposis (FAP) is an inherited autosomal-dominant colorectal cancer syndrome resulting from the germline mutations in the adenomatous polyposis coli [APC] gene on chromosome 5q21.11,13 FAP is characterized by adenomatous colorectal polyps that progress to colorectal cancer at 35 to 40 years of age. Gardner syndrome is considered a variant of FAP with extracolonic manifestations such as osteomas, skin cysts, congenital hypertrophy of the retinal pigmented epithelium, and desmoid tumors (aggressive fibromatosis).21 Desmoid tumors have been reported to occur in 7.5% to 16% of patients with FAP, and the relative risk of developing desmoid tumors is much higher in patients with FAP than in the general population.2225 In an International Dutch Cohort study involving 2,260 patients with FAP, positive family history for desmoid tumors, abdominal surgery, and the APC mutation site were identified as significant risk factors for the development of desmoid tumors.25 The median age at diagnosis was 31 years, with most desmoid tumors arising in the intra-abdominal and abdominal wall locations (53% and 24%, respectively).

Carney-Stratakis syndrome is an autosomal-dominant familial syndrome characterized by a predisposition to GISTs and paragangliomas.26 Germline loss-of-function mutations within the succinate dehydrogenase (SDH) gene subunits (SDHB, SDHC, and SDHD) have been identified in individuals with GISTs associated with Carney-Stratakis syndrome.27 In an analysis of 11 patients from 9 families presenting with the GISTs and paragangliomas associated with Carney-Stratakis syndrome, Pasini et al27 identified germline mutations in SDHB, SDHC, or SDHD genes in 8 patients (from 7 untreated families) with GISTs. The tumors also lacked activating KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations associated with sporadic GISTs. GISTs associated with Carney-Stratakis syndrome are also reported to be negative for SDHB protein expression by immunohistochemistry (IHC), in contrast to GIST with KIT or PDGFRA mutations or sporadic GIST.28,29

Hereditary retinoblastoma caused by a germline mutation in the retinoblastoma tumor suppressor gene (RB1) is also associated with an increased risk for the development of STS.12,30 Leiomyosarcoma is the most frequent STS subtype (with 78% of leiomyosarcomas diagnosed ≥30 years after the diagnosis of retinoblastoma). Although patients who underwent RT for retinoblastoma are at significantly increased risk of developing STS, the risks of developing STS are also increased in nonirradiated patients, indicating a genetic predisposition to STS that is independent of RT in patients with hereditary retinoblastoma.12

Neurofibromatoses are hereditary conditions caused by mutations in the neurofibromin 1 gene (NF1) or neurofibromin 2 gene (NF2).31 Approximately 5% of patients with neurofibromatosis are thought to develop STS. Most commonly occurring are malignant peripheral nerve sheath tumors (MPNSTs), a type of sarcoma that can arise from previously benign neurofibromas.32 For information on the treatment of MPNSTs, see the NCCN Guidelines for Central Nervous System Cancers (available at NCCN.org).

NCCN Recommendations for Genetic Testing and Counseling for Patients With Germline Mutations

  • Patients (and their families) with a personal and/or family history suggestive of Li-Fraumeni syndrome should be considered for further genetic assessment, as outlined in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian (available at NCCN.org).

  • SDH gene mutational analysis for the identification of germline mutations in the SDH gene subunits should be considered for patients with GIST lacking KIT or PDGFRA mutations. Loss of SDHB protein expression by IHC is a useful screen to identify patients who would be appropriate for germline mutation testing, but it is not diagnostic of a germline mutation.

  • Evaluation for family history of FAP or Gardner syndrome is recommended for patients diagnosed with desmoid tumors (aggressive fibromatoses).

Pathology of STS

Biopsy

A pretreatment biopsy is highly preferred for the diagnosis and grading of STS and should be performed by an experienced surgeon or radiologist. Biopsy should establish the malignancy and provide a specific diagnosis where possible and a grade where appropriate or feasible, recognizing that limited biopsy material may underestimate grade. Biopsy may be accomplished via open incisional or core needle technique. Core needle biopsy is preferred; however, an open incisional biopsy may be considered by an experienced surgeon. In patients without a definitive diagnosis after initial biopsy due to limited sampling size, repeat image-guided core needle biopsy should be considered to make a diagnosis. Although fine-needle aspiration (FNA) is a convenient technique, it can be difficult to make an accurate primary diagnosis with FNA alone due to small specimen size; thus it is discouraged.33 FNA may be acceptable in selected institutions with clinical and pathologic expertise. Endoscopic or needle biopsy may be indicated for deep thoracic, abdominal, or pelvic STS.

Principles of Pathologic Assessment

Pathologists with expertise in STS should review the pathologic assessment of biopsies and resected specimens, especially for initial histopathologic classification. Margins must be thoroughly evaluated in these specimens. Morphologic assessment based on microscopic examination of histologic sections remains the gold standard of sarcoma diagnosis. The differential diagnosis of a soft tissue mass includes malignant lesions (such as primary or metastatic carcinoma, melanoma, or lymphoma), desmoids, and benign lesions (such as lipomas, lymphangiomas, leiomyomas, and neuromas). However, because identification of the histopathologic type of a sarcoma is often difficult, several ancillary techniques have been used as an adjunct to morphologic diagnosis. These techniques include conventional cytogenetics, IHC, electron microscopy, and molecular genetic testing. Pathologists should have access to optimal cytogenetic and molecular diagnostic techniques. The results of appropriate ancillary studies used as an adjunct to morphologic diagnosis should be included in the pathology report.

The pathology report should include specific details about the primary diagnosis (using standardized nomenclature according to the WHO Classification of Soft Tissue Tumors); the organ and site of sarcoma; depth, size, and histologic grade of the tumor; presence or absence of necrosis; status of excision margins and lymph nodes; TNM stage; and additional features, such as mitotic rate, presence or absence of vascular invasion, and the type and extent of inflammatory infiltration.

Molecular Diagnosis of STS

Molecular genetic testing has emerged as a particularly useful ancillary technique, because many subtypes of STS are associated with characteristic genetic aberrations, including single base-pair substitutions, deletions, amplifications, and translocations. STS can be divided into 2 major genetic groups: (1) sarcomas with specific genetic alterations (eg, chromosomal translocations or point mutations) and usually simple karyotypes; and (2) sarcomas with nonspecific genetic alterations and complex unbalanced karyotypes.34

STS with recurrent chromosomal translocations can be classified into subtypes depending on the presence of fusion gene transcripts (eg, EWSR1-ATF1 in clear cell sarcoma, TLS-CHOP [also known as FUS-DDIT3] in myxoid or round cell liposarcoma, SS18-SSX [SS18-SSX1 or SS18-SSX2] in synovial sarcoma, and PAX-FOXO1 [PAX3-FOXO1 or PAX7-FOXO1] in alveolar RMS). The fusion genes resulting from chromosomal translocations can provide useful diagnostic and prognostic information. See “Principles of Ancillary Techniques Useful in the Diagnosis of Sarcomas” for a list of recurrent genetic aberrations associated with other subtypes (SARC-B; pages 761–763).

Conventional cytogenetic analysis, fluorescence in situ hybridization, and polymerase chain reaction (PCR) are the most common techniques used in the molecular diagnosis of STS.35 In a prospective study, Hill et al36 concluded that PCR-based molecular analysis is more sensitive than conventional cytogenetics and is a useful adjunct for the diagnosis of alveolar RMS, synovial sarcoma, and myxoid liposarcoma that have variation in fusion gene partners.

The molecular heterogeneity of fusion gene transcripts has been suggested to predict prognosis in certain sarcoma subtypes. In patients with alveolar RMS presenting with metastatic disease, PAX7-FOXO1 was associated with a favorable prognosis compared with PAX3-FOXO1.37 In patients with synovial sarcoma, the prognostic impact of SS18-SSX1 or SS18-SSX2 is less clear, with 2 large studies showing conflicting results.38,39 In myxoid liposarcoma, the variability of fusion gene transcript has no effect on clinical outcome.40

Although molecular genetic testing appears promising, it involves highly complex techniques and the methods are not absolutely sensitive or do not provide specific results. Molecular testing should be performed by a pathologist with expertise in the use of molecular diagnostic techniques for the diagnosis of STS. In addition, technical limitations associated with molecular testing suggest that molecular evaluation should be considered only as an ancillary technique. Molecular test results should therefore only be interpreted in the context of the clinical and pathologic features of a sarcoma.35

Staging

The AJCC staging system for STS has historically used a 4-grade system, but within the staging groups, this effectively functioned as a 2-tiered system (G1/G2 [low] and G3/G4 [high]). The 2 most widely used systems, the French Federation of Cancer Centers Sarcoma Group (FNCLCC) and the NCI system, are 3-tiered grading systems. The NCI system is based on the evaluation of tumor histology, location, and amount of tumor necrosis. The FNCLCC system is based on tumor differentiation, mitosis count, and tumor necrosis. In a comparative study of these systems in 410 adult patients with STS, the FNCLCC system showed a slightly increased ability to predict distant metastasis development and tumor mortality.41 Riad et al42 examined the impact of lymph node involvement on survival in patients with extremity sarcoma. Lymph node metastases developed in 3.7% of patients (39 of 1,066) who had surgery. The outcome of patients with isolated lymph node metastases was significantly better than with synchronous systemic and lymph node involvement (the estimated 4-year survival rates were 71% and 21%, respectively).42 The outcome for patients with isolated lymph node involvement, treated with lymph node dissection, was also similar to that of patients with AJCC stage III extremity sarcomas.42,43 The revised 2010 AJCC staging system incorporates a 3-tiered grading system, and lymph node disease has been re-classified as stage III rather than stage IV disease.44 However, many clinicians prefer the 2-tiered system, which is also used in the algorithm.

Surgery

Surgical resection (with appropriately negative margins) is the standard primary treatment for most patients with STS, although close margins may be necessary to preserve uninvolved critical neurovascular structures. RT and/or chemotherapy (in the case of chemosensitive histologies) are often used before surgery in many centers to downstage large, high-grade tumors to enable effective surgical resection, because the risk of failure in the surgical bed can be high. Postoperative RT should be considered after resections with close soft tissue margins (<1 cm) or a microscopically positive margin on bone, major blood vessels, or a nerve. In selected cases when margin status is uncertain, consultation with a radiation oncologist is recommended.

The biopsy site should be excised en bloc with the definitive surgical specimen. Dissection should be through grossly normal tissue planes uncontaminated by tumor. If the tumor is close to or displaces major vessels or nerves, these need not be resected if the adventitia or perineurium is removed and the underlying neurovascular structures are not involved with gross tumor. Radical excision or entire anatomic compartment resection is not routinely necessary. If resections with microscopically positive or grossly positive margins are anticipated, surgical clips should be left in place to identify high-risk areas for recurrence, particularly for retroperitoneal or intra-abdominal sarcomas to help guide future RT. If closed suction drainage is used, the drains should exit the skin close to the edge of the surgical incision (in case repeat resection or RT is indicated).

Both the surgeon and the pathologist should document surgical margins while evaluating a resected specimen. If surgical margins are positive on final pathology, reresection to obtain negative margins should strongly be considered if it will not have a significant impact on functionality.45 In an analysis of 666 consecutive patients with localized STS treated with an apparent macroscopic total tumor resection, 295 patients underwent reresection of their tumor bed (residual tumor was found in 46% of patients, including macroscopic tumor in 28% of patients).45 Reresection remained a significant predictor of local control. The local control rates at 5, 10, and 15 years were 85%, 85%, and 82%, respectively, for patients who underwent reresection. The corresponding local control rates were 78%, 73%, and 73%, respectively (P=.03), for patients who did not undergo reresection.

Radiation Therapy

RT can be administered as primary, preoperative, or postoperative treatment. Total RT doses are always determined based on the tissue tolerance. Newer RT techniques, such as brachytherapy, intraoperative RT (IORT), and intensity-modulated RT (IMRT), have led to the improvement of treatment outcomes in patients with STS. Brachytherapy involves the direct application of radioactive seeds into the tumor bed through catheters placed during surgery. Options include low-dose-rate (LDR) brachytherapy, fractionated high-dose-rate (HDR) brachytherapy, or intraoperative HDR brachytherapy. LDR and HDR brachytherapy are associated with similar rates of local control.46 It has been suggested that HDR brachytherapy may be associated with lower incidences of severe toxicity; however, this has not been proven in randomized clinical trials.46 The main advantage of IMRT is its ability to more closely contour the high-dose radiation volume, thereby minimizing the volume of high-dose radiation to the surrounding normal tissues.47 Additionally, image-guided techniques may allow for reduced target volumes, further minimizing toxicity.48 IORT is the delivery of radiation during surgery and can be performed using different techniques, such as electron beam RT or brachytherapy.49

Preoperative RT may reduce seeding during the surgical manipulation of the tumor. The tumor may or may not regress with preoperative RT, but the pseudocapsule may thicken and become acellular, easing resection and decreasing the risk of recurrence.5052 Most institutions include the entire operative bed within the RT field. The main disadvantage of preoperative RT, however, is its effect on wound healing.53,54 After preoperative RT, a 3- to 6-week interval is necessary before resection to allow acute reactions to subside and decrease the risk of wound complications. Involvement of a plastic surgeon in the team may be necessary to reduce wound complications when preoperative RT is contemplated.

Postoperative RT is associated with higher rates of long-term treatment-related side effects. In one retrospective analysis, although no evidence was seen for differences in disease outcome associated with the use of either preoperative or postoperative RT, a slight increase in late treatment-related side effects was seen with postoperative RT, mainly due to the higher doses used.55 Positive surgical margins are associated with higher rates of local recurrence.56 Postoperative RT has been shown to improve local control in patients with positive surgical margins.57 Of those with positive margins, RT doses greater than 64 Gy, microscopically positive margins, superficial location, and extremity site are associated with improved local control.

A postoperative RT boost of 16 Gy has been used in patients with positive surgical margins after the wound has healed. However, the results of a retrospective analysis showed that postoperative RT boost did not provide any advantage in preventing local recurrence in some patients with positive surgical margins (such as those with low-grade, well-differentiated liposarcoma and a focally, “planned” positive margin on an anatomically fixed critical structure).58 Similarly, another retrospective matched cohort of patients with extremity STS found no added benefit of postoperative RT boost when evaluating local recurrence, distant metastasis, and mortality.59

The advantage of adding postoperative RT boost has not yet been evaluated in a randomized clinical trial. Intervals beyond 8 weeks between resection and postoperative RT are not recommended because of the development of late fibrosis and the proliferation of malignant cells. The risk of local recurrence versus the toxicity of postoperative RT should be assessed before making a decision regarding the use of postoperative RT.

Chemotherapy/Chemoradiation

Resectable Disease

Preoperative Therapy: Preoperative chemotherapy6063 or chemoradiation6471 has been evaluated in single and multicenter studies in patients with high-grade tumors.

Studies that have evaluated preoperative chemotherapy followed by surgery have reported inconsistent findings. The results of the only randomized study that compared surgery alone versus preoperative chemotherapy followed by surgery in 134 evaluable patients with high-risk tumors (tumors ≥8 cm of any grade, grade 2/3 tumors <8 cm, grade 2/3 locally recurrent tumors, or tumors with inadequate surgery) did not show a major survival benefit for patients receiving chemotherapy.61 At a median follow-up of 7.3 years, the estimated 5-year disease-free survival (DFS) rate was 52% for the no-chemotherapy arm and 56% for the chemotherapy arm (P=.3548). The corresponding 5-year overall survival (OS) rate for both arms was 64% and 65%, respectively (P=.2204). A cohort analysis of 674 patients with stage III STS of extremity treated at a single institution revealed that clinical benefits associated with preoperative or postoperative doxorubicin-based chemotherapy were not sustained beyond 1 year.62 In another retrospective study, the benefit of preoperative chemotherapy was only seen in patients with high-grade extremity tumors larger than 10 cm but not in patients with tumors 5 to 10 cm.63

In a single-institution study involving 48 patients with high-grade extremity STS (≥8 cm), the outcome of patients treated with preoperative chemoradiation with the MAID (mesna, doxorubicin, ifosfamide, and dacarbazine) regimen followed by surgery and postoperative chemotherapy with the same regimen was superior to that of historical controls.66 The 5-year actuarial local control, freedom from distant metastasis, DFS, and OS rates were 92% and 86% (P=.1155); 75% and 44% (P=.0016); 70% and 42% (P=.0002); and 87% and 58% (P=.0003) for the MAID and control groups, respectively.66 The same protocol was later evaluated in the RTOG 9514 study of 66 patients with large (≥8 cm), high-grade (stage II or III; grade 2 or 3 in a 3-tier grading system), primary, or locally recurrent STS of the extremities or trunk.68,69 The 5-year rates of locoregional failure (including amputation) and distant metastasis were 22% and 28%, respectively, with a median follow-up of 7.7 years. The estimated 5-year DFS, distant DFS, and OS rates were 56%, 64%, and 71%, respectively.69 Long-term follow-up data of these studies confirmed that preoperative chemoradiation followed by resection and postoperative chemotherapy with a doxorubicin-based regimen improves local control and OS and DFS rates in patients with high-grade STS of extremity and body wall; however, preoperative chemoradiation was associated with significant short-term toxicities.69,70

Postoperative Therapy: Available evidence from meta-analyses7276 and randomized clinical trials 7782 suggests that postoperative chemotherapy improves relapse-free survival (RFS) in patients with STS of extremities. However, data regarding OS advantage are conflicting.

The Sarcoma Meta-Analysis Collaboration (SMAC) performed a meta-analysis of 14 randomized studies (1,568 patients) that compared postoperative chemotherapy with follow-up and in some cases RT after surgery with a variety of sarcomas.73 The result of the meta-analysis showed that doxorubicin-based chemotherapy prolongs local and distant recurrence and overall RFS in adults with localized, resectable STS of the extremity and is associated with decreased recurrence rates. The OS advantage was not significant, although there was a trend in favor of postoperative chemotherapy.

An updated meta-analysis also confirmed the marginal efficacy of postoperative chemotherapy in terms of local, distant, and overall recurrence as well as OS (which is contrary to that reported in the SMAC meta-analysis) in patients with localized STS (n=1,953).75 A recent large, cohort-based analysis with a median follow-up of 9 years indicated that postoperative chemotherapy may be associated with significantly improved 5-year metastasis-free survival (58% vs 49%; P=.01) and 5-year OS (58% vs 45%; P=.0002) in patients with FNCLCC grade 3 STS, whereas it was not significantly different in those with FNCLCC grade 2 STS (5-year metastasis-free survival: 76% vs 73%; P=.27 and 5-year OS: 75% vs 65%; P=.15).76

In the Italian randomized cooperative study (n=104), which randomized patients with high-grade or recurrent extremity sarcoma to receive postoperative chemotherapy with epirubicin and ifosfamide or observation alone, median DFS (48 vs 16 months) and median OS (75 vs 46 months) were significantly better in the treatment group after a median follow-up of 59 months; the absolute benefit for OS from chemotherapy was 13% at 2 years. The benefit increased to 19% at 4 years for patients receiving chemotherapy.78 After a median follow-up of 90 months, the estimated 5-year OS rate was 66% and 46%, respectively (P=.04), for the treatment group and the control group; however, the difference was not statistically different in the intent-to-treat analysis.83

In another phase III randomized study (EORTC-62931), 351 patients with macroscopically resected grade 2/3 tumors with no metastases were randomized to observation or postoperative chemotherapy with ifosfamide and doxorubicin with lenograstim.80 A planned interim analysis of this study showed no survival advantage for postoperative chemotherapy in patients with resected high-grade STS. The estimated 5-year RFS was 52% in both arms, and the corresponding OS rates were 64% and 69%, respectively, for patients assigned to postoperative chemotherapy and observation. These findings are consistent with the results reported in an earlier EORTC study by Bramwell et al.77 In that study, postoperative chemotherapy with CYVADIC (cyclophosphamide, vincristine, doxorubicin, and dacarbazine) was associated with higher RFS rates (56% vs 43% for the control group; P=.007) and significantly lower local recurrence rates (17% vs 31% for the control group; P=.004). However, no differences in distant metastases (32% and 36%, respectively, for CYVADIC and the control group; P=.42) or OS rates (63% and 56%, respectively, for CYVADIC and the control group; P=.64) were seen.

A recent pooled analysis of these 2 randomized EORTC studies (pooled, n=819) evaluated whether adjuvant doxorubicin-based chemotherapy provided survival benefits in any particular subset of patients with resected STS in these trials.82 Postoperative doxorubicin-based chemotherapy was associated with improved RFS in male patients and those older than 40 years, although female patients and those 40 years or younger who received adjuvant chemotherapy had marginally worse OS. However, RFS and OS were significantly improved in patients with R1 resection who received adjuvant chemotherapy compared with those who did not.

Long-term follow-up results of another prospective randomized study also showed that postoperative chemotherapy with IFADIC (ifosfamide, dacarbazine, and doxorubicin given every 14 days with growth factor support) did not result in significant benefit in terms of RFS (39% for IFADIC and 44% for the control group; P=.87) as well as OS (P=.99) for patients with grade 2 or 3 STS.81

Advanced, Unresectable, or Metastatic Disease

Chemotherapy with single agents (dacarbazine, doxorubicin, epirubicin, or ifosfamide) or anthracycline-based combination regimens (doxorubicin or epirubicin with ifosfamide and/or dacarbazine) have been widely used for patients with advanced, unresectable, or metastatic disease.8496 Other chemotherapeutic agents such as gemcitabine, docetaxel, vinorelbine, pegylated liposomal doxorubicin, and temozolomide have also been evaluated in clinical trials.

Gemcitabine in combination with docetaxel, vinorelbine, or dacarbazine has been shown to be active in patients with unresectable or metastatic STS of various histologic subtypes.97100 In a randomized phase II study, the combination of gemcitabine and docetaxel was associated with superior progression-free survival (PFS; 6.2 and 3.0 months, respectively) and OS (17.9 and 11.5 months, respectively) compared with gemcitabine alone in patients with metastatic STS.98 In another phase II study, the combination of gemcitabine and vinorelbine was also associated with clinically meaningful rates of disease control in patients with advanced STS.99 Clinical benefit (complete response [CR], partial response [PR], or stable disease at 4 months or more) was seen in 25% of patients.

In a more recent randomized study, the combination of gemcitabine and dacarbazine resulted in superior PFS (4.2 vs 2 months; P=.005), OS (16.8 vs 8.2 months; P=.014), and objective response rate (49% vs 25%; P=.009) compared with dacarbazine alone in patients with previously treated advanced STS.100

Temozolomide,101103 pegylated liposomal doxorubicin,104 and vinorelbine105,106 have also shown activity as single agents in patients with advanced, metastatic, relapsed, or refractory disease. In a phase II study by the Spanish Group of Research on Sarcomas, temozolomide resulted in an overall response rate of 15.5% with a median OS of 8 months in patients with advanced pretreated STS.103 The PFS rates at 3 and 6 months were 39.5% and 26%, respectively. In a prospective randomized phase II study, pegylated liposomal doxorubicin had equivalent activity and improved toxicity profile compared with doxorubicin; response rates were 9% and 10% for doxorubicin and pegylated liposomal doxorubicin, respectively, in patients with advanced or metastatic STS.104 In a retrospective study of pretreated patients with metastatic STS, vinorelbine induced overall response in 6% of patients and 26% had stable disease.105

Trabectedin is a novel DNA-binding agent that has shown objective responses in phase II and III studies of patients with advanced STS.107115 Recent phase III data from a randomized, multicenter trial revealed a 2.7-month PFS benefit versus dacarbazine in metastatic liposarcoma or leiomyosarcoma that progressed after anthracycline-based therapy; the study is ongoing to determine OS.113 Another recent study supported the efficacy of trabectedin in translocation-related sarcoma 115 A phase III trial comparing trabectedin and doxorubicin-based chemotherapy revealed that neither arm showed superiority for PFS and OS; however, the trial was underpowered.116

Eribulin is a novel microtubule inhibiting agent that has been evaluated as single-agent therapy for STS, including leiomyosarcoma, adipocytic sarcoma, synovial sarcoma, and other tumor types.117 Recent data from a phase III trial compared the survival benefit of eribulin and dacarbazine in 452 patients with advanced leiomyosarcoma or liposarcoma, revealing a median OS of 13.5 and 11.5 months, respectively (hazard ratio [HR], 0.77; 95% CI, 0.62–0.95; P=.017).118 In January 2016, the FDA approved eribulin for the treatment of liposarcomas only.

Targeted Therapy

More recently, a number of targeted therapies have shown promising results in patients with certain histologic types of advanced or metastatic STS. Pazopanib, a multitargeted tyrosine kinase inhibitor, has demonstrated single-agent activity in patients with advanced STS subtypes except liposarcomas.119 In a phase III study (EORTC 62072), 369 patients with metastatic nonlipogenic STS for whom at least one anthracycline-based chemotherapy regimen had failed were randomized to either pazopanib or placebo.120 Pazopanib significantly prolonged median PFS (4.6 vs 1.6 months for placebo; P<.0001) and there was also a trend toward improved OS (12.5 and 11 months, respectively; P=.25), although it was not statistically significant. Pooled data from individuals who received pazopanib in phase II and III trials (n=344) revealed a subset of long-term responders/survivors presenting at baseline with good performance status, low/intermediate-grade primary tumors, and normal hemoglobin levels.121 The guidelines have included pazopanib as an option for palliative therapy for patients with progressive, unresectable, or metastatic nonlipogenic STS.

Imatinib122 and sunitinib123,124 have also shown efficacy in patients with advanced and/or metastatic STS other than GIST. Crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, was active in inflammatory myofibroblastic tumor with ALK translocation.125 The updated guidelines also include ceritinib, a next-generation ALK-inhibitor that has been successful in treating ALK-rearranged non–small cell lung cancer.126

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus have also shown promising results in patients with metastatic perivascular epithelioid cell tumors and in those with recurrent lymphangi-oleiomyomatosis or angiomyolipomas.127133 Additionally, sorafenib may be active in select subtypes of advanced and/or metastatic STS other than GIST (eg, leiomyosarcoma, desmoid tumors).134,135

Bevacizumab either alone or in combination with temozolomide was well tolerated and effective in patients with metastatic or locally advanced or recurrent epithelioid hemangiopericytoma and malignant solitary fibrous tumor.136,137

Palbociclib, an inhibitor of cyclin-dependent kinases 4 and 6, induced objective tumor response and a favorable PFS of 56% to 66% in patients with cyclin-dependent kinase-4–amplified, well-differentiated, or dedifferentiated liposarcoma.138,139

Individual Disclosures of the NCCN Soft Tissue Sarcoma Panel

T1

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    NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma, Version 2.2016

    Version 2.2016, 02-19-16 ©2016 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma, Version 2.2016

    Version 2.2016, 02-19-16 ©2016 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma, Version 2.2016

    Version 2.2016, 02-19-16 ©2016 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

  • View in gallery

    NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma, Version 2.2016

    Version 2.2016, 02-19-16 ©2016 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

  • View in gallery

    NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma, Version 2.2016

    Version 2.2016, 02-19-16 ©2016 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

  • View in gallery

    NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma, Version 2.2016

    Version 2.2016, 02-19-16 ©2016 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

  • View in gallery

    NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma, Version 2.2016

    Version 2.2016, 02-19-16 ©2016 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

  • View in gallery

    Soft Tissue Sarcoma, Version 2.2016

    Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are category 2A unless otherwise indicated.

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