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Second and later lines of therapy for metastatic soft tissue sarcoma

Second and later lines of therapy for metastatic soft tissue sarcoma
Literature review current through: May 2024.
This topic last updated: Apr 30, 2024.

INTRODUCTION — Soft tissue sarcomas (STS) are a heterogeneous group of rare tumors that arise from mesenchymal cells, such as muscle, adipose, fibrous, cartilage, nerve, and vascular tissue. STS arise most frequently in the limbs (particularly the lower extremity), followed by the abdominal cavity/retroperitoneum, the trunk/thoracic region, and the head and neck. There are many histologic subtypes of STS which have distinct clinical profiles, molecular alterations, treatment responses, and prognoses. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma".)

Second- and later-line therapies for common metastatic STS histologies that will be reviewed here. For most patients, we offer clinical trials specific to their histologic subtype, where available. For those who decline or are ineligible for clinical trials, our treatment approach is based on the specific STS histology and treatments previously received.

An overview of the initial treatment of common advanced or metastatic STS histologies, the management of other types of advanced or metastatic STS (as noted below), bone sarcomas (Ewing sarcoma, osteosarcoma, chondrosarcoma), tenosynovial giant cell tumors, and select uncommon sarcoma subtypes are presented separately.

Overview of the initial treatment of metastatic soft tissue sarcoma (see "Overview of the initial treatment of metastatic soft tissue sarcoma")

Gastrointestinal stromal tumors (see "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors")

Breast sarcoma (see "Breast sarcoma: Treatment")

Uterine leiomyosarcoma (see "Treatment and prognosis of uterine leiomyosarcoma")

Head and neck sarcomas (see "Head and neck sarcomas")

Rhabdomyosarcoma (see "Rhabdomyosarcoma in childhood, adolescence, and adulthood: Treatment")

Desmoid tumors (see "Desmoid tumors: Systemic therapy")

Solitary fibrous tumors (see "Solitary fibrous tumor")

Dermatofibrosarcoma protuberans (see "Dermatofibrosarcoma protuberans: Treatment")

Kaposi sarcoma (see "Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment" and "AIDS-related Kaposi sarcoma: Staging and treatment")

Ewing sarcoma (see "Treatment of Ewing sarcoma")

Osteosarcoma (see "Chemotherapy and radiation therapy in the management of osteosarcoma")

Chondrosarcoma (see "Chondrosarcoma")

Tenosynovial giant cell tumors (see "Treatment for tenosynovial giant cell tumor and other benign neoplasms affecting soft tissue and bone", section on 'Tenosynovial giant cell tumor')

Uncommon sarcoma subtypes (see "Uncommon sarcoma subtypes")

ANGIOSARCOMA

Second-line therapy — Anthracycline-based regimens and taxanes are both used as initial therapy for most patients with metastatic angiosarcoma [1]. (See "Overview of the initial treatment of metastatic soft tissue sarcoma", section on 'Angiosarcoma'.)

Prior anthracyclines – For patients with metastatic angiosarcoma who progress on initial anthracycline-based therapy, we suggest second-line therapy with a taxane (such as paclitaxel (table 1)) rather than other systemic agents.

Paclitaxel was evaluated in a single-arm phase II trial (ANGIOTAX) of 30 patients with unresectable angiosarcoma. At median follow-up of eight months, within the subgroup of 11 patients who had progressed on anthracycline-based chemotherapy, the progression-free survival (PFS) rate was 77 percent [2]. Data for the entire study population, including chemotherapy-naïve patients, is discussed separately. (See "Overview of the initial treatment of metastatic soft tissue sarcoma", section on 'Angiosarcoma'.)

Prior taxanes – For patents with metastatic angiosarcoma who progress on taxanes, we suggest second-line therapy with an anthracycline-based regimen rather than other systemic agents. The rationale for anthracyclines as second-line therapy is mainly extrapolated from data on these agents as initial therapy for metastatic angiosarcoma that suggest similar efficacy to taxanes [3-5]. Although clinical practice is variable and many anthracycline-based regimens are available, we use pegylated liposomal doxorubicin which is relatively well tolerated and effective in angiosarcomas previously treated with taxanes [3].

Later-line therapy (angiosarcoma) — Later-line options for metastatic angiosarcoma include gemcitabine-based regimens, pazopanib, and immune checkpoint inhibitors (ie, immunotherapy) such as pembrolizumab or nivolumab plus ipilimumab. Immunotherapy is especially effective for those with cutaneous or head and neck angiosarcomas.

Gemcitabine-based regimens — Gemcitabine-based regimens used as later-line therapy for angiosarcomas are the same as those used as initial therapy for select anthracycline-responsive metastatic STS histologies and are discussed separately. (See "Overview of the initial treatment of metastatic soft tissue sarcoma", section on 'Ineligible for anthracyclines'.)

Pazopanib (angiosarcoma) — Pazopanib has activity as later-line therapy in patients with angiosarcoma, including those with cutaneous disease [6-8]. Pazopanib improved PFS in a randomized placebo-controlled phase III trial (PALETTE) of patients with metastatic STS who had previously received chemotherapy (including anthracyclines) [6]. Although this study presumably included patients with angiosarcoma, the specific number is unreported. (See 'Pazopanib' below.)

Pazopanib was also evaluated as the control therapy in a separate randomized study of 123 patients with treatment-refractory advanced angiosarcoma. Among the 64 patients with cutaneous angiosarcoma treated with pazopanib alone, median PFS and overall survival (OS) were six and eight months, respectively [8]. However, for cutaneous angiosarcoma, it is challenging to accurately measure objective responses to pazopanib. For example, clinical benefit could present as a change in color and appearance rather a decrease in tumor size, whereas disease progression could present as tumor thickening and bleeding rather than an increase in tumor size.

Pembrolizumab (angiosarcoma) — Pembrolizumab, an immune checkpoint inhibitor, is a later-line treatment option for patients with angiosarcoma, especially those with cutaneous disease or tumors involving the head and neck region. In one case series, seven patients with angiosarcoma (five of whom had cutaneous angiosarcoma) were treated with immune checkpoint inhibitors, included four patients treated with pembrolizumab [9]. At three-month follow-up, partial responses were seen in five patients (71 percent) either on imaging or clinical exam [9]. (See "Head and neck sarcomas", section on 'Angiosarcoma'.)

Nivolumab plus ipilimumab — Combination immunotherapy with nivolumab plus ipilimumab is an option for patients with previously treated angiosarcoma, especially those with cutaneous disease or tumors involving the head and neck region. Nivolumab plus ipilimumab was evaluated in a single-arm phase II trial of 16 patients with unresectable angiosarcoma, including nine patients with cutaneous disease [10]. Objective responses were seen in four patients (25 percent) and complete responses were seen in three of five patients with cutaneous scalp or face tumors (60 percent). The six-month PFS was 38 percent.

Other agents (angiosarcoma) — Other agents with modest clinical activity (objective response rates of less than 20 percent) include vinorelbine [11], regorafenib [12], sorafenib [13,14], sunitinib [15], and bevacizumab [16,17]. There is no role for the addition of bevacizumab to paclitaxel, which failed to improve OS in a randomized phase II trial of advanced angiosarcoma (ANGIOTAX-PLUS) [18].

LEIOMYOSARCOMA

Second-line therapy — For patients with metastatic leiomyosarcoma (LMS), either anthracycline-based regimens or gemcitabine plus docetaxel are appropriate options for initial therapy. (See "Overview of the initial treatment of metastatic soft tissue sarcoma", section on 'Leiomyosarcoma' and "Treatment and prognosis of uterine leiomyosarcoma", section on 'Metastatic disease'.)

Gemcitabine plus docetaxel (LMS) — For patients with metastatic LMS who progress on initial therapy with anthracycline-based regimens, we suggest second-line therapy with gemcitabine plus docetaxel (table 2) rather than other gemcitabine-based regimens. Studies also suggest that this combination has specific activity in treatment-refractory LMS.

For those who are unable to tolerate the potential toxicities of adding docetaxel to gemcitabine, appropriate alternatives include other gemcitabine-based combinations (gemcitabine plus vinorelbine, gemcitabine plus dacarbazine) and single-agent gemcitabine, extrapolating from studies of these agents as initial systemic therapy. Single-agent gemcitabine is favored in patients with limited disease burden without impending organ dysfunction, older adults, or those with significant comorbidities. (See "Overview of the initial treatment of metastatic soft tissue sarcoma", section on 'Ineligible for anthracyclines'.)

Gemcitabine plus docetaxel is an active agent in anthracycline-refractory LMS [19-24] that can stabilize disease in a majority of patients [25], although data are mixed for its efficacy.

In a retrospective analysis, 133 patients with unresectable or metastatic STS (a majority of whom had previously received doxorubicin and/or ifosfamide) were treated with gemcitabine plus docetaxel. The study included 76 patients with leiomyosarcoma and 57 patients with other histologic subtypes. Among patients with leiomyosarcoma, gemcitabine plus docetaxel demonstrated objective response rate of 24 percent and one-year overall survival (OS) of 56 percent [19]. Among patients receiving this combination, LMS was associated with improved OS compared with other histologies, which has also been confirmed in other studies [20,22].

By contrast, in a randomized phase II trial (TAXOGEM), the addition of docetaxel to gemcitabine failed to improve outcomes in patients with anthracycline-refractory nonuterine LMS. However, this regimen stabilized disease in over half of patients.

In the TAXOGEM study, 90 patients with metastatic LMS of uterine (n = 46) or nonuterine (n = 44) origin who had previously received one prior anthracycline-based regimen were randomly assigned to either gemcitabine (900 mg/m2 on days 1 and 8) plus docetaxel (100 mg/m2 on day 8 of a 21-day cycle) or gemcitabine alone (1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle) [25]. Among those with nonuterine LMS, the addition of docetaxel to gemcitabine demonstrated lower objective response rates (5 versus 14 percent) and failed to improve progression-free survival (PFS; median 3.8 versus 6.3 months). However, the stable disease rate was similar between the two treatment arms (58 versus 53 percent).

Anthracycline-based regimens (LMS) — For patients with metastatic leiomyosarcoma (LMS) who progress on initial therapy with gemcitabine plus docetaxel, we suggest second-line therapy with an anthracycline-based regimen rather than other systemic agents, extrapolating from studies of these agents as initial systemic therapy. Effective regimens include doxorubicin plus dacarbazine and doxorubicin plus trabectedin, which are discussed separately. (See "Overview of the initial treatment of metastatic soft tissue sarcoma", section on 'Leiomyosarcoma'.)

Later-line therapy (LMS) — The selection of later-line therapy for metastatic leiomyosarcoma (LMS) is based on patient co-morbidities and performance status as well as patient and clinician preference. Options (if not previously received), include trabectedin, pazopanib, eribulin, and dacarbazine, among other agents.

Trabectedin (LMS)

Dosing and administration — Trabectedin is an antineoplastic agent that kills cells by poisoning the DNA nucleotide excision repair machinery [26]. Trabectedin was originally isolated from the Caribbean sea sponge Ecteinascidia turbinata, but it is now synthetically produced.

Trabectedin is administered at 1.5 mg/m2 intravenously over 24 hours on day 1 of a 21-day cycle. Dexamethasone (20 mg) is administered intravenously 30 minutes prior to each dose to reduce hepatotoxicity risk [27,28]. (See "Hepatotoxicity of chemotherapy and other cytotoxic agents", section on 'Trabectedin'.)

Trabectedin is administered on an every-three-week schedule because this approach prolonged treatment response over weekly dosing in a randomized phase II trial of patients with previously treated advanced leiomyosarcoma (LMS) or liposarcoma. In this study, administering trabectedin at 1.5 mg/m2 intravenously on day 1 of a 21-day cycle improved the median time to tumor progression compared with 0.58 mg/m2 intravenously on days 1, 8, and 15 of a 28-day cycle (3.7 versus 2.3 months, hazard ratio [HR] 0.73, 95% CI 0.55-0.97) [29].

Hepatic toxicity of trabectedin is greatest on days 5 to 7 of each cycle. Liver function tests checked on one of these days will help guide dosing for the subsequent cycle. If the total bilirubin is elevated or alkaline phosphatase is elevated, the subsequent cycle should be given with a dose reduction to decrease the risk of toxicity of the subsequent cycle.

Efficacy and toxicity — Trabectedin improved PFS and had similar OS compared with dacarbazine in a phase III trial of patients with treatment-refractory leiomyosarcoma [30,31].

The efficacy of trabectedin in LMS was initially established in phase II trials of both chemotherapy-naïve and refractory LMS [32-36]. In a subsequent phase III trial (ET743-SAR-3007), 577 patients with advanced LMS or liposarcoma previously treated with anthracycline-based chemotherapy were randomly assigned to trabectedin versus dacarbazine [30,31]. Most of the patients with LMS had received both doxorubicin-based and gemcitabine-based therapy. Approximately three-fourths of those enrolled had LMS (423 patients), and the remaining one-third had liposarcomas (154 patients).

At median follow-up of approximately 21 months, trabectedin resulted in the following, relative to dacarbazine [30,31]:

Entire study population – Improved PFS (median 4 versus 2 months, HR 0.55, 95% CI 0.44-0.70) and similar overall survival (OS; median 14 versus 13 months, HR 0.93, 95% CI 0.75-1.15).

Pretreated LMS

Improved PFS and similar OS (median PFS 4 versus 2 months, HR 0.56, 95% CI 0.42-0.73; median OS 14 versus 13 months, HR 0.89, 95% CI 0.69-1.15).

Improved PFS in both nonuterine and uterine disease (nonuterine disease, median five versus two months, HR 0.58, 95% CI 0.37-0.92; uterine disease, four versus two months, HR 0.58, 95% CI 0.41-0.81).

Improved clinical benefit rates (ie, objective disease response plus stable disease rate; 37 versus 20 percent). Although the objective response rate for trabectedin by conventional criteria is low [32-34,37,38], stable disease is also a beneficial endpoint for metastatic STS [29,32-34,37,39]. (See "Overview of the initial treatment of metastatic soft tissue sarcoma", section on 'Assessment of treatment response'.)

Grade ≥3 toxicities for trabectedin included neutropenia, thrombocytopenia, anemia, and transient elevations in aminotransferases. Nine treatment-related deaths were reported due to infection, rhabdomyolysis, and renal failure. Trabectedin carries a warning for risk of severe and fatal neutropenic sepsis; rhabdomyolysis and hepatotoxicity; skin and soft tissue necrosis following extravasation; and heart failure. (See "Rhabdomyolysis: Epidemiology and etiology" and "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines", section on 'Trabectedin' and "Extravasation injury from cytotoxic and other noncytotoxic vesicants in adults", section on 'Selective use of antidotes'.)

Based on these data, trabectedin was approved by the US Food and Drug Administration (FDA) for patients with unresectable or metastatic LMS or liposarcoma who have received a prior anthracycline-containing therapy [40].

Pazopanib (LMS) — Pazopanib is an option for patients with leiomyosarcoma (LMS) who progress on prior chemotherapy, including but not limited to anthracycline-based regimens. In a randomized, double-blind, placebo-controlled phase III trial (PALETTE), pazopanib demonstrated a non-statistically significant trend towards improved PFS in a subgroup of patients with anthracycline-refractory leiomyosarcoma (HR 0.88, 95% CI 0.63-1.21) [6]. Data on pazopanib for the entire study population are discussed separately. (See 'Efficacy and toxicity' below.)

Eribulin (LMS) — Eribulin is an option for treatment-refractory LMS, though it does not have regulatory authorization. A randomized phase III trial compared eribulin to dacarbazine in 452 patients with advanced LMS or liposarcoma previously treated with an anthracycline [41-43]. Among the subgroup of 309 patients with leiomyosarcoma, eribulin demonstrated similar PFS (2.2 versus 2.6 months, HR 1.07, 95% CI 0.84-1.38), OS (median 12.7 versus 13 month; HR 0.93, 95% CI 0.71-1.20), and objective response rate (5 versus 7 percent) compared with dacarbazine [43].

Further details on the efficacy of eribulin in this study for liposarcoma are discussed separately. (See 'Eribulin (liposarcoma)' below.)

Dacarbazine — Dacarbazine is an option for treatment-refractory LMS. In separate randomized trials of patients with LMS who had progressed on prior chemotherapy including anthracyclines, dacarbazine demonstrated similar OS compared with trabectedin [30,31] and eribulin [43].

Other agents (LMS) — Other agents with modest activity in treatment-refractory LMS include temozolomide [44,45], and regorafenib [46].

We do not routinely use the combination of pazopanib plus gemcitabine to treat LMS. The addition of gemcitabine to pazopanib improved PFS rates in a randomized phase II trial of patients with STS (predominantly LMS and liposarcoma) who had progressed on prior anthracycline and/or ifosfamide-based therapy [47] and had similar efficacy compared with gemcitabine plus docetaxel in a separate phase II trial [20]. However, further data are necessary before incorporating this combination into routine clinical practice.

SYNOVIAL SARCOMA

Second-line therapy — For patients with metastatic synovial sarcoma, anthracyclines with or without ifosfamide are the preferred initial therapy. (See "Overview of the initial treatment of metastatic soft tissue sarcoma", section on 'Histologies where anthracyclines are preferred'.)

Prior single-agent anthracycline – For patients with metastatic synovial sarcoma who progress on a single-agent anthracycline, we suggest second-line therapy with an ifosfamide-based regimen rather than other agents, as synovial sarcoma is highly sensitive to ifosfamide [48-51].

Prior anthracyclines and ifosfamide – For those patients with metastatic synovial sarcoma who progress on anthracyclines and ifosfamide (either in combination or in sequence), we suggest pazopanib or trabectedin rather than other systemic agents. Both agents are acceptable options that have improved progression-free survival (PFS) over placebo or best supportive care in randomized trials, although they have not been directly compared. (See "Overview of the initial treatment of metastatic soft tissue sarcoma", section on 'Ineligible for anthracyclines'.)

T-cell therapy is an investigational strategy being evaluated in synovial sarcoma, as discussed below. (See 'T-cell therapy' below.)

Pazopanib (synovial sarcoma) — Pazopanib is an option for patients with synovial sarcoma who progress on initial chemotherapy (including but not limited to anthracycline-based chemotherapy). In a randomized, double-blind, placebo-controlled phase III trial (PALETTE), pazopanib demonstrated a non-statistically significant trend towards improved PFS in a subgroup of patients with anthracycline-refractory synovial sarcoma (HR 0.82, 95% CI 0.51-1.32) [6]. Data on pazopanib for the entire study population are discussed separately. (See 'Efficacy and toxicity' below.)

Trabectedin (synovial sarcoma) — Trabectedin is an option for patients with synovial sarcoma who progress on anthracycline-based chemotherapy. Trabectedin has demonstrated activity as subsequent therapy in translocation-related sarcomas (table 3), including synovial sarcomas [52,53]. (See "Pathogenetic factors in soft tissue and bone sarcomas", section on 'Chromosomal translocations'.)

In an open-label phase II trial, 76 patients with advanced, translocation-related sarcoma previously treated with an anthracycline (including 18 patients with synovial sarcoma) were randomized to trabectedin (1.2 mg/m2 over 24 hours on day 1 every 21 days) versus best supportive care [52]. After a median follow-up of approximately nine months, trabectedin improved PFS in the entire study population (5.6 versus 0.9 months, HR 0.07, 95% CI 0.03-0.16), including those with synovial sarcoma (HR 0.14, 95% CI 0.03-0.68). Common grade ≥3 toxicities for trabectedin included nausea (9 percent), decreased appetite (8 percent), febrile neutropenia (11 percent), and increased alanine aminotransferase (47 percent).

Data for trabectedin in other STS histologies such as non-uterine leiomyosarcoma and liposarcoma are discussed separately. (See 'Trabectedin (LMS)' above and 'Trabectedin (liposarcoma)' below.)

Later-line therapy (synovial sarcoma) — Regorafenib is a later-line treatment option for metastatic synovial sarcoma. Gemcitabine-based therapy is also an option but has limited efficacy in this population [54].

Regorafenib — Regorafenib was evaluated in a double-blind, randomized, placebo-controlled trial (REGOSARC) of 182 patients with liposarcoma, LMS, synovial sarcoma, and other types of STS previously treated with an anthracycline [46]. Six patients had previously received pazopanib. Among patients with synovial sarcoma, regorafenib improved PFS over placebo (6 versus 1 month; HR 0.10, 95% CI 0.30-0.35). The most common adverse events, seen in more than one-third of the regorafenib-treated patients, were asthenia, diarrhea, mucositis, acral erythema, anorexia, and arterial hypertension.

MALIGNANT PERIPHERAL NERVE SHEATH TUMORS

Second-line therapy — For most patients with metastatic malignant peripheral nerve sheath tumors (MPNST), options for initial therapies include doxorubicin with or without ifosfamide, and ifosfamide plus etoposide. (See "Overview of the initial treatment of metastatic soft tissue sarcoma", section on 'Histologies where anthracyclines are preferred'.)

For patients with metastatic MPNST progress on initial therapy with anthracycline and/or ifosfamide-based regimens, we suggest second-line therapy with pazopanib rather than other systemic therapies. Patients are also encouraged to enroll in clinical trials, where available, since metastatic MPNST has a poor prognosis and effective treatment options are limited.

Pazopanib is a relatively well-tolerated agent that improved progression-free survival (PFS) in a placebo-controlled randomized phase III trial (PALETTE) of patients with treatment-refractory STS; although this study presumably included patients with MPNST, the specific number is unreported [6]. Further details of this study are discussed separately. (See 'Pazopanib' below.)

In a separate phase II trial of patients with metastatic MPNST previously treated with anthracycline-based therapy, the clinical benefit rate (objective responses and stable disease) was 50 percent. Median PFS and overall survival (OS) were 5 and 11 months, respectively [55].

Other systemic regimens have minimal efficacy when used as subsequent-line therapy for metastatic MPNST, such as platinum-based therapy; dacarbazine; gemcitabine plus docetaxel; and single-agent etoposide [56].

LIPOSARCOMA

Second-line therapy — For patients with metastatic liposarcoma, anthracycline-based regimens are the preferred initial therapy. (See "Overview of the initial treatment of metastatic soft tissue sarcoma", section on 'Histologies where anthracyclines are preferred'.)

For those with metastatic liposarcoma who progress on anthracyclines-based regimens, we suggest second-line therapy with gemcitabine plus docetaxel rather than other systemic agents. Gemcitabine plus docetaxel may be an effective treatment option for patients with metastatic liposarcoma who progress on anthracycline-based therapy, especially those with pleomorphic and well-differentiated/dedifferentiated liposarcoma [23,24]. Single-agent gemcitabine is an appropriate alternative for patients with poor performance status or multiple comorbidities who are unable to tolerate the potential toxicities of gemcitabine-based combination therapy.

In a randomized phase II trial of 122 patients with STS of various histologies treated with an average of one prior line of therapy, the addition of docetaxel to gemcitabine improved progression-free survival (PFS) and overall survival (OS) [23]. Among the eight patients with liposarcoma who received gemcitabine plus docetaxel, the best responses were seen among those with the pleomorphic (two partial responses and one with stable disease <24 weeks) and well-differentiated/dedifferentiated (four with stable disease for <24 weeks) subtypes.

Later-line therapy (liposarcoma) — Our approach to selecting later-line therapy for treatment-refractory liposarcoma is based on the primary histologic subtype of the liposarcoma and patient preference:

Dedifferentiated or pleomorphic liposarcoma – For most patients with dedifferentiated or pleomorphic liposarcoma who progress on anthracyclines as well as gemcitabine plus docetaxel, eribulin is an appropriate later-line treatment option. In phase III trials, eribulin conferred an OS benefit over chemotherapy in these histologies, whereas trabectedin did not. (See 'Eribulin (liposarcoma)' below and 'Trabectedin (liposarcoma)' below.)

For the subset of patients with well-differentiated or dedifferentiated liposarcoma and more indolent disease, a CDK4/6 inhibitor, such as palbociclib, is an alternative to further chemotherapy. (See 'CDK4/6 inhibitors' below.)

Myxoid-round cell liposarcoma – For patients with myxoid-round cell liposarcoma who progress on anthracyclines and gemcitabine plus docetaxel, trabectedin is an effective strategy because it targets a unique fusion protein in this translocation-related sarcoma (table 3). Eribulin is a reasonable alternative but is associated with a lower response rate. (See 'Trabectedin (liposarcoma)' below.)

Eribulin (liposarcoma) — Eribulin is one preferred option for most patients with liposarcoma who progress on multiple prior regimens, including anthracycline-based therapy. In a randomized phase III trial, relative to chemotherapy, eribulin improved PFS and OS in patients with liposarcoma of various subtypes (including dedifferentiated, myxoid-round cell, and pleomorphic liposarcoma) but increased toxicity [41,42].

Eribulin inhibits microtubules via a mechanism that is distinct from other microtubule-targeting agents, such as taxanes. An initial phase II trial suggested that eribulin was active in a variety of STS histologies, including LMS, adipocytic sarcoma such as liposarcoma, synovial sarcoma, and others [57]. The specific efficacy of eribulin over dacarbazine in advanced liposarcoma was subsequently confirmed in a randomized phase III trial [41]. In this trial, 452 patients with advanced LMS or liposarcoma previously treated with at least two prior systemic regimens (including an anthracycline) were randomly assigned to eribulin (1.4 mg/m2 intravenously on days 1 and 8) or dacarbazine (between 850 and 1200 mg/m2 intravenously on day 1) every 21 days [41-43]. Approximately one-third of patients enrolled had liposarcomas (143 patients). The remaining two-thirds of enrolled patients had LMS (309 patients), of which over one-half had nonuterine disease (57 percent). The use of eribulin in advanced or metastatic LMS of uterine origin is discussed separately. (See "Treatment and prognosis of uterine leiomyosarcoma", section on 'Eribulin'.)

At a median follow-up of 31 months, relative to dacarbazine, eribulin improved overall survival (OS; median 13.5 versus 11.5 months, HR 0.77, 95% CI 0.62-0.95) and demonstrated similar PFS (median 2.6 months in both arms) in the entire study population (LMS and liposarcoma) [41]. Among those with liposarcoma, eribulin improved both OS (15.6 versus 8.4 months, HR 0.51, 95% CI 0.35-0.75) and PFS (median 2.9 versus 1.7 months, HR 0.52, 95% CI 0.35-0.78) [42]. OS benefit was seen across multiple liposarcoma subtypes including dedifferentiated, myxoid-round cell, and pleomorphic liposarcoma [42]. One possible reason for this discrepancy between PFS and OS is that patients who failed eribulin on the clinical trial could receive standard of care trabectedin. However, patients progressing on trabectedin could not receive eribulin.

Eribulin increased treatment-related toxicity relative to chemotherapy in all patients (67 versus 56 percent), including higher rates of neutropenia (43 versus 24 percent), pyrexia (28 versus 14 percent), peripheral sensory neuropathy (21 versus 4 percent), and alopecia (35 versus 3 percent) [41,43].

Based on these data, eribulin was approved by the US Food and Drug Administration (FDA) for patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen [58]; and for similar indications in Canada and Europe. Eribulin is also approved for both leiomyosarcoma and liposarcoma in Japan and the Philippines. (See 'Eribulin (LMS)' above.)

Trabectedin (liposarcoma) — Trabectedin is one option for patients with liposarcoma who progress on anthracycline-based chemotherapy. Eribulin is particularly effective for myxoid-round cell liposarcoma, as it improved PFS for this subgroup in a phase III trial [30,31].

Trabectedin represents a unique form of molecularly targeted therapy in myxoid liposarcoma. Myxoid liposarcoma, a translocation-related sarcoma (table 3), is defined by unique chromosomal translocations that results in the expression of specific fusion oncoproteins. Trabectedin interferes with the ability of these fusion proteins to bind to DNA promoter regions, resulting in antineoplastic effects [59]. (See "Pathogenetic factors in soft tissue and bone sarcomas", section on 'Myxoid liposarcomas' and 'Translocation-related sarcomas' below.)

Based on initial data from observational studies [60,61] and phase II trials [53,62], trabectedin was evaluated in a randomized, controlled phase III trial (ET743-SAR-3007) of 577 patients with advanced LMS or liposarcoma previously treated with anthracycline-based chemotherapy and at least one additional systemic regimen. Among the subgroup of 154 patients with pretreated liposarcoma, trabectedin resulted in the following, relative to dacarbazine [30,31]:

Similar OS but improved PFS (median OS 13.1 versus 12.6 months, HR 1.05, 95% CI 0.69-1.60; median PFS 3.0 versus 1.5 months, HR 0.55, 95% CI 0.34-0.87).

Improved PFS in those with myxoid-round cell histology (median 5.6 versus 1.5 months, HR 0.41, 95% CI 0.17-0.98) but not in those with dedifferentiated or pleomorphic histology (median 2.2 versus 1.9 months, HR 0.68, 95% CI 0.37-1.25, and 1.5 versus 1.4 months, HR 0.33, 95% CI 0.07-1.64, respectively).

Clinical benefit rates were numerically higher but not statistically significant (28 versus 15 percent).

Grade ≥3 toxicities for trabectedin included neutropenia (37 percent) and transient elevation of transaminases (26 percent for ALT and 13 percent for AST).

Data from this trial for trabectedin in leiomyosarcoma and the entire study population, along with toxicity information, are discussed separately. (See 'Trabectedin (LMS)' above.)

Based on these data, the FDA approved trabectedin for patients with advanced leiomyosarcoma and liposarcoma previously treated with an anthracycline-containing chemotherapy regimen [40].

CDK4/6 inhibitors — A majority of well-differentiated or dedifferentiated liposarcomas (>90 percent) express amplification of cyclin-dependent kinase (CDK) 4. For such patients, a CDK4/6 inhibitor, such as palbociclib, is a subsequent-line treatment option with modest efficacy. These agents are a reasonable alternative for patients with more indolent disease who are unable to tolerate or decline chemotherapy.

In separate phase II trials of patients with well-differentiated or dedifferentiated liposarcoma, palbociclib demonstrated a twelve-week PFS of up to 66 percent [63,64], while abemaciclib demonstrated a twelve-week PFS of 77 percent [65].

The use of other CDK4/6 inhibitors such as ribociclib or abemaciclib remains investigational [66,67].

Agents not used for liposarcoma — Agents that are not used to treat advanced or metastatic liposarcoma due to lack of activity include regorafenib [46,68], pazopanib [55,69,70], and pembrolizumab [71,72].

We do not use pazopanib for adipocytic STS (eg, myxoid-round cell or well differentiated/dedifferentiated liposarcoma) due to limited efficacy, consistent with its lack of regulatory approval for this subtype. In phase II trials of various treatment-refractory STS histologies, pazopanib demonstrated low response rates compared with other STS histologies [55,69,70]. Based on these data, adipocytic histologies such as liposarcoma were excluded from the randomized phase III trial (PALETTE) that evaluated pazopanib in treatment-refractory STS. These data are discussed separately. (See 'Pazopanib' below.)

Pembrolizumab has limited activity in dedifferentiated and myxoid-round cell liposarcoma. Although data from a phase II trial (SARC028) suggested that pembrolizumab was active in dedifferentiated liposarcoma [71], this was not confirmed in a subsequent expansion cohort [72]. Nonetheless, NCCN guidance indicates that programmed cell death 1 inhibitors with or without cytotoxic T-lymphocyte-associated antigen 4 inhibition is a reasonable option for patients with recurrent and/or metastatic dedifferentiated liposarcoma.

UNDIFFERENTIATED AND UNCLASSIFIED SARCOMAS — Undifferentiated and unclassified STS (eg, undifferentiated pleomorphic sarcoma, myxofibrosarcoma, and sarcoma not otherwise specified [NOS]) are tumors with aneuploid karyotypes. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Most common subtypes'.)

Second-line therapy — For patients with metastatic undifferentiated/unclassified STS, anthracycline-based regimens are the preferred initial therapy. (See "Overview of the initial treatment of metastatic soft tissue sarcoma", section on 'Histologies where anthracyclines are preferred'.)

For patients who metastatic undifferentiated or unclassified STS who progressed on anthracyclines, we suggest second-line therapy with gemcitabine plus docetaxel rather than other systemic agents, as UPS is more responsive to this combination than other histologies. As an example, a randomized phase II trial of 122 patients with metastatic STS of various histologies demonstrated an overall survival (OS) benefit for gemcitabine plus docetaxel over gemcitabine monotherapy [23]. Among the eleven patients with UPS treated with gemcitabine plus docetaxel, partial responses were seen in four patients (36 percent), which was higher than the partial response rate seen in the entire study population (16 percent).

Later-line therapy (undifferentiated/unclassified sarcoma) — Later-line treatment options for undifferentiated/unclassified sarcomas include pazopanib and immune checkpoint inhibitors such as pembrolizumab and nivolumab plus ipilimumab.

Pazopanib — In the placebo-controlled phase III trial (PALETTE), pazopanib improved progression-free survival (PFS) across various non-adipocytic STS histologies previously treated with anthracycline-based regimens. Although this study presumably included patients with undifferentiated/unclassified sarcoma, the specific number is unreported. Further details of this trial are discussed separately. (See 'Efficacy and toxicity' below.)

PembrolizumabPembrolizumab is an option for subsequent-line therapy in undifferentiated and unclassified STS, extrapolating from studies of undifferentiated pleomorphic sarcoma (UPS).

In an open-label phase II trial (SARC028), pembrolizumab was administered to patients with metastatic STS and bone sarcomas who had received up to three prior lines of systemic therapy. There were 10 patients enrolled to each of four cohorts of STS: undifferentiated pleomorphic sarcoma (UPS), poorly differentiated/dedifferentiated liposarcoma, synovial sarcoma, and LMS [71,72]. In the entire cohort of STS histologies, at median follow-up of 19 months, the objective response rate was 18 percent, and 12-week PFS was 55 percent. Among those with UPS, objective responses were seen in four patients (40 percent) and was subsequent confirmed in an expansion cohort [72]. The other STS histologies (liposarcoma, synovial sarcoma, and LMS) had limited objective responses to pembrolizumab (20 percent or less).

Nivolumab plus ipilimumabNivolumab plus ipilimumab is an option for subsequent-line therapy in undifferentiated and unclassified STS, extrapolating from studies of UPS.

In two noncomparative phase II trials (Alliance A091401), 85 patients with metastatic STS of various histologies previously treated with at least one line of therapy were randomly assigned to either nivolumab plus ipilimumab for four doses followed by maintenance nivolumab or single-agent nivolumab [73]. Nivolumab plus ipilimumab demonstrated a higher objective response rate (16 percent; six patients, including those with UPS histology) versus nivolumab (5 percent; two patients). Similar results were seen in an expansion cohort study of A091401. In preliminary results, among the 24 patients with UPS, the objective response rates at six months for nivolumab and ipilimumab was 14 percent [74]. Median duration of response and PFS were approximately 7 and 3 months, respectively.

NON-SPECIFIC HISTOLOGIES

Pazopanib — We suggest pazopanib rather than chemotherapy for patients with other non-specific advanced or metastatic STS histologies who progress on chemotherapy (including but not limited to anthracycline-based regimens) and do not have a histology-specific treatment approach available. In a phase III trial (PALETTE) of patients with anthracycline-resistant metastatic STS, pazopanib improved progression-free survival (PFS) over placebo [6]. Of note, pazopanib is not approved in the United States for the treatment of adipocytic tumors such as liposarcoma, or gastrointestinal stromal tumors (GIST). (See 'Efficacy and toxicity' below.)

Administration — Pazopanib is a multitargeted, orally active small molecule inhibitor of several tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor alpha (PDGFRA) and beta (PDGFRB).

Pazopanib should be taken either one hour before or two hours after a meal. It should not be administered with proton pump inhibitors or histamine H2 receptor antagonists. Short-acting antacids could be offered in place of these agents, as long as the dosing of antacids and pazopanib are separated by several hours. The solubility of pazopanib is pH dependent, and an elevated gastric pH (which occurs with gastric acid suppressive agents) may decrease bioavailability [75,76].

Patients receiving pazopanib should have close monitoring of liver function tests, given the risk for potentially fatal hepatotoxicity. (See "Hepatotoxicity of molecularly targeted agents for cancer therapy", section on 'Pazopanib'.)

Cardiac and non-cardiac toxicities of pazopanib and other VEGFR tyrosine kinase inhibitors are discussed separately. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents" and "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents".)

Efficacy and toxicity — Single-agent pazopanib showed activity in phase II trials that included various treatment-refractory STS subtypes [55,69]. Pazopanib met the primary endpoint for activity in three of the four histology-specific cohorts (leiomyosarcoma [LMS], synovial sarcoma, and other eligible STS types). However, pazopanib demonstrated low response rates in liposarcoma compared with the other STS histologies [69,70,77]. (See 'Agents not used for liposarcoma' above.)

Based on those results, pazopanib was evaluated in a randomized, double-blind, placebo-controlled phase III study (the PALETTE trial) conducted by the European Organisation for Research and Treatment of Cancer (EORTC). In this study, 369 patients with various histologic STS subtypes (except for adipocytic sarcomas or GIST) whose disease had progressed during or after first-line chemotherapy (including an anthracycline) were randomly assigned to either pazopanib at 800 mg orally daily or placebo [6]. Patients with the most common histologic subtypes were allowed to enroll, including LMS, fibrosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor (MPNST), vascular STS (such as angiosarcoma), and undifferentiated/unclassified sarcomas (also known as sarcoma not otherwise specified).

At median follow-up of 15 months, compared with placebo, pazopanib improved PFS (median 5 versus 2 months, HR 0.31, 95% CI 0.24-0.40), with consistent benefit across all histologic subtypes. Overall survival (OS) was similar between the two treatment arms (median 13 versus 11 months, HR 0.86, 95% CI 0.67-1.1). Overall response (6 versus 0 percent) and stable disease rates (67 versus 38 percent) were higher for pazopanib versus placebo. The efficacy of pazopanib for those with leiomyosarcoma or synovial sarcoma is discussed separately. (See 'Pazopanib (LMS)' above and 'Pazopanib (synovial sarcoma)' above.)

Grade ≥3 treatment-related toxicities for pazopanib included were fatigue (14 percent), hypertension (7 percent), anorexia (6 percent), and diarrhea (5 percent). Pazopanib also increased any grade liver function tests more frequently than placebo for alanine aminotransferase (10 versus 3 percent) and aspartate aminotransferase (8 versus 2 percent). A drop in left ventricular ejection fraction occurred more frequently with pazopanib compared with placebo (7 versus 3 percent); only three cases were symptomatic. Venous thromboembolism was also more common in the pazopanib group (5 versus 2 percent, all grades). In addition, pneumothorax occurred in eight patients in the pazopanib group (3 percent), possibly due to necrosis of pleural lesions. Pazopanib did not improve quality of life metrics in this study compared with placebo [77].

Based on these data, pazopanib was approved in the United States for treatment of patients with advanced STS (but not adipocytic tumors or GIST) who have received prior chemotherapy [78]. Pazopanib also has regulatory approval from the European Medicines Agency (EMA).

Trabectedin — Trabectedin is also approved by the European Medicines Agency (EMA) for patients with advanced STS who experience disease progression on doxorubicin and ifosfamide [79]. However, we do not use trabectedin for histologies other than leiomyosarcoma (LMS), liposarcoma, or translocation-related sarcomas. (See 'Trabectedin (LMS)' above and 'Trabectedin (liposarcoma)' above and 'Translocation-related sarcomas' below.)

The activity of trabectedin in STS histologies other than LMS, liposarcoma, and translocation-associated sarcomas was addressed in the phase III T-SAR trial [80]. In this study, 103 patients with advanced STS unresponsive to or intolerant of previous chemotherapy were randomly assigned to trabectedin or best supportive care. Sixty percent of tumors were liposarcoma or LMS, and the remainder were other histotypes. In those with non-liposarcoma/LMS histotypes, trabectedin had no objective tumor responses relative to the liposarcoma/LMS group (0 versus 19 percent) and had similar PFS to those receiving best supportive care (median 1.8 versus 1.5 months). In contrast, for those with liposarcoma/LMS, trabectedin improved PFS relative to best supportive care (median 5.1 versus 1.4 months).

Chemotherapy — Chemotherapy is an option for patients with anthracycline-refractory metastatic STS who progress on or are ineligible for pazopanib and do not have a histology-specific treatment approach available. Patients should be treated with a chemotherapy regimen not previously received during initial therapy. However, treatment responses for chemotherapy are limited in this setting.

For patients with good ECOG performance status (table 4) and minimal comorbidities, options include gemcitabine in combination with either docetaxel [21,23], vinorelbine [81], or dacarbazine [82]. Ifosfamide, if not previously received, is also an option, although toxicity makes its use challenging [83-91]. (See "Overview of the initial treatment of metastatic soft tissue sarcoma", section on 'Ineligible for anthracyclines'.)

For older adults or patients with significant comorbidities, we offer single-agent chemotherapy to reduce toxicity risk. Options include pegylated liposomal doxorubicin (if no prior treatment with an anthracycline), dacarbazine [82,92-94], temozolomide [44], vinorelbine [11,95], and single-agent gemcitabine. All are associated with objective response rates of less than 20 percent, but some patients may have stable, durable treatment responses. Ifosfamide is not generally used in this population due to significant toxicity.

SPECIAL CONSIDERATIONS

Translocation-related sarcomas — Trabectedin is an option for subsequent-line therapy for the group of STS histologies known as translocation-related sarcomas (table 3) [52,53]. (See "Pathogenetic factors in soft tissue and bone sarcomas", section on 'Chromosomal translocations'.)

In an open-label phase II trial, 76 patients with advanced, translocation-related, predominantly pretreated sarcoma (including myxoid-round cell liposarcoma and synovial sarcoma) were randomized to trabectedin (1.2 mg/m2 over 24 hours on day 1 every 21 days) versus best supportive care [52]. After a median follow-up of approximately nine months, trabectedin improved progression-free survival (PFS; 5.6 versus 0.9 months, HR 0.07, 95% CI 0.03-0.16). Common grade ≥3 toxicities for trabectedin included nausea (9 percent), decreased appetite (8 percent), febrile neutropenia (11 percent), and increased alanine aminotransferase (47 percent).

The efficacy of trabectedin for specific translocation-related sarcomas and other STS histologies are discussed separately. (See 'Trabectedin (synovial sarcoma)' above and 'Trabectedin (liposarcoma)' above and 'Trabectedin (LMS)' above.)

Tumors with dMMR, MSI-H, or high levels of TMB — Immune checkpoint inhibitors are an option for patients with metastatic STS of any histologic subtype that harbors either high levels of microsatellite instability (MSI-H)/deficient mismatch repair (dMMR) or high tumor mutational burden (TMB). These molecular alterations are rare in STS.

Deficient mismatch repair and DNA microsatellite instability – Approximately 1 to 2 percent of STS tumors are dMMR or express DNA MSI-H [96] (figure 1). Furthermore, sarcoma is not a cancer that is typically associated with Lynch syndrome. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis".)

Tumor mutational burden – High TMB (ie, ≥10 mutations/megabase) is observed at very low frequencies in most STS. High TMB expression is seen in angiosarcomas and pleomorphic dermal sarcomas, although it is rare for the latter to recur after surgery and require systemic therapy. (See 'Angiosarcoma' above.)

Further details on using immune checkpoint inhibitors to treat solid tumors that are dMMR/MSI-H or high TMB is discussed separately. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)

TRK fusion sarcomas — Patients with STS harboring neurotrophic tyrosine receptor kinase (TRK) gene fusions who are treated with larotrectinib (an agent which targets TRK fusion proteins) may achieve a durable response and survival benefit, rendering larotrectinib as a viable treatment option. We often use this as initial therapy in patients with TRK fusion sarcomas, as discussed elsewhere. (See "Overview of the initial treatment of metastatic soft tissue sarcoma", section on 'NTRK gene fusion-positive tumors'.)

However, for patients who did not receive an TRK inhibitor in the initial setting, data suggest activity in the subsequent line setting as well. In a pooled analysis of three trials, including 36 patients with STS, the majority of whom (70 percent) had received prior therapy, the objective response rate to larotrectinib was 53 percent and the 36-month overall survival was 71 percent [97]. Grade 3 treatment related adverse events occurred in 42 percent of patients. The most common toxicities of any grade included constipation (42 percent), nausea (31 percent), and dizziness (28 percent). However, TRK fusions are rare in unselected sarcomas, with one analysis indicating a <1 percent frequency of such alterations. (See "TRK fusion-positive cancers and TRK inhibitor therapy".)

RET and other rare gene fusions — For patients with a treatment-refractory STS harboring a rearranged at transfection (RET) gene fusion and no other actionable molecular alterations, selpercatinib is an available treatment option, The use of selpercatinib, a selective RET kinase inhibitor, is based on limited data from two patients with metastatic STS treated in a phase I/II basket trial (LIBRETTO-001) [98]. Selpercatinib is approved by the US Food and Drug Administration (FDA) for adult patients with locally advanced or metastatic solid tumors with RET gene fusion that progress on or following prior systemic treatment or who have no satisfactory alternative treatment options [99].

In a similar fashion, the rare patient with metastatic that involves a gene fusion/translocation other than well-recognized entities (eg, dermatofibrosarcoma protuberans with a PDGFRB gene fusion) can be evaluated for treatment with specific kinase-specific agents, ideally on a clinical trial. (See "Dermatofibrosarcoma protuberans: Treatment".)

INVESTIGATIONAL AGENTS — Given the large information gaps in treatment, we encourage patients with metastatic sarcoma to enroll in clinical trials, where available (www.clinicaltrials.gov). Most clinical trials are conducted at a national and international level at centers of excellence in sarcoma, due to the rarity of the disease.

T-cell therapy — T-cell therapy does not yet have regulatory approval, but studies have shown promising results.

As an example, in patients with heavily pretreated synovial and myxoid-round cell liposarcoma, engineered T-cell receptor T-cell therapy demonstrated durable responses [100]. In this study, patients with HLA-A*02 haplotype with tumors expressing MAGE-A4 were treated with the T-cell therapy afamitresgene autoleucel. The median number of prior systemic treatments was three. All patients underwent leukapheresis for collection of T cells that were then engineered to recognize the MAGE-A4 peptide. Patients received lymphodepleting chemotherapy, followed by a single infusion of the engineered T cells. At a median follow-up of 33 months, the overall response rate was 39 percent in 44 patients with synovial sarcoma and 25 percent in 8 patients with myxoid-round cell liposarcoma. The median duration of response was 12 months in patients with synovial sarcoma and 4 months in patients with myxoid-round cell liposarcoma. Cytokine release syndrome occurred in 71 percent of patients, but there was only one grade 3 event. Other common grade 3 or higher side effects included lymphopenia (96 percent), neutropenia (85 percent), and leukopenia (81 percent).

Based on the data from patients with synovial sarcoma, the United States Food and Drug Administration has accepted a priority review of the biologics license application seeking the approval of afamitresgene autoleucel.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Soft tissue sarcoma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Soft tissue sarcoma (The Basics)")

SUMMARY AND RECOMMENDATIONS

Second and later lines of therapy for metastatic STS – Second and later lines of therapy for common metastatic soft tissue sarcomas (STS) histologies will be reviewed here. Enrollment in clinical trials is encouraged, where available.

An overview of initial therapy for metastatic STS is discussed separately. (See "Overview of the initial treatment of metastatic soft tissue sarcoma".)

Angiosarcomas

Prior anthracyclines – For patients with metastatic angiosarcoma who progress on anthracycline-based therapy, we suggest second-line therapy with a taxane (such as paclitaxel (table 1)) rather than other systemic agents (Grade 2C). (See 'Second-line therapy' above.)

Prior taxanes – For patients with metastatic angiosarcoma who progress on taxanes, we suggest second-line therapy with an anthracycline-based regimen rather than other systemic agents (Grade 2C), extrapolating from studies of anthracyclines as initial therapy that demonstrate similar efficacy to taxanes. (See 'Second-line therapy' above.)

Later-line therapy – Later-line options include gemcitabine-based regimens, pazopanib, or immune checkpoint inhibitors (eg, pembrolizumab, nivolumab plus ipilimumab) which are particularly effective for cutaneous and head and neck angiosarcomas. (See 'Later-line therapy (angiosarcoma)' above.)

Leiomyosarcoma – For patients with metastatic leiomyosarcoma (LMS) who progress on initial therapy with anthracycline-based regimens, we suggest second-line therapy with gemcitabine plus docetaxel (table 2) rather than other gemcitabine-based regimens (Grade 2C). Other gemcitabine-based combination (gemcitabine plus vinorelbine, gemcitabine plus dacarbazine) and single-agent gemcitabine are appropriate alternatives for those unable to tolerate the potential toxicities of combining docetaxel with gemcitabine (See 'Gemcitabine plus docetaxel (LMS)' above.)

For patients with metastatic LMS who progress on initial therapy with gemcitabine plus docetaxel, we suggest second-line therapy with an anthracycline-based regimen rather than other systemic agents (Grade 2C). Options include doxorubicin plus dacarbazine and doxorubicin plus trabectedin. (See 'Anthracycline-based regimens (LMS)' above.)

Later-line treatment options (if not previously received) include trabectedin, pazopanib, eribulin, and dacarbazine, among other agents. (See 'Later-line therapy (LMS)' above.)

Synovial sarcoma

Prior anthracyclines – For patients with metastatic synovial sarcoma who progress on a single-agent anthracycline, we suggest second-line therapy with an ifosfamide-based regimen rather than other agents (Grade 2C). (See 'Second-line therapy' above.)

Prior anthracyclines and ifosfamide – For patients with metastatic synovial sarcoma who progress on anthracyclines and ifosfamide (either in combination or in sequence), we suggest pazopanib or trabectedin rather than other systemic agents (Grade 2C). (See 'Pazopanib (synovial sarcoma)' above and 'Trabectedin (synovial sarcoma)' above.)

Malignant peripheral nerve sheath tumors – For patients with metastatic malignant peripheral nerve sheath tumors (MPNST) who progress on initial therapy with anthracyclines and/or ifosfamide-based regimens, we suggest second-line therapy with pazopanib rather than other systemic therapies (Grade 2C). (See 'Malignant peripheral nerve sheath tumors' above.)

Liposarcoma – For those with metastatic liposarcoma who progress on anthracyclines-based regimens, we suggest second-line therapy with gemcitabine plus docetaxel rather than other systemic agents (Grade 2C), especially in those with pleomorphic and well-differentiated/dedifferentiated subtypes. (See 'Liposarcoma' above.)

Our approach to selecting later-line therapy is based on the primary histologic subtype of liposarcoma and patient preference (see 'Later-line therapy (liposarcoma)' above):

Dedifferentiated or pleomorphic liposarcoma – For most patients with dedifferentiated or pleomorphic liposarcoma who progress on anthracyclines as well as gemcitabine plus docetaxel, eribulin is an appropriate later-line treatment option. In phase III trials, eribulin conferred an overall survival benefit over chemotherapy in these histologies, whereas trabectedin did not. (See 'Eribulin (liposarcoma)' above and 'Trabectedin (liposarcoma)' above.)

For the subset of patients with well-differentiated/dedifferentiated liposarcoma and more indolent disease, a CDK4/6 inhibitor, such as palbociclib, is an alternative to further chemotherapy. (See 'CDK4/6 inhibitors' above.)

Myxoid-round cell liposarcoma – For patients with myxoid-round cell liposarcoma who progress on anthracyclines and gemcitabine plus docetaxel, trabectedin is an effective strategy because it targets a unique fusion protein in this translocation-related sarcoma (table 3). Eribulin is a reasonable alternative but is associated with a lower response rate. (See 'Trabectedin (liposarcoma)' above.)

No role for pazopanib – We do not use of pazopanib for adipocytic STS due to limited efficacy and lack of regulatory approval for this subtype. (See 'Agents not used for liposarcoma' above and 'Pazopanib' above.)

Undifferentiated and unclassified sarcomas – For patients with metastatic undifferentiated and unclassified STS (eg, undifferentiated pleomorphic sarcoma, myxofibrosarcoma, and sarcoma not otherwise specified [NOS]) who progress on anthracycline-based chemotherapy, we suggest second-line therapy with gemcitabine plus docetaxel rather than other systemic agents. (Grade 2C). (See 'Undifferentiated and unclassified sarcomas' above.)

Later-line treatment options include pazopanib, pembrolizumab, and nivolumab plus ipilimumab. (See 'Later-line therapy (undifferentiated/unclassified sarcoma)' above.)

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Topic 139327 Version 8.0

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