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Systemic treatment of metastatic soft tissue sarcoma
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Systemic treatment of metastatic soft tissue sarcoma
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Nov 16, 2016.

INTRODUCTION — Soft tissue sarcomas (STS) are a heterogeneous group of rare tumors that arise from mesenchymal cells at all body sites. The malignant precursor cell(s) can differentiate along one or several lineages, such as muscle, adipose, fibrous, cartilage, nerve, or vascular tissue. These tumors arise most often in the limbs (particularly the lower extremity), followed in order of frequency by the abdominal cavity/retroperitoneum, the trunk/thoracic region, and the head and neck. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Clinical presentation' and "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Introduction'.)

The classification of STS, insight into their molecular pathogenesis, and the definition of optimal treatment strategies have evolved considerably over the past 10 to 25 years. There are more than 50 histologic subtypes of STS, many of which are associated with distinctive clinical profiles, responses to individual therapies, and prognoses. While in the past these tumors were all "lumped" together and treated similarly, consensus is emerging that the selection of treatment should be histology driven, particularly in the setting of advanced disease. (See 'Histology-driven treatment' below.)

Systemic chemotherapy for metastatic non-gastrointestinal stromal tumor STS will be reviewed here. The primary management of localized STS of the extremity, chest wall, breast, uterus, head and neck, and retroperitoneum; adjuvant and neoadjuvant chemotherapy; surgical management of metastatic STS; and systemic therapy for specific types of STS, including gastrointestinal stromal tumor, rhabdomyosarcoma, desmoids, dermatofibrosarcoma protuberans, and Kaposi sarcoma, are discussed separately:

(See "Surgical resection of primary soft tissue sarcoma of the extremities".)

(See "Local treatment for primary soft tissue sarcoma of the extremities and chest wall".)

(See "Breast sarcoma: Treatment".)

(See "Treatment and prognosis of uterine leiomyosarcoma".)

(See "Clinical features, evaluation, and treatment of retroperitoneal soft tissue sarcoma".)

(See "Head and neck sarcomas".)

(See "Adjuvant and neoadjuvant chemotherapy for soft tissue sarcoma of the extremities".)

(See "Surgical treatment and other localized therapy for metastatic soft tissue sarcoma".)

(See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors".)

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

(See "Desmoid tumors: Systemic therapy".)

(See "Dermatofibrosarcoma protuberans: Treatment".)

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

GENERAL PRINCIPLES

Patterns of spread — While local complications from primary or recurrent sarcomas can cause significant morbidity and occasional mortality, the most life-threatening aspect of sarcomas is their propensity for hematogenous dissemination. The pattern of tumor spread varies according to tumor type and location:

For most STS of the extremity, chest wall, or head or neck, the primary metastatic site is the lung [1,2]. However, there are exceptions. Extrapulmonary metastases to the retroperitoneum, spine, and paraspinous soft tissues predominate with myxoid/round cell liposarcomas, although lung metastases develop eventually in almost all [3]. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Pattern of spread' and "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Pattern of recurrence'.)

With retroperitoneal and visceral sarcomas, the primary site of failure is local. Less commonly, these tumors spread hematogenously to the liver [4].

Spread to locoregional lymph nodes is rare except with clear cell and epithelioid sarcomas, angiosarcomas, synovial sarcomas, and rhabdomyosarcomas [5].

Natural history of metastatic disease and implications for treatment — The majority of patients who develop metastatic STS are incurable; however, therapeutic nihilism is unwarranted for the following reasons:

Potentially curative options should be sought in appropriate patients so that the opportunity for cure is not overlooked. As an example, in selected patients, resection of pulmonary metastases is feasible, with reported a five-year survival of 25 to 40 percent [6,7]. (See "Surgical treatment and other localized therapy for metastatic soft tissue sarcoma".)

For patients with unresectable disease, judicious use of systemic therapy provides meaningful palliation and may prolong survival. The selection of systemic therapy must be individualized and based upon several factors, including the histology and biologic behavior of the disease, as well as the health status and preferences of the patient. (See 'Overview of the therapeutic approach' below.)

The median survival after development of distant metastases is 11 to 15 months, and 20 to 25 percent of patients with unresectable disease are still alive at two to three years [1,8]. The prognostic factors for more prolonged survival differ from those predicting response to chemotherapy [8], suggesting that survival is more dependent upon disease biology rather than solely upon treatment-associated considerations. This variability in the natural history of metastatic STS can be illustrated by the following reports:

In a report in an era before gastrointestinal stromal tumor (GIST) was recognized as a distinct clinical entity, outcomes from over 2000 patients treated with anthracycline-based chemotherapy for advanced STS were examined [8]. Median survival was approximately one year for the entire cohort, regardless of the specific regimen used. The likelihood of a chemotherapy response was greater in younger patients with high-grade non-leiomyosarcoma histology and no hepatic metastases, while longer median survival was predicted by a good performance status, low-grade histology, the absence of liver metastases, and a longer recurrence-free interval.

In a more modern series, 488 patients were treated with first-line chemotherapy for advanced and/or metastatic STS [9]. In multivariate analysis, age <40 years, liposarcoma or synovial sarcoma histology, lack of bone metastases, and combination, rather than single agent, therapy were associated with a better outcome.

These principles can be applied to therapeutic decision making. As an example, for some patients with asymptomatic, low-grade, unresectable disease (eg, low-grade intraabdominal leiomyosarcoma), it might be reasonable to follow the patient without active chemotherapy. Conversely, for patients with a high-grade chemotherapy-sensitive tumor, such as synovial sarcoma or liposarcoma, early use of combination chemotherapy may be preferable.

End points to define benefit — Unresectable metastatic STS is, with rare exception, a fatal disease eventually. A few patients may enter a prolonged remission. However, for the majority of patients with metastatic STS, chemotherapy is administered with palliative intent to decrease tumor bulk, diminish symptoms, improve quality of life, and prolong survival.

The specific endpoints that best reflect benefit from systemic therapy in metastatic STS remain unclear. Objective response rates, as judged by a decrease in the size of measurable lesions, are increasingly considered to be poor surrogates for benefit in this family of cancers. Even in cases where systemic treatment successfully induces massive tumor cell kill in vivo, hyalinized acellular tissue remains, leading to a falsely negative assessment of the true response to treatment and an underestimation of antitumor efficacy. The "disconnect" between objective tumor response and disease stabilization is particularly evident in studies of drugs like trabectedin and molecularly targeted therapies.

Increasing attention is being paid to other important indicators of clinical outcomes, such as progression-free survival, the progression-free rate at a specific time point (often 12 weeks), percentage survival at a given time point, overall survival, and disease stabilization. A therapeutic agent that is associated with a low objective antitumor response may slow tumor progression and prolong survival. Stabilization of disease is increasingly viewed as a realistic endpoint for metastatic STS. However, the generation of clinical and radiologic data to support these alternative endpoints requires rigorous attention to the consistency of follow-up.

Histology-driven treatment — Most studies of chemotherapy for metastatic STS have been hampered by the admixture of a variety of histologic subtypes in the analysis of outcome, making it difficult to assess the clinical activity of any given treatment in a specific histology. The interpretation of clinical trial results will be heavily weighted by the distribution of histologic subtypes. This, in turn, complicates the assessment of chemotherapy efficacy, making it impossible to determine whether high or low response rates are due to the specific treatment or to the specific population under study [10].

These data have led to the emergence of the concept of histology-driven treatment rather than the "one size fits all" approach to therapy in patients with metastatic STS. As examples:

Synovial sarcomas and myxoid/round cell liposarcomas are among the more chemotherapy-sensitive subtypes when specific agents are used [11-14]. In particular, myxoid/round cell liposarcomas tend to be sensitive to doxorubicin-based chemotherapy, and synovial sarcoma appears especially sensitive to alkylating agents such as ifosfamide [14]. In contrast, other subtypes, such as clear cell sarcoma and fibromyxoid sarcoma (Evans tumor), appear to have lower response rates to conventional anthracycline and ifosfamide-based chemotherapy [8,15]. GISTs are well recognized for the inactivity of standard cytotoxic agents.

Leiomyosarcomas and liposarcomas (particularly myxoid/round cell liposarcomas) appear to be sensitive to trabectedin, and liposarcomas are also sensitive to eribulin. (See 'Trabectedin' below and 'Sirolimus' below.)

In contrast to virtually every other histology, angiosarcomas are sensitive to single-agent taxanes. (See "Head and neck sarcomas", section on 'Treatment' and 'Taxanes and angiosarcoma' below.)

Benefit has been shown for sunitinib in patients with solitary fibrous tumor/hemangiopericytoma, alveolar soft part sarcoma, clear cell sarcoma, and extraskeletal myxoid chondrosarcoma (at least those that carry the characteristic EWSR1-NR4A3 fusion gene); for the mechanistic (previously called mammalian) target of rapamycin (mTOR) inhibitor sirolimus in patients with neoplasms with perivascular epithelioid cell differentiation (PEComas; including recurrent angiomyolipoma/lymphangioleiomyomatosis) that are characterized by dysregulated mTOR signaling; and for imatinib and nilotinib in patients with pigmented villonodular synovitis/tenosynovial giant cell tumor. (See 'Newer treatment strategies' below and "Antineoplastic therapy for miscellaneous benign diseases affecting soft tissue and bone", section on 'Tenosynovial giant cell tumor' and "Sporadic lymphangioleiomyomatosis: Treatment and prognosis" and "Solitary fibrous tumor" and "Giant cell tumor of bone" and "Pathogenetic factors in soft tissue and bone sarcomas", section on 'Extraskeletal myxoid chondrosarcoma'.)

There are also data supporting activity of imatinib in patients with metastatic dermatofibroma protuberans and for sorafenib in patients with desmoid tumors. However, there are better data for single-agent liposomal doxorubicin, single-agent vinorelbine, and combination methotrexate/vinorelbine or methotrexate/vinblastine in patients with desmoid tumors. (See "Dermatofibrosarcoma protuberans: Epidemiology, pathogenesis, clinical presentation, diagnosis, and staging" and "Desmoid tumors: Systemic therapy", section on 'Non-cytotoxic approaches'.)

Emerging data suggest that sorafenib, an orally active multitargeted tyrosine kinase inhibitor (TKI) that inhibits Raf kinase and blocks the intracellular portion of the vascular endothelial growth factor (VEGF) receptor, may be an active agent for certain angiosarcomas, as well as perhaps some subtypes of leiomyosarcoma, although additional study is needed to confirm the initial reports. Furthermore, sunitinib and other multitargeted VEGF receptor inhibitors seem to be active agents for alveolar soft part sarcoma. The approval of pazopanib for advanced STS lends some evidence to the possibly important role of VEGF receptor and related pathways in the growth of other sarcoma subtypes, although the specific relevant targets in these diseases is not well elucidated. (See 'Pazopanib' below.)

However, for most STS tumor types, the notion of histology-driven treatment is now a consideration for second-line therapy and beyond, given the approval of olaratumab in combination with an anthracycline for first-line therapy of anthracycline-sensitive histologies. However, histology-driven treatment is still recommended as initial therapy for some anthracycline-resistant histologies (eg, alveolar soft part sarcoma, solitary fibrous tumor/hemangiopericytoma, clear cell sarcoma, PEComa, and dermatofibrosarcoma protuberans). (See 'Initial therapy' below.)

OVERVIEW OF THE THERAPEUTIC APPROACH

Initial therapy — Enrollment in a clinical trial is always preferred, if available. If a clinical trial option does not exist, the following represents our general approach to initial therapy for metastatic STS other than a gastrointestinal stromal tumor (GIST).

Patients should be assessed for their potential responsiveness to doxorubicin, to gauge whether an anthracycline should be used as part of first-line therapy or if other agents should be considered first. As noted below, the standard of care for many years for symptomatic patients has been doxorubicin plus ifosfamide, with single-agent doxorubicin being considered for asymptomatic patients or for those patients thought unlikely to tolerate combination therapy. The accelerated approval of olaratumab in 2016 as a first-line agent in combination with doxorubicin has resulted in the first change in strategy for first-line therapy of metastatic STS in many years, since the toxicity of doxorubicin and olaratumab is considered less than that of doxorubicin and ifosfamide. (See 'Doxorubicin-based regimens' below and 'Doxorubicin' below.)

For patients with a good performance status and an STS histology that is known to have at least some sensitivity to anthracyclines, doxorubicin plus olaratumab represents a first-line standard of care off-study. Given their unique sensitivity to ifosfamide, it is possible that synovial sarcoma and myxoid/round cell liposarcomas could be more sensitive to doxorubicin plus ifosfamide than to doxorubicin plus olaratumab; however, there are no data comparing these two combinations directly in any histology, including synovial sarcoma and myxoid/round cell sarcoma. (See 'Doxorubicin plus olaratumab' below.)

Whether initial therapy with a gemcitabine-based regimen is preferable to anthracycline-based therapy with olaratumab for patients with a good performance status and any histologic type of STS is uncertain. However, given the survival benefit of olaratumab plus doxorubicin over doxorubicin alone, the approval of olaratumab in combination with doxorubicin for first-line therapy of all anthracycline-sensitive STS histologies, and preliminary data from the GeDDis trial, which showed similar progression-free and overall survival along with less toxicity for single-agent doxorubicin [16], a gemcitabine-based combination can no longer be considered a first-line regimen for any histology. However, a gemcitabine-based combination may be considered for first-line therapy in a patient for whom an anthracycline is relatively contraindicated (eg, clinical heart failure, prior treatment with >400 mg/m2 doxorubicin in the adjuvant setting). (See 'Gem/docetaxel versus doxorubicin alone' below.)

For patients with an angiosarcoma, a taxane is also a reasonable option for first-line therapy. (See 'Taxanes and angiosarcoma' below.)

Patients with poorer performance status or extensive comorbidity who remain eligible for chemotherapy can be considered for treatment with pegylated liposomal doxorubicin (Doxil, Caelyx), gemcitabine alone, or a gemcitabine-based combination.

For patients with STS histologies that are not sensitive to anthracyclines, other options should be considered first, even though these may represent off-label use of existing drugs that are approved for other conditions:

For patients with advanced progressive alveolar soft part sarcoma, solitary fibrous tumor (SFT)/hemangiopericytoma, and clear cell sarcoma, we suggest a trial of pazopanib or sunitinib. For SFT/hemangiopericytoma, another reasonable option is dacarbazine, or temozolomide plus bevacizumab. (See 'Sunitinib' below and 'Pazopanib' below and "Solitary fibrous tumor", section on 'Cytotoxic chemotherapy'.)

For patients who have advanced progressive neoplasms with perivascular epithelioid cell differentiation (PEComa), including recurrent angiomyolipoma/lymphangioleiomyomatosis, we suggest a trial of sirolimus. (See 'Sirolimus' below.)

For tenosynovial giant cell tumor and dermatofibrosarcoma protuberans, we suggest imatinib or a trial of another tyrosine kinase inhibitor (TKI) that inhibits the macrophage colony stimulating factor 1 (CSF1) receptor. (See 'Imatinib' below and "Antineoplastic therapy for miscellaneous benign diseases affecting soft tissue and bone", section on 'Tenosynovial giant cell tumor' and "Dermatofibrosarcoma protuberans: Treatment", section on 'Treatment of locally advanced, recurrent, and metastatic disease'.)

Treatment at progression — For most patients with progression on the first-line regimen, we prefer enrollment in a clinical trial, if one is available. If protocol treatment is not available or declined, our recommendations for therapy at progression for patients who retain a good performance status are histology-driven.

Trabectedin is approved for use in advanced leiomyosarcoma and liposarcoma in the United States after failure of anthracycline-based therapy. Myxoid/round cell liposarcoma is particularly sensitive to trabectedin. (See 'Trabectedin' below.)

Eribulin is approved for use in advanced liposarcomas in the United States, and for leiomyosarcoma and liposarcoma in other countries. Dedifferentiated liposarcoma and pleomorphic liposarcoma may be more sensitive to eribulin than to trabectedin. (See 'Eribulin' below.)

Pazopanib is approved for advanced STS other than liposarcoma or GIST that fail anthracycline therapy. (See 'Pazopanib' below.)

For patients with advanced progressive angiosarcomas despite anthracycline-based therapy, a weekly taxane is a good option. Single-agent gemcitabine or a gemcitabine-based combination is also a reasonable option. (See 'Taxanes and angiosarcoma' below.)

Other options for second-line treatment and beyond in patients who retain a good performance status include pegylated liposomal doxorubicin, an ifosfamide-containing regimen, or gemcitabine or a gemcitabine-based combination. (See 'Pegylated liposomal doxorubicin' below and 'Ifosfamide' below and 'Gemcitabine and other agents' below and 'Gemcitabine-based combinations' below.)

In our experience, undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma is the one histologic subtype that responds better to gemcitabine/docetaxel than to other chemotherapy combinations, and we would choose this combination for second-line therapy after failure of initial doxorubicin plus olaratumab.

DETAILS REGARDING EFFICACY OF CYTOTOXIC CHEMOTHERAPY — Most trials of conventional cytotoxic therapy were conducted in a variety of patients with different histologic subtypes of STS, evaluating various doses and schedules; few have analyzed outcomes separately according to histology.

Single agent therapy — The only single agents that are consistently associated with response rates of more than 20 percent in metastatic STS are doxorubicin, epirubicin, and ifosfamide. Even for these agents, the range of objective activity between various small (and even larger) trials is impressive, demonstrating the variability in disease sensitivity (noted above) and the fact that any given STS patient population could serve as an important confounding variable for interpretation of drug efficacy.

Doxorubicin — The sensitivity of STS to systemic chemotherapy was first demonstrated with single agent doxorubicin in the early 1970s [17], and subsequent studies suggested a dose-response relationship. The threshold dose for optimal activity appears be ≥60 mg/m2 per cycle, usually administered once every three weeks, with lower doses associated with inferior antitumor activity [18]. It is difficult to demonstrate a clinically meaningful dose-response relationship with single agent doxorubicin at doses beyond 75 mg/m2 per cycle, which has become the standard dose.

Even in modern multi-institutional series using 70 to 80 mg/m2 per cycle, there is significant variability in reported response rates, which range from 10 to 25 percent [18-24]. The vast majority are partial, rather than complete, responses [25].

Doxorubicin is associated with reversible myelosuppression, mucositis, alopecia, nausea and vomiting, and both acute and chronic cardiotoxicity. This drug has a relatively narrow therapeutic index; even small variations of dose beyond 75 mg/m2 can drastically worsen patient tolerance, and even 75 mg/m2 is considered by many patients to be significantly more toxic than 60 mg/m2. Infusional, rather than bolus, administration reduces the likelihood of cardiotoxicity. Other methods to diminish cardiotoxicity include the concomitant use of the cardioprotectant dexrazoxane or the use of liposome-encapsulated doxorubicin. (See "Cardiotoxicity of anthracycline-like chemotherapy agents".)

Pegylated liposomal doxorubicin — Liposomal encapsulation appears to improve the side effect profile of doxorubicin, thereby increasing the therapeutic index. The most widely used preparation (Doxil in the United States and Caelyx in Europe) is a large liposome with polyethylene glycol (PEG) anchored within the lipid bilayer, which acts as a hydrophilic coating to prolong the circulating half-life of the liposome by preventing degradation within the reticuloendothelial system. The toxicity profile is somewhat different from nonencapsulated doxorubicin, mainly consisting of an acute hypersensitivity-like reaction, in approximately 8 percent of patients, palmar-plantar erythrodysesthesia ("hand-foot syndrome"), and esophagitis. (See "Cutaneous complications of conventional chemotherapy agents", section on 'Acral erythema (hand-foot syndrome)'.)

Liposomal anthracyclines are active in STS, but it is unclear if they are as efficacious as unencapsulated doxorubicin [19,26-28]. In a randomized phase II trial, Doxil (50 mg/m2 every four weeks) was compared with unencapsulated doxorubicin (75 mg/m2 every three weeks) [19]. Although Doxil was well tolerated and appeared to have similar efficacy compared with doxorubicin, the response rates in both arms were low, 10 and 9 percent, respectively. Of note, there was a high proportion of gastrointestinal stomal tumor (GIST) in this study population, emphasizing the importance of disease subtype as a confounding factor in studies of chemotherapy efficacy. (See 'Histology-driven treatment' above.)

On the basis of this trial, rigorous clinical trial rules would have discarded both unencapsulated doxorubicin and Doxil as putatively "inactive" agents in STS, with response rates <20 percent. This would be a major error since doxorubicin has important clinical activity, proven over the past 30 years, in patients with advanced STS. These data underscore the poor correlation between objective response rate and clinical benefit, and the need for caution in interpreting any clinical trial of a new drug as "negative" based upon objective tumor shrinkage. (See 'End points to define benefit' above.)

Others report response rates of 50 percent or higher with pegylated liposomal doxorubicin, which are durable in many patients [29]. Doxil is a widely used agent for metastatic STS, particularly outside of the US and in patients aged 65 or older.

Like paclitaxel, pegylated liposomal doxorubicin also has activity in angiosarcoma [28,30,31]. (See 'Taxanes and angiosarcoma' below.)

Epirubicin — Compared with doxorubicin, epirubicin is less cardiotoxic on a mg to mg basis. At least two trials have directly compared epirubicin with single agent doxorubicin for STS [23,32]:

An European Organisation for Research and Treatment of Cancer (EORTC) trial randomly assigned 334 patients with untreated metastatic STS to doxorubicin (75 mg/m2 on day 1) or epirubicin on one of two different schedules (50 mg/m2 daily for three days or 150 mg/m2 on day 1) [32]. Neither epirubicin schedule was associated with better response rate or survival, and cardiovascular and hematologic toxicity were worse than with doxorubicin.

In the second trial, 210 patients received either epirubicin or doxorubicin (both dosed at 75 mg/m2) once every three weeks [23]. There was a slight trend toward a lower response rate with epirubicin (18 versus 25 percent), but response duration and median survival were similar.

Ifosfamide — Single agent ifosfamide has similar antitumor activity as doxorubicin. Response rates range from 7 to 41 percent (average 25 percent) among patients who previously failed a doxorubicin-based regimen [10,33-40].

Ifosfamide is challenging to administer, especially considering the variety of published doses and schedules [10,40]. Ifosfamide can be delivered over one or several consecutive days; infusional schedules may be less toxic than bolus administration [35-38,40,41]. Ifosfamide-related toxicities differ from those associated with doxorubicin; they include hemorrhagic cystitis, renal tubular acidosis, salt-wasting nephropathy, and central nervous system toxicity.

Concurrent administration of the uroprotectant mesna decreases hemorrhagic cystitis. Mesna binds to the active metabolite acrolein, decreasing the incidence of hemorrhagic cystitis (a different metabolite, chloroacetaldehyde, is thought to be responsible for the nephrotoxicity). Mesna is usually administered immediately following, and four and eight hours after each ifosfamide dose. (See "Ifosfamide nephrotoxicity" and "Cystitis in patients with cancer".)

A dose-response relationship has been shown for ifosfamide in metastatic STS; the threshold is approximately 6 g/m2 per cycle [10,37]. Additional responses can be demonstrated with ≥10 g/m2 per cycle [42,43].

At least one trial directly compared single agent doxorubicin (75 mg/m2 every three weeks) versus two different doses of ifosfamide (3 g/m2 over four hours daily for three days or 9 g/m2 over 72 hours by continuous infusion) in patients with advanced STS [44]. Antitumor efficacy was similar, and toxicity was worse in both ifosfamide groups.

Taxanes and angiosarcoma — Taxanes as single agents are relatively inactive except in angiosarcoma. Paclitaxel is particularly useful for advanced angiosarcomas [28,45-50]. Weekly therapy was more active than every-three-week therapy in one report [49].

Doxorubicin (including pegylated liposomal doxorubicin) is also an active agent for angiosarcoma [51], and whether the antitumor efficacy of taxanes surpasses that of doxorubicin for this histology is unclear [52]. (See 'Pegylated liposomal doxorubicin' above.)

Gemcitabine and other agents — Other conventional cytotoxic drugs with modest antitumor activity include vinorelbine [53,54], methotrexate [55], dacarbazine and temozolomide (particularly for leiomyosarcoma) [56-59], cisplatin [60], and carboplatin [61]. All are associated with response rates <20 percent, but additional patients have stable disease, some for prolonged periods.

There are conflicting data as to the efficacy of gemcitabine [62-69]:

In one report, gemcitabine administered by fixed-dose rate infusion (mg/m2/min) was associated with a partial response in 4 of 10 patients with non-GI leiomyosarcoma [63]. Gemcitabine is also an active agent in patients with angiosarcoma [69].

Other studies suggest little activity for gemcitabine monotherapy, both in previously treated and untreated patients [65-67]. In most of these studies, the drug was administered over 30 minutes, but a preliminary report of a French trial reported an objective response rate of only 5 percent in 20 patients treated with fixed-dose rate gemcitabine, but two-thirds had prolonged periods of stable disease [68].

In contrast, combinations of gemcitabine (administered by dose rate infusion) with docetaxel, vinorelbine, or dacarbazine appear to be active in leiomyosarcoma of uterine and gastrointestinal origin, as well as other histologies. (See 'Gemcitabine-based combinations' below.)

As a single agent, topotecan has low activity overall, but response rates are modest in non-uterine leiomyosarcoma [70]. Cyclophosphamide plus topotecan has activity in Ewing sarcoma and rhabdomyosarcoma [71-73].

Combination chemotherapy — Many different combination regimens have been studied in patients with metastatic disease; most include doxorubicin and an alkylating agent. Several of these regimens are outlined in the table (table 1) (see "Treatment protocols for soft tissue and bone sarcoma"):

Doxorubicin plus olaratumab [74]

Doxorubicin plus ifosfamide with mesna (AIM) [20,21,75,76] or AIM with dacarbazine (mesna, doxorubicin, ifosfamide, and dacarbazine [MAID]) [77-79]

Gemcitabine plus either docetaxel [80,81], vinorelbine [82], or dacarbazine

Ifosfamide and etoposide alone [83] or alternating with vincristine, doxorubicin, and cyclophosphamide (VAC/IE) for Ewing sarcoma, rhabdomyosarcoma, or desmoplastic small round cell tumor [84]

Doxorubicin plus dacarbazine (AD) [18,55,77,85]

These moderately intensive combination chemotherapy regimens are associated with overall response rates in the range of 16 to 46 percent, with complete responses in 5 to 10 percent. Approximately one-third of the complete responders (ie, 1 to 3 percent of patients with advanced STS overall) are long-term disease-free survivors [78,86-89].

Doxorubicin-based regimens — Several randomized studies and a pooled analysis have compared several doxorubicin-based combinations with each other and to single-agent doxorubicin [18,20,21,24,55,74,77,85,86,90-92]. The following general conclusions can be drawn from these data:

In most randomized prospective trials, combination regimens delivered at conventional doses, such as MAID, AIM (table 2 and table 3 and table 4), AD, and doxorubicin plus olaratumab, are associated with higher response rates (range 18 to 46 percent) than are seen with single-agent doxorubicin (typically 12 to 18 percent), but fewer than 10 percent are complete. Responses are generally short lived (median approximately eight months).

However, in general, combination therapy has not improved overall survival, with one exception. Only the combination of olaratumab plus doxorubicin has been associated with a significant survival benefit compared with doxorubicin alone in a randomized phase II trial, which led to drug approval. Confirmatory phase III trial results are pending [74]. (See 'Doxorubicin plus olaratumab' below.)

Combination regimens are clearly associated with greater toxicity than single-agent doxorubicin.

Doxorubicin plus olaratumab — For patients with a good performance status and an STS histology that is known to have at least some sensitivity to anthracyclines (eg, leiomyosarcoma, liposarcoma, synovial sarcoma, undifferentiated sarcoma, angiosarcoma), we suggest doxorubicin and olaratumab rather than doxorubicin alone. We also prefer first-line doxorubicin plus olaratumab over other combinations, such as doxorubicin plus ifosfamide or a gemcitabine-based regimen, despite the lack of comparative trials.

Olaratumab is a human immunoglobulin G subclass 1 (IgG1) monoclonal antibody that binds to platelet-derived growth factor receptor alpha (PDGFRA) and blocks PDGF ligands from binding. Although the influence of PDGFRA and PDGF signaling pathways in STS are not completely understood, PDGFRA signaling in stromal tumor cells stimulates angiogenesis in a vascular endothelial growth factor (VEGF)-independent manner and exhibits tumorigenic properties [93].

Antitumor efficacy for olaratumab against a variety of STS histologic subtypes was demonstrated in an open-label, randomized, phase II study comparing doxorubicin with and without olaratumab [74]. The results of this study led to accelerated approval of olaratumab in combination with doxorubicin for first-line therapy of anthracycline-sensitive STS in 2016.

Patients with locally advanced or unresectable STS not previously treated with doxorubicin were eligible; the predominant histology was leiomyosarcoma (38 percent of enrolled patients), followed by undifferentiated pleomorphic sarcoma and liposarcoma (17 and 18 percent, respectively). Patients were randomly assigned to doxorubicin alone (75 mg/m2 on day 1 every 21 days for a maximum of eight courses) or the same dose of doxorubicin plus olaratumab (15 mg/kg on days 1 and 8 every 21 days). After the completion of doxorubicin plus olaratumab, patients had the option to continue the antibody alone after 24 weeks; patients receiving doxorubicin alone could be treated with olaratumab at the time of disease progression. Combination therapy was associated with a modest and borderline-significant gain in median progression-free survival (PFS; the primary endpoint; 6.6 versus 4.1 months; hazard ratio [HR] for progression 0.67, 95% CI 0.44-1.02, p = 0.05). In addition, despite crossover to olaratumab in the doxorubicin monotherapy group, initial combination therapy was also associated with a significant near doubling of median overall survival (26.5 versus 14.7 months; HR for death 0.46, 95% CI 0.30-0.71), which was consistent across all subgroups, including histologic subtype and the presence or absence of tumoral expression of PDGFRA. Inexplicably, the survival advantage for initial combination therapy seemed more pronounced in the subgroup of patients with a shorter disease duration (<15 months). The objective response rate was similarly low in both groups (18 versus 12 percent), and the response duration was similar (8.3 versus 8.2 months). The reason why the survival benefit far exceeded the gain in PFS is unclear; differences in the pace of progression prior to study enrollment might have contributed. Combined treatment was associated with more side effects. Grade 3 or 4 neutropenia, mucositis, nausea, vomiting, and diarrhea were more common with combined therapy.

Other side effects seen with olaratumab include fatigue, musculoskeletal pain, alopecia, neuropathy, and headache. In addition, infusion-related reactions have been reported in 70 of 485 patients (14 percent) who received at least one dose across clinical trials. The initial reaction occurred after the first or second cycle of therapy in 98 percent. (See "Infusion reactions to therapeutic monoclonal antibodies used for cancer therapy".)

A larger confirmatory phase III trial of doxorubicin with and without olaratumab (the ANNOUNCE trial) has completed accrual, but results are not yet available. However, based upon the results of the open-label, randomized, phase II trial described above, olaratumab was approved in the United States in October 2016, in conjunction with doxorubicin, for treatment of patients with STS that cannot be cured with radiation or surgery who have a type of STS for which an anthracycline is an appropriate chemotherapy [94].

The recommended dose and schedule of olaratumab is 15 mg/kg administered as an intravenous infusion over 60 minutes on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity [95]. For the first eight cycles, olaratumab is administered with doxorubicin (75 mg/m2 on day 1). Premedication with diphenhydramine and dexamethasone is recommended for cycle 1, day 1 only.

Olaratumab is being studied in other combinations, but there are presently no data to support its use with other agents for patients with advanced STS.

Gemcitabine-based combinations

Gemcitabine plus docetaxel — Activity for gemcitabine plus docetaxel (table 5) was initially reported in a study of 34 patients with leiomyosarcoma of uterine (n = 29) or gastrointestinal (GI, n = 5) origin [80]; 53 percent had an objective response, including two of the five with GI leiomyosarcoma. More recent data suggest that this regimen may have a broader range of activity, although response rates appear to be lower in histologies other than leiomyosarcoma [81,96]. As an example, a retrospective review of 133 patients treated with gemcitabine and docetaxel included 76 leiomyosarcomas and 57 other histologies [96]. Only 17 percent were chemotherapy-naive. The overall response rate was 18 percent (24 versus 10 percent for leiomyosarcoma and other histologies, respectively). At 12 and 24 months, 51 and 15 percent of patients were still alive, respectively.

Lower doses (particularly of docetaxel) may be needed for patients with prior radiation to fields encompassing large amounts of marrow.

Gem/docetaxel versus gemcitabine alone — As noted above, gemcitabine alone is an active single agent in metastatic STS when administered as a fixed rate infusion. The superiority of gemcitabine/docetaxel over gemcitabine alone was addressed in an open-label multicenter phase II trial comparing gemcitabine with and without docetaxel that used a novel Bayesian adaptive randomization strategy [97]. This allows for continuous outcomes monitoring, incrementally assigning more patients to the superior treatment arm, while accounting for possible treatment-subgroup interactions (eg, histology, prior radiation therapy [RT] versus none, performance status [98]).

The treatment arms were gemcitabine alone (1200 mg/m2 days 1 and 8 every 21 days; 900 mg/m2 in patients with prior pelvic RT) or gemcitabine (900 mg/m2 on days 1 and 8; 675 mg/m2 if prior pelvic RT) plus docetaxel (100 mg/m2 on day 8; 75 mg/m2 if prior pelvic RT), with courses repeated every 21 days. In both arms, gemcitabine was given via fixed dose rate infusion (10 mg/m2/min). All patients received growth factor support.

Forty-nine patients were adaptively randomized to gemcitabine alone and 73 to gemcitabine plus docetaxel. The primary endpoint (tumor response, a complete or partial response or stable disease for at least 24 weeks) was met by 27 versus 32 percent of patients receiving gemcitabine alone and combined therapy, respectively. The objective response rate with combined therapy was higher (16 versus 8 percent), as was PFS (6.2 versus 3 months) and overall survival (17.9 versus 11.5 months). Patients with leiomyosarcoma and undifferentiated/unclassified STS (previously included in the broad category of "malignant fibrous histiocytoma," a subset of which is the undifferentiated pleomorphic sarcoma variant [99]) appeared to derive the most benefit. However, these benefits came at the cost of greater toxicity (particularly edema and constitutional symptoms). Significantly more patients receiving combined therapy discontinued treatment due to toxicity. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Histopathology'.)

On the other hand, the benefit of combined therapy over gemcitabine alone, particularly for non-uterine leiomyosarcomas, was called into question by the results of a randomized phase II trial in which 90 patients with metastatic leiomyosarcoma of uterine (n = 46) or non-uterine (n = 44) origin were randomly assigned to gemcitabine alone (1000 mg/m2 on days 1, 8, and 15 of each 28-day cycle) or with docetaxel (100 mg/m2 on day 8 of a 21-day cycle), with primary prophylaxis with a granulocyte colony-stimulating factor [100]. Among patients with uterine leiomyosarcoma, response rate was only modestly higher with combined therapy (24 versus 19 percent), and median PFS was not better (4.7 versus 5.5 months). Among those with non-uterine leiomyosarcomas, the response rate to combined therapy was low (5 versus 14 percent with gemcitabine alone), and median PFS was only 3.8 months (versus 6.3 months for gemcitabine monotherapy). Patients receiving single agent gemcitabine experienced less toxicity.

Although the authors concluded that both treatments were similarly efficacious, at least for uterine leiomyosarcomas, the trial was conducted as a parallel set of two phase II studies, and the study lacked power to determine which treatment was better [101]. An important finding was that a high proportion of patients in both arms (>40 percent, highest in the non-uterine leiomyosarcoma group) had durable stable disease, and the six-month PFS rate in all groups was ≥47 percent.

Gem/docetaxel versus doxorubicin alone — Whether initial therapy with a gemcitabine-based regimen is preferable to anthracycline-based therapy with olaratumab for patients with a good performance status and any histologic type of STS (including leiomyosarcoma) is uncertain. However, given the approval of olaratumab in combination with doxorubicin for first-line therapy of all anthracycline-sensitive STS histologies and a preliminary report of data from the GeDDis trial, which showed no significant difference in PFS or overall survival along with less toxicity with single-agent doxorubicin [16], a gemcitabine-based combination can no longer be considered a first-line regimen for any population. Some clinicians still prefer gemcitabine/docetaxel for metastatic uterine leiomyosarcoma over doxorubicin-based therapy since only 51 patients with leiomyosarcoma from all sites were treated on the randomized phase II trial that led to the approval of first-line olaratumab with doxorubicin for anthracycline-sensitive advanced STS. However, in a subset analysis, leiomyosarcoma patients, including those with uterine leiomyosarcoma, fared at least as well as patient with other histologies on the trial. (See 'Doxorubicin plus olaratumab' above.)

The preliminary report of the randomized GeDDis trial comparing combined gemcitabine/docetaxel versus doxorubicin alone in 257 previously untreated patients with a variety of histologies of advanced/metastatic STS was presented at the 2015 American Society of Clinical Oncology annual meeting [16]. Doxorubicin was less toxic and easier to administer than gemcitabine/docetaxel, and the proportion of patients who were progression-free at 24 weeks (the primary endpoint) was identical (46 percent in both groups); median overall survival slightly favored doxorubicin (71 versus 63 weeks, HR for death 1.07, 95% CI 0.77-1.49).

Results were not stratified according to histologic subtype. It should be noted that undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma was underrepresented in this trial. In our experience, undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma is the one histologic subtype that responds better to gemcitabine/docetaxel, and we would choose this combination for second-line therapy after failure of initial doxorubicin plus olaratumab in this group.  

Dose intensification — In view of the demonstrated dose-response relationship with doxorubicin and ifosfamide, higher than standard dose chemotherapy has been studied in STS. Higher doses of doxorubicin and ifosfamide can be administered in combination regimens with the support of hematopoietic growth factors [75,90,102-107] or autologous hematopoietic stem cells [108-112]; however, there is no clear overall survival benefit for higher, as compared with standard, dosing regimens.

These approaches must be considered investigational for metastatic STS and performed only in the context of innovative exploratory new trials or appropriately controlled phase III clinical trials.

NEWER TREATMENT STRATEGIES — Given the limited efficacy of conventional cytotoxic chemotherapy, STS remains a fertile ground for the field of drug development. Clinical trials in a number of areas have shown promise in metastatic STS.

Performing valid clinical trials in STS is challenging because the different histologic types can behave differently; as a result, clinical trials must be stratified by histologic subtype for adequate interpretation of results. In order to generate studies of sufficient size and power, large-scale collaborations are required on a national and international level. Such collaborations are already in place in the United States and among the nations of Europe, in Scandinavia, Italy, and Canada. With these collaborations, it is hoped that further research will rapidly translate research findings into the novel therapeutics which are so desperately required by patients with sarcomas.

Drugs approved for sarcoma in the United States, Europe, or Canada

Imatinib — The most dramatic example of translation of molecular understanding of STS to a novel therapy is with the use of the selective tyrosine kinase inhibitor (TKI) imatinib to treat gastrointestinal stromal tumors (GISTs). Unfortunately, this agent is of limited utility for treatment of non-GIST STS, with the exception of dermatofibrosarcoma protuberans, desmoid tumors, and tenosynovial giant cell tumor/pigmented villonodular synovitis (TGCT/PVNS). However, there are better data for initial therapy with single agent liposomal doxorubicin, single agent vinorelbine, and combination methotrexate/vinblastine in patients with desmoid tumors. The use of imatinib for these specific histologic soft tissue tumor types is discussed in detail separately. (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors" and "Antineoplastic therapy for miscellaneous benign diseases affecting soft tissue and bone", section on 'Tenosynovial giant cell tumor' and "Dermatofibrosarcoma protuberans: Epidemiology, pathogenesis, clinical presentation, diagnosis, and staging" and "Desmoid tumors: Systemic therapy".)

Trabectedin — Trabectedin is an approved option for treatment of advanced liposarcoma and leiomyosarcoma in patients who have previously been treated with at least an anthracycline-containing chemotherapy combination.

Trabectedin (ecteinascidin, ET-743), which is now synthesized but was originally isolated from the Caribbean sea sponge Ecteinascidia turbinata, kills cells by poisoning the deoxyribonucleic acid (DNA) nucleotide excision repair machinery [113]. Trabectedin is an active agent for advanced STS, although the objective response rate, by conventional criteria, is fairly low [114-118]. Response rates have been highest in the myxoid/round cell liposarcoma and leiomyosarcoma subtypes.

Experience with this agent has also underscored the relevance of stable disease as a beneficial endpoint for metastatic STS [114-117,119,120]. (See 'End points to define benefit' above.)

Phase II studies of trabectedin (1.5 mg/m2 over 24 hours every 21 days), performed both in patients failing prior chemotherapy and in those with previously untreated disease, have been promising [115-117,121,122]; the largest of these studies randomly assigned 76 patients with advanced, predominantly pretreated, translocation-associated sarcoma (main subtypes were myxoid/round cell liposarcoma and synovial sarcoma) to best supportive care versus trabectedin (1.2 mg/m2 over 24 hours on day 1 every 21 days) [121]. The primary endpoint, median progression-free survival (PFS), was significantly longer with trabectedin (5.6 versus 0.9 months, hazard ratio [HR] 0.07, 95% CI 0.03-0.16). The most common drug-related adverse effects for patients treated with trabectedin were nausea (89 percent, 8 percent grade 3), decreased appetite (58 percent, 8 percent grade 3), neutropenia (83 percent, 67 percent grade 3 or 4, with febrile neutropenia in 14 percent), and increased alanine aminotransferase (67 percent, 61 percent grade 3 or 4).

On the basis of these data, trabectedin was approved by European regulators in 2007 for patients with advanced STS who experienced failure of treatment with doxorubicin and ifosfamide.

Administration of the drug over 24 hours every three weeks was significantly superior to weekly dosing over three hours in a randomized phase II trial conducted in patients with previously treated advanced liposarcoma or leiomyosarcoma (median time to tumor progression 3.7 versus 2.3 months) [119]. This was the dose chosen for the randomized phase III multicenter United States trial, which compared trabectedin (starting dose 1.5 mg/m2 over 24 hours on day 1) with dacarbazine (starting dose 1000 mg/m2 as a 20- to 120-minute infusion on day 1) every 21 days in 518 patients with advanced leiomyosarcoma or adipocytic sarcoma previously treated with conventional chemotherapy [123]. While median overall survival (the primary endpoint) was not significantly different with trabectedin (12.4 versus 12.9 months), there was a significant improvement in PFS with trabectedin (median 4.2 versus 1.5 months). The objective response rate was slightly, but not significantly, higher with trabectedin (10 versus 7 percent), but the clinical benefit rate (reflecting both objective disease response and durable stable disease) was significantly higher with trabectedin (34 versus 19 percent). Benefit was seen in both uterine and non-uterine leiomyosarcomas and in all liposarcoma subtypes, although the benefit compared with dacarbazine was most pronounced (median PFS 5.6 versus 1.5 months) in the myxoid/round cell liposarcoma subset and marginal (median PFS 2.2 versus 1.9 months) in the dedifferentiated subgroup. The most common serious (grade 3 or 4) adverse effects were neutropenia (37 percent), thrombocytopenia (17 percent), anemia (14 percent), and transient elevations in aminotransferases (26 percent elevated alanine aminotransferase [ALT] and 13 percent elevated aspartate aminotransferase [AST]).

Based upon these results, trabectedin was approved in the United States for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who have received a prior anthracycline-containing regimen [124]. Trabectedin carries a warning about the risk for severe and fatal neutropenic sepsis, rhabdomyolysis, hepatotoxicity, skin and soft tissue necrosis following extravasation [125], and heart failure. Dexamethasone pretreatment (20 mg IV 30 minutes prior to each dose) is recommended to ameliorate drug-related hepatotoxicity [126,127].

A particularly high response rate has been seen in patients with advanced pretreated myxoid/round cell liposarcoma (MRCL); in one study of 51 such patients, 51 percent had either a complete or partial response, and 88 percent were progression-free at six months [128]. In a later analysis of 32 of these patients, followed for an average of 25 months, the median PFS duration was 28 months [129]. Tumor response was marked by early radiologic alterations (decreased tumor density on computed tomography [CT] or decrease in magnetic resonance imaging [MRI] contrast enhancement) followed by delayed tumor shrinkage [128]. The benefit of trabectedin in this subtype is consistent with clinical activity reported with this agent in patients with the so-called "translocation-related" sarcomas, of which the MRCL variant is included [130]. (See "Pathogenetic factors in soft tissue and bone sarcomas", section on 'Chromosomal translocations'.)

Others report a high objective response rate (60 percent) and a high rate of disease control overall (92 percent) with a tolerable side effect profile for trabectedin in combination with doxorubicin for first-line treatment of leiomyosarcoma [131]. Median overall survival was 20.2 months in the uterine leiomyosarcoma cohort and 34.5 months in the soft tissue leiomyosarcoma cohort. While these results seem better than those achievable with single-agent doxorubicin or combination doxorubicin, and/or ifosfamide-based chemotherapy (median survival 9 to 12 months), randomized trials are needed to confirm benefit in this subgroup. One randomized phase II trial failed to confirm a survival benefit for combined trabectedin plus doxorubicin versus doxorubicin alone as first-line therapy in 115 patients with advanced STS of a variety of histologic subtypes (median overall survival 13.3 versus 13.7 months) [132]. While the study lacked power to assess outcomes in histologic subgroups, patients with leiomyosarcoma (35 of the 115 enrolled patients) had a better median PFS (7 versus 3.9 months) and overall survival (24.2 versus 10.3 months) as compared with other histologies. Nevertheless, appropriately powered randomized trials are needed in this subgroup before it can be concluded that combination therapy is better than doxorubicin alone for patients with leiomyosarcoma.

Preliminary work suggests that the sensitivity of myxoid liposarcomas to trabectedin may be related to the unique presence of a fusion oncoprotein that results from chromosomal translocation in this disease, and the ability of trabectedin to interfere with the ability of some fusion proteins to bind to promoters [133]. These data suggest that trabectedin represents a unique form of molecularly targeted therapy. (See "Pathogenetic factors in soft tissue and bone sarcomas".)

Pazopanib — For patients with advanced or metastatic STS (other than liposarcoma, leiomyosarcoma, or GIST) who progress after an anthracycline-containing regimen and, typically, after other chemotherapy such as ifosfamide, gemcitabine, or gemcitabine combinations, we recommend pazopanib.

Pazopanib is a multitargeted, orally active, small molecule inhibitor of several TKs, including the vascular endothelial growth factor receptor (VEGFR) and the platelet-derived growth factor receptor alpha and beta (PDGFRA and PDGFRB). Single-agent pazopanib showed activity in a phase II clinical trial that included various STS subtypes [134]. Pazopanib met the primary endpoint for activity in three of the four histology-specific cohorts: leiomyosarcomas, synovial sarcomas, and other eligible STS types, but not liposarcoma. Based upon those results, a worldwide, randomized, double-blinded, phase III study (the PALETTE trial) was designed by the European Organisation for Research and Treatment of Cancer (EORTC) and other investigators to compare pazopanib (800 mg daily) versus placebo in 369 patients with a variety of histologic subtypes (leiomyosarcoma, fibrosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor [MPNST], vascular STS, sarcoma not otherwise specified, but not adipocytic sarcomas or GIST) whose disease had progressed during or after first-line chemotherapy (including an anthracycline) [135]. The median PFS was significantly higher in the pazopanib group (4.6 versus 1.6 months), and benefit was consistent across all histologic subtypes. There was no significant difference in overall survival (12.5 versus 10.7 months, HR 0.86, 95% CI 0.67-1.1) [136]. The best overall response was partial response in 6 versus 0 percent of the pazopanib and placebo groups, respectively, and stable disease in 67 versus 38 percent.

The most common grade 3 or 4 treatment-related toxicities were fatigue, hypertension, diarrhea, anorexia, and transient elevation in liver function tests. A drop in left ventricular ejection fraction occurred in 16 patients treated with pazopanib, compared with three cases in the placebo group (6.5 versus 2.4 percent); only three cases were symptomatic. Venous thromboembolism was 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. This toxicity profile did not translate into significantly worse global health status during treatment [137], Treatment-related toxicity in patients treated with TKIs that target vascular endothelial growth factor (VEGF) is discussed in more detail separately. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects" and "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects".)

Based upon these data, in April 2012, pazopanib was approved in the United States for treatment of patients with advanced STS (but not for adipocytic or GIST) who have received prior chemotherapy. Given the risk for potentially fatal hepatotoxicity, close monitoring of liver function tests is recommended, particularly in the first nine weeks of therapy. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease", section on 'Pazopanib'.)

The utility of pazopanib in liposarcomas remains uncertain; at least two prospective trials of pazopanib in this STS subtype are underway. The efficacy of pazopanib in advanced GIST is addressed elsewhere. (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors", section on 'Sorafenib and other TKIs'.)

The solubility of pazopanib is pH dependent, and an elevated gastric pH may decrease bioavailability [138]. The US Food and Drug Administration (FDA)–approved prescribing information recommends against concomitant use of drugs that raise gastric pH (proton pump inhibitors or histamine H2 receptor antagonists) in patients receiving pazopanib [139]. Short-acting antacids could be considered in place of these agents, but dosing of antacids and pazopanib should be separated by several hours.

Eribulin — Eribulin is an approved option for treatment of unresectable or metastatic liposarcoma for patients who received prior anthracycline-containing chemotherapy in the United States, and for leiomyosarcoma and liposarcoma in other countries.  

Eribulin inhibits microtubules via a mechanism that is distinct from other microtubule-targeting agents, such as taxanes. Modest efficacy in leiomyosarcoma (LMS) and adipocytic sarcomas was suggested in a phase II trial in which 128 patients with a variety of sarcoma histotypes all received eribulin (1.4 mg/m2 IV on days 1 and 8 of every three week cycle) [140]. Twelve of 38 patients with LMS (32 percent), 15 of 32 patients with adipocytic sarcoma (47 percent), 4 four of 19 patients with synovial sarcoma (21 percent), and 5 of 26 with other sarcoma histotypes (19 percent) achieved the primary endpoint (PFS at 12 weeks).

In a multicenter phase III trial comparing eribulin (1.4 mg/m2 IV days 1 and 8) with dacarbazine (850 to 1200 mg/m2 IV day 1) every 21 days in 452 patients with advanced leiomyosarcoma or adipocytic sarcoma previously treated with an anthracycline, median overall survival, the primary endpoint, was modestly, but significantly, better with eribulin (13.5 versus 11.5 months, HR for death 0.77, 95% CI 0.62-0.95), although median PFS was the same in both arms (2.6 months) [141]. In a preplanned exploratory subgroup analysis, treatment benefits for eribulin were limited to patients with liposarcoma (median overall survival 15.6 versus 8.4 months) and not leiomyosarcoma (median overall survival 12.8 versus 12.3 months) [142]. Treatment-emergent adverse effects that were more common with eribulin included neutropenia (43 versus 24 percent), pyrexia (28 versus 14 percent), peripheral sensory neuropathy (21 versus 4 percent), and alopecia (35 versus 3 percent).

Sirolimus — For patients who have advanced neoplasms with perivascular epithelioid cell differentiation (PEComa), such as recurrent angiomyolipoma/lymphangioleiomyomatosis, we suggest a trial of sirolimus if a clinical trial option does not exist and the patient has demonstrated progressive disease.

The PEComa family of tumors consists of related mesenchymal neoplasms that exhibit myomelanocytic differentiation and share a distinctive cell type, the perivascular epithelioid cell (PEC) [143-145]. The major members of this family are lymphangioleiomyomatosis (LAM), a disease predominantly presenting as numerous nodular, cystic, and interstitial pulmonary lesions in premenopausal women; angiomyolipoma (AML), commonly identified as an asymptomatic renal lesion with evidence of vascular, muscle, or adipocytic differentiation; and PEComa, an epithelioid malignancy typically arising in the gastrointestinal tract, retroperitoneum, uterus, or somatic soft tissues and intimately related to blood vessel walls. Although most PEComas are benign, a subset exhibit malignant behavior, with locally invasive recurrences or development of distant metastases most commonly in the lung. (See "Sporadic lymphangioleiomyomatosis: Epidemiology and pathogenesis".)

In many instances, tumors of the PEComa family share dysregulated activation of the mechanistic (previously called mammalian) target of rapamycin (mTOR) signaling through mutations in the TSC1 or TSC2 genes, which may be inherited (tuberous sclerosus complex) or sporadic [146-151]. Activation results in cellular proliferation and release of lymphangiogenic growth factors. (See "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis" and "Sporadic lymphangioleiomyomatosis: Epidemiology and pathogenesis", section on 'Pathogenesis'.)

Benefit has been shown for the mTOR inhibitor sirolimus in patients with PEComas, including recurrent angiomyolipoma/lymphangioleiomyomatosis [146,152-155]. As an example, in one report of three patients with metastatic PEComa, radiographic responses to sirolimus were observed in all three, which was durable in two. Sirolimus is approved in the United States for treatment of pulmonary LAM [156]. (See "Sporadic lymphangioleiomyomatosis: Treatment and prognosis".)

Studies supporting some activity using drugs with regulatory approval for other cancers

Sunitinib — We suggest sunitinib for first-line treatment for patients with advanced alveolar soft part sarcoma, solitary fibrous tumor/hemangiopericytoma, and clear cell sarcoma if a clinical trial option does not exist, and the patient has demonstrated progressive disease.

The activity of sunitinib for most histologic types of non-GIST sarcomas is limited [157,158]. However, sunitinib appears active against the rare and chemotherapy-refractory alveolar soft part sarcoma and has anecdotal activity against solitary fibrous tumor/hemangiopericytoma and clear cell sarcoma [157,159-163]. In a case series, two of four patients with progressive metastatic alveolar soft part sarcoma had an objective partial response with sunitinib 37.5 mg daily (one sustained for 12 months), and one had stable disease for at least three months [163]. Treatment was reasonably well tolerated. (See "Solitary fibrous tumor", section on 'Molecularly targeted agents'.)

Pazopanib is a similar compound that is expected to have similar activity in these histologic STS subtypes, but data are not reported specifically regarding its utility. Nevertheless, it represents a reasonable alternative. (See 'Pazopanib' above.)

Sorafenib — Sorafenib is another multitargeted TKI that has limited activity in metastatic non-GIST STS, as evidenced by the following reports:

In a phase II trial of 120 patients with six different histologic types of STS who received sorafenib 400 mg twice daily, there was one objective partial response among 37 leiomyosarcomas, one complete and four partial responses among 37 angiosarcomas (14 percent), and no objective responses in MPNST, malignant fibrous histiocytoma (most of which are now reclassified as undifferentiated/unclassified STS [99]), synovial sarcoma, or other histotypes [164]. Treatment-related toxicity was not trivial, despite the use of the US FDA-approved dose and schedule. Over 60 percent of patients required dose reduction, the majority due to dermatologic toxicity. There were three grade 5 toxicities (one GI hemorrhage, one intestinal perforation, and one fatal tension pneumothorax in a patient with pulmonary metastases).

More modest activity against angiosarcoma was seen in another phase II trial of 51 patients with advanced vascular sarcomas, high-grade liposarcoma, and leiomyosarcoma [165]. Six of the eight patients with some form of "vascular sarcoma" had prolonged periods of stable disease in this nonrandomized trial, although no objective antitumor responses were observed. Median PFS in this group of "vascular sarcomas" was five months, compared with two to three months for the other sarcoma histologies. Despite the same dose, the toxicity profile was more favorable than seen in the prior study; 50 percent required at least one dose reduction, but there were no grade 5 toxicities.

However, sorafenib may be of modest benefit in patients with advanced epithelioid hemangioendothelioma. In a phase II study of 15 patients with progressive disease (12 with metastatic disease) who were treated with sorafenib 800 mg daily, there were two partial responses lasting two and nine months, and the nine-month PFS rate was 31 percent (4 of 13 patients) [166]. The PFS data may be difficult to interpret due to the multifocality of disease that is typically present and the often more indolent nature of this entity compared with other metastatic STS.

Regorafenib — Regorafenib is an orally active inhibitor of angiogenic (including the VEGFRs 1 to 3), stromal, and oncogenic receptor TKs. It is structurally similar to sorafenib and targets a variety of kinases implicated in angiogenic and tumor growth-promoting pathways. It is approved for refractory GIST but not for non-GIST STS subtypes. (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors", section on 'Regorafenib'.)

Potential activity for regorafenib in 182 patients with liposarcoma, leiomyosarcomas, synovial sarcomas, and other types of STS previously treated with doxorubicin, trabectedin, ifosfamide, and/or pazopanib was suggested in a double-blind, randomized placebo-controlled trial of regorafenib (160 mg per day for 21 of each 28-day cycle) [167]. Compared with placebo, there was a significant benefit for PFS with regorafenib treatment in all subgroups but liposarcoma, and there were four objective responses, one in synovial sarcoma, two in angiosarcoma, and one in solitary fibrous tumor. The most common adverse events, seen in more than one-third of in the regorafenib-treated patients, were asthenia, diarrhea, mucositis, acral erythema, anorexia, and arterial hypertension.

Importantly, only six patients had received prior pazopanib. In our view, these data support the view that broad spectrum VEGFR TKIs have activity in subsets of non-adipocytic STS, but there are no data to support the use of regorafenib over the approved option of pazopanib. Additional experience with regorafenib for non-liposarcoma non-GIST STS subtypes after failure of pazopanib is needed.

Cediranib — Cediranib is a potent oral inhibitor of all three VEGFRs. Activity in alveolar soft part sarcoma was suggested in a phase II trial of 46 patients with unresectable disease [168]. The objective response rate was 35 percent, and 60 percent had stable disease; the six-month disease control rate was 84 percent. Cediranib is not yet commercially available in any country.

Other available drugs, such as sunitinib or pazopanib, are active for alveolar soft part sarcomas after failure of other therapy and represent a non-clinical trial option for this diagnosis. (See 'Sunitinib' above and 'Pazopanib' above.)

Bevacizumab — Bevacizumab is a monoclonal antibody targeting VEGF. The combination of bevacizumab plus doxorubicin was evaluated in 17 anthracycline-naive patients with metastatic STS [169]. Although there were only two partial responses (lasting for 21 to 36 weeks, both in patients with uterine leiomyosarcoma), 11 had stable disease for 12 weeks or more. Of concern, six patients developed grade 2 cardiac toxicity at cumulative doxorubicin doses of 75 to 300 mg/m2.

Given that efficacy was not substantially different from that expected with doxorubicin alone and the worrisome cardiotoxicity, bevacizumab has been largely abandoned, except in highly vascular tumors such as angiosarcoma. However, the available data are quite limited:

In a phase II trial of bevacizumab in 32 patients with metastatic or locally advanced angiosarcoma or epithelioid hemangioendothelioma, four patients (two angiosarcoma and two epithelioid hemangioendothelioma) had a partial response (17 percent), while 50 percent had tumor stabilization with a mean time to tumor progression of 26 weeks [170].

The multicenter randomized phase II ANGIOTAX-PLUS trial evaluated weekly paclitaxel, with or without bevacizumab, in 50 patients with advanced primary or radiation-induced angiosarcoma, 16 of whom had received prior anthracycline chemotherapy [171]. The addition of bevacizumab did not lead to higher rates of being progression-free at six months (57 versus 54 percent), longer median PFS, or overall survival (15.9 versus 19.5 months).

The use of chemotherapy without bevacizumab represents a standard option for angiosarcoma. Based upon the ANGIOTAX-PLUS study, there is no role for combining paclitaxel with bevacizumab.

Palbociclib — More than 90 percent of well-differentiated or dedifferentiated liposarcomas have amplification of cyclin-dependent kinase 4 (CDK4), and a modest degree of benefit from the selective CDK4/CDK6 inhibitor palbociclib was suggested in a phase II open label trial (one complete response among 35 assessable patients, 12-week PFS 57 percent) [172]. Randomized trials are needed to confirm benefit relative to other available therapies, such as eribulin.

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

General principles

Soft tissue sarcomas (STS) are a heterogeneous group of rare tumors arising from mesenchymal cells at all body sites. While in the past these tumors were all "lumped" together and treated similarly, consensus is emerging that the selection of treatment should be histology driven, particularly in the setting of advanced disease. (See 'Histology-driven treatment' above.)

Surgical resection of metastatic disease can provide long-term relapse-free survival and perhaps cure in selected patients, the majority of whom have isolated pulmonary metastatic disease. (See "Surgical treatment and other localized therapy for metastatic soft tissue sarcoma".)

However, for the majority of patients with metastatic STS, chemotherapy is administered with palliative intent, with the goals of decreasing tumor bulk, diminishing symptoms, improving quality of life, and prolonging survival. Objective response rates, as judged by a decrease in the size of measurable lesions, are increasingly considered to be poor surrogates for benefit in metastatic STS. The "disconnect" between objective tumor response and disease stabilization is particularly evident in studies of drugs like trabectedin and molecularly targeted therapies. (See 'End points to define benefit' above.)

The natural history of patients with unresectable metastatic disease is variable and is more dependent on disease biology than treatment. For some patients with asymptomatic, low-grade, unresectable disease (eg, low-grade intraabdominal leiomyosarcoma), it might be reasonable to follow the patient without active chemotherapy. Conversely, for patients with a high-grade chemotherapy-sensitive tumor, such as synovial sarcoma or liposarcoma, early use of combination chemotherapy may be preferable. (See 'Natural history of metastatic disease and implications for treatment' above.)  

Patients with advanced unresectable STS are appropriate candidates for clinical trials to identify more active single agents, combinations, or novel approaches. If participation in clinical trials is not feasible, conventional systemic therapy is an appropriate option for selected patients. The following represents our general approach to advanced, unresectable, non-uterine, non-gastrointestinal stromal tumor (GIST) STS. Treatment of patients with advanced uterine leiomyosarcoma and GIST is discussed separately. (See "Treatment and prognosis of uterine leiomyosarcoma" and "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors".)

Choice of initial therapy

Patients should be assessed for their potential responsiveness to doxorubicin, to gauge whether an anthracycline should be used as part of first-line therapy or if other agents should be considered first.

For patients with a good performance status and an STS histology that is known to have at least some sensitivity to anthracyclines (eg, leiomyosarcoma, liposarcoma, synovial sarcoma, pleomorphic or undifferentiated sarcoma, angiosarcoma, malignant nerve sheath tumor), we suggest doxorubicin and olaratumab rather than doxorubicin alone (Grade 2B). We also prefer first-line doxorubicin plus olaratumab over other combinations, such as doxorubicin plus ifosfamide or a gemcitabine-based regimen, despite the lack of comparative trials. (See 'Doxorubicin plus olaratumab' above.)

A gemcitabine-based combination could be considered for first-line therapy in a patient for whom an anthracycline is relatively contraindicated (eg, clinical heart failure, prior treatment with >450 mg/m2 doxorubicin in the adjuvant setting). A taxane is a reasonable option for first-line treatment for patients with an angiosarcoma. (See 'Gemcitabine-based combinations' above and 'Taxanes and angiosarcoma' above.)

Patients with a poorer performance status or extensive comorbidity who remain eligible for chemotherapy can be considered for treatment with pegylated liposomal doxorubicin (Doxil, Caelyx), gemcitabine alone, or a gemcitabine-based combination. (See 'Pegylated liposomal doxorubicin' above and 'Gemcitabine and other agents' above and 'Gemcitabine-based combinations' above.)

For patients with STS histologies that are not sensitive to anthracyclines, other options should be considered first, even though these may represent off-label use of existing drugs:

For patients with advanced alveolar soft part sarcoma, solitary fibrous tumor/hemangiopericytoma, and clear cell sarcoma, we suggest a trial of sunitinib or pazopanib, if a clinical trial option does not exist and the patient has demonstrated progressive disease (Grade 2C). (See 'Sorafenib' above and 'Pazopanib' above.)

For patients who have advanced neoplasms with perivascular epithelioid cell differentiation (PEComa), including recurrent angiomyolipoma/lymphangioleiomyomatosis, we suggest a trial of sirolimus if a clinical trial option does not exist and the patient has demonstrated progressive disease (Grade 2C). (See 'Histology-driven treatment' above.)

For tenosynovial giant cell tumor and dermatofibrosarcoma protuberans, we suggest a trial of imatinib if a clinical trial option does not exist and the patient has demonstrated progressive disease (Grade 2C). (See 'Imatinib' above and "Antineoplastic therapy for miscellaneous benign diseases affecting soft tissue and bone", section on 'Tenosynovial giant cell tumor' and "Dermatofibrosarcoma protuberans: Treatment", section on 'Treatment of locally advanced, recurrent, and metastatic disease'.)

High-dose chemotherapy with stem cell rescue is not a standard approach to treatment of advanced STS of the usual adult types, and we recommend that this approach not be pursued outside of the context of a clinical trial (Grade 1A). (See 'Dose intensification' above.)

Treatment at progression — For patients with progression on olaratumab plus doxorubicin who retain a good performance status, we prefer enrollment in a clinical trial, if one is available. If protocol treatment is not available or declined, our recommendations for second-line and later therapy for patients who retain a good performance status are histology driven:

Trabectedin is approved for advanced leiomyosarcoma and liposarcoma in many countries, including the United States. It is particularly active in myxoid/round cell liposarcoma. (See 'Trabectedin' above.)

Eribulin is approved for use in liposarcoma in the United States, and in liposarcoma and leiomyosarcoma in other countries. It may have more activity in pleomorphic liposarcoma and dedifferentiated liposarcoma than does trabectedin. (See 'Eribulin' above.)

Pazopanib is approved in many countries for advanced sarcomas other than liposarcoma or GIST. It may have more activity in leiomyosarcoma, synovial sarcoma, angiosarcoma, and solitary fibrous tumor than in other histologic types. (See 'Pazopanib' above.)

For angiosarcomas, a weekly taxane as a good option for second-line therapy. (See 'Taxanes and angiosarcoma' above.)

Other options for second-line treatment and beyond in patients who retain a good performance status include pegylated liposomal doxorubicin, an ifosfamide-containing regimen, or gemcitabine or a gemcitabine-based combination.

In our experience, undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma is the one histologic subtype that responds better to gemcitabine/docetaxel than to other chemotherapy combinations, and we would choose this combination for second-line therapy after failure of initial doxorubicin plus olaratumab. (See 'Pegylated liposomal doxorubicin' above and 'Ifosfamide' above and 'Gemcitabine and other agents' above and 'Gemcitabine-based combinations' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge George Demetri, MD, who contributed to an earlier version of this topic review.

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