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REVIEW article

Front. Oncol., 30 November 2017
Sec. Surgical Oncology

Systemic Therapy in Metastatic or Unresectable Well-Differentiated/Dedifferentiated Liposarcoma

\r\nYevette McGovernYevette McGovern1 \r\nCharlie D. ZhouCharlie D. Zhou2 \r\nRobin L. Jones*\r\nRobin L. Jones1*
  • 1Royal Marsden Hospital/Institute of Cancer Research, London, United Kingdom
  • 2Royal Free London NHS Foundation Trust, London, United Kingdom

Liposarcoma is one of the most common subtypes of soft-tissue sarcoma and consists of three main subtypes, of which well-differentiated liposarcoma and dedifferentiated liposarcoma account for 40–45%. The current mainstay of systemic treatment for patients with metastatic or unresectable disease remains doxorubicin with or without ifosfamide in the first-line setting. Recently, eribulin and trabectedin have been approved by the US Food and Drug Administration for recurrent liposarcomas and progress in molecular characterization of these tumors has opened up new and potential novel treatment targets. This review will focus on the evidence base for current treatment strategies and will also discuss potential future options.

Introduction

Liposarcoma accounts for around 15% of the overall incidence of soft-tissue sarcomas (STSs). Well-differentiated liposarcoma (WDLS) and dedifferentiated liposarcoma (DDLS) are the most common histological subgroups of liposarcoma (1). WDLS/DDLS tumors are particularly associated with aberrations in chromosome 12q13-15 involving oncogenes including CDK4 and MDM2 (2). The other major subtypes include myxoid liposarcoma and pleomorphic liposarcoma.

Well-differentiated liposarcoma often present as slow growing masses in the retroperitoneum and the extremities. While pure WDLS have no propensity for metastatic spread, local recurrence is a major problem for WDLS located in the retroperitoneum (3). Furthermore, the development of DDLS is an ominous feature associated with higher risk of developing metastatic disease.

Of the other histological subtypes, myxoid liposarcoma is considered to be relatively chemosensitive, particularly to anthracyclines and trabectedin (4, 5). As a result, neoadjuvant or adjuvant chemotherapy may have a role in this disease. In pleomorphic liposarcoma, the role of systemic therapy is poorly defined; there are only a few retrospective studies that suggest a degree of chemosensitivity in the metastatic setting. Here, we focus specifically on the management of WDLS/DDLS.

Surgical resection remains the definitive management for operable WDLS/DDLS disease. The vast majority of extremity WDLS can be resected with negative margins and their clinical behavior does not warrant the use of chemotherapy in either the adjuvant or neoadjuvant setting. However, in the metastatic or unresectable setting, WDLS/DDLS are considered relatively chemotherapy resistant and there is no consensus to warrant use of systemic treatment currently in the adjuvant or neoadjuvant setting.

For patients with unresectable or metastatic WDLS and DDLS, the standard treatment consists of chemotherapy, usually with an anthracycline in the first line, perhaps in combination with ifosfamide when rapid disease control is required. However, recent studies evaluating combination treatments with monoclonal antibodies and targeted agents have the potential to completely alter the current status quo and it is possible that the next few years will see a significant shift in the standard management of this disease.

In this review, we aim to discuss the evidence behind the current treatment strategies and to discuss the latest novel treatment options, both possible and potential (Appendix S1 in Supplementary Material). Where possible/available, specific evidence in WDLS and DDLS will be explored.

Conventional Cytotoxic Chemotherapy/Marine-Derived Compounds Doxorubicin/Ifosfamide

Anthracycline-based chemotherapy and doxorubicin, in particular, has been the standard first-line chemotherapy in metastatic STS for over 30 years (6, 7). Due to the rarity of STS, early clinical trials enrolled patients of diverse histological subtypes into the same studies. Early reported response rates of metastatic STS to single-agent doxorubicin were in the order of 20% associated with a median survival of approximately 8 months (8). Subsequent pooled analyses have reported comparable response rates (16–27%) and median survival (7.3–12.7 months) for single-agent doxorubicin in the context of advanced or metastatic STS (9).

In one phase II study, single-agent ifosfamide demonstrated a response rate of up to 25% [95% confidence interval (CI): 13–39%] as first-line therapy with median survival of 44–52 weeks (10). In pretreated patients, including those who had initially received single-agent doxorubicin, ifosfamide as second-line demonstrated a response rate of up to 8% (CI: 2–20%) with median survival of 36–45 weeks.

Multiple clinical trials have investigated the efficacy of combined chemotherapy schedules of doxorubicin with ifosfamide compared to doxorubicin alone. They have consistently demonstrated improvement in disease response rates but no statistically significant difference in overall survival at the expense of increased toxicity (9). These findings have been most recently reaffirmed in the EORTC 62012 phase III trial which concluded that combination therapy resulted in significantly higher response rates (26 vs 14%, p < 0.0006) and median progression-free survival (7.4 vs 4.6 months, p = 0.003) (11). However, no significant benefit was demonstrated for median overall survival (14.3 vs 12.8 months, respectively, p = 0.073). Combination therapies with other alkylating agents, including palifosfamide and evofosfamide, have similarly failed to demonstrate any improvements in overall survival (1214).

On the basis of these findings, single-agent doxorubicin remains the first-line standard of care for systemic treatment of liposarcoma. Combination with ifosfamide may be considered where rapid symptomatic control due to tumor volume is favorable. However, as will be discussed later, first-line combination treatment of doxorubicin and olaratumab may now be employed as an alternative to single-agent doxorubicin depending on availability in individual countries.

Single-agent ifosfamide has also been considered in the context of second-line therapy. In a phase II clinical trial comparing two schedules of 3 weekly ifosfamide as second-line treatment in unselected STS, objective response rates and median survival was 6% and 45 weeks in patients assigned to ifosfamide 5 g/m2 as a 24-h infusion compared to 8% and 36 weeks, respectively, in patients assigned to ifosfamide 3 g/m2 given over 4 h on three consecutive days (10). Recent small cohort retrospective studies have further suggested a role for high dose continuous infusion ifosfamide specifically in liposarcoma; reporting response rates of 23 and 32% for DDLS, even in patients already pretreated with doxorubicin/ifosfamide combination therapy (15, 16).

At present, only retrospective studies have investigated the role of systemic therapy specifically in the context of WDLS/DDLS. Objective response rates of WDLS/DDLS to systemic therapy have been reported at 11% in an initial cohort of 32 cases (17) and 12% in a subsequent larger cohort of 208 cases (18). All cases that demonstrated objective responses were treated with an anthracycline-based regimen. Comparable to that of STS in general, combination therapy of doxorubicin/ifosfamide resulted in better response rates but no improvement in overall survival. Median overall survival of WDLS/DDLS treated with systemic therapy was 15 months (18).

Trabectedin

Originally isolated from the Caribbean tunicate Ecteinascidia turbinata, trabectedin is thought to mediate its antineoplastic effects in STS both directly on cancerous cells and by modulating the tumor microenvironment. At the cellular level, trabectedin binds to specific selected triplet in the DNA minor groove of activated genes, thereby inhibiting transcription and inducing double strand breaks (19, 20). The inhibition of transcription is thought to occur by three synergistic biochemical pathways: blockade and degradation of RNA polymerase II, displacement of transcription factors from gene promoters, and mechanical obstruction of DNA strand separation. Trabectedin further exhibits cytotoxic activities against tumor-associated macrophages and modulates the cytokine profile of the tumor microenvironment with an associated reduction in angiogenesis (21).

A number of non-randomized phase II studies have evaluated the role of trabectedin in pretreated STS reporting response rates of 2–8% and median overall survival of 9.2–12.8 months (2225). Despite relatively low objective response rates, a sizeable proportion of patients derived significant benefits in terms of disease control, with one study reporting disease control in 54% of trabectedin patients (24). A comparative randomized phase II trial favored the trabectedin dosing schedule of 1.5 mg/m2 24-h infusion every 3 weeks over a 0.58 mg/m2 3-h infusions every week for 3 weeks of a 4-week cycle in a selected cohort of leiomyosarcoma and liposarcoma, with response rates of 5.6 vs 1.6% and median overall survival of 13.9 vs 11.8 months (26).

While phase IIb and phase III studies have failed to demonstrate any evidence supporting the role of trabectedin over doxorubicin as standard in untreated STS (27, 28). A phase III study has provided evidence supporting the superiority of trabectedin over dacarbazine as an active control in pretreated leiomyosarcoma and liposarcoma with a median PFS for trabectedin vs dacarbazine of 4.2 vs 1.5 months; hazard ratio, 0.55; p < 0.001. There was no statistically significant difference in overall response rates (9.9 vs 6.9%, p = 0.33) or median overall survival (12.4 vs 12.9 months, p = 0.37) between trabectedin and dacarbazine, respectively, but the trabectedin arm did achieve greater rates of clinical benefit (objective response or durable stable disease; 34 vs 19%, p < 0.001) and prolonged median duration of stable disease (6.0 vs 4.2 months, p < 0.001) (29). Where stable disease is achieved with trabectedin, there is evidence to support continued clinical benefit of continued treatment beyond six cycles—median overall survival in the continuation group was 27.9 months (95% CI: 22.8–33.6) compared to 16.5 months (95% CI: 13.0–22.2) in those who discontinued trabectedin (30).

The role of trabectedin in potential combination regimens, including doxorubicin (3133) and gemcitabine (34), remains to be defined.

Eribulin

Eribulin is another marine-derived compound, originally isolated from the marine sponge halichondria okadai. It appears to exert its mechanism of action by binding to microtubule ends, driving the formation of abnormal mitotic spindles which cannot pass through the metaphase/anaphase checkpoint and thereby inducing apoptosis (35). In a phase II study, eribulin was demonstrated to have activity against an unselected population of STS; however, treatment activity was particularly notable in patients with adipocytic sarcoma as well as leiomyosarcoma (36). In 37 patients with liposarcoma (of which 24 were dedifferentiated liposarcoma), 46.9% were progression-free at 12 weeks with a median progression-free survival of 2.6 months. Two patients with dedifferentiated liposarcoma demonstrated objective responses to eribulin treatment.

Subsequently, a randomized comparative phase III study was conducted comparing eribulin to dacarbazine in advanced liposarcoma and leiomyosarcoma (37). Although there was no difference in median progression-free survival between the two arms (2.6 vs 2.6 months, p = 0.23), eribulin demonstrated a statistically significant improvement in overall survival (13.5 vs 11.5 months, p = 0.0169). Subgroup analyses suggested that liposarcoma patients benefited from eribulin over dacarbazine with median overall survival estimates of 15.6 vs 8.4 months and this benefit was observed irrespective of liposarcoma histology (18.0 vs 8.1 months, HR = 0.43 in patients with DDLS) (38); consequently, eribulin has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of liposarcoma.

Gemcitabine/Docetaxel/Dacarbazine

Other second-line systemic treatment options for STS following the failure of anthracycline-based therapies include ifosfamide (as discussed above), gemcitabine and dacarbazine monotherapies as well as combination therapies of gemcitabine/docetaxel and gemcitabine/dacarbazine. The prospective trial study populations for these therapeutic agents have been composed of histologically heterogeneous STS and, as a result, it is difficult to draw conclusions regarding the efficacy of these regimens specifically in the context of liposarcoma.

Six phase II trials have investigated the efficacy of gemcitabine monotherapy in unselected pretreated STS, reporting response rates of 3.2–27% and median overall survival of 7.2–20 months (3944), although many of these studies were conducted on small cohorts consisting primarily of leiomyosarcoma. Combination therapy demonstrated improved response rates (16 vs 8%) and median overall survival (17.9 vs 11.5 month) at the expense of greater toxicity. The ongoing phase III GeDDiS trial is investigating gemcitabine/docetaxel combination against doxorubicin standard therapy as first-line STS treatment. Although not yet published, preliminary reports from the investigators suggest non-superiority of the combination arm despite increased toxicity. The existing body of evidence would suggest that gemcitabine-based schedules may not be particularly active in WDLS/DDLS.

Initial phase II trials reported STS response rates of 18% with dacarbazine monotherapy (45) and 4% with gemcitabine/dacarbazine doublet therapy (46). This was followed by a phase II direct comparison which demonstrated the superiority of combination gemcitabine/dacarbazine (response rates 4 vs 12%, p = 0.009; median overall survival 16.8 vs 8.2 months, p = 0.014).

Targeted Treatments: Cyclin-Dependent Kinase 4 (CDK4) Inhibitors

Cyclin-dependent kinase 4 allows progression of the cell cycle through phosphorylation of the tumor suppressor retinoblastoma protein (47). Amplification of the CDK4 oncogene is noted in over 90% of cases of WDLS/DDLS (48) and two phase II trials have investigated the CDK4/CDK6 inhibitor palbociclib in patients with CDK4 amplification and advanced disease.

The results from the first phase II trial were promising with evidence of objective response in one patient (PR), a 12-week PFS rate of 66% and a median PFS of 17.9 weeks in patients with WDLS or DDLS who had received prior systemic treatment. 29 patients were treated with 200 mg of palbociclib for 14 days followed by a 7-day rest period. The most common adverse events noted were hematological, with the most reported grade 3 or 4 adverse events being neutropenia (50%), thrombocytopenia (30%), and anemia (17%) (49).

A second phase 2 trial was reported in 2016 to assess whether a new dose and schedule would result in more manageable toxic effects with similar efficacy. Sixty patients were enrolled in this non-randomized open-label study and participants received palbociclib at a dose of 125 mg once daily for 21 days of a 28-day cycle. The median PFS was 17.9 weeks with a 12-week PFS rate of 57.2%. There was one complete response. The adverse event profile was similar in terms of events seen with the most common grade 3 or events being neutropenia (36%), anemia (22%), thrombocytopenia (7%), and no occurrences of neutropenic fever (50).

Given the heterogeneous behavior seen in WDLS and DDLS, the main caution with the results of these studies is the potential that the results are biased by the more indolent behavior of WDLS in comparison to DDLS although the initial phase II study of palbociclib did require that patients have investigator determined progression of disease prior to study entry. Further studies with drugs targeting this pathway are ongoing (such as in NCT02571829).

The possibility of a combination treatment with conventional chemotherapy is also being investigated; a phase 1 study combining flavopiridol (a pan-CDK inhibitor) in combination with 60 mg/m2 of doxorubicin reported that 7 of the 12 evaluable patients with WDLS/DDLS had stable disease at 3 months and one patient with WDLS and DDLS had prolonged stability of 99 weeks before withdrawing consent to remain on trial (51).

Mouse Double Minute 2 Homolog (MDM2) Antagonism

MDM2 amplification is a further target in the treatment of WD/DD liposarcoma. Over 90% of WD/DD liposarcomas express MDM2 amplification. MDM2 regulates transcription and degradation of the tumor suppressor gene p53 (52, 53), and its amplification is therefore thought to reduce levels of p53 resulting in downregulation of its tumor suppressor pathway (54).

An exploratory study enrolled patients with primary or relapsed, chemotherapy-naive WDLS or DDLS eligible for surgery who were then treated with RG7112, a small molecule MDM2 antagonist, neoadjuvantly. Biomarker assessment of RG7112 on MDM2 inhibition and p53 reactivation was the primary end point of this study. 20 patients were analyzed as part of the study (11 with WDLS and 9 with DDLS), 14 patients had MDM2 amplification and 18 patients had tumors which were p53 wild type. In most patients, the biomarker response was suggestive of the drug working via the planned molecular target with restoration of p53 and downstream p21 expression, a reduction in Ki67-expressing cells and an increase in the amount of apoptotic cells (although this was not significant). One patient experienced a partial response and 14 patients had stable disease (55).

Further studies into MDM2 inhibition are ongoing including a completed phase 1b study looking at MDM2 inhibition in combination with doxorubicin in STS patients (NCT01605526) from which results are awaited.

Others: Tyrosine Kinase Receptor Inhibitors

Inhibition of angiogenesis pathways has produced therapeutic benefit in a number of cancer types. There is a growing body of evidence that biomolecular markers of angiogenesis in sarcoma correlate clinically with advanced disease and worsened prognosis (56). Several multi-target tyrosine kinase inhibitors acting on angiogenic pathways have been investigated in phase II trials in the context of liposarcoma.

In a small cohort of non-selected STS, sunitinib treatment demonstrated a median progression-free survival of 3.9 months and a median overall survival of 18.6 months in patients with liposarcoma (n = 17) (57). Median progression-free survival of 2 months and median overall survival of 15 months has similarly been reported for sorafenib in LS (n = 10) (58). However, due to lack of response according to RECIST criteria, neither of these inhibitors has progressed for further evaluation in clinical trials.

Accrual of adipocytic sarcoma in a phase II trial of pazopanib was discontinued after completion of the first step due to disappointing results at the primary endpoint—with a progression-free rate at 12 weeks of just 26% according to RECIST criteria (59). Despite this, outcomes for non-adipocytic STS subtypes were promising and the subsequent phase III PALETTE trial demonstrated improved progression-free survival comparing pazopanib to placebo in STS excluding liposarcoma (4.6 vs 1.6 months, p < 0.0001) (60).

There continues to be ongoing investigation into pazopanib and other tyrosine kinase inhibitors in liposarcoma—the results of which will better inform the therapeutic potential of these agents. Preliminary results from the NCT01506596 phase II study reports 12-week progression-free rate of 68.3%, median progression-free survival of 4.4 months, and median overall survival of 12.6 months of pazopanib in high- or intermediate-grade LS (n = 41) (61). Preclinical studies have demonstrated that tyrosine kinase receptors are constitutively activated in WDLS/DDLS and that selective inhibition of these pathways inhibits proliferation of these cell lines in vitro (62). As a result, further phase II studies are ongoing investigating novel inhibitors specifically in WDLS and DDLS subtypes (63).

Olaratumab

Olaratumab is a recombinant human immunoglobulin G subclass 1 (IgG1) monoclonal antibody that specifically binds PDGFRα, blocking PDGF-AA, PDGF-BB, and PDGF-CC binding and receptor activation (64).

A randomized phase 1b/phase II study assessing the combination of doxorubicin and olaratumab vs doxorubicin alone in patients with locally advanced or metastatic STS who had not received prior anthracycline treatment was published in 2016. 133 patients were randomized to receive olaratumab plus doxorubicin or doxorubicin alone, this included a subgroup of 23 patients with liposarcoma in the phase II portion (8 in the combination cohort and 15 in the doxorubicin alone arm). The results showed a median PFS of 6.6 (95% CI, 4.1–8.3) and 4.1 months (2.8–5.4), a median OS of 26.5 (20.9–31.7) and 14.7 months (9.2–17.1), and an objective RR of 18.2% (9.8–29.6) and 11.9% (5.3–22.2), respectively (65).

Although the results regarding overall survival are striking, there appears to be a mismatch with the more modest PFS findings. This apparent discrepancy requires further evaluation and the precise mechanism of action of olaratumab in sarcoma remains unidentified. There is an ongoing pre-operative trial collecting tissue sample before and after olaratumab therapy to better define its mechanism of action in sarcoma. The results of a randomized phase III trial comparing doxorubicin plus olaratumab vs doxorubicin plus placebo are eagerly awaited and will help to define the role of this agent in advanced STS (NCT02451943). Nevertheless, the combination has been granted accelerated and conditional approval by the FDA and EMA.

Aldoxorubicin

Aldoxorubicin is a novel albumin-binding prodrug of doxorubicin. A randomized phase 2b clinical trial published in 2015 showed statistically significant improvement in median PFS (5.6 vs 2.7 months) favoring aldoxorubicin over doxorubicin. There was no statistically significant improvement in overall survival. This study treated 123 advanced soft-tissue patients with first-line aldoxorubicin or doxorubicin. There were 19 patients with a diagnosis of liposarcoma included in this study but further conclusion based on subtype is not possible (66).

A recent abstract presented at ASCO 2017 from a phase III study of aldoxorubicin vs investigator’s choice (IC) showed benefit in patients with “L-Sarcomas”; patients with liposarcomas and leiomyosarcoma. 433 patients were enrolled in this study with 15% of the patients having a diagnosis of liposarcoma. In the presented results, patients with liposarcomas and leiomyosarcomas were grouped together and accounted for 57.5% of the enrolled total. The IC drugs included dacarbazine, doxorubicin, pazopanib, ifosfamide, and gemcitabine/docetaxel. Prior doxorubicin therapy was not an exclusion criterion. There was a statistically significant increased median PFS of 5.32 months in those receiving aldoxorubicin vs 2.96 months in those who received IC (67).

These data are not yet mature and the precise role of this agent for patients with WDLS and DDLS remains to be defined.

Immune Checkpoint Inhibitors

While immunotherapy is not yet standard treatment in STS generally, there is considerable interest in its role as a treatment option of STS and it is an area of active research with trials currently ongoing.

Specific to WDLS and DDLS; a tissue-based study has looked at the immunogenicity of WDLS and DDLS by exploring the tumor microenvironment of these tumors. Tumor infiltrating lymphocytes were isolated from all eight resected retroperitoneal liposarcoma included in the study. This included five WDLS tumors and 3 DDLS tumors (68). Another recent tissue-based study has also examined WDLS and DDLS tumors, in addition to other STS tumors, to assess the immune phenotype of these subtypes using multiple techniques including NanoString gene expression analysis and analysis of PD-1 and PD-L1 expression (69). Overall these findings are suggestive of a naturally occurring immune response and within these tumors and they are a tempting target for immune checkpoint inhibition.

This is a rapidly evolving field and a recent abstract from the SARC028 trial is suggestive of a response in patients with UPS and DDLS; with 2 of 10 DDLS patients having a partial response with a median follow-up period across all STS patients of 14.5 months. This was a phase II study looking at the overall response rate of pembrolizumab in pretreated patients with advanced sarcoma (bone and soft-tissue) as its primary endpoint (70).

Nuclear Export Inhibitors

A phase 1b study of the first in class nuclear export inhibitor selinexor showed some promise in STS patients. This agent is a small molecule indirect inhibitor against Exportin 1 (XPO1) which is involved in the movement of cargo proteins from the nucleus to the cytoplasm. These proteins include tumor suppressor proteins which can be inactivated through nuclear exclusion in the presence of XPO1 overactivity.

Although there were no patients who achieved objective response of the 52 evaluated, the patients with DDLS in particular showed some potentially promising findings with 6 (40%) of 15 patients showing a reduction in target lesion size from baseline, and 7 (47%) of 15 patients showing SD for 4 months or longer.

Across all dosing cohorts, the most common all grade adverse effects noted included nausea, vomiting, and diarrhea as well as fatigue, hematological toxicity, and hyponatremia. Dose escalation did not appear to correlate with a higher grade of adverse events in most cases (71).

Based on the findings from this study, a phase2/3 placebo-controlled study of selinexor is underway in patients with advanced dedifferentiated liposarcoma (NCT0260646).

Discussion/Conclusion

Well- and dedifferentiated liposarcoma remain challenging diseases to treat. The mainstay of management is surgical resection for localized disease. Historically, the options for patients with advanced disease have been limited. The response rate and median PFS with anthracycline-based schedules are disappointing. However, recently both trabectedin and eribulin have been approved for advanced liposarcoma. Furthermore, olaratumab (in combination with doxorubicin) has been granted breakthrough designation by the FDA.

A number of promising agents are currently being evaluated in advanced WDLS and DDLS including the phase 2/3 study into selinexor in DDLS. CDK4 and MDM2 inhibitors are ongoing possibilities, particularly as potential combination therapies with conventional chemotherapy.

Immunotherapy with checkpoint inhibition is a rapidly evolving area in the story of systemic therapy for liposarcoma and recent early reports are very encouraging, particularly in the case of undifferentiated pleomorphic sarcoma but also dedifferentiated liposarcoma.

There are now a number of systemic agents available for patients with metastatic or unresectable WDLS/DDLS. The optimal treatment options for each individual patient will depend on a number of factors including extent of disease, performance status, comorbid conditions, and patient symptoms. Any potential toxicities should be outlined in detail and the relative advantages and disadvantages of treatment options should be weighed up on a case-by-case basis. For patients with solitary or oligoprogressive disease, radiation and ablation techniques may be considered if feasible. In patients with poor performance statuses and multiple comorbidities, best supportive care is an entirely reasonable approach. Unilateral nephrectomy is frequently indicated in the surgical management of retroperitoneal liposarcomas (72). In such populations, the use of ifosfamide should be very carefully considered. Similarly, the cumulative cardiotoxicity of doxorubicin needs to be taken into account in patients with concurrent cardiovascular disease.

The recommendation regarding first-line systemic therapy is dependent on the goals of therapy. In rapidly progressive symptomatic disease or in patients with tumors that could potentially be down staged for surgical resection, the combination of doxorubicin and ifosfamide could be considered in the context of comorbidities. In the palliative setting, doxorubicin and olaratumab may be considered. As discussed previously, olaratumab has been approved in a number of countries following the results of a randomized phase II trial (65); however, funding is not available in all countries.

Second-line therapy and beyond again depends on comorbidities and to a certain extent patient preference. There are a number of systemic options available, including gemcitabine (in combination with docetaxel or dacarbazine), trabectedin, and pazopanib. The National Comprehensive Cancer Network and the European Society for Medical Oncology do not define a set treatment sequence in advanced disease. Depending on availability, the sequence could be gemcitabine-based therapy followed by trabectedin and pazopanib. However, there have been no randomized comparative trials to inform the decision making process and the comparison of data between different randomized trials is exploratory and cannot be used for definitive recommendations. As a result, choosing between second-line options is to a certain extent arbitrary and can be guided by the relative advantages and disadvantages of each option in the context of each individual patient.

In DDLS, clear heterogeneity in tumor response to systemic therapy has been observed in a number of clinical trials. As of yet, no biomarkers are available which predict therapeutic response. However, in the context of rapidly progressive, symptomatic disease, a clear dose–response relationship of combination doxorubicin/ifosfamide has previously been demonstrated (11).

Well-differentiated liposarcoma and DDLS are frequently grouped together for histological subtype analysis in clinical trials. In up to 15% of patients, imaging can reveal concurrent areas of WDLS and DDLS within the same tumor mass (73). Is such cases, assessment of treatment response can be challenging as the predominantly fatty portions of WDLS are unlikely to exhibit any volumetric shrinkage and thereby underestimate treatment response by the DDLS component. As a result, there are limitations to available response criteria such as RECIST. Functional imaging may have a role in the future (74); however, as of yet they require further evaluation and validation in the context of WDLS and DDLS. Currently, the generalizability of trials grouping these patients remains questionable, due to the variable proportional representation of WDLS and DDLS in individual patients and their differing clinical response to treatment. More prospective data are required to answer these challenging questions.

The exciting developments as described in this study must, however, be tempered with the knowledge that histological specific evidence is scant still in this area but it does appear to be improving. Where it is available, the robustness of evidence is weakened by small patient numbers and subsequent difficulty with adequately powering of these studies. The difficulties enrolling patients with rare histological subtypes are a common theme across the spectrum of STS due to the heterogeneity of disease. Greater collaboration across specialist centers is imperative to improve the quality of research and subsequent evidence for subtype-driven management.

Given the recent developments in this area and the abundance of ongoing trials targeting multiple possible therapeutic pathways, the near future appears hopeful for the emergence of more definitive options and greater outcomes for patients with advanced disease.

Author Contributions

YM and CZ wrote the first draft of the manuscript with input and guidance from RJ. All authors provided input into subsequent drafts.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

We acknowledge support from the BRC.

Supplementary Material

The Supplementary Material for this article can be found online at http://www.frontiersin.org/article/10.3389/fonc.2017.00292/full#supplementary-material.

References

1. Ducimetière F, Lurkin A, Ranchère-Vince D, Decouvelaere AV, Péoc’h M, Istier L, et al. Incidence of sarcoma histotypes and molecular subtypes in a prospective epidemiological study with central pathology review and molecular testing. PLoS One (2011) 6(8):e20294. doi:10.1371/journal.pone.0020294

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Barretina J, Taylor BS, Banerji S, Ramos AH, Lagos-Quintana M, Decarolis PL, et al. Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nat Genet (2010) 42:715–21. doi:10.1038/ng.619

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Conyers R, Young S, Thomas DM. Liposarcoma: molecular genetics and therapeutics. Sarcoma (2011) 2011:483154. doi:10.1155/2011/483154

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Tseng WW, Somaiah N, Lazar AJ, Lev DC, Pollock RE. Novel systemic therapies in advanced liposarcoma: a review of recent clinical trial results. Cancers (Basel) (2013) 5(2):529–49. doi:10.3390/cancers5020529

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Saponara M, Stacchiotti S, Gronchi A. Pharmacological therapies for liposarcoma. Expert Rev Clin Pharmacol (2017) 10(4):361–77. doi:10.1080/17512433.2017.1289086

PubMed Abstract | CrossRef Full Text | Google Scholar

6. O’Bryan RM, Luce JK, Talley RW, Gottlieb JA, Baker LH, Bonadonna G. Phase II evaluation of adriamycin in human neoplasia. Cancer (1973) 32:1–8. doi:10.1002/1097-0142(197307)32:1<1::AID-CNCR2820320101>3.0.CO;2-X

CrossRef Full Text | Google Scholar

7. Gottlieb GA. Adriamycin (NSC-123127) used alone and in combination for soft tissue and bony sarcomas. Cancer Chemother Rep (1975) 3:271–82.

Google Scholar

8. Borden EC, Amato DA, Rosenbaum C, Enterline HT, Shiraki MJ, Creech RH, et al. Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas. J Clin Oncol (1987) 5:840–50. doi:10.1200/JCO.1987.5.6.840

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Bramwell V, Anderson D, Charette M, Sarcoma Disease Site Group. Doxorubicin-based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatic soft tissue sarcoma. Cochrane Database Syst Rev (2003) 1–23. doi:10.1002/14651858.CD003293

CrossRef Full Text | Google Scholar

10. Van Oosterom AT, Mouridsen HT, Nielsen OS, Dombernowsky P, Krzemieniecki K, Judson I, et al. Results of randomised studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) with two different ifosfamide regimens in first-and second-line chemotherapy in advanced soft tissue sarcoma patients. Eur J Cancer (2002) 38:2397–406. doi:10.1016/S0959-8049(02)80608-6

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Judson I, Verweij J, Gelderblom H, Hartmann JT, Schöffski P, Blay J-Y, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol (2014) 15:415–23. doi:10.1016/S1470-2045(14)70063-4

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Desar IME, Constantinidou A, Kaal SEJ, Jones RL, van der Graaf WTA. Advanced soft-tissue sarcoma and treatment options: critical appraisal of trabectedin. Cancer Manag Res (2016) 8:95. doi:10.2147/CMAR.S86746

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Ryan CW, Merimsky O, Agulnik M, Blay J-Y, Schuetze SM, Van Tine BA, et al. PICASSO III: a phase III, placebo-controlled study of doxorubicin with or without palifosfamide in patients with metastatic soft tissue sarcoma. J Clin Oncol (2016) 34:3898–905. doi:10.1200/JCO.2016.67.6684

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Tap WD, Papai Z, Van Tine BA, Attia S, Ganjoo KN, Jones RL, et al. Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial. Lancet Oncol (2017) 18:1089–103. doi:10.1016/S1470-2045(17)30381-9

CrossRef Full Text | Google Scholar

15. Martin-Liberal J, Alam S, Constantinidou A, Fisher C, Khabra K, Messiou C, et al. Clinical activity and tolerability of a 14-day infusional Ifosfamide schedule in soft-tissue sarcoma. Sarcoma (2013) 2013:868973. doi:10.1155/2013/868973

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Sanfilippo R, Bertulli R, Marrari A, Fumagalli E, Pilotti S, Morosi C, et al. High-dose continuous-infusion ifosfamide in advanced well-differentiated/dedifferentiated liposarcoma. Clin Sarcoma Res (2014) 4:16. doi:10.1186/2045-3329-4-16

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Jones RL, Fisher C, Al-Muderis O, Judson IR. Differential sensitivity of liposarcoma subtypes to chemotherapy. Eur J Cancer (2005) 41:2853–60. doi:10.1016/j.ejca.2005.07.023

CrossRef Full Text | Google Scholar

18. Italiano A, Toulmonde M, Cioffi A, Penel N, Isambert N, Bompas E, et al. Advanced well-differentiated/dedifferentiated liposarcomas: role of chemotherapy and survival. Ann Oncol (2012) 23:1601–7. doi:10.1093/annonc/mdr485

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Larsen AK, Galmarini CM, D’Incalci M. Unique features of trabectedin mechanism of action. Cancer Chemother Pharmacol (2016) 77:663–71. doi:10.1007/s00280-015-2918-1

PubMed Abstract | CrossRef Full Text | Google Scholar

20. De Sanctis R, Marrari A, Santoro A. Trabectedin for the treatment of soft tissue sarcomas. Expert Opin Pharmacother (2016) 17:1569–77. doi:10.1080/14656566.2016.1204295

PubMed Abstract | CrossRef Full Text | Google Scholar

21. D’Incalci M, Frapolli R, Germano G, Allavena P. New activities for the anti-tumor agent trabectedin: taking two birds with one stone. Oncotarget (2013) 4:496–7. doi:10.18632/oncotarget.968

CrossRef Full Text | Google Scholar

22. Yovine A, Riofrio M, Blay JY, Brain E, Alexandre J, Kahatt C, et al. Phase II study of ecteinascidin-743 in advanced pretreated soft tissue sarcoma patients. J Clin Oncol (2004) 22:890–9. doi:10.1200/JCO.2004.05.210

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Garcia-Carbonero R, Supko JG, Manola J, Seiden MV, Harmon D, Ryan DP, et al. Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy. J Clin Oncol (2004) 22:1480–90. doi:10.1200/JCO.2004.02.098

PubMed Abstract | CrossRef Full Text | Google Scholar

24. Le Cesne A, Blay J-Y, Judson I, Van Oosterom A, Verweij J, Radford J, et al. Phase II study of ET-743 in advanced soft tissue sarcomas: a European Organisation for the Research and Treatment of Cancer (EORTC) soft tissue and bone sarcoma group trial. J Clin Oncol (2005) 23:576–84. doi:10.1200/JCO.2005.01.180

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Paz-Ares L, López-Pousa A, Poveda A, Balañá C, Ciruelos E, Bellmunt J, et al. Trabectedin in pre-treated patients with advanced or metastatic soft tissue sarcoma: a phase II study evaluating co-treatment with dexamethasone. Invest New Drugs (2012) 30:729–40. doi:10.1007/s10637-010-9561-9

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Demetri GD, Chawla SP, Von Mehren M, Ritch P, Baker LH, Blay JY, et al. Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules. J Clin Oncol (2009) 27:4188–96. doi:10.1200/JCO.2008.21.0088

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Bui-Nguyen B, Butrynski JE, Penel N, Blay JY, Isambert N, Milhem M, et al. A phase IIb multicentre study comparing the efficacy of trabectedin to doxorubicin in patients with advanced or metastatic untreated soft tissue sarcoma: the TRUSTS trial. Eur J Cancer (2015) 51:1312–20. doi:10.1016/j.ejca.2015.03.023

CrossRef Full Text | Google Scholar

28. Blay J-Y, Leahy MG, Nguyen BB, Patel SR, Hohenberger P, Santoro A, et al. Randomised phase III trial of trabectedin versus doxorubicin-based chemotherapy as first-line therapy in translocation-related sarcomas. Eur J Cancer (2014) 50:1137–47. doi:10.1016/j.ejca.2014.01.012

PubMed Abstract | CrossRef Full Text | Google Scholar

29. Demetri GD, von Mehren M, Jones RL, Hensley ML, Schuetze SM, Staddon A, et al. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial. J Clin Oncol (2015) 34:786–93. doi:10.1200/JCO.2015.62.4734

CrossRef Full Text | Google Scholar

30. Le Cesne A, Blay J-Y, Domont J, Tresch-Bruneel E, Chevreau C, Bertucci F, et al. Interruption versus continuation of trabectedin in patients with soft-tissue sarcoma (T-DIS): a randomised phase 2 trial. Lancet Oncol (2015) 16:312–9. doi:10.1016/S1470-2045(15)70031-8

PubMed Abstract | CrossRef Full Text | Google Scholar

31. Sessa C, Perotti A, Noberasco C, De Braud F, Gallerani E, Cresta S, et al. Phase I clinical and pharmacokinetic study of trabectedin and doxorubicin in advanced soft tissue sarcoma and breast cancer. Eur J Cancer (2009) 45:1153–61. doi:10.1016/j.ejca.2008.11.019

PubMed Abstract | CrossRef Full Text | Google Scholar

32. Blay J-Y, von Mehren M, Samuels BL, Fanucchi MP, Ray-Coquard I, Buckley B, et al. Phase I combination study of trabectedin and doxorubicin in patients with soft-tissue sarcoma. Clin Cancer Res (2008) 14:6656–62. doi:10.1158/1078-0432.CCR-08-0336

PubMed Abstract | CrossRef Full Text | Google Scholar

33. Pautier P, Floquet A, Chevreau C, Penel N, Guillemet C, Delcambre C, et al. Trabectedin in combination with doxorubicin for first-line treatment of advanced uterine or soft-tissue leiomyosarcoma (LMS-02): a non-randomised, multicentre, phase 2 trial. Lancet Oncol (2015) 16:457–64. doi:10.1016/S1470-2045(15)70070-7

PubMed Abstract | CrossRef Full Text | Google Scholar

34. Kasper B, Reichardt P, Pink D, Sommer M, Mathew M, Rauch G, et al. Combination of trabectedin and gemcitabine for advanced soft tissue sarcomas: results of a phase I dose escalating trial of the German Interdisciplinary Sarcoma Group (GISG). Mar Drugs (2015) 13:379–88. doi:10.3390/md13010379

PubMed Abstract | CrossRef Full Text | Google Scholar

35. Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, et al. In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B. Cancer Res (2001) 61:1013–21.

PubMed Abstract | Google Scholar

36. Schöffski P, Ray-Coquard IL, Cioffi A, Bui NB, Bauer S, Hartmann JT, et al. Activity of eribulin mesylate in patients with soft-tissue sarcoma: a phase 2 study in four independent histological subtypes. Lancet Oncol (2011) 12:1045–52. doi:10.1016/S1470-2045(11)70230-3

PubMed Abstract | CrossRef Full Text | Google Scholar

37. Schöffski P, Chawla S, Maki RG, Italiano A, Gelderblom H, Choy E, et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet (2016) 387:1629–37. doi:10.1016/S0140-6736(15)01283-0

CrossRef Full Text | Google Scholar

38. Chawla S, Schoffski P, Grignani G, Blay JY, Maki R, d’Adamo D, et al. Subtype-specific activity in liposarcoma (LPS) patients (pts) from a phase 3, open-label, randomized study of eribulin (ERI) versus dacarbazine (DTIC) in pts with advanced LPS and leiomyosarcoma (LMS). J Clin Oncol (2016) 34(Suppl):Abstr11037. doi:10.1200/JCO.2016.34.15_suppl.11037

CrossRef Full Text | Google Scholar

39. Pautier P, Floquet A, Penel N, Piperno-Neumann S, Isambert N, Rey A, et al. Randomized multicenter and stratified phase II study of gemcitabine alone versus gemcitabine and docetaxel in patients with metastatic or relapsed leiomyosarcomas: a Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) French Sarcoma Group. Oncologist (2012) 17:1213–20. doi:10.1634/theoncologist.2011-0467

CrossRef Full Text | Google Scholar

40. Patel SR, Gandhi V, Jenkins J, Papadopolous N, Burgess MA, Plager C, et al. Phase II clinical investigation of gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation. J Clin Oncol (2001) 19:3483–9. doi:10.1200/JCO.2001.19.15.3483

PubMed Abstract | CrossRef Full Text | Google Scholar

41. Hartmann JT, Oechsle K, Huober J, Jakob A, Azemar M, Horger M, et al. An open label, non-comparative phase II study of gemcitabine as salvage treatment for patients with pretreated adult type soft tissue sarcoma. Invest New Drugs (2006) 24:249–53. doi:10.1007/s10637-005-3537-1

PubMed Abstract | CrossRef Full Text | Google Scholar

42. Švancárová L, Blay JY, Judson IR, van Hoesel Q, Van Oosterom AT, Le Cesne A, et al. Gemcitabine in advanced adult soft-tissue sarcomas. A phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer (2002) 38:556–9. doi:10.1016/S0959-8049(01)00408-7

PubMed Abstract | CrossRef Full Text | Google Scholar

43. Ferraresi V, Ciccarese M, Cercato MC, Nuzzo C, Zeuli M, Di Filippo F, et al. Gemcitabine at fixed dose-rate in patients with advanced soft tissue sarcomas: a mono-institutional phase II study. Cancer Chemother Pharmacol (2008) 63:149–55. doi:10.1007/s00280-008-0723-9

CrossRef Full Text | Google Scholar

44. Maki RG, Wathen JK, Patel SR, Priebat DA, Okuno SH, Samuels B, et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002. J Clin Oncol (2007) 25:2755–63. doi:10.1200/JCO.2006.10.4117

CrossRef Full Text | Google Scholar

45. Buesa JM, Mouridsen HT, Van Oosterom AT, Verweij J, Wagener T, Steward W, et al. Short report: high-dose DTIC in advanced soft-tissue sarcomas in the adult A phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Ann Oncol (1991) 2:307–9. doi:10.1093/oxfordjournals.annonc.a057942

CrossRef Full Text | Google Scholar

46. Losa R, Fra J, Lopez-Pousa A, Sierra M, Goitia A, Una E, et al. Phase II study with the combination of gemcitabine and DTIC in patients with advanced soft tissue sarcomas. Cancer Chemother Pharmacol (2007) 59:251–9. doi:10.1007/s00280-006-0263-0

PubMed Abstract | CrossRef Full Text | Google Scholar

47. Kato J, Matsushime H, Hiebert SW, Ewen ME, Sherr CJ. Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes Dev (1993) 7:331–42. doi:10.1101/gad.7.3.331

PubMed Abstract | CrossRef Full Text | Google Scholar

48. Binh MB, Sastre-Garau X, Guillou L, de Pinieux G, Terrier P, Lagacé R, et al. MDM2 and CDK4 immunostainings are useful adjuncts in diagnosing well-differentiated and dedifferentiated liposarcoma subtypes: a comparative analysis of 559 soft tissue neoplasms with genetic data. Am J Surg Pathol (2005) 29:1340–7. doi:10.1097/01.pas.0000170343.09562.39

PubMed Abstract | CrossRef Full Text | Google Scholar

49. Dickson MA, Tap WD, Keohan ML, D’Angelo SP, Gounder MM, Antonescu CR, et al. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol (2013) 31(16):2024–8. doi:10.1200/JCO.2012.46.5476

PubMed Abstract | CrossRef Full Text | Google Scholar

50. Dickson MA, Schwartz GK, Keohan ML, D’Angelo SP, Gounder MM, Chi P, et al. Progression-free survival among patients with well-differentiated or dedifferentiated liposarcoma treated with CDK4 inhibitor palbociclib: a phase 2 clinical trial. JAMA Oncol (2016) 2(7):937–40. doi:10.1001/jamaoncol.2016.0264

PubMed Abstract | CrossRef Full Text | Google Scholar

51. Luke JJ, D’Adamo DR, Dickson MA, Keohan ML, Carvajal RD, Maki RG, et al. The cyclin-dependent kinase inhibitor flavopiridol potentiates doxorubicin efficacy in advanced sarcomas: preclinical investigations and results of a phase I dose-escalation clinical trial. Clin Cancer Res (2012) 18(9):2638–47. doi:10.1158/1078-0432.CCR-11-3203

PubMed Abstract | CrossRef Full Text | Google Scholar

52. Michael D, Oren M. Semin. Cancer Biol (2003) 13:49. doi:10.1016/S1044-579X(02)00099-8

CrossRef Full Text | Google Scholar

53. Freedman DA, Wu L, Levine AJ. Functions of the MDM2 oncoprotein. Cell Mol Life Sci (1999) 55:96–107. doi:10.1007/s000180050273

PubMed Abstract | CrossRef Full Text | Google Scholar

54. Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ, et al. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science (1996) 274:948–53. doi:10.1126/science.274.5289.948

PubMed Abstract | CrossRef Full Text | Google Scholar

55. Ray-Coquard I, Blay JY, Italiano A, Le Cesne A, Penel N, Zhi J, et al. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol (2012) 13(11):1133–40. doi:10.1016/S1470-2045(12)70474-6

PubMed Abstract | CrossRef Full Text | Google Scholar

56. DuBois S, Demetri G. Markers of angiogenesis and clinical features in patients with sarcoma. Cancer (2007) 109:813–9. doi:10.1002/cncr.22455

PubMed Abstract | CrossRef Full Text | Google Scholar

57. Mahmood ST, Agresta S, Vigil CE, Zhao X, Han G, D’Amato G, et al. Phase II study of sunitinib malate, a multitargeted tyrosine kinase inhibitor in patients with relapsed or refractory soft tissue sarcomas. Focus on three prevalent histologies: leiomyosarcoma, liposarcoma and malignant fibrous histiocytoma. Int J Cancer (2011) 129:1963–9. doi:10.1002/ijc.25843

PubMed Abstract | CrossRef Full Text | Google Scholar

58. von Mehren M, Rankin C, Goldblum JR, Demetri GD, Bramwell V, Ryan CW, et al. Phase 2 Southwest Oncology Group-directed intergroup trial (S0505) of sorafenib in advanced soft tissue sarcomas. Cancer (2012) 118:770–6. doi:10.1002/cncr.26334

PubMed Abstract | CrossRef Full Text | Google Scholar

59. Sleijfer S, Ray-Coquard I, Papai Z, Le Cesne A, Scurr M, Schöffski P, et al. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European Organisation for Research and Treatment of Cancer–Soft Tissue and Bone Sarcoma Group (EORTC study 62043). J Clin Oncol (2009) 27:3126–32. doi:10.1200/JCO.2008.21.3223

CrossRef Full Text | Google Scholar

60. van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet (2012) 379:1879–86. doi:10.1016/S0140-6736(12)60651-5

PubMed Abstract | CrossRef Full Text | Google Scholar

61. Study of Pazopanib in the Treatment of Surgically Unresectable or Metastatic Liposarcoma. (2016). Available from: https://clinicaltrials.gov/ct2/show/NCT01506596

Google Scholar

62. Patwardhan PP, Ivy KS, Musi E, de Stanchina E, Schwartz GK. Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma. Oncotarget (2016) 7(4):4093. doi:10.18632/oncotarget.6547

PubMed Abstract | CrossRef Full Text | Google Scholar

63. Phase 2 Trial of Novel Multi-Receptor Tyrosine Kinase Inhibitor Sitravatinib in Well-Differentiated/Dedifferentiated Liposarcoma. (2017). Available from: http://abstracts.asco.org/199/AbstView_199_187921.html

Google Scholar

64. Loizos N, Xu Y, Huber J, Liu M, Lu D, Finnerty B, et al. Targeting the platelet-derived growth factor receptor alpha with a neutralizing human monoclonal antibody inhibits the growth of tumour xenografts: implications as a potential therapeutic target. Mol Cancer Ther (2005) 4:369–79. doi:10.1158/1535-7163.MCT-04-0114

CrossRef Full Text | Google Scholar

65. Tap WD, Jones RL, Van Tine BA, Chmielowski B, Elias AD, Adkins D, et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet (2016) 388:488–97. doi:10.1016/S0140-6736(16)30587-6

PubMed Abstract | CrossRef Full Text | Google Scholar

66. Chawla SP, Papai Z, Mukhametshina G, Sankhala K, Vasylyev L, Fedenko A, et al. First-line aldoxorubicin vs doxorubicin in metastatic or locally advanced unresectable soft-tissue sarcoma: a phase 2b randomized clinical trial. JAMA Oncol (2015) 1:1272–80. doi:10.1001/jamaoncol.2015.3101

PubMed Abstract | CrossRef Full Text | Google Scholar

67. Chawla SP, Ganjoo KN, Schuetze S, Papai Z, van Tine BA, Choy E, et al. Phase III study of aldoxorubicin vs investigators’ choice as treatment for relapsed/refractory soft tissue sarcomas. J Clin Oncol (2017) 35(Suppl):abstr11000. doi:10.1200/JCO.2017.35.15_suppl.11000

CrossRef Full Text | Google Scholar

68. Tseng WW, Malu S, Zhang M, Chen J, Sim GC, Wei W, et al. Analysis of the intratumoral adaptive immune response in well differentiated and dedifferentiated retroperitoneal liposarcoma. Sarcoma (2015) 2015:547460. doi:10.1155/2015/547460

PubMed Abstract | CrossRef Full Text | Google Scholar

69. Pollack SM, He Q, Yearley JH, Emerson R, Vignali M, Zhang Y, et al. T-cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death-ligand 1 expression in patients with soft tissue sarcomas. Cancer (2017) 123:3291–304. doi:10.1002/cncr.30726

CrossRef Full Text | Google Scholar

70. Burgess MA, Bolejack V, Van Tine BA, Schuetze S, Hu J, D’Angelo SP, et al. Multicenter phase II study of pembrolizumab (P) in advanced soft tissue (STS) and bone sarcomas (BS): final results of SARC028 and biomarker analyses. J Clin Oncol (2017) 35(Suppl):abstr11008. doi:10.1200/JCO.2017.35.15_suppl.11008

CrossRef Full Text | Google Scholar

71. Gounder MM, Zer A, Tap WD, Salah S, Dickson MA, Razak ARA, et al. Phase IB study of selinexor, a first-in-class inhibitor of nuclear export, in patients with advanced refractory bone or soft tissue sarcoma. J Clin Oncol (2016) 34(26):3166–74. doi:10.1200/JCO.2016.67.6346

CrossRef Full Text | Google Scholar

72. Neuhaus SJ, Barry P, Clark MA, Hayes AJ, Fisher C, Thomas JM. Surgical management of primary and recurrent retroperitoneal liposarcoma. Br J Surg (2005) 92(2):246–52. doi:10.1002/bjs.4802

PubMed Abstract | CrossRef Full Text | Google Scholar

73. Murphey MD, Smith WS, Smith SE, Kransdorf MJ, Temple HT. From the archives of the AFIP: imaging of musculoskeletal neurogenic tumors: radiologic-pathologic correlation. Radiographics (1999) 19(5):1253–80. doi:10.1148/radiographics.19.5.g99se101253

PubMed Abstract | CrossRef Full Text | Google Scholar

74. Desar IM, van Herpen CM, van Laarhoven HW, Barentsz JO, Oyen WJ, van der Graaf WT. Beyond RECIST: molecular and functional imaging techniques for evaluation of response to targeted therapy. Cancer Treat Rev (2009) 35(4):309–21. doi:10.1016/j.ctrv.2008.12.001

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: sarcoma, chemotherapy, treatment outcome, phase II trials, phase III trials, preclinical research

Citation: McGovern Y, Zhou CD and Jones RL (2017) Systemic Therapy in Metastatic or Unresectable Well-Differentiated/Dedifferentiated Liposarcoma. Front. Oncol. 7:292. doi: 10.3389/fonc.2017.00292

Received: 23 July 2017; Accepted: 15 November 2017;
Published: 30 November 2017

Edited by:

William W. Tseng, University of Southern California, United States

Reviewed by:

Marcus Lehnhardt, Bg-University Hospital Bergmannsheil Bochum, Germany
Robert J. Canter, University of California, Davis, United States

Copyright: © 2017 McGovern, Zhou and Jones. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Robin L. Jones, robin.jones4@nhs.net

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.