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Current management options for liposarcoma and challenges for the future Expert Rev. Anticancer Ther. 14(3), 297–306 (2014)
Attila Kolla´r* and Charlotte Benson The Royal Marsden Hospital, Sarcoma Unit, Fulham Road, SW3 6JJ, London, UK *Author for correspondence: Tel.: +44 207 808 2137 Fax: +44 207 808 2672 [email protected]
Liposarcoma (LS) represents one of the most common soft tissue sarcomas. There are three major subtypes, namely, well/dedifferentiated, myxoid/round cell and pleomorphic LS. In general, LS is known to be a relatively chemo-resistant sarcoma subtype with the exception of the myxoid variant. Conventional chemotherapy with doxorubicin and ifosfamide represents the mainstay of systemic treatment in the first line. Other active cytotoxic agents include gemcitabine and docetaxel and the marine-derived compounds trabectedin. Recent progress in molecular diagnostics of each single LS subtype has improved the knowledge of the molecular characteristics and has led to two recent treatment targets: the amplification of mouse double minute 2 homolog and cyclin-dependent kinase-4 in well- and dedifferentiated LS. Thus far, only early-phase trials are reported and no new drugs have been introduced in daily clinical practice. The focus of this review is on current systemic treatment options, including novel strategies. KEYWORDS: CDK4 • chemotherapy • eribulin • liposarcoma • MDM2 • pazopanib • soft tissue sarcoma • trabectedin
Soft tissue sarcomas (STSs) are a rare and heterogeneous group of malignant tumors of mesenchymal origin accounting for approximately 1% of all malignant tumors. STS encompass more than 50 different histologic subtypes, as classified by the WHO. The most frequently occurring histological subtypes are gastrointestinal stromal tumor (18%), unclassified sarcoma (16%), liposarcoma (LS) (15%) and leiomyosarcoma (11%) [1]. LS appears to arise from precursors of adipocytes and represents 24% of extremity and 45% of retroperitoneal STS [2]. The peak incidence lies between 50 and 65 years of age [3]. Histopathology
The three main morphologic LS subgroups are well-differentiated/dedifferentiated LS (WD/ DDLS), myxoid/round cell LS (MLS/RCLS) and pleomorphic LS (PLS). WDLS and DDLS represent the most common biological group of LS (40–45%) [4]. The WHO classifies WDLS into three main subtypes according to morphologic features: adipocytic, sclerosing and inflammatory LS. Adipocytic variant (lipoma-like) LS is the most frequent subtype, which is composed of mature adipocytes and exhibits variation in cell informahealthcare.com
10.1586/14737140.2014.869173
size with focal nuclear atypia and hyperchromasia. About 90% of WD/DDLS have amplification of chromosome 12q13–15, which contains several oncogenes, including MDM2, HMGA2 and CDK4. There is evidence that they play an essential role in liposarcomagenesis [5]. Therefore, intensive research is ongoing to target these ongogenic changes. DDLP mostly arises de novo, but progression from pure WDLS to high-grade nonlipogenic morphology within a WDLS may also occur [6]. MLS is the second most common subtype of LS and accounts for more than one-third of LS. MLS is characterized by the presence of spindle or ovoid cells set in a myxoid stroma with signet ring lipoblasts and a distinctive chickenwire pattern vasculature. The presence of areas with greater cellularity, known as round cell dedifferentiation, is associated with a worse prognosis [7]. The round cell variant of MLS is defined as >5% round cell phenotype in a given MLS tumor. MLS is characterized by a unique chromosome rearrangement, t(12;16)(q13;p11) that results in the FUSCHOP gene fusion that is present in over 95% of cases [8]. Rarely, another translocation t(12;22)(q13;q12) is found resulting in the formation of a novel fusion oncogene known
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as the EWS-CHOP oncogene [9]. Due to the nearly normal karyotype in these LS subtypes, these chromosomal changes are thought to be the first change on a genetic level leading to a malignant behavior. As CHOP plays an important role in regulating the differentiation of adipocytes, it is suggested that FUS-CHOP functions by inhibiting adipogenesis and maintaining immature adipocytes in a continuous cycle of proliferation without differentiation [10]. The pleomorphic variant of LS is considered to be a separate subentity and accounts for only 5% of LS. Histologically, PLSs are characterized by a disorderly growth pattern, extreme cellularity and cellular pleomorphism, including bizarre giant cells and the presence of lipoblasts [11]. Molecular studies show that PLS harbor diverse chromosomal rearrangements and genomic profiles without unifying molecular alterations, making targeted drug development more challenging in this subtype. In contrast to the other LS subtypes, p53 mutations were identified in 16.7%, whereas they are rarely seen in MLS and WD/ DDLS [12]. PLS is the most aggressive LS subtype with a very poor outcome [13]. Clinical characteristics & adjuvant therapy
Regarding the clinical behavior of the LS subtypes DDLS, RCLS and PLS are high-grade, aggressive tumors with metastatic potential, while WDLS and MLS may follow a more indolent clinical course [2]. Depending on the subtype, the 5-year overall survival (OS) is as follows: 93.3% for WDLS, 75.7% for MLS, 54.5% for DDLS, 40% for RCLS and lower for PLS patients, respectively [14]. The main prognostic factors that correlate for survival are tumor grade, histologic subtype, primary location, stage, and margin status [15]. For example, in WDLS patients, retroperitoneal/ intra-abdominal location is associated with a worse outcome than the extremity counterparts [16]. Surgery is the cornerstone of curative treatment for primary disease with the goal to widely resect the tumor with negative margins. The addition of a postoperative radiotherapy to extremity sarcoma patients in limb-sparing surgery was shown in 2 randomized trials to be beneficial in terms of reducing the risk of local recurrence but not affecting OS [17,18]. Therefore, in the European Society of Medical Oncology Guidelines, additive radiotherapy is recommended mainly in high-grade sarcoma patients (G2-G3, >5 cm, deep tumors), although it is a matter of debate how high the risk of local recurrence must be to justify radiotherapy. The use of adjuvant chemotherapy to treat patients with resected STS remains a controversial issue. The most recent meta-analysis included 18 randomized trials and was associated with an absolute risk of death reduction of 11% for the use of doxorubicin and ifosfamide. In the multivariate analysis histologic subtype in particular was not found to be a relevant predictor of benefit [19]. The interpretation of these results was tempered by the largest pooled analysis of the two largest adjuvant trials performed by the European Organisation of Research and Treatment of Cancer (EORTC), which was negative and not 298
included in the latest meta-analysis [20]. Thus, the impact of histology on the effect of adjuvant chemotherapy is unclear. One retrospective study evaluated (neo-)/adjuvant systemic treatment in high-risk LS patients. LSs were considered high grade if they showed evidence of greater than 25% dedifferentiated morphology, greater than 5% round cell morphology or pleomorphic morphology. WDLS and pure MLS were considered to be low-grade lesions and were not included in the present study. Of 245 patients, 34% were treated with doxorubicin-based chemotherapy, 26% with ifosfamide-based chemotherapy and 40% without systemic treatment. In a contemporary cohort analysis, the 5-year disease-specific survival (DSS) was 64% for doxorubicin-treated patients, 92% for the ifosfamide cohort and 56% for the patients group without systemic therapy. Only ifosfamide treatment was associated with a significant improved DSS. Interestingly, there was a benefit for treatment with ifosfamide in MLS/RCLS and in PLS, as well, with a survival benefit at 5 years of 22% for MLS/RCLS and 31% for the pleomorphic variant. This trial suggests there may be a role for ifosfamide-based treatment in the (neo-) adjuvant setting of this specific cohort of LS patients although this would need to be confirmed by randomized prospective studies before being adopted into clinical practice [21]. In summary, the role of adjuvant chemotherapy remains uncertain and is therefore not routinely recommended. The potential of benefit should be discussed on case-by-case basis taking into consideration the patient and tumor characteristics as performance score, age, comorbidities, site of primary tumor and histologic subtype. Despite surgery and adjuvant treatment options, more than half of patients will develop recurrent or metastatic disease. The majority of patients who develop metastatic soft tissue sarcoma are incurable with a median survival of 11–12 months [22]. Systemic treatment options for metastatic liposarcoma
The aim of systemic treatment in the palliative setting is to improve tumor-associated symptoms, quality of life and to increase DSS. The rarity of sarcoma explains why historically trials investigating the efficacy of systemic treatment have included a variety of sarcoma subtypes. More recently trials have been stratified, which may provide useful information about the sensitivity of LS to systemic therapy. Additionally, increased understanding of the molecular background and pathogenesis of LS allows us to tailor treatment accordingly. Although the evidence from randomized Phase III trials that systemic treatment prolongs OS is lacking, a prolonged progression-free survival (PFS) and OS might be achieved by widening systemic treatment options. In the following section, we will review the role of systemic therapy in LS to date and discuss what future studies are forthcoming. Conventional cytotoxic chemotherapy Doxorubicin/ifosfamide
Doxorubicin was the first systemic chemotherapy described to be active in STS. The response rate in a histologically diverse Expert Rev. Anticancer Ther. 14(3), (2014)
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Current management options for liposarcoma & challenges for the future
cohort of sarcoma patients lies in the range of 10–25% [23]. Single-agent ifosfamide is also a well-studied systemic agent in STS. In one cohort, ifosfamide has a similar antitumor activity to doxorubicin with a response rate of around 25% in patients who previously failed a doxorubicin-based chemotherapy regimen [24]. Many different combination regimens have been studied in patients with metastatic disease and almost always include doxorubicin and an alkylating agent. There are a few randomized trials investigating combination regimens that show a higher response rate up to 46% but no increase in OS. These results have been confirmed recently by the EORTC 62012 trial presented at European Society of Medical Oncology 2012 (Ref Judson Ann Oncology supplement 9 pages ixe1–ixe30). Although the median PFS (7.4 vs 4.6 months; p = 0.003) and response rates were significantly increased in the combination arm with doxorubicin and ifosfamide, no difference was seen in the 2-year OS rate, which was 31% for the combined arm versus 28% for doxorubicin alone [25]. Therefore, single-agent doxorubicin remains the standard first-line treatment option in LS patients. Combination chemotherapy may be reserved for clinical situations where a high response rate has to be achieved for fast symptom alleviation. It is increasingly recognized that different histologic subtypes of STS exhibit variable patterns of chemosensitivity. Jones and colleagues published a retrospective analysis of 88 patients evaluating the chemosensitivity of different LS subtypes. A statistically higher response rate was observed for MLS than for all other LS patients, 48% (95% CI: 28–69) versus 18% (95% CI: 8–31), respectively. However, there was no statistically significant difference between the 33% (95% CI: 10–65) response rate achieved in PLS and 38% (95% CI: 23–55) in patients with MLS and those who had progressed to RCLS. Extremity LS patients seemed to have a better response rate than those with LS of other sites, 75% (95% CI: 19–99) for upper limb, 36% (95% CI: 19– 56) for lower limb and 18% for other sites (95% CI: 8–32), respectively. With respect to the different chemotherapy regimes, treatment responses were mainly achieved with doxorubicinbased chemotherapy, whereas the best treatment effect of ifosfamide was disease stabilization. These results are limited by their retrospective nature and the small number of patients, largely as a consequence of the rarity of this condition [26]. The increased chemosensitivity of MLS patients has been confirmed in two other retrospective studies. The first examined the efficacy of first-line doxorubicin and ifosfamide (doxorubicin 75–90 mg/m2 over 72 h; ifosfamide 10 gm/m2) in 37 patients. The overall response rates were 43.2% using Response Evaluation Criteria in Solid Tumors (RECIST) and 86.5% using the Choi criteria. The authors conclude that the combination regimen should play a role in the treatment of MLS and that the Choi criteria may be more sensitive in evaluating response to chemotherapy in MLS [27]. A second small study reviewed 20 patients with MLS patients treated with a doxorubicin- and dacarbizine-based chemotherapy regimen achieving a response rate of 44% (one complete response and seven partial responses) [28]. informahealthcare.com
Review
Recently, the efficacy of chemotherapy in patients with WD/ DDLS was investigated in a retrospective manner reviewing databases from 11 sarcoma centers. Two hundred and eight patients were included for analysis. Combination chemotherapy was delivered in 85 cases (41%) and single agent in 123 cases (59%), respectively. One hundred and seventy-one patients (82%) received an anthracycline-containing regimen. According to the RECIST criteria, objective response was observed in 21 patients (12%), all treated with anthracyclines. A clinical benefit, defined as the rate of complete or partial response or stable disease of at least 6 months’ duration, was seen in 46% of the patients. Patients with a performance status of 2 had a significantly worse OS than those of performance status 0 or 1 [29]. There is some emerging evidence that a prolonged infusion of ifosfamide could lead to a higher response in patients with DDLS [30]. This fact is supported by a recently presented retrospective report from our own institution, which investigated clinical activity and tolerability of a 14-day infusional ifosfamide schedule in 35 STS patients. The main subtypes included were DDLS, MLS and synovial sarcomas. The overall response rate and disease stabilization rate were 20% for LS and 29%, respectively. Particularly, the DDLS were seen to respond in a notable manner with a partial response in 5 patients (22.7%), stable disease in 7 patients (31.8%), hence disease control rate of 54.5%. Median PFS and OS were 4.2 and 11.2 months, respectively [31]. In summary, MLS appears to be the only subgroup of LS that is highly chemosensitive. Recent trials, although all conducted retrospectively, suggest that other subtypes, that is, PLS and DDLS have a reasonable stabilization rate with doxorubicin and/or ifosfamide. However, the schedule of chemotherapy given seems to affect efficacy and certainly toxicity. The optimal use of doxorubicin and ifosfamide is still worthy of further research, and these agents should act as comparators in forthcoming studies. Prolonged infusional ifosfamide is due to be explored further in a forthcoming randomized EORTC study comparing this regimen with cabazitaxel in the second-line setting (NCT01913652). Gemcitabine/docetaxel
These two drugs, either as single agents or in combination, are known to have modest activity in STS [32,33]. Maki and colleagues reported in an open-label, randomized Phase II trial about the efficacy of single-agent gemcitabine versus combined therapy with docetaxel. They reported most activity in leiomyosarcoma and pleomorphic sarcoma. Reviewing the LS patients, 9 out of 16 (56%) experienced mainly disease stabilization. Interestingly, 2 patients with PLS had a partial response [34]. In a retrospective review of 39 patients published by Italiano and colleagues, the effect of systemic treatment on PLS patients was investigated. While there was a response rate seen in 37.5% in first-line treatment with mainly anthracycline-based chemotherapy, 3 out of 19 patients in the second-line setting experienced a partial response, all treated with gemcitabine and 299
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docetaxel. This small study highlights that this regimen has a role in the systemic treatment of PLS [35]. Marine-derived drugs
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Trabectedin
Trabectedin is a marine-derived, DNA-binding antineoplastic agent isolated from the Caribbean tunicate Ecteinascidia turbinata and produced synthetically. Trabectedin covalently binds to the minor groove of the DNA, resulting in a DNA–drug complex. This cytotoxic complex retards progression through the S phase of the cell cycle, eventually resulting in a G2/M block and interacts with the transcription-coupled nucleotide excision repair machinery to induce lethal DNA strand breaks [36]. In addition to the direct antiproliferative effect, recently, an effect on micro-environment has been described. Trabectedin leads to inhibition of angiogenesis and has got a cytotoxic effect on monocytes and tumor-associated macrophages, which are mainly involved in tumor proliferation and dissemination [37]. The antitumor activity has been investigated in in vitro and in vivo studies showing cytotoxic activity against different cancer cell lines, of which STS cell lines were found to be particularly sensitive [38]. The efficacy of trabectedin 1.5 mg/m2 24-h intravenous infusion every 3 weeks (q3 weeks 24-h) in patients with heavily pretreated, advanced/metastatic STS was previously evaluated in three nonrandomized Phase II studies. Although the objective response rate in patients with anthracyclineresistant advanced STS has not exceeded 10%, trabectedin has resulted in meaningful control of disease with PFS exceeding 20% at 6 months [39–41]. A pooled analysis of these trials suggested a higher proportion of objective responses and better PFS with trabectedin treatment for LS and leiomyosarcomas compared with other STS subtypes [42]. An EORTC study in previously treated patients and a US study in chemotherapy-naive and refractory patients confirmed this finding. For example, in the US study, three of nine patients with LS responded, and all three responsive patients had the myxoid variant [40,43]. On this basis, a randomized Phase II study evaluating two different trabectedin schedules in a more homogeneous population of patients with lipo- and leiomyosarcoma was conducted showing a superior disease control with the q3 weeks 24-h trabectedin regimen compared to the qwk 3-h regimen [44]. Recently, Samuels et al. reported their results about a worldwide expanded access program confirming that LS patients exhibit longer OS compared with other histologies, 16.2 versus 8.4 months, and a slightly higher objective response rate 6.9 versus 4.0% [45]. The treatment with trabectedin beyond 6 cycles seems to be associated with an improved OS [46]. The efficacy of trabectedin in advanced pretreated MLS was investigated by Grosso et al. According to RECIST, after a median follow-up of 14 months, out of 51 patients two had complete responses and 24 patients had partial responses with an overall response of 51%. The noted patterns of tumor response were such that tissue density changes occurred before 300
tumor shrinkage in several patients. In some patients, only tissue-density changes were seen. Long-lasting tumor control was noted in responsive patients [47]. This analysis has resulted in the initiation of a prospective Phase II study to assess the role of trabectedin in the treatment of patients with MLS in the preoperative setting. Objective response rate was 24% and no disease progression was reported. These findings support that trabectedin 1.5 mg/m2 given as a 24-h intravenous infusion every 3 weeks is a therapeutic option with significant efficacy and minimal toxicity in the neoadjuvant setting of patients with MLS [48]. The side effects of trabectedin are generally mild and most drug-related adverse events are grade 2 according to Common Terminology Criteria. Apart from laboratory abnormalities, fatigue (8%), nausea and vomiting (each 5%) were the most common trabectedin-related grade 3/4 AEs. The most common grade 3/4 hematologic toxicity was neutropenia (47%), although neutropenic fever occurred very rarely (90% of WDLS/DDLS patients CDK4 is overexpressed, a small subset of WDLS with good prognosis does not have increased levels of CDK4 protein [57]. In contrast to LSs with CDK4 amplification, which are generally localized in the retroperitoneum, most of these tumors were localized in the limbs [58]. Different CDK4 inhibitors have been investigated in early preclinical and Phase I studies for solid tumors, including sarcomas as a single agent or in combination, showing disappointing results relating to clinical outcome and intolerable side effects [59,60]. The best evidence comes from a Phase II trial examining the efficacy and safety of PD0332991, a potent CDK4 and CDK6 inhibitor, in patients with advanced WDLS or DDLS. Inclusion criteria included documented progression while receiving systemic therapy before trial enrolment, CDK4 amplification documented by FISH and retinoblastoma protein expression seen on immunohistochemistry. The primary endpoint was PFS at 12 weeks. Treatment with PD0332991 was generally well tolerated. Although grades 3 to 4 myelosuppression was common (neutropenia in 50%, thrombocytopenia in 30%) this rarely resulted in serious sequelae. The progression-free rate at 12 weeks of the 29 evaluable patients was 66%, which is promising in this specific patient cohort, meeting its primary endpoint. A potential weakness is that progression at the time of study entry was not formally defined but rather was assessed by the treating physician. One patient (3%) achieved a partial response according to RECIST at 74 weeks and three other patients had evidence of favorable response to treatment that did not meet RECIST criteria. This study provides important proof of principle and the data suggest that this CDK4 and 6 inhibitor might have activity in this selected LS population [61]. Tyrosine kinase receptor inhibitors
Pazopanib is a multitargeted tyrosine kinase inhibitor, with activity against VEGF 1, 2 and 3, and platelet-derived growth factors. Pazopanib was approved recently for second-line treatment in STS other than adipocytic sarcoma patients after 301
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showing activity mainly in leiomyosarcoma and synovial sarcoma in a Phase II trial and these results have been confirmed in a large multicentric Phase III trial (PALETTE trial) in terms of significantly increase in PFS and trend toward increase in OS [62,63]. In the Phase II trial, proportion of LS patients who were free of progression after 12 weeks did not reach 40% and were therefore rejected for further investigation. Nevertheless, there are a few ongoing trials evaluating the role of pazopanib in LS and results are eagerly awaited (NCT01506596 and NCT01692496). Sorafenib is another drug of this class being tested in a Phase II trial including LS patients. In all, 37 patients with different STS subtypes were evaluated. No RECIST responses were reported, although two (20%) of DDLS patients demonstrated disease stabilization. Although the response rate was disappointing, the low number of LS patients makes it difficult to draw any definite conclusions [64]. Further investigation of tyrosine kinase inhibitors in LS is supported by a Phase II trial of sunitinib in relapsed or refractory STS that included 48 patients in total. Of 17 (82%) LS patients, 14 experienced disease stabilization and a 3-month PFS of >40% is reported, therefore, suggesting clinical activity [65]. The difference of efficacy between these anti-angiogenic agents is unclear and the usual caveats apply with regard to small patient numbers and underlying disease biology. Whereas sunitinib seems to have a beneficial effect in the treatment of LS patients, pazopanib and sorafenib have thus far failed to show a significant activity in LS patients. This may be due to small differences in the molecular receptors targeted by these drugs and different affinity to the specific targets. Translational research is critical here in order to inform further drug development. Expert commentary
Conventional chemotherapy with doxorubicin and/or ifosfamide has been the mainstay of systemic treatment for all STSs, including LS, for a long period of time and remains so to this day. Prolonged infusional ifosfamide, which allows delivery of relatively high doses of drug has shown particular promise in the DDLS subtype and is undergoing further evaluation as part of a forthcoming EORTC study. Trabectedin has become a very valuable addition to systemic treatment options, especially in MLS. Much interest surrounds its mechanism of action with respect to the role of the tumor microenvironment. Additionally, the combination of Gemcitabine and Docetaxel remains a treatment option for PLS in the second-line setting and beyond, despite the fact that data are largely retrospective. The role of anti-angiogenetic drugs in the form of multitargeted tyrosine kinase inhibitors in LS patients is not yet fully defined. While pazopanib has recently been approved for second-line treatment in STSs, this is only for nonadipocytic STS. Nevertheless, sunitinib has shown signs of activity in LS patients, which raises the hope that anti-angiogentic drugs may become a future treatment option. In the past decade, we have witnessed a major evolution in molecular diagnostics in all tumor types, including STS. 302
Increasing number of STS subtypes are defined according to their genotypic footprint and the treatment may be targeted to specific oncogenic changes and thus increase the therapeutic armamentarium. Equally, continued collaboration of different national and international research groups give us the possibility to study rare tumor entities and gather results to build treatment recommendations and guidelines. The main research achievements in recent years have been made by investigating the role of different molecular changes in liposarcomatogenesis and exploiting the molecular characteristics of different LS subentities. As a consequence, two promising potential strategies for therapeutic intervention have been highlighted. MDM2 and CDK-inhibitors showed proof-ofprinciple with very good clinical results that warrant further prospective testing as a single agent and in combination with cytotoxic treatment. Incorporation of translational science remains crucial in this setting. Nevertheless, there is no certainty that a novel compound, although based on well-studied preclinical results will automatically end in a successful story. PPARgamma (peroxisome proliferator-activated receptor) is a nuclear receptor and its activation has been seen to have the potential to terminally differentiate human liposarcoma cells in vitro by activating genes responsible for lipocyte differentiation [66]. Thiazizolidinedione drugs (i.e., troglitazone, rosiglitazone) are used as oral antidiabetic drugs and has been identified to be PPARgamma agonists. After troglitazone showed proof-of-mechanism evidence for differentiation of LS in three patients in a Phase I trial, a Phase II study was conducted. Disappointingly, no significant changes on histologic appearance or on the level of gene expression were seen. Furthermore, there were no clinical responses seen in the 12 patients taking part in the trial [67,68]. Finally, there is an increasing awareness that RECIST criteria may not always be the best method of evaluating tumor response. Utilizing changes in density as an indication of tumor response as in the Choi criteria also plays an important role particularly in MLS. Consideration should be made to adopt other functional imaging modalities in clinical trial design [69]. Five-year view
Based on the growing knowledge of the molecular characteristics of LS, some noteworthy preclinical data and clinical trials have been published recently. Experience of MDM2 and CDK4-inhibitors show promise nevertheless, more mature data in the form of Phase II and III studies in larger patient cohorts are clearly needed before making any definitive conclusions. Until then, novel targeted treatment options cannot be part of our current treatment paradigm and should only be available within the context of clinical trials. There are a few novel systemic drugs with different molecular targets, which are under investigation and may have a future impact on treatment of LS patients. Nelfinavir, a known HIV proteosome inhibitor, was evaluated further after the clinical syndrome of peripheral lipoatrophy was described following clinical experience of this drug [70]. Expert Rev. Anticancer Ther. 14(3), (2014)
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Current management options for liposarcoma & challenges for the future
In translational studies, nelfinavir was shown to induce LS apoptosis and cell-cycle arrest by altering the sterol regulatory element binding protein-1, which itself is involved in fatty acid and cholesterol synthesis as a transcriptional regulator [71]. As a consequence, nelfinavir was tested in a Phase I trial including 20 patients with unresectable LS (17 patients with WDLS/ DDLS, two MLS/RCLS and one PLS). One patient experienced grade 3 pancreatitis, but no other dose-limiting toxicities were described. One partial response was documented in a DDLS patient and four patients were reported having stable disease [72]. A Phase II trial recently completed accrual, but the results are pending (NCT00233948). Another very interesting approach that definitely will be further investigated in the near future is immunotherapy, which to date was shown to play a significant role mainly in the treatment of metastatic melanoma [73]. This therapeutic approach is supported by a preliminary study of Tseng et al. suggesting the presence of a natural immune response in WD retroperitoneal LS [74]. Again, translational studies found that NY-ESO-1, known as a cancer-testis antigen or cancer germ cell antigen, is almost uniformly expressed in MLS/RCLS. As a consequence, this highly immunogenic antigen, which was proved to be effective in vaccine trials and adoptive T-cell therapy trials for the treatment of several solid tumors, could serve as a target antigen [75]. Extensive translational research has highlighted PI3Kinhibition as a future potential therapy due to involvement of
Review
this pathway in progression of MLS/RCLS and DDLS [76]. Findings revealing epigenetic abnormalities in DDLS suggest a role of histone acetylation and/or DNA demethylation as a therapeutic option [77,78]. While a lot of new agents are being explored, there are a lot of questions unanswered concerning the sequence of systemic therapy and if combination of drugs with different mode of action would improve the outcome. A Phase I trial published by Luke et al. emphasizes that a combination approach with flavopiridol, a CDK-inhibitor and doxorubicin might be synergistic. Although these data are immature, 8 out of 12 patients with WDLS/DDLS patients were reported to have disease stabilization, which is promising [79]. There is no doubt that there is much progress in the evaluation of treatment options for LS. As collaboration between research groups have improved and molecular analysis of tumors becomes routine, we await with interest new information about the genesis of LS and potential therapeutic targets. We should not forget the main endpoints in the palliative setting, which are overall survival and quality of life. Financial & competing interest disclosure
A Kolla´r is on the advisory board for GSK. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues • Liposarcoma represents one of the most common soft tissue sarcomas. • Three different major subtypes can be distinguished (well-/dedifferentiated, myxoid/round cell and pleomorphic liposarcoma), which are defined by their morphology and molecular diagnostics. • Conventional cytotoxic chemotherapy remains the mainstay of systemic treatment in the first-line setting. • The marine-derived drug trabectedin plays an important role mainly in myxoid liposarcoma with a high response rate and lack of cumulative toxicity. • The amplification of mouse double minute 2 homolog and cyclin-dependent kinase-4 represents two important unique molecular features that have been targeted in well-/dedifferentiated liposarcoma. Phase I and II trials have demonstrated encouraging results. • The exact role of angiogenic treatment in liposarcoma is unclear and further evaluation to clarify it is needed. • Novel treatment targets and strategies including PI3K-inhibitors, nelfinavir, epigenetic modulation and immunotherapy are under investigation. Their future impact on liposarcoma therapy is unknown, but encouraging.
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First Phase II trial with a marine-compound drug that reports successful results in liposarcomas, particularly the myxoid variant.
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Current management options for liposarcoma and challenges for the future Expert Rev. Anticancer Ther. 14(3), 297–306 (2014)
Attila Kolla´r* and Charlotte Benson The Royal Marsden Hospital, Sarcoma Unit, Fulham Road, SW3 6JJ, London, UK *Author for correspondence: Tel.: +44 207 808 2137 Fax: +44 207 808 2672 [email protected]
Liposarcoma (LS) represents one of the most common soft tissue sarcomas. There are three major subtypes, namely, well/dedifferentiated, myxoid/round cell and pleomorphic LS. In general, LS is known to be a relatively chemo-resistant sarcoma subtype with the exception of the myxoid variant. Conventional chemotherapy with doxorubicin and ifosfamide represents the mainstay of systemic treatment in the first line. Other active cytotoxic agents include gemcitabine and docetaxel and the marine-derived compounds trabectedin. Recent progress in molecular diagnostics of each single LS subtype has improved the knowledge of the molecular characteristics and has led to two recent treatment targets: the amplification of mouse double minute 2 homolog and cyclin-dependent kinase-4 in well- and dedifferentiated LS. Thus far, only early-phase trials are reported and no new drugs have been introduced in daily clinical practice. The focus of this review is on current systemic treatment options, including novel strategies. KEYWORDS: CDK4 • chemotherapy • eribulin • liposarcoma • MDM2 • pazopanib • soft tissue sarcoma • trabectedin
Soft tissue sarcomas (STSs) are a rare and heterogeneous group of malignant tumors of mesenchymal origin accounting for approximately 1% of all malignant tumors. STS encompass more than 50 different histologic subtypes, as classified by the WHO. The most frequently occurring histological subtypes are gastrointestinal stromal tumor (18%), unclassified sarcoma (16%), liposarcoma (LS) (15%) and leiomyosarcoma (11%) [1]. LS appears to arise from precursors of adipocytes and represents 24% of extremity and 45% of retroperitoneal STS [2]. The peak incidence lies between 50 and 65 years of age [3]. Histopathology
The three main morphologic LS subgroups are well-differentiated/dedifferentiated LS (WD/ DDLS), myxoid/round cell LS (MLS/RCLS) and pleomorphic LS (PLS). WDLS and DDLS represent the most common biological group of LS (40–45%) [4]. The WHO classifies WDLS into three main subtypes according to morphologic features: adipocytic, sclerosing and inflammatory LS. Adipocytic variant (lipoma-like) LS is the most frequent subtype, which is composed of mature adipocytes and exhibits variation in cell informahealthcare.com
10.1586/14737140.2014.869173
size with focal nuclear atypia and hyperchromasia. About 90% of WD/DDLS have amplification of chromosome 12q13–15, which contains several oncogenes, including MDM2, HMGA2 and CDK4. There is evidence that they play an essential role in liposarcomagenesis [5]. Therefore, intensive research is ongoing to target these ongogenic changes. DDLP mostly arises de novo, but progression from pure WDLS to high-grade nonlipogenic morphology within a WDLS may also occur [6]. MLS is the second most common subtype of LS and accounts for more than one-third of LS. MLS is characterized by the presence of spindle or ovoid cells set in a myxoid stroma with signet ring lipoblasts and a distinctive chickenwire pattern vasculature. The presence of areas with greater cellularity, known as round cell dedifferentiation, is associated with a worse prognosis [7]. The round cell variant of MLS is defined as >5% round cell phenotype in a given MLS tumor. MLS is characterized by a unique chromosome rearrangement, t(12;16)(q13;p11) that results in the FUSCHOP gene fusion that is present in over 95% of cases [8]. Rarely, another translocation t(12;22)(q13;q12) is found resulting in the formation of a novel fusion oncogene known
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´ r & Benson Kolla
as the EWS-CHOP oncogene [9]. Due to the nearly normal karyotype in these LS subtypes, these chromosomal changes are thought to be the first change on a genetic level leading to a malignant behavior. As CHOP plays an important role in regulating the differentiation of adipocytes, it is suggested that FUS-CHOP functions by inhibiting adipogenesis and maintaining immature adipocytes in a continuous cycle of proliferation without differentiation [10]. The pleomorphic variant of LS is considered to be a separate subentity and accounts for only 5% of LS. Histologically, PLSs are characterized by a disorderly growth pattern, extreme cellularity and cellular pleomorphism, including bizarre giant cells and the presence of lipoblasts [11]. Molecular studies show that PLS harbor diverse chromosomal rearrangements and genomic profiles without unifying molecular alterations, making targeted drug development more challenging in this subtype. In contrast to the other LS subtypes, p53 mutations were identified in 16.7%, whereas they are rarely seen in MLS and WD/ DDLS [12]. PLS is the most aggressive LS subtype with a very poor outcome [13]. Clinical characteristics & adjuvant therapy
Regarding the clinical behavior of the LS subtypes DDLS, RCLS and PLS are high-grade, aggressive tumors with metastatic potential, while WDLS and MLS may follow a more indolent clinical course [2]. Depending on the subtype, the 5-year overall survival (OS) is as follows: 93.3% for WDLS, 75.7% for MLS, 54.5% for DDLS, 40% for RCLS and lower for PLS patients, respectively [14]. The main prognostic factors that correlate for survival are tumor grade, histologic subtype, primary location, stage, and margin status [15]. For example, in WDLS patients, retroperitoneal/ intra-abdominal location is associated with a worse outcome than the extremity counterparts [16]. Surgery is the cornerstone of curative treatment for primary disease with the goal to widely resect the tumor with negative margins. The addition of a postoperative radiotherapy to extremity sarcoma patients in limb-sparing surgery was shown in 2 randomized trials to be beneficial in terms of reducing the risk of local recurrence but not affecting OS [17,18]. Therefore, in the European Society of Medical Oncology Guidelines, additive radiotherapy is recommended mainly in high-grade sarcoma patients (G2-G3, >5 cm, deep tumors), although it is a matter of debate how high the risk of local recurrence must be to justify radiotherapy. The use of adjuvant chemotherapy to treat patients with resected STS remains a controversial issue. The most recent meta-analysis included 18 randomized trials and was associated with an absolute risk of death reduction of 11% for the use of doxorubicin and ifosfamide. In the multivariate analysis histologic subtype in particular was not found to be a relevant predictor of benefit [19]. The interpretation of these results was tempered by the largest pooled analysis of the two largest adjuvant trials performed by the European Organisation of Research and Treatment of Cancer (EORTC), which was negative and not 298
included in the latest meta-analysis [20]. Thus, the impact of histology on the effect of adjuvant chemotherapy is unclear. One retrospective study evaluated (neo-)/adjuvant systemic treatment in high-risk LS patients. LSs were considered high grade if they showed evidence of greater than 25% dedifferentiated morphology, greater than 5% round cell morphology or pleomorphic morphology. WDLS and pure MLS were considered to be low-grade lesions and were not included in the present study. Of 245 patients, 34% were treated with doxorubicin-based chemotherapy, 26% with ifosfamide-based chemotherapy and 40% without systemic treatment. In a contemporary cohort analysis, the 5-year disease-specific survival (DSS) was 64% for doxorubicin-treated patients, 92% for the ifosfamide cohort and 56% for the patients group without systemic therapy. Only ifosfamide treatment was associated with a significant improved DSS. Interestingly, there was a benefit for treatment with ifosfamide in MLS/RCLS and in PLS, as well, with a survival benefit at 5 years of 22% for MLS/RCLS and 31% for the pleomorphic variant. This trial suggests there may be a role for ifosfamide-based treatment in the (neo-) adjuvant setting of this specific cohort of LS patients although this would need to be confirmed by randomized prospective studies before being adopted into clinical practice [21]. In summary, the role of adjuvant chemotherapy remains uncertain and is therefore not routinely recommended. The potential of benefit should be discussed on case-by-case basis taking into consideration the patient and tumor characteristics as performance score, age, comorbidities, site of primary tumor and histologic subtype. Despite surgery and adjuvant treatment options, more than half of patients will develop recurrent or metastatic disease. The majority of patients who develop metastatic soft tissue sarcoma are incurable with a median survival of 11–12 months [22]. Systemic treatment options for metastatic liposarcoma
The aim of systemic treatment in the palliative setting is to improve tumor-associated symptoms, quality of life and to increase DSS. The rarity of sarcoma explains why historically trials investigating the efficacy of systemic treatment have included a variety of sarcoma subtypes. More recently trials have been stratified, which may provide useful information about the sensitivity of LS to systemic therapy. Additionally, increased understanding of the molecular background and pathogenesis of LS allows us to tailor treatment accordingly. Although the evidence from randomized Phase III trials that systemic treatment prolongs OS is lacking, a prolonged progression-free survival (PFS) and OS might be achieved by widening systemic treatment options. In the following section, we will review the role of systemic therapy in LS to date and discuss what future studies are forthcoming. Conventional cytotoxic chemotherapy Doxorubicin/ifosfamide
Doxorubicin was the first systemic chemotherapy described to be active in STS. The response rate in a histologically diverse Expert Rev. Anticancer Ther. 14(3), (2014)
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Current management options for liposarcoma & challenges for the future
cohort of sarcoma patients lies in the range of 10–25% [23]. Single-agent ifosfamide is also a well-studied systemic agent in STS. In one cohort, ifosfamide has a similar antitumor activity to doxorubicin with a response rate of around 25% in patients who previously failed a doxorubicin-based chemotherapy regimen [24]. Many different combination regimens have been studied in patients with metastatic disease and almost always include doxorubicin and an alkylating agent. There are a few randomized trials investigating combination regimens that show a higher response rate up to 46% but no increase in OS. These results have been confirmed recently by the EORTC 62012 trial presented at European Society of Medical Oncology 2012 (Ref Judson Ann Oncology supplement 9 pages ixe1–ixe30). Although the median PFS (7.4 vs 4.6 months; p = 0.003) and response rates were significantly increased in the combination arm with doxorubicin and ifosfamide, no difference was seen in the 2-year OS rate, which was 31% for the combined arm versus 28% for doxorubicin alone [25]. Therefore, single-agent doxorubicin remains the standard first-line treatment option in LS patients. Combination chemotherapy may be reserved for clinical situations where a high response rate has to be achieved for fast symptom alleviation. It is increasingly recognized that different histologic subtypes of STS exhibit variable patterns of chemosensitivity. Jones and colleagues published a retrospective analysis of 88 patients evaluating the chemosensitivity of different LS subtypes. A statistically higher response rate was observed for MLS than for all other LS patients, 48% (95% CI: 28–69) versus 18% (95% CI: 8–31), respectively. However, there was no statistically significant difference between the 33% (95% CI: 10–65) response rate achieved in PLS and 38% (95% CI: 23–55) in patients with MLS and those who had progressed to RCLS. Extremity LS patients seemed to have a better response rate than those with LS of other sites, 75% (95% CI: 19–99) for upper limb, 36% (95% CI: 19– 56) for lower limb and 18% for other sites (95% CI: 8–32), respectively. With respect to the different chemotherapy regimes, treatment responses were mainly achieved with doxorubicinbased chemotherapy, whereas the best treatment effect of ifosfamide was disease stabilization. These results are limited by their retrospective nature and the small number of patients, largely as a consequence of the rarity of this condition [26]. The increased chemosensitivity of MLS patients has been confirmed in two other retrospective studies. The first examined the efficacy of first-line doxorubicin and ifosfamide (doxorubicin 75–90 mg/m2 over 72 h; ifosfamide 10 gm/m2) in 37 patients. The overall response rates were 43.2% using Response Evaluation Criteria in Solid Tumors (RECIST) and 86.5% using the Choi criteria. The authors conclude that the combination regimen should play a role in the treatment of MLS and that the Choi criteria may be more sensitive in evaluating response to chemotherapy in MLS [27]. A second small study reviewed 20 patients with MLS patients treated with a doxorubicin- and dacarbizine-based chemotherapy regimen achieving a response rate of 44% (one complete response and seven partial responses) [28]. informahealthcare.com
Review
Recently, the efficacy of chemotherapy in patients with WD/ DDLS was investigated in a retrospective manner reviewing databases from 11 sarcoma centers. Two hundred and eight patients were included for analysis. Combination chemotherapy was delivered in 85 cases (41%) and single agent in 123 cases (59%), respectively. One hundred and seventy-one patients (82%) received an anthracycline-containing regimen. According to the RECIST criteria, objective response was observed in 21 patients (12%), all treated with anthracyclines. A clinical benefit, defined as the rate of complete or partial response or stable disease of at least 6 months’ duration, was seen in 46% of the patients. Patients with a performance status of 2 had a significantly worse OS than those of performance status 0 or 1 [29]. There is some emerging evidence that a prolonged infusion of ifosfamide could lead to a higher response in patients with DDLS [30]. This fact is supported by a recently presented retrospective report from our own institution, which investigated clinical activity and tolerability of a 14-day infusional ifosfamide schedule in 35 STS patients. The main subtypes included were DDLS, MLS and synovial sarcomas. The overall response rate and disease stabilization rate were 20% for LS and 29%, respectively. Particularly, the DDLS were seen to respond in a notable manner with a partial response in 5 patients (22.7%), stable disease in 7 patients (31.8%), hence disease control rate of 54.5%. Median PFS and OS were 4.2 and 11.2 months, respectively [31]. In summary, MLS appears to be the only subgroup of LS that is highly chemosensitive. Recent trials, although all conducted retrospectively, suggest that other subtypes, that is, PLS and DDLS have a reasonable stabilization rate with doxorubicin and/or ifosfamide. However, the schedule of chemotherapy given seems to affect efficacy and certainly toxicity. The optimal use of doxorubicin and ifosfamide is still worthy of further research, and these agents should act as comparators in forthcoming studies. Prolonged infusional ifosfamide is due to be explored further in a forthcoming randomized EORTC study comparing this regimen with cabazitaxel in the second-line setting (NCT01913652). Gemcitabine/docetaxel
These two drugs, either as single agents or in combination, are known to have modest activity in STS [32,33]. Maki and colleagues reported in an open-label, randomized Phase II trial about the efficacy of single-agent gemcitabine versus combined therapy with docetaxel. They reported most activity in leiomyosarcoma and pleomorphic sarcoma. Reviewing the LS patients, 9 out of 16 (56%) experienced mainly disease stabilization. Interestingly, 2 patients with PLS had a partial response [34]. In a retrospective review of 39 patients published by Italiano and colleagues, the effect of systemic treatment on PLS patients was investigated. While there was a response rate seen in 37.5% in first-line treatment with mainly anthracycline-based chemotherapy, 3 out of 19 patients in the second-line setting experienced a partial response, all treated with gemcitabine and 299
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docetaxel. This small study highlights that this regimen has a role in the systemic treatment of PLS [35]. Marine-derived drugs
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Trabectedin
Trabectedin is a marine-derived, DNA-binding antineoplastic agent isolated from the Caribbean tunicate Ecteinascidia turbinata and produced synthetically. Trabectedin covalently binds to the minor groove of the DNA, resulting in a DNA–drug complex. This cytotoxic complex retards progression through the S phase of the cell cycle, eventually resulting in a G2/M block and interacts with the transcription-coupled nucleotide excision repair machinery to induce lethal DNA strand breaks [36]. In addition to the direct antiproliferative effect, recently, an effect on micro-environment has been described. Trabectedin leads to inhibition of angiogenesis and has got a cytotoxic effect on monocytes and tumor-associated macrophages, which are mainly involved in tumor proliferation and dissemination [37]. The antitumor activity has been investigated in in vitro and in vivo studies showing cytotoxic activity against different cancer cell lines, of which STS cell lines were found to be particularly sensitive [38]. The efficacy of trabectedin 1.5 mg/m2 24-h intravenous infusion every 3 weeks (q3 weeks 24-h) in patients with heavily pretreated, advanced/metastatic STS was previously evaluated in three nonrandomized Phase II studies. Although the objective response rate in patients with anthracyclineresistant advanced STS has not exceeded 10%, trabectedin has resulted in meaningful control of disease with PFS exceeding 20% at 6 months [39–41]. A pooled analysis of these trials suggested a higher proportion of objective responses and better PFS with trabectedin treatment for LS and leiomyosarcomas compared with other STS subtypes [42]. An EORTC study in previously treated patients and a US study in chemotherapy-naive and refractory patients confirmed this finding. For example, in the US study, three of nine patients with LS responded, and all three responsive patients had the myxoid variant [40,43]. On this basis, a randomized Phase II study evaluating two different trabectedin schedules in a more homogeneous population of patients with lipo- and leiomyosarcoma was conducted showing a superior disease control with the q3 weeks 24-h trabectedin regimen compared to the qwk 3-h regimen [44]. Recently, Samuels et al. reported their results about a worldwide expanded access program confirming that LS patients exhibit longer OS compared with other histologies, 16.2 versus 8.4 months, and a slightly higher objective response rate 6.9 versus 4.0% [45]. The treatment with trabectedin beyond 6 cycles seems to be associated with an improved OS [46]. The efficacy of trabectedin in advanced pretreated MLS was investigated by Grosso et al. According to RECIST, after a median follow-up of 14 months, out of 51 patients two had complete responses and 24 patients had partial responses with an overall response of 51%. The noted patterns of tumor response were such that tissue density changes occurred before 300
tumor shrinkage in several patients. In some patients, only tissue-density changes were seen. Long-lasting tumor control was noted in responsive patients [47]. This analysis has resulted in the initiation of a prospective Phase II study to assess the role of trabectedin in the treatment of patients with MLS in the preoperative setting. Objective response rate was 24% and no disease progression was reported. These findings support that trabectedin 1.5 mg/m2 given as a 24-h intravenous infusion every 3 weeks is a therapeutic option with significant efficacy and minimal toxicity in the neoadjuvant setting of patients with MLS [48]. The side effects of trabectedin are generally mild and most drug-related adverse events are grade 2 according to Common Terminology Criteria. Apart from laboratory abnormalities, fatigue (8%), nausea and vomiting (each 5%) were the most common trabectedin-related grade 3/4 AEs. The most common grade 3/4 hematologic toxicity was neutropenia (47%), although neutropenic fever occurred very rarely (90% of WDLS/DDLS patients CDK4 is overexpressed, a small subset of WDLS with good prognosis does not have increased levels of CDK4 protein [57]. In contrast to LSs with CDK4 amplification, which are generally localized in the retroperitoneum, most of these tumors were localized in the limbs [58]. Different CDK4 inhibitors have been investigated in early preclinical and Phase I studies for solid tumors, including sarcomas as a single agent or in combination, showing disappointing results relating to clinical outcome and intolerable side effects [59,60]. The best evidence comes from a Phase II trial examining the efficacy and safety of PD0332991, a potent CDK4 and CDK6 inhibitor, in patients with advanced WDLS or DDLS. Inclusion criteria included documented progression while receiving systemic therapy before trial enrolment, CDK4 amplification documented by FISH and retinoblastoma protein expression seen on immunohistochemistry. The primary endpoint was PFS at 12 weeks. Treatment with PD0332991 was generally well tolerated. Although grades 3 to 4 myelosuppression was common (neutropenia in 50%, thrombocytopenia in 30%) this rarely resulted in serious sequelae. The progression-free rate at 12 weeks of the 29 evaluable patients was 66%, which is promising in this specific patient cohort, meeting its primary endpoint. A potential weakness is that progression at the time of study entry was not formally defined but rather was assessed by the treating physician. One patient (3%) achieved a partial response according to RECIST at 74 weeks and three other patients had evidence of favorable response to treatment that did not meet RECIST criteria. This study provides important proof of principle and the data suggest that this CDK4 and 6 inhibitor might have activity in this selected LS population [61]. Tyrosine kinase receptor inhibitors
Pazopanib is a multitargeted tyrosine kinase inhibitor, with activity against VEGF 1, 2 and 3, and platelet-derived growth factors. Pazopanib was approved recently for second-line treatment in STS other than adipocytic sarcoma patients after 301
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showing activity mainly in leiomyosarcoma and synovial sarcoma in a Phase II trial and these results have been confirmed in a large multicentric Phase III trial (PALETTE trial) in terms of significantly increase in PFS and trend toward increase in OS [62,63]. In the Phase II trial, proportion of LS patients who were free of progression after 12 weeks did not reach 40% and were therefore rejected for further investigation. Nevertheless, there are a few ongoing trials evaluating the role of pazopanib in LS and results are eagerly awaited (NCT01506596 and NCT01692496). Sorafenib is another drug of this class being tested in a Phase II trial including LS patients. In all, 37 patients with different STS subtypes were evaluated. No RECIST responses were reported, although two (20%) of DDLS patients demonstrated disease stabilization. Although the response rate was disappointing, the low number of LS patients makes it difficult to draw any definite conclusions [64]. Further investigation of tyrosine kinase inhibitors in LS is supported by a Phase II trial of sunitinib in relapsed or refractory STS that included 48 patients in total. Of 17 (82%) LS patients, 14 experienced disease stabilization and a 3-month PFS of >40% is reported, therefore, suggesting clinical activity [65]. The difference of efficacy between these anti-angiogenic agents is unclear and the usual caveats apply with regard to small patient numbers and underlying disease biology. Whereas sunitinib seems to have a beneficial effect in the treatment of LS patients, pazopanib and sorafenib have thus far failed to show a significant activity in LS patients. This may be due to small differences in the molecular receptors targeted by these drugs and different affinity to the specific targets. Translational research is critical here in order to inform further drug development. Expert commentary
Conventional chemotherapy with doxorubicin and/or ifosfamide has been the mainstay of systemic treatment for all STSs, including LS, for a long period of time and remains so to this day. Prolonged infusional ifosfamide, which allows delivery of relatively high doses of drug has shown particular promise in the DDLS subtype and is undergoing further evaluation as part of a forthcoming EORTC study. Trabectedin has become a very valuable addition to systemic treatment options, especially in MLS. Much interest surrounds its mechanism of action with respect to the role of the tumor microenvironment. Additionally, the combination of Gemcitabine and Docetaxel remains a treatment option for PLS in the second-line setting and beyond, despite the fact that data are largely retrospective. The role of anti-angiogenetic drugs in the form of multitargeted tyrosine kinase inhibitors in LS patients is not yet fully defined. While pazopanib has recently been approved for second-line treatment in STSs, this is only for nonadipocytic STS. Nevertheless, sunitinib has shown signs of activity in LS patients, which raises the hope that anti-angiogentic drugs may become a future treatment option. In the past decade, we have witnessed a major evolution in molecular diagnostics in all tumor types, including STS. 302
Increasing number of STS subtypes are defined according to their genotypic footprint and the treatment may be targeted to specific oncogenic changes and thus increase the therapeutic armamentarium. Equally, continued collaboration of different national and international research groups give us the possibility to study rare tumor entities and gather results to build treatment recommendations and guidelines. The main research achievements in recent years have been made by investigating the role of different molecular changes in liposarcomatogenesis and exploiting the molecular characteristics of different LS subentities. As a consequence, two promising potential strategies for therapeutic intervention have been highlighted. MDM2 and CDK-inhibitors showed proof-ofprinciple with very good clinical results that warrant further prospective testing as a single agent and in combination with cytotoxic treatment. Incorporation of translational science remains crucial in this setting. Nevertheless, there is no certainty that a novel compound, although based on well-studied preclinical results will automatically end in a successful story. PPARgamma (peroxisome proliferator-activated receptor) is a nuclear receptor and its activation has been seen to have the potential to terminally differentiate human liposarcoma cells in vitro by activating genes responsible for lipocyte differentiation [66]. Thiazizolidinedione drugs (i.e., troglitazone, rosiglitazone) are used as oral antidiabetic drugs and has been identified to be PPARgamma agonists. After troglitazone showed proof-of-mechanism evidence for differentiation of LS in three patients in a Phase I trial, a Phase II study was conducted. Disappointingly, no significant changes on histologic appearance or on the level of gene expression were seen. Furthermore, there were no clinical responses seen in the 12 patients taking part in the trial [67,68]. Finally, there is an increasing awareness that RECIST criteria may not always be the best method of evaluating tumor response. Utilizing changes in density as an indication of tumor response as in the Choi criteria also plays an important role particularly in MLS. Consideration should be made to adopt other functional imaging modalities in clinical trial design [69]. Five-year view
Based on the growing knowledge of the molecular characteristics of LS, some noteworthy preclinical data and clinical trials have been published recently. Experience of MDM2 and CDK4-inhibitors show promise nevertheless, more mature data in the form of Phase II and III studies in larger patient cohorts are clearly needed before making any definitive conclusions. Until then, novel targeted treatment options cannot be part of our current treatment paradigm and should only be available within the context of clinical trials. There are a few novel systemic drugs with different molecular targets, which are under investigation and may have a future impact on treatment of LS patients. Nelfinavir, a known HIV proteosome inhibitor, was evaluated further after the clinical syndrome of peripheral lipoatrophy was described following clinical experience of this drug [70]. Expert Rev. Anticancer Ther. 14(3), (2014)
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Current management options for liposarcoma & challenges for the future
In translational studies, nelfinavir was shown to induce LS apoptosis and cell-cycle arrest by altering the sterol regulatory element binding protein-1, which itself is involved in fatty acid and cholesterol synthesis as a transcriptional regulator [71]. As a consequence, nelfinavir was tested in a Phase I trial including 20 patients with unresectable LS (17 patients with WDLS/ DDLS, two MLS/RCLS and one PLS). One patient experienced grade 3 pancreatitis, but no other dose-limiting toxicities were described. One partial response was documented in a DDLS patient and four patients were reported having stable disease [72]. A Phase II trial recently completed accrual, but the results are pending (NCT00233948). Another very interesting approach that definitely will be further investigated in the near future is immunotherapy, which to date was shown to play a significant role mainly in the treatment of metastatic melanoma [73]. This therapeutic approach is supported by a preliminary study of Tseng et al. suggesting the presence of a natural immune response in WD retroperitoneal LS [74]. Again, translational studies found that NY-ESO-1, known as a cancer-testis antigen or cancer germ cell antigen, is almost uniformly expressed in MLS/RCLS. As a consequence, this highly immunogenic antigen, which was proved to be effective in vaccine trials and adoptive T-cell therapy trials for the treatment of several solid tumors, could serve as a target antigen [75]. Extensive translational research has highlighted PI3Kinhibition as a future potential therapy due to involvement of
Review
this pathway in progression of MLS/RCLS and DDLS [76]. Findings revealing epigenetic abnormalities in DDLS suggest a role of histone acetylation and/or DNA demethylation as a therapeutic option [77,78]. While a lot of new agents are being explored, there are a lot of questions unanswered concerning the sequence of systemic therapy and if combination of drugs with different mode of action would improve the outcome. A Phase I trial published by Luke et al. emphasizes that a combination approach with flavopiridol, a CDK-inhibitor and doxorubicin might be synergistic. Although these data are immature, 8 out of 12 patients with WDLS/DDLS patients were reported to have disease stabilization, which is promising [79]. There is no doubt that there is much progress in the evaluation of treatment options for LS. As collaboration between research groups have improved and molecular analysis of tumors becomes routine, we await with interest new information about the genesis of LS and potential therapeutic targets. We should not forget the main endpoints in the palliative setting, which are overall survival and quality of life. Financial & competing interest disclosure
A Kolla´r is on the advisory board for GSK. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues • Liposarcoma represents one of the most common soft tissue sarcomas. • Three different major subtypes can be distinguished (well-/dedifferentiated, myxoid/round cell and pleomorphic liposarcoma), which are defined by their morphology and molecular diagnostics. • Conventional cytotoxic chemotherapy remains the mainstay of systemic treatment in the first-line setting. • The marine-derived drug trabectedin plays an important role mainly in myxoid liposarcoma with a high response rate and lack of cumulative toxicity. • The amplification of mouse double minute 2 homolog and cyclin-dependent kinase-4 represents two important unique molecular features that have been targeted in well-/dedifferentiated liposarcoma. Phase I and II trials have demonstrated encouraging results. • The exact role of angiogenic treatment in liposarcoma is unclear and further evaluation to clarify it is needed. • Novel treatment targets and strategies including PI3K-inhibitors, nelfinavir, epigenetic modulation and immunotherapy are under investigation. Their future impact on liposarcoma therapy is unknown, but encouraging.
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••
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