REVIEW

Systemic Therapy for Soft Tissue Sarcoma: Proposalsfor the Optimal Use of Pazopanib, Trabectedin,and Eribulin

Akira Kawai . Kan Yonemori . Shunji Takahashi . Nobuhito Araki .

Takafumi Ueda

Received: March 31, 2017 / Published online: May 25, 2017� The Author(s) 2017. This article is an open access publication

ABSTRACT

Soft tissue sarcoma (STS) is a rare tumor withmore than 50 histologic subtypes. Althoughtreatment outcomes for patients with STS haveimproved greatly over the past few decadesowing to the adoption of a multidisciplinaryapproach, patients with advanced disease havea poor prognosis. The development of

anticancer drugs has been directed towardimproving overall survival (OS). Doxorubicinmonotherapy is currently the only standardoption for the first-line treatment of STS. How-ever, there is no standard therapy for sec-ond-line and later treatment at present. Since2012, three anticancer drugs—pazopanib, tra-bectedin, and eribulin—have been approved inJapan for the second-line or later treatment ofpatients with advanced STS of any histologicsubtype. However, the chemosensitivity of STSto each of these drugs varies by histologic sub-type and their safety profiles differ; thus, histo-logic subtype and patient characteristics mustbe considered when determining optimaltreatment. In this article, we review data fromclinical studies related to the efficacy of all threedrugs, including their effect on OS, and proposeoptimal treatment strategies for advanced STSby histologic subtype. In addition, with regardto the safety profiles, we highlight the key issuesto be considered when selecting patients fortreatment with pazopanib, trabectedin, oreribulin and ensuring their appropriate use,based on our combined clinical experience asspecialists in the treatment of patients with STS.The proposed treatment strategies as well astreatment precautions based on clinical experi-ence would benefit patients by maximizing thetherapeutic effects and enhancing the properuse of these drugs.Funding: Eisai Co., Ltd.

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A. Kawai (&)Department of Musculoskeletal Oncology andRehabilitation Medicine, National Cancer CenterHospital, Tokyo, Japane-mail: akawai@ncc.go.jp

K. YonemoriDepartment of Breast and Medical Oncology,National Cancer Center Hospital, Tokyo, Japan

S. TakahashiDepartment of Medical Oncology, The CancerInstitute Hospital of Japanese Foundation forCancer Research, Tokyo, Japan

N. ArakiDepartment of Orthopaedic Surgery, OsakaPrefectural Hospital Organization, OsakaInternational Cancer Institute, Osaka, Japan

T. UedaDepartment of Orthopaedic Surgery, NationalHospital Organization, Osaka National Hospital,Osaka, Japan

Adv Ther (2017) 34:1556–1571

DOI 10.1007/s12325-017-0561-4

Keywords: Eribulin; Evidence-based medicine;Japan; Leiomyosarcoma; Liposarcoma; Optimaluse; Pazopanib; Proper use; Soft tissue sarcoma;Trabectedin

INTRODUCTION

Epidemiology of Soft Tissue Sarcoma

Soft tissue sarcoma (STS) is a rare tumor (lessthan 1% of all tumors) with an age-adjustedannual incidence of 2.8 per 100,000 people(World Health Organization world standardpopulation) [1] and an age-adjusted incidencerate of 2.40 per 100,000 person-years (based onUS data) [2]. In the USA, there are expected tobe 12,390 new cases of STS in 2017, resulting in4990 deaths [3]. In Japan, 1769 cases of STS wereregistered in 2015, and a 5-year overall survival(OS) of about 78% was reported [4] (these datawere collected by orthopedic surgeons only,which may explain differences from data fromother sources). STS can arise in almost anyanatomic site, including the extremities (60% ofcases), thorax, abdomen, retroperitoneum, andhead and neck region [5]. More than 50 histo-logic subtypes of STS, each with different treat-ment response and prognosis, have beenidentified and are defined in accordance withthe World Health Organization classification[6, 7]. The wide range of histologic subtypes ofSTS, and its occurrence at various sites, meansthat affected patients are treated by variousclinical departments; thus, it is difficult toobtain a general overview of STS.

Treatment outcomes for patients with STShave improved greatly over the past few dec-ades. This is attributable to the adoption of amultidisciplinary approach to management ofthe disease, including surgery, radiotherapy,and systemic therapy. However, the 5-year OSof STS patients taken as a whole remains about50%, which is far from satisfactory [5, 8]. This isbecause, although a 5-year OS of approximately90% is achieved in patients with early-stage STS,cases of unresectable tumor (which cannot becured by surgical removal), including thosewith locally advanced or metastatic disease atdiagnosis, have a particularly poor prognosis;

for these cases, the 5-year survival rate is only20–50% [5]. Therefore, treatment with anti-cancer drugs has been directed toward improv-ing OS.

Current Systemic Therapy for AdvancedSTS

In cases of unresectable and/or metastatic STS,i.e., advanced STS, anticancer drugs used infirst-line treatment include doxorubicin, ifos-famide, and dacarbazine; these are used alone orin combination to prolong OS [9–14]. Severalclinical studies have shown that combinationtherapy with doxorubicin and other anticancerdrugs can improve treatment response andprogression-free survival (PFS), but there is nosignificant difference from doxorubicinmonotherapy in OS [11–14]. Moreover, the useof combination therapy may be limited byadverse effects and reduced feasibility; thus,doxorubicin monotherapy is currently thestandard first-line treatment. Nevertheless, theEuropean Society for Medical Oncology guide-lines suggest that combination therapy includ-ing anthracyclines may be the treatment ofchoice in patients with good performance status[15]. Therefore, a combination of anticancerdrugs to achieve a good tumor response may beconsidered in patients with increased symptomsand decreased quality of life due to tumorgrowth.

Against this background, three new anti-cancer drugs—pazopanib, trabectedin, anderibulin—have been approved in Japan since2012 as second-line or later treatment optionsfor patients with advanced STS.

Objectives

Because STS is a rare tumor, can occurthroughout the body, and is treated by variousclinical departments, it is difficult for physiciansto gain sufficient clinical experience in itstreatment. Moreover, few comprehensivereviews are available to guide them in the use ofpazopanib, trabectedin, and eribulin. Therefore,in this article we aim to provide information oneach drug’s profile, appropriate target patients,

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and proper use of the drugs, which will even-tually lead to benefits for STS patients and forphysicians treating STS patients. We also aim tohighlight the key issues regarding treatmentstrategies and proper use of the three anticancerdrugs for the treatment of advanced STS, basedon our review of research conducted in accor-dance with evidence-based medicine and ourcombined clinical experience as sarcoma spe-cialists and oncologists.

METHODS

To achieve our stated objectives, we reviewedand discussed data from clinical studies ofpazopanib, trabectedin, and eribulin. Whenselecting prospective clinical studies, the levelof evidence was considered to avoid positionalbias and maintain objective impartiality. Inaccordance with our review criteria, fromreports published up to December 2016 ofclinical studies of the three drugs that enrolledpatients with advanced STS who had receivedprevious treatment, we used data from phase IIIstudies (highest evidence level), subgroup anal-yses of phase II and III studies according tohistologic subtype, and prospective clinicalstudies in Japanese. This article is based onpreviously conducted studies and does notinvolve any new studies of human or animalsubjects performed by any of the authors.

In the first section, ‘‘Review of Key Evi-dence’’, we assess the efficacy of each drug byusing data from the main analyses of the rele-vant phase III studies, which have the highestlevel of clinical evidence. In the second section,‘‘Review of Histologic Subtypes’’, we evaluatethe efficacy of each drug for different histologicsubtypes of STS. Because the numbers ofpatients with each histologic subtype werelimited and we aim to maximize the data col-lected, we reviewed the relevant data fromsubgroup analyses of both phase II and phase IIIstudies. In the third section, ‘‘Safety Considera-tions’’, we review the safety of each drug. Toinclude prospective information on safety ofeach drug in Japanese patients, we used safetydata from the phase III studies, subgroup anal-yses of data from Japanese patients included in

the international phase III study, and twophase II studies conducted in Japan. In addi-tion, we discuss the safety issues to be consid-ered when selecting patients for treatment withpazopanib, trabectedin, and eribulin, based onour combined clinical experience.

RESULTS

Review of Key Evidence

We reviewed data from the main analyses of thephase III studies of the three drugs [16–18]; theirefficacy is summarized in Table 1. The patientcharacteristics varied between the studies.Regarding the main histologic subtype, theproportions of patients with liposarcoma,leiomyosarcoma, and other histologic subtypeswere 0%, 44.7%, and 55.3%, respectively, in thephase III study of pazopanib; 27%, 73%, and0%, respectively, in the phase III study of tra-bectedin; and 33.8%, 65.7%, and less than 1%,respectively, in the phase III study of eribulin.Regarding the number of previous chemother-apy regimens for advanced STS defined in theinclusion criteria, for pazopanib the require-ment was at least one regimen containinganthracycline and a maximum of four previouslines of systemic therapy for metastatic disease(no more than two lines of combination regi-mens); for trabectedin, the requirement was atleast either a combination of an anthracyclineand ifosfamide or an anthracycline plus one ormore additional cytotoxic chemotherapy regi-men(s); for eribulin, the requirement was atleast two standard systemic regimens includingan anthracycline. All studies included patientswho had received the standard treatment forSTS, namely an anthracycline (e.g., doxoru-bicin)-containing regimen, and the mediannumber of previous chemotherapy regimens inthe three studies was two.

Impact of Prolonged Overall Survivalin Cancer Therapy

The aims of treatment for advanced STS are toreduce symptoms and prolong survival.

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Therefore, improvements in OS have a largeclinical impact, particularly in cases of recurrentSTS with a poor prognosis. Recent phase IIIstudies for cancer therapy tend to have OS asthe primary end point. In a phase III studydesigned to evaluate the new drug olaratumabas a first-line treatment option for advancedSTS, the primary end point is OS [19].

PazopanibThe PALETTE (PAzopanib expLorEd insofT-Tissue sarcoma—a phasE III study) trial wasan international, multicenter, randomized,double-blind, placebo-controlled phase III studydesigned to evaluate the clinical benefits ofpazopanib in patients with advanced STS [16].Patients with metastatic STS progressing despite

Table 1 Efficacy reported in phase III studies

Treatment Pazopanib Trabectedin Eribulin

Study PALETTE ET743-SAR-3007 E7389-G000-309

n 369 518 452

Previous chemotherapy

At least one regimen containing

anthracycline and a maximum of

four previous lines of systemic

therapy for metastatic disease (no

more than two lines of

combination regimens)

At least either a combination of an

anthracycline and ifosfamide or an

anthracycline plus one or more

additional cytotoxic chemotherapy

regimen(s)

At least two standard systemic regimens

including an anthracycline

Median numbers of previous

chemotherapy regimen2 2 2

Experimental

arm (n)

Comparator

arm (n)

Pazopanib

(246)Placebo (123)

Trabectedin

(345)Dacarbazine (173) Eribulin (228) Dacarbazine (224)

Primary end pointPFS OS OS

Met Unmet Met

Secondary end pointOS PFS PFS

Unmet Met Unmet

Histology Non-liposarcoma Liposarcoma, leiomyosarcoma Liposarcoma, leiomyosarcoma

OS

Median (months) 12.5 10.7 12.4 12.9 13.5 11.5

HR (95% CI) 0.86 (0.67–1.11) 0.87 0.77 (0.62–0.95)

P value 0.25a 0.37b 0.0169c

PFS

Median (months) 4.6 1.6 4.2 1.5 2.6 2.6

HR (95% CI) 0.31 (0.24–0.40) 0.55 (0.44–0.70) 0.88 (0.71–1.09)

P value < 0.0001a < 0.001b 0.23c

CI confidence interval, HR hazard ratio, OS overall survival, PFS progression-free survivala By two-sided stratified Wald testb By unstratified log-rank testc By two-sided stratified log-rank test

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previous standard chemotherapy (n = 369) wererandomized to either the pazopanib arm(800 mg orally once daily; n = 246) or the pla-cebo arm (n = 123) of the study in a ratio of 2:1.The primary end point was PFS, and the sec-ondary end points included OS. Median PFS was4.6 months in the pazopanib arm and1.6 months in the placebo arm, showing a sig-nificant improvement in PFS in the pazopanibarm (hazard ratio, HR 0.31; 95% confidenceinterval, CI 0.24–0.40; P\0.0001); however,there was no significant improvement in OS(HR 0.86; 95% CI 0.67–1.11; P = 0.25) (Table 1).Patients with liposarcoma were excluded fromthis phase III study, because the phase II studyshowed insufficient evidence for the efficacy ofpazopanib in the treatment of liposarcoma [20].

TrabectedinThe ET743-SAR-3007 trial was a multicenter,randomized, open-label, active-controlled, par-allel-group, phase III study designed to evaluatethe clinical benefits of trabectedin in patientswith advanced STS [17]. Patients with locallyadvanced or metastatic STS after previous ther-apy with an anthracycline and at least oneadditional systemic regimen (n = 518) wererandomized to either the trabectedin arm(n = 345) or the dacarbazine arm (n = 173) ofthe study in a ratio of 2:1. In the trabectedinarm, trabectedin (1.5 mg/m2) was administeredas a 24-h intravenous infusion, whereas in thedacarbazine arm, dacarbazine (1 g/m2) wasadministered by intravenous infusion over20–120 min. In each arm, the study drug wasadministered on day 1 of every 21-day cycle. OSwas the primary end point, and PFS was a sec-ondary end point. PFS was significantlyimproved in the trabectedin arm comparedwith the dacarbazine arm (median PFS, 4.2versus 1.5 months; HR 0.55; 95% CI 0.44–0.70;P\0.001); however, interim analysis showedno improvement in OS, the primary end point(HR 0.87; P = 0.37) (Table 1). One reason for thenon-significant result for OS may be the effectof the active comparator, dacarbazine [17].

It should be noted that the approved dose oftrabectedin in Japan is different from that in theUSA and Europe; the approved dose in Japan,1.2 mg/m2, which was used in the

ET743-SAR-3007 phase III study, is lower thanthe 1.5 mg/m2 dose used in other countries. Theapproved dose in Japan is based on the results ofa phase I study in Japanese advanced STSpatients who had received treatment with atleast one anthracycline-based regimen [21].Dose-limiting toxicity was experienced by twoof three patients who received trabectedin at adose of 1.5 mg/m2; one had grade 3 increasedcreatine phosphokinase and grade 3 anorexia,and the other had grade 4 decreased plateletcount.

EribulinThe phase III E7389-G000-309 trial was con-ducted as a multicenter, open-label,active-controlled, parallel-group study to eval-uate the clinical benefits of eribulin in patientswith advanced STS [18]. Patients with locallyrecurrent, locally advanced, or metastatic STSwho had received treatment with systemic reg-imens including an anthracycline (n = 452)were randomized to either the eribulin arm(n = 228) or the dacarbazine arm (n = 224) in aratio of 1:1. In the eribulin arm, eribulin mesy-late (1.4 mg/m2) was administered as an intra-venous infusion over 2–5 min on days 1 and 8of every 21-day cycle, whereas in the dacar-bazine arm, dacarbazine (850, 1000, or1200 mg/m2) was administered as an intra-venous infusion over 15–60 min on day 1 ofevery 21-day cycle. The primary end point wasOS, and the secondary end points included PFS.OS was significantly improved in the eribulinarm compared with the dacarbazine arm (me-dian OS, 13.5 versus 11.5 months; HR 0.77; 95%CI 0.62–0.95; P = 0.0169); however, there wasno significant difference between the two armsin the secondary end point of PFS (HR 0.88; 95%CI 0.71–1.09; P = 0.23) (Table 1).

Review of Histologic Subtypes

In the treatment of advanced STS, it is necessaryto choose an anticancer drug that is effectiveagainst the specific histologic subtype. How-ever, because STS is a rare tumor, it is difficult toprospectively accumulate clinical data frompatients with different histologic subtypes to

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evaluate the efficacy of particular drugs againsteach subtype. Therefore, the findings of sub-group analyses by histologic subtype should betaken into account when deciding which drugto use in clinical practice. The chemosensitivityof each histologic subtype to anticancer drugsmust also be considered. Therefore, in this sec-tion, we review subgroup analyses of data fromthe phase III studies [16–18] and phase II studies[20, 22] of pazopanib, trabectedin, and eribulin,and propose treatment strategies for advancedSTS.

Chemosensitivity of Different HistologicSubtypes of STSThe chemosensitivity of each histologic subtypeto anticancer drugs is described in UK guidelinesfor the management of STS [23] and in an articlesummarizing the opinions of internationalexperts regarding patient-tailored managementof STS [24]. On the basis of this information andour combined clinical experience, we examinedthe treatment for each histologic subtype, andlist the primary drugs of choice and substitutiondrugs of choice in Table 2.

LiposarcomaIn the international multicenter phase III studyof pazopanib [16], patients with liposarcomawere not included in the study. This is becausein the phase II study [20], the primary endpoint, namely progression-free rate at 12 weeks(PFR12 weeks), was 26%, which was lower thanthe 44% value for leiomyosarcoma, 49% forsynovial sarcoma, and 39% for other types ofSTS, as well as the benchmark value of PFR12 -

weeks (40%); this last value was used as theminimum at which an anticancer drug can beconsidered effective as a second-line treatmentfor STS in phase II studies, based on informationfrom a database of clinical studies includingdata from patients with various subtypes of STS[25]. Therefore, current evidence suggests thateribulin and trabectedin are preferable to pazo-panib for the treatment of liposarcoma.

Subgroup analysis by histologic subtype,using data from a phase III study, has showntrabectedin to be effective in terms ofimprovement in PFS for patients with myxoid/

round-cell liposarcoma (HR 0.41; 95% CI0.17–0.98) [17]. The effect of trabectedin onthese subtypes was also shown in a randomized,phase II study in Japanese patients withtranslocation-related sarcoma (HR 0.03; 95% CI\0.01–0.22) [22].

Subgroup analysis by histologic subtype,using data from a phase III study (theE7389-G000-309 trial), has shown eribulin to beeffective in terms of improvement in OS forpatients with liposarcoma (HR 0.51; 95% CI0.35–0.75) [18]. Therefore, eribulin can beexpected to improve OS in patients withliposarcoma. Further analyses showed eribulinto be effective for patients with dedifferentiatedliposarcoma (HR 0.45; 95% CI 0.25–0.82) andpleomorphic liposarcoma (HR 0.21; 95% CI0.06–0.76) [26].

On the basis of the above information, wepropose the treatment strategy for liposarcomashown in Fig. 1. Eribulin may be the optimaltreatment option for liposarcoma, particularlydedifferentiated liposarcoma and pleomorphicliposarcoma after doxorubicin treatment.Trabectedin may be the first option for myxoid/round-cell liposarcoma after doxorubicin treat-ment. Also, either eribulin or trabectedin can beused for each liposarcoma, depending on con-ditions such as safety issues and method ofadministration (for inpatients or outpatients).

LeiomyosarcomaPatients with leiomyosarcoma made up thegreatest proportion (44.7%) of the study popu-lation in the international phase III study ofpazopanib [16], in which the primary end pointof PFS was met. Subgroup analysis by histologicsubtype, as well as predictive analysis for his-tology subtype using Cox models, showedpazopanib to be effective for leiomyosarcoma interms of PFS [16].

In the phase III study of trabectedin, patientswith leiomyosarcoma made up the greatest pro-portion (73%) of the study population, and theprimary end point of OS was not met [17]; how-ever, trabectedin treatment resulted in similarOScompared with dacarbazine (the active com-parator).On theotherhand, subgroupanalysis ofdata for the secondary end point (PFS) showed animprovement with trabectedin compared with

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dacarbazine (HR 0.55; 95% CI 0.42–0.73). Thisfinding suggests that trabectedin may be usefulin improving PFS.

In the phase III study of eribulin [18],patients with leiomyosarcoma made up thegreatest proportion (65.7%) of the study

Table 2 Chemosensitivity of different histologic subtypes of soft tissue sarcoma and treatment options

Histologic subtype Relative chemosensitivity Primary drug(s) of choice Substitution drug(s) of choice

Liposarcoma

Myxoid / round-cell liposarcoma Chemosensitive DXRTrabectedin, IFM/IFM + DXR,

eribulin

Pleomorphic liposarcoma Moderately chemosensitive DXRIFM, eribulin, trabectedin, GEMa,

DTICa

Dedifferentiated liposarcoma Moderately chemosensitive DXR IFM, eribulin, trabectedin

Well-differentiated liposarcoma Chemoresistant – –

Leiomyosarcoma

Uterine leiomyosarcomaModerately chemosensitive DXR

GEMa + DTXa, IFM, eribulin,

pazopanib, trabectedinNon-uterine leiomyosarcoma

Other types

RhabdomyosarcomaChemotherapy integral to

management

VAC or VAI/VIE regimen

Ewing sarcoma VDC/IE or VAIA regimen

Synovial sarcoma Chemosensitive IFM, DXRDTICa, eribulin, pazopanib,

trabectedin

Epithelioid sarcoma

Moderately chemosensitive

DXRIFM, eribulin, pazopanib,

trabectedin

Myxofibrosarcoma DXRDTICa, eribulin, pazopanib,

trabectedin

Fibrosarcoma DXRDTICa, GEMa, eribulin, pazopanib,

trabectedin

Angiosarcoma DXR, PTXIFM, GEMa, eribulin, trabectedin,

pazopanib

Alveolar soft part sarcoma

Chemoresistant

Sunitiniba Pazopanib

Clear cell sarcoma– –

Extraskeletal myxoid chondrosarcoma

DTIC dacarbazine, DTX docetaxel, DXR doxorubicin, GEM gemcitabine, IFM ifosfamide, PTX paclitaxel, VAC vincristine,actinomycin D, and cyclophosphamide, VAI vincristine, actinomycin D, and ifosfamide, VAIA vincristine, doxorubicin,ifosfamide, and actinomycin D, VDC/IE vincristine, doxorubicin, cyclophosphamide, and ifosfamide and etoposide, VIEvincristine, ifosfamide, and etoposidea Not approved for the treatment of STS in Japan

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Fig. 1 Treatment strategies for advanced STS in clinical practice. aNot approved for the treatment of STS in Japan. DTICdacarbazine, DXR doxorubicin, GEM gemcitabine, DTX docetaxel

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population, and the primary end point of OSwas met for the overall population. Subgroupanalysis by histologic subtype of the data for OSshowed the effect of eribulin on leiomyosar-coma to be similar to that of dacarbazine (HR0.93; 95% CI 0.71–1.20). This is thought to bebecause dacarbazine, known to be effective forpatients with leiomyosarcoma [27], was theactive comparator. Therefore, eribulin isdeemed to be similarly effective to dacarbazinefor patients with leiomyosarcoma. Our pro-posed strategy for the treatment of leiomyosar-coma based on the above information is shownin Fig. 1.

Safety Considerations

The selection of patients for treatment with anyanticancer drug is based not only on consider-ations of efficacy but also on considerations ofsafety of the drug. Safety information frompreapproval clinical studies is based on safetydata from the limited patients selected inaccordance with the inclusion criteria. How-ever, in clinical practice, STS patients have morevaried baseline characteristics, and some havepoor performance status and decreased organfunction. Therefore, the information obtainedfrom clinical studies should be supplementedby expert opinions from specialists with appro-priate clinical experience.

In this section, we review the results of thesafety analyses from the phase III studies ofpazopanib, trabectedin, and eribulin [16–18]; asubgroup analysis of Japanese patients in thephase III study of pazopanib [28]; Japanesephase II studies of trabectedin and eribulin[22, 29]; and the Japanese package insert foreach drug [30–32]. We summarize the safetyprecautions that should be considered whenselecting patients for treatment with thesedrugs in clinical practice, taking into accountthe administration methods for each drug andour combined clinical experience.

The main safety issues to be considered whenselecting patients for treatment with pazopanib,trabectedin, and eribulin are summarized inTable 3. The safety profile of each drug shouldbe considered in addition to its efficacy, and

appropriate follow-up should be carried outafter administration. Moreover, apart from theadverse events listed here, any potential safetyissues should be addressed carefully, and treat-ment should be individualized according to theclinical condition of each patient.

PazopanibIn both the international phase III study ofpazopanib [16] and the associated subgroupanalysis of data from Japanese patients [28], liverdysfunction was reported as an adverse event. Inthe pazopanib arm of the overall population(n = 240) and in the Japanese subgroup (n = 31),the incidence of increased alanine aminotrans-ferase (ALT) (all grades) was 46% and 52%,respectively; the incidence of increased aspartateaminotransferase (AST) was 51% and 65%,respectively; and the incidence of increased totalbilirubin was 29% and 42%, respectively [28].Therefore, liver function should be monitoredbefore and during treatment.

In the phase III study, pneumothorax occur-red in 3% of patients (8/240) in the pazopanibarm [16], but there were no occurrences in theJapanese subgroup [28]. However, in apost-marketing report based on data from Japa-nese patients, the prevalence of pneumothoraxwas reported to be 10.3% (6/58 patients) [33];therefore, physicians should be aware of thepossible onset or worsening of pneumothorax,particularly in patients with lung metastases.

Because the mechanism of action of pazo-panib includes antiangiogenic effects [34],hemorrhage is possible in patients with brainmetastases. Therefore, safety informationshould be provided and explained to patientsbefore administration of this drug.

The Japanese package insert for pazopanibstates that patients with risk factors for cardiacdysfunction may have exacerbation of symp-toms [30]. Anthracyclines such as doxorubicin,which have cardiotoxic effects, may be used asfirst-line treatment for advanced STS; thus,caution is required when pazopanib is used asthe second-line treatment.

In the phase III study, hypertension (grade 3or higher) occurred in the pazopanib arm, inboth the overall population (grade 3, 7%;

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grade 4, 0%) and the Japanese subgroup(grade 3, 16%; grade 4, 0%) [28]. However, pro-tocols for the management of hypertensionhave been established; thus, control of associ-ated symptoms should be possible in patientswho experience hypertension as an adverse

effect of pazopanib. Safety information shouldbe provided to patients before administration ofthe drug, and appropriate monitoring of bloodpressure during treatment is essential.

In the pazopanib arm of the phase III study,grade 3 or higher fatigue was reported in less

Table 3 Major safety issues to be considered when selecting patients for treatment with pazopanib, trabectedin, and eribulin,based on expert opinion

a Based on expert opinion; information was obtained from the package inserts of each drug (sections such as warnings,contraindications, and careful administration)

Adv Ther (2017) 34:1556–1571 1565

than 14% and in 3% of patients in the overallpopulation and the Japanese subgroup, respec-tively; and grade 3 or higher diarrhea in 5% and6%, respectively [28]. These adverse effects arereadily recognized by patients, but the symp-toms are difficult to control. No management offatigue has been established, and it may becomenecessary to reduce the dosage of pazopanib inpatients experiencing this adverse effect.Regarding diarrhea, if symptoms fail to improvewith supportive care, interruption or reductionof dosage is necessary.

In regard to the administration of pazopanib,the oral route is convenient for patients.

TrabectedinAbnormal changes in laboratory test valuesassociated with bone marrow suppression wererecorded in the clinical studies of trabectedin.In the trabectedin arm (n = 340) of the phase IIIstudy, neutropenia (grade 3, 21%; grade 4, 16%)and anemia (grade 3, 14%; grade 4, 0%) werereported [17]. In the trabectedin arm (n = 36) ofthe Japanese phase II study, neutropenia(grade 3, 31%; grade 4, 36%), leukopenia(grade 3, 31%; grade 4, 25%), thrombocytope-nia (grade 3, 11%; grade 4, 6%), lymphopenia(grade 3, 19%; grade 4, 3%), and anemia (grade3, 19%; grade 4, 0%) were reported [22].Therefore, blood tests and careful examinationof patients for the presence of infection shouldbe carried out before administration of tra-bectedin; regular blood tests are also requiredduring treatment.

Febrile neutropenia (grade 3, 11%; grade 4,3%) was reported in the trabectedin arm of theJapanese phase II study [22].

Abnormal changes in laboratory test valuesassociated with liver dysfunction were alsorecorded in the clinical studies of trabectedin.In the trabectedin arm of the phase III study,increased ALT (grade 3, 25%; grade 4, 1%),increased AST (grade 3, 12%; grade 4, 1%), andincreased alkaline phosphatase (ALP) (grade 3,1%; grade 4, 0%) were reported [17]. In thetrabectedin arm of the Japanese phase II study,increased ALT (grade 3, 47%; grade 4, 14%),increased AST (grade 3, 33%; grade 4, 8%),increased gamma-glutamyltransferase (grade 3,22%; grade 4, 3%), and increased ALP (grade 3,

6%; grade 4, 0%) were reported [22]. In the samestudy, grade 1 or 2 increased blood bilirubin(11%) was also reported in the trabectedin arm[22]. In clinical practice, we have encounteredserious cases of liver dysfunction in patientstreated with trabectedin. Therefore, monitoringof liver function is required in these patients,both before and during treatment.

As with pazopanib, trabectedin may alsocause the onset or worsening of cardiac dys-function when administered to patients with ahistory of treatment with anthracycline drugsand those with cardiac dysfunction. Beforeadministration of trabectedin, patients arelikely to have a history of treatment with dox-orubicin, which has cardiotoxic effects; there-fore particular caution is required.

Rhabdomyolysis (grade 4, 3%) and increasedcreatine phosphokinase (grade 3, 6%; grade 4,0%) were reported in the trabectedin arm of theJapanese phase II study [22], and we haveencountered serious cases in trabectedin-treatedpatients in clinical practice. In addition to vig-ilance for the initial symptoms (e.g., muscularpain and weakness), monitoring is required forincreased creatine phosphokinase or increasedblood or urinary myoglobin concentration.Appropriate management, including discontin-uation of treatment, should be taken if patientshad abnormal changes in these values, andphysicians and medical staff should be aware ofthis before the start of treatment.

Fatigue of grade 3 or higher was reported in6% and 3% of patients in the trabectedin arm ofthe phase III study and the Japanese phase IIstudy, respectively.

Because trabectedin is administered by 24-hintravenous infusion using a central venouscatheter or port, hospitalization is required.Tissue necrosis may occur, and extravasation isa concern. If extravasation occurs, the admin-istration of trabectedin should be interruptedimmediately; medical staff should be aware ofthis measure.

EribulinAbnormal changes in laboratory test valuesassociated with bone marrow suppression wererecorded in the clinical studies of eribulin. Inthe phase III study (eribulin arm, n = 226),

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neutropenia (grade 3, 20%; grade 4, 15%),leukopenia (grade 3, 8%; grade 4, 2%), andthrombocytopenia (grade 3,\1%; grade 4, 0%)were reported [18]. In the Japanese phase IIstudy (n = 51), neutropenia (grade C3, 86%),leukopenia (grade C3, 75%), lymphopenia(grade C3, 33%), anemia (grade C3, 14%), andfebrile neutropenia (grade C3, 8%) were repor-ted [29]. The incidence of adverse events asso-ciated with bone marrow suppression reportedin the clinical studies of eribulin was lower thanin those of trabectedin [17, 22], although directcomparison of safety data is difficult because ofthe different background characteristics of thepatients in these studies. However, close exam-ination for signs of bone marrow suppression isstill required before administration of eribulin,as well as appropriate monitoring after admin-istration, because bone marrow suppression canaffect vital functions. The incidence of febrileneutropenia was higher in the Japanese phase IIstudy [29] than the phase III study [18]. How-ever, the overall incidence of febrile neutrope-nia was less than 10% in both studies.

Abnormal changes in laboratory test valuesassociated with liver dysfunction were recordedin the Japanese phase II study, namely ALTincrease (grade C3, 6%) and AST increase (gradeC3, 4%) [29]. In clinical practice, we have notencountered any serious cases of liver dysfunc-tion in patients treated with eribulin; however,it is essential to assess liver function before itsadministration.

In the phase III study of eribulin, grade 3 orhigher peripheral sensory neuropathy (grade 3,2%; grade 4, 0%)was recorded in the eribulin arm[18]. In contrast, in the Japanese phase II study,the severity of peripheral sensory neuropathywas grade 1 and 2 [29]. The likelihood of theonset of peripheral sensory neuropathy dependslargely on previous treatment; therefore, cautionis required in patients previously treated withdrugs such as vincristine that cause peripheralsensory neuropathy. However, vincristine isgenerally administered to young children withrhabdomyosarcoma; therefore, its target patientsdiffer from those of eribulin. However, asperipheral sensory neuropathy may occur as aresult of cumulative toxicity, caution is requiredin the long-term administration of eribulin.

Overall, we consider that the toxicities oferibulin are manageable, and that managementof adverse effects of eribulin is relativelystraightforward on the basis of our experience.

Eribulin needs to be administered by intra-venous infusion. However, as this takes only2–5 min, it is possible to administer the drug inan outpatient visit.

DISCUSSION

In light of new treatment options that havebeen developed with the aim of improving OSin patients with advanced STS, we propose inthis article an optimal treatment approach tothe use of pazopanib, trabectedin, and eribulinbased on current evidence from the relevantclinical studies. In addition, regarding the safetyprofiles of each drug, the review of clinical studydata and our experience in clinical practice maybe useful for the selection of appropriatepatients for treatment with these drugs. Theprimary end points of pivotal studies were usedin this article. However, because the primaryend point of trabectedin and eribulin was OS,and that of pazopanib was PFS, the results ofthese studies were not directly comparable. Forthis reason, in this article we have described, inan objective manner, the characteristics of thesedrugs.

In Japan, pazopanib, trabectedin, and eribu-lin can be used for all histologic subtypes of STS.However, each drug has a different profile. Forthe proper use of these drugs, and to maximizetheir benefit to patients, it is necessary tounderstand the efficacy and safety profiles ofeach drug, and to provide treatment in accor-dance with evidence-based medicine. Toachieve these objectives in clinical practice,first, anticancer drugs should be selectedaccording to their sensitivity to histologic sub-types and safety profile on the basis of thefindings of clinical trials, as described in thisarticle. In addition, consideration of expertopinions based on clinical experience is rec-ommended. For instance, when choosing ananticancer drug for second-line treatment ofliposarcoma and leiomyosarcoma, in additionto the clinical evidence, safety issues such as the

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onset or worsening of cardiac dysfunctioncaused by doxorubicin should be considered.Furthermore, retrospective studies from Japanhave shown the inferior efficacy of pazopanib inthe treatment of liposarcoma compared withother subtypes [35, 36]. Ifosfamide can also bean option for second-line and later treatmentfor metastatic STS, especially in cases offibrosarcoma and synovial sarcoma. However,the response rate for leiomyosarcoma has beenshown to be lower than for fibrosarcoma andsynovial sarcoma [37–39]. In addition, thistreatment requires hospitalization, and atten-tion should be paid to the possibility of renaldysfunction. The efficacy of gemcitabine, givenalone or in combination with other drugs, hasbeen studied. In a randomized phase II study inpatients with metastatic soft tissue sarcoma, thecombination of gemcitabine and docetaxelresulted in superior PFS and OS compared withgemcitabine alone, but with increased toxicity[40]. However, the combination regimens ofgemcitabine with dacarbazine or vinorelbinehave not been approved in Japan.

For other histologic subtypes, pazopanibmay be effective for synovial sarcoma on thebasis of the results of the subgroup analysis ofthe international phase III study, although thenumber of patients was limited (n = 30) [16].Predictive analysis, using Cox models, of PFSaccording to histologic subtype also showed theeffectiveness of pazopanib against synovial sar-coma, with no significant interaction betweenhistologic subtypes [16]. The number of STSpatients with histologic subtypes other thanliposarcoma and leiomyosarcoma is small, andit is therefore difficult to evaluate the efficacy ofeach drug in clinical studies. The phase IIIstudies of trabectedin and eribulin includedpatients with leiomyosarcoma and liposarcomabut not undifferentiated pleomorphic sarcoma[17, 18]. In contrast, the phase III study ofpazopanib included patients with undifferenti-ated pleomorphic sarcoma [16]. Therefore, it isinappropriate to discuss in this article thetreatment of undifferentiated pleomorphic sar-comas. The phase II studies of pazopanib, tra-bectedin, and eribulin included patients withundifferentiated pleomorphic sarcoma, but thedata are insufficient to enable us to make

specific recommendations for treatment[20, 29, 41, 42]. A more practical approach toevaluation of the effectiveness of pazopanib,trabectedin, and eribulin against specific histo-logic subtypes of STS is recommended, namelyto generate evidence by obtaining clinical dataretrospectively. For example, the JapaneseMusculoskeletal Oncology Group have con-ducted a study to evaluate the effects of pazo-panib in Japanese STS patients, based on safetydata gathered by post-marketing surveillanceand efficacy data obtained at the study groupsites [35]. It is expected to accumulate real-world data including information on varioushistologic subtypes.

To provide more effective treatment, it ispreferable to identify biomarkers. Trabectedinhas been shown to reduce the risk of progressivedisease or death in patients with advancedtranslocation-related sarcoma [22]. In addition,tumor biomarkers for safety and efficacy endpoints have been incorporated into the phase IIIstudy of eribulin as a planned exploratory anal-ysis [18]; the results are awaited with interest.

It may be necessary in future clinical studiesto evaluate sequential therapy, for example theefficacy in terms of OS of trabectedin aftereribulin or OS of eribulin after trabectedin inthe treatment of liposarcoma. In a phase IIIstudy, eribulin monotherapy resulted in nosignificant difference in PFS but significantlyimproved OS compared with dacarbazine, sug-gesting that eribulin might have induced bio-logical effects on tumor vascularization,microenvironment, and metastasis [18].

We have proposed treatment strategies foradvanced STS by histologic subtype as well assafety considerations based on our clinicalexperience in the use of pazopanib, trabectedin,and eribulin. These would benefit patients bymaximizing the therapeutic effects andenhancing the proper use of these drugs.

ACKNOWLEDGEMENTS

Sponsorship for this article, including process-ing charges, was funded by Eisai Co., Ltd(Tokyo, Japan).

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All named authors meet the InternationalCommittee of Medical Journal Editors (ICMJE)criteria for authorship for this manuscript, takeresponsibility for the integrity of the work as awhole, and have given final approval for theversion to be published. All authors had fullaccess to all of the data in this study and takecomplete responsibility for the integrity of thedata and accuracy of the data analysis.

Medical writing assistance was provided byHiroki Matsushita of ShiftZero K.K. (Tokyo,Japan) and editorial assistance was provided byRie Ishibashi on behalf of inScience Commu-nications, Springer Healthcare (Tokyo, Japan).Support for these assistances was funded byEisai Co., Ltd.

Disclosures. Akira Kawai has receivedhonoraria for serving as an advisory boardmember for Novartis Pharma K.K., TaihoPharmaceutical Co., Ltd., Eisai Co., Ltd., andEli Lilly Japan K.K. Kan Yonemori has receivedspeakers’ honoraria from Eisai Co., Ltd., TaihoPharmaceutical Co., Ltd., and NovartisPharma K.K. Shunji Takahashi has receivedresearch funding and speakers’ honoraria fromTaiho Pharmaceutical Co., Ltd., Eisai Co.,Ltd., and Novartis Pharma K.K. NobuhitoAraki has received speakers’ honoraria andresearch funding from Taiho PharmaceuticalCo., Ltd. Takafumi Ueda serves as a chieforganizer of the Japanese MusculoskeletalOncology Group and received research fund-ing from Novartis Pharma K.K., receivedhonoraria for serving as speaker and advisoryboard member for Taiho Pharmaceutical Co.,Ltd., and received research funding andhonoraria for serving as an advisory boardmember and a speaker from Eisai Co., Ltd.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not involve any new studies of humanor animal subjects performed by any of theauthors.

Data Availability. Data sharing is notapplicable to this article, because no datasetswere generated or analyzed in the course of ourresearch.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

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