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Trabectedin in the Neoadjuvant Treatment of High-Grade Pleomorphic Sarcoma: Report of a Rare Case and Literature Review

Trabectedin in the Neoadjuvant Treatment of High-Grade Pleomorphic Sarcoma: Report of a Rare Case... HindawiPublishingCorporation CaseReportsinOncologicalMedicine Volume2013,ArticleID320797,5pages http://dx.doi.org/10.1155/2013/320797 CaseReport TrabectedinintheNeoadjuvantTreatmentof High-GradePleomorphicSarcoma:ReportofaRareCaseand LiteratureReview 1 1 2 3 MarkusK.Schuler, StephanRichter, IvanPlatzek, BettinaBeuthien-Baumann, 4 5 6 1 KathrinWieczorek, ChristineHamann, JohannesMohm, andGerhardEhninger DepartmentofInternalMedicineI,UniversityHospitalCarlGustavCarus,DresdenUniversityofTechnology, 01307Dresden,Germany DepartmentofRadiology,UniversityHospitalCarlGustavCarus,DresdenUniversityofTechnology,01307Dresden,Germany DepartmentofNuclearMedicine,UniversityHospitalCarlGustavCarus,DresdenUniversityofTechnology,01307Dresden,Germany DepartmentofPathology,UniversityHospitalCarlGustavCarus,DresdenUniversityofTechnology,01307Dresden,Germany DepartmentofOrthopaedics,UniversityHospitalCarlGustavCarus,DresdenUniversityofTechnology,01307Dresden,Germany Hämatologisch-OnkologischePraxis,Dresden,Germany CorrespondenceshouldbeaddressedtoMarkusK.Schuler;markus.schuler@uniklinikum-dresden.de Received6December2012;Accepted31December2012 AcademicEditors:D.V.Jones,F.A.Mauri,andJ.I.Mayordomo Copyright©2013MarkusK.Schuleretal. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background.Pleomorphicsarcomaisanaggressivesotissuesarcoma.Inpatientswithhigh-riskextremitysarcomas,thesigni�cant survivalbene�tsconferredbyanintenseregimenofneoadjuvantchemoradiotherapyandsurgerywerereported.Toourknowledge, this is the �rst report in the literature of the neoadjuvant use of trabectedin in a patient with high-grade pleomorphic sarcoma, ineligibleforstandardneoadjuvantcombinationtherapywithananthracycline-basedregimen.CasePresentation.Herewepresent a58-year-oldWhitemalewithalargetumorinthelethigh,butwithnosignsofmetastases.Owingtothehistoryofsevereheart attack, three cycles of neoadjuvant trabectedin were administrated to achieve surgically wide margins. Aer two cycles, an 18F- FDG-PET showed a large proportion of the central tumor area was without metabolic activity. According to RECIST and Choi criteria, the tumor was stable. Aer the third cycle of trabectedin, the patient underwent a complete resection, which revealed completelynecrotichigh-gradepleomorphicsarcoma(stagepT2b),withonlyasmallvitalarea.Conclusion.epresentpaperon a promising treatment with neoadjuvant trabectedin of patients with high-grade pleomorphic sarcoma might suggest that such treatmentapproachmayprovideagreaterchanceofcureandsurvivalofsuchpatients. 1.Background inthishighlymalignantdisease.Mullenandcolleagueshave reported the signi�cant survival bene�ts in patients with e high-risk stage III so tissue sarcomas (STS) are a het- high-risk, extremity STS who received an intense regimen erogeneousgroupofrelativelyraremesenchymalneoplasms ofneoadjuvant chemoradiotherapy with concomitant radio- with important differences in chemosensitivity. e use of therapy [1]. Another prospective phase II trial by Kraybill chemotherapy in the neoadjuvant and adjuvant settings in et al. demonstrated a comparably good outcome with an STS is controversial. When preoperative chemotherapy is overall survival of 71% aer 5 years in patients with high- used, tumor responses can result in clinically meaningful grade,high-riskSTStreatedwithneoadjuvantchemotherapy, tumor shrinkage prior to surgery and, thus, may facilitate preoperative radiotherapy, and adjuvant chemotherapy [2]. subsequent surgical resection. Nowadays there are some Meta-analysis found a signi�cant advantage in relapse-free piecesofevidencefortheuseofperioperativechemotherapy 2 CaseReportsinOncologicalMedicine andoverallsurvival.Nevertheless,inlightofmissingprospec- application of systemic therapy, consecutively leading to an tiverandomizedtrialsshowingareproduciblebene�titisstill undertreatmentofhigh-riskpatients. a matter of debate which patients will have a bene�t from Herein we present the results of the neoadjuvant use of trabectedin in a patient with high-grade pleomorphic this approach. Besides, apart from certain entities, such as myxoidliposarcoma,nohistology-driventrialshaveyetbeen sarcoma, ineligible for standard neoadjuvant combination performed [3, 4]. erefore, there is still lacking evidence therapywithananthracycline-basedregimen. for the use of chemotherapy in the neoadjuvant setting in patientswithSTS. 2.CaseReport Treatment guidelines of sarcoma research and treatment organizations so far recommend a shared decision-making A58-year-oldWhitemalepresentedwithalargetumorinthe process considering among others patients age, tumor- lethigh.epatienthadahistoryofseverecardiacproblems subtype,grading,andsize[5].AccordingtoaFrenchanalysis with myocardial infarction two years before diagnosis and especially patients with grade 3 tumors might bene�t from consecutivelyunderwentprophylacticde�brillatorimplanta- adjuvantchemotherapy[6]. tion,havinganejectionfractionof45%aersurgery.Across- To date, the standard for perioperative chemotherapy sectionalimagingshowedanapproximately30×14×11cm is combining anthracycline with high-dose ifosfamide [5, lobulatedtumor.Stagingwascompletedwithacomputerized 7]. is regimen is quite toxic and not applicable to a tomography (CT) scan of the chest and abdomen and signi�cant proportion of elderly and frail people. erefore, a �uorine-18 �uorodeoxyglucose (FDG)-positron emission thesepatientscannotbetreatedinaperioperativeway,since tomography (PET) scan. is scan con�rmed the presence lesstoxicregimenshavenotyetbeenevaluated. of the mass and revealed an increased FDG uptake with a Trabectedin(Yondelis)isamarine-derivedantineoplastic maximal standardized uptake value of 10.5 in the proximal compoundisolatedfromtheCaribbeantunicateEcteinascid- region. No metastases were detected. Incision biopsy �nally ia turbinata and currently produced synthetically [8]. Tra- con�rmed a high-grade sarcoma without distinct classi�ca- bectedinisapprovedintheEuropeanUnionandmanyother tion.Microscopic�ndingsdiscoveredupto10mitosesin10 countriesworldwideforthetreatmentofadvancedSTSaer high-power�elds(HPF)anda30%necrosis. the failure of anthracyclines and ifosfamide or for patients Neoadjuvant chemotherapy was recommended in order who are unsuited to receive these agents. It has a unique to achieve surgically wide margins. Because of the his- mechanism of action based on interaction with the minor tory of severe heart attack, the patient was unsuited to grooveoftheDNAdouble helix, which triggers a cascade of receive anthracycline-based chemotherapy. As an individual events that interfere with several transcription factors, DNA approach with the patient, trabectedin was chosen for the bindingproteinsandDNArepairpathways,resultinginG2- patient-tailored treatment. ree cycles of trabectedin were M cell cycle arrest and ultimately apoptosis [9]. Moreover, given on day 1 every 3 weeks at the dose of 1.5mg/m body trabectedin at therapeutic concentrations has selective anti- surface area, administered as an intravenous infusion over in�ammatory and immunomodulatory properties on tumor 24hours.Aertwocycles,an18F-FDG-PETwasperformed, microenvironment as it decreases the production of factors showingnosigni�cantdecreaseinstandardizeduptakevalue potentiallyrelevantfortumorgrowth,progression,angiogen- (SUV)inthehyper-metabolicregionsofthetumor:maximal esis, and metastasization. In particular, the in vitro produc- SUVwas9.5versus10.5intheproximaland4.4versus5.2in tionofproin�ammatorymediators,suchasinterleukin-6(IL- the distal tumor (Figure 1). However, a large proportion of 6)andCCL2,wasmarkedlydownregulatedbytrabectedinin the central tumor area showed no metabolic activity. When circulating monocytes, macrophages, and tumor-associated applying the response evaluation criteria in solid tumors macrophages(TAM)fromhumantumors[9–11].erefore, (RECIST)andtheChoicriteria(Figure2)totheCTscan,the the mechanism of action of trabectedin has dual effect: it tumorwasstable.Ananalysisoftumorvolumetricrevealeda actsnotonly ontumorgrowthbutalsoontumorimmune 3 3 35%decrease(from956cm to621cm )ofthetumormass. in�ammation and angiogenesis, providing a consolidated Aer three cycles of trabectedin the patient was referred therapeuticapproachasamultitargetdrug. to resection. e postoperative classi�cation aer complete Trabectedin shows nearly similar response rates in resection of the femur was stage pT2b high-grade pleo- leiomyosarcoma and liposarcomas (L-sarcomas) as those morphic sarcoma with 0.5cm negative margins towards the in combination-therapies and by far is less toxic [12]. acetabulum. e only vital tumor area was in the dorso- In addition, trabectedin was generally well tolerated and cranialareawithviabilityof15%,whileallotherpartsshowed showed manageable toxicity when administered to patients acompletenecrosis(Figure3). with myxoid liposarcoma as neoadjuvant chemotherapy [3]. Based on these �ndings, a neoadjuvant treatment strategy with trabectedin could be extremely bene�cial for those 3.LiteratureReview patients,especiallythosewhoarenoteligibleforanaggressive combination therapy. Apart from its potential local and In a former phase II clinical trial three of 23 patients with systemicbene�t,trabectedintreatmentpriortosurgerycould myxoid liposarcoma treated with neoadjuvant trabectedin result in a higher completion rate of planned chemotherapy achieved a pathological complete response (13%; 95% 95% cycles. Morbidity aer local resection can oen hinder the con�denceinterval[CI]:3%–34%)andanother12of23had at least a good regression rate (>50% regression) as assessed CaseReportsinOncologicalMedicine 3 (a) (b) F1:18F-FDG-PETmaximum-intensity-projections(MIPS),(a)beforethestartofCTxand(b)aer2cyclesofCTx. (a) (b) F2:CTscan,(a)beforethestartofCTxand(b)aer2cyclesofCTx. (a) (b) F 3: (a) Densely cellular neoplasm composed of round- and spindle-shaped cells.; (b) necrosis and hyalinization aer neoadjuvant therapy,(H&Estaining,10x). 0 6.96 SUV (BW) 0 6.96 SUV (BW) 4 CaseReportsinOncologicalMedicine by central pathological review [3]. In all the regressed images. A copy of the written consent is available for review cases, the decrease of cellular components paralleled the bytheeditorofthisjournal. replacementwithanacellularstromalcomponent.erefore, earlier studies using trabectedin in advanced disease might Con�ictof�nterests have underestimated the bene�t of this drug on tumor devitalisationwhenusingconventionalmeasurementforthe eauthorsdeclarethattheyhavenocon�ictofinterests. assessmentoftumorresponse[13–15]. Aer only three cycles of the recommended dose of Authors’Contributions trabectedin (1.5mg/m given intravenously over 24 hours every 21 days) the tumor showed a very good pathological M. K. Schuler, S. Richter, G. Ehninger, C. Hamann and J. responsewith85%ofnecroticarea.Giventhathistopatholog- Mohmtreatedandobservedthepatient,includingfollowup. icalresponsecantranslateintoabetteroverallresponse,this I. Platzek and B. Beuthien-Baumann provided the radio- represents a promising and meaningful �nding [16]. Since graphicimagesandK.Wieczorekperformedthehistopatho- prospective data about pathological response in sarcoma logical examinations and established the diagnosis. All other than myxoid liposarcoma are missing, our results in authors participated in writing the paper and all read and thisnon-L-typesarcomamayhelptobettercorrelatedifferent approvedofthe�nalpaper. imaging techniques with the biology of the tumor. e fact that upon simultaneous functional and cross-sectional References imaging there was only a minor response again raises the question, whether the use of RECIST criteria will be the [1] J.T.Mullen,W.Kobayashi,J.J.Wangetal.,“Long-termfollow- adequatemarkerofresponse.Recently,ithasbeenpublished up of patients treated with neoadjuvant chemotherapy and that Choi criteria much better match with overall survival radiotherapy for large, extremity so tissue sarcomas,” Cancer, than RECIST criteria in patients undergoing preoperative vol.118,no.15,pp.3758–3765,2012. chemotherapy[17]. [2] W. G. Kraybill, J. Harris, I. J. Spiro et al., “Long-term results of a phase 2 study of neoadjuvant chemotherapy and radio- e duration of therapy was chosen in concordance therapyinthemanagementofhigh-risk,high-grade,sotissue to the publication of Gronchi et al., showing that three sarcomas of the extremities and body wall: Radiation erapy cycles of neoadjuvant chemotherapy are equal to �ve cycles Oncology Group Trial 9514,” Cancer, vol. 116, no. 19, pp. administeredperioperatively[3].Todayitremainsunknown, 4613–4621,2010. whether three cycles of single drug trabectedin are equal [3] A. Gronchi, B. N. Bui, S. Bonvalot et al., “Phase II clinical trial to three cycles of combination therapy with anthracycline ofneoadjuvanttrabectedininpatientswithadvancedlocalized and ifosfamide in the neoadjuvant setting. Furthermore, myxoid liposarcoma,” Annals of Oncology, vol. 23, no. 3, pp. one must question the appropriate duration of neoadjuvant 771–776,2012. trabectedin. When Gronchi and colleagues compared their [4] P. G. Casali, “Histology- and non-histology-driven therapy for work with the results of trabectedin used in the same treatment of so tissue sarcomas,” Annals of Oncology, vol. 23, histology in palliative treatment, they found that differences supplement10,pp.x167–x169,2012. in objective response by RECIST criteria could be partially [5] P.G.CasaliandJ.Y.Blay,“Sotissuesarcomas:ESMOclinical explained by differences in treatment duration between practice guidelines for diagnosis, treatment and follow-up,” the neoadjuvant and the advanced therapy. For instance, AnnalsofOncology,vol.21,supplement5,pp.v198–v203,2010. neoadjuvant treatment was limited in the study of Gronchi [6] A. Italiano, F. Delva, S. Mathoulin-Pelissier et al., “Effect of etal.toamaximumofsixcycles,whileinthestudybyGrosso adjuvant chemotherapy on survival in FNCLCC grade 3 so et al. patients received a median number of 10 cycles in the tissue sarcomas: a multivariate analysis of the French Sarcoma advanced setting [18, 19]. Late responses are oen observed Group Database,” Annals of Oncology, vol. 21, no. 12, pp. with trabectedin; therefore, our patient might also have 2436–2441,2010. experienced a further remission aer continued treatment [7] N.Penel,M.VanGlabbeke,S.Marreaud,M.Ouali,J. Y.Blay, [20]. and P. Hohenberger, “Testing new regimens in patients with advancedsotissuesarcoma:analysisofpublicationsfromthe last10years,”AnnalsofOncology,vol.22,no.6,pp.1266–1272, 4.Conclusions [8] N. J. Carter and S. J. Keam, “Trabectedin: a review of its use in Inconclusion,thisisthe�rstreportonapromisingtreatment sotissuesarcomaandovariancancer,”Drugs,vol.70,no.3,pp. with neoadjuvant trabectedin of high-grade pleomorphic 355–376,2010. sarcoma. More research is needed, particularly regarding [9] M. D’Incalci and C. M. Galmarini, “A review of trabectedin the selection of patients who would bene�t the most from (ET-743): a unique mechanism of action,” Molecular Cancer appropriateneoadjuvantperioperativechemotherapy. erapeutics,vol.9,no.8,pp.2157–2163,2010. [10] P. Allavena, M. Signorelli, M. Chieppa et al., “Anti-in�amma- Consent tory properties of the novel antitumor agent yondelis (trabect- edin): inhibition of macrophage differentiation and cytokine Written informed consent was obtained from the patient production,” Cancer Research, vol. 65, no. 7, pp. 2964–2971, for publication of this Case report and any accompanying 2005. CaseReportsinOncologicalMedicine 5 [11] G.Germano,R.Frapolli,M.Simoneetal.,“Antitumorandanti- in�ammatoryeffectsoftrabectedinonhumanmyxoidliposar- comacells,”CancerResearch,vol.70,no.6,pp.2235–2244,2010. [12] G. D. Demetri, S. P. Chawla, M. von Mehren et al., “Efficacy andsafetyoftrabectedininpatientswithadvancedormetastatic liposarcomaorleiomyosarcomaaerfailureofprioranthracy- clinesandifosfamide:resultsofarandomizedphaseIIstudyof two different schedules,” Journal of Clinical Oncology, vol. 27, no.25,pp.4188–4196,2009. [13] R. Garcia-Carbonero, J. G. Supko, R. G. Maki et al., “Ecteinascidin-743 (ET-743) for chemotherapy-naive patients with advanced so tissue sarcomas: multicenter phase II and pharmacokinetic study,” Journal of Clinical Oncology, vol. 23, no.24,pp.5484–5492,2005. [14] A. Yovine, M. Riofrio, J. Y. Blay et al., “Phase II study of ecteinascidin-743 in advanced pretreated so tissue sarcoma patients,” Journal of Clinical Oncology, vol. 22, no. 5, pp. 890–899,2004. [15] A.LeCesne,J.Y.Blay,I.Judsonetal.,“PhaseIIstudyofET-743 in advanced so tissue sarcomas: a European Organisation for theResearchandTreatmentofCancer(EORTC)sotissueand bonesarcomagrouptrial,”JournalofClinicalOncology,vol.23, no.3,pp.576–584,2005. [16] K.Herrmann,M.R.Benz,J.Czerninetal.,“18F-FDG-PET/CT Imagingasanearlysurvivalpredictorinpatientswithprimary high-grade so tissue sarcomas undergoing neoadjuvant ther- apy,” Clinical Cancer Research, vol. 18, no. 7, pp. 2024–2031, [17] S. Stacchiotti, P. Verderio, A. Messina et al., “Tumor response assessmentbymodi�edChoicriteriainlocalizedhigh-riskso tissuesarcomatreatedwithchemotherapy,”Cancer,vol.118,no. 23,pp.5857–5866,2012. [18] F. Grosso, R. L. Jones, G. D. Demetri et al., “Efficacy of trabectedin(ecteinascidin-743)inadvancedpretreatedmyxoid liposarcomas:aretrospectivestudy,”LancetOncology,vol.8,no. 7,pp.595–602,2007. [19] F.Grosso,R.San�lippo,E.Virdisetal.,“Trabectedininmyxoid liposarcomas(MLS):along-termanalysisofasingle-institution series,”AnnalsofOncology,vol.20,no.8,pp.1439–1444,2009. [20] P. G. Casali, R. San�lippo, and M. D�Incalci, “Trabectedin therapyforsarcomas,”CurrentOpinioninOncology,vol.22,no. 4,pp.342–346,2010. 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Trabectedin in the Neoadjuvant Treatment of High-Grade Pleomorphic Sarcoma: Report of a Rare Case and Literature Review

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HindawiPublishingCorporation CaseReportsinOncologicalMedicine Volume2013,ArticleID320797,5pages http://dx.doi.org/10.1155/2013/320797 CaseReport TrabectedinintheNeoadjuvantTreatmentof High-GradePleomorphicSarcoma:ReportofaRareCaseand LiteratureReview 1 1 2 3 MarkusK.Schuler, StephanRichter, IvanPlatzek, BettinaBeuthien-Baumann, 4 5 6 1 KathrinWieczorek, ChristineHamann, JohannesMohm, andGerhardEhninger DepartmentofInternalMedicineI,UniversityHospitalCarlGustavCarus,DresdenUniversityofTechnology, 01307Dresden,Germany DepartmentofRadiology,UniversityHospitalCarlGustavCarus,DresdenUniversityofTechnology,01307Dresden,Germany DepartmentofNuclearMedicine,UniversityHospitalCarlGustavCarus,DresdenUniversityofTechnology,01307Dresden,Germany DepartmentofPathology,UniversityHospitalCarlGustavCarus,DresdenUniversityofTechnology,01307Dresden,Germany DepartmentofOrthopaedics,UniversityHospitalCarlGustavCarus,DresdenUniversityofTechnology,01307Dresden,Germany Hämatologisch-OnkologischePraxis,Dresden,Germany CorrespondenceshouldbeaddressedtoMarkusK.Schuler;markus.schuler@uniklinikum-dresden.de Received6December2012;Accepted31December2012 AcademicEditors:D.V.Jones,F.A.Mauri,andJ.I.Mayordomo Copyright©2013MarkusK.Schuleretal. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background.Pleomorphicsarcomaisanaggressivesotissuesarcoma.Inpatientswithhigh-riskextremitysarcomas,thesigni�cant survivalbene�tsconferredbyanintenseregimenofneoadjuvantchemoradiotherapyandsurgerywerereported.Toourknowledge, this is the �rst report in the literature of the neoadjuvant use of trabectedin in a patient with high-grade pleomorphic sarcoma, ineligibleforstandardneoadjuvantcombinationtherapywithananthracycline-basedregimen.CasePresentation.Herewepresent a58-year-oldWhitemalewithalargetumorinthelethigh,butwithnosignsofmetastases.Owingtothehistoryofsevereheart attack, three cycles of neoadjuvant trabectedin were administrated to achieve surgically wide margins. Aer two cycles, an 18F- FDG-PET showed a large proportion of the central tumor area was without metabolic activity. According to RECIST and Choi criteria, the tumor was stable. Aer the third cycle of trabectedin, the patient underwent a complete resection, which revealed completelynecrotichigh-gradepleomorphicsarcoma(stagepT2b),withonlyasmallvitalarea.Conclusion.epresentpaperon a promising treatment with neoadjuvant trabectedin of patients with high-grade pleomorphic sarcoma might suggest that such treatmentapproachmayprovideagreaterchanceofcureandsurvivalofsuchpatients. 1.Background inthishighlymalignantdisease.Mullenandcolleagueshave reported the signi�cant survival bene�ts in patients with e high-risk stage III so tissue sarcomas (STS) are a het- high-risk, extremity STS who received an intense regimen erogeneousgroupofrelativelyraremesenchymalneoplasms ofneoadjuvant chemoradiotherapy with concomitant radio- with important differences in chemosensitivity. e use of therapy [1]. Another prospective phase II trial by Kraybill chemotherapy in the neoadjuvant and adjuvant settings in et al. demonstrated a comparably good outcome with an STS is controversial. When preoperative chemotherapy is overall survival of 71% aer 5 years in patients with high- used, tumor responses can result in clinically meaningful grade,high-riskSTStreatedwithneoadjuvantchemotherapy, tumor shrinkage prior to surgery and, thus, may facilitate preoperative radiotherapy, and adjuvant chemotherapy [2]. subsequent surgical resection. Nowadays there are some Meta-analysis found a signi�cant advantage in relapse-free piecesofevidencefortheuseofperioperativechemotherapy 2 CaseReportsinOncologicalMedicine andoverallsurvival.Nevertheless,inlightofmissingprospec- application of systemic therapy, consecutively leading to an tiverandomizedtrialsshowingareproduciblebene�titisstill undertreatmentofhigh-riskpatients. a matter of debate which patients will have a bene�t from Herein we present the results of the neoadjuvant use of trabectedin in a patient with high-grade pleomorphic this approach. Besides, apart from certain entities, such as myxoidliposarcoma,nohistology-driventrialshaveyetbeen sarcoma, ineligible for standard neoadjuvant combination performed [3, 4]. erefore, there is still lacking evidence therapywithananthracycline-basedregimen. for the use of chemotherapy in the neoadjuvant setting in patientswithSTS. 2.CaseReport Treatment guidelines of sarcoma research and treatment organizations so far recommend a shared decision-making A58-year-oldWhitemalepresentedwithalargetumorinthe process considering among others patients age, tumor- lethigh.epatienthadahistoryofseverecardiacproblems subtype,grading,andsize[5].AccordingtoaFrenchanalysis with myocardial infarction two years before diagnosis and especially patients with grade 3 tumors might bene�t from consecutivelyunderwentprophylacticde�brillatorimplanta- adjuvantchemotherapy[6]. tion,havinganejectionfractionof45%aersurgery.Across- To date, the standard for perioperative chemotherapy sectionalimagingshowedanapproximately30×14×11cm is combining anthracycline with high-dose ifosfamide [5, lobulatedtumor.Stagingwascompletedwithacomputerized 7]. is regimen is quite toxic and not applicable to a tomography (CT) scan of the chest and abdomen and signi�cant proportion of elderly and frail people. erefore, a �uorine-18 �uorodeoxyglucose (FDG)-positron emission thesepatientscannotbetreatedinaperioperativeway,since tomography (PET) scan. is scan con�rmed the presence lesstoxicregimenshavenotyetbeenevaluated. of the mass and revealed an increased FDG uptake with a Trabectedin(Yondelis)isamarine-derivedantineoplastic maximal standardized uptake value of 10.5 in the proximal compoundisolatedfromtheCaribbeantunicateEcteinascid- region. No metastases were detected. Incision biopsy �nally ia turbinata and currently produced synthetically [8]. Tra- con�rmed a high-grade sarcoma without distinct classi�ca- bectedinisapprovedintheEuropeanUnionandmanyother tion.Microscopic�ndingsdiscoveredupto10mitosesin10 countriesworldwideforthetreatmentofadvancedSTSaer high-power�elds(HPF)anda30%necrosis. the failure of anthracyclines and ifosfamide or for patients Neoadjuvant chemotherapy was recommended in order who are unsuited to receive these agents. It has a unique to achieve surgically wide margins. Because of the his- mechanism of action based on interaction with the minor tory of severe heart attack, the patient was unsuited to grooveoftheDNAdouble helix, which triggers a cascade of receive anthracycline-based chemotherapy. As an individual events that interfere with several transcription factors, DNA approach with the patient, trabectedin was chosen for the bindingproteinsandDNArepairpathways,resultinginG2- patient-tailored treatment. ree cycles of trabectedin were M cell cycle arrest and ultimately apoptosis [9]. Moreover, given on day 1 every 3 weeks at the dose of 1.5mg/m body trabectedin at therapeutic concentrations has selective anti- surface area, administered as an intravenous infusion over in�ammatory and immunomodulatory properties on tumor 24hours.Aertwocycles,an18F-FDG-PETwasperformed, microenvironment as it decreases the production of factors showingnosigni�cantdecreaseinstandardizeduptakevalue potentiallyrelevantfortumorgrowth,progression,angiogen- (SUV)inthehyper-metabolicregionsofthetumor:maximal esis, and metastasization. In particular, the in vitro produc- SUVwas9.5versus10.5intheproximaland4.4versus5.2in tionofproin�ammatorymediators,suchasinterleukin-6(IL- the distal tumor (Figure 1). However, a large proportion of 6)andCCL2,wasmarkedlydownregulatedbytrabectedinin the central tumor area showed no metabolic activity. When circulating monocytes, macrophages, and tumor-associated applying the response evaluation criteria in solid tumors macrophages(TAM)fromhumantumors[9–11].erefore, (RECIST)andtheChoicriteria(Figure2)totheCTscan,the the mechanism of action of trabectedin has dual effect: it tumorwasstable.Ananalysisoftumorvolumetricrevealeda actsnotonly ontumorgrowthbutalsoontumorimmune 3 3 35%decrease(from956cm to621cm )ofthetumormass. in�ammation and angiogenesis, providing a consolidated Aer three cycles of trabectedin the patient was referred therapeuticapproachasamultitargetdrug. to resection. e postoperative classi�cation aer complete Trabectedin shows nearly similar response rates in resection of the femur was stage pT2b high-grade pleo- leiomyosarcoma and liposarcomas (L-sarcomas) as those morphic sarcoma with 0.5cm negative margins towards the in combination-therapies and by far is less toxic [12]. acetabulum. e only vital tumor area was in the dorso- In addition, trabectedin was generally well tolerated and cranialareawithviabilityof15%,whileallotherpartsshowed showed manageable toxicity when administered to patients acompletenecrosis(Figure3). with myxoid liposarcoma as neoadjuvant chemotherapy [3]. Based on these �ndings, a neoadjuvant treatment strategy with trabectedin could be extremely bene�cial for those 3.LiteratureReview patients,especiallythosewhoarenoteligibleforanaggressive combination therapy. Apart from its potential local and In a former phase II clinical trial three of 23 patients with systemicbene�t,trabectedintreatmentpriortosurgerycould myxoid liposarcoma treated with neoadjuvant trabectedin result in a higher completion rate of planned chemotherapy achieved a pathological complete response (13%; 95% 95% cycles. Morbidity aer local resection can oen hinder the con�denceinterval[CI]:3%–34%)andanother12of23had at least a good regression rate (>50% regression) as assessed CaseReportsinOncologicalMedicine 3 (a) (b) F1:18F-FDG-PETmaximum-intensity-projections(MIPS),(a)beforethestartofCTxand(b)aer2cyclesofCTx. (a) (b) F2:CTscan,(a)beforethestartofCTxand(b)aer2cyclesofCTx. (a) (b) F 3: (a) Densely cellular neoplasm composed of round- and spindle-shaped cells.; (b) necrosis and hyalinization aer neoadjuvant therapy,(H&Estaining,10x). 0 6.96 SUV (BW) 0 6.96 SUV (BW) 4 CaseReportsinOncologicalMedicine by central pathological review [3]. In all the regressed images. A copy of the written consent is available for review cases, the decrease of cellular components paralleled the bytheeditorofthisjournal. replacementwithanacellularstromalcomponent.erefore, earlier studies using trabectedin in advanced disease might Con�ictof�nterests have underestimated the bene�t of this drug on tumor devitalisationwhenusingconventionalmeasurementforthe eauthorsdeclarethattheyhavenocon�ictofinterests. assessmentoftumorresponse[13–15]. Aer only three cycles of the recommended dose of Authors’Contributions trabectedin (1.5mg/m given intravenously over 24 hours every 21 days) the tumor showed a very good pathological M. K. Schuler, S. Richter, G. Ehninger, C. Hamann and J. responsewith85%ofnecroticarea.Giventhathistopatholog- Mohmtreatedandobservedthepatient,includingfollowup. icalresponsecantranslateintoabetteroverallresponse,this I. Platzek and B. Beuthien-Baumann provided the radio- represents a promising and meaningful �nding [16]. Since graphicimagesandK.Wieczorekperformedthehistopatho- prospective data about pathological response in sarcoma logical examinations and established the diagnosis. All other than myxoid liposarcoma are missing, our results in authors participated in writing the paper and all read and thisnon-L-typesarcomamayhelptobettercorrelatedifferent approvedofthe�nalpaper. imaging techniques with the biology of the tumor. e fact that upon simultaneous functional and cross-sectional References imaging there was only a minor response again raises the question, whether the use of RECIST criteria will be the [1] J.T.Mullen,W.Kobayashi,J.J.Wangetal.,“Long-termfollow- adequatemarkerofresponse.Recently,ithasbeenpublished up of patients treated with neoadjuvant chemotherapy and that Choi criteria much better match with overall survival radiotherapy for large, extremity so tissue sarcomas,” Cancer, than RECIST criteria in patients undergoing preoperative vol.118,no.15,pp.3758–3765,2012. chemotherapy[17]. [2] W. G. Kraybill, J. Harris, I. J. Spiro et al., “Long-term results of a phase 2 study of neoadjuvant chemotherapy and radio- e duration of therapy was chosen in concordance therapyinthemanagementofhigh-risk,high-grade,sotissue to the publication of Gronchi et al., showing that three sarcomas of the extremities and body wall: Radiation erapy cycles of neoadjuvant chemotherapy are equal to �ve cycles Oncology Group Trial 9514,” Cancer, vol. 116, no. 19, pp. administeredperioperatively[3].Todayitremainsunknown, 4613–4621,2010. whether three cycles of single drug trabectedin are equal [3] A. Gronchi, B. N. Bui, S. Bonvalot et al., “Phase II clinical trial to three cycles of combination therapy with anthracycline ofneoadjuvanttrabectedininpatientswithadvancedlocalized and ifosfamide in the neoadjuvant setting. Furthermore, myxoid liposarcoma,” Annals of Oncology, vol. 23, no. 3, pp. one must question the appropriate duration of neoadjuvant 771–776,2012. trabectedin. When Gronchi and colleagues compared their [4] P. G. 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