Les tumeurs thymiques
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Lestumeurs duthymus NicolasGirard Institut deCancérologie desHospicesCivilsdeLyon Lyon,France Liensd’intérêt Jesuis coordonateur adjoint duréseau RYTHMIC. Jenesuis pasmembre ducomité destagingdel’IASLC. Jenesuis pasmembre ducomité depublicationdel’ITMIG. Jesuis consultantpourleslaboratoires BMS,MSD,Novartis,Pfizer. Tumeurs thymiques 2016 Tumeurs thymiques • Incidence:0,15-0,30/100000people • 250casesinFrance/year Retinoblastoma GIST 100 Mesothélioma 900 Hodgkin 800 1800 Melanoma 10000 Breast Prostate Colo-rectal 55000 70000 LUNG 41000 40000 Thymomas 250 Engelsetal.IntJCancer2003;105:546 InstitutNationalduCancer,e-cancer.fr Updated incidence of Thymic Epithelial Tumors (TET) in France and clinical presentation at diagnosis Bluthgen MV1 , Dansin E2 , Kerjouan M3 , Mazieres J4 , Pichon E5 , Thillays F6 , Massard G7 , Quantin X8 , Oulkhouir Y9 , Westeel V10 , Thiberville L11 , Clement-Duchene C12 , Thomas P13 , Girard N14 , Besse B1 1 Gustave Roussy, Villejuif, France; ²Oscar Lambret, Lille, France; ³Centre Hospitalier Universitaire de Rennes, Rennes, France; 4Centre Hospitalier Universitaire de Tolouse, Tolouse, France; 5Hôpital Bretonneau, Tours, France; 6Institut de Cancérologie de l’ouest, Rouen, France; 7Centre Hospitalier Universitaire de Strasbourg, Strasbourg, France; 8Centre Hospitalier Universitaire de Montpellier, Montpellier, France; 9Centre Hospitalier Universitaire de Caen, Caen, France; 10Centre Hospitalier Universitaire de Besancon, Besancon, France; 11Centre Hospitalier Universitaire de Rouen, Rouen, France; 12Centre Hospitalier Universitaire de Nancy, Nancy, France; 13Hôpital Nord, Marseille, France; 14Hôpital Louis Pradel, Lyon, France BACKGROUND AND OBJECTIVE TETs are rare malignancies with an overall incidence of 0.13 per 100.000 person-years. Given this, most of our knowledge is largely derived from small single-institution series. RYTHMIC (Réseau tumeurs THYMiques et Cancer) is a French network for TET created by INCa (French National Cancer Institute) with the objective of territorial coverage by 14 regional expert centers, systematic discussion of patients at national tumor board and collection of nationwide data within a centralized database. OBJECTIVE: We reviewed our activity in 2016 in order to describe the epidemiology and main characteristics at diagnosis of Tumeurs thymiquesin France. PATIENTS AND METHODS -We prospectively collected all patients (pts) with new diagnosis of primary TET in France discussed at national or regional RYTHMIC tumor board from January to December 2016. -Epidemiologic, clinical, pathologic and surgical data were prospectively collected within a centralized database. -Histologic sub-type was centrally reviewed according to the WHO classification and stage by modified Masaoka-Koga classification. -Fisher exact test was used for correlations. RESULTS Frequency n=226 (%) Age Median [range] Patient’s characteristics and treatment Frequency n=226 (%) 62 [25 – 86] Gender Male Female 129(57) 97(43) Auto-inmune disorder Myasthenia Anemia Thyroiditis Hypogammaglobulinemia A Others 46 (20) 35 3 2 2 4 Previous cancer Prostate Breast Melanoma Hematologic Other 34 (15) 9 7 4 2 11 Mode of diagnosis Resection Surgical biopsy Imaging guided biopsy 158 (70) 35 (15) 33 (15) Primary treatment Upfront Surgery Neo-adjuvant chemotherapy Chemotherapy Adjuvant radiotherapy 170 (75) 8 (3) 40 (18) 55 (24) Surgery Approach Sternotomy Videothoracoscopy Robot assisted Thoracotomy Other 178 (100) 108 (61) 37 (21) 15 (8) 9 (5) 9 (5) Chemotherapy CAP Carboplatin-paclitaxel Carboplatin-etoposide 5,00 Distribution of stage (Masaoka-Koga ITMIG modified) and histology (WHO 2004 classification). C Men 0,00 33 (63) 16 (31) 3 (6) UK: unknown; CAP: cisplatin, doxorubicin, cyclophosphamide; VIP: cisplatin, etoposide, ifosfamide. B. Age-specific incidence of TET 25 75 A. Observed incidence of TET in France (per 100.000-person-year) according to gender. *Based on INSEE (Institut National de la Statistique et des Etudes Economiques) population data registries according to gender for France 2016. B. Age-specific incidence of thymoma: observed values for thymoma incidence (per 100,000 person-years) plotted in function of age. CONCLUSION A The estimated incidence of TETS in France in 2016 is 0.34 per 100.000 persons, based on our activity. The inclusion in the RYTHMIC network is mandatory but is still based on physician’s request. Although we might underestimate the incidence, it seems to be higher compared to Significant correlations were found between histologic sub-type (Thymoma vs. Thymic carcinoma) and presence of an autoimmune disorder (p=0.01) B B no significant correlations were seen with and stage (I-II vs. III-IV, p=0.004); gender (p=0.27) other countries’ registries. The high occurrence of previous cancer might underlie variations in environmental or genetic risk factors. Updated incidence of Thymic Epithelial Tumors (TET) in France and clinical presentation at diagnosis Bluthgen MV1 , Dansin E2 , Kerjouan M3 , Mazieres J4 , Pichon E5 , Thillays F6 , Massard G7 , Quantin X8 , Oulkhouir Y9 , Westeel V10 , Thiberville L11 , Clement-Duchene C12 , Thomas P13 , Girard N14 , Besse B1 1 Gustave Roussy, Villejuif, France; ²Oscar Lambret, Lille, France; ³Centre Hospitalier Universitaire de Rennes, Rennes, France; 4Centre Hospitalier Universitaire de Tolouse, Tolouse, France; 5Hôpital Bretonneau, Tours, France; 6Institut de Cancérologie de l’ouest, Rouen, France; 7Centre Hospitalier Universitaire de Strasbourg, Strasbourg, France; 8Centre Hospitalier Universitaire de Montpellier, Montpellier, France; 9Centre Hospitalier Universitaire de Caen, Caen, France; 10Centre Hospitalier Universitaire de Besancon, Besancon, France; 11Centre Hospitalier Universitaire de Rouen, Rouen, France; 12Centre Hospitalier Universitaire de Nancy, Nancy, France; 13Hôpital Nord, Marseille, France; 14Hôpital Louis Pradel, Lyon, France BACKGROUND AND OBJECTIVE TETs are rare malignancies with an overall incidence of 0.13 per 100.000 person-years. Given this, most of our knowledge is largely derived from small single-institution series. RYTHMIC (Réseau tumeurs THYMiques et Cancer) is a French network for TET created by INCa (French National Cancer Institute) with the objective of territorial coverage by 14 regional expert centers, systematic discussion of patients at national tumor board and collection of nationwide data within a centralized database. OBJECTIVE: We reviewed our activity in 2016 in order to describe the epidemiology and main characteristics at diagnosis of Tumeurs thymiquesin France. PATIENTS AND METHODS -We prospectively collected all patients (pts) with new diagnosis of primary TET in France discussed at national or regional RYTHMIC tumor board from January to December 2016. -Epidemiologic, clinical, pathologic and surgical data were prospectively collected within a centralized database. -Histologic sub-type was centrally reviewed according to the WHO classification and stage by modified Masaoka-Koga classification. -Fisher exact test was used for correlations. RESULTS Frequency n=226 (%) Age Median [range] Patient’s characteristics and treatment Frequency n=226 (%) 62 [25 – 86] Gender Male Female 129(57) 97(43) Auto-inmune disorder Myasthenia Anemia Thyroiditis Hypogammaglobulinemia A Others 46 (20) 35 3 2 2 4 Previous cancer Prostate Breast Melanoma Hematologic Other 34 (15) 9 7 4 2 11 Mode of diagnosis Resection Surgical biopsy Imaging guided biopsy 158 (70) 35 (15) 33 (15) Primary treatment Upfront Surgery Neo-adjuvant chemotherapy Chemotherapy Adjuvant radiotherapy 170 (75) 8 (3) 40 (18) 55 (24) Surgery Approach Sternotomy Videothoracoscopy Robot assisted Thoracotomy Other 178 (100) 108 (61) 37 (21) 15 (8) 9 (5) 9 (5) Chemotherapy CAP Carboplatin-paclitaxel Carboplatin-etoposide 5,00 Distribution of stage (Masaoka-Koga ITMIG modified) and histology (WHO 2004 classification). C Men 0,00 33 (63) 16 (31) 3 (6) UK: unknown; CAP: cisplatin, doxorubicin, cyclophosphamide; VIP: cisplatin, etoposide, ifosfamide. B. Age-specific incidence of TET 25 75 A. Observed incidence of TET in France (per 100.000-person-year) according to gender. *Based on INSEE (Institut National de la Statistique et des Etudes Economiques) population data registries according to gender for France 2016. B. Age-specific incidence of thymoma: observed values for thymoma incidence (per 100,000 person-years) plotted in function of age. CONCLUSION A The estimated incidence of TETS in France in 2016 is 0.34 per 100.000 persons, based on our activity. The inclusion in the RYTHMIC network is mandatory but is still based on physician’s request. Although we might underestimate the incidence, it seems to be higher compared to Significant correlations were found between histologic sub-type (Thymoma vs. Thymic carcinoma) and presence of an autoimmune disorder (p=0.01) B B no significant correlations were seen with and stage (I-II vs. III-IV, p=0.004); gender (p=0.27) other countries’ registries. The high occurrence of previous cancer might underlie variations in environmental or genetic risk factors. Tumeurs thymiques Specificities 2016 Tumeurs thymiques Specificities - Thymic origin 2016 Thethymus Thymus Apoptose Celluleépithéliale médullaire Celluledendritique Lymphocyte immature Toléranceimmunitaire Auxantigènesdusoi Délétion clonale Thymus Apoptose Celluleépithéliale médullaire Celluledendritique Lymphocyte immature Toléranceimmunitaire Auxantigènesdusoi Délétion clonale Thymus Apoptose Celluleépithéliale médullaire Celluledendritique Lymphocyte immature Toléranceimmunitaire Auxantigènesdusoi Délétion clonale Sélection positivedeslymphocytes Celluleépithéliale thymique Apoptose CORTEX Celluleépithéliale médullaire Celluledendritique Lymphocyte immature Toléranceimmunitaire Auxantigènesdusoi Délétion clonale Sélectionnégativedeslymphocytes Apoptose Celluleépithéliale thymique Celluledendritique MEDULLA Lymphocyte immature Toléranceimmunitaire Auxantigènesdusoi Délétion clonale Mathisetal.AnnuRevImmunol2009;27:287 Sélectionnégativedeslymphocytes Apoptose Celluleépithéliale thymique Celluledendritique Lymphocyte immature Toléranceimmunitaire Auxantigènesdusoi Délétion Apoptose clonale Mathisetal.AnnuRevImmunol2009;27:287 Sélectionnégativedeslymphocytes Apoptose Celluleépithéliale thymique Celluledendritique Lymphocyte immature Toléranceimmunitaire aux antigènesdusoi Délétion Apoptose clonale Mathisetal.AnnuRevImmunol2009;27:287 Sélectionnégativedeslymphocytes Apoptose Celluleépithéliale thymique Celluledendritique Lymphocyte immature Toléranceimmunitaire Auxantigènesdusoi Délétion Apoptose clonale Mathisetal.AnnuRevImmunol2009;27:287 Sélectionnégativedeslymphocytes Apoptose Celluleépithéliale thymique Celluledendritique Lymphocyte immature Toléranceimmunitaire Auxantigènesdusoi Délétion Apoptose clonale Mathisetal.AnnuRevImmunol2009;27:287 Tumeurs thymiques Specificities - Thymic origin - Complexhistology 2016 Histo-pathologicclassification • WorldHealthOrganization2016 Carcinoma Thymoma A “Médullary” AB Mixed B1 B2 “Cortical” B3 SCC Reproductibilité delaclassification? • Reproductibilité imparfaite - Variabilité delaproportion dechaque type - Etudedereproductibilité inter-observateur:k=0,45-0,49 Marchevsky etal.Cancer2008; 112:2780 Rieker etal.Int JCancer2002;98:900;Verghese etal.Histopathology2008;53:218 Reproductibilité delaclassification? • Reproductibilité imparfaite - Hétérogénéité tumorale desthymomes detypeA InternationalThymic MalignancyInterestGroup2011 Reproductibilité delaclassification? • Reproductibilité imparfaite: - Formes combinées :25%descas? - Formes frontières InternationalThymic MalignancyInterestGroup2011 Genomicprofilingofthymic epithelialtumors • MSKCC,45patients Thymome type A (n=8) Thymome type B2 (n=22) Thymome type B3 (n=8) Carcinome thymique (n=7) Girardetal.Clin CancerRes2009; 15:6790 The2016 WHOclassification Actualisation delaclassificationhisto-pathologique Actualisation delaclassificationhisto-pathologique Actualisation delaclassificationhisto-pathologique Intérêt deladoublelectureanatomopathologique Intérêt deladoublelectureanatomopathologique Intérêt deladoublelectureanatomopathologique Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity 2016 Sélectionnégativedeslymphocytes Apoptose Celluleépithéliale thymique Celluledendritique Lymphocyte immature Toléranceimmunitaire Auxantigènesdusoi Délétion Apoptose clonale Mathisetal.AnnuRevImmunol2009;27:287 Lesthymomesn’exprimentpasAIRE ExpressiondeAIRE(ARNm)dans 20thymomes (controle :thymussain). Ströbeletal.JPathol2007;211:563 Manifestationsauto-immunes Apoptose Celluleépithéliale thymique tumorale Celluledendritique Lymphocyte immature Auto-immunité Pasdedélétion Pasd’apoptose Délétion clonale clonale Mathisetal.AnnuRevImmunol2009;27:287 Auto-immunedisorders Neuromuscular Myastheniagravis Peripheralneuropathy Polymyositis Dermatomyositis Encephalitis Opticalmyelitis Haematologicdisorders Redcellaplasia Perniciousanaemia Erythrocytosis Pancytopoenia Haemolyticanaemia Leukaemia Multiplemyeloma Auto-immunedisorders Systemiclupuserythematosus Rheumatoidarthritis Sjogren’ssyndrome Scleroderma Endocrinedisorders Multipleendocrineneoplasia Cushing’ssyndrome Thyrotoxicosis Pneumonitis Dermatologicdisorders Pemphigus Lichenplanus Chronicmucosalcandidiasis Alopeciaareata Miscellaneous Giantcellmyocarditis Nephroticsyndrome Ulcerativecollitis Hypertrophicosteoarthropathy Interstitialpneumonitis Immunedeficiencydisorders Hypogammaglobulinaemia T-celldeficiencysyndrome Syndromespara-thymiques • Bilan minimalrecommandé encas desuspiciondemanifestationsautoimmunesassociées auxtumeurs thymiques Rinaldietal.NeurolSci2009;30:237 Prognosisofthymoma • Causesofdeath: Huangetal.JThorac Oncol 2010;5:2017 Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging 2016 Masaoka-Kogastagingsystem ClassificationMasaoka-Koga-ITMIG • Classificationanatomo-clinique:pTNM • Evaluableaprèsrésection chirurgicale Detterbecketal.JThorac Oncol 2011;6:S1710 Stade I Detterbecketal.JThorac Oncol 2011;6:S1710 Stade IIA Detterbecketal.JThorac Oncol 2011;6:S1710 Stade IIB Detterbecketal.JThorac Oncol 2011;6:S1710 Stade IIB Detterbecketal.JThorac Oncol 2011;6:S1710 Stade III Detterbecketal.JThorac Oncol 2011;6:S1710 Stade III Detterbecketal.JThorac Oncol 2011;6:S1710 Stade IVA Detterbecketal.JThorac Oncol 2011;6:S1710 Stade IVB Detterbecketal.JThorac Oncol 2011;6:S1710 Masaoka-Kogastagingsystem Surgicalpathologystaging Noclinicalstaging Thymic epithelialtumors:stageandhistology WHO,2016 PrognosticvalueoftheMasaoka stagingsystem Regnard etal.JThorac Cardiovasc Surg 1996;112:376 Mooreetal.AnnThorac Surg 2001;72:203 Gawrychowski etal,EurJ Surg Oncol 2000;26:203-8 Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging 2016 InternationalThymic MalignancyInterestGroup Masaoka-Koga :I,IIA,IIB,III Masaoka-Koga :III Masaoka-Koga :III Masaoka-Koga :IVA,IVB Masaoka-Koga :IVB Prognosisofthymoma • Causesofdeath: Huangetal.JThorac Oncol 2010;5:2017 Stage,Histology,Other? • ThemostsignificantprognosticfactorinTumeurs thymiquesis the completionofsurgicalresection,whateverclassificationisused. Rossietal.Histopathology2008;53:483 TreatmentofTumeurs thymiques • Firstquestionis:resectable ornot? NationalComprehensiveCancerNetworkGuidelines TreatmentofTumeurs thymiques • Firstquestionis:resectable ornot? NationalComprehensiveCancerNetworkGuidelines Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging Resectable tumors 2016 Diagnosticdifférentiel • Lestumeursprimitivesdumédiastinantérieur ontunaspectradiologiquesouventsimilaire Tératome MaladiedeHodgkin Tumeurgerminalenon séminomateuse Thymome Tumeurs médiastinales:signes cliniques • Absencedetabagisme:80%destumeursmédiastinales • Age<40ans:50%destumeursmédiastinales JThorac Oncol 2014;9:S102 Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging Resectable tumors 2016 Nécessitéd’unebiopsiepré-thérapeutique • Lachirurgieestrecommandéed’embléepourcertainestumeursdu médiastin: - Tumeursbénignes:tératomes - Tumeurskystiques - Thymomesnoninvasifs/encapsulés/avecenvahissementlimité Kesler etal.AnnThorac Surg 2008;85:371 Kesler etal.ThorSurg Clin 2009;19:63 Lemarié etal.Chest1992;102:1477 Nécessitéd’unebiopsiepré-thérapeutique • Lachirurgieestrecommandéed’embléepourcertainestumeursdu médiastin: - Tumeursbénignes:tératomes - Tumeurskystiques - Thymomesnoninvasifs/encapsulés/avecenvahissementlimité • Lachimiothérapieestuneurgenceencasdetumeurgerminalemaligne: - silesmarqueurssontélevés:14-35%ofcases - α-foeto-protéine>1000kUI/L - tumeurgerminalenonséminomateuse (sacvitellin) - β-human chorionic gonadotrophin >5000kUI/L - tumeurgerminalenonséminomateuse (choriocarcinome) - rareencasdeséminome Kesler etal.AnnThorac Surg 2008;85:371 Kesler etal.ThorSurg Clin 2009;19:63 Lemarié etal.Chest1992;102:1477 Nécessitéd’unebiopsiepré-thérapeutique • Lachirurgieestrecommandéed’embléepourcertainestumeursdu médiastin: - Tumeursbénignes:tératomes - Tumeurskystiques - Thymomesnoninvasifs/encapsulés Dans tous lesautres cas • Lachimiothérapieestuneurgenceencasdetumeurgerminalemaligne: - silesmarqueurssontélevés:14-35%ofcases - α-foeto-protéine>1000kUI/L - tumeurgerminalenonséminomateuse (sacvitellin) - β-human chorionic gonadotrophin >5000kUI/L - tumeurgerminalenonséminomateuse (choriocarcinome) - rareencasdeséminome biopsie Kesler etal.AnnThorac Surg 2008;85:371 Kesler etal.ThorSurg Clin 2009;19:63 Lemarié etal.Chest1992;102:1477 Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging Resectable tumors 2016 Thymome ou hyperplasie thymique? • CTscan:low-attenuation,symmetricandfattypattern,maintaining thebi-pyramidalshapeofthethymus • “Rebound”hyperplasia: - stress:pneumonia,surgery,burns,corticoidtreatment - chemotherapy: - 10-25%ofcases,youngadults,intensivetreatment • Lymphoidhyperplasia - autoimmuneandinflammatorydisorders - connectivetissuediseasesandvasculitis - myasthenia Hendrick etal.Rofo 1989:150:268; Miniero R.BoneMarrowTransplant.1993;11:67 Gerhardtetal.Dtsch MedWochenschr 2004;129:1916 Thymome ou hyperplasie thymique? • ELCAPlung cancerscreeningstudy: - forme ovoïdeettaille<3cm:hyperplasie Henschke etal.Radiology 2006;23:239:586 Imagerie pré-thérapeutique - UtilisationduPET-scan:corrélationavecclassifications Kimar etal.AnnNucl Med2009;23:569 Endoetal.LungCancer2008;61:350 Imagerie pré-thérapeutique - UtilisationduPET-scan:hyperplasie vs.thymomevs.carcinomethymique Igai etal.Eur JCardiothor Surg 2011;40:143 Kimar etal.AnnNucl Med2009;23:569;Endoetal.LungCancer2008;61:350 Kaira etal.JClin Oncol 2011;28:3746;Shibataetal.Cancer2009;115:2531 Hyperplasie thymique T2WFS Inphase Opposedphase Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging Resectable tumors 2016 Imagerie pré-thérapeutique - Prédictionde l’invasivité parlatomodensitométrie: MDAnderson,99patients JThorac Oncol 2011;6:1274 JThorac Oncol.2014;9:1023 Définition delarésécabilité Masaoka-Koga :I,IIA,IIB,III Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging Resectable tumors - Surgery 2016 Surgeryrecommendations • Mediansternotomy isthestandardapproach • Completeexplorationofthepleuralcavities • Completethymectomy,including tumor,normalthymus,andmediastinal fat • enbloc resectionofinvolvedstructures: - lung,vessels,pleuralimplants,phrenicnerves - surgicalclipsinareasofconcern • Mediastinal notessampling/resection (stageIIItumor/thymic carcinoma) • Frozensectionnotrecommendedformarginsassessment Orientationand markingintheoperativeroom • Useofamediastinal board Minimally-invasivesurgery? Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging Resectable tumors - Surgery - Postoperativeradiotherapy 2016 Postoperativeradiotherapy:SEERdatabase • Population: - thymomas andthymic carcinomas - 1973-2005,901patients:275stageI,626stageII-III StageIStageII-III ```` …butno benefit after complete resection (p=0.12) Forquer etal.Int JRadiatOncol Biol Phys2008;76:440 Postoperativeradiotherapy:“meta-analysis” • Inclusioncriteria: - studiespublishedfrom1981to2008 - surgeryvs.surgery+radiotherapy - thymoma andthymic carcinoma - completeresection - stageIIandIII • Results: - 13studies,542patients - radiotherapy:250patients - noradiotherapy:342patients - OR=1.05(0.63;1.75-0.84)onrecurrencerate Korst etal.AnnThorac Surg 2009;87:1641 Postoperativeradiotherapy:ITMIGdatabase Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging Resectable tumors - Surgery - Postoperativeradiotherapy 2016 Recurrencerates ITMIGretrospective database Cumulativeincidenceofrecurrences inMasaoka-Koga groups 100 Thymomas (n = 7 005) % 100 80 80 60 60 40 40 20 20 0 0 0 5 10 15 20 25 Thymic carcinomas (n = 977) % 0 5 10 Years Stage I/II Stage III Stage IVA Stage IVB Events/n 121/3 097 140/654 64/109 17/38 15 20 Years 10-year recurrence % (IC95) 8 (7-8) 29 (27-31) 71 (34-100) 57 (24-90) Events/n Stage I/II Stage III Stage IVA Stage IVB 28/112 68/143 19/26 20/37 10-year recurrence % (IC95) 25 (22-29) 59 (44-76) 76 (58-100) 54 (37-67) Detterbecketal.WCLC2013,abstr.MS16.2 RecurrencebyWHOHistology,R0,stageI,II P<0.006forTCvs anyWHOtype TC B2 B1 B3 A AB }P=NS }P=NS Population: AllR0stageI,IIpts withrecurrenceoutcomeandWHOsubtypeinformation P<0.01 Weissetal.ITMIG2014 Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging Resectable tumors - Surgery - Postoperativeradiotherapy 2016 Recommandations RYTHMIC ESMOClinicalPracticeGuidelines Girardetal.AnnOncol 2016;26:v40 Recommandations RYTHMIC ESMOClinicalPracticeGuidelines Girardetal.AnnOncol 2016;26:v40 Recommandations RYTHMIC ESMOClinicalPracticeGuidelines Girardetal.AnnOncol 2016;26:v40 Recommandations RYTHMIC ESMOClinicalPracticeGuidelines Girardetal.AnnOncol 2016;26:v40 Recommandations RYTHMIC ESMOClinicalPracticeGuidelines Girardetal.AnnOncol 2016;26:v40 Recommandations RYTHMIC ESMOClinicalPracticeGuidelines Girardetal.AnnOncol 2016;26:v40 Recommandations RYTHMIC ESMOClinicalPracticeGuidelines Girardetal.AnnOncol 2016;26:v40 Recommandations RYTHMIC ESMOClinicalPracticeGuidelines Girardetal.AnnOncol 2016;26:v40 Recommandations RYTHMIC ESMOClinicalPracticeGuidelines Girardetal.AnnOncol 2016;26:v40 Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging Resectable tumors - Surgery - Postoperativeradiotherapy Unresectable tumors 2016 Tumeur thymiques localement avancée • Critèresd’inclusiondanslesessaisencours - Diamètre supérieur à 8cm - Diamètre compris entre5et8cm,avecl’un descritères suivants: - calcificationmultifocale - apparence hétérogène - bords irréguliers - invasionou engainement vasculaire - Diamètre inférieur à 5cmetinvasionou engainement vasculaire NCT00387868(PI:R.Korst) Définition delanon-résécabilité? Masaoka-Koga :III Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging Resectable tumors - Surgery - Postoperativeradiotherapy Unresectable tumors - Primarychemotherapy 2016 Locally-advancedtumors:multimodaltreatment NationalComprehensiveCancerNetworkGuidelines Pre-operativechemotherapy Response rate 80% Parketal,2013CDDP-Doc27T/TCIII/IVPhaseII 63 GirardN.Eur Respir Rev2013;22:75 Chimiothérapie pré-opératoire Enpratique: Response rate 80% CAP 2+2cycles Parketal,2013CDDP-Doc27T/TCIII/IVPhaseII63 GirardN.ASCO2012EducationalBook Parketal.JThorac Oncol 2013;8:959 RYTHMIC:Chimiothérapie d’induction Etoposide 3% Other/Unk VIP nown 3% 9% PE 4% Carboplatin Paclitaxel 16% CAP 65% Etoposide +/- Platin Others 6% 8% Paclitaxe l+… CAP 76% Proposedregimens Administeredregimens n=149 n=91 MerveilleuxduVignaux,etal.ITMIG2016 RYTHMIC:Chimiothérapie d’induction Etoposide +/- Platin Others 6% 8% Paclitaxe l+… CAP 76% Administeredregimens n=91 MerveilleuxduVignaux,etal.ITMIG2016 RYTHMIC:Chimiothérapie d’induction 100% 100% 4% Etoposide90% +/- Platin 80%Others 8% 70% 6% Paclitaxe 60% 77% l+… 50% 90% 36% 20% CAP 76% 10% 17% 0% 2% Primary 60% 36% 50% 36% 28% Exclusive 4% 7% 19% Progression 44% 77% 42% 40% 20% 13% 19% 30% Administeredregimens n=91 80% 70% 40% 30% 7% 4% 10% 31% 17% 0% 2% Stable 36% Partial response Complete response 42% 28% 13% 31% Progression 71% 42% 44% Stable Partial 54% 25%31% response Complete response 42% 15% Recurrence1 Primary Recurrence2 Exclusive Recurrence3 Recurrence1Recurrence4 Recurrence2 Tumorresponse MerveilleuxduVignaux,etal.ITMIG2016 RYTHMIC:Chimiothérapie d’induction 100% 100% 4% Etoposide90% +/- Platin 80%Others 8% 70% 6% Paclitaxe 60% 77% l+… 50% 90% 36% 20% CAP 76% 10% 17% 0% 2% Primary 60% 36% 50% 36% 28% Exclusive 4% 7% Median:20.7months 13% 19% Progression 44% 77% 42% 40% 20% 13% 19% 30% Administeredregimens n=91 80% 70% 40% 30% 7% 4% 10% 31% 17% 0% 2% Stable 36% Partial response Complete response 42% 28% 31% Progression 71% 42% 44% Stable Partial 54% 25%31% response Complete response 42% 15% Recurrence1 Primary Recurrence2 Exclusive Recurrence3 Recurrence1Recurrence4 Recurrence2 Tumorresponse Recurrence-free survival MerveilleuxduVignaux,etal.ITMIG2016 Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging Resectable tumors - Surgery - Postoperativeradiotherapy Unresectable tumors 2016 - Primarychemotherapy - Surgery Treatmentofthymic tumors • Locallyadvancedtumors:primarychemotherapy NationalComprehensiveCancerNetworkGuidelines Pre-operativechemotherapy Complete resection 50% (14-78%) Response rate 80% Parketal,ASCO2012CDDP-Doc27T/TCIII/IV70 63425 GirardN.Eur Respir Rev2013;22:75 Chirurgie destumeurs destade IVA Pleuralchemo-hyperthermia Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging Resectable tumors - Surgery - Postoperativeradiotherapy Unresectable tumors 2016 - Primarychemotherapy - Surgery - postoperativetreatment Recommandations RYTHMIC ESMOClinicalPracticeGuidelines Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging Resectable tumors - Surgery - Postoperativeradiotherapy Unresectable tumors 2016 - Primarychemotherapy - Surgery - postoperativetreatment - Definitiveradiotherapy Treatmentofthymic tumors • Locallyadvancedtumors:primarychemotherapy NationalComprehensiveCancerNetworkGuidelines Chimio-radiothérapie exclusive Response rate 20-30% 80% of patients Parketal,ASCO2012CDDP-Doc27T/TCIII/IV70 63425 GirardN.Eur Respir Rev2013;22:75 Definitivechemo-radiotherapyforthymomas • Limiteddataintheliterature…noconsensus - Sequentialapproach: - 23patients,stageIII-IVunresectable thymoma - inductionwithCAP(4cycles),thenradiotherapy - 5-yearPFS:54% - 5-yearOS:53% Loehrer etal.JClin Oncol 1997;15:3093 - Concurrentapproach: Korst etal.JThorac Cardiovasc Surg 2014;147:36 Stades localement avancés:chimio-radiothérapie Enpratique: Loehrer,JClin Oncol 1997;15:3093 Réponse partielle: radiothérapie séquentielle Progression/stabilisation (B2-B3): Kitamietal.Jpn JClin Oncol 2001;31:601 radio-chimiothérapie Nakamuraetal.Jpn concomitante JClin Oncol 2000;30:385 Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging Resectable tumors - Surgery - Postoperativeradiotherapy Unresectable tumors 2016 - Primarychemotherapy - Surgery - postoperativetreatment - Definitiveradiotherapy Metastatic tumors - First-linechemotherapy Palliative-intentchemotherapy chemotherapy NationalComprehensiveCancerNetworkGuidelines Palliative-intentchemotherapyregimens GirardN.ASCO2012EducationalBook Palliative-intentchemotherapyregimens Anthracyclin-based Response:70-80% Non-anthracyclin-based Response:30-50% GirardN.ASCO2012EducationalBook Carboplatine-Paclitaxel Thymoma Thymic carcinoma 100% 80% - Reproductibleresults 60% Progression 40% Stabledisease 20% - Anewstandardfor thymic carcinomas? - Dowe need atrialof platine-paclitaxel vs.CAP? Objectiveresponse 0% Lemma Current n=21 study n=13 Lemma n=23 Hirai n=39 Current study n=27 PFS(months) Thymoma Thymic carcinoma Currentstudyn=13 Lemman=21 Currentstudyn=27 Hirain=39 Lemman=23 0 5 10 15 20 Stades avancés ou métastatiques Anthracyclines Réponse:70-80% Enpratique Premièreligne:CAP Sansanthracyclines Réponse:30-50% Carboplatine-Paclitaxel 4-6cycles GirardN.ASCO2012EducationalBook Corticosteroidsandthymomas •Depletionofthelymphocyticpopulation - “thymolytic effect” •Steroidreceptorsin83%ofthymomas •TumorresponsesreportedintypeBthymomas - 18cases,mixedthymoma:10partial responses,4completeresponses - responsemaybeprolonged>12months - re-responsemaybeprolonged •Specificities: - opportunisticinfections - increasedriskofmyasthenic crisis Cravenetal.MuscleNerve1981;4:425 Mimae etal.Cancer2011;117:4396 Kirkove Cetal.Clin Oncol 1992;4:64 RYTHMIC:Exclusive(first-line)chemotherapy VIP 3% Other/Unkn own 11% PE 19% Etoposide +/- Platin 12% CAP 35% Carboplatin Paclitaxel 32% Paclitaxel + Carboplat in 20% Others 2% CAP 66% Proposedregimens Administeredregimens n=37 n=41 RYTHMIC:Exclusive(first-line)chemotherapy Etoposide +/- Platin 12% Others 2% Paclitaxel+ Carboplatin 20% CAP 66% Administeredregimens n=41 RYTHMIC:Exclusive(first-line)chemotherapy 100% Etoposide +/- Platin90% 12% 100% 4% Others 80% 80% 4% 100% 90% 36% 80% 70% 70% 70% 60% 60% 60% 2% 90% 77% 50% Paclitaxel+ Carboplatin 40% 20% 30% 20% 77% 50% 36% 50% 40% 40% CAP 30% 66% 20% 30% 10% 17% 10% 0% 2% 0% Primary 20% 28% 17% 10% 2% 13%7% 19%36% 19% 36% Progression 44% 77% 42% 36% 31% 28% 17% Stable 42% 36% Partial response Complete response 42% 31% 28% 4% 7% 13% 19% 4% 13% 31% Progression Progression Stable Stable 71%44% 42% Partial response Complete response 42% 25%31% 44% 71% Partial 54% response Complete response 42% 25% 15% 2% Exclusive Primary Recurrence2 Exclusive Recurrence3 Recurrence1Recurrence4 Recurrence2 Primary Recurrence1 Exclusive Recurrence1 Recurrence2 Recurrence3 Administeredregimens n=41 0% 7% 4% Tumorresponse RYTHMIC:Exclusive(first-line)chemotherapy 100% Etoposide +/- Platin90% 12% 100% 4% Others 80% 80% 4% 100% 90% 36% 80% 70% 70% 70% 60% 60% 60% 2% 90% 77% 50% Paclitaxel+ Carboplatin 40% 20% 30% 20% 77% 50% 36% 50% 40% 40% CAP 30% 66% 20% 30% 10% 17% 10% 0% 2% 0% Primary 20% 28% 17% 10% 2% 13%7% 19%36% 19% 36% Progression 44% 77% 42% 36% 31% 28% 17% Stable 42% 36% Partial response Complete response 42% 31% 28% 4% 7% 4% Median:6.2months 13% 13% 19% 31% Progression Progression Stable Stable 71%44% 42% Partial response Complete response 42% 25%31% 44% 71% Partial 54% response Complete response 42% 25% 15% 2% Exclusive Primary Recurrence2 Exclusive Recurrence3 Recurrence1Recurrence4 Recurrence2 Primary Recurrence1 Exclusive Recurrence1 Recurrence2 Recurrence3 Administeredregimens n=41 0% 7% 4% Tumorresponse Progression-free survival Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging Resectable tumors - Surgery - Postoperativeradiotherapy Unresectable tumors 2016 - Primarychemotherapy - Surgery - postoperativetreatment - Definitiveradiotherapy Metastatic tumors - First-linechemotherapy - Recurrences: - second-linetreatment Surgeryforrecurrences Surgeryforrecurrences Bae etal.JThorac Oncol 2012;7:1304 Second-linechemotherapyandbeyond GirardN.ASCO2012EducationalBook Second-linetreatmentofTumeurs thymiques Thymoma Thymic carcinoma 100% 80% 60% 40% 20% 0% Progression Stabledisease Objectiveresponse Thymoma Amrubicine Everolimus Octreotide SUNITINIB CAP-GEM Pemetrexed Thymic carcinoma Amrubicine Everolimus Octreotide SUNITINIB CAP-GEM Pemetrexed PFS(months) 0 2 4 6 8 10 12 14 Seconde ligne etplus Enpratique: Carbo-Px,PE,Pemetrexed re-administrationduCAP (PS=0/1,réponse antérieure,rechute tardive;max.8cycles) GirardN.ASCO2012EducationalBook RYTHMIC:Systemictreatmentsforrecurrence Pemetrexed Capecitabine 4% Gemcitabine 4% driamycin 2% Proposed regimens Other 7% Carboplatin Paclitaxel 38% CAP 12% Etoposide 16% PE 11% Paclitaxel 6% Lucitanib* Everolimus 11% 4% Milciclib* 8% Sunitinib Somatostatin 47% e 12% Bevacizumab Sorafenib 15% 3% Chemotherapy Targetedagents n=114 n=67 RYTHMIC:Systemictreatmentsforrecurrence Administered regimens Others Milciclib Othe Pemetrex 6% 3% rs… ed Paclitaxel Sunitin 3% +/Pemetr… ib/oth Sunitinib/Lu… Carboplat er… Etopos in CAP 44% ide Paclitaxel 13% 12% +/Etoposid Carbopl… Etoposid e e+Platin Recurrence 2 4% 16% Firstrecurrence n=79 n=54 Others 28% Other s Sunitin 31% ib/oth er VEGF… Everoli mus 7% Paclitax Pemetre el+/xed… Platin… Everolim us… Pemetre Etoposi xed… de+… Recurrence 3 Recurrence 4 n=29 n=13 Su n 1 RYTHMIC:Systemictreatmentsforrecurrence 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 4% 36% 100% 7% 90% 19% 80% 77% 70% 36% 4% 13% 44% 42% 60% 17% 2% 28% 31% 7% 31% 42% 30% 20% 10% 17% 0% 2% Primary 71% Progression 25% Stable 15% Partial response Complete response 42% 31% 28% 44% 54% 42% 36% Exclusive 13% 19% 36% 77% 50% 40% 4% Recurrence1 Recurrence2 n=91n=41n=79n=64n=29 n=13 Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging Resectable tumors - Surgery - Postoperativeradiotherapy Unresectable tumors 2016 - Biopsy - Primarychemotherapy - Surgery - postoperativetreatment - Definitiveradiotherapy Metastatic tumors - First-linechemotherapy - Recurrences: - second-linetreatment - Targetedagents Octreotide • About50%ofthymomas doexpresshighlevelsofsomatostatin receptorsat 111In-DTPA-octreotide(OctreoScan®) • Responseratesarehigherinthymoma vs.thymic carcinoma: Corticoids Palmieri,2002 Loehrer,2004 Schalke,ASCO2012 + +/+ n 10 32 17 Thymoma CR+PR 4 12 15 SD 4 11 0 Thymic carcinoma n CR+PR SD 3 1 1 5 0 3 0 0 0 Palmieri etal.Cancer2002;94:1414;Loehrer etal.JClin Oncol 2004;22:293 Schalke B,etal.JClin Oncol 2012;30(suppl;abstr 7105) Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging Resectable tumors - Surgery - Postoperativeradiotherapy Unresectable tumors 2016 - Biopsy - Primarychemotherapy - Surgery - postoperativetreatment - Definitiveradiotherapy Metastatic tumors - First-linechemotherapy - Recurrences: - second-linetreatment - Targetedagents KITandthymictumors • Overexpression: - collectively20%of501tumors - correlationwithhistologic type: - 2%ofthymomas - vs. 87%ofcarcinomas (p=0.003) - diagnosticbiomarkerforthymic carcinoma • Mutations: Zucali et al. - 11%ofthymic carcinomas (14/129tested) Sensitivity toKITinhibitors Imatinib Sunitinib Sorafenib 107 4 (3%) Mutation E490K Y553N W557R V559A V560del L576P P577-D579del D579del H697Y D820E 6 13 (46%) Exon 9 11 11 11 11 11 11 11 14 17 Neoangiogenesis • Expressionofangiogenesis-relatedbiomarkers - increasednumberofcellsexpressingVEGF-A,-C,-D,andVEGFR-1,-2 - increasedserumlevelsofVEGFinthymic carcinomas Cimpean etal.AnnAnat 2008;190:238; Sasakietal.Surg Today2001;31:1038;MarinoetPiantelli.ThorSurg Clin 2011;21:33 KIT wild-typetumors Thymic carcinoma SSP : 7,6 mois Thymoma SSP : 6,7 mois LancetOncol 2016;16:177 Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging Resectable tumors - Surgery - Postoperativeradiotherapy Unresectable tumors 2016 - Biopsy - Primarychemotherapy - Surgery - postoperativetreatment - Definitiveradiotherapy Metastatic tumors - First-linechemotherapy - Recurrences: - second-linetreatment - Targetedagents PhaseItrials 21patients DCR=60%withmTOR inhibitors n=10 Oncotarget2013;4:890 PhaseItrials Median:11.6months Median:2.3months ASCO2014:everolimus [TITLE] ASCO2014:everolimus [TITLE] Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging Unresectable tumors 2016 Resectable tumors - Surgery - Postoperativeradiotherapy Initiatives&Opportunities - Biopsy - Primarychemotherapy - Surgery - postoperativetreatment - Definitiveradiotherapy Metastatic tumors - First-linechemotherapy - Recurrences: - second-linetreatment - Targetedagents Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging Unresectable tumors 2016 Resectable tumors - Surgery - Postoperativeradiotherapy Initiatives&Opportunities - ITMIG:databases - Biopsy - Primarychemotherapy - Surgery - postoperativetreatment - Definitiveradiotherapy Metastatic tumors - First-linechemotherapy - Recurrences: - second-linetreatment - Targetedagents ITMIGDatabases:website is ccehub.org Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging Unresectable tumors 2016 Resectable tumors - Surgery - Postoperativeradiotherapy Initiatives&Opportunities - ITMIG:databases - ETOP/EORTC:translationalmedicine - Biopsy - Primarychemotherapy - Surgery - postoperativetreatment - Definitiveradiotherapy Metastatic tumors - First-linechemotherapy - Recurrences: - second-linetreatment - Targetedagents Targetingimmunecheckpoints? Giaconne.ASCO2014 Pembrolizumab phaseIItrial(NCI,GGiaccone) TATcongress 2016 with&a&close&monitor&of&toxicity&for&the&first&10&pa=ents& EORTC-ETOPNIVOTHYM:B3andcarcinomas Primary&objec=ve:& To!detect!ac@vity!of!nivolumab!as!single!agent!versus!the!best! inves@gator’s!choice!as!second!line!treatment!for!thymic!malignancies! Eligible&pa=ents& SecondCline& 50!pa@ents! ! Nivolumab&3&mg/kg&IV&q2&weeks&& Stra=fica=on&factors& • !Histology!(squamous!vs!non1sq!vs!small!cell)! • !Previous!RT!(yes!versus!no)! • !Best!response!to!first!line!treatment!(PR!vs!SD!vs!PD)! • !Center! Primary&endpoint:&PFS&at&6&months& Secondary&endpoints:&TTP,!Response,!! ! !!!!!!!Dura@on!of!response,!OS! !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!QOL,!Safety! Biomarkers& & PDCL1&at&baseline&and&PD& Others:&immune&paQerns,&& molecular&profile& ! & Courtesy JMenis Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging Unresectable tumors 2016 Resectable tumors - Surgery - Postoperativeradiotherapy Initiatives&Opportunities - ITMIG:databases - ETOP/EORTC:translationalmedicine - RYTHMIC:Tumorboardandnetwork - Biopsy - Primarychemotherapy - Surgery - postoperativetreatment - Definitiveradiotherapy Metastatic tumors - First-linechemotherapy - Recurrences: - second-linetreatment - Targetedagents RYTHMIC:aregionalnetworkofexpertcenters Coordinator: B.Besse Gustave Roussy RYTHMIC:Infrastructureofthenetwork Guidelines CME activities Prospectivedatabaseandtrials National Pathology Panel Nationalexpert tumorboard Treating Physician Regionalexpertcenter Patients RCPRYTHMIC Onlinevirtualtumorboard Regional expert teams Thoracic surgeons Medical oncologists Radiationoncologists Pathologists Radiologists Pneumonologists Neurologists RYTHMIC:Multidisciplinarytumorboard - 1000patients:1401questionsraisedatthemulti-disciplinarytumorboard UpfrontSurgery? n=182(13%) Diagnosis / Imaging n=82 (6%) Surgery? Primary Chemo therapy? n=28(2%) n=494 (35%) Postoperative Chemo therapy? n=5(0%) Definitive Radiotherapy? Diagnosis? n=47(3%) Surgery? n=30(2%) Radiotherapy? n=45(3%) n=17(1%) ExclusiveChemotherapy? Chemotherapy? n=37(3%) n=114(8%) n=149(11%) Initial management Postoperative Radio therapy? Recurrences Follow-up? n=104(7%) Targetedagent? n=67(5%) Tumeurs thymiques Specificities - Thymic origin - Complexhistology - Auto-immunity - Staging Unresectable tumors 2016 Resectable tumors - Surgery - Postoperativeradiotherapy Initiatives&Opportunities - ITMIG:databases - ETOP/EORTC:translationalmedicine - RYTHMIC:Tumorboardandnetwork - Biopsy - Primarychemotherapy - Surgery - postoperativetreatment - Definitiveradiotherapy Metastatic tumors - First-linechemotherapy - Recurrences: - second-linetreatment - Targetedagents Tumeurs thymiques Specificities Unresectable tumors - Thymic origin - Complexhistology - Auto-immunity - Staging Thankyou! 2016 - Biopsy - Primarychemotherapy - Surgery - postoperativetreatment - Definitiveradiotherapy Resectable [email protected] tumors - Surgery - Postoperativeradiotherapy www.rythmic.org Initiatives&Opportunities - ITMIG:databases - ETOP/EORTC:translationalmedicine - RYTHMIC:Tumorboardandnetwork Metastatic tumors - First-linechemotherapy - Recurrences: - second-linetreatment - Targetedagents
