Nicolas Girard - splf.frsplf.fr/wp-content/uploads/2016/09/GOLFTHY5.pdf · Les tumeurs du thymus...

Lestumeurs duthymus

NicolasGirardInstitut 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.

2016

Tumeurs thymiques

Tumeurs thymiques

• Incidence:0,15-0,30/100000people

• 250casesinFrance/year

Engelsetal.IntJCancer2003;105:546InstitutNationalduCancer,e-cancer.fr

Prostate70000

Breast55000Colo-rectal

41000Hodgkin1800

Mesothélioma800

GIST900

Melanoma10000 LUNG

40000

Thymomas250

Retinoblastoma100

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 14regional 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.

BACKGROUND AND OBJECTIVE

B

C

A

B

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’srequest. Although we might underestimate the incidence, it seems to be higher compared to

other countries’ registries. The high occurrence of previous cancer might underlie variations in

environmental or genetic risk factors.

A

PATIENTS AND METHODS

RESULTS

CONCLUSION

-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.

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

Updated incidence of Thymic Epithelial Tumors (TET) in France and clinical presentation at diagnosis

UK: unknown; CAP: cisplatin, doxorubicin,cyclophosphamide; VIP: cisplatin, etoposide,ifosfamide.

Patient’s characteristics and treatment

Frequencyn=226 (%)

Primary treatmentUpfront SurgeryNeo-adjuvant chemotherapy ChemotherapyAdjuvant radiotherapy

170 (75)8 (3)

40 (18)55 (24)

Surgery ApproachSternotomyVideothoracoscopyRobot assisted ThoracotomyOther

178 (100)108 (61)37 (21)15 (8)9 (5)9 (5)

ChemotherapyCAPCarboplatin-paclitaxelCarboplatin-etoposide

33 (63)16 (31)3 (6)

Frequency n=226 (%)

Age Median [range] 62 [25 – 86]

GenderMaleFemale

129(57)97(43)

Auto-inmune disorderMyastheniaAnemiaThyroiditisHypogammaglobulinemiaOthers

46 (20)353224

Previous cancerProstateBreastMelanomaHematologicOther

34 (15)974211

Mode of diagnosisResectionSurgical biopsyImaging guided biopsy

158 (70)35 (15)33 (15)

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) populationdata 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.

Significant correlations were found between histologic sub-type (Thymomavs. Thymic carcinoma) and presence of an autoimmune disorder (p=0.01)and stage (I-II vs. III-IV, p=0.004); no significant correlations were seen withgender (p=0.27)

0,00

5,00

25 75

MenB. Age-specific incidence of TET

Distribution of stage (Masaoka-Koga ITMIG modified) and histology (WHO2004 classification).

Specificities

2016

Tumeurs thymiques

Specificities- Thymic origin

2016

Tumeurs thymiques

Thethymus

Thymus

Celluleépithélialemédullaire

Celluledendritique

Apoptose

ToléranceimmunitaireAuxantigènesdusoi

Délétionclonale

Lymphocyteimmature

Sélection positivedeslymphocytes

Celluleépithélialemédullaire

Celluledendritique

Apoptose


Délétionclonale

Celluleépithélialethymique

CORTEX

Lymphocyteimmature


MEDULLACelluledendritique

Apoptose


Délétionclonale

Lymphocyteimmature

Sélectionnégativedeslymphocytes

Mathisetal.AnnuRevImmunol2009;27:287

Celluledendritique

Apoptose


Délétionclonale

Lymphocyteimmature




Apoptose

Celluledendritique

Apoptose

Toléranceimmunitaireaux antigènesdusoi

Délétionclonale

Lymphocyteimmature




Apoptose

Celluledendritique

Apoptose


Délétionclonale

Lymphocyteimmature




Apoptose

Specificities- Thymic origin- Complexhistology

2016

Tumeurs thymiques

• WorldHealthOrganization2016

A AB B1 B2 B3

“Médullary” Mixed “Cortical”

Histo-pathologicclassification

SCC

Thymoma Carcinoma

Reproductibilité delaclassification?

• Reproductibilité imparfaite

- Variabilité delaproportiondechaque type

- Etudedereproductibilitéinter-observateur:k=0,45-0,49

Marchevsky etal.Cancer2008; 112:2780Rieker etal.Int JCancer2002;98:900;Verghese etal.Histopathology2008;53:218


• Reproductibilité imparfaite

- Hétérogénéité tumorale desthymomes detypeA

InternationalThymic MalignancyInterestGroup2011


• Reproductibilité imparfaite:

- Formes combinées :25%descas?- Formes frontières

InternationalThymic MalignancyInterestGroup2011

Thymome type B2 (n=22)

Thymome type A (n=8)

Thymome type B3 (n=8)

Carcinome thymique (n=7)

Genomicprofilingofthymic epithelialtumors

Girardetal.Clin CancerRes2009; 15:6790

• MSKCC,45patients

The2016 WHOclassification

Actualisation delaclassificationhisto-pathologique

Intérêt deladoublelectureanatomopathologique

Specificities- Thymic origin- Complexhistology- Auto-immunity

2016

Tumeurs thymiques

Celluledendritique

Apoptose


Délétionclonale

Lymphocyteimmature




Apoptose

Lesthymomesn’exprimentpasAIRE

Ströbeletal.JPathol2007;211:563

ExpressiondeAIRE(ARNm)dans 20thymomes (controle :thymussain).

Celluledendritique

Apoptose


Délétionclonale

Lymphocyteimmature

Manifestationsauto-immunes

Celluleépithélialethymiquetumorale

Délétionclonale

Auto-immunitéPasdedélétion

clonalePasd’apoptose

NeuromuscularMyastheniagravisPeripheralneuropathyPolymyositisDermatomyositisEncephalitisOpticalmyelitis

HaematologicdisordersRedcellaplasiaPerniciousanaemiaErythrocytosisPancytopoeniaHaemolyticanaemiaLeukaemiaMultiplemyeloma

Auto-immunedisordersSystemiclupuserythematosusRheumatoidarthritisSjogren’ssyndromeScleroderma

EndocrinedisordersMultipleendocrineneoplasiaCushing’ssyndromeThyrotoxicosisPneumonitis

DermatologicdisordersPemphigusLichenplanusChronicmucosalcandidiasisAlopeciaareata

MiscellaneousGiantcellmyocarditisNephroticsyndromeUlcerativecollitisHypertrophicosteoarthropathyInterstitialpneumonitis

ImmunedeficiencydisordersHypogammaglobulinaemiaT-celldeficiencysyndrome

Auto-immunedisorders

Syndromespara-thymiques

• Bilan minimalrecommandé encas desuspiciondemanifestationsauto-immunesassociées auxtumeurs thymiques

Rinaldietal.NeurolSci2009;30:237

• Causesofdeath:

Huangetal.JThorac Oncol 2010;5:2017

Prognosisofthymoma

Specificities- Thymic origin- Complexhistology- Auto-immunity- Staging 2016

Tumeurs thymiques

Masaoka-Kogastagingsystem

ClassificationMasaoka-Koga-ITMIG

Detterbecketal.JThorac Oncol 2011;6:S1710

• Classificationanatomo-clinique:pTNM

• Evaluableaprèsrésection chirurgicale

Stade I


Stade IIA


Stade IIB


Stade III


Stade IVA


Stade IVB


Masaoka-Kogastagingsystem

Surgicalpathologystaging

Noclinicalstaging

Thymic epithelialtumors:stageandhistology

WHO,2016

Regnard etal.JThorac Cardiovasc Surg 1996;112:376Mooreetal.AnnThorac Surg 2001;72:203

Gawrychowski etal,EurJ Surg Oncol 2000;26:203-8

PrognosticvalueoftheMasaoka stagingsystem


Tumeurs thymiques

InternationalThymic MalignancyInterestGroup

Masaoka-Koga :I,IIA,IIB,III

Masaoka-Koga :III

Masaoka-Koga :IVA,IVB Masaoka-Koga :IVB

• Causesofdeath:

Huangetal.JThorac Oncol 2010;5:2017

Prognosisofthymoma

Stage,Histology,Other?

• ThemostsignificantprognosticfactorinTumeurs thymiquesis thecompletionofsurgicalresection,whateverclassificationisused.

Rossietal.Histopathology2008;53:483

TreatmentofTumeurs thymiques

• Firstquestionis:resectable ornot?

NationalComprehensiveCancerNetworkGuidelines

Specificities- Thymic origin- Complexhistology- Auto-immunity- Staging

Resectabletumors

2016

Tumeurs thymiques

• Lestumeursprimitivesdumédiastinantérieurontunaspectradiologiquesouventsimilaire

Diagnosticdifférentiel

Tératome

MaladiedeHodgkin

Tumeurgerminalenonséminomateuse

Thymome

Tumeurs médiastinales:signes cliniques

• Absencedetabagisme:80%destumeursmédiastinales

• Age<40ans:50%destumeursmédiastinales

JThorac Oncol 2014;9:S102


Resectabletumors

2016

Tumeurs thymiques

Nécessitéd’unebiopsiepré-thérapeutique

• Lachirurgieestrecommandéed’embléepourcertainestumeursdumédiastin:- Tumeursbénignes:tératomes- Tumeurskystiques- Thymomesnoninvasifs/encapsulés/avecenvahissementlimité

Kesler etal.AnnThorac Surg 2008;85:371Kesler etal.ThorSurg Clin 2009;19:63

Lemarié etal.Chest1992;102:1477


• Lachirurgieestrecommandéed’embléepourcertainestumeursdumédiastin:- 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




• Lachirurgieestrecommandéed’embléepourcertainestumeursdumédiastin:- Tumeursbénignes:tératomes- Tumeurskystiques- Thymomesnoninvasifs/encapsulés

• Lachimiothérapieestuneurgenceencasdetumeurgerminalemaligne:- silesmarqueurssontélevés:14-35%ofcases

- α-foeto-protéine>1000kUI/L- tumeurgerminalenonséminomateuse (sacvitellin)

- β-human chorionic gonadotrophin >5000kUI/L- tumeurgerminalenonséminomateuse (choriocarcinome)- rareencasdeséminome



Dans tous lesautres cas

biopsie


Resectabletumors

2016

Tumeurs thymiques

• CTscan:low-attenuation,symmetricandfattypattern,maintainingthebi-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?

Thymome ou hyperplasie thymique?

• ELCAPlung cancerscreeningstudy:- forme ovoïdeettaille<3cm:hyperplasie

Henschke etal.Radiology 2006;23:239:586

Imagerie pré-thérapeutique

Kimar etal.AnnNucl Med2009;23:569Endoetal.LungCancer2008;61:350

- UtilisationduPET-scan:corrélationavecclassifications


Igai etal.Eur JCardiothor Surg 2011;40:143Kimar etal.AnnNucl Med2009;23:569;Endoetal.LungCancer2008;61:350

Kaira etal.JClin Oncol 2011;28:3746;Shibataetal.Cancer2009;115:2531

- UtilisationduPET-scan:hyperplasie vs.thymomevs.carcinomethymique

T2WFS Inphase Opposedphase

Hyperplasie thymique


Resectabletumors

2016

Tumeurs thymiques

JThorac Oncol 2011;6:1274 JThorac Oncol.2014;9:1023


- Prédictionde l’invasivité parlatomodensitométrie:MDAnderson,99patients

Masaoka-Koga :I,IIA,IIB,III

Définition delarésécabilité


Tumeurs thymiques

- Surgery

Resectabletumors

• Mediansternotomy isthestandardapproach• Completeexplorationofthepleuralcavities

• Completethymectomy,including tumor,normalthymus,andmediastinal fat• enbloc resectionofinvolvedstructures:

- lung,vessels,pleuralimplants,phrenicnerves- surgicalclipsinareasofconcern

• Mediastinal notessampling/resection (stageIIItumor/thymic carcinoma)

• Frozensectionnotrecommendedformarginsassessment

Surgeryrecommendations

Orientationand markingintheoperativeroom

• Useofamediastinal board

Minimally-invasivesurgery?


Tumeurs thymiques

- Surgery- Postoperativeradiotherapy

Resectabletumors

StageIStageII-III

…butnobenefitaftercompleteresection

```` (p=0.12)

• Population: - thymomas andthymic carcinomas- 1973-2005,901patients:275stageI,626stageII-III

Postoperativeradiotherapy:SEERdatabase

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


Resectabletumors

68/143

20/37

0

20

40

60

80

100

0 5 10 15 20 25

Stage I/IIStage IIIStage IVAStage IVB

%

Years

Events/n 10-year recurrence % (IC95)121/3 097140/65464/10917/38

8 (7-8)29 (27-31)71 (34-100)57 (24-90)

0

20

40

60

80

100

0 5 10 15 20

Stage I/IIStage IIIStage IVAStage IVB

%

Years

28/112

19/26

25 (22-29)59 (44-76)

76 (58-100)54 (37-67)

Thymomas(n = 7 005)

Thymic carcinomas(n = 977)

Cumulativeincidenceofrecurrences inMasaoka-Koga groups

ITMIGretrospective database

Detterbecketal.WCLC2013,abstr.MS16.2

Recurrencerates

Events/n 10-year recurrence % (IC95)

Population: AllR0stageI,IIpts withrecurrenceoutcomeandWHOsubtypeinformation

RecurrencebyWHOHistology,R0,stageI,II

P<0.006forTCvs anyWHOtype

TC

B3

A AB

B2B1

}P=NS}P=NS

P<0.01

Weissetal.ITMIG2014


Tumeurs thymiques


Resectabletumors

Girardetal.AnnOncol 2016;26:v40

Recommandations RYTHMICESMOClinicalPracticeGuidelines


Tumeurs thymiques


Resectabletumors

Unresectabletumors

• 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

Tumeur thymiques localement avancée

NCT00387868(PI:R.Korst)

Définition delanon-résécabilité?

Masaoka-Koga :III


Tumeurs thymiques


Resectabletumors

Unresectabletumors

- Primarychemotherapy

Locally-advancedtumors:multimodaltreatment


Pre-operativechemotherapy

Responserate80%

GirardN.Eur Respir Rev2013;22:75

Parketal,2013CDDP-Doc27T/TCIII/IVPhaseII 63

Responserate80%

Chimiothérapie pré-opératoire

GirardN.ASCO2012EducationalBookParketal.JThorac Oncol 2013;8:959

Parketal,2013CDDP-Doc27T/TCIII/IVPhaseII63

Enpratique:

CAP2+2cycles

CAP65%

CarboplatinPaclitaxel

16%

PE4%

VIP3%

Etoposide3% Other/Unk

nown9%

Proposedregimens

n=149

Administeredregimens

n=91

CAP76%

Paclitaxel+…

Etoposide+/- Platin

8%

Others6%

RYTHMIC:Chimiothérapie d’induction

MerveilleuxduVignaux,etal.ITMIG2016


n=91

CAP76%

Paclitaxel+…

Etoposide+/- Platin

8%

Others6%




n=91

CAP76%

Paclitaxel+…

Etoposide+/- Platin

8%

Others6%

2%

28% 31%42%

25%15%17%

36%42%

44%71%

54%

77%

36% 19%

13%4%

31%

4% 7%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Primary Exclusive Recurrence1 Recurrence2 Recurrence3 Recurrence4

Progression

Stable

PartialresponseCompleteresponse

2%

28% 31%42%

25%15%17%

36%42%

44%71%

54%

77%

36% 19%

13%4%

31%

4% 7%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%


Progression

Stable


Tumorresponse




n=91

CAP76%

Paclitaxel+…

Etoposide+/- Platin

8%

Others6%

2%

28% 31%42%

25%15%17%

36%42%

44%71%

54%

77%

36% 19%

13%4%

31%

4% 7%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%


Progression

Stable


2%

28% 31%42%

25%15%17%

36%42%

44%71%

54%

77%

36% 19%

13%4%

31%

4% 7%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%


Progression

Stable


TumorresponseRecurrence-free

survival

Median:20.7months




Tumeurs thymiques


Resectabletumors

Unresectabletumors

- Primarychemotherapy- Surgery

Treatmentofthymic tumors

• Locallyadvancedtumors:primarychemotherapy


Pre-operativechemotherapy

Responserate80%Complete

resection50%

(14-78%)


Parketal,ASCO2012CDDP-Doc27T/TCIII/IV70 63425

Chirurgie destumeurs destade IVA

Pleuralchemo-hyperthermia


Tumeurs thymiques


Resectabletumors

Unresectabletumors

- Primarychemotherapy- Surgery- postoperativetreatment


Tumeurs thymiques


Resectabletumors

Unresectabletumors


- Definitiveradiotherapy

Treatmentofthymic tumors

• Locallyadvancedtumors:primarychemotherapy


Chimio-radiothérapie exclusive

Responserate80%20-30%of

patients


Parketal,ASCO2012CDDP-Doc27T/TCIII/IV70 63425

Definitivechemo-radiotherapyforthymomas

• Limiteddataintheliterature…noconsensus

- Sequentialapproach:- 23patients,stageIII-IVunresectable thymoma- inductionwithCAP(4cycles),thenradiotherapy- 5-yearPFS:54%- 5-yearOS:53%

- Concurrentapproach:Loehrer etal.JClin Oncol 1997;15:3093

Korst etal.JThorac Cardiovasc Surg 2014;147:36

Loehrer,JClin Oncol 1997;15:3093

Kitamietal.Jpn JClin Oncol 2001;31:601Nakamuraetal.Jpn JClin Oncol 2000;30:385

Stades localement avancés:chimio-radiothérapie

Enpratique:

Réponse partielle:radiothérapie séquentielle

Progression/stabilisation (B2-B3):radio-chimiothérapie concomitante


Tumeurs thymiques


Resectabletumors

Unresectabletumors



Metastatictumors

- First-linechemotherapy

Palliative-intentchemotherapy

chemotherapy


Palliative-intentchemotherapyregimens

GirardN.ASCO2012EducationalBook

Anthracyclin-basedResponse:70-80%

Non-anthracyclin-basedResponse:30-50%

Palliative-intentchemotherapyregimens


Carboplatine-Paclitaxel

0%

20%

40%

60%

80%

100%

Lemman=21

Currentstudyn=13

Lemman=23

Hirain=39

Currentstudyn=27

Progression

Stabledisease

Objectiveresponse

Thymoma

Thymoma

Thymiccarcinoma

Thymic carcinoma

- Reproductibleresults

- Anewstandardforthymic carcinomas?

- Dowe need atrialofplatine-paclitaxel vs.CAP?

0 5 10 15 20

Lemman=23

Hirain=39

Currentstudyn=27

Lemman=21

Currentstudyn=13

PFS(months)

AnthracyclinesRéponse:70-80%

SansanthracyclinesRéponse:30-50%


Stades avancés ou métastatiques

Enpratique

Premièreligne:CAP

Carboplatine-Paclitaxel

4-6cycles

Kirkove Cetal.Clin Oncol 1992;4:64

Corticosteroidsandthymomas

•Depletionofthelymphocyticpopulation- “thymolytic effect”

•Steroidreceptorsin83%ofthymomas

•TumorresponsesreportedintypeBthymomas- 18cases,mixedthymoma:10partial

responses,4completeresponses- responsemaybeprolonged>12months- re-responsemaybeprolonged

•Specificities:- opportunisticinfections- increasedriskofmyasthenic crisis

Cravenetal.MuscleNerve1981;4:425Mimae etal.Cancer2011;117:4396

RYTHMIC:Exclusive(first-line)chemotherapy

CAP35%


32%

PE19%

VIP3%

Other/Unknown11%

Proposedregimens

n=37


n=41

CAP66%

Paclitaxel+

Carboplatin20%

Etoposide+/- Platin

12%

Others2%


n=41

CAP66%

Paclitaxel+Carboplatin

20%

Etoposide+/- Platin

12%

Others2%



n=41

CAP66%


20%

Etoposide+/- Platin

12%

Others2%

2%

28% 31%42%

25%15%17%

36%42%

44%71%

54%

77%

36% 19%

13%4%

31%

4% 7%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%


Progression

Stable


2%

28% 31%42%

25%15%17%

36%42%

44%71%

54%

77%

36% 19%

13%4%

31%

4% 7%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%


Progression

Stable


2%

28% 31%42%

25%15%17%

36%42%

44%71%

54%

77%

36% 19%

13%4%

31%

4% 7%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%


Progression

Stable


Tumorresponse



n=41

CAP66%


20%

Etoposide+/- Platin

12%

Others2%

2%

28% 31%42%

25%15%17%

36%42%

44%71%

54%

77%

36% 19%

13%4%

31%

4% 7%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%


Progression

Stable


2%

28% 31%42%

25%15%17%

36%42%

44%71%

54%

77%

36% 19%

13%4%

31%

4% 7%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%


Progression

Stable


2%

28% 31%42%

25%15%17%

36%42%

44%71%

54%

77%

36% 19%

13%4%

31%

4% 7%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%


Progression

Stable


TumorresponseProgression-free

survival

Median:6.2months



Tumeurs thymiques


Resectabletumors

Unresectabletumors



Metastatictumors

- First-linechemotherapy- Recurrences:

- second-linetreatment

Surgeryforrecurrences

Bae etal.JThorac Oncol 2012;7:1304

Surgeryforrecurrences

Second-linechemotherapyandbeyond


Second-linetreatmentofTumeurs thymiques

Thymoma

Thymiccarcinoma

Thymoma

Thymic carcinoma

0%20%40%60%80%

100%Progression

Stabledisease

Objectiveresponse

PFS(months)

0 2 4 6 8 10 12 14

PemetrexedCAP-GEMSUNITINIBOctreotideEverolimusAmrubicine

PemetrexedCAP-GEMSUNITINIBOctreotideEverolimusAmrubicine

Seconde ligne etplus


Enpratique:

Carbo-Px,PE,Pemetrexed

re-administrationduCAP(PS=0/1,réponse antérieure,rechute tardive;max.8cycles)


38%

Paclitaxel6%

PE11%

Etoposide16%

CAP12%

Adriamycin2%

CapecitabineGemcitabine

4%

Pemetrexed4% Other

7%

Chemotherapy

n=114

Targetedagents

n=67

Proposed regimens

Sunitinib47%

Sorafenib3%

Bevacizumab15%

Somatostatine

12%

Milciclib*8%

Lucitanib*4%

Everolimus11%

RYTHMIC:Systemictreatmentsforrecurrence


Administered regimens

Paclitaxel+/-

Carboplatin44%

Etoposide+Platin

16%

Etoposide4%

CAP13%

Sunitinib/Lu…

Pemetrexed3%

Milciclib3%

Others6%

Firstrecurrence

n=79

Sunitinib/other…

Paclitaxel+/-

Carbopl…

Etoposide12%

Pemetr…

Others…

Recurrence 2

n=54

Recurrence 3

n=29

Recurrence 4

n=13

Sunitinib/other

VEGF…

Paclitaxel+/-Platin…

Pemetrexed…

Everolimus7%

Others28%

Everolimus…

Sunitinib16%

Etoposide+…

Pemetrexed…

Others

31%

2%28% 31% 42%

25% 15%17%

36%42%

44% 71%

54%77%

36% 19%13% 4%

31%4% 7%

0%10%20%30%40%50%60%70%80%90%

100%

2%

28% 31%42%

25%15%17%

36%42%

44%71%

54%

77%

36% 19%

13%4%

31%

4% 7%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%


Progression

Stable


n=91n=41n=79n=64n=29 n=13



Tumeurs thymiques


Resectabletumors

Unresectabletumors

- Biopsy- Primarychemotherapy- Surgery- postoperativetreatment


Metastatictumors


- second-linetreatment- Targetedagents

• About50%ofthymomas doexpresshighlevelsofsomatostatin receptorsat111In-DTPA-octreotide(OctreoScan®)

• Responseratesarehigherinthymoma vs.thymic carcinoma:

Palmieri etal.Cancer2002;94:1414;Loehrer etal.JClin Oncol 2004;22:293Schalke B,etal.JClin Oncol 2012;30(suppl;abstr 7105)

Octreotide

Corticoids Thymoma Thymic carcinoman CR+PR SD n CR+PR SD

Palmieri,2002 + 10 4 4 3 1 1Loehrer,2004 +/- 32 12 11 5 0 3Schalke,ASCO2012 + 17 15 0 0 0 0


Tumeurs thymiques


Resectabletumors

Unresectabletumors



Metastatictumors



• Overexpression:- collectively20%of501tumors- correlationwithhistologic type:

- 2%ofthymomas- vs. 87%ofcarcinomas(p=0.003)

- diagnosticbiomarkerforthymiccarcinoma

• Mutations: - 11%ofthymic carcinomas(14/129tested)

KITandthymictumors

Zucali et al. 107 4 (3%) 6 13 (46%)

Mutation Exon

E490K 9Y553N 11W557R 11V559A 11V560del 11L576P 11P577-D579del 11D579del 11H697Y 14D820E 17

Sensitivity toKITinhibitorsImatinibSunitinibSorafenib

• Expressionofangiogenesis-relatedbiomarkers- increasednumberofcellsexpressingVEGF-A,-C,-D,andVEGFR-1,-2- increasedserumlevelsofVEGFinthymic carcinomas

Neoangiogenesis

Cimpean etal.AnnAnat 2008;190:238;Sasakietal.Surg Today2001;31:1038;MarinoetPiantelli.ThorSurg Clin 2011;21:33

LancetOncol 2016;16:177

Thymic carcinomaSSP : 7,6 mois

ThymomaSSP : 6,7 mois

KIT wild-typetumors


Tumeurs thymiques


Resectabletumors

Unresectabletumors



Metastatictumors



PhaseItrials

21patients

DCR=60%withmTORinhibitors

n=10

Oncotarget2013;4:890

PhaseItrials

Median:11.6months

Median:2.3months

[TITLE]

ASCO2014:everolimus


Tumeurs thymiques


Resectabletumors

Unresectabletumors



Metastatictumors



Initiatives&Opportunities


Tumeurs thymiques


Resectabletumors

Unresectabletumors



Metastatictumors



Initiatives&Opportunities- ITMIG:databases

ITMIGDatabases:website is ccehub.org


Tumeurs thymiques


Resectabletumors

Unresectabletumors



Metastatictumors



Initiatives&Opportunities- ITMIG:databases- ETOP/EORTC:translationalmedicine

Targetingimmunecheckpoints?

Giaconne.ASCO2014

Pembrolizumab phaseIItrial(NCI,GGiaccone)

TATcongress 2016

EORTC-ETOPNIVOTHYM:B3andcarcinomasStudy&design&–&open&label&phase&II&&

with&a&close&monitor&of&toxicity&for&the&first&10&pa=ents&

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!&

Eligible&pa=ents&SecondCline& Nivolumab&3&mg/kg&IV&q2&weeks&&

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!

Biomarkers&&

PDCL1&at&baseline&and&PD&Others:&immune&paQerns,&&

molecular&profile&!

50!pa@ents!!

Courtesy JMenis


Tumeurs thymiques


Resectabletumors

Unresectabletumors



Metastatictumors



Initiatives&Opportunities- ITMIG:databases- ETOP/EORTC:translationalmedicine- RYTHMIC:Tumorboardandnetwork

Coordinator:B.BesseGustave Roussy

RYTHMIC:aregionalnetworkofexpertcenters

Prospectivedatabaseandtrials

Regionalexpertcenter

NationalPathologyPanel

Guidelines

Patients

CMEactivities

TreatingPhysician

Nationalexperttumorboard

RYTHMIC:Infrastructureofthenetwork

RCPRYTHMIC

avec imagerie partagée/équipes

Onlinevirtualtumorboard

Regional expertteams

Thoracic surgeonsMedical oncologistsRadiationoncologists

PathologistsRadiologists

PneumonologistsNeurologists

RYTHMIC:Multidisciplinarytumorboard

Diagnosis/

Imaging Surgery?

PrimaryChemotherapy? Definitive Radiotherapy?

UpfrontSurgery? Post-operativeRadio

therapy?

Follow-up?

Initialmanagement

ExclusiveChemotherapy?

Post-operativeChemotherapy?

- 1000patients:1401questionsraisedatthemulti-disciplinarytumorboard

n=149(11%) n=45(3%)

n=182(13%)

n=82(6%)

n=28(2%)

n=37(3%)

n=494(35%)

n=104(7%)

n=5(0%)Surgery?

Radiotherapy?

Chemotherapy?

Targetedagent?

n=17(1%)

n=30(2%)

Diagnosis?n=47(3%)

n=67(5%)

n=114(8%)

Recurrences


Tumeurs thymiques


Resectabletumors

Unresectabletumors



Metastatictumors





Tumeurs thymiques


Resectabletumors

Unresectabletumors



Metastatictumors




Thankyou!

[email protected]

www.rythmic.org

Nicolas Girard - splf.frsplf.fr/wp-content/uploads/2016/09/GOLFTHY5.pdf · Les tumeurs du thymus...

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