Evaluation, prévention et gestion des toxicités de la...

Evaluation, prévention et gestion des toxicités de la chimiothérapie,

des anti-angiogéniques et de l’immunothérapie DrLavoléArmelle,AP-HP,HôpitalTenon

DrCréquitPerrine,CRESS-UMR1153etAP-HP,HôpitalHôtel-Dieu

Questions isolées: QRM1 et QRM2

QRM1: Prévention des nausées et vomissements chimio-induits. Quelles sont les propositions vraies?

1)pourlecisplatine,letraitementrecommandéassocie:J1aprépitant(Emend®)125mg+sétrons+corticoïdes

J2-J3aprépitant(Emend®)80mg+corticoïdes

J4corticoïdes.

2)pourlecisplatine:l’associationNEPA(Akynzeo®)J1+corticoïdesJ1-4estunealternative.

3)Iln’estpasrecommandédeprescrireunantagonisteNK1avecduCarboplatineAUC5.

4)L’olanzapine(Zyprexa®)peut-êtreutiliséenpréventiondesNVCIencasdechimiothérapiehautementémétisante.

5)Lesite«http://www.riskcinv.org/»estunoutilenligned’aideàlaprescriptiond’anti-émétiques.

1)pourlecisplatine,letraitementrecommandéassocie:J1aprépitant(Emend®)125mg+sétrons+corticoïdes

J2-J3aprépitant(Emend®)80mg+corticoïdes

J4corticoïdes.



1)pourlecisplatine,letraitementrecommandéassocie:J1®)125mg+sétrons+corticoïdes

J2-J380mg+corticoïdes


-NEPA:associationfixeoraledenetupitant300mgetpalonosetron0.5mg-1heureavantlachimiothérapieparcisplatineauJ1uniquement-  Efficacitéencombinaisonàladexamethasonenon-inférieureautriplethabituel(aprépitant+granisetron+dexamethasone)-AKYNZEO®remboursédansl’indicationsuivante:≪traitementde1èreintentionenpréventiondesnauséesetvomissementsaigusetretardésassociésauxchimiothérapiesanticancéreuseshautementémétisantesàbasedecisplatine≫.


1)pourlecisplatine,letraitementrecommandéassocie:J1aprépitant(Emend®)125mg+sétrons+corticoïdesJ2-J3aprépitant(Emend®)80mg+corticoïdesJ4corticoïdes.



4)L’olanzapine(Zyprexa®)peut-êtreutiliséenpréventiondesNVCIencasdechimiothérapiehautementémétisante.

5)Lesite«http://www.riskcinv.org/»estunoutilenligned’aideàlaprescriptiond’anti-émétiques.

QRM2: Prophylaxie des neutropénies chimio-induites. Quelles sont les propositions vraies?

1)  LesFCHsontrecommandésenprophylaxieprimaireencasderisquedeneutropéniefébrilesupérieurà20%.

2)  Lerisquedeneutropéniefébrileest>20%pourcarboplatine-paclitaxel-bevacizumab.

3)  L’antibioprophylaxiedesneutropéniesn’estpasrecommandéeaucoursdeschimiothérapiesutiliséesenoncologiethoracique.

4)  Danslessituationspalliatives,lerecoursauxFCHenprophylaxiesecondaireestsystématique.

5)  LesFCHsontrecommandésdansletraitementcuratifdesneutropénienonfébriles.

Cas clinique 1 et 2

65 ans, adénocarcinome IV, C51 nivolumab

•  50curesdenivolumab:toléranceetefficacitéexcellentes•  Intercure:«J-7aprèsavoirbuunjusd’orangedouteux,4sellesliquides,MT:traitementsymptomatique+flagyl+coprocultureettoxineC.Difficilenégatives»pasdesellesliquidesdepuis48hle16/12/2018:réalisationdela51ècure•  Le20/12/2018:lepatientvousappellecariladessellesliquidesdepuisle17/12/2018,actuellement8à10sellesparjour,trèsliquides

1)  Vousconseillezaumédecintraitantdedébuterdescorticoïdesoraux.2)  Vousproposezd’hospitaliserlepatientenurgence.3)  Vousréalisezrapidementunerecto-sigmoïdoscopie.4)  VousdébutezimmédiatementdescorticoïdesIV.5)  Vousprescrivezuniquementdestraitementssymptomatiquesenattendantlarecto-

sigmoïdoscopie.

Cas Clinique 1: Que faites vous ?

<4selles

Coproculturetoxine

Ttsymptomatique

Okimmunothérapie

grade1

<4selles

4-6selles Coproculturetoxine

Rectosigmoïdoscopie

Ttsymptomatique

Corticoidessansattendrerecto

Okimmunothérapie

Ambulatoire+/-Suspensionimmuno

grade1

grade2

<4selles

4-6selles

>6selles

CorticoïdesIV1-2mg/kg

Coproculturetoxine

Rectosigmoïdoscopie

DuréePO2à8semainesdégressif

Ttsymptomatique

Corticoidessansattendrerecto

Okimmunothérapie

HospitalisationStopimmunothérapie

Ambulatoire+/-Suspensionimmuno

grade1

grade2

grade3-4

1)  Vousconseillezaumédecintraitantdedébuterdescorticoïdesoraux.2)  Vousproposezd’hospitaliserlepatientenurgence.3)  Vousréalisezrapidementunerecto-sigmoïdoscopie.4)  VousdébutezimmédiatementdescorticoïdesIV.5)  Vousprescrivezuniquementdestraitementssymptomatiquesenattendantlarecto-

sigmoïdoscopie.

Cas Clinique 1: Que faites vous ?

Nivolumabarrêtédepuis1an,pasderécidive,larepriseseradiscutéedefaçoncollégiale

Cas Clinique 2: Patient de 64 ans, épidermoïde IV

•  Inclusionessaithérapeutique

•  Pasd’antécédent

•  le23/01,ilreçoit:•  Carboplatine•  Paclitaxel•  IpilimumabantiCTLA4•  NivolumabantiPD1

Le02/02:consultationenurgencepouruneéruptioncutanée+aphtesNFS:PNN850,plaquettes80000,pasdefièvre

1)  Leséruptionsmaculo-papuleusessontunetoxicitéimmédiatefréquentedel’immunothérapie.

2)  Vousdébutezdescorticoïdesenurgence.3)  Voussollicitezunavisdermatologique.4)  Voussuspectezunetoxicitécutanéeliéeàl’immunothérapie.5)  Vousarrêtezdéfinitivementl’immunothérapie.

Cas Clinique 2: Quelles sont les propositions vraies?

•  Leseffetssecondairescutanéssontfréquents•  Rarementgravesounécessitantl’arrêtdel’immunothérapie•  Lesplusfréquents:rashetprurit

AntiCTLA4 AntiPD1 Lesdeux

EffetsIIcutanés 45% 34%

rash 24% 15% 40%

grade3-4 <3% <3% <5%

prurit 25-35% 13-20% 33%

grade3-4 <2% <2% <2%

grade1éruption<10%

émollients+/-corticoïdeslocauxokimmuno

grade2éruption10-30%

émollientscorticoïdeslocauxokimmuno

avisdermato

dgdifférentiel

grade1éruption<10%

émollients+/-corticoïdeslocauxokimmuno

grade2éruption10-30%

émollientscorticoïdeslocauxokimmuno

Avisdermato

grade3éruption>30%

suspensionimmunoémollientscorticoïdesorauxdiscuterrepriseimmuno

dgdifférentiel

avisdermatobiopsiecutanée

1)  Leséruptionsmaculo-papuleusessontunetoxicitéimmédiatefréquentedel’immunothérapie.

2)  Vousdébutezdescorticoïdesenurgence.3)  Voussollicitezunavisdermatologique.4)  Voussuspectezunetoxicitécutanéeliéeàl’immunothérapie.5)  Vousarrêtezdéfinitivementl’immunothérapie.

Cas Clinique 2: Quelles sont les propositions vraies?

Biopsie:nonspécifiqueAspectpurpuriquefavoriséparlathrombopénie

Aphte:neutropénie/chimiothérapie

Staffdermato

Virose?PasdecorticoïdesgénérauxAméliorationrapidedel’éruptionReprisedel’immunothérapie

Questions isolées: QRM 3 et 4

1)  Letableauradiologiquen’estpasspécifique.2)  Sonincidencevarieentre3et12%avec1à2%degrade3-4.3)  L’arrêtdel’immunothérapieestobligatoiredèsl’apparitiond’uneanomalie

radiologique.4)  Elleestplusfréquenteencasd’associationd’unanti-CTLA4etd’unanti-PD1.5)  Encasdesymptômerespiratoireaigu,l’immunothérapiedoitêtreinterrompueetun

bilanétiologiquedoitêtreréaliséenurgence.

QRM3: Toxicité pulmonaire de l’immunothérapie. Quelles sont les propositions vraies?

*DiapoJulienMazières,DelaunayERJ2017

grade1

anomalieradiologique(verredepoli,infiltrat)pasdesymptôme

discuterimmunotherapiesurveillersymptôme

Grade2

Symptômerespiratoiremodérédyspnée,toux,

suspensionimmunotherapiecorticoïdes0,5-1mg/kg

gestionambulatoirescannerfibroLBA

Grade3

arrêtimmunotherapiecorticoïdesIV1-2mg/kg

1)  Letableauradiologiquen’estpasspécifique.2)  Sonincidencevarieentre3et12%avec1à2%degrade3-4.3)  L’arrêtdel’immunothérapieestobligatoiredèsl’apparitiond’uneanomalie

radiologique.4)  Elleestplusfréquenteencasd’associationd’unanti-CTLA4etd’unanti-PD1.5)  Encasdesymptômerespiratoireaigu,l’immunothérapiedoitêtreinterrompueetun

bilanétiologiquedoitêtreréaliséenurgence.

QRM3: Toxicité pulmonaire de l’immunothérapie. Quelles sont les propositions vraies?

Naidoo,JCO;NischinoetalJamaoncol2016

QRM4: Toxicité de l’immunothérapie. Quelles sont les propositions vraies? 1)  Leseffetsindésirablesimmunologiqueslesplusfréquentssontlestoxicitéscutanées

etdigestivesdevantcellesendocriniennes,hépatiques,pulmonairesetrénales.

2)  Lestoxicitésgraves(grade3-4)surviennentmajoritairementlespremiersmoisetnesurviennentjamaistardivement.

3)  LesprincipalestoxicitésliéesauxCTLA-4sontlescolitesetleshypophysites;etcellesliéesauxanti-PD1,lespneumopathiesinterstitiellesetlesdysthyroïdies.

4)  Lesdysthyroïdiessousimmunothérapiespeuventsedévelopperjusqu’à3ansaprèsl’initiation.

5)  Lesdécèsimputablessontexceptionnellementrares:0,3à1,3%despatientstraités.

Weber et al. JCO 2016

Pooled Safety AnalysisAt the time of analysis, 149 patients (26%) had died. The most

commonly reported cause of death was disease progression (140 of149; 94%). Other reported causes of death were acute myocardialinfarction, cardiopulmonary arrest, heart failure, hypoxia, sepsiswith multiorgan failure, subarachnoid bleeding (suspected cause),and probable pulmonary embolism; in two patient cases, the causeof death was unknown. No deaths were attributed to nivolumabtoxicity.

Treatment-related AEs of any grade occurred in 71% of pa-tients (95% CI, 67% to 75%). The most frequently reported eventswere fatigue (25%), pruritus (17%), diarrhea (13%), and rash(13%), as listed in Table 1 and Appendix Table A3 (online only).AEs regardless of attribution are listed in Appendix Table A4,(online only). Grade 3 to 4 treatment-related AEs were reportedin 57 patients (10%; 95% CI, 8% to 13%). Of note, grade 3 to4 neurologic AEs (all grade 3) were reported in five patients(1%): dizziness (resolved); autoimmune neuropathy (resolvedin 16 weeks); central demyelination (ongoing for . 3 weeksbefore death resulting from disease progression); Guillain-Barresyndrome (unresolved for. 16 weeks at time of database lock);and involuntary muscle contractions (resolved).

Treatment-related AEs leading to discontinuation were re-ported in 17 patients (3%), with the most common being colitis,increased alanine aminotransferase, increased lipase, and pneu-monitis (two patients [0.3%] each). There were no instances of GIperforation.

The rates of any-grade and grade 3 to 4 treatment-related AEsin patients who had received prior ipilimumab were 69% and 8%,respectively, similar to the rates in the overall study population.Likewise, AE rates in the overall population were consistent withthose in patients $ 65 years of age (any grade, 73%; grade 3 to 4,15%);$ 75 years of age (any grade, 72%; grade 3 to 4, 18%); withbrain metastases (any grade, 61%; grade 3 to 4, 8%); with M1cstage disease (any grade, 71%; grade 3 to 4, 9%); with PD-L1expression greater than 5% (any grade, 80%; grade 3 to 4, 14%);and with elevated LDH (any grade, 67%; grade 3 to 4, 8%).

Treatment-related select AEs occurred in 49% of patients andwere most commonly observed in the skin (34%) and GI tract(13%); grade 3 to 4 treatment-related select AEs were reported in4% of patients (Table 1). Median time to onset for treatment-related select AEs of any grade ranged from 5.0 weeks for skin AEsto 15.1 weeks for renal AEs (Fig 1A). Select AEs generally resolvedwithin several weeks, with the shortest time to resolution for GIevents (Fig 1B). Endocrine select AEs had the longest median timeto resolution, because some events, although clinically resolved andmedically controlled, were not considered resolved while there wasa continuing need for hormone replacement therapy. The kinetics ofonset and resolution of the most common treatment-related selectAEs are shown in Figure 2, which demonstrates the median times toonset and resolution of select AEs of all grades by organ category.Among 282 patients who experienced new treatment-related selectAEs, 85% did so within the first 16 weeks of treatment (Fig 3).

Impact of AEs on Response Rates and PFSIn all patients receiving nivolumab monotherapy (N = 576),

the ORR was 31.4%, and median PFS was 4.7 months (95% CI, 3.4

to 5.6). In a multivariable analysis adjusting for differences innumber of nivolumab doses received, baseline LDH, and tumorPD-L1 expression, ORR was significantly better in patients whoexperienced treatment-related select AEs of any grade comparedwith those who did not, with greater benefit in patients who re-ported three or more or one to two treatment-related select AEs,compared with those with none (Table 2). In contrast, there was nosignificant difference in ORR on the basis of the occurrence ofgrade 3 to 4 treatment-related select AEs (Table 2). Exclusion ofpatients who experienced progression before 12 weeks in a land-mark PFS analysis revealed no difference in PFS between patientswithout AEs and those with one to two AEs or between those withany-grade AE and all patients (Appendix Fig A1, online only).

Use of IMs to Manage Select AEsA total of 114 of 474 (24%) of patients in the two phase III

trials received systemic corticosteroids to manage treatment-related AEs of any kind. In addition, 76 (16%) were adminis-tered topical corticosteroids to manage skin-related AEs, and five(1%) received inhaled corticosteroids (Appendix Table A5, online

A

Appro

ximate

Prop

ortion

of Pa

tients

(%)

5

10

15

20

25

30

35

Median Time (weeks)

Skin

GI

0 10 20 30 40

B

1

2

3

4

5

6

7

Median Time (weeks)

EndocrineHepaticPulmonaryRenal

8

0 10 20 30 40

Appro

ximate

Prop

ortion

of Pa

tients

(%)

Fig 2. Kinetics of onset and resolution of (A) most common ($ 10%) and (B) lesscommon (, 10%) treatment-related select adverse events (AEs) of any grade. Thebeginning and end of each curve represent the median time to onset and mediantime to resolution, respectively. The peak of each curve shows the proportion ofpatients who developed that AE, and the tail represents the proportion of patientswhose AE did not resolve.

4 © 2016 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Weber et al

Downloaded from ascopubs.org by Gustave Roussy Cancer Centre on February 1, 2017 from 194.167.111.061Copyright © 2017 American Society of Clinical Oncology. All rights reserved.

Pooled Safety AnalysisAt the time of analysis, 149 patients (26%) had died. The most

commonly reported cause of death was disease progression (140 of149; 94%). Other reported causes of death were acute myocardialinfarction, cardiopulmonary arrest, heart failure, hypoxia, sepsiswith multiorgan failure, subarachnoid bleeding (suspected cause),and probable pulmonary embolism; in two patient cases, the causeof death was unknown. No deaths were attributed to nivolumabtoxicity.

Treatment-related AEs of any grade occurred in 71% of pa-tients (95% CI, 67% to 75%). The most frequently reported eventswere fatigue (25%), pruritus (17%), diarrhea (13%), and rash(13%), as listed in Table 1 and Appendix Table A3 (online only).AEs regardless of attribution are listed in Appendix Table A4,(online only). Grade 3 to 4 treatment-related AEs were reportedin 57 patients (10%; 95% CI, 8% to 13%). Of note, grade 3 to4 neurologic AEs (all grade 3) were reported in five patients(1%): dizziness (resolved); autoimmune neuropathy (resolvedin 16 weeks); central demyelination (ongoing for . 3 weeksbefore death resulting from disease progression); Guillain-Barresyndrome (unresolved for. 16 weeks at time of database lock);and involuntary muscle contractions (resolved).

Treatment-related AEs leading to discontinuation were re-ported in 17 patients (3%), with the most common being colitis,increased alanine aminotransferase, increased lipase, and pneu-monitis (two patients [0.3%] each). There were no instances of GIperforation.

The rates of any-grade and grade 3 to 4 treatment-related AEsin patients who had received prior ipilimumab were 69% and 8%,respectively, similar to the rates in the overall study population.Likewise, AE rates in the overall population were consistent withthose in patients $ 65 years of age (any grade, 73%; grade 3 to 4,15%);$ 75 years of age (any grade, 72%; grade 3 to 4, 18%); withbrain metastases (any grade, 61%; grade 3 to 4, 8%); with M1cstage disease (any grade, 71%; grade 3 to 4, 9%); with PD-L1expression greater than 5% (any grade, 80%; grade 3 to 4, 14%);and with elevated LDH (any grade, 67%; grade 3 to 4, 8%).

Treatment-related select AEs occurred in 49% of patients andwere most commonly observed in the skin (34%) and GI tract(13%); grade 3 to 4 treatment-related select AEs were reported in4% of patients (Table 1). Median time to onset for treatment-related select AEs of any grade ranged from 5.0 weeks for skin AEsto 15.1 weeks for renal AEs (Fig 1A). Select AEs generally resolvedwithin several weeks, with the shortest time to resolution for GIevents (Fig 1B). Endocrine select AEs had the longest median timeto resolution, because some events, although clinically resolved andmedically controlled, were not considered resolved while there wasa continuing need for hormone replacement therapy. The kinetics ofonset and resolution of the most common treatment-related selectAEs are shown in Figure 2, which demonstrates the median times toonset and resolution of select AEs of all grades by organ category.Among 282 patients who experienced new treatment-related selectAEs, 85% did so within the first 16 weeks of treatment (Fig 3).

Impact of AEs on Response Rates and PFSIn all patients receiving nivolumab monotherapy (N = 576),

the ORR was 31.4%, and median PFS was 4.7 months (95% CI, 3.4

to 5.6). In a multivariable analysis adjusting for differences innumber of nivolumab doses received, baseline LDH, and tumorPD-L1 expression, ORR was significantly better in patients whoexperienced treatment-related select AEs of any grade comparedwith those who did not, with greater benefit in patients who re-ported three or more or one to two treatment-related select AEs,compared with those with none (Table 2). In contrast, there was nosignificant difference in ORR on the basis of the occurrence ofgrade 3 to 4 treatment-related select AEs (Table 2). Exclusion ofpatients who experienced progression before 12 weeks in a land-mark PFS analysis revealed no difference in PFS between patientswithout AEs and those with one to two AEs or between those withany-grade AE and all patients (Appendix Fig A1, online only).

Use of IMs to Manage Select AEsA total of 114 of 474 (24%) of patients in the two phase III

trials received systemic corticosteroids to manage treatment-related AEs of any kind. In addition, 76 (16%) were adminis-tered topical corticosteroids to manage skin-related AEs, and five(1%) received inhaled corticosteroids (Appendix Table A5, online

A

Appro

ximate

Prop

ortion

of Pa

tients

(%)

5

10

15

20

25

30

35

Median Time (weeks)

Skin

GI

0 10 20 30 40

B

1

2

3

4

5

6

7

Median Time (weeks)

EndocrineHepaticPulmonaryRenal

8

0 10 20 30 40

Appro

ximate

Prop

ortion

of Pa

tients

(%)

Fig 2. Kinetics of onset and resolution of (A) most common ($ 10%) and (B) lesscommon (, 10%) treatment-related select adverse events (AEs) of any grade. Thebeginning and end of each curve represent the median time to onset and mediantime to resolution, respectively. The peak of each curve shows the proportion ofpatients who developed that AE, and the tail represents the proportion of patientswhose AE did not resolve.

4 © 2016 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Weber et al

Downloaded from ascopubs.org by Gustave Roussy Cancer Centre on February 1, 2017 from 194.167.111.061Copyright © 2017 American Society of Clinical Oncology. All rights reserved.

IrAEs les plus frequents (≥ 10%) IrAEs les moins fréquents (<10%)

Effets indésirables immunologiques

N=576melanomesousnivolumabmonotherapie

B.DuchemannCPLF2018




3)  LesprincipalestoxicitésliéesauxCTLA-4sontlescolitesetlesetcellesliéesauxanti-PD1,lespneumopathiesinterstitiellesetlesdysthyroïdies.



Les toxicités les plus fréquentes

Boutros C et al. Nat Rev Clin Oncol 2016;13:473-86

CA-184-002, KEYNOTE-001, KEYNOTE-001 (randomized cohorts), KEYNOTE-002 , KEYNOTE-006, CheckMate-037, CheckMate-066 , CheckMate-067, and CheckMate-069 .

Digestives

CutanéesGénérales

B.DuchemannCPLF2018

Les toxicités spécifiques

Boutros C et al. Nat Rev Clin Oncol 2016;13:473-86

Digestives Endocriniennes Pulmonaires

B.DuchemannCPLF2018




3)  LesprincipalestoxicitésliéesauxCTLA-4sontlescolitesetleshypophysites;etcellesliéesauxanti-PD1,lespneumopathiesinterstitiellesetlesdysthyroïdies.



http://www.sfendocrino.org/article/46/consensus-et-recommandations-de-la-sfe-et-partenaires-et-du-gte

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