Predic've/prognos'cvalueofanorexia-cachexia

Prognos'cvalueofAnorexia-Cachexia

Rela%onshipbetweenPrognosis•  Weight•  Appe%te•  Nutri%onalImpactSymptoms•  BodyComposi%on•  Mul%pleDomainsofcachexia

uncertainty

•  Widevaria%oninguidelines1anduseofweightlosscriteria•  Systema%creviewofcachexiadomainsandweightlosscriteria25%loss[n=12]10%[n=20]specific%[n=29]kglost[n=10]%meperiod6months[n=18],3months[n=4],unspecified[n=16]•  Oncologistsunclearwhichcut-offsareclinicallysignificant3,4

1.MauriBMJSuppPall20142.BlumCritRevOncHem20112.SpiroBJC20063.DelFabbroJSO2015

Defini'onofCancerCachexia

•  BMI,bodymassindex.FearonK,etal.LancetOncol.2011;12:489-495.

–  Mul%-factorialsyndrome• Characterizedbyongoinglossofskeletalmusclemass±lossoffatmass• Cannotbereversedfullybyconven%onalnutri%onalsupport•  Leadstoprogressivefunc%onalimpairment

5

Weight loss >5% over 6 mo that cannot be attributed to simple starvation

or BMI <20 + weight loss >2%

or Appendicular skeletal muscle mass index consistent

with sarcopenia + weight loss >2%

StagesofCancerCachexia

•  FearonK,etal.LancetOncol.2011;12:489-495.

6

Refractory cachexia

Death Normal

Low performance score Immunocompromise,

<3-mo expected survival

Pre-cachexia

Weight loss ≤5%

Metabolic/endocrine change

“Inthebeginningofthemaladyitiseasytocurebutdifficulttodetect,butinthecourseof%me,nothavingbeeneitherdetectedortreatedinthebeginning,itbecomeseasytodetectbutdifficulttocure.”

—NiccoloMachiavelli

Cachexia

Weight loss >5%

Reduced food intake/ systemic inflammation

Weight-RelatedOutcomesinPa'entswithCancer

1.DeWysWB,etal.AmJMed.1980;69:491-497;2.RossPJ,etal.BrJCancer.2004;90:1905-1911;3.Kazemi-BajestaniSM.SemincellDev2016;4.ParmarMP,etal.SupportCareCancer.2013;21:2049-2057;5.MarianiL,etal.SupportCareCancer.2012;20:301-309;6AndreyevEurJCancer1998;7Chlebowski,8.ThoresenEurJCancerCare2012

•  Increasedriskforcomplica%ons,death1

• Decreasedtreatmentresponse2• Greaterfailuretocompletecyclesoftherapy2,6

•  Increasedtoxicity3•  Increasedfa%gue4•  LowerQoL5,8• DecreasedPerformancestatus•  Lowtestsoterone

Weightlossandprognosis

•  Obesityincreasingworldwide•  Classifica%onofWeightlossbasedoncontemporarydata•  EuropeanandCanadianstudyof8160pa%ents•  Prognos%csignificanceofWeightlossinpa%entswhoini%allyhavealow,intermediate,orhighBMI

•  Published in: Lisa Martin; Pierre Senesse; Ioannis Gioulbasanis; Sami Antoun; Federico Bozzetti; Chris Deans; Florian Strasser; Lene Thoresen; R. Thomas Jagoe; Martin Chasen; Kent Lundholm; Ingvar Bosaeus; Kenneth H. Fearon; Vickie E. Baracos; JCO 2015, 33, 90-99.

Fig 1. Line graphs representing the relationships between deciles of (A) body mass index (BMI) and (B) percent weight loss (%WL) to overall survival. Decile 1 represents (A) the lowest BMI and (B) the highest %WL. Decile 10 represents (A) the highest BMI and (B) the lowest %WL. Blue lines represent unadjusted estimated hazard ratios (HRs) associated with reduced overall survival. Reference categories are BMI decile 10 (BMI > 30.9 kg/m2; HR, 1.0) and weight stable (WS; ± 2.4%; HR, 1.0). Risk of reduced survival increases with decreasing BMI and increasing %WL. Gold lines represent the estimated median overall survival in months. Median survival decreases with decreasing BMI and increasing %WL. Different shades of blue in the figures indicate significant differences (P < .05) in median survival between deciles. (*) WS is ± 2.4%.

Published in: Lisa Martin; Pierre Senesse; Ioannis Gioulbasanis; Sami Antoun; Federico Bozzetti; Chris Deans; Florian Strasser; Lene Thoresen; R. Thomas Jagoe; Martin Chasen; Kent Lundholm; Ingvar Bosaeus; Kenneth H. Fearon; Vickie E. Baracos; JCO 2015, 33, 90-99.

Weightloss,BMI,prognosis

Panels A to C represent a 5 × 5 matrix analysis of the five categories of BMI and five categories of %WL for a total of 25 possible combinations. The (A) sample size, (B) median overall survival (months), and (C) unadjusted estimated hazard ratios (HRs; HR, 1.0) are presented for each cell. (*) Reference categories are BMI ≥ 28.0 kg/m2 and weight stable ± 2.4%. Different colors represent significant differences (P < .05) in median overall survival and HRs within and between cells of the matrix. Panel D represents the BMI-adjusted WL grading system (grades 0 to 4) Lisa Martin; Pierre Senesse; Ioannis Gioulbasanis; Sami Antoun; Federico Bozzetti; Chris Deans; Florian Strasser; Lene Thoresen; R. Thomas Jagoe; Martin Chasen; Kent Lundholm; Ingvar Bosaeus; Kenneth H. Fearon; Vickie E. Baracos; JCO 2015, 33, 90-99.

Mediansurvivalbygrade0=20.9months1=14.62=10.83=7.64=4.3

Reducedsurvival=afunc'onofbodymassindex&percentweightloss

Survivalcurvesfromthesubgroupanalysisfor(A)gastroesophagealand(B)headandneckcancersbygrade

Published in: Lisa Martin; Pierre Senesse; Ioannis Gioulbasanis; Sami Antoun; Federico Bozzetti; Chris Deans; Florian Strasser; Lene Thoresen; R. Thomas Jagoe; Martin Chasen; Kent Lundholm; Ingvar Bosaeus; Kenneth H. Fearon; Vickie E. Baracos; JCO 2015, 33, 90-99. DOI: 10.1200/JCO.2014.56.1894 Copyright © 2014

Gradingsystemforweightlossincancer

•  Func%onof%weightlossandBMI•  PrognosisIndependentofcancersite,stageorperformancestatus

•  Implica%onsforclinicaltrialenrollment•  Limita%ons%meframeofweightlossperformancestatusmeasurestypeofchemo

Applicabilityofaweightlossgradingsystemincancercachexia:alongitudinalanalysis

JournalofCachexia,SarcopeniaandMuscleVolume8,Issue5,pages789-797,18JUN2017

Confirm the system‘s prognostic validity Relationship to cachexia domains Ability to predict cachexia progression

Theapplicabilityofaweightlossgradingsystemincancercachexia:alongitudinalanalysis

JournalofCachexia,SarcopeniaandMuscleVolume8,Issue5,pages789-797,18JUN2017

Iden'fyingprogressionorreversibility

Panels A to C represent a 5 × 5 matrix analysis of the five categories of BMI and five categories of %WL for a total of 25 possible combinations. The (A) sample size, (B) median overall survival (months), and (C) unadjusted estimated hazard ratios (HRs; HR, 1.0) are presented for each cell. (*) Reference categories are BMI ≥ 28.0 kg/m2 and weight stable ± 2.4%. Different colors represent significant differences (P < .05) in median overall survival and HRs within and between cells of the matrix. Panel D represents the BMI-adjusted WL grading system (grades 0 to 4) Lisa Martin; Pierre Senesse; Ioannis Gioulbasanis; Sami Antoun; Federico Bozzetti; Chris Deans; Florian Strasser; Lene Thoresen; R. Thomas Jagoe; Martin Chasen; Kent Lundholm; Ingvar Bosaeus; Kenneth H. Fearon; Vickie E. Baracos; JCO 2015, 33, 90-99.

Mediansurvivalbygrade0=20.9months1=14.62=10.83=7.64=4.3

Reducedsurvival=Func'onofbodymassindex&percentweightloss

Addi'onaldomains

•  1.Prado.ProcnutrSoc2016QuintenLancetOncology2011.2.Farhangfar2010OralOnc.3.ZhouJPSM20174.DelFabbroJPM20106.NasrahClinNutr.20169.BurneyJCEM2012

•  Bodycomposi%on1•  Pa%entreportedoutcomesAppe%te2Nutri%onImpactsymptoms3,4Fa%gueandfunc%on5•  Dietaryintake6•  PhysicalFunc%on7•  Chronicinflamma%on8•  Other-chemo&endocrinedysfunc%on9

Extensivemusclewas%ngcanbeobscuredbylargefatmass

Fearon,K.etal.(2012)Understandingthemechanismsandtreatmentop%onsincancercachexiaNat.Rev.Clin.Oncol.

Bodycomposi'onandprognosis

Varia'onbetweenskeletalmuscleindex(SMI)andbodymassindex(BMI)

forfemales(n=645)

Martin L et al. JCO 2013;31:1539-1547 ©2013 by American Society of Clinical Oncology

Pa%entswithcancercachexiabytheconven%onalcriterion(involuntaryweightloss)andbytwoaddi%onalcriteria(muscledeple%onandlowmuscleaoenua%on)shareapoorprognosis,regardlessofoverallbodyweight

DelFabbroOncologist2012

•  Sarcopeniaoddsforresponse29%lowerforeachunithigherBMI•  Normalweight(26pCRsof44total)responsebeoerinsarcopenia•  Howfarupordownstreamshouldbodycomposi%onbeevaluated?•  Dosingofchemotherapybeoerdeterminedbybodycomposi%on?•  Othermethodsforevalua%ngbodycomposi%onUltrasound,Bioimpedance,DEXA,MRI

Bodycomposi'onandprognosisin3262early-stage(I-III)colorectalcancer

Bette J. Caan et al. Cancer Epidemiol Biomarkers

Pa'entReportedOutcomesHRQOL,symptomsandprognosisincancer

•  HRQOLhasindependentprognos%cvalueforsurvival

•  104studiesshowglobalqualityoflife,func%ondomainsandsymptomscoressuchasappe%te,fa%gueandpainwerethemostimportantindicators,individuallyorincombina%on,forsurvivalMontezariHealthQualLifeout2009

Overallsurvivalcurvesstra%fiedbyQLQ-C30appe%telossscoreQLQ-C30=theEuropeanOrganisa%onforResearchandTreatmentofCancerquality-of-lifecoreques%onnaire

Chantal Quinten, Corneel Coens, Murielle Mauer, Sylvie Comte, Mirjam AG Sprangers, Charles Cleeland, David Osoba, Kristin Bjordal, Andrew Bottomley

Baselinequalityoflifeasprognos%cindicatorofsurvivalMeta-analysisofindividualpa%entdataEORTCclinicaltrials

Lancet Oncol Volume 10, Issue 9, 2009, 865–871

BaselineQoL:aprognos'cindicatorofsurvivalMeta-analysis:pa'entdatafromEORTCclinicaltrialsQuinten2009LancetOncol

•  HRQOLparametersofphysicalfunc%oning,painandappe%telossp<0·0001providedsignificantprognos%cinforma%oninaddi%onto

•  age•  sex•  distantmetastasesp<0·0001

Nutri%onalImpactSymptomsandtreatment

InaCancerCachexiaClinic

•  DelFabbro,Hui,Dalal,Dev,Brueraetal.JPallMed.2011;14:1004-1008.

Nutri'onImpactSymptoms

NumberAffected(%)

CorrespondingInterven'on

NumberTreatedAmongAffected(%)

Earlysa'ety 94(62) Metoclopramide 74(79)

Cons'pa'on 78(52) Laxa've 68(87)

Nausea/vomi'ng 67(44) An'eme'c(metoclopramide) 54(81)

Depressedmood 63(42) An'depressant(mirtazapine) 51(81)

Dysgeusia 42(28) Zincsupplement 20(48)

Dysphagia 21(14) GI/speechtherapy 5(24)

Drymouth 14(9) Ar'ficialsaliva 2(14)

Mucosi'spain 11(7) Opioid,topicalmouthwash 3(27)

Dentalissues 8(5) Dentalreferral 2(25)

FindingsandClinicaloutcomes

•  ThemediannumberofNIS=366%=2-4NIS20%=5-8NIS•  HighernumberofNISassociatedwithpoorappe%tep=0.008weightlossp=0.036•  Appe%tescoreimprovedfrom7to5p=0.001•  34%ofpa%entsgainedweight

Cumulative hazard plots of survival (days) for total symptom score quintiles.

Arazm Farhangfar, Marcin Makarewicz, Sunita Ghosh, Naresh Jha, Rufus Scrimger, Leah Gramlich, Vickie Baracos

Nutrition impact symptoms in a population cohort of head & neck cancer patients: Multivariate regression analysis of symptoms on oral intake, weight loss and survival

Oral Oncology, Volume 50, Issue 9, 2014, 877–883

UsingMul'pleDomainsWeightloss,BMI,appe'te,imaging,labdataforCancerCachexiastages

•  1.ViganoA,etal.CritRevOncog.2012;17:293-303;2..BlumD,etal.AnnOncol.2014;25:1635-16423.Argiles,CASCOJCSM2011

–  N=207 –  Metastases, 66%1

29 ■  N=861 ■  Metastases, 85%2

Time, d 0 200 400 600

0

1.0

0.8

0.6

0.4

0.2 Su

rviva

l

P<0.001 for cachexia or refractory cachexia vs no cachexia

Log-rank test P<0.001

Cum

ulat

ive S

urviv

al

Time, wk 0 50 100 150

0

1.0

0.8

0.6

0.4

0.2

150

No cachexia

Pre-cachexia

Cachexia

Refractory cachexia

No cachexia

Pre-cachexia

Cachexia

Refractory cachexia

ConsensuscriteriaforweightandBMImul'plecancertypes

ConsensuscriteriaforweightandBMI,plusbiochemicalmarkersandpa'entcharacteris'cs:LungandGIcancer

Development and validation of a clinically applicable score to classify cachexia stages in advanced cancer patients

Zhou T.J Cachexia Sarcopenia Muscle. 2018

Othermarkersordomainsincachexia

Survival analyses (Kaplan-Meier) with comparisons of curves . Survival of male patients with testosterone levels ≤185 ng/dL (blue) was decreased

Egidio Del Fabbro, David Hui, Zohra I. Nooruddin, Shalini Dalal, Rony Dev, Gina Freer, Lynn Roberts, J. Lynn Palmer, Eduardo Bruera

Associations Among Hypogonadism, C-Reactive Protein, and Survival in Male Cancer Patients with Cachexia

Journal of Pain and Symptom Management, Volume 39, Issue 6, 2010, 1016–1024

Summary

•  ConsensusCancerCachexiadefini%onupdated•  Corecriterion=weightlossWeightlosscriteriamodifiedbyini%alBMI•  Validatedbylargestudyresul%ngingradingsystem0-4•  Addi%onaldomainsmayenhancethesystem•  Importanceofappe%teandNIS•  Bodycomposi%onthroughouttrajectory•  Iden%fypa%entsinclinicalprac%ce,prognos%cate,designandinclusionofsubjectsinclinicaltrials