ColorectalCancerandTargetedTherapy

AnnMarieSiney,RN,ANP‐BCN214Spring2012

ColorectalCancer 3rdmostcommoncancerinUS 3rdcauseofcancerdeathinUS 2012estimatednewcases;103,170Colonand40,290Rectal

Incidence&DeathRatedecreasingoverlast20yrsOver90%ofcasesoccur>age50 Incidenceisrisingin<50agegroup

Colorectal Cancer

Sex:incidenceequalmen/womenuntilage50;thenbecomeshigherinmenthanwomen

Incidenceandmortalitygreaterinmenthanwomen–35%to40%overall

Race/ethnicity:incidence&deathshighestinblacks,lowestinIndian/AlaskaNatives&Hispanics

RiskFactors Age:peakincidence6th/7thdecades Personaland/orfamilyhistoryofCRC Adenomatouscolonicpolyps>2mm InflammatoryBowelDisease

Ulcerativecolitis&Crohn’sdisease Geneticmutations;5‐6%ofallCRC’s

FAP(Familialpolyposis)100%risk HNPCC(Hereditarynonpolyposiscolorectalcancer)

Type2DM

Risk FactorsModifiable

Obesity Sedentarylifestyle Smoking HeavyAlcoholUse Dietary

↑inred,processedmeat ↓infruitsandvegetables

DecreasedRisk Lowfat,highfiberdiet Exercise VitaminsD,calcium, Estrogenreplacementtherapy(HRT)post‐menopausal,NSAIDs

ColectomyforhighriskFAP

ScreeningTests Goal:detect&removeadenomatouspolyps Beginage50 Increasedsurveillanceforthoseathighrisk

1stdegreerelativebegin10yrspriortodx Hxofpolyps,geneticmutationsetc.

Collaborativeeffort–ACS,ACR,USCRCtaskforce.

CRCScreeningatAge50

Fecal Occult Blood Test

2/3ofcoloncancersandsomepolypsbleed Avoidfoodsfor3daysbeforeexamthatcanaltertest

results: Aspirin NSAIDs,suchasibuprofen(Advil,Motrin,others) Anticoagulants,suchaswarfarin(Coumadin) Artichokes,freshbroccoli,cabbage,cauliflower,

cucumbers,horseradish,mushrooms,potatoes,radishesandturnips

Meatandfish VitaminCsupplements Ironsupplements

Colonscopy

Similarequipmentandpatientpositioningforsigmoidoscopy

Underutilized Sedationrecommended Fullbowelpreprequired Ifheartvalvedisease–musthaveantibioticsbeforeandafter

Arrangefortransportationwillbedizzy(duetomeds)afterprocedure

Computer TomographicColonography VirtualColonscopy–CTC

Carcinogenesis MalignantTransformation

Metaplasia Dysplasia Carcinomainsitu Invasivecancer Metastasis

Carcinogenesis

Keygenesmutated Oncogenes Tumorsuppressorgenes DNArepairgenes Signalingcascade Tumormicroenvironment

TargetedTherapies MonoclonalAntibodyMab

Largemolecules‐IV Extracellulartargets Preventligandbinding Stimulatetheimmunesystem

Tyrosinekinaseinhibitors Smallmolecules‐Oral MultipleTargets‐outsideandinsidethecell Inhibitsignalingcascade

SignsandSymptoms RightSided

Vague,dullpain,darkstools,massRLQ Anemia–fatigue,wtloss,weakness

LeftSided ↑gas,pain,cramps,brightredblood, Changeinbowelhabit–const/diarr ∆incaliberofstool–Obstruction Rectal–fullness,frankblood,tenesmus

PathophysiologyColon vs Rectal Cancer

Adenocarcinoma;>90%,arisinginglandularepithelialtissueofmucosa

Squamouscell;<10% Metastasis

lymphatic,venous, directextension,implantation

1°Liver,Lungs,PeritonealCavity alsobone,adrenals,ovary,brain Colon→liverRectal→lung

Colorectal Case Study

52yroldAfricanAmericanmale Lastphysical5yrago H&P:occasionalbloodonstooldeniespain,∆inbowelhabit,wtlossorfatigue

Family;Daddied50ish,unknown

CRCCaseStudy PhysicalExamWNL

Nondistended,+BSx4,‐pain,HSMormasses,DREneg

DifferentialDx Tests:CBC(anemia) RefertoGIforcolonoscopy

Invasiveadenocaofsigmoidcolon

Diagnostic Studies

Stagingworkup CBC,CMP,CEA,+/‐CA19‐9,bili CTscanofchest,abdomen&pelvistor/ometastaticdisease

PETscan SurgicalConsult MedicalOncologyConsult

SurgicalOp>ons Coloncancer,Goal:Cure

Hemicolectomy Laparoscopicvslaperotomy Colostomy:rare,d/tbowelobstructedtemporaryvspermanent

ResectionofLiverorLungMetastasis Intenttocure MayincludeRFA(radiofrequencyablation) Mayneedneo‐adjuventchemotodownstage

SurgicalOp>ons RectalCancer,Goal:Cure

Preventlocalrecurrence Maintainbowel,bladderandsexualfunction Maintain&improveptsQOL

20%impotency,sexualdys,urinaryretention,bladderdys,fecalincont&urgency,stoma

SurgicalOp>ons RectalCancer

TAE:smallearlystagelesions,8cmfromanalverge TME:resectsnodebearingmesorectum,↓localrecurrencefrom30%to<10%

Lowantresection:proximallesions,>6cmfromanalverge APresection:<6cmfromanalverge,colostomy

Colorectal Case Study

Surgicalconsult CTCAPw&w/outcontrast CMP,CEA,PT,PTT,EKG,CXR Lhemicolectomyw/anastomosis 6cmmoderatelydifferentiatedinvasiveadenocarcinoma

Pathologypending

Staging Criteria

Pathologic/histologicstage T:depthoftumorpenetrationinto&throughtheintestinalwall

N:regionallymphnodeinvolvementM:absenceorpresenceofdistantmetastases

G:Grading1‐4,degreeofdifferentiation

AJCC7thEdition

PathologicReview TNMclassificationwithGrade Margins–proximal,distal,radial KRasmutationgeneanalysis

Wild‐typevsmutationatcodon12&13 Mutationsoccurin30‐50%CRC Indicateresistancetoanti–EGFRmabs

MSI‐HvsMSI‐L,BRAF,p53

TNMStagesforCRC

MOMOMO

N1N2aN2b

T3‐T4aT2‐T3T1‐T2

IIIB

MOMOMO

N2aN2bN1‐N2

T4aT3‐T4aT4b

IIIC

MOMO

N1N2a

T1‐T2T1

IIIA

MOMOMO

NONONO

T3T4aT4b

IIAIIBIIC

MONOT1orT2IMNTSTAGE

TNMSTAGESFORCRCM1aM1b

AnyNAnyN

AnyTAnyT

IVA

MNTSTAGE

ChemotherapyABriefHistory

5FU/LV–50yrsago,↑OS‐12m CPT‐11–late90’sIFL,FOLFIRI Oxaliplatin–FOLFOX4

↑OSfrom10‐12mthsto14‐16mths N9741Trial–bestcombination

FOLFOX–responserate,↑OS19.5m,s/eprofile, FDAapproved2004formCRC

Chemotherapy&TargetedTherapy Oral5FUequivalenttoIV5FU

XeloxequivalenttoFOLFOX FOLFOX≈FOLFIRIinmCRC TargetedTherapies

Bevacizumab(Avastin) Cetuximab(Erbitux) Panitumumab(Vectibix) Withchemo↑OSto>20mths

Angiogenesis VEGF:VascularEndothelialGrowthFactor

EGFRInhibitors

Treatment,ColonCa StageIColonCancer

SurgicalResection&Observation Surveillencex5years H&P,CEA,CTCAP+/‐PETscan Colonoscopy

StageIIColonCa SurgicalResection&dilemma ObservationvsAdjuventTherapyx6m

↓Risk–Obsvs5FUvsclinicaltrial ↑Risk–ObsvsFOLFOXvsclinicaltrial

HighRiskFeatures T4lesion,perforation,+margins,<12LN, MSI‐Lstability,lymphovascularinvasion,Grade3‐4,

StageIIIColonCa SurgicalResection&AdjuventChemotherapyx6mths

FOLFOXq2wx12cycles FolinicAcid,5FU,Oxaliplatin

Restaging–CEA,CTCAP,+/‐PET, Colonoscopyw/in1yrofsurgery Surveillencex5years

StageIVColonCa SingleMetinLiverorLung

Surg:resectcolonandmetlesion Adjchemo:Avastin+Folfoxx6mth Restageandsurveillance

MultipleMets Adjchemo:Avastin+Folfoxorother Restagein2mthsforsurgresectionandefficacyofchemotherapy

RectalCancer StageI‐resection&observation StageII,StageIII,earlyStageIV

neo‐adjchemo/rad:cont5FU/radx6wk,Oxaliplatinnowbeingused

followedbysurgicalresection Followedbyadjuventchemox4mthsFOLFOX AvastinwresectedStageIV

RectalCaner StageIV–widelymetastatic

Combinationchemo+Avastinmaybegiventocontroldiseasepriortostartingchemo/radiation

AvastinisnotgivenduringXRT

NPRole H&P

Assessphysicalandmentalhealth Assessptsknowledgeofdzanddx

Staging Pathreviewforstaging ReviewCT/PET,labs:CEA,CBC,CMP,LFT’s

NPRole TreatmentPlanning

Baselinelabs/scans,+/‐port‐a‐cath Educate:tx,schedule,sideeffects Writechemoorders,prescriptions Txplantobilling/authorization

Management Tolerance,sideeffects,response Complications

CRCCaseStudy Surg:lefthemicolectomy&port Path:T3,N1,+2/14LNMx,G2,KRASwild‐typegene CTCAPscannegative Pre‐opCEA56,kidney,liverwnl Treatmentplan?

TreatmentPlan Labs:CBC,CMP,CEA PETscan‐baseline FOLFOX6q2wksx12cycles Education

Scheduleoftx,chemos/e,pump Whoandwhentocall

Rxforanti‐nausea

SideEffects IV5FU&OralXeloda Mucositis Nausea,vomiting Diarrhea Palmar‐PlantarErythrodysesthesia Neutropenia

Irinotecan,FOLFIRI Nausea,vomiting:mild–severe

Utilizecombinationanti‐emetics Diarrhea–doselimitings/e

Loperamideq2huntilresolved Myelosuppression–doselimiting

Parameterstoholdordosereduce Alopecia‐complete Fatigue‐moderate

Oxalipla>n,FOLFOX Nausea,vomiting,fatique:mild‐mod Myelosuppression

Thrombocytopenia:doesadjust Neuropathy

Transientnumbnesstingling1‐5d Hands,feet,oral,exacerbatedbycold

*Cumulativedosedependant&limiting Persistsbetweencycles,stocking/glove,hold/reintroducewhenresolved

Avas>n,Bevacizumab HTN(RPLS)

Monitorqvisit,QD,txwithanti‐HTN

ReversableProteinuria Monitorurineeatx,holdfor3+,

Hypothyroidism TSHatbaseline&q2mth,Synthroid

Avas>nBlackBoxWarning

Hemorrhage– Epistaxis–fatalhemorrhagicevents

WoundHealingComplications Holdtherapypre&postsurgery

GIPerforations abdopain,constipation,vomiting

Erbitux&Vec>bix Infusionreaction:Loadingdose

Premedicatewithanti‐histamine Administerover2hrs,then60m, StopDrug,fluids,benadryl,steroid

Acnelikerash Grade1‐4,onsetw/in2wksoftx Lotions,oralantibiotics,steroids

Diarrhea:25%mild

Erbituxrash

Face,neck,chestandback GradeI‐macularpapularrash GradeII–pruritis+/‐interfering

withdailylife

GradeIII–severeerythroderma,vesiculareruptions

GradeIV–ulcerating,blistering,exfoliativedermatitis

Image:ONSSIGnewsletter,April2005

EGFRInhibitors Hypomagnesia

Cause:renalwasting ↑likelihoodwithongoingtx,50% MonitorMgqmth Replaceorallyatleast400mgsQD IVreplacement

NProleinManagement Tolerancetotherapy

Managementofsideeffects Adjustmenttochemoregimen Copingwithdzandtherapy Supportivetherapy/Advocateforpt

Advanceddisease RestagingPET/CT Monitormarkers

Colorectal Case Study

S/PFOLFOXx6cyles Mildnauseax2d, Neuropathy:fingertipstonailbed,resolvesw/in10d

Plts75k PE–WNL Plan?

CRCCaseStudy Toleratingtxwelloverall Nausea–discussinterventions Thrombocytopenia‐Doseadjustments,discusssignsandsymptoms

Neuropathy–discusssymptoms&continuetomonitor

Complica>ons SideEffectstoTx BowelObstruction DVT BiliaryObstruction Ascites Pain

RecurrentDisease ProgressiveDisease AdvancedDisease

Treatvsstoptherapy Hospice EndofLifeIssues

ReferenceList ACS(2012),ColorectalFacts&Figures2011 ACS(2008),ColorectalFacts&Figures2008‐2010. Davies,L.&Goldberg,R.,(2008).First‐LineTherapeuticStrategiesin

MetastaticColorectalCancer.Oncology. Dotan,E.,Browner,I.,Hurria,A&Denlinger,C.(2012)Challengesin

theManagementofOlderPatientswithCancer. Lindsetmo,R.O.,Yong&Delaney,(2009),Surgicaltreatmentfor

RectalCancer:AnInternationalPerspective Meyerhardt,J.&Mayer,R.(2009).DrugTherapy;SystemicTherapy

forColorectalCancer.NEJM.

ReferenceList Morse,M.(2006),SupportiveCareintheManagementofColon

Cancer,SupportiveCancerTherapy NCCN(2012),ClinicalPracticeGuidelinesinOncology,Colorectal

Cancer.

http://www.cancer.gov/flash/targetedtherapies/flex/main.html

http://www.cancerstaging.org/staging/posters/colon8.5x11.pdf