J. Coloproctol. (Rio J.) vol.37 número3

w w w . j c o l . o r g . b r

Journal

of

Coloproctology

Review

Article

Coloretal

cancer

in

pregnant

women

Helena

Margarida

Cruz

Gens

_,

_Laura

_Elisabete

_Ribeiro

_Barbosa

a_{UniversidadedoPorto,FaculdadedeMedicina,Porto,Portugal}

b_{CentroHospitalarSãoJoão,Servic¸odeCirurgiaGeral,Porto,Portugal}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received1February2017 Accepted19June2017

Keywords:

Coloncancer Rectalcancer Pregnancy Cancerdiagnosis Cancertreatment

a

b

s

t

r

a

c

t

Background:Colorectalcancerinpregnancyisararepathologywithlimitedhigh-grade evi-denceavailableforguidance.ThediagnosisofCRCinpregnantwomenisusuallydelayed, andoncediagnosisismade,challengesexistastreatmentoptionsmaybelimited.

Objective:Thestudyaimstohighlighttheimportanceofearlyinvestigationofsymptomatic patientsduringpregnancy,aswellastoupdatetreatmentandprognosisinCRC.

Methods:AliteraturesearchinPubMeddatabase,includingarticlesfrom2006to2016and cross-researcharticleswiththeinitialresearch.

Results:Pregnancycanlimitandcontraindicatetheutilizationofstandarddiagnosticand therapeutictools,whichinparticularcanhampertheliberaluseofcolonoscopyandCT. PhysicalevaluationandabdominalUSarefirstrecommended;besides,MRIorCTmaybe used,onlyinindicatedcases.Surgeryisthemainstayoftreatmentbutradiotherapyand chemotherapyhavesignificantroleinposteriormanagementoftumour.

Conclusions: ManystudiesareneededinordertoachievedevelopmentinCRCpathogenesis duringpregnancyaswellasintreatmentoutcomes.Thepotentialcurativetreatmentofthe diseaseshouldbethemainaimoftreatmentwhenconsideringCRCinpregnancy.However, itiscrucialtoadaptthetreatmenttoeachpatient,takingintoaccountconsciousdecision onpregnancyfurthermanagement.

©2017SociedadeBrasileiradeColoproctologia.PublishedbyElsevierEditoraLtda.This isanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Cancro

colorectal

na

mulher

grávida

Palavras-chave:

Cancrodocólon Cancrodoreto Gravidez

Diagnósticodocancro Tratamentodocancro

r

e

s

u

m

o

Introduc¸ão: Ocancrocolorretalnagravidezéumapatologiarara,comlimitadaevidência científicaparaorientac¸ãoterapêutica.Odiagnósticodecancrocoloretalemmulheres grávi-dasétardioe,quandoodiagnósticoéfeito,asopc¸õesdetratamentopodemserlimitadas.

Objetivo:Oobjetivo deste estudoé ressalvar a importânciada investigac¸ão precoce de pacientessintomáticasduranteagravidez,assimcomoavaliarosatuaismétodosde trata-mentoeprognósticonoCCR.

∗ _{Correspondingauthor.}

E-mail:helenagens93@gmail.com(H.M.Gens).

http://dx.doi.org/10.1016/j.jcol.2017.06.001

Métodos: ApesquisabibliográficafoirealizadanabasededadosPubMed,incluindoartigos apartirde2006até2016,assimcomoartigosdepesquisacruzadacomosartigosiniciais.

Resultados: Agravidezpodelimitarecontra-indicarautilizac¸ãodeferramentasde diag-nóstico e terapêuticas convencionais, assim como dificultar o uso indiscriminado de colonoscopiaetomografiacomputadorizada.Aavaliac¸ãofísicaea ecografiaabdominal sãoaprimeiralinhaparadiagnóstico.Noentanto,emcasosselecionados,aressonância magnéticaouatomografiacomputadorizadatambémpodemserusadas.Acirurgiaéo gold-standardmasaradioterapiaeaquimioterapiaassumemumpapelcadavezmaisrelevante notratamentomultidisciplinardestestumores.

Discussão: Como os sintomas abdominais são comuns nagravidez e cancro coloretal pode simulá-los,odiagnósticodiferencialentreestas duaspatologiasé crucial,jáque intervenc¸õesprecocespodemsercurativas.Apósdiagnóstico,oseguimentodasgrávidas deveserindividualizado,dependendodeváriosfatores.Porém,jáqueatualmenteo trata-mentodocancroépossívelnagravidez,aprobabilidadedesobrevivênciadapacientenão deveserdiminuídadevidoaodiagnósticotardio.

Conclusões: Maisestudossãonecessáriosparasabermaisacercadapatogénesedocancro coloretalnagravidez,assimcomoosresultadosapóstratamento.Opotencialobjetivoéo tratamentooncológicodocancrocoloretal.Noentanto,écrucialadaptarotratamentoa cadapaciente,tendoemcontaasuadecisãoconscienteacercadacontinuac¸ãodagravidez. ©2017SociedadeBrasileiradeColoproctologia.PublicadoporElsevierEditoraLtda.Este ´eumartigoOpenAccesssobumalicenc¸aCCBY-NC-ND(http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Introduction

Background

Colorectalcancer(CRC)inpregnancyisaconditionthat repre-sentsadistinctentityfromCRCinthegeneralpopulation,as itisararepathologywithlimitedhigh-gradeevidence avail-ableforguidance.Infact,theliteratureonthissubjectisscant withfewerthan300casesreported,1_{whichmeansthereis}

lim-itedexperienceonthemanagementofCRCdiagnosedduring pregnancy.

The diagnosis of CRC in pregnant women is usually delayed,becausethereisasignificantoverlap insignsand symptoms between a colorectal malignancy and normal pregnancy,impeding properdiagnosis.2–4 _{Oncediagnosis is}

made,challengesexistastreatmentoptionsmaybelimited.2

Thatiswhymanagementrequiresjudiciouslyindividualized strategiesafterthoroughpatientcounsellingtodealwith con-sequent emotional and physical stress, inorder to ensure adequatepsychologicalsupportandrealisticexpectations.2,5

Theprimaryobjectiveofthisreviewwastohighlightthe importance ofearly investigation of symptomaticpatients duringpregnancy, aswellas therole ofchemotherapeutic, radiologicalandsurgicalinterventions.Secondaryobjectives includearesearchaboutepidemiologyofCRCduring preg-nancy,itsimplicationsandprognosticfeatures.

Methods

TheliteraturesurveywasconductedinPubMeddatabase.The words“colonpregnancycancer”and“rectumpregnancy can-cer”wereused.Onlythearticlespublishedfrom2006to2016 were considered. After reading the title and abstract, and

subject to an availability of the article, 31 articles were obtainedinPubMed.Articlesobtainedbycross-searchingwith thearticlesoftheinitialresearchwithrelevantinformation werealsoadded.

Results

Epidemiology

CRCisthethirdmostcommontypeofcancerinwomen4_with

itshighestincidenceoccurringinpatientsaged50yearsold6_;

womenolderthan40yearstendtobe11timesmorelikelyto developCRCthanthoseyoungerthan30yearsofage.7,8

While the overall incidence ofCRC is steady or falling, somestudiesreportanincreasedincidenceofCRCinyounger patients(<40years),1_{whichmeansthat3%ofpatientswith}

thiscancerareyoungerthan40yearsold.6_{Nevertheless,for}

thisagegroup,studiesreportthatoverallsurvivalofCRCfor womenhasimprovedsubstantially,with5-yearoverall sur-vivalnowapproaching80%.9

BecauseoftheincreaseintheincidenceofCRCinyounger patients,itmayoccurduringthereproductiveage,interfering withpregnancy.1_{Cruveilhierreportedthefirstcaseofrectal}

carcinomainpregnancyin1842,butnowitistheseventhmost common typeof cancerin pregnancy.5,6 _However,its

inci-dencerateiscontroversial;somestudiesreportanincidenceof 0.002%3,4,6–8,10,11 _{whileothersconsider0.07–0.1%,}12–14 _which

meansabout1caseper13,000gestations.3,5,15_Themeanage

ofwomenwithCRCduringpregnancyhasbeenreportedas31 yearsofage,4–6,16_{withrangeof16–48years.}12

Most of CRC in pregnancy is an aggressive mucinous subtype,8_{whichhavepoorerprognosis,}17_butprimary

signet-cellcarcinoma(SRCC)ofthecolonandrectumalsorepresents aformofadenocarcinoma ofthe largeintestine. Although itsrareincidenceofaboutlessthan0.1%ofcasesofCRCin pregnancy,patientswithSRCCareyounger.14

AetiologyandpathogenesisofCRCinpregnancy

CRC isone of the three mostcommon typesof cancer in womenandcanpresentinwomenofchildbearingage, espe-ciallyifthereisageneticpredisposition.12

Infact,environmentalfactorsplayadominantroleinthe aetiologyofmostCRCbutinheritedgeneticfactorsarealso significantinbetween15%and30%ofcases.Inabout5%of allcases,CRCisassociatedwithahighlypenetrantdominant orrecessiveinheritedsyndrome.18_{Whenconsideringfamilial}

clusteringofCRCandendometrialcancers,itisimportantto considerLynch’ssyndrome(hereditarynon-polyposis colorec-talcancer(HNPCC)),asacauseofcancerinpregnantwomen.19

Itisanautossomicdominantinheritedgeneticdisease,20_and

thusmultiplegenerations candevelopCRCatanearlyage (mean,45years).Lynchsyndromeislikelyifafamilyhistory meetstheModifiedAmsterdamCriteriaorrevisedBethesda guidelines.11

Familial adenomatous polyposis (FAP) is another inher-itedsyndrome,responsible for<1%ofallCRCcases.FAP is transmittedasanautosomaldominanttrait,andiscausedby truncatingmutationsinthe(APC)adenomatosispolyposiscoli gene.Recently,theMUTYH(mutYhomologue(Escherichiacoli)) genehasbeenidentifiedasafurtherpolyposisgene, display-inganautosomalrecessivepatternofinheritance.18

Inwhatconcernstoenvironmentalfactors,delayed child-bearingandincreasedmaternalagemayleadtoanincreased incidenceofCRCcomplicatingpregnancy.6,21

Some investigators demonstrated that 20–54% of colon cancershaveoestrogenreceptors(Ers),whereasothershave demonstratedprogesterone receptors(PgRs), whichmay be stimulatedbytheoestrogenandprogesteroneproduced dur-ingpregnancy.Theroleofthesehormonesintheaetiology andprogressionofCRCarelimitedandconflicting,12_Infact,

CRCpathogenesisand its relationtopregnancyisnotwell understood,8,12,17_{andstudiesshowthatparityisnotpositively}

neithernegativelyassociatedwithCRC.8

Whendiscoveredduringpregnancy,two-thirdsofCCRin pregnant women tend to involve the rectum and sigmoid colon,unlikethegeneralpopulationwheretwo-thirdsarise fromtheextrapelviccolon.4,12–14,17_{Infact,itiswasreported}

thatabout85%ofCRCinpregnancyarebelowtheperitoneal reflection.1,5,12,16

Preventionandscreening

AdvancesinmolecularbasisofCRCincludeidentifyingthe adenomatouspolyposiscoli(APC)gene,P53 _{gene,mismatch}

repairgenes,andlossofallelicheterozygosity.17

Accordingly,asfamilialadenomatouspolyposis(PAF)isa known riskfactor forCRC duringpregnancy, patients with familyhistoryofHNPCCshouldperformgenetictesting.1,5

WhenapatientdevelopCRCatayoungage,itis impor-tanttoconsiderthepossibilityofahereditarycause,sowe shouldconfirmherfamilymedicalhistoryinwhatconcerns tocancers.IdentificationofthegermlinemutationinaLynch syndromefamily allowstheir inclusioninlifesavingcancer surveillanceprograms,whichhasbeenproventoreduceCRC mortality.22_{Therefore,screeningtestsshouldbeperformedon}

tumourtissuestohelpdeterminethelikelihoodofthis con-ditionandmicrosatelliteinstability(MSI)analysisisthefirst approachtoidentifypatientswithLynchsyndrome.Germline testing formismatch repair(MMR) gene alterations should beperformed,11_{asanautosomaldominantMMRdeficiency}

leadingtoatumourwithMSIwasassumedtobetheprimary mechanismforLynchsyndrome.23_{Infact,germlinemutations}

inthegenesMLH1,MLH2,MSH6and PMS2canleadtothe developmentofthesyndrome,andheterozygosityfora muta-tioninoneofthesegenescanresultinincreasedsusceptibility tocancer.11

IfLynchsyndromehadbeensuspectedearlydiagnosisis essential. The American Cancer Society guidelines recom-mendcolonoscopybeginningatanearlierageforhigh-risk individuals.11,24_{Periodicexaminationbycolonoscopyleadsto}

thedetectionofCRCatanearlierstage,toa63%reduction oftheriskofCRCandtoasignificantreductionofthe mor-talityassociated.25_{Annualcolonoscopyprogramsperformed}

attheageof25yearsinpatientswithfamiliesthathaveat least3relativeswithahistoryofCRCorotherHNPCC-related tumours andinfamilieswithidentifiedMMRdefect.18_Itis

recommendeda3-yeargapbetweencolonoscopies because thistimeintervalhasproveneffectiveforthedetectionofthis condition.11

When pregnant women with SRCC are analyzed for microsatelliteinstability,studiesconfirmtheyrepresentabout 30%oftumours.Moreover,mutationsofK-rasandP53_gene

havebeenreportedinSRCC.Furthermore,replicationsofDNA arealsosuggestedtobeatleastpartlyinvolvedin carcinogen-esisofSRCC.14

Notedownthatgenetictestingisonlyrecommendedfor thosewithafamilyhistorysuggestiveofLynchsyndromeor otherhereditarypattern,asmostCRCaresporadic.11

Clinicalfeaturesanddiagnosis

DiagnosisofCRCduringpregnancyischallengingsecondary tothedifficultyindistinguishingpainofgynaecologicandGI origin,16,26_{andtheoverlapinsignsandsymptomsofcancer}

andpregnancy.1–3,5,13,16_{Consequently,usuallythereisadelay}

indiagnosisofCRCduringpregnancy.4–7,10,12,26 _Thosesigns

and symptoms include nausea, vomiting, abdominalpain, weightloss, anaemia,abdominalmass,rectalbleeding and alteredbowelhabitssuchasconstipation.

Physiologicadaptationsinpregnancymayalsoalterclinical presentations12_{so,highdegreeofsuspicionifclinicalfeatures}

aresuggestiveofGIobstruction.17

However,sometimesthereisnosuspicionofCRCbecause itssymptomsareabsent3_{andfoetalmovementsarenormal.}17

WhenconsideringSRCC,symptomsusuallydeveloplater, leadingtothenon-detectionofcancerslimitedtomucosaand sub-mucosa.14

Palpable abdominal mass is a uncommon finding17

but a common problem can be excluded with a careful anorectalexam,1 _{yielding67–84%accuracyinstagingrectal}

carcinomas.14

Intestinal obstructions are extremely rare in pregnant women2_{butwhenpresent,exploratorylaparotomymustbe}

commenced,28 _{aspromptoperativeinterventionmaximizes}

outcomeforbothfoetusandmother.3

Haemorrhoids or anal fissure, common causes ofrectal bleeding,shouldbeevaluated,andrectalexaminationshould beperformedwhenapatientpresentswithacomplaintof painand/orrectalbleeding.6,13 _{Persistentanorectalbleeding}

orrectalpassageoftissueatthetimeofdeliveryisanominous sighofCRCcancerandshouldbeinvestigated.12

Ifapatientstartstoloseweightwhilepregnant,sheshould beevaluatedformaternaland foetal aetiologies. Persistent nauseaorvomiting,speciallyinthethirdtrimester,should alsobeevaluatedfurther.6

Aboveall,itiscrucialtoconsidercomplaintsthatare spe-cific,severeorperseverate.3,4

Thediagnosis ofCRC in anon-pregnant patient entails thetumourmarkerserum carcinoembryonicantigen(CEA), toraco-abdomino-pelvicimaging,andendoscopywithbiopsy.

CEA

Evaluationofabnormallaboratoryvaluesisimportantto opti-mize patient diagnosis. CEA levels have been used during pregnancyforthediagnosis,monitoringandprognosisofCRC. Unfortunately,CEAlevels tendtobenormalorslightly ele-vatedduringpregnancy,14,16,17_{andarenotconsideredauseful}

screeningtoolduetotheirlowsensitivityandspecificity.12

Colonoscopy

Colonoscopy is the gold standard to confirm diagnosis as it provides direct visualization, accurate determination of location, and the opportunity to obtain tumour tissue for pathological diagnosis of CRC.4,14 _{The American Society}

of Gastrointestinal Endoscopy indicate that an endoscopic intervention is safer than radiologically guided or surgical operations.1,5_{However,pregnancyisarelative}

contraindica-tionasthis proceduremaycomplicatepregnancy,4,12–14 _due

totheriskoffoetal exposuretopotentialteratogenic med-ications,uteroplacentalinsufficiencywithmaternalhypoxia or hypotension, and the risk for placental abruption with themechanicalpressure tothe uterus.1,2,5,12 _{Accordingly,it}

isadvisedthatstrongindicationshouldbepresenttoproceed withanendoscopy,itshouldbedelayeduntilsecondtrimester wherepossible,1,5_{theproceduretimemustbeminimizedand}

thelowestpossibledoseofsedativemedications shouldbe used.2

With informed patient approval, the procedure may be performed with possiblereduction in risk withthe use of meperidine,becauseofitssaferfoetalprofile,maternal oxy-genadministration,andgentleabdominalcompression.12,14

Becausemostcasesof CRCduring pregnancyare rectal carcinomas,ifthelesionisconfinedtothedistalcolon,a flex-iblerectosigmoidoscopy(preferablywithoutsedation)maybe

performed,asanalternativetocolonoscopy.1,5,12,13_Theseone

couldbedelayedinordertolookforsynchronouslesions.

Staging

Intheliterature,mostCRCareusuallydetectedinitsadvanced stages,secondarytolatediagnosis,3_{duringsecondorthird}

trimesterofpregnancy.6,12,13_{Astudythatreviewed41patients}

with CRC duringpregnancy observed that all patients had stageIIorgreaterdisease,12 _{whileotherrefersthat60%are}

alreadydiagnosedatstageIIIorIV.13_{ItcorrespondstoDukes}

stageBorhigheratpresentation.4

Staging is critical to ensure one is not dealing with advancedstageIVdisease,aslocalmanagementofcolorectal malignancywouldchangeconsiderably.2

CTscan

Imagingevaluationduringpregnancyisdifficultsince toraco-abdomino-pelvic CT scan, is relatively contraindicated in pregnancy.Thisprocedureshouldbeavoidedparticularlyin the firsttrimester, secondarytothe foetal riskofradiation exposure teratogenicity and carcinogenicity.2–4,12–14,17

How-ever,itissuggestedthatriskofadversefoetaleffectsisvery lowatdosesofradiationusedfordiagnosticpurposes,soCTof pelvisandabdomencanbeperformedwithminimalrisk.2,28

Ultrasound

Ultrasound(US)evaluationisareasonablealternativetoCT.17

Itisespeciallyusefulfordetectionofhepaticmetastases2_(75%

of sensitivity)12,14 _{but, because ofthe gravid uterus, it has}

limitedaccuracyindetectingcolonandrectalmasses.3,12,13

Further diagnostics are frequently necessary when ultra-soundsarenegative.3

Transrectalultrasoundishelpfulinlatepregnancyto deter-minerectalcancerlocationandismoreaccurateinstaging rectalcancerpreoperatively,althoughithasnotbeenproven toprolongsurvival.17

MRI

Similarly,magneticresonanceimaging(MRI)isrelativelysafe inpregnancyandshouldbeconsideredafterUS indetermi-natefindings,28_{butisgoodpracticetoavoidnon-urgentMRI,}

particularlyinthefirsttrimester.1,2_{Moreover,itshouldbe}

per-formed withoutcontrast3 _{becausecontrasts havenot been}

approvedforthefoetus,12,13_{beinggadoliniumknownas}

ter-atogenicagent.2

Treatment

Treatment during pregnancy is another challenging issue; Walsh et al. have proposed an algorithm to manage CRC diagnosedduringpregnancybasedonthegestationalageof thefoetus,foetallungmaturity,cancerstage,needfor adju-vant chemotherapy, and if elective or emergent surgery is indicated.1,5,6,12,14,15

Thetreatmentgoalistoimplementtherapyassoonas pos-sibleforthemother,6,13_{andbalancethiswithdeliveryofthe}

Treatmentmodalitiesmayincludesurgery,radiation ther-apyandchemotherapy,dependingonthestageofthecancer.6

Surgery

Surgery is the primary therapy for CRC outside of pregnancy.8,12,14 _{In pregnant women with CRC it is}

rec-ognizedassafeandfeasible1_{butitstiminginaisapivotal}

issue2_{soitshouldbeconsideredonacase-by-casebasis.}

However,asthemajorityofCRCmalignanciesdiagnosed inpregnancyoccurbelowtheperitonealreflection,thelevel oftechnicaldifficultyassociatedwithsurgeryisincreased.2

Ifbowelobstructiondevelopsduringthepregnancy,a self-expandingmetallicstent (SEMS)canbe useful asit allows solving the acute condition, providing time toprepare the patientforsurgery,thusreducingbothpost-surgicalmorbidity andmortality.29

Althoughno high-gradeevidence existsregarding man-agement ofCRCinpregnancy, someclinical guidelines are reportedinliterature:

– If diagnosis is made inthe first 20 weeks ofpregnancy, treatmentdelaycanleadtodiseaseprogressionand com-promiseofmother’slife.Therefore,therecommendationis discontinuationofthe pregnancy,accordingmother’s fol-lowed byearly cancer treatmentwith surgicalresection, asinnon-pregnantpatients.2,13,14,16_{However,controversial}

dataregardingrisktothepregnancywithsurgery,if imag-ing suggeststhatthe tumourmayberesectedwithclear margins,surgerymightbeanoption.2_{Infact,lowanterior}

orabdominoperinealresectionhasalreadybeenperformed upto20weeksgestationwithoutdisturbanceofthegravid uterus.12_{However,asCRCdiagnosisisrarelymadepriorto}

20weeksofgestation,thereislimiteddataonfoetal out-comeaftersurgicalresection.12

– If colon cancer is diagnosed after 20 weeks gestation, surgery can be delayed until delivery, in order to save thefoetus,5,13,14,16 _{althoughendangeringthepatientwith}

significant risk of disease progression,3 _{due to the}

pro-angiogenic state of pregnancy.2 _{The ultimate goal is to}

achieve foetal lung maturation8,16_{; nevertheless, delivery}

may varyfrom28to32weeksgestation,basedon multi-specialityteamdecision.2,6,12_{Afterthat,treatmentofCRC}

shouldtakeplaceasinanon-pregnantpatient.2,14,15

In bothcases, the extent ofresection isdetermined by tumoursize,location,histologicgradeandtumourextension intothecolonwallandintoadjacenttissueandorgans.14

Chemotherapy

Theneedforchemotherapydependsuponthefinalhistology ofthetumour,2_{beingconsideredinstageIIwithhighriskof}

recurrence14_{andstageIIIwhennodalinvolvementispresent.}8

Asalargeportionofpatientsarediagnosedinadvanced stages,iscommonthatneoadjuvantchemoradiationbefore surgical resection is needed in rectal cancer.13 _Adjuvant

chemotherapyhasbeenshowntoimprovethesurvivalrate by5–10%forstageIIorIIICRC,12_{butevidenceshowsthatin}

pregnantwomenwithmetastaticrectalcanceritmightspare thefoetus,butnotcurethemothers.13

Moreover, pelvic radiation is not recommended during organogenesis,inthefirsttrimesterofpregnancy,5,15,16_asitis

associatedwithlethaldamagetothefoetus,withembryonic or foetal death,malformation, and growth retardation.13,15

Althoughsomestudiesreportedthatchemotherapyshouldbe givenonlyafterdelivery,otheronessuggestthat chemother-apycanbeadministeredinthesecondorthethirdtrimesters with dose maternal/foetal surveillence.1,5,15 _The

recom-mended therapeutic agent is 5-fluoruracil (5-FU), which is an inhibitor of DNA synthesis.4 _{Although 5-FU is reported}

tobeassociatedwithlowornoriskofadversereproductive outcomes,9,10_{someinvestigatorshavesuggestedathe}

possi-bilityofspontaneousabortion1,5_{andteratogenicityassociated}

with5-FU.5,12,15,16

Othernewchemotherapeuticagentsplatinum-basedlike cisplatinandoxiliplatinareavailablebut,accordingtotheU. S.FoodandDrugAdministration,theyarenotrecommended duringpregnancy.12,15,16

The previous reasons could explain why women with pregnancy-associated CRC were less likely to undergo chemotherapy,incomparisontonon-pregnantwomeninthe samecondition.8

Itisalsoimportanttoreportthat,consideringLynch syn-drome,tumourswithMSIweremoreresponsivetoadjuvant chemotherapythantumourswithoutMSI.11

Radiotherapy

AdjuvantradiotherapyisindicatedforDuke’sB2andC rec-tal cancers,12 _{T4 lesions adherent to the pelvic structure}

and in patients withclose or positive surgicalmargins.8,14

Nevertheless,radiationtreatmentofthepelvisis contraindi-cated during pregnancy2,5,15 _{and is usually delayed until}

after delivery12,16 _{as it has been implicatedin sexual and}

gonadaldysfunction,foetalgrowthrestrictionorspontaneous miscarriage.9

Biologicaltherapies

Biological agents like bevacizumab, cetuximab or panitu-mumabproviderelativelymodestsurvivalincreaseinaddition tostandardchemotherapy,withholdingtheiruseuntil deliv-erywouldnotbelikelytopreventcurativetreatment.10

In stage IV disease, palliative management should be performed and emphasis should be to lengthen the progression-free and overall survival in the unresectable metastaticCRC.12,14

Vaginaldeliveryvscaesarean

Thedeliverymodeiscontroversialascancerpersiisnotan indicationtoperformacaesareansection.5,16_{Howeverstudies}

showthatcaesareansectionismorepracticedinwomenwith pregnancyassociatedwithCRC.8

Outside thenormalobstetricalindicationsforcaesarean section,indicationsforanoperativedeliveryinCRCpatients includeatumouralongtheanteriorrectalwall,secondaryto increasedriskofbleedingwithvaginalbirthpressureorbirth canalobstruction bytumour.12 _{Caesareanalsocan be}

There hasbeen a recentmove towards vaginaldelivery forwomenwithrectalcarcinoma,evenwithanunripecervix requiringacervicalripeningagent.12

Complications

Thedelayindiagnosisleadtoanincreaseofcomplications as the uterus, cervix and adnexa share the same visceral innervationasthelowerileum,sigmoidcolon,andrectum.26

About25% ofpregnantwomenwithCRCwillhaveovarian metastases.12,14,16 _{If tumour resection is performed during}

pregnancy, prophylactic ovarian removal may be deferred secondary tothe possible riskfor aspontaneous abortion, especiallyinthefirsttrimester.Bilateraloophorotomyis per-formedduringpregnancy,ifevidenceofinvasion.12,16

The liver is the most common site for synchronous metastases14_{buttherearenoreportsofliverresectionforCRC}

livermetastasesduringpregnancy.10,16

Colonobstruction,perforation, andmetastasis are more frequent in pregnant women with CRC than the average population,17_{possiblyduetotheimmunosuppressivestateof}

pregnancy.12

Foetalrisk

Itsreportedthat higher ratesofpreterm labourand major puerperal infections are noted in women with pregnancy associatedwithCRC, asthis malignant condition prone to infectionsthatmaybesub-clinicalbeforedelivery.8_Thiscould

beexplainedbythemalignancy-relatedimmunesuppression, asCRCinitiatesaninflammatoryreactionthatconsequently starts the preterm labour cascade secondarilyto the close proximitytotheuterus.8

Despite high rates of preterm delivery, some studies reportedanabsenceofadversefoetaloutcomes,5,8_while

oth-ers refer that only 78% of foetus from women with CRC survived.5_{Conversely,thereisagreementthattheriskoffoetal}

malignancyisrarelyobserved,evenwhenthedisease isin anadvancedstagewithwidespreadmetastasis.5,17_However,

metastasistotheplacentawasreportedonceinmaternal col-orectalmalignancy.

Eventhoughacompleteevaluationoftheplacentais rec-ommended,thereisnoevidencetosupportperiodicfollow-up ofthebaby.5

Prognosis

PregnantwomenwithCRCtendtohavepooroutcome,which usuallyincludeswidespreadmetastasis,5_{mainlysecondaryto}

delayeddiagnosis.4,6,8,12,16_{Moreover,whenconsideringSRCC,}

itismorelikelytoexperiencelymphnodemetastasis,havean aggressiveclinicalcourseandpoorprognosis.14

PreviousstudiesreportedthatpatientswithCCRregarding LynchsyndromewithMSIsurvivedlongerthanpatientswith non-MSItumoursdid;accordingly,the formeronesshowed lowermortalityrateswhenstratifiedbytumourstage, includ-ingpatientswithstageIVcancer.11 _{Hence,thedetectionof}

MSIinaCCRisapositiveprognosticfactor,particularlyamong youngpatients.11,20

Mostofall,itisimportanttonoticethatwomenthatare notsurgicallytreateddiedataratethatwas4.2timesthatof womenwhoundergosurgicaltreatment.8

Whencomparingpregnanttonon-pregnantwomenwith CRC,5yearcancersurvivalisthesame.12_{Womenwithcolon}

cancer died ata fasterrate than those withrectal or anal cancer,eventhoughitisreportedthatpregnancywasnot asso-ciatedwithasignificantdifferenceinsurvivalbetweenthese twogroups.5,8

Discussion

After this reviewit appears that there is still muchto be clarified,especiallyinthetreatmentarea.Despitearising inci-denceofCRCinpregnancydueto,atleastinpart,morewomen fallingpregnantatanadvancedmaternalage,onlyfew stud-ieswereperformedaboutthisissue.Moreover,mostofthose havenotbeencompletedduetoethicalreasons,sothereis informationevaluatingnewtherapies.

CRCinpregnancyisrarebutitsincidenceisincreasingnot onlybecause morewomenare postponing pregnancyuntil laterinlifebutalsobecausethereisanincreasedriskforthis cancerinwomenwithmorethan40yearsold.5,10

This cancer in gravidity is not well understood but, as geneticalterationscontributetothesusceptibilitytoCRCitis importanttooffergeneticcounselling,especiallywhenother CRCisrecognizedinthefamilyhistory.8

Asabdominalsymptomsarecommon inpregnancy and CRCcanmimicthem,theyareoverlooked.6,13,16_Thus,

differ-entialdiagnosisshouldincludethepatient’shistory,physical examination,laboratorydata,andradiologicfindingsthatmay assistinidentifyingthediagnosis12_{;anappropriatework-up}

mayresultinpromptevaluation,detectionandappropriate interventionstotreatCRC6,12,28 _{asearlydiagnosis improves}

survivalandtreatment outcomes.1,2,6 _{Intheera ofpossible}

cancertreatmentinpregnancy, patient’schanceofsurvival shouldnotbediminishedbydelayeddiagnosis.7

Further management is individualized and dependent on various factors including maternal age, patient’s desire forfuture fertility,gestational ageatdiagnosis,and cancer stage.12_{However,pregnancycanlimitandcontraindicatethe}

utilization ofstandarddiagnosticandtherapeutictoolsdue toagraviduterusandapotentiallyvulnerablefoetus,which canhampertheliberaluseofcolonoscopyandCT.1,13

Physi-calevaluationplaysanessentialrole,speciallytheevaluation ofliversizeandarectalexaminationtoscreenformasses.6

AbdominalUSisfirstrecommended,butitsuseislimiteddue tothepatient’schangeinbodyhabitus.28_MRIorCTmaybe

usedifnecessary,althoughCTisnotdesirableduetofoetal irradiation.28 _{Laparoscopy, EGD, and sigmoidoscopy can be}

performedduringpregnancy,whenstronglyindicated.12

Mostmedicationsappeartoberelativelysafetothe foe-tusandcanbeusedwhenbenefitstothemotheroutweigh potentialfoetalrisks.12

betweenpregnancyoutcomeandtreatmentwith chemother-apeuticagents,usedintreatmentofCRC.12_{Therefore,itmay}

still difficultto provide preciseguidance to patients about long-termeffectsofthistreatment.9,16

Conclusion

The coexistence of malignant tumour and pregnancy is a stateofsimultaneousoccurrenceoftwocompletely contra-dictoryphenomena– thedevelopment ofa newlifeand a life-threatening terminalillness. In fact, CRC isan aggres-sivecancerthatisrarelyfoundduringpregnancy,butwhenit appearsitisexpectedpooroutcome,asitsusuallydiagnosed inlatestages.6,12,13

Becausetherearenoabsoluteguidelines,itisassociated withdiagnosticandtherapeuticchallenges,10,13 _asgravidity

requiresfurtherquickandadequatediagnosis.3

Thereisnecessaryfurtherinvestigationsaboutdiagnostic andtreatmentmodalitieswithreducedfoetalsideeffects,in ordertodiminishitsincidenceandmortalityrate.1_Follow-up

oftheinfantsinlaterchildhoodandadolescenceasthecentral nervoussystemcontinuetodevelop,withadditionalreporting ofcases,isneededtoestablishthesafetyofchemotherapeutic treatmentofCRCduringpregnancy.16

In fact, treatment during pregnancy varies widely and posessignificantlegal,ethical,religious,emotionaland scien-tificchallenges;therapyshouldbeindividualizedanddefined byamultidisciplinaryteam12_{thatconsidersnotonlythrough}

patientcounselling,butalsothebestmanagementforboth thepatientand herfoetus.2 _{Allthe professionalswholook}

aftersucha specialpatient shouldinform her considering the most current and reliable knowledge, providing her a multidisciplinarycare,andunderstandingthecomplexityof coexistenceofcancerandpregnancy.Thepatientshouldhave theopportunitytodecideaboutthefateofherpregnancyand itshouldnotbeaffectedbythemoralbeliefsofthedoctor;the finaldecisionconcernsonlytothepatient.1,21,30,31

Aboveall,thetreatmentstrategyforCRCshouldbeno dif-ferentforpregnantandnon-pregnantpatientsintermsofthe aim,whichispotentialcurativetreatmentofthedisease,but shouldalwaysconsider thepatient’s consciousdecisionon pregnancyfurthermanagement.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgement

IwouldliketoacknowledgeLauraElisabeteBarbosa,MD,for allthesupportanddedicationgivenduringthisreview.

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