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What is non-small-cell lung cancer?

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Non-Small-Cell Lung Cancer

ESMO/ACF Patient Guide Seriesbased on the ESMO Clinical Practice Guidelines

www.anticancerfund.org www.esmo.org

NSCLC:aguideforpatients-InformationbasedonESMOClinicalPracticeGuidelines-v.2016.1 Page1ThisdocumentisprovidedbytheAnticancerFundwiththepermissionofESMO.The information in this document does not replace amedical consultation. It is for personal use only and cannot bemodified,reproducedordisseminatedinanywaywithoutwrittenpermissionfromESMOandtheAnticancerFund.

NON-SMALLCELLLUNGCANCER(NSCLC)AGUIDEFORPATIENTS

PATIENTINFORMATIONBASEDONESMOCLINICALPRACTICEGUIDELINES

Thisguide forpatientshasbeenpreparedby theAnticancerFundasa service topatients, tohelppatientsandtheirrelativesbetterunderstandthenatureofnon-smallcell lungcancer(NSCLC)andappreciatethebesttreatmentchoicesavailableaccordingtothesubtypeofNSCLC.Werecommendthatpatientsasktheirdoctorsaboutwhattestsortypesoftreatmentsareneededfortheirtypeandstageofdisease.ThemedicalinformationdescribedinthisdocumentisbasedontheclinicalpracticeguidelinesoftheEuropeanSocietyforMedicalOncology(ESMO)forthemanagementofearlystage,locally advanced ormetastatic NSCLC. This guide for patients has been produced in collaborationwith ESMO and is disseminated with the permission of ESMO. It has been written by a medicaloncologist and reviewed by two oncologists from ESMO including the lead author of the clinicalpractice guidelines for professionals. It has also been reviewed by patient representatives fromESMO’sCancerPatientWorkingGroup.MoreinformationabouttheAnticancerFund:www.anticancerfund.orgMoreinformationabouttheEuropeanSocietyforMedicalOncology:www.esmo.orgForwordsmarkedwithanasterisk,adefinitionisprovidedattheendofthedocument.

http://www.anticancerfund.org

http://www.esmo.org


Tableofcontents

FactsheetaboutNon-SmallCellLungCancer(NSCLC)...........................................................................3

DefinitionofNSCLC.................................................................................................................................5

IsNSCLCfrequent?.................................................................................................................................6

WhatcausesNSCLC?..............................................................................................................................7

HowisNSCLCdiagnosed?.......................................................................................................................9

Whatisimportanttoknowtogettheoptimaltreatment?.................................................................12

Whatarethetreatmentoptions?........................................................................................................15

Whatarethepossiblesideeffectsofthetreatment?..........................................................................22

Whathappensafterthetreatment?....................................................................................................24

Definitionsofmedicalterms................................................................................................................26

This textwaswrittenbyDr.GiulioMetro (for theAnticancerFund)and reviewedbyDr.GauthierBouche (theAnticancerFund),Dr.SvetlanaJezdic(ESMO),Dr.GiannicolaD’Addario(ESMO),Dr.LucioCrinò(ESMO),Dr.EnriquetaFelip(ESMO),Pr.GabrielaKornek(ESMOCancerPatientWorkingGroup),Pr.LorenzJost(ESMOCancerPatientWorkingGroup)andStefaniaVallone(WomenAgainstLungCancerinEuropeandGlobalLungCancerCoalition).

ThefirstupdatewasdonebyDr.GiulioMetro(fortheAnticancerFund)andwasreviewedbyDr.SvetlanaJezdic(ESMO),StefaniaVallone(WomenAgainstLungCancerinEurope)andSimonettaRapetti(WomenAgainstLungCancerinEurope).

This is the second update of this guide.Updates reflect changes in the successive versions of the ESMOClinical PracticeGuidelines.ThesecondupdatewasdonebyDr.AnaUgarte (ACF)andwas reviewedbyDr.Svetlana Jezdic (ESMO),Prof.MartinReck(ESMO),andVanessaMarchesi,PhD(ESMO).


FACTSHEETABOUTNON-SMALLCELLLUNGCANCER(NSCLC)Definitionofnon-smallcelllungcancer(NSCLC)• NSCLCisagroupoflungcancersinwhichthetumourcellsdonotlooksmallunderamicroscope,

asopposedtosmallcelllungcancer,anothertypeoflungcancer.• The threemain types of NSCLC are squamous cell carcinoma, adenocarcinoma, and large cell

carcinomaofthelung.Theyarediagnosedinthesamewaybuttreatmentmaydifferaccordingtothetypeofdisease.

Diagnosis• Lungcancercanbesuspectedifapersonhassymptomssuchascough,increasedproductionof

sputum,shortnessofbreath,hoarseness,chestpainandbloodinthesputum,orafteraclinicalexamination.

• Radiologicalexaminations*aremandatorytodefinetheextensionandstageofthedisease.• A piece of the tumour (biopsy) must be obtained for analysis in a laboratory to confirm the

diagnosisandgetmoredetailsaboutthecharacteristicsofthetumour.Treatmentaccordingtotheextensionofthedisease(classifiedintodifferentstages)• StageIandstageIINSCLCarecalledlocalizedorearly-stagecancers.

o Removalofthetumourbysurgeryisthetreatmentofchoice.o Radiotherapyisanalternativeifsurgeryisnotfeasiblebecauseofmedicalreasonsorifthe

patientrefusesit.o Chemotherapyaftersurgeryshouldbeconsidered inallpatientswithstage IIdiseasewho

cantolerateit.• StageIIINSCLCiscalledlocallyadvancedcancer.

o The most important question for this stage of NSCLC is: can the tumour be resected bysurgeryornot?Thisquestionanddecisionaboutthebesttreatmentmustbediscussedbyateam of several specialists (surgeons, medical oncologists*, radiation oncologists*radiologists*etc.).

o Ifthetumourisconsideredresectable:• Surgeryisthebestoption.Theuseofchemotherapybeforesurgerymayhelptoreduce

theextentofthediseaseandmakeitsremovalbysurgerypossible.• Radiotherapy*aftersurgerymaybeconsideredwhenthetumourisremovedentirely.

o Ifthetumourisconsideredunresectable,radiotherapyshouldbegiven,eitherduringorafterchemotherapy.

o Chemotherapyshouldbeconsideredinallpatientswhocantolerateit.• Stage IVNSCLC is calledmetastatic*because ithas spreadbeyond the lungwhichwas initially

affected.o Since the tumour has spread, it is not possible to remove it by surgery. Only systemic

therapies (therapies that travel throughout the body in the bloodstream) will be able toreachandaffectthetumour.

o Intravenous* chemotherapy with a two-drug combination is standard of care in patientswithout pre-definedmolecular characteristics (i.e.modification of genes called EGFR* andALK*),whichareidentifiedwhenthetumourbiopsy*isanalysed.Thechoiceofdrugsusedwillmainlydependonthefitnessofthepatientandonthetypeoftumour.


o Patients with EGFR* mutations or ALK* rearrangements, are best treated with orallyadministeredbiologicaldrugs.

o Maintenancetherapymaybegiventopatientsingoodclinicalcondition.Theaimofthistypeoftherapyistoprolongtheeffectoffirst-linechemotherapyontumourcontrol.Thiscanbeadministeredascontinuationmaintenance(therapyusingoneormoreoftheagentsusedasfirst-linetherapy)orswitchmaintenancetherapy(usinganagentdifferentfromthoseusedinthefirst-linesetting).Thechoiceofmaintenancetreatmentmightberelatedtoresponseafterfirst-linechemotherapyandrecoveryfromtoxicityoftheprevioustreatment.

o Second-andthird-linetreatmentsmaybeproposed,dependingonthetreatmentreceivedinthefirst-lineandonthegeneralstatusofthepatient.

Follow-up• Patientswithcompletelyresectedtumoursarefollowed-upwithclinicalexaminationsevery3to

6monthsandayearlyCT-scan*.• Patientswithadvanceddiseasewhoaretreatedwithsystemictherapyareseenbydoctorsevery

monthinordertoevaluatetoleranceofthetreatment.Efficacyisassessedthroughradiologicalexaminations*performedeveryto2to3months.


DEFINITIONOFNON-SMALLCELLLUNGCANCERNon-smallcelllungcancer(NSCLC)describesagroupoflungcancers.Thesecancersarenamed“non-smallcell”becausethecellsfoundinthetumourdonotlooksmallunderamicroscope,asopposedto another less common type of lung cancer called small-cell lung cancer (SCLC), which ischaracterisedbythesmallsizeofthecellsthatitiscomposedof.NSCLCmayariseanywhere inthetissuethat linestheairpassages inthe lung.Wheneverpossible,NSCLC is further divided into squamous (squamous cell cancer) and non-squamous (mainlyadenocarcinoma) cancer based on specific histopathological* features, which has importanttherapeuticimplications.ThisguideisexclusivelyfocusedonNSCLC,whichaccountsfor85to90%ofalllungcancercases.

Anatomyoftherespiratorysystem,showingthetracheaandbothlungsandtheir lobes*andairways.Lymphnodes* and the diaphragm* are also shown. Oxygen is inhaled into the lungs and passes through the thinmembranesofthealveoli*andintothebloodstream(seeinset).


ISNSCLCFREQUENT?In developed areas, such asNorthAmerica and Europe, lung cancer is the second and thirdmostcommonlydiagnosedcancerinmenandwomen,respectively.Lungcanceralsorepresentsthemostfrequentcauseofcancer-relateddeathsinbothsexesworldwide.In Europe, approximately 291,000 men and 100,000 women were diagnosed with lung cancer in2008.Everyyear,93outof100,000individualsarediagnosedwithlungcancer.ThereareconsiderablevariationsinlungcancerratesacrossdifferentcountriesinEurope,whichisreflectedbythelifetimeriskofdevelopingthistypeofcancer.Betweenbirthand75years,lessthan3outof100Swedishmenandabout4outof100Portuguesemenwilldeveloplungcancer,whicharethelowestratesinEurope.Thisestimategoesuptomorethan9inevery100meninCroatiaand10 in every 100 men in some areas of Poland. These variations are not only observed betweencountriesbutalsowithincountries.Inwomen,theriskofdevelopinglungcancerislowerandvariesbetweencountriesand lesswithincountries.Northerncountrieshavethehighest rates (upto4 inevery100women in Iceland,DenmarkandUK)while the lowest ratesareobserved inSpain (withlessthan1 inevery100women).Thesevariationsaremainlyexplainedbysmokinghabitsdecadesago.Therefore,inthemajorityofEuropeancountriestheincidencecontinuestoriseinwomen,butis decreasing inmen. This trend seems to occur later in Southern and Eastern Europe than in theNorthernregions.Thesevariationsreflectthedifferentsmokinghabitsbetweenregions.NSCLCrepresents85to90%ofalllungcancers.Approximately90%oflungcancersamongmenand80%amongwomenarerelatedtosmoking.


WHATCAUSESNSCLC?NSCLCisacancerforwhichactivecigarettesmokingrepresentsawell-establishedandcharacterisedrisk factor.However, as for other cancers, the cause ofNSCLCmay bemultifactorial,with severalother factors potentially contributing to its development in a synergisticmanner. In addition, theemerging understanding of NSCLC genetics indicates the relevance of interactions betweenenvironmentalandgeneticfactorsincausingNSCLC.BeforereviewingthemainriskfactorsforNSCLC,itisimportanttostatethatariskfactorincreasesthe risk of cancer occurring, but is neither necessary nor sufficient to cause cancer. In fact, a riskfactorisnotacauseinitself.Therefore,itcouldbethatsomepeoplewiththefollowingriskfactorswill never develop NSCLC and some people without any of the following risk factors maynonethelessdevelopNSCLC.

• Activecigarettesmoking:NSCLCisoneofthefewcancerswhereasingleriskfactor,namelycigarette smoking, can be recognised by far as the leading cause. Epidemiologic studies*haveshownthatactivecigarettesmokingisresponsibleforupto90%ofalllungcancers.Ofnote,thedurationofsmokingseemstobemuchmorerelevantas a contributing risk factor compared with the number ofcigarettessmokedperday.Therefore,givingupsmokingatanyage can translate into a much more significant reduction inNSCLC risk than simply reducing the number of cigarettessmokedperday.

• Passive smoking: Also referred to as “second-hand smoke” or “environmental tobaccosmoke”, this increases the risk of NSCLC, albeit far less markedly compared to activecigarettesmoking.

• Radon:A radioactivegasproduced fromthedecayofnaturallyoccurringuranium*.Radongas isubiquitousatvery low levels inoutdoorair,andcanaccumulate indoorsbyenteringhomesthroughcracksinfloors,wallsandfoundations.However,domesticradonexposureisverymuch dependent on how houses are built and ventilated. On the other hand, as anoccupational risk factor, it is particularly relevant for undergroundminerswho are usuallyexposedtohighlevelsofradon.

• Asbestos:Thismineral isawell-establishedoccupationalcarcinogen*. It isusedinavarietyofproductsforthepurposeofthermalinsulation,fireproofing,acousticinsulation,roofing,flooringandinseveralotherbuildingmaterials.Inthepresenceofactivecigarettesmoking,asbestosexposurehasasynergisticeffectontheincreaseofNSCLCrisk.At the present time, many countries (including those in the EuropeanUnion)havebannedtheuseofasbestos,inwholeorinpart,duetothestrong relationship that exists between asbestos exposure andmesothelioma*(anotherthoraciccancerwhicharisesinthepleura*).


OtherfactorshavebeensuspectedtobeassociatedwithanincreasedriskofNSCLC.Theseincludeoutdoor air pollutants, acquired lung diseases (including those that develop as a result ofoccupationalexposure toduste.g.as forminers), indoorairpollution (e.g. coal-fuelled stovesandcooking fumes) suspected to contribute to non-smoking-related lung cancer in women, dietaryhabits, viral factors and genetic susceptibility. The evidence that these factors increase the risk ofdeveloping NSCLC is far less consistent compared with the previously mentioned risk factors.However, alongwith other non-smoking-related risk factors, theymight play an important role inthosecasesofNSCLCthatariseinindividualswhohaveneverbeenexposedtosmokingduringtheirlifetime.


HOWISNSCLCDIAGNOSED?Atthepresenttime,there isnoclearevidencethatscreening1with low-doseCT-scan*shouldbearoutineprocedureinpeoplewhoareathigherriskofdevelopingNSCLC(i.e.smokers).Therefore,thediagnosis ofNSCLC can only be suspected on the basis of the symptoms reported by the patient.Here, the most common symptoms are described. Non-specific symptoms may include loss ofappetite, weight loss and fatigue, whereas more specific symptoms, such as cough, increasedproduction of sputum, shortness of breath (dyspnoea), hoarseness/lowering of the voice(dysphonia), chest pain and presence of blood in the sputum, are related to the presence of theprimary tumour. In addition, the intrathoracic* spread of lung cancer by direct extension of theprimarytumourmayproduceavarietyofothersymptoms.Thesemaybecausedbytheinvolvementof nerves, chestwall and pleura*, or visceral* structures (e.g. pericardium* and oesophagus). Forinstance,chestwallandpleuralinvasionbytheprimarytumourusuallycauselocalisedchestpainorpleuraleffusion*.Ontheotherhand,pericardialandoesophagealinvolvementcancausepericardialeffusion*anddysphagia(difficultyinswallowing),respectively.Insomeothercases,NSCLCbecomesevidentwhenithasalreadyspreadtootherpartsofthebody,inwhichcasethefirstsymptomsofthediseasemayreflectthismetastatic*spread(e.g.bonepaininthecaseofbonemetastases*,orheadacheand/orneurologicsymptomsinthecaseofbrainmetastases).Besidestheaforementionedsymptomsandsigns, thediagnosisofNSCLC isbasedonthefollowingexaminations:

1. Clinical examination: Even if the diagnosis of lung cancer cannot bemadebasedonthefindingsoftheclinicalrespiratoryexamination,thisexaminationshould always be part of a patient’s work-up if respiratory symptoms arereportedand/orabnormalfindingsaredetectedonradiologicaltest(s)*.The clinical respiratory examination includes chest inspection, palpation,percussion,andauscultation.Lungauscultationfindingsmustbeinterpretedcarefully and put into context with the patient’s medical background andother clinical findings. Clinical examination should include physical palpation of superficiallymph node* groups of the neck as well as those located just above the clavicles(supraclavicular*).

2. Radiologicalexamination*:RadiologicaltestsarecrucialinordertobothconfirmadiagnosisofNSCLCandtodefineitsextension.

o ChestX-ray*:This iscommonlythefirst testduringapatient’swork-up.

1Screeningconsistsofperforminganexaminationinordertodetectcanceratanearlystage,beforeanysignofthecancerappears.Asystematicscreeningisproposedifasafeandacceptableexaminationcanbeperformedandifthisexaminationisabletodetectcancerinthemajorityofcases.Itshouldalsobeproventhattreatingcancersdetectedbyscreeningismoreeffectivethantreatingcancersdiagnosedbecausesignsofcancerwerepresent.


o CT-scan* of the chest and upper abdomen: This is an X-ray*-based medical testwhichisnecessaryforcorrectstaging*ofNSCLC.Itallowsapreciseevaluationoftheextensionoftheprimarytumour inthe lungandthepresence/absenceofenlargedregional lymph node(s)* as well as the presence/absence of other nodules in thelung(s)and/ormetastatic*diseaseintheabdomen(e.g.liver).

o CT-scan* of the brain: This is necessary in order to exclude the presence of brainmetastases*. It is recommended as a pre-operative tool in nearly all cases ofsurgically-resectableNSCLC, aswell as in those patientswithmetastatic NSCLC forwhombraininvolvementissuspectedbasedonclinicalsymptoms.

o MRI* of the brain: This is often preferred to a CT-scan* since it allows a moreaccuratestudyofthebrain.

o PET/CT-scan: This is a nuclear medical imaging test, which allows both themorphologyandmetabolicactivityofthetumourtobeexamined.Itisrecommendedasapre-operativetestinallcasesofsurgically-resectableNSCLC.

o Bone scan: This is a nuclear medical imaging test which is performed in order tocheck if NSCLC hasmetastasised* to the bones. It is indicated by the presence ofbonepain,elevatedserumcalcium*oranelevatedalkalinephosphatase test*. IfaPET/CT-scan*isdoneaspartofthestaging*work-up,abonescandoesnotneedtobeperformed.

3. Histopathologicalexamination*:Thisisthelaboratoryexaminationof

thecellsmadebytakingasampleofthetumourtissue(abiopsy*)anddissecting it. Histopathological examination* is recommended invirtually all casesofNSCLCas it is theonlymethod that can confirmsuch a diagnosis. Below, we report themost common examinationsthat can be performed in order to obtain a biopsy*. Generallyspeaking,biopsies*canbeobtained fromtheprimary tumour (bronchoscopyorCT-guidedneedlelungbiopsy),fromtheregionallymphnode(s)*locatedinthechest(biopsy*takenbyendobronchial or oesophageal ultrasound*-guided route, or bymediastinoscopy), or frommetastases*ifthediseasehasspreadoutsidethelung.

o Bronchoscopy:Thisisatechniqueusedtovisualisetheinsideoftheairwayswithaninstrumentinsertedthroughthenoseormouth.Itallowsthepractitionertoexaminethepatient'sairwaysforabnormalitiessuchastumoursfromwhichbiopsies*canbetaken.

o CT-guided needle lung biopsy*: This is used when bronchoscopy is unlikely tosucceedinobtainingabiopsy(e.g.incaseofperipheralNSCLC).AneedleisinsertedthroughthechestintothetumourwiththeguidanceofaCT-scan*.

o Endobronchial ultrasound*-guided sampling (EBUS): This technique allowsconfirmation of the involvement of regional lymph node(s)* in case radiologicaltests*suggestthatthisisthecase.Duringabronchoscopy,anultrasound*probe*isused to help identify any suspicious lymph nodes* that may be present in thesurroundings of the airways, from which a biopsy is collected via trans-bronchialneedleaspiration*.

o Oesophagealultrasound*-guidedsampling(EUS):SimilartoEBUS,thistechniqueisuseful in determining the involvement of regional lymph nodes*.Unlike EBUS, theinstrumentisinsertedthroughtheoesophagus.

http://en.wikipedia.org/wiki/Medical_procedure

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o Mediastinoscopy: This procedure enables visualisation of thecontentsofthemediastinum*withascopethatisinsertedthroughan incision approximately 1cm above the junction of thebreastbonewiththecollarbone.Itisusedtoobtainabiopsy*ofthemediastinal lymph nodes*. Less invasive techniques, such as thepreviously mentioned EBUS and EUS, are progressively replacingmediastinoscopy for histopathological* confirmation ofinvolvement of the mediastinal* lymph nodes* when this isclinicallysuspectedbasedonradiologicalexamination.

o Incasethediseasehasspreadtodistantsitesofthebody,abiopsy*canbeobtainedfrom a metastatic* lesion (this does not apply to brain metastases*). Differentimagingtechniques(e.g.ultrasound*,CT-scan*)or justclinicalexamination(incaseofasuperficiallypalpablelesion)canhelpguidethebiopsy*ofthemetastasis*.

4. Cytologicalexamination: Incontrasttohistopathologicalexamination*,whichiscarriedout

ona tissuesampleof thetumour,cytologicalexamination is the laboratoryexaminationofcancerous cells spontaneously detached from the tumour. However, although it may besufficient for thediagnosisofNSCLC,cytologymayhavesome limitations in thedistinctionbetween squamous versus non-squamous cancer due to the scarcity of the examinedmaterial. Also, biological examination of the tumour (see next paragraph) may be lessreliable if performed on cancerous cells comparedwith that carried out on tumour tissuesamples.HerewereportthemostcommonmethodsforobtainingsamplesforacytologicalexaminationofNSCLC:

o Bronchoscopy: Bronchial washings* and collection of secretions are usuallyperformed during bronchoscopy in order to search for the presence of cancerouscells.

o Thoracentesis/pleural drainage: These techniques allow fluid aspiration from thepleuralcavity*incaseofpleuraleffusion*.Theremovedfluidisthenanalysedinthelaboratoryforthedetectionofcancerouscells.Ifnecessary,chemicalpleurodesis*toavoidrecurrence*ofpleuraleffusioncanbeperformedaftertotalfluidaspiration.

o Paricardiocentesis/pericardial drainage: These techniques allow fluid aspirationfrom the pericardial cavity* in case pericardial effusion* is present. Again, theremovedfluidisanalysedinthelaboratorytolookforcancerouscells.

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http://en.wikipedia.org/wiki/Mediastinum

http://en.wikipedia.org/wiki/Biopsy


WHATISIMPORTANTTOKNOWTOGETTHEOPTIMALTREATMENT?Doctorswillneedtoconsidermanyfactors,relatedbothtothepatientandthecancer, inordertodecideonthebesttreatment.Relevantinformationaboutthepatient• Age• Performance status*, which evaluates patients’ general well-being and ability to perform

activitiesofdailylife.• Personalmedical history, including type and number of other diseases, such as heart disease,

pulmonarydiseaseanddiabetes*• Smokinghistory• Results from blood tests performed to assess the white blood cells*, red blood cells*, and

platelets*,aswellasliverandrenalfunction.• Ifasurgicalinterventionseemstobeanoptiontotreatthecancer,sometestswillbeperformed

prior to surgery to evaluate lung function. The goal of these tests is to estimatewhether theexpectedlungfunctionthatwillremainafterthesurgicalremovalofthelung(orpartofit)willbesufficienttoavoidseriousshortnessofbreath.

Relevantinformationaboutthecancer

• Staging*Doctorsusestaging*toassesstheextentofthecancerandtheprognosis*ofthepatient.TheTNMstaging system is commonly used. The combination of size of the tumour and invasion of nearbytissue(T),involvementofregionallymphnodes*(N)andmetastatic*spreadofthecancertodistantsitesand/ororgansofthebody(M),willclassifythecancerintooneofthestagesdescribedbelow.Thestageisfundamentalinordertomaketherightdecisionaboutthetreatment.Asageneralrule,thelowerthestage,thebettertheprognosis*.Staging*isusuallyperformedtwice:afterclinicalandradiologicalexaminations*andaftersurgery,incaseofsurgicallyresectedtumours.Staging*ismoreaccurate when surgery is performed since it is also based on information obtained during thelaboratoryexaminationoftheremovedtumour.ThetablebelowpresentsthedifferentstagesofNSCLC.Thedefinitionsaresomewhattechnical,soitisrecommendedtoaskyourdoctorforamoredetailedexplanation.StageI Thetumourislessthanorequalto5cminitsgreatestdimensionandthereisno

involvementoftheregionallymphnodes*

StageIIA Thetumourislargerthan5cmbutdoesnotgobeyond7cminitsgreatestdimensionandthereisnoinvolvementoftheregionallymphnodes*

orThetumourislessthanorequalto5cminitsgreatestdimension,butthereisinvolvementofthehomolateral*regionallymphnodes*locatedatthehilum*


StageIIB Thetumourislargerthan5cmbutdoesnotgobeyond7cminitsgreatestdimensionandthereisinvolvementofthehomolateral*regionallymphnodes*locatedatthehilum*

orThetumourislargerthan7cminitsgreatestdimension(butstillcontainedwithinthelung),orthereisasecondtumournoduleinthesamelobe*andthereisnoinvolvementoftheregionallymphnodes

StageIIIA Thetumourdoesnotgobeyond7cminitsgreatestdimensionandthereisinvolvementofthehomolateral*regionallymphnodes*locatedatthemediastinum*

orThetumourislargerthan7cminitsgreatestdimension(butstillcontainedwithinthelung),orthereisasecondtumournoduleinthesamelobe*andthereisinvolvementofthehomolateral*regionallymphnodes*locatedatthehilum*ormediastinum*

orThetumourinvades,bydirectextension,thetissuebetweenthelungs(e.g.heart,oesophagus),orthereisasecondtumournoduleinanotherlobe*ofthesamelung,withorwithoutinvolvementofthehomolateral*regionallymphnodes*locatedatthehilum*

StageIIIB Thetumourinvades,bydirectextension,thetissuebetweenthelungs(e.g.heart,oesophagus),orthereisasecondtumournoduleinanotherlobe*ofthesamelung,andthereisinvolvementofthehomolateral*regionallymphnodes*locatedatthemediastinum*

orRegardlessofthetumourdimensionthereisinvolvementofthecontralateral*regionallymphnodes*locatedatthehilum*ormediastinum*orthoselocatedatsupraclavicularsites*

StageIV Regardlessofthetumourdimensionandinvolvementoftheregionallymphnodes*,thetumourhasspreadtodistantsitesand/ororgansofthebody.Involvementofthepleura*(includingpleuraleffusion*withdocumentedcancerouscells)andofthecontralateral*lungisconsideredstageIV

• Resultsofthebiopsy*

Thebiopsy*willbeexaminedinthelaboratory.Thisexaminationiscalledhistopathology*.Asecondhistopathologicalexamination*involvestheexaminationofthetumourandthelymphnodes*ifthetumourissurgicallyresected.Resultsoftheexaminationofthebiopsy*shouldinclude:

o Histologicaltype*Histological type* isbasedon the typeof cells that the tumour is composedof. Ingeneral, NSCLC is mainly divided into squamous cancer, which comprisesapproximatelyonequarterofallNSCLCsandusuallyoriginatesinthetissuethatlinesthe larger airways, or non-squamous cancer (including the two numericallyimportantgroupsofadenocarcinomaandlargecellcarcinoma),whichusuallybeginsinmore distal airways. This distinction (squamous versus non-squamous cancer) isrelevantfortherapeuticpurposes. Infact,non-squamouscancersmaybenefit fromcertainsystemicanti-cancertherapiesthathavebeenshowntobeeffectiveonly inpatientswiththishistologicalsubtype(seesystemictherapy*undertreatmentplanforstageIVNSCLC).


o GradeGradeisbasedonhowdifferentfromnormallungcellstumourcellslookandonhowquickly they grow. The grade will be any value between one and three, althoughsometumourcellsmaylooksodifferentfromnormallungcellsthatagradecannotbe assigned. These tumours are usually referred to as undifferentiated. The gradereflects the aggressiveness of tumour cells: the higher the grade, the moreaggressivethetumour.

o BiologicalexaminationofthetumourTissue specimens frommetastatic*NSCLCbelonging to thenon-squamous subtypeshouldbeevaluatedforthepresenceofspecificmutations*intheepidermalgrowthfactorreceptor(EGFR*)gene.Eventhoughsuchmutations*arerare(approximately10% in Caucasians, with a higher prevalence in never smokers, tumours ofadenocarcinomasubtype,womenandpatientsofEast-Asianorigin),thedetectionofan EGFR* genemutation has important prognostic and therapeutic implications inpatients with metastatic NSCLC (see systemic therapy* under treatment plan forstage IVNSCLC).EGFR* testing isnot recommended inpatientswithadiagnosisofsquamouscellcarcinoma,exceptinnever/formerlightsmokers(<15packsperyear).

Routine testing for rearrangement in the ALK* gene is now standard of care andshould be carried out, if possible, in parallel with EGFR* mutation analysis. ALK*rearrangement is more frequent in never smokers, the adenocarcinoma subtype(5%), and in younger patients. Detecting ALK* rearrangements has importanttherapeutic implications forpatientswithmetastaticNSCLC (see systemic therapy*under treatment plan for stage IVNSCLC), due to the existence of drugs targetingALK*(e.g.crizotinib*).


WHATARETHETREATMENTOPTIONS?Planning of the treatment involves an inter-disciplinary team of medicalprofessionalswhoareinvolvedinthetreatmentofcancerpatients.Thisisameetingofdifferentspecialists,calledmultidisciplinaryopinion*ortumourboardreview. Inthismeeting, theplanningof treatmentwillbediscussedaccordingto therelevantinformationmentionedbefore.Thetreatmentwillusuallycombinetherapiesthat:

• Actonthecancerlocally,suchassurgeryorradiotherapy*• Actonthecancercellsalloverthebodybysystemictherapy*suchaschemotherapy*and

biologicaltherapy*Thetypeoftreatmentwillgenerallydependonthepatient’sclinicalconditionandpreferences,thestageofthecancerandthecharacteristicsofthetumour.The treatments listed below have their benefits, their risks and their contraindications*. It isrecommended that patients ask their doctors about the expected benefits and risks of everytreatmentinordertobefullyinformedabouttheconsequencesofthetreatment.Forsomepatients,severalpossibilitiesareavailableandthechoiceshouldbediscussedafterweighingupthebenefitsandrisksofeachoption.Ateverystepofthetreatment,itmayalsobepossibletoparticipateinaclinicaltrial.Aclinicaltrialisaresearchstudyconductedwithpatientstoevaluatewhetheranewtreatmentissafeandwhetheritworks.Clinicaltrialsareperformedtotesttheefficacyofdrugsandalsonon-drugtreatments,suchasradiotherapy*orsurgery,andcombinationsofdifferenttreatments.Sometimes,doctorswillpropose thatyouparticipate inaclinical trial.Youhave the right toacceptorrefusewithoutanyconsequencesforthequalityofyourtreatment.Ifyourdoctordoesnotproposeanyclinicaltrialbutyoureallywanttoparticipateinone,thebestwayistoaskyourdoctororoncologist*ifthereisanyclinicaltrialforyourtypeofcancertakingplacenearyourhomeorinyourcountry.TreatmentplanforstageI-II(early)NSCLCStageI-IINSCLCisonethatislocalisedwithinthelung,and,thus,curablewithradicalsurgery*inthemajority of cases. At these stages, only factors such as old age and the presence of other severediseasecondition(s)mayrepresentacontraindication*tocurativesurgicalresection.Surgery:Surgeryistheonlytreatmentofferingachanceforacureatthesestages.Therefore,radical surgery consisting of removal of the involved lobe*, namely lobectomy, plusremovalofthelymphnodes*locatedinthechestisthestandardformofcareinsuchpatients.


Radiotherapy*:Radiotherapy* is an option for patients who are not candidates for surgery because of medicalconditions contraindicating* surgery or if they refuse surgery. Among different techniques,conformal stereotactic radiotherapy*, namely a type of external radiation therapy that preciselydeliversahighdoseofradiationtothetumourinashortperiodoftime,isusuallyadoptedforstageIpatients.Bycontrast,otherstandardschedulesofradiotherapyareusedtotreatstageIIpatients.Systemictherapy*:Intravenous*adjuvant*chemotherapy*isanoptionfollowingsurgeryforstageIINSCLC,especiallyin the presence of lymph node* involvement. Chemotherapy* with four cycles of a two-drugcombination including a platinum agent (about three months of treatment) has the potential tosignificantly reduce the risk of disease recurrence* and significantly improve survival. In clinicalpractice, the best candidates for adjuvant chemotherapy* are patients in good clinical condition,withoutsignificantconcomitantdiseases*andwhorecoveredquicklyaftersurgery.TreatmentplanforstageIII(locallyadvanced)NSCLCAlthoughstill localisedwithinthe lung,stage IIINSCLC isgenerallyonethatcannotbetreatedwithradicalsurgery,atleastnotasinitialtreatment,duetolocalextension.However,itshouldbenotedthat stage III NSCLC represents a very heterogeneous disease conditionwhere it is not possible torecommenda“onesizefitsall”strategytofollowsincethetreatmentmodalitymayvaryfromcasetocase.Thatiswhymultidisciplinary*involvementofdifferentspecialistsiskeytotreatmentsuccessofstage III NSCLC, and the best approach for patients with locally advanced NSCLC may be anintegrationofalltreatmentmodalities(surgery,radiotherapy*andchemotherapy*).Surgery:Thelong-termoutcomeofsurgeryforstageIIINSCLCisstrictlydependentontheextentoftumourbasedon the involvementof the lymphnodes* located in themediastinum*whichmayseparatestageIIINSCLCintoresectable(mostpatientswithstageIIIAdisease)andunresectable(allpatientswithstageIIIBdisease).

Surgery is generally employed as an initial treatment only in patients whose mediastinal* lymphnode* involvement becomes evident at histological examination* of the removed tumour.Alternatively,surgerycanbeemployedfollowingtheadministrationofneoadjuvant*chemotherapy*with orwithout concurrent radiotherapy* in those patientswith resectable stage III NSCLCwheremediastinal*lymphnode*involvementhasbeendetectedpre-operativelyduringtumourstaging*.

Teststhatdeterminetheamountof lungfunctionthatisexpectedtoremainaftersurgeryareveryimportant when making a decision about the possibility of an operation which seems to betechnicallyfeasible.Thelungfunctionthatisexpectedtoremainshouldbesufficienttoavoidseriousshortness of breath. Insufficient expected lung function after surgery may prevent the operationfrombeingperformed.


Radiotherapy:Radiotherapy*isemployedwiththeintenttopreventloco-regionalspreadofthedisease.Itcanbeadministered either as post-operative treatment following surgery or with curative intent inreplacementofsurgeryforunresectablestageIIINSCLC.Inthelattercase,concurrentchemotherapyisoftenadministered(seenextparagraph).Systemictherapy*:Intravenous* chemotherapy* with a two-drug combination including a platinum agent should beoffered toall stage IIIpatientswhocan tolerate it.Chemotherapy*maybeadministeredeitherasneoadjuvant* or adjuvant* therapy in those patients with resectable or resected stage III NSCLC,respectively.Ontheotherhand,patientswithunresectablestage IIINSCLCarebettertreatedwithchemotherapy* given either concomitantly or before radiotherapy*. In this case, concomitantchemo-radiotherapyisgenerallypreferredbecauseofhigherefficacy.However,concomitantchemo-radiotherapy is usually more toxic compared with the sequential approach of chemotherapy*followed by radiotherapy*; therefore it should be reserved for selected patients, such as youngerpatientsandthosewithgoodperformancestatus*.

TreatmentplanforstageIV(metastatic*)NSCLCStageIVNSCLCisonethathasspreadtodistantsitesand/ororgansofthebody.Themostcommonsites ofmetastases* are the bones, brain, liver, adrenal glands, pleura* and the other lung. Sincemetastasesspreadthroughthebloodstream,theycanbepresenteitheratdiagnosis(innearly40%ofpatients),orbecomeevidentovertimeduringthefollow-upofaradicallyresectedNSCLC.Surgery:SincestageIVNSCLChasspreadbeyondthelung,itisconsideredtobeinoperableassurgerywouldbe unable to remove the entire tumour and offer a chance of cure. Exceptions to this rule arepatients with a solitary brain, lung or adrenal metastasis* and no evidence of other metastaticdiseasesitesapartfromtheprimarytumour.Surgicalinterventionscanalsobeusefultorelievethesymptomscausedbythediseaseinthethoraxorinthebones.Radiotherapy*:Radiotherapy* may be indicated as palliative treatment for patients who complain of specificsymptoms that derive frommetastatic* involvement of certain organs. For instance, radiotherapycanbehelpful incontrollingbonepaindue toNSCLCspreading to thebonesor to treatheadacheand/orweaknessassociatedwiththepresenceofbrainmetastases.


Systemictherapy*:SystemictherapyisthemainstayoftreatmentofstageIVNSCLC.Themaingoalsofsystemictherapyare:

o Toimprovequalityoflifeo Toprolongsurvival

Decisions regarding systemic therapy should take into account several issues,includingclinico-pathological*characteristics(suchashistology*,age,performancestatus*, presence of other diseases and the patient’s preferences) and biologicalfeatures (such as the presence of an EGFR* gene mutation* or ALK*rearrangement).Theinitialtreatmentproposediscalledfirst-linetreatment.Second-andthird-linesoftreatmentmaybeproposedafterwards,dependingontheresponsetoprevioustherapiesandonthegeneralstatusofthepatient.First-linetreatment

• First-linetreatment:chemotherapy*o Intravenous*chemotherapywithatwo-drugcombinationincludingaplatinumagent

(either cisplatin* or carboplatin*) is standard of care in patients without EGFR*mutationsorALK*rearrangement.

o In the subgroup of non-squamous tumours and in patients treated with third-generation regimens, including gemcitabine* and taxanes*, cisplatin shouldbe theplatinumagentofchoice.

o Pemetrexed-basedchemotherapyshouldbethetreatmentofchoiceinpatientswithnon-squamous tumoursand it shouldbe restricted tonon-squamousNSCLC inanylineoftreatment.

o Carboplatin* is preferred to cisplatin in patients with contraindications* tointravenous*hydration(e.g.cardiacorrenalimpairment).

o Non-platinum-based combination chemotherapy should only be considered ifplatinumtherapyiscontraindicated.

o Chemotherapy achieves benefits in patients with performance status equal to 2when compared to best supportive care. Single-agent chemotherapy withgemcitabine, vinorelbine, or taxanes represents an option for these patients.Carboplatin-based combinations have shown good results with acceptable toxicityandshouldbeconsideredineligiblepatientswithperformancestatusof2.

o Patientswhoarenotingoodclinicalcondition(performancestatus3or4)shouldbeofferedbestsupportivecare.

o In elderly patients (aged ≥ 70 years), carboplatin-based chemotherapy should beconsideredineligiblepatientsingoodclinicalcondition(performancestatus0to2)and without concomitant diseases*. In other patients, single agent chemotherapymaybeconsidered.Thisshouldbediscussedwithyourdoctor.


• First-linetreatment:biologicaltherapy*

o Mono-therapywithanorallyadministeredtyrosinekinaseinhibitor*ofEGFR*,suchas gefitinib*, erlotinib* and afatinib*, is the preferred option in patients whosetumour carries an EGFR gene mutation* (approximately 15% of all NSCLCs). Alltumoursofnon-squamoushistology*shouldbetestedforthepresenceofanEGFRgenemutation,particularlythosethatariseinpatientswhoareeithernon-smokersorhavesmokedmoderatelyinthepast.Sincetheyaregenerallywell-toleratedandhaveaconvenientoralformulation,anEGFRinhibitorcanalsobeofferedtopatientswithaverypoorperformancestatus*of3and4aslongasanEGFRgenemutationisdetectedinthetumour.

o PatientswithNSCLCtumoursharbouringanALK*rearrangementshouldbeofferedtreatmentwiththeALK*inhibitorcrizotinib.

o Bevacizumab* is a monoclonal antibody* that binds to the vascular endothelialgrowthfactor(VEGF*),whichisaproteincirculatinginthebloodthatisrequiredforthegrowthofbloodvessels.BevacizumabpreventsVEGF fromactivating theVEGFreceptoron thecells and therefore inhibits thegrowthofbloodvesselswithin thetumour. Intravenous* bevacizumab may be added to a carboplatin*-paclitaxel*regimen only in patients with tumours of non-squamous histology* and goodperformancestatus*(0or1).Forsafetyreasons,carefulpatientselectioniscrucialinorder to limit the potential adverse effects of bevacizumab. Squamous histologyrepresents a major contraindication* to bevacizumab therapy. Also, patients whocomplain of severe haemoptysis* as well as those with centrally-located orexcavated tumours are usually excluded from bevacizumab therapy. Thecombination of bevacizumab and other platinum-based chemotherapies may beconsideredineligiblepatientswithnon-squamousNSCLC.

• First-linetreatment:timing,durationandmaintenancetherapy

o First-line treatment should always be initiated while the patient has good

performance status*, namely at a timewhenhe/she is able to better tolerate thepotentialsideeffectsofsystemictherapies*.

o Formostpatients,fourcyclesofchemotherapyarerecommended,withamaximumofsixcycles.

o Inpatientswithgoodclinicalcondition,maintenancetherapymaybegiveninorderto prolong the effect of first-line chemotherapy on tumour control. This can beadministered as continuation maintenance or switch maintenance therapy. Thisreferseithertothemaintaineduseofanagentincludedinfirst-linetreatmentortheintroduction of a new agent after four cycles of platinum-based chemotherapy,respectively.

o Theswitchmaintenance therapy includeserlotinib*and it isanoption forpatientswithstablediseaseafterinductiontreatment.

o Continuingmaintenance therapy includes pemetrexed and it is indicated followingcompletion of first-line cisplatin plus pemetrexed chemotherapy in patients withnon-squamous histology, stabilisation of disease, or response after first-linechemotherapyandrecoveryfromtoxicityoftheprevioustreatment.


Second-andthird-linetreatmentsThese treatments may be administered following disease progression after first-line therapy inpatientswhoarestillfitenoughtoreceivefurthertherapy(performancestatus*of0to2).Monochemotherapywith docetaxel or pemetrexed* (the latter for non-squamous cancer only) ortargeted agent erlotinib* (in patients with unknown EGFR* status or without EGFR* mutations)improves tumour-related symptomsand survival. InpatientswithEGFR*mutated tumours, single-agenterlotinib*,gefitinib*orafatinib*shouldbegivenassecond-line*therapy,ifpatientshavenotreceivedthempreviously. Insubsequent linesoftreatment,erlotinib is indicatedforpatientswithunknownEGFR*statusorthosewithoutEGFR*mutationswhohavenotyetreceivedEGFRtyrosinekinaseinhibitors(TKIs)*,andhaveperformancestatus0to3.Ingeneral,anypatientwithatumourbearing an EGFR* mutation should receive an EGFR TKI* in any line of therapy, if not receivedpreviously.PatientswithatumourcarryingarearrangementoftheALKgene(about5%ofallpatients)canalsobetreatedwithcrizotinib*inthesecondandthird-lineiftheyhavenotreceiveditpreviously.TreatmentofoligometastaticNSCLCOligometastasesisatermthatreferstothepresenceofamaximumoffivemetastaticlesions.Iftheyappearonemonthbeforeor after theprimary tumourwas identified theyare called synchronousmetastases.Whentheyappearaftertheprimarytumourwastreatedtheyarecalledmetachronousmetastases. The biology and prognoses of these two disease statesmay differ. Radical treatmentwithsurgery,radiotherapyandchemotherapycouldbeconsideredbut,sincethereisnostandardofcare yet to treat oligometastases, it is suggested that in these cases patients are treatedpreferentiallyinaclinicaltrial.TreatmentofbrainmetastasesPatients with poor performance status are given best supportive care. Patients with goodperformancestatusandyoungerthan65yearsold,withnootherextracranialmetastasesandwithmorethanthreebrainmetastasescouldreceivewholebrainradiotherapy.Asinglebrainmetastasiscouldbe treatedeitherwithsurgeryor stereotactic radiosurgery (a special typeof radiotherapy inwhich the radiation beams are very precise to reduce damage to the surrounding normal tissue).Stereotacticradiosurgeryispreferredwhentwoorthreebrainmetastasesarepresent.Palliativetherapies:OthertherapieshelpatdifferentstagesinNSCLCtreatment:endoscopycanbeusedtorelieveairwayobstruction, surgical procedures can be used in case of pleural effusions, and radiotherapy couldalso,togetherwithitspalliativeeffectsinbrainmetastases,helptotreatbonemetastases,especiallyiftheyarecausingpain.Bonemodifyingagents(zoledronicacidanddenosumab)alsohelptotreatbonemetastases. In general, earlypalliative care is recommended inparallelwith the standardofcare for the cancer itself. It has been shown that it could improve quality of life andmood, anddiminishestheneedforaggressivetreatmentandmayevenimprovesurvival.Clinical trials of new drugs are often proposed to patients with stage IV NSCLC. Participation inclinicaltrialsshouldbeencouraged.


Responseevaluation:The response to treatment has to be evaluated to check if there is any benefit of the treatmentcompared to the adverse events experienced. Response evaluation is recommended after 2-3months of systemic therapy* for stage IVNSCLC. This evaluation relies on repetition of the initialradiographictestshowingthetumourlesions.In the case of curative radiotherapy* for stage III NSCLC, aminimumof 2months have to elapsebetween the end of treatment and response evaluation in order to see the beneficial effects ofradiotherapy*.


WHATARETHEPOSSIBLESIDEEFFECTSOFTHETREATMENT?In this paragraph we report the most common side effects of surgery, radiotherapy* andchemotherapy*.However, the following list is not exhaustive. Therefore, patients should carefullydiscussthepotentialsideeffectsrelatedtotheproposedtreatment(s)withtheirdoctor.

• Surgery− Haemothorax:Aconditionthatresultsfrombloodaccumulatinginthepleuralcavity.*− Pulmonarycontusion:Abruiseofthelungtissuecausedbydamage,typicallydueto

traumaduringsurgery.− Post-operativepneumonia− Persistent air leak: A condition where the lung is unable to re-inflate properly

followingsurgeryduetosurgicaldamagetothelungtissue.• Radiotherapy*

− Sideeffectswithanearlyonset:Thesesideeffectsusuallyoccurwithinsixmonthsafter completion of radiotherapy. They often include esophagitis (inflammation oftheoesophagus),pneumonia,coughandprolongedhoarseness.

− Sideeffectswithalateonset:Thesesideeffectstypicallyoccuraftersixmonthsfromcompletionofradiotherapyandmostcommonlyincludeshortnessofbreath,causedbyalossinlungelasticity,andpneumonia.

• Systemictherapy*− Chemotherapy*: The side effects of chemotherapy vary in frequency and severity

based on the type of agent and/or combination regimens employed. Therefore,patientsareencouragedtothoroughlydiscusswiththeirdoctorthemainsideeffectsassociatedwith the chemotherapy regimen thathasbeenproposed.However, theside effects of chemotherapy often include: loss of appetite, fatigue, hair loss,nausea and/or vomiting, increased susceptibility to infections and bleeding,anaemia*anddiarrhoea.Apart from these, each drug can also have different unwanted effects. The mostcommon ones are listed above, although not everyone will have side effects, orexperiencethemtothesameextent.

o Cisplatin*may lead to hearing loss and kidney damage. Kidney function istestedbeforestartingtreatment.Topreventdamageit isveryimportanttodrinkalotofwaterduringtreatmentwiththisdrug.

o Paclitaxel* can causeperipheralneuropathy*which isdependentupon thedose administered, the duration of the infusion, and the schedule ofadministration. Presenting symptoms includenumbness, paraesthesia* andburning pain in a glove-and-stocking distribution*. Symptoms are oftensymmetrical,andusuallyhavetheiroriginsdistally inthe lowerextremities.Patientscommonlyreportthesimultaneousonsetofsymptomsintoesandfingers, but asymmetric presentations have been described too. Facialinvolvement is less common.Althoughmild symptomshavebeen reportedto improve or resolve completely within several months afterdiscontinuationoftherapy,thesymptomsanddeficitshavebeenreportedtopersistlongerinpatientswhodevelopsevereneuropathy*.


− Biological therapy*:These sideeffects areusually termed ‘class-related’ since theyarespecifictothebiologicalagentadministered.

o Bevacizumab* may give rise to hypertension*, proteins in the urine andincreasedriskofthromboembolic*orhaemorrhagicdisorders*.

o Gefitinib*,erlotinib*andafatinib*cancausecutaneousrashanddiarrhoea.o Crizotinib*cancausevisiondisorder,nausea,diarrhoea,vomiting,oedema*,

constipation,fatigue,elevationofliverenzymesandneutropenia(adecreaseinthenumberofatypeofwhitebloodcell*calledneutrophils).


WHATHAPPENSAFTERTHETREATMENT?Regular follow-up visits are an important step for patients who haveundergoneradicalsurgeryforNSCLC.Follow-upwithdoctorsAfterthetreatmenthasbeencompleted,doctorswillproposeafollow-upprogrammeaimingto:

• Evaluatetreatmentcomplications:Treatment complications related to surgery, adjuvant* chemotherapy* or radiotherapy* (see sideeffectsofthetherapies)shouldbecarefullyevaluatedevery3to6months.

• Detectpossiblediseaserecurrence*:At the present time, no evidence suggests that earlier detection of recurrence* (and thereforeinitiationof specific treatment)may lead toabetter clinicaloutcome.Notwithstanding, given thatmost recurrences* occur within the fourth year after surgery, follow-up visits (including physicalexaminationandevaluationofanysymptoms)aregenerally recommendedatan intervalof3 to6monthsforthefirstthreeyearsfollowingsurgeryandannuallythereafter.AnnualchestCTscanand,toalesserextent,chestX-ray*arebothconsideredappropriatetoolsforradiologicalfollow-up;CTscanispreferredbecauseithasthepotentialadvantageoverchestX-ray*ofearlydetectionofanewprimarylungtumour.

• Detectpossiblenewprimarylungtumours:Patientswhohaveundergone radical surgery forNSCLCareathigher risk fordevelopinga secondnewprimary lung tumour. It is sometimeshard todistinguishbetween tumour recurrence* andanew primary lung tumour based on the radiographic tests only. Case discussion within amultidisciplinaryopinion/team*canhelpdifferentiatethetwoscenariosand,therefore,choosethemostappropriatetreatmentoption.SmokingcessationGiven the strong linkbetween smokingand thedevelopmentof lungcancer, givingup smokingatanytimeisalwaysadvisableinpatientsaffectedwithNSCLC.Therefore,smokingcessationshouldbeviewedasanintegralpartofNSCLCtreatment(s),regardlessofthestageofthedisease.Remarkably,smoking cessation in stage I to III patients has been associated with a decrease in both risk ofrecurrence* and risk of a second primary lung tumour, eventually resulting in decreased NSCLC-related mortality. Smoking may also interact with systemic therapy. For example, it reduces theproportionoferlotinibthatentersintothecirculationand,therefore,itsactiveeffect.


ReturningtonormallifeIt can be hard to live with the idea that the cancer might return. Patients having difficulties inreturningtonormallifemaybeprovidedwithpsychologicalsupport,whereasotherpeoplemayfindhelpfulsupportfromex-patientsgroups.Whatifthecancercomesback?If the cancer comes back it is called a recurrence.* The treatment depends on the extent of therecurrence.Somepatientsinwhomthetumourcomesbackasarecurrenceatasinglesitemaybenefitfromaloco-regionalapproach,suchassurgicalremovalorradiotherapy*.However,thisapproachislimitedto a very small group of patients. Recurrent tumours should normally be regarded asmetastatic*cancers and therefore approached as explained in the paragraph “Treatment plan for Stage IVNSCLC”.In somecases, biopsy*of themetastasis*maybe indicated since itmay result in a change in thetreatmentdecision.Thismaybeparticularlytrueforpatientswithalongdisease-freeinterval*aftersurgical resection. Re-biopsy in these patients may be useful in order to differentiate betweendiseaserecurrenceandanewprimarylungtumour(incaseswheretherecurrenceisdetectedinthelung), to ascertain the histologic type* of lung tumour (non-squamous versus squamous versusother),ortorepeattheEGFR*mutation*testifanon-squamouscancerisdetected.


DEFINITIONSOFMEDICALTERMSAdjuvant(treatment)Adjuvanttreatmentincancerisatherapythathelpsanothertherapytoreachitsultimategoalandreinforcesitseffect.Forexample,radiotherapyand/orchemotherapy*helpasurgerytoaccomplishits goal of eliminating a cancerous tumour. In a non-oncological context, it can also be an agentaddedtovaccinestostimulatetheimmunesystem'sresponsetoanantigen.AfatinibAfatinib is a targeted agent for use in EGFR* mutated, metastatic NSCLC. Afatinib acts as anirreversibleinhibitorofEGFR*andhumanepidermalgrowthfactor2(HER2).ALKTheALKgenemakesaproteincalledALK (anaplasticlymphomakinase).ALKgenerearrangement ismainly found in the adenocarcinoma lung cancer subtype, never smokers and younger patients.Testing for the presence of the rearrangement is important because a targeted therapy calledcrizotinibisavailableforpatientswithALK-positivetumours.Alkalinephosphatase(test)Anenzymethatisnormallypresentinhighconcentrationsingrowingboneandinbile.Abnormallyhighlevelsofitinthebloodmayindicatediseaseinbone,liverorbileduct.AlveoliTinyairsacsat theendof thebronchioles (tinybranchesofair tubes) in the lungs.Thealveoliarewhere the lungsand thebloodstreamexchangecarbondioxideandoxygen.Carbondioxide in thebloodpassesintothelungsthroughthealveoli.Oxygeninthelungspassesthroughthealveoli intotheblood.AnaemiaAconditioncharacterizedbytheshortageofredbloodcells*orhemoglobin.Hemoglobinisthepartof the red blood cell that carries oxygen from the lungs to the whole body and in patients withanemiathisprocessisdiminished.BevacizumabBevacizumab isamonoclonalantibody* thathasbeendesigned to recognizeandattach itself toaspecificstructure(calledanantigen)thatisfoundincertaincells inthebodyoriscirculatinginthebody. Bevacizumab has been designed to attach to vascular endothelial growth factor (VEGF*), aproteincirculatinginthebloodthatisrequiredforthegrowthofbloodvessels.ByattachingtoVEGF,bevacizumabstopsithavinganeffectand,asaresult,cancercellscannotdeveloptheirownbloodsupplyandarestarvedofoxygenandnutrients,helpingtoslowdownthegrowthoftumours.BiologicaltherapyTreatmenttostimulateorrestoretheabilityofthe immunesystemtofightcancer, infections,andother diseases. Also used to lessen certain side effects that may be caused by some cancertreatments.Alsocalledimmunotherapy,biotherapy,orbiologicalresponsemodifier(BRM)therapy.

http://www.anticancerfund.org/glossary/term/5356


BiopsyTheremovalofcellsortissuesforexaminationbyapathologist.Thepathologistmaystudythetissueunderamicroscopeorperformothertestsonthecellsortissue.Therearemanydifferenttypesofbiopsyprocedures.Themostcommontypesinclude:(1)incisionalbiopsy,inwhichonlyasampleoftissueisremoved;(2)excisionalbiopsy,inwhichanentirelumporsuspiciousareaisremoved;and(3)needlebiopsy,inwhichasampleoftissueorfluidisremovedwithaneedle.Whenawideneedleisused,theprocedureiscalledacorebiopsy.Whenathinneedleisused,theprocedureiscalledafine-needleaspirationbiopsy.BronchialwashingsA procedure in which cells are taken from the inside of the airways that lead to the lungs. Abronchoscope(athin,tube-likeinstrumentwithalightandalensforviewing)isinsertedthroughthenoseormouthintothelungs.Amildsaltsolutioniswashedoverthesurfaceoftheairwaystocollectcells,whicharethenlookedatunderamicroscope.Bronchialwashingisusedtofindinfectionsanditmayalsohelptodetectcancerorchangesincellsthatmayleadtocancer.CarboplatinAdrug that isused to treatadvancedovariancancer thathasneverbeen treatedor symptomsofovariancancerthathavecomebackaftertreatmentwithotheranticancerdrugs.Itisalsousedwithother drugs to treat advanced, metastatic*, or recurrent* NSCLC and is being studied in thetreatmentofothertypesofcancer.Carboplatinisaformoftheanticancerdrugcisplatin*butcausesfewersideeffectsthancisplatin*inpatients.ItattachestoDNAincellsandmaykillcancercells.Itisatypeofplatinumcompound.CarcinogenSomethingthatcausescancer.ChemotherapyAtypeofcancertreatmentusingdrugsthatkillcancercellsand/or limit theirgrowth.Thesedrugsare usually administered to the patient by slow infusion into a vein but can also be administeredorally, by direct infusion to the limb or by infusion to the liver, according to the location of thecancer.CisplatinAdrugusedtotreatmanytypesofcancer.Cisplatincontainsthemetalplatinum.ItkillscancercellsbydamagingtheirDNAandstoppingthemfromdividing.Cisplatinisatypeofalkylatingagent.Clinico-pathologicalConcerningthesignsandsymptomsofthediseaseobserveddirectlybythedoctorandthedamagethatthediseaseproducestothecellsobservedinlaboratory.ConcomitantdiseasesDiseaseswhichoccuratthesametime.


ContraindicationCondition or symptom that prevents the administration of a given treatment or procedure to thepatient. Contraindications are either absolute, meaning the treatment should never be given topatientswiththisconditionorsymptom,orrelative,meaningthattheriskcanbeoutweighedbythebenefitsinsomepatientswiththisconditionorsymptom.ContralateralRelatingtotheoppositesideofthebody.CrizotinibCrizotinib is used to treat adultswith NSCLCwhen the disease is advanced and has already beentreated before. It is only used for ALK-positive NSCLC, whichmeans that the cancer cells containcertaindefectsaffectingthegeneresponsibleforaproteincalledALK*.CT-scanAformofradiographyinwhichbodyorgansarescannedwithX-raysandtheresultsaresynthesizedbyacomputertogenerateimagesofpartsofthebody.DiabetesAnyofseveraldiseasesinwhichthekidneysmakealargeamountofurine.Diabetesusuallyreferstodiabetesmellitusinwhichthereisalsoahighlevelofglucose(atypeofsugar)inthebloodbecausethebodydoesnotmakeenoughinsulin(ahormoneneededforcellstoabsorbanduseglucose)oruseitthewayitshould.DiaphragmThethinmusclebelowthelungsandheartthatseparatesthechestfromtheabdomen.Disease-freeintervalIncancer, the lengthof timethatapatientsurviveswithoutanysignsorsymptomsoftheoriginalcancer or any other type of cancer after the end of treatment. In a clinical trial, measuring thedisease-freesurvivalisonewaytoseehowwellanewtreatmentworks.AlsocalledDFSanddisease-freesurvivaltime.EGFR(Epidermalgrowthfactorreceptor)This is a type of protein called a tyrosine kinase which is found on the surface of some cells.EpidermalgrowthfactorbindstoEGFR,causingcellstodivide. It isfoundatabnormallyhighlevelsonthesurfaceofmanytypesofcancercells,whichmeansthatthesecellsdivideexcessivelyinthepresenceofepidermalgrowthfactor.AlsocalledErbB1andHER1.EpidemiologicstudyResearch conducted in human populations in which the investigator(s) examines the associationsbetweenthepresenceofahealtheffect,forinstancecancer,andafactorthatisspeculatedtocauseit,forinstanceachemical.


ErlotinibErlotinibisananticancermedicinethatbelongstothegroup‘EGFRinhibitors’.ErlotinibblocksEGFRs,whichcanbefoundonthesurfaceofsometumourcells.Asaresultofthis,thetumourcellscannolongerreceivethemessagesneededforgrowth,progressionandspreading(metastasis*).Thisstopsthecancerfromgrowing,multiplyingandspreadingthroughthebody.GefitinibGefitinibisatyrosinekinaseinhibitor*.Thismeansthatitblocksspecificenzymesknownastyrosinekinases.Theseenzymescanbefoundonthesurfaceofcancercells.OneexampleofatyrosinekinaseisEGFR*,whichisinvolvedinthegrowthandspreadofcancercells.ByblockingEGFR,Gefitinibhelpstoslowdownthegrowthandspreadofthecancer.Gefitinibonlyworksinnon-smallcelllungcancercellsthathaveamutation*inEGFR.GemcitabineTheactiveingredientinadrugthatisusedtotreatpancreaticcancerthatisadvancedorhasspread.Itisalsousedwithotherdrugstotreatbreastcancerthathasspread,advancedovariancancer,andnon-smallcelllungcancerthatisadvancedorhasspread.Itisalsobeingstudiedinthetreatmentofothertypesofcancer.GemcitabineblocksthecellfrommakingDNAandmaykillcancercells.Itisatypeofantimetabolite.Glove-and-stockingdistributionTerm to describe the pattern of signs and symptoms of a disorder that affects hands and feetsymmetrically.Thesignsandsymptomsofsuchadiseasewraparoundhandslikeglovesandfeetlikesocks.HaemoptysisHaemoptysis is the coughingofbloodoriginating from the respiratory tractbelow the levelof thelarynx.Haemoptysis should be differentiated fromhaematemesis,which is a term for vomiting ofblood from the gastrointestinal tract, and pseudohaemoptysis, a situationwhere a cough reflex isstimulatedbybloodnotderivedfromthelungsorbronchialtubes,thismaybefromtheoralcavityornasopharynx(eg,followinganepistaxis–nosebleeding)orfollowingaspirationofhaematemesisintothelungs.HaemorrhagicdisorderAnyoneofagroupofdiseasesinwhichbleedingoccurswithnoapparentreasonorwhenheavyandprolongedbleedingoccursafteraninjury.Itoriginatesfromaproblemincoagulationorflawsinthestructureofbloodvessels.HilumA notch or deep depression in a bodily organ or gland throughwhich nerves, ducts and/or bloodvesselsenterandexittheorganorgland.Histologic(al)typeThe category in which a tumour is grouped, considering the characteristics of its cells and otherstructuresunderthemicroscope.


Histopathology/Histology/HistopathologicalexaminationThestudyofdiseasedcellsandtissuesusingamicroscope.HomolateralReferringtothesamesideofthebodyincomparisontoagivenpointinthebody.HypertensionA blood pressure of 140/90 or higher. Hypertension usually has no symptoms. It can harm thearteriesandcauseanincreaseintheriskofstroke,heartattack,kidneyfailure,andblindness.Alsocalledhighbloodpressure.IntrathoracicOccurring,locatedorperformedinsidethethoraxorchestcavity.IntravenousIntoorwithinavein.Intravenoususuallyreferstoawayofgivingadrugorothersubstancethroughaneedleortubeinsertedintoavein.AlsocalledIV.LobeAportionofanorgan,suchastheliver,lung,breast,thyroidorbrain.LymphnodeA roundedmass of lymphatic tissue that is surrounded by a capsule of connective tissue. Lymphnodesfilterlymph(lymphaticfluid)andtheystorelymphocytes(atypeofwhitebloodcell).Theyarelocatedalonglymphaticvessels.Alsocalledlymphgland.Mediastinum/mediastinalTheareabetweenthelungs.Theorgansinthisareaincludetheheartanditslargebloodvessels,thetrachea,theoesophagus,thethymus,andlymphnodes*butnotthelungs.MesotheliomaA benign (not cancerous) or malignant (cancerous) tumour affecting the lining of the chest orabdomen. Exposure to asbestos particles in the air increases the risk of developing malignantmesothelioma.Metabolicactivity/metabolismThe chemical changes that take place in a cell or an organism. These changes make energy andmaterialsthatcellsandorganismsneedtogrow,reproduce,andstayhealthy.Metabolismalsohelpsgetridoftoxicsubstances.Metastasis/Mestastatic/MetastizeThe spread of cancer from one part of the body to another. A tumour formed by cells that havespreadiscalledametastatictumourorametastasis.Themetastatictumourcontainscellsthatarelikethoseintheoriginaltumour.


MonoclonalantibodyMonoclonal antibodies are antibodies that aremade in a laboratory andbind toonly one specifictypeofprotein.Theseantibodiesareexactlythesameastheyareproducedbyclonesofthesameparentcell.MagneticResonanceImaging(MRI)Animagingtechniqueusedinmedicinethatusesmagneticresonance(magnetismandradiowaves)tocreateapictureoforgansandtissuesinsidethebody.Sometimes,afluidisinjectedthatenhancesthecontrastbetweendifferenttissuestomakestructuresmoreclearlyvisible.Multidisciplinaryopinion/teamAtreatmentplanningapproachinwhichanumberofdoctorswhoareexpertsindifferentspecialties(disciplines)reviewanddiscussthemedicalconditionandtreatmentoptionsofapatient.Incancertreatment, a multidisciplinary opinion may include that of a medical oncologist* (who providescancer treatmentwithdrugs), a surgical oncologist (whoprovides cancer treatmentwith surgery),andaradiationoncologist(whoprovidescancertreatmentwithradiation).Alsocalledtumourboardreview.MutationAchangeinthesequenceofbasepairsintheDNAthatmakesupagene.Mutationsinagenedonotnecessarilychangethegenepermanently.Neoadjuvant(chemo)therapyTreatment given as a first step to shrink a tumour before the main treatment, which is usuallysurgery, isgiven.Thegoalofneoadjuvant therapy isnot tocure thediseasebut to lower the sideeffects or strengthen the effects of the main therapy and to increase the chances for long-termsurvival.Examplesofneo-adjuvanttherapy includechemotherapy,radiationtherapy,andhormonetherapy.OedemaAnabnormalcollectionoffluidbeneaththeskinorinabodycavity.Oncologist(medical/radiation)Adoctorwhospecializesintreatingcancer.Someoncologistsspecializeinaparticulartypeofcancertreatment.Forexample,aradiationoncologistspecializesintreatingcancerwithradiation.PaclitaxelAdrugusedtotreatbreastcancer,ovariancancer,andAIDS-relatedKaposisarcoma.ItisalsousedtogetherwithanotherdrugtotreatNSCLC.Paclitaxelisalsobeingstudiedinthetreatmentofothertypesofcancer.Itblockscellgrowthbystoppingcelldivisionandmaykillcancercells.Itisatypeofantimitoticagent.ParaesthesiaAnabnormaltouchsensation,suchasburningorprickling,thatoccurswithoutanoutsidestimulus.


PerformancestatusThe performance status evaluates the patient’s physical abilities by giving a score from 0 (a fullyactivepatient)to4(apatientthatiscompletelydisabledduetohis/herdisease).PericardialeffusionAnabnormalcollectionoffluidinsidethesacthatcoverstheheart.PericardialcavityThespacebetweenthelayeroftissuethatwrapsaroundtheheart(thevisceral*pericardium*)andthetissuethatlinesthecavitythatcontainstheheart(theparietalpericardium).Thisspacecontainsafluidthatlubricatesthesurfaceofbothpericardiaandallowseasymovementoftheheart.PericardiumThepericardium is a double-walled sac that surrounds theheart and the roots of the great bloodvessels.Ithasseveralfunctions:itkeepstheheartcontainedinthechestcavityandalsopreventstheheartfromoverexpandingwhenbloodvolumeincreases.Withinthepericardiumliesthepericardialcavity*. This cavity is filled with pericardial fluid which reduces friction between the pericardialmembranes.PeripheralneuropathyA type of nerve damage that causes pain, numbness, tingling, swelling, or muscle weakness indifferentpartsofthebody.Itusuallybeginsinthehandsorfeetandgetsworseovertime.Peripheralneuropathymaybe causedby physical injury, infection, toxic substances, disease (such as cancer,diabetes*, kidney failure or malnutrition), or drugs, including anticancer drugs. Also calledneuropathy.PemetrexedA drug used alone or with another drug to treat certain types of NSCLC and malignant pleural*mesothelioma*.Itisbeingstudiedinthetreatmentofothertypesofcancer.PemetrexeddisodiumblocksDNAsynthesisandmaykillcancercells.Itisatypeoffolateantagonist.PlateletSmallcellfragmentsthatplayafundamentalroleintheformationofbloodclots.Patientswithalowplatelet count are at risk of severe bleeding. Patients with a high platelet count are at risk ofthrombosis, the formationofbloodclots thatcanblockbloodvesselsandresult instrokeorothersevereconditions,andcanalsobeatriskofseverebleedingbecauseofplateletdysfunction.PleuraAthinlayeroftissuethatcoversthelungsandlinestheinteriorwallofthechestcavity.Itprotectsandcushionsthelungs.Thistissuesecretesasmallamountoffluidthatactsasalubricant,allowingthelungstomovesmoothlyinthechestcavitywhilebreathing.PleuraleffusionAnabnormalcollectionoffluidbetweenthethinlayersoftissue(pleura*)liningthelungandthewallofthechestcavity.


PleuralcavityThespaceenclosedbythepleura*,whichisathinlayeroftissuethatcoversthelungsandlinestheinteriorwallofthechestcavity.PleurodesisAmedicalprocedurethatuseschemicalsordrugstocauseinflammationandadhesionbetweenthelayersof thepleura* (a thin layerof tissue that covers the lungsand lines the interiorwall of thechest cavity). Thisprevents thebuild-upof fluid in thepleural cavity. It isusedasa treatment forseverepleuraleffusion*.ProbeAlong,thininstrumentusedtoexplorewounds,cavitiesorbodypassages.PrognosisThelikelyoutcomeorcourseofadisease;thechanceofrecoveryorrecurrence*.Radiologicalexamination/testA test that uses imaging technology (such as radiography, ultrasound*, CT-scan* and nuclearmedicine) to visualize organs, structures and tissues within the body to both diagnose and treatdiseases.RadiologistAdoctorwhospecializesinthediagnosisofdiseaseandinjurywiththeuseofimagingdevicessuchasthoseusedforX-rays,CT-scans*orMRIs*.RadiationOncologistAspecialist treatingcancerwith radiation.Heor she isdifferent froma radiologist*whoperformsimagingteststodiagnoseandfollowupondifferentconditions.RadiotherapyAtherapyinwhichradiation,orientedtothespecificlocationofthecancer,isusedinthetreatmentofcancer.RecurrenceCancerordisease (usuallyauto-immune) thathascomeback,usuallyafteraperiodof timeduringwhichthecancerordiseasewasnotpresentorcouldnotbedetected.Thismayhappenatthesamelocationastheoriginal(primary)tumourorinanotherpartofthebody.Alsocalledrecurrentcancerorrecurrentdisease.RedbloodcellThemostcommontypeofbloodcell.Itisthesubstancethatmakesthebloodappearred.Themainfunctionofthesecellsistotransportoxygenfromthelungstotissuesthroughoutthebody.SerumcalciumLevelofcalciumthat is found intheblood.Thiscanbemeasuredbyperformingaspecial test inalaboratory.


StagingPerforming exams and tests to determine the extent of the cancer within the body, especiallywhetherthediseasehasspreadfromtheoriginalsitetootherpartsofthebody. It is importanttoknowthestageofthediseaseinordertoplanthebesttreatment.SupraclavicularsitesAreaofthebodysituatedrightabovetheclavicleorcollarbone.Systemictherapy/treatmentTreatmentusingsubstancesthattravelthroughthebloodstream,reachingandaffectingcellsalloverthebody.Chemotherapy*andimmunotherapyareexamplesofsystemictherapy.TaxaneA type of drug that blocks cell growth by stopping mitosis (cell division). Taxanes interfere withmicrotubules (cellular structures that help move chromosomes during mitosis). They are used totreatcancer.Ataxaneisatypeofmitoticinhibitorandatypeofantimicrotubuleagent.ThromboembolicdisorderCondition inwhichabloodclot (thrombus) forms inside thebloodvessels,duetoabnormalities intheprocessofcoagulationorflawsinthestructureofthebloodvessels.Thesebloodclotscanbreakoffandstartcirculatinginthebloodstream(oftenknownasemboli)andcausemajororgandamageordeathbyblockingnormalbloodcirculation.TKI/TyrosinekinaseinhibitorAdrugthatinhibitstyrosinekinases,whichareproteinsinvolvedincellcommunicationandgrowthandmaythereforepreventtumourgrowth.Sometyrosinekinaseinhibitorsareusedtotreatcancer.Trans-bronchialneedleaspirationTechnique to obtain a sample of the pulmonary tissue or tissues surrounding the trachea andbronchia. A needle is inserted through thewall of the airways (trachea or bronchia) to reach thetissuefromwhichasampleisneeded.UltrasoundAprocedureinwhichhigh-energysoundwavesarebouncedoffinternaltissuesororgansandmakeechoes.Theechopatternsareshownonthescreenofanultrasoundmachine,formingapictureofbodytissuesUraniumAsilvery-whitemetallicradioactiveelement.Itnaturallyoccursinnatureanditisfoundworldwideinsoil.Itsnormaldecayresultsintheproductionofradon,agasassociatedwiththeoccurrenceoflungcancer.Vascularendothelialgrowthfactor(VEGF)Asubstancemadebycellsthatstimulatesnewbloodvesselformation.


VinorelbineAnanticancerdrugthatbelongstothefamilyofplantdrugscalledvincaalkaloids.VisceralHavingtodowiththeviscera,whicharethesoftinternalorgansofthebody,includingthelungs,theheart,andtheorgansofthedigestive,excretory,reproductive,andcirculatorysystems.WhitebloodcellCellsoftheimmunesystemthatareinvolvedinthebody'sdefenseagainstinfections.X-rayAformofradiationusedtotake imagesofthe insideofobjects. Inmedicine,X-raysarecommonlyusedtotakeimagesoftheinsideofthebody.

The ESMO / Anticancer Fund Guides for Patients are designed to assist patients, their relatives and caregivers to understand the nature of different types of cancer and evaluate the best available treatment choices. The medical information described in the Guides for Patients is based on the ESMO Clinical Practice Guidelines, which are designed to guide medical oncologists in the diagnosis, follow-up and treatment in different cancer types.These guides are produced by the Anticancer Fund in close collaboration with the ESMO Guidelines Working Group and the ESMO Cancer Patient Working Group.

For more information please visit www.esmo.org and www.anticancerfund.org

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