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HeadandNeckCancerImprovementsInNonOpera9ve

ApproachesVivekMehta,MD

SwedishCancerIns9tute

Introduc9on

•  40,000peopleintheUSdiagnosedwithH&Ncancer

•  5yearsurvivalrateapproximates50%

•  20,000peopleintheUSbecomeH&Nsurvivorseachyear

Basic Anatomy – Primary Sites

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Basic Anatomy – Lymph Nodes

HeadandNeckCancerClassifica9onNasalantrum

Nasopharynx

Oropharynx Base of tongue Soft palate Tonsillar pillar and fossa

Hypopharynx

Esophagus

Larynx Supraglottis False cords Arytenoids Epiglottis Arytenoepiglottic fold

Glottis Subglottis

Oral cavity Lip Buccal mucosa Alveolar ridge and retromolar trigone

Floor of mouth Hard palate Oral tongue (anterior two thirds)

44%

31%

25%

ModifiedfromPazdurR,CoiaL,HoskinsW,etal,eds.CancerManagement:AMul0disciplinaryApproach.9thed.Melville,NY:PRR;1999.

Pathology

•  90%ofH&Ncancersaresquamouscellcarcinomas

•  Overthelastdecade,wehaveseenanincreasingnumberofyoungerpeoplediagnosedwithH&Ncancer– ThisincreasehasbeenassociatedwithHPV

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StagingofHeadandNeckCancer

•  Assesstumorsby– Sizeofprimarytumor(T)

– Degreetowhichlymphnodesareinvolved(N)

– Absenceorpresenceofmetastases(M)

•  Stagingisimportantforassessingoutcomesandeffec9venessoftreatment

.

PrognosisofHeadandNeckCancerbyStage:IandII

Stage I Small primary tumor without nodes (T1-N0); usually curable with surgery or radiotherapy (RT) alone (85%–90%)

Stage II Medium primary tumor without nodes (T2N0); frequently cured with surgery or RT alone (70%–80%); chemotherapy (CT) considered (combined chemoradiotherapy)

OncologyChannelHeadandNeckCancerStaging.Availableat:hFp://www.oncologychannel.com/headneck/staging.shtml.AccessedApril23,2005.

PrognosisofHeadandNeckCancerbyStage:IIIandIV

Stage III Larger primary tumor and/or early node involvement Treatment with surgery + RT; b.i.d. RT Concurrent RT + CT is standard of care

Stage IVa-b (Non-met)

Very common stage at presentation More advanced primary tumor or node involvement. Concurrent RT + CT is standard of care

OncologyChannelHeadandNeckCancerStaging.Availableat:hFp://www.oncologychannel.com/headneck/staging.shtml.AccessedApril23,2005.

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5-YearRela9veSurvival:SCCoftheOropharynx(AJCCCombinedStage)

GreeneFLetal,eds.AmericanJointCommi.eeonCancerStagingHandbook.6thed.NewYork,NY:Springer-Verlag;2002.

AJCC=AmericanJointCommiFeeonCancerSystem

0 1 2 3 4 5

IIIIIIIV

Stage

Years

Alive(%

)

100

80

60

40

20

0

WhatToolsAreUsedinStaging

•  PhysicalExamina9on•  Directvisualiza9onbyendoscopy•  CT•  MRI•  PET/CT

GeneralTreatmentConcepts

•  Surgery

•  Radia9on

•  Chemotherapy

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ImprovedSurvivalBenefitwithConcurrentRT+CTMeta-analysisof69trials:MACH-NCcollabora0vegroup

No. of patients (N = 10,850)

Risk reduction (%)

5-year survival benefit (%)

Adjuvant CT 1854 2 ± 7 1

Neoadjuvant CT 5269 5 ± 3 2

Concurrent RT + CT 3727 19 ± 3 8 (P < 0.001)

PignonJPetal.Lancet.2000;355:949–955.KhuriFR,JainSR.SeminOncol.2004;31:3–10.

Head & Neck EB Side Effects PossibleAcuteSideEffectsDuringTreatment

• Moderate-significantdiscomfortinthroatormouth

-soothingmouthrinseswillbeused

-mayneedpainpillsorpainpatch

• Difficultyea9ng&drinking

-weightlossof10-20poundscommon

-mayneedatemporaryfeeding(PEG)tube

-willreceivedietrecommenda9ons

• Drymouthwithlossoftaste

-dentalhygieneamust-brush,rinse&floss!!

-seeyourden9stforcleaningASAP

• Dryirritatedskin-especiallyovershoulderarea

• Tirednessandfa9gue• Hoarseness• Possiblenauseaandvomi9ng

-especiallywithchemotherapy

PossiblePermanentSideEffects

• Permanentdrymouthanddecreasedtaste

• Riskfordentalcavi9esandperiodontaldisease

-longtermdentalcareneeded!!

• Slowreturnofweight• Swellingunderchin• Hairlossonface

• Difficultyswallowing

• Mayneedrehab

OnsetandDura9onofRT-InducedOralComplica9ons:Schema0cRepresenta0on

VissinkAetal.CritRevOralBiolMed.2003;14:199–212.MaxymiwWG,WoodRE.JCanDentAssoc.1989;55:193–198.

Radia_ondose(Gy)

Time(weeks)

Complica_

ons(arbitrary

units)

0 1 2 3 4 5 6 10 14 18 32 58 110

0 30 60

Suscep_bilitytoosteoradionecrosis

Hyposaliva_on

TastelossMucosi_sInfec_ons

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PathogenesisofMucosi9s:4Phases

ScullyCetal.HeadNeck.2003;25:1057–1070.ReprintedfromPetersonDE,CarielloA.SeminOncol.2004;31:35–44,withpermissionfromElsevier.

IL-1=Interleukin-1;TNFα=tumornecrosisfactorα;LPS=liposaccharide

IL-1TNFα IL-1

TNFαIL-1TNFα

LPS

Chemotherapyradia_on

Day0 Day6 Day12 Day16

Inflamma_on Epithelialatrophy

Ulcera_on/bacterialinfec_on

Healing

PhaseI PhaseII PhaseIII PhaseIV

Xerostomia:MarkedReduc0oninSalivary-GlandSecre0on

•  Xerostomia–  MostcommonadverseeffectofRTforheadandneckcancer–  RTcausesirreparabledamagetosalivaryglandsthatincreasestheriskfor

severelong-termoralandpharyngealdisorders–  Diminishesqualityoflife

•  Acuteinflammatoryreac9on•  Lateeffect:occurs9–12monthspostradia9on

–  Permanentwhenradia9ondoseexceeds4–26Gy

•  70%ofpa9entsexperienceslighttoseveredrynessofthemouthevenamerIMRT

AmossonCMetal.IntJRadiatOncolBiolPhys.2003;56:136–144.EisbruchAetal.IntJRadiatOncolBiolPhys.1999;45:577–587.

IncreasedIncidenceofToxicitywithAggressiveRT+CT

0

10

20

30

40

50

60

70

Oral complications

Myelosuppression

Dehydration

Nausea and vomiting

Anorexia

Hearing loss

Hypotension

RT aloneRT + CT

Incide

nce(%

)

McLaurinKKetal.Presentedat:41stAnnualMee_ngoftheAmericanSocietyofClinicalOncology;May13–17,2005;Orlando,Fla.Abstract8042.

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Adapted from Calais G et al. J Natl Cancer Inst. 1999;91:2081-2086.

0

10

20

30

40

50 RT Alone

CRT

Mucositis

Skin

Nutrition

Hematologic * *P ≤ .05

*

*

*

* * *

Patchy Mucositis

Confluent Fibrinous Mucositis

Erythema Moist Weight Loss

Tube Feeding

Neutro- penia

Low Platelets

Anemia Toxic Death

Perc

enta

ge o

f Pat

ient

s

HeadandNeckCancerCombined-modalityRegimen:

AcuteTreatment-relatedToxiciIes

RT = Cobalt-60 (total dose, 70 Gy). CRT = RT + 5-FU and carboplatin.

Desquamation

HeadandNeckCancerHealthConsequencesforPaIents

•  Xerostomiacanbesevereandnega9velyaffectabilityto–  Chew–  Swallow–  Speak–  Sleep–  Maintainproperdentalhygiene

•  Xerostomiacanleadto–  Mucosi9s–  Malnourishment–  Weightloss

•  Mucosi9sisassociatedwith–  Pain–  Odynophagia–  Dysgeusia–  Subsequentdehydra9on

andmalnutri9on–  Reducedqualityoflife–  Systemicinfec9ons,

par9cularlyinneutropenicpa9ents

Köstler WJ et al. CA Cancer J Clin. 2001;51:290-315. Wasserman T et al. Int J Radiat Oncol Biol Phys. 2000;48:1035-1039.

AcuteandLateEffectsImpactonaPa9entsWellBeing

•  Appearance•  Communica9onAbility•  AbilitytoEat

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HeadandNeckCancerCycleofOralTissueDamageTheRoleofXerostomia

Adapted from Köstler WJ et al. CA Cancer J Clin. 2001;51:290-315.

Tissue injury from CT and/or RT

Impairment of tissue regeneration

Damage by inflammatory mediators

Decrease in nutrition intake

Mucositis

Emergence of infectious bacteria

Xerostomia

Neutropenia

HeadandNeckCancerTreatmentDelaysDecreaseSurvival*

*Survivalratepercentagewasobtainedbystra9fyingdataof41pa9entswhoreceivedinduc9onchemotherapyandstandard-frac9ona9onradia9ontherapyaccordingtothenumberoftreatmentdaysmissed(P=.003).

Adapted from Alden ME et al. Radiology. 1996;201:675-680.

Months

< 5 Days

> 5 Days

% S

urvi

val

0 12 24 36 48 60 72 84 0

20

40

60

80

100

ImpactofTreatmentInterrup_ons

•  Forheadandneckcancer,Localcontrolisreducedbyabout0.4to2.5%foreachdaythattheoveralltreatment9meisprolonged

•  Anotherinterpreta9on,–  Amerthefirst4weeksofafrac9onatedschedulethefirst0.61Gyofeachday’sdosefrac9onisrequiredtoovercomeprolifera9onfromthepreviousday

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Frac9ona9on

Ra_onaleforFrac_ona_on

•  Repairofsublethaldamage

•  Reassortmentofcellswithinthecellcycle

•  Repopula9on

•  Reoxygena9on

Mul_pleFrac_onsPerDay

Hyperfrac9ona9on

Acceleratedtreatment

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Hyperfrac_ona_onTrialEORTC22791

•  80.5Gyin70frac9ons(1.15Gytwiceperday),7weeks

•  70Gyin35frac9ons,7weeks

•  LC,5years,increased40-59%reflectedinimprovedsurvival

•  Noincreaseinsideeffects

AcceleratedTreatment•  “Pure”acceleratedtreatmentmightbedefinedasthesame

totaldosedeliveredinhalftheoverall9mebygivingmoretotalfrac9ons–  Prac9cally–acuteeffectsbecomelimi9ng.Eitherneedabreakorto

reducethedoseslightly

•  Intentistoreducerepopula9oninrapidlyprolifera9ngtumors.

•  Thereshouldbelitleornochangeinthelateeffects,becausethenumberoffrac9onsandthedoseperfrac9onareunaltered

Con_nuousHyperfrac_onatedAcceleratedRadia_onTherapy

•  36frac9onsover12consecu9vedays,withthreefrac9onsdelivereddailywithaninterfrac9onintervalof6hours

•  Thedoseperfrac9onwas1.4to1.5Gytoatotaldoseof50.4to54Gy

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CHARTResults

•  Localtumorcontrolisgoodbecauseoverall9meisshort

•  Acutereac9onsarebriskbutpeakamertreatmentiscompleted

•  Mostlateeffectsareacceptablebecausethedoseperfrac9onissmall

Hyperfrac_ona_on•  Separate“early”and“late”effects

–  Frac9onsizeisthedominantfactorindetermininglateeffects(noeffectfromtreatment9me)

–  Frac9onsizeandoveralltreatment9medeterminetheresponseofacuteresponding9ssues

•  PureForm:Sametotaldosedeliveredinmul9plefrac9onsperdayoverthesameperiodof9me–  “Impure”Form:increasethetotaldose&overalltreatment9me

RadiotherapyImprovements•  ImprovedTarge9ng

– delinea9onofthetargetimprovedwithCT,MRI,andrecentlyPET

•  ImprovedDelivery– 2D-->3DCRT--->IMRT

•  Future:Adap9veIGRT– RealTimeTracking,ResponseMonitoring

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TargetDefini9onisCri9cal

IMRTforHead&NeckCancer

• MostnumbersofavoidancestructuresSalivarygland,op9cnerves,re9na,lacrimalglands

spinalcord,mandible,etc.

• Predictablepaternofdiseasespread• Easytoimmobilize• Opportunitytoimprovecureratesandsimultaneouslyimprovequalityoflife

• DocumentedbenefittoAlteredfrac9ona9on

IntensityModulatedRadia9onTherapy

•  Op9malweigh9ngofindividualrayswithinasinglebeam(i.e.Microscopicmanipula9onofradia9onbeam)

•  Poten9altoproducedosedistribu9onsthataremoreconformalthan3DCRT

•  Homogeneousdosedistribu9onswithinthetargetvolumewithsharperfalloffatPTVboundary

•  Deliveryofdifferentdosestovariousstructureswithinthetargetvolume

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IMRT-idealfortheheadandneckregion

IMRTReducesLateSalivaryToxicityWithoutCompromisingTumorControl

Chao K Radiother Oncol 2001;61:275-280

IMRTandGrade2XerostomiaModernExperience

0

10

20

30

40

50

60

70

2-3 mos 6 mos 9 mos 24 mos

UCSFMSKCCHong KongWash U

Kam et al, IJROBP, 2004. Dec 1;60(5):1440-50 De Arruda FF, et al, IJROBP, 2006 Feb 1;64(2):363-73 Lee N, et al, IJROBP, 2002 May 1;53(1):12-22. Chao KSC, et al, Radiother Oncol, 2001, 61;275-80.

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H&NCancerTreatmentToxicity

•  Mucosi9s

•  Dysphagia

•  Aspira9on

ImprovedIMRT

UMIMRTwithsparingPC,GSL

Feng FY, et al, IJROBP, 2007 Aug 1;68(5):1289-98

IMRT w/ sparing of PC, GSL, esophagus and major salivary glands GTV 70 Gy, high risk CTV 64 Gy, low risk CTV to 60 Gy in 35 fractions Pharyngeal Constrictors and Glottic and supraglottic larynx

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DysphagiaOp9mizedIMRTPlans

Eisbruch, et al, IJROBP, 2004;60(5):1425-1429

The Dysphagia Optimized IMRT plans demonstrate less dose to the pharyngeal constrictors and the larynx, and maintain adequate dose to the PTV without an increase to the spinal cord and parotid glands.

IMRT–MucosalSparingApproaches

•  Adosevolumeobjec9veonmucosa–  20%meanabsolutereduc9oninmucosaexposedto27.5Gy(p=0.001)–  12%meanabsolutereduc9oninmucosaexposedto63.1Gy(p=0.03)

•  Clinically,therewasasignificantdecreaseinmucosi9sscoreusingRTOGcriteria

Sanguineti, et al, IJROBP, 2006;66(3):931-938

IGRTinHeadandNeckCancer

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CanwedobeterthanIMRT

•  WithIGRT,ifweareableto“see”changesineitherparo9dposi9onortumorvolume

•  Canweadaptourtreatmentplansquicklyenoughtoimproveonparo9dsparing?

IGRTInAc9on

Analyze images

Treat

Adjust set up

Acquire images

HeadandNeckSet-UpUncertainty

•  Dependingonthemaskandtypeofimmobiliza9on,thesetupaccuracyonagivendayforaheadandneckpa9entis1-3mm

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SetupInaccuracyCanResultinBlurredDoseGradients

LymphNodeRegressionduringTreatment

VMATHasReplacedIMRT

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VMAT

•  IntensityModulatedRadiotherapy

•  Merges

•  DynamicArcTherapy

•  Merges

•  VolumeView--IGRT

VMAT

•  Promisestobemoreconformalwith9ghterdosedistribu9on

•  Promisestobemuchquicker– Treatment9mescuttounder7minutes

•  FewerMU

H&NVMATTreatments

# Delivery Time

Nasopharynx 3 5 min 31 secs

BOT 3 5 min 12 secs

Piriform sinus 2 4 min 31 secs

BOT 2 3 min 47 secs

BOT 2 4 min 27 secs

Nasopharynx 1 3 min 38 secs

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SingleArcvsMul9Arc

Results:SummaryofHead-&-NeckCases

Single arc Three arcs

MU 468 499

mean dose parotids per fraction (cGy)

37.3 38.3

standard deviation of PTV dose

per fraction (cGy) 6.25 5.51

V95 97.1 98.1

Delivery time 5 min 34 sec 5 min

Better target dose uniformity and coverage

Comparable delivery efficiency

ImprovingIGRT-IMRT

•  Pa9entstreatedwithIMRTexperienceDysphagia,Aspira9onPneumonia,andImpairedSpeechQuality.–  Emergingdatademonstratesthattheserisksarepropor9onaltothe

dosetopharyngealconstrictorsandlarynx

•  VMAT:TheFuture–  Deliveryofthesamedoseofradia0ontothetarget0ssuesbutmore

carefullypaintedsothattheswallowingstructuresarespared.–  Deliveryquickly,sothatmorepa0entsarecandidates.

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DysphagiaOp9mizedVMATPlan

DysphagiaOp9mizedVMATPlan

DysphagiaOp9mizedVMATPlan

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DO-VMATvs9FldIMRT

v  9 field IMRT plan Ø  169 segments Ø  1045 MUs Ø  Delivery time of 15 to 20 minutes

v  2 arc VMAT plan Ø  598 MUs Ø  Delivery time of 4 minutes

DysphagiaOp9mizedVMATPlanSummary

Introduc9onRecurrentDisease

•  5yearsurvivalrateis40-50%intheUS•  Recurrentdiseaseremainsasignificantproblem– 50-60%ofpa9entsdiebecauseofrecurrentdisease

•  Cureratesamerrecurrenceareapproximately16%orless

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SRSforPersistentH&NCanceramerDefini9veRT

Author # SRS dose Results

Cmelak 1997 11 7-16 Gy 2 yr LC=100% 2 yr OS=100%

Chang 1999 23 7-15 Gy 2 yr LC=100%

Chua 2003 7 11-14 Gy 2 yr LC=72% 2 y OS=86%

Le 2003 45 7-15 Gy 3 yr LC=100% 3y OS=75%

Ra9onaleforSBRT:HypoFrac9ona9on

•  BiologicEquivalentDose(BED)

•  MolecularRa9onale

•  TechnologicalImprovements

BEDComparison

Early Effects Late Effects

SRS 16 Gy x 1

42 Gy

144 Gy

SBRT 6 Gy x 6

58 Gy

144 Gy

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SRS/SBRTAllowsforTightDoseDistribu9on

HeronetalIJROBP2009

SBRTAdvantages

•  IncreasestheBEDtothetumorwithoutanincreaseinriskoflateeffects

•  TheprimarytoxicityofSRShasbeenlatetoxicity

•  Theorec9cally,SBRTshouldimproveefficacywithoutanincreaseintoxicity

SBRTforPersistentDisease

# Dose Outcomes

Ahn 2000 19 8-40 Gy 4 yr LC 89% 4 yr OS=75%

Wu 2007 34 6 Gy x 3

3yr LC=89.4% 3 yr PFS=72.3%

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SBRTforRecurrentDiseaseCengiz 2011 46 18-35 Gy in

1-5 fxs 1 yr OS 46% MS 10.5 mos

Kodani 2011 21 19.5-42 Gy in 3-8 fxs

2 yr OS 50%

Unger 2010 38 21-35 Gy in 2-5 fxs

2 yr OS = 41% 2 yr LC = 31%

Siddiqui 2009

19 6 Gy x 6 2 yr OS = 14.3% 2 yr LC = 40%

Heron 2009* 25 25-44 Gy in 5 fxs

MS = 6 months

Wu 2007 56 8 Gy x 6 3 yr LC=75.1% 3 yr PFS=42.9%

Orecchia 1999

13 24 Gy 3yr OS=31%

Ahn 2000 12 45-65Gy 2yr LC=92% 2yr OS=60%

ReportedToxici9esofSBRT

•  Heron2009– NoAcutegrade3or4toxicityin25pa9ents

•  Unger2010– 19of65pa9entshadgrade1-3AcuteToxicity– NoAcutegrade4toxicityin65pa9ents– 6LateGrade4Toxici9es

DetailReportedLateToxicityfromSBRT

UngeretalIJROBP2010

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PETAssessmentforResponse

PreTreatment

PostTreatment

Heronetal2009

PETResponseofNodalFailure

PreTx

PostTx

Heronetal2009

ThankYou