Cagliari, 23/24 giugno 2005

Combination of Combination of cetuximab cetuximab and and ……in HNCin HNC

Marco Marco MerlanoMerlanoS. Croce Gen. HospitalS. Croce Gen. Hospital

Table 2 EGFR monoclonal antibodies in clinical trials_____________________________________________________________________________________Agent Type Generic/trade name Institution_____________________________________________________________________________________IMC-C225 Chimeric IgG1 *Cetuximab/Erbitux ImClone/BMS/MerckABX-EGF Fully human IgG2 panitumumab Abgenix/AmgenEMD 72000 Humanized IgG1 — EMD Pharms/MerckMDX-447 Humanized, bispecific HuMab-Mouse Medarex/Merck KGaAh-R3 Humanized TheraCIM YM Biosciences/CIMMab 806 Anti-EGFR VIII — Ludwig Institute_____________________________________________________________________________________*Approved.

P M Harari

Epidermal growth factor receptorinhibition strategies in oncology

Endocrine-Related Cancer (2004) 11 689–708

M. M. Kies Kies (refractory)(refractory)C+C+cetuximab cetuximab (SD)(SD) O.R.R. 24%O.R.R. 24%

(PD)(PD) O.R.R. 12%O.R.R. 12%

E5397

4(6.9%)4(6.9%)4(7%)4(7%)UnknownUnknown2(3.7%)2(3.7%)2(3.7%)2(3.7%)unevaluneval

9(16.7%)9(16.7%)4(7.6%)4(7.6%)PDPD38(70.4%)38(70.4%)35(66%)35(66%)SDSD

5(9.3%)p=5(9.3%)p=00.0508.050812 (22.6%)12 (22.6%)RRRR3(5.6%)3(5.6%)9(17%)9(17%)PRPR2(5.7%)2(5.7%)3(5.7%)3(5.7%)CRCR

N(%)N(%)N(%)N(%)Best Best responseresponseC + PlaceboC + PlaceboC + C225C + C225

Single agent cisplatin in randomized trials Single agent cisplatin in randomized trials testing single agent testing single agent vs polichemotherapyvs polichemotherapy

Jacobs, Jacobs, Cancer 1983Cancer 1983 R.RR.R. 18%. 18%Jacobs, Jacobs, J.J.ClinClin..OncolOncol.. 19921992 R.R. 17%R.R. 17%ClavelClavel, , Ann.Ann.OncolOncol. 1994. 1994 R.RR.R. 15%. 15%

EGFr IS A POTENT MEDIATOR OF RADIORESISTANCE EGFr IS A POTENT MEDIATOR OF RADIORESISTANCE (and (and chemoresistancechemoresistance?)?)

((KeKe LiangLiang MS MS etet al al ““The The growthgrowth factorfactor receptorreceptor mediatesmediates radioresistanceradioresistance”” IntInt J J RadiatRadiatOncolOncol BiolBiol PhysPhys 2003;57:2462003;57:246--254254))

VIA:VIA:UpUp--regulationregulation ofof BclBcl--22 ((downdown--regulationregulation of of apoptoticapoptotic responseresponse inducedinduced byby RT [or CT])RT [or CT])

UpUp--regulationregulation ofof DNA DNA repairrepair mechanismsmechanisms ((repairrepairof of potentialpotential lethallethal damagedamage RT [or CT] RT [or CT] inducedinduced))

UpUp--regulation of cyclin regulation of cyclin activating cell activating cell proliferationproliferation (enlarging proportion of cells in(enlarging proportion of cells inradioresistantradioresistant phasephase of of cellcell cyclecycle))

((MendelshonMendelshon J J ““TargetingTargeting the the epidermalepidermal growthgrowth factorfactor receptorreceptor forfor cancercancer therapytherapy””J.Clin.OncolJ.Clin.Oncol. 2002;20:1s. 2002;20:1s--13s13s))((Ochs J:Ochs J:””Rationale and clinical basis for combining gefitinib (IRESSA) wiRationale and clinical basis for combining gefitinib (IRESSA) with radiation th radiation therapy in therapy in solidsolid tumourstumours””IntInt J J RadiatRadiat OncolOncol BiolBiol PhysPhys 2004;58:9412004;58:941--9)9)

RADIATION ITSELF DIRECTLY ACTIVATES RADIATION ITSELF DIRECTLY ACTIVATES EGFrEGFr IN TUMOR CELLS (REPOPULATION?)IN TUMOR CELLS (REPOPULATION?)THE EFFECT IS OBSERVED ONLY IN TUMOURS THE EFFECT IS OBSERVED ONLY IN TUMOURS WITH WITH EGFrEGFr HIGH LEVEL HIGH LEVEL AkimotoAkimoto T T etet al: al: ““Inverse Inverse relationshiprelationship betweenbetween EGFrEGFr expressionexpression and and radiocurabilityradiocurability of of murinemurine carcinomascarcinomas”” ClinClin CancerCancer Res 1999;5:2884Res 1999;5:2884--9090

•• RT RT inducesinduces twotwo phasesphases of of EGFrEGFr activationactivation::–– Initial (transient) activation (autophosphorylation)Initial (transient) activation (autophosphorylation)–– Second phase resulting from the release of the EGFr ligand Second phase resulting from the release of the EGFr ligand

TGFTGF--∝∝Dent P et al:Dent P et al:””RTRT--induced release of TGFinduced release of TGF--∝∝ activatesactivates the the EGFrEGFr and and mitogenmitogen--activatedactivated

PK PK pathwaypathway in carcinoma in carcinoma cellscells, , leadingleading toto increasedincreased proliferationproliferation and and protectionprotectionfromfrom RTRT--inducedinduced cellcell deathdeath”” MolMol BiolBiol CellCell 1999;10:24931999;10:2493--506506

BLOCKADE OF THEBLOCKADE OF THE EGFrEGFr SIGNAL SIGNAL TRANSDUCTION INCREASES RT TRANSDUCTION INCREASES RT

ACTIVITYACTIVITY……

•• HuangHuang SS--M M etet al:al:””ModulationModulation of RT of RT responseresponse after after EGFrEGFrblockadeblockade in SCC: in SCC: inhibitioninhibition of of damagedamage repairrepair, , cellcell cyclecyclekinetickinetic and and tumortumor angiogenesisangiogenesis”” ClinClin CancerCancer Res 2000;6:2166Res 2000;6:2166--7474

……ANDAND ENHANCES APOPTOTIC RESPONSE. ENHANCES APOPTOTIC RESPONSE.

HarariHarari P P etet al, al, Int.Int. J J RadRad. . OncolOncol 2001:49;4272001:49;427--3333

PROPOSED MECHANISMS of PROPOSED MECHANISMS of INTERACTION BETWEEN CT AND RTINTERACTION BETWEEN CT AND RT

•• CELL KINETIC:CELL KINETIC:–– CHEMOTHERAPY KILLS CELLS IN CHEMOTHERAPY KILLS CELLS IN

RADIORESISTANT CELL CYCLE PHASES RADIORESISTANT CELL CYCLE PHASES AND ACCUMULATES DAMAGED CELLS IN AND ACCUMULATES DAMAGED CELLS IN HIGHLY RADIOSENSITIVE PHASE GHIGHLY RADIOSENSITIVE PHASE G22--M.M.

•• DOWNDOWN--REGULATION OF DAMAGE REGULATION OF DAMAGE REPAIR.REPAIR.

•• INCREASED APOPTOTIC RESPONSE INCREASED APOPTOTIC RESPONSE ((BaxBax mediatedmediated))

BLOCKADE OF THE BLOCKADE OF THE EGFrEGFr SIGNAL SIGNAL TRANSDUCTION INCREASES RT TRANSDUCTION INCREASES RT

ACTIVITYACTIVITY•• PROLIFERATIVE GROWTH PROLIFERATIVE GROWTH

INHIBITION (stop at G1)INHIBITION (stop at G1)•• INHIBITION OF DAMAGE INHIBITION OF DAMAGE

REPAIR REPAIR •• ENHANCEMENT OF ENHANCEMENT OF

APOPTOTIC RESPONSE APOPTOTIC RESPONSE ((inhibitioninhibition of Bclof Bcl--2)2)

Merlano M Merlano M etet al: al: ““RadiochemotherapyRadiochemotherapy in Hin H--NCNC””in in ““Progress in antiProgress in anti--cancer chemotherapycancer chemotherapy”” D.KhayattD.Khayatt, , GN GN HortobagyiHortobagyi EditorsEditors; ; BlackwellBlackwell ScienceScience, , LondonLondon 19971997

EpidemiologyEpidemiology of of EGFrEGFr

•• OverexpressionOverexpression isis usuallyusually due due tototranscriptionaltranscriptionalactivationactivation mediatedmediated bybyTGFTGF--αα autocrineautocrine productionproduction

butbut......

KK Ang et al KK Ang et al ““epidermal growth factor receptor and response of HNC epidermal growth factor receptor and response of HNC to therapyto therapy”” Int.l J Int.l J RadiatRadiat. . OncolOncol. . BiolBiol. . PhysPhys 2004;58:9592004;58:959--6565

OtherOther waysways toto overexpressoverexpress EGFr...EGFr...

GENE AMPLIFICATION due GENE AMPLIFICATION due toto......

EXPOSURE OF HUMAN TUMOUR CELLS TO HYPOXIA EXPOSURE OF HUMAN TUMOUR CELLS TO HYPOXIA INDUCES INDUCES EGFrEGFr OVEROVER--EXPRESSIONEXPRESSION

(Laderoute KR (Laderoute KR etet al al ““EnhancedEnhanced EGFrEGFr synthesissynthesis in in humanhuman squamoussquamous carcinomacarcinomaCells exposed to low levels of oxygenCells exposed to low levels of oxygen””Int.J.Cancer 52:428Int.J.Cancer 52:428--432,1992432,1992))

VIA ACTIVATION OF STRESS RESPONSE GENESVIA ACTIVATION OF STRESS RESPONSE GENES(EX.: Egr(EX.: Egr--1)1)

((Nishi H et al Nishi H et al ““Early growth response Early growth response --1 gene mediates up1 gene mediates up--regulation of regulation of EGFrEGFrExpressionExpression duringduring hypoxiahypoxia”” CancerCancer Res 2002;62:827Res 2002;62:827--834834))

CC--225 AND CHEMORADIATION225 AND CHEMORADIATIONPfisterPfister DG DG etet al, ASCO 2003, al, ASCO 2003, abstrabstr 1993, ASCO 2005, 1993, ASCO 2005, abstrabstr 55295529

•• PHASE II C 225 + CISPLATIN + RT PHASE II C 225 + CISPLATIN + RT –– CT: CISPLATIN 100 mg/m2 d 1CT: CISPLATIN 100 mg/m2 d 1--5 5 c.i.c.i. wkswks 1 & 41 & 4–– RT: RT: wkswks 11--4 + 4 + conc.tconc.t boostboost ((wkswks 55--6)6)–– CC--225: 400mg/m2 wk 1; 250mg/m2 225: 400mg/m2 wk 1; 250mg/m2 wkswks 22--1010

CC--225 AND CHEMORADIATION225 AND CHEMORADIATIONPfisterPfister DG DG etet al, ASCO 2003, al, ASCO 2003, abstrabstr 19931993

•• TREATMENT INTERRUPTED DUE TO TREATMENT INTERRUPTED DUE TO TOXICITY after 22 TOXICITY after 22 ptspts::–– GRADE IV TOX: GRADE IV TOX: AnaphylaxisAnaphylaxis (1); (1); arrhythmiaarrhythmia (1);(1); bacteriemiabacteriemia (1); (1);

hypokalemiahypokalemia (1); (1); hyponatremiahyponatremia (1); (1); mucositismucositis (2) (2) -- myocardialmyocardialinfarctioninfarction (1);(1); -- DeathsDeaths ON treatment (2)ON treatment (2)

–– ROBERTROBERT’’S trial (S trial (phasephase I) (16 I) (16 ptspts) ) –– GRADE IV TOX: GRADE IV TOX: AnaphylaxisAnaphylaxis (1); (1); arrhythmiaarrhythmia (0); (0); bacteriemiabacteriemia (0); (0);

hypokalemiahypokalemia (0); (0); hyponatremiahyponatremia (0); (0); mucositismucositis (0) (0) -- myocardialmyocardialinfarctioninfarction (0); (0); -- DeathsDeaths ON treatment (0)ON treatment (0)

CC--225 AND CHEMORADIATION225 AND CHEMORADIATIONPfisterPfister DG DG etet al, ASCO 2003, al, ASCO 2003, abstrabstr 19931993

•• TREATMENT INTERRUPTED DUE TO TREATMENT INTERRUPTED DUE TO TOXICITY after 22 TOXICITY after 22 ptspts::–– GRADE IV TOX: GRADE IV TOX: AnaphylaxisAnaphylaxis (1); (1); arrhythmiaarrhythmia (1);(1); bacteriemiabacteriemia (1); (1);

hypokalemiahypokalemia (1); (1); hyponatremiahyponatremia (1); (1); mucositismucositis (2) (2) -- myocardialmyocardialinfarctioninfarction (1);(1); -- DeathsDeaths ON treatment (2)ON treatment (2)

–– ROBERTROBERT’’S trial (S trial (phasephase I) (16 I) (16 ptspts) ) –– GRADE IV TOX: GRADE IV TOX: AnaphylaxisAnaphylaxis (1); (1); arrhythmiaarrhythmia (0); (0); bacteriemiabacteriemia (0); (0);

hypokalemiahypokalemia (0); (0); hyponatremiahyponatremia (0); (0); mucositismucositis (0) (0) -- myocardialmyocardialinfarctioninfarction (0); (0); -- DeathsDeaths ON treatment (0)ON treatment (0)

CC--225 AND CHEMORADIATION225 AND CHEMORADIATIONPfisterPfister DG DG etet al, ASCO 2003, al, ASCO 2003, abstrabstr 19931993

•• THE INTERGROUP TRIAL (1)THE INTERGROUP TRIAL (1): THE WINNER SCHEDULING: THE WINNER SCHEDULING–– CisCis--platinplatin 100mg/m2 d 1100mg/m2 d 1--2222--4343–– RT standard RT standard fr.fr. 2 2 GyGy d x 5/7wksd x 5/7wks–– All Grade 3All Grade 3--5 toxicity 85/95pts5 toxicity 85/95pts–– Deaths OF treatment 4/95ptsDeaths OF treatment 4/95pts

•• THE RTOG TRIAL 9003 (2)THE RTOG TRIAL 9003 (2)–– RT standard, tox G. IIIRT standard, tox G. III--IV = 35%IV = 35%

»» P<0.0001P<0.0001–– RT concomitant boost RT concomitant boost G.IIIG.III--IVIV = 59%= 59%

(1) (1) AdelsteinAdelstein DJ DJ etet al:al:””AnAn intergroupintergroup phasephase III III comparisoncomparison …”…” J J ClinClin OncolOncol 2003;21:922003;21:92--9898(2) Fu KK (2) Fu KK etaeta al:al:””A RTOG A RTOG phasephase III III randomizedrandomized studystudy……”” IntInt J J RadRad OncolOncol 2000;48:72000;48:7--16 16

P<0.0001 P<0.0001 comparedcompared toto RT aloneRT alone

CC--225 AND CHEMORADIATION225 AND CHEMORADIATIONPfisterPfister DG DG etet al, ASCO 2003, al, ASCO 2003, abstrabstr 19931993

•• THE INTERGROUP TRIAL (1)THE INTERGROUP TRIAL (1): THE WINNER SCHEDULING: THE WINNER SCHEDULING–– CisCis--platinplatin 100mg/m2 d 1100mg/m2 d 1--2222--4343–– RT standard RT standard fr.fr. 2 2 GyGy d x 5/7wksd x 5/7wks–– All Grade 3All Grade 3--5 toxicity 85/95pts5 toxicity 85/95pts–– Deaths OF treatment 4/95ptsDeaths OF treatment 4/95pts

•• THE RTOG TRIAL 9003 (2)THE RTOG TRIAL 9003 (2)–– RT standard, tox G. IIIRT standard, tox G. III--IV = 35%IV = 35%

»» P<0.0001P<0.0001–– RT concomitant boost RT concomitant boost G.IIIG.III--IVIV = 59%= 59%

(1) (1) AdelsteinAdelstein DJ DJ etet al:al:””AnAn intergroupintergroup phasephase III III comparisoncomparison …”…” J J ClinClin OncolOncol 2003;21:922003;21:92--9898(2) Fu KK (2) Fu KK etaeta al:al:””A RTOG A RTOG phasephase III III randomizedrandomized studystudy……”” IntInt J J RadRad OncolOncol 2000;48:72000;48:7--16 16

P<0.0001 P<0.0001 comparedcompared toto RT aloneRT alone

A HIGHLY TOXIC CT/RT REGIMENA HIGHLY TOXIC CT/RT REGIMEN……plusplus

A HIGHLY TOXIC RT SCHEDULINGA HIGHLY TOXIC RT SCHEDULING……plusplus

AN EXPERIMENTAL DRUGAN EXPERIMENTAL DRUG……

CC--225 AND CHEMORADIATION225 AND CHEMORADIATIONPfisterPfister DG DG etet al, ASCO 2003, al, ASCO 2003, abstrabstr 1993, ASCO 2005, 1993, ASCO 2005, abstrabstr 55295529

•• 22 PTS ENROLLED22 PTS ENROLLED•• 16 EVALUABLE FOR TREATMENT ACTIVITY16 EVALUABLE FOR TREATMENT ACTIVITY•• MEDIAN F.U. 44 MEDIAN F.U. 44 monthsmonths•• 36 MONTHS 36 MONTHS ACT.LACT.L PROGRESSION FREE SURVIVAL 59%PROGRESSION FREE SURVIVAL 59%•• 36 MONTHS OVERALL SURVIVAL 76%36 MONTHS OVERALL SURVIVAL 76%

ALTEALTErnatingrnating RRadiotherapy andadiotherapy and CChemotherapyhemotherapy plus plus CCetuximabetuximab

ALTERCC STUDYALTERCC STUDY

WEEK 1 2 3 4 5 6 7 8 9_ RADIOTH.RADIOTH._ RADIOTH.RADIOTH._ RADIOTH.RADIO

STEP 1

CHEMOTH._ _ CHEMOTH._ _ CHEMOTH._ _STEP 2

RADIOTH. = RADIOTH. = 10 10 GyGy/5 /5 fractionsfractions/1 /1 fractionfraction per dayper day

CHEMOTH. = CHEMOTH. = CisCis--PtPt 20mg/m2/day per 5 20mg/m2/day per 5 daysdays

55--Fu 200mg/m2/day per 5 Fu 200mg/m2/day per 5 daysdays

= C225

ongoingongoing30 05 0530 05 05IVIVHYPOHYPOPHARYNXPHARYNX111947194766

LysisLysis22ongoingongoing04 04 0504 04 05IVrIVrTONGUE TONGUE FLOORFLOOR111943194355

lysislysis1118 04 0518 04 0528 02 0528 02 05IVIVORALORALFLOORFLOOR111946194644

lysislysisHH--F F syndrsyndr..2217 2 0517 2 0513 12 0413 12 04IVIVSOVRA SOVRA

GLOTTISGLOTTIS001943194333

lysislysisIpo Ipo Mg Mg arrhythmiaarrhythmia2211 2 0511 2 0506 12 0406 12 04IVIVTONGUETONGUE001953195322

lysislysis3313 1 0513 1 0508 11 0408 11 04IVIVTONSILTONSIL001941194111

skinskinAsthAsthENDENDSTARTSTARTSTSTSITESITEPSPSBIRTHBIRTH

SKIN TOXICITY OCCURRING AT SKIN TOXICITY OCCURRING AT 4646--60 Gy60 Gy

SKIN TOXICITY OCCURRING AT SKIN TOXICITY OCCURRING AT 4646--60 Gy60 Gy

Cetuximab+Carboplatin+ReCetuximab+Carboplatin+Re--irradiationirradiationpalliative approachpalliative approach

•• Highly motivated pts with very advanced diseaseHighly motivated pts with very advanced disease•• Previously treated with chemoPreviously treated with chemo--radioradio--surgerysurgery•• Request of therapyRequest of therapy

RTRTCBDCACBDCA

CC--225225

sisi--676799MascMasc..11Reggio Reggio EE1956195688

sisi--575777MascMasc..11CuneoCuneo1931193177

sisi--5050fegatofegato1010LarinLarin..22ParmaParma1946194666

sisi--646466IpofIpof..11CuneoCuneo1930193055

sisiTPF/RTPF/RTT5050LNF LNF

medias.medias.55RinofRinof..11GenovaGenova1952195244

sisi--66661010LarinLarin..11FoggiaFoggia1941194133

sisiCisp/Cisp/RTRT696944IpofIpof..22LeccoLecco1954195422

sisiTax/RTax/RTT7272LNF LNF ascasc..1010OrofOrof..44CremonaCremona1948194811

CT CT palliatpalliatCT/RTCT/RTRTRTM1M1painpain

An.An.visvis..sitesiteP.S.P.S.Where Where

leavingleavingborneborneptspts

NP (+)NP (+)VV1100RPRP30 Gy30 Gy19 05 0519 05 0514 04 0514 04 0588

P (+)P (+)31 05 0531 05 05VV2200N.V.N.V.40 Gy40 Gy02 04 0502 04 0528 02 0528 02 0577

NP (+)NP (+)11 4 05 11 4 05 strokestrokeNVNV0000SDSD30 Gy30 Gy14 01 0514 01 0506 12 0406 12 0466

PP20 2 0520 2 05VV1111SDSD30 Gy30 Gy31 12 0431 12 0415 11 0415 11 0455

P (*)P (*)16 1 0516 1 05VV1100RCRC30 Gy30 Gy13 11 0413 11 0404 10 0404 10 0444

PP4 11 044 11 04VV1122RPRP30 Gy30 Gy06 10 0406 10 0430 08 0430 08 0433

PP20 6 0420 6 04VV1100RPRP30 Gy30 Gy16 04 0416 04 0410 03 0410 03 0422

NPNP8 1 04 8 1 04 pneumpneum..NVNV0022N.V.N.V.30 30

Gy*Gy*Morte Morte in in terapiaterapia24 12 0324 12 0311

P/NPP/NPA/DA/DRush Rush skinskin

painpainAn.An.visvis..

RespResp..Dose Dose RTRTendendstartstartptspts

TOXICITYTOXICITY

11330011000000000088

22000000001100000077

11110011000022000066

11110011001100000055

11110011000000000044

11000000000000000033

11110022000000000022

00330033113322333311

rushrushstomstomDiarrDiarrAsthAsthN&VN&VPltPltHgbHgbNeNeWbcWbcPtsPts

ReRe--irradiationirradiation

A 66 y.o. man, supraglottic cancer pT2 pN0 (2001)

Nodal relapse (2002)Soft tissues relapse (2003)

Surgery (2001)Radiotherapy (2002) 66 GyPalliative CT (2003-4):

CFTXTVBM

AReRe--irradiationirradiation

• A: starting treatment

• B: after 1 week

B

AReRe--irradiationirradiation

• A: starting treatment

• B:5 days RT (10 Gy),

2 administrations of Cetuximab1 course of CBDCA AUC 5

BB

August 2004August 2004 October 2004October 2004

CONCLUSIONSCONCLUSIONSEGFr InhibitorsEGFr Inhibitors

1.1. Encouraging preliminary data combined with RT Encouraging preliminary data combined with RT w/t w/t increased toxicityincreased toxicity

2.2. Lack of data in combination with CT/RT (trials in Lack of data in combination with CT/RT (trials in progress) but concerns on a possible increased progress) but concerns on a possible increased toxicitytoxicity

3.3. RERE--IRRADIATION ?IRRADIATION ?1.1. Immediate pain relief (Immediate pain relief (≈≈ 7 7 gggg))2.2. Objective responsesObjective responses3.3. Very short PFS (Very short PFS (manteinance manteinance therapy?)therapy?)

Criteri di tossicitCriteri di tossicitàà limitantelimitante

EmatologicaEmatologica:: neutrofilineutrofili < 500 per pi< 500 per piùù di 7 giornidi 7 giornineutrofili < 100 per pineutrofili < 100 per piùù di 3 giornidi 3 giorni

netropenia febbrile, definita come netropenia febbrile, definita come neutrofilineutrofili < 500 associati a T>38< 500 associati a T>38°° in due valutazioni in due valutazioni successive eseguite a distanza di 12 ore lsuccessive eseguite a distanza di 12 ore l’’una dalluna dall’’altra.altra.

NonNon--ematologicaematologica:: qualunque tossicitqualunque tossicitàà g3 secondo la definizione NCIg3 secondo la definizione NCI--CTC versione 2.0, eccetto:CTC versione 2.0, eccetto:stomatitestomatite –– si considera limitante una stomatite g4 che non riduca a g3 si considera limitante una stomatite g4 che non riduca a g3 o meno entro 7 giorni;o meno entro 7 giorni;toxtox cutaneacutanea-- vedi sopra.vedi sopra.

I pazienti che manifestino una tossicitI pazienti che manifestino una tossicitàà limitante escono dallo studio e proseguono il solo trattamento limitante escono dallo studio e proseguono il solo trattamento chemiochemio--radioterapicoradioterapico pianificato, ma senza Cetuximab.pianificato, ma senza Cetuximab.