THE INTEGRATION OF CHEMOTHERAPY THE INTEGRATION OF CHEMOTHERAPY IN CURATIVE TREATMENT OF HEAD AND IN CURATIVE TREATMENT OF HEAD AND NECK CANCER: NECK CANCER

THE INTEGRATION OF CHEMOTHERAPY THE INTEGRATION OF CHEMOTHERAPY IN CURATIVE TREATMENT OF HEAD AND IN CURATIVE TREATMENT OF HEAD AND

NECK CANCER:NECK CANCER:

Marshall Posner, MDMarshall Posner, MDDanaDana--Farber Cancer InstituteFarber Cancer Institute

Biologic Principles, Changing Paradigms, Biologic Principles, Changing Paradigms, and New Therapies for 2009and New Therapies for 2009

Chemotherapy Is Part Of An Integrated Chemotherapy Is Part Of An Integrated Combined Modality Treatment PlanCombined Modality Treatment Plan

Multidisciplinary ClinicMultidisciplinary Clinic–– Determine the Stage/ExtentDetermine the Stage/Extent

»» Establish Prognostic/Predictive FactorsEstablish Prognostic/Predictive Factors

–– Establish and Coordinate the Treatment PlanEstablish and Coordinate the Treatment Plan»» Prepare the PatientPrepare the Patient

–– Monitor Response and ToxicityMonitor Response and Toxicity»» Modify Therapy Based on Response/PrognosisModify Therapy Based on Response/Prognosis

–– Long Term Follow Up for Toxicity, Recurrence Long Term Follow Up for Toxicity, Recurrence and Second Primaryand Second Primary

SCCHN Differs from Many Other Tumor SitesSCCHN Differs from Many Other Tumor Sites–– The Structures of the Head and Neck are Constantly FunctioningThe Structures of the Head and Neck are Constantly Functioning–– Patients Can Spend a Year or More to Reasonable RecoveryPatients Can Spend a Year or More to Reasonable Recovery

Morbidity Can be Significant and ProlongedMorbidity Can be Significant and Prolonged–– ChemotherapyChemotherapy

»» Mucositis, Neutropenia, Nausea/Vomiting, Neuropathy Mucositis, Neutropenia, Nausea/Vomiting, Neuropathy –– Radiotherapy and ChemoradiotherapyRadiotherapy and Chemoradiotherapy

»» Pain, Mucositis, Esophageal Stenosis, Muscular Dysfunction, Pain, Mucositis, Esophageal Stenosis, Muscular Dysfunction, Scarring/Fibrosis, Dry Mouth, Carotid Stenosis, Radiation InduceScarring/Fibrosis, Dry Mouth, Carotid Stenosis, Radiation Induced d Second CancersSecond Cancers

–– SurgerySurgery»» Impaired Swallowing, Breathing and Speech, Shoulder Dysfunction Impaired Swallowing, Breathing and Speech, Shoulder Dysfunction

Therapy is IntensiveTherapy is Intensive–– A Coordinated Team Approach is Vital for SuccessA Coordinated Team Approach is Vital for Success

»» Nursing is Critical During Aggressive Chemotherapy and Nursing is Critical During Aggressive Chemotherapy and ChemoradiotherapyChemoradiotherapy

»» Hydration; Pain and Symptom Management; Swallowing Therapy; Hydration; Pain and Symptom Management; Swallowing Therapy; Psychosocial SupportPsychosocial Support

Head and Neck Cancer: Head and Neck Cancer: Morbidity of TreatmentMorbidity of Treatment

Chemoradiotherapy Induced Mucositis

What Do Patients Want?What Do Patients Want?

List MA, et al. Head Neck. 2004; 26(2):163-170.

Cited Among Top 3 PrioritiesCited Among Top 3 Priorities

Factors Important in Determining the Factors Important in Determining the Intensity of Treatment and Organ PreservationIntensity of Treatment and Organ Preservation

PatientPatient»» Age, Fragility, Rehab PotentialAge, Fragility, Rehab Potential»» Psychosocial Issues Psychosocial Issues --Compliance, Addictions, MotivationCompliance, Addictions, Motivation»» CoCo--Morbid IllnessesMorbid Illnesses-- Modifications of TherapyModifications of Therapy»» Performance StatusPerformance Status

TumorTumor»» Location Location -- Anterior Lesions Anterior Lesions -- Oropharynx, Larynx, HypopharynxOropharynx, Larynx, Hypopharynx--

Nasopharynx, Posterior pharynxNasopharynx, Posterior pharynx»» Biology Biology -- Growth RateGrowth Rate»» Stage Stage -- N2/N3N2/N3»» HPV StatusHPV Status

GoalsGoals»» Organ Preservation, Survival, Distant MetastasesOrgan Preservation, Survival, Distant Metastases

HearHear No Induction No Induction SeeSee No InductionNo Induction

SpeakSpeak No InductionNo Induction

INDUCTION APHASIAINDUCTION APHASIA

Effects of Chemotherapy on Survival at 5 Years:Effects of Chemotherapy on Survival at 5 Years:From the MetaFrom the Meta--AnalysisAnalysis

Trial CategoryTrial Category No. of TrialsNo. of Trials No. PatientsNo. Patients Difference(%)Difference(%) PP valuevalueAll trialsAll trials 6565 1085010850 +4+4 <0.0001<0.0001AdjuvantAdjuvant 88 18541854 +1+1 0.740.74InductionInduction 3131 52695269 +2+2 0.100.10PFPF 1515 24872487 +5+5 0.010.01Other ChemoOther Chemo 1616 27822782 00 0.910.91ConcomitantConcomitant 2626 37273727 +8+8 <0.0001<0.0001

Monnerat, et al. Annals of Oncology, 13: 995-1006, 2002.

The STUDIO Induction Chemotherapy Trial:The STUDIO Induction Chemotherapy Trial:A Phase III Study of PF Induction ChemotherapyA Phase III Study of PF Induction Chemotherapy

RANDOMIZE

P

F

Radiotherapy4 Cycles of Chemotherapy

Surgery

No Surgery

Radiotherapy

Surgery

Radiotherapy

STRATIFY

No Chemotherapy

Chemotherapy

No Surgery(-) Biopsy

Nodal Surgery

(-) Biopsy

Nodal Surgery

Paccagnella A, et al. J Natl Cancer Inst. 1994;86:265-272

Studio Induction Chemotherapy Trial: Studio Induction Chemotherapy Trial: Overall Survival for Operable PatientsOverall Survival for Operable Patients

A group, initial chemotherapy (cisplatin and infusional fluorouracil) followed by locoregional treatment (n=118).B group, locoregional treatment alone (n=119).Paccagnella A, et al. J Natl Cancer Inst. 1994;86:265-272.

0

0.5

1

0 12 24 36 48

A groupB group

Months from randomization

Ove

rall

surv

ival 27

1915

106

60

28

19

14 9 6

•• Conclusion: postConclusion: post--CT surgery did CT surgery did not improve survival in operable not improve survival in operable patientspatients−− Surgery may Surgery may ↑↑ risk of localrisk of local--

regional recurrenceregional recurrence−− Surgical Margins InadequateSurgical Margins Inadequate−− Tumor repopulation and Tumor repopulation and

resistance enhanced by resistance enhanced by delay to XRTdelay to XRT

−− Lack of primary site Lack of primary site preservationpreservation

Studio Induction Chemotherapy Trial: Studio Induction Chemotherapy Trial: Overall Survival for Inoperable Patients Overall Survival for Inoperable Patients –– 10 Year Data10 Year Data

PF group, initial chemotherapy (cisplatin and infusional fluorouracil) followed by locoregional treatment (n=118).XRT group, locoregional treatment alone (n=119).Zorat, P. L. et al. J Natl Cancer Inst 2004

•• ConclusionConclusion

−− PF Induction Chemotherapy PF Induction Chemotherapy Improves Survival In Improves Survival In Patients With Unresectable Patients With Unresectable DiseaseDisease

−− LocalLocal--Regional FailureRegional Failure and and Distant Metastases were Distant Metastases were Reduced by PFReduced by PF0

20

40

60

80

100

0 20 40 60 80 100 120

SUR

VIVA

L (%

)

MONTHS

XRT

PF

Domenge C, et al. Br J Cancer. 2000;83:1594-1598.

Patients at risk

Overall Survival Oropharynx: Overall Survival Oropharynx: GETTECGETTEC

161157

137138

101105

6586

4859

2833

1619

77

Perc

ent

YearsNo chemotherapy Chemotherapy

0

40

20

60

80

100

0 1 2 3 4 5 6 7 8

BIOLOGICAL ASSUMPTIONS OF BIOLOGICAL ASSUMPTIONS OF CHEMORADIOTHERAPYCHEMORADIOTHERAPY

SCCHN is a Local Regional DiseaseSCCHN is a Local Regional DiseaseLocal Regional Failure Became the Dominant Local Regional Failure Became the Dominant

Concern Concern LocalLocal--Regional Control Regional Control --Persistent DiseasePersistent Disease

LocalLocal--Regional Control Regional Control --Recurrent DiseaseRecurrent Disease

LocalLocal--Regional Control Regional Control --New DiseaseNew Disease

Distant DiseaseDistant Disease

BIOLOGICAL ASSUMPTIONS OF BIOLOGICAL ASSUMPTIONS OF CHEMORADIOTHERAPYCHEMORADIOTHERAPY

Which Mechanism is Active?Which Mechanism is Active?–– Direct AntiDirect Anti--Tumor ActivityTumor Activity–– Radiation Sensitizing EffectRadiation Sensitizing Effect–– Combined EffectsCombined Effects

Which Mechanism is Desired?Which Mechanism is Desired?–– For Local/Regional TreatmentFor Local/Regional Treatment–– For Systemic TreatmentFor Systemic Treatment

How is Toxicity Effected?How is Toxicity Effected?–– Local/Regional ToxicityLocal/Regional Toxicity

»» SHORT TERM SHORT TERM vsvs LONG TERMLONG TERM–– Systemic ToxicitySystemic Toxicity

CHEMORADIOTHERAPY INCREASES LOCAL REGIONAL CONTROL BY INCREASING LOCAL-REGIONAL DOSE

INTENSITY

Calais Chemoradiotherapy Regimen: Calais Chemoradiotherapy Regimen: OropharynxOropharynx

1 2 3 4Weeks

Carboplatinum 70 mg/M2 /day x 4 days

QD RADIOTHERAPY200 cGy/ Fx

5-FU 600 mg/M2/days x 4 days

5 60 7

J Natl Cancer Inst. 1999;91:2081-2086.

Denis, F et al. JCO. 2004.

Calais Chemoradiotherapy Study:Calais Chemoradiotherapy Study:5 Year Survival 5 Year Survival

•• Conclusions:Conclusions:

−− Borderline statistically Borderline statistically significant (p = .05) better significant (p = .05) better overall survival with CRT overall survival with CRT (22% (22% vsvs 16%)16%)

−− Absolute 6% ImprovementAbsolute 6% Improvement

−− Better LRC (48% Better LRC (48% vsvs 25%), 25%), No Change in DM (20%)No Change in DM (20%)

−− CRT is Better then XRT CRT is Better then XRT alone for Oropharynx alone for Oropharynx CancerCancer

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60 66 72

SUR

VIVA

L (%

)

MONTHS

CRT

XRT

A Phase III Trial of Chemoradiotherapy and A Phase III Trial of Chemoradiotherapy and Concomitant Boost Radiotherapy in Locally Advanced Concomitant Boost Radiotherapy in Locally Advanced

SCCHN of the Oropharynx and HypopharynxSCCHN of the Oropharynx and Hypopharynx

RANDOMIZE

A

F

B

Staar , IJROBP, 2001; 50: 1161-1171

C

Concomitant Boost XRT

70 cGy

Carboplatinum 70 mg/M2/day x 5 days

5-FU 600 mg/M2/day x 5 days

Concomitant Boost XRT

70 cGy

A Phase III Trial of Chemoradiotherapy and A Phase III Trial of Chemoradiotherapy and Concomitant Boost RadiotherapyConcomitant Boost Radiotherapy

Boost Boost --XRTXRT CFCF--XRTXRTPatientsPatients 127127 113113T4T4 102 (80%)102 (80%) 91 (82%)91 (82%)N2 + N3N2 + N3 109 (85%) 109 (85%) 93 (82%)93 (82%)55--Year SurvivalYear Survival

OropharynxOropharynx 13% 13% 26%26% p < .008p < .008HypopharynxHypopharynx 22%22% 22%22%

Distant MetastasesDistant Metastases 19% 21%19% 21%Mucositis Mucositis >> Grade 3Grade 3 52%52% 68%68% p < .01p < .01Esophageal StenosisEsophageal Stenosis 25%25% 50% 50% (Survivors at 2 years)(Survivors at 2 years)

Staar , IJROBP, 2001; 50: 1161-1171, Semrau, IJROBP, 2006,

INTINT--026: A Phase III Trial of Chemoradiotherapy in 026: A Phase III Trial of Chemoradiotherapy in Unresectable PatientsUnresectable Patients

RANDOMIZE

A

P

P

XRT

F

B

C

XRT

XRTSurgery

Adelstein, et al: JCO, 2003; 21:92-98

INT INT --026026 -- Survival OutcomesSurvival Outcomes

AA BB CCXRTXRT PP--XRTXRT PFPF--SCSC--XRTXRT

Evaluable PatientsEvaluable Patients 9595 8787 8989Disease Specific (3 yr)Disease Specific (3 yr) 34% 34% 56%56%** 42%42%Overall Survival (3 yr)Overall Survival (3 yr) 23%23% 37%37%** 27%27%MedianMedian SurvivalSurvival 12.6 Mo12.6 Mo 19.1 Mo19.1 Mo 13.8 Mo13.8 MoRate of DMRate of DM 18% (30%) 22% (18% (30%) 22% (51%51%) 19% (29%) ) 19% (29%)

““Feeding TubeFeeding Tube”” 40%40% 52% 52% 51%51%Toxic DeathToxic Death 2%2% 4%4% 2%2%NonNon--Cancer DeathCancer Death 11%11% 19%19% 15%15%

* Significant Difference A vs B Adelstein, et al: JCO, 2003; 21:92-98

RTOG 91RTOG 91--1111Phase III Trial of Larynx PreservationPhase III Trial of Larynx Preservation

RANDOMIZE

A

P

P

XRT

F

B

C

XRT

XRT Surgery

+/- Surgery

Forastiere, NEJM, 2003

Forastiere, ASCO, 2006

547 ptsSt III/IV glottic,

supraglottic intermed. stage

+/- Surgery

Forastiere. ASCO. 2006LFS=laryngectomy-free survival

LFSLFS Overall SurvivalOverall Survival

RTOG 91RTOG 91--1111Phase III Trial of Larynx PreservationPhase III Trial of Larynx Preservation

PFPF CRTCRT XRTXRTLFSLFS 44.6%44.6% 46.6%46.6% 33.9% p < .01133.9% p < .011LRCLRC 54.9%*54.9%* 68.8%*68.8%* 51% p < .001851% p < .0018DMDM 14.3%14.3% 13.2%13.2% 22.3% p = .0622.3% p = .06DFSDFS 38.6%*38.6%* 39%39% 27.3%* p < .001627.3%* p < .0016Survival 59.2% 54.6% 53.5%Survival 59.2% 54.6% 53.5%

RTOG 91RTOG 91--11:Phase III Trial of Larynx 11:Phase III Trial of Larynx Preservation: ASCOPreservation: ASCO-- 55--Year UpdateYear Update

1.1. PF was PF was EquivalentEquivalent to CRT for LFS to CRT for LFS 2.2. CRT had Better LRC Than PFCRT had Better LRC Than PF3.3. DFS Was Identical But Overall Survival DFS Was Identical But Overall Survival

Favored PFFavored PF4.4. Did Patients Fare Better With PF Because Did Patients Fare Better With PF Because

They Had Subtle Improvements in Function They Had Subtle Improvements in Function Forastiere, ASCO, 2006

PF PF vsvs Alternating Chemoradiotherapy for Alternating Chemoradiotherapy for Resectable Larynx/Hypopharynx: Resectable Larynx/Hypopharynx: EORTCEORTC 2495424954

* P 100 mg/M2 plus 5FU 1000 mg/M2 D1* P 100 mg/M2 plus 5FU 1000 mg/M2 D1--55** P 20 mg/M2 D1** P 20 mg/M2 D1--5 plus 5FU 200 mg/M2 D15 plus 5FU 200 mg/M2 D1--55

RANDOMIZE

IND

P**

XRT

FALT

XRT

P*F

Lefebvre, JNCI, 2009

Survival with a Functional LarynxSurvival with a Functional Larynx

(years)

0 2 4 6 8 10

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Arm160 224 105 64 28 12154 226 117 73 39 18

SequentialAlternating

Overall Logrank test: p=0.155Hazard ratio 0.85 CI (0.68, 1.06)

Lefebvre, JNCI, 2009

Adjuvant ChemoradiotherapyAdjuvant Chemoradiotherapy

RANDOMIZE

CisplatinCisplatin100 mg/m100 mg/m22 d 1, 22, 43d 1, 22, 43

XRTXRT

XRT

Cooper , NEJM, 2004; 350: 1937 Bernier, NEJM, 2004;350:1945

SURGERY

RTOG 95RTOG 95--0101459 patients459 patients

EORTC 22931EORTC 22931334 patients334 patients

EORTC (66 Gy over 6 EORTC (66 Gy over 6 ½½ wks)wks)RTOG (60RTOG (60--66 Gy over 666 Gy over 6--6 6 ½½ wks)wks)

PostPost--Operative ChemoradiotherapyOperative Chemoradiotherapy

INT TrialINT TrialCRTCRT RTRT

AliveAlive 50%50% 41%41%LRFLRF 16%16% 29% *29% *DMDM 20%20% 23%23%

DM/FDM/F 60%60% 45%45%

EORTC Trial**EORTC Trial**CRTCRT RTRT

AliveAlive 53%53% 40% *40% *LRFLRF 18%18% 31% *31% *DMDM 21%21% 25%25%SPTSPT 12%12% 13%13%DM/FDM/F 54%54% 45%45%

* P < .05

Cooper , NEJM, 2004; 350: 1937 Bernier, NEJM, 2004;350:1945

**PNI, LVI

RTOG 01RTOG 01--29: A Randomized Phase III Trial of 29: A Randomized Phase III Trial of Chemoradiotherapy With Two SchedulesChemoradiotherapy With Two Schedules

RANDOMIZE

P - 100 mg/M2

XRT

XRT

P - 100 mg/M2

Trial Completed Accrual in 6/05

The Rate of Stomach Tube Dependence in the Phase III is ~16% at The Rate of Stomach Tube Dependence in the Phase III is ~16% at 2 years (Ang, ASTRO, 2007) 2 years (Ang, ASTRO, 2007)

The Cetuximab/Radiotherapy Phase III TrialThe Cetuximab/Radiotherapy Phase III Trial

RANDOMIZE

ERB

XRT

XRT

Surgery

Surgery

Bonner, NEJM, 2006

QD, BID or ACB Allowed

Stratify byKarnofsky score:90-100 vs. 60-80Regional Nodes:Negative vs. PositiveTumor stage:AJCC T1-3 vs. T4RT fractionation:Concomitant boostvs. Once dailyvs. Twice daily

The Cetuximab/Radiotherapy Phase The Cetuximab/Radiotherapy Phase III TrialIII Trial

RadiotherapyRadiotherapy BioRadiotherapyBioRadiotherapyToxicityToxicityMucositisMucositis 52%52% 54%54%RashRash 18%18% 34%34%Infusion ReactionsInfusion Reactions NANA 14%14%Late Peg DependencyLate Peg Dependency 17%17% 19%19%

EfficacyEfficacy33--Yr SurvivalYr Survival 44%44% 55%55%33--Yr LRCYr LRC 34%34% 47%47%22-- Yr DMYr DM 17%17% 16%16%DM/LRFDM/LRF 24%24% 30%30%

Bonner, NEJM, 2006; Bonner, Palm Springs, 2007

Overall Survival By Treatment: Overall Survival By Treatment: Median FollowMedian Follow--up 60 Monthsup 60 Months

31

1.01.00.90.90.80.80.70.70.60.60.50.50.40.40.30.30.20.20.10.10.00.0

00 1010 2020 3030 4040 5050 6060 7070Month

Ove

rall

Surv

ival

Stratified Logrank p = 0.018, HR=0.73 (0.56-0.95)

Treatment Total Death Alive Median

Radiation AloneRadiation Alone 213213 130130 8383 29.329.3RT + CetuximabRT + Cetuximab 211211 110110 101101 49.049.0

Bonner, ASTRO, 2008

Forest Plot of the Hazard Ratios by PreForest Plot of the Hazard Ratios by Pre--Treatment Treatment Characteristics Characteristics ––FiveFive--year Median Followyear Median Follow--upup

32

Bonner, ASTRO, 2008

Improvement With Cetuximab

****

* NS* NS

INDUCTION CHEMOTHERAPYINDUCTION CHEMOTHERAPY

ConsCons–– Systemic Toxicity Acute and Systemic Toxicity Acute and

IncreasedIncreased–– Survival Improvement may be Survival Improvement may be

Site and Stage RelatedSite and Stage Related–– Increased Duration of Therapy, Increased Duration of Therapy,

Change in Tumor BiologyChange in Tumor Biology–– No Improvement in No Improvement in

Local/Regional Dose IntensityLocal/Regional Dose Intensity–– CisplatinumCisplatinum--Based PF Based PF waswas the the

Only Effective Chemotherapy Only Effective Chemotherapy RegimenRegimen

ProsPros–– High Dose Treatment, Systemic Exposure, High Dose Treatment, Systemic Exposure,

Transient ToxicityTransient Toxicity–– Improved Nutrition and PSImproved Nutrition and PS–– Reduced Tumor VolumeReduced Tumor Volume

»» Better Preparation for Definitive Radiotherapy Better Preparation for Definitive Radiotherapy and IMRT Planningand IMRT Planning

»» Improved FunctionImproved Function–– Established Efficacy in Resectable Disease Established Efficacy in Resectable Disease

and Organ Preservationand Organ Preservation–– Improved Survival Improved Survival –– Intermediate Assessment of Intermediate Assessment of

Response/PrognosisResponse/Prognosis»» Adjusted Intensity of PostAdjusted Intensity of Post--Induction TherapyInduction Therapy

CHEMORADIOTHERAPYCHEMORADIOTHERAPY

ProsPros–– Improved Local Regional Improved Local Regional

IntensityIntensity–– Shortened Treatment TimeShortened Treatment Time–– Efficacy in Unresectable Efficacy in Unresectable

DiseaseDisease–– Efficacy in Organ PreservationEfficacy in Organ Preservation–– Effective PostEffective Post--Operative Operative

TherapyTherapy

ConsCons–– Local Toxicity Increased Local Toxicity Increased

»» Long Term Toxicity Not Defined and Long Term Toxicity Not Defined and LateLate

Esophageal Stenosis, Swallowing Esophageal Stenosis, Swallowing ImpairedImpairedLate Mortality from Unrecognized Late Mortality from Unrecognized ToxicityToxicity

»» Acute Severe Systemic ToxicityAcute Severe Systemic Toxicity–– Systemic Chemotherapy ResistanceSystemic Chemotherapy Resistance–– No Acceptable StandardNo Acceptable Standard–– Assessment of Response/Prognosis Assessment of Response/Prognosis

CompromisedCompromised–– No Effect on Distant Metastases in No Effect on Distant Metastases in

Advanced DiseaseAdvanced Disease–– IMRT Planning DifficultIMRT Planning Difficult

TAX 323TAX 323-- TPF TPF vsvs PF Followed by RadiotherapyPF Followed by RadiotherapyA Phase III Study in Unresectable SCCHNA Phase III Study in Unresectable SCCHN

RANDOMIZE

P

P

F

F

Daily Radiotherapy

EUA

T

Surgery

TPF: Docetaxel 75D1 + Cisplatin 75D1 + 5-FU 750 CI- D1-5 Q 3 weeks x4 PF: Cisplatin 100 D1 + 5-FU 1000 CI-D1-5 Q 3 weeks x 4

Vermorken NEJM, 2007

TN Stage of PrimaryTN Stage of Primary

StageStage T1T1 T2T2 T3T3 T4T4 TotalTotal

N0N0 1 (<1)1 (<1) 12 (3)12 (3) 29 (8)29 (8) 42 (12)42 (12)

N1N1 4 (1)4 (1) 13 (4)13 (4) 39 (11)39 (11) 56 (16)56 (16)

N2N2 1 (<1)1 (<1) 13 (4)13 (4) 38 (11)38 (11) 153 (43)153 (43) 205 (57)205 (57)

N3N3 3 (1)3 (1) 7 (2)7 (2) 11 (3)11 (3) 31 (9)31 (9) 52 (15)52 (15)

TotalTotal 4 (1)4 (1) 25 (7)25 (7) 77* (22)77* (22) 252 (70)252 (70) 358358* 3 patients were T3Nx

Vermoken, NEJM, 2007

TAX323 : SURVIVAL UPDATETAX323 : SURVIVAL UPDATE

Survival Time (months)

Sur

viva

l Pro

babi

lity

(%)

0 6 12 18 24 30 36 42 48 54 60 66 72

0

10

20

30

40

50

60

70

80

90

100

TPF (n=177)

PF (n=181)

Number of patients at riskTPF: PF:

177 163 127 91 74 64 60 43 26 16 7181 150 98 77 57 47 39 33 25 15 8 4

Log-Rank P = 0.0052 Hazard Ratio = 0.71

Vermorken, NEJM, 2007

Severe Adverse Events: ChemotherapySevere Adverse Events: ChemotherapyToxicity in PF (n=179) TPF (n=174)> 3% of pts N (%) N (%) Alopecia 0 20 (11.5)Stomatitis / oral 20 (11.2) 8 (4.6)Infection 13 (7.3) 15 (8.6)Nausea 13 (7.3) 1 (0.6)Vomiting 9 (5.0) 1 (0.6)Diarrhea 8 (4.5) 5 (2.9)Dyspnea 8 (4.5) 6 (3.4)Dysphagia 5 (2.8) 6 (3.4)Pain 7 (3.9) 11 (6.3)Death 12 (6.6) 6 (3.4)

Vermorken, NEJM, 2007

Can TPF Can TPF ImproveImprove OverallOverall SurvivalSurvival??

Zorat JNCI 2004

0.5

0.0

1.0

12010896847260483624120

Log-Rank = 4.04 ; p = .04

PF

RT

2013

11

469

An Analysis of Failure in Phase II An Analysis of Failure in Phase II TPF Induction Trials*TPF Induction Trials*

Trials:Trials: TPF, TPFL5, TPFL4, opTPF, TPFL5, TPFL4, op--TPFLTPFLEntered:Entered: 84* 84* Local/Regional Failure:Local/Regional Failure: 26 (31%)26 (31%)Local/Regional and DMLocal/Regional and DM 5 (6%)5 (6%)DM onlyDM only 00

*Excludes 17 Patients with NPC

Three Cycles of Induction Three Cycles of Induction TherapyTherapy Followed by:Followed by:BID RadiotherapyBID Radiotherapy

Haddad, Cancer, 2003

An Analysis of Failure in Phase III An Analysis of Failure in Phase III Chemoradiotherapy Trials*Chemoradiotherapy Trials*

Trials:Trials: INT EORTC RTOG GORTEC BonnerINT EORTC RTOG GORTEC BonnerLRFLRF 22% 18% 16% 57%22% 18% 16% 57% 53%53%DMDM 23% 21% 20% 18% 17%23% 21% 20% 18% 17%DM % of Failure DM % of Failure 51% 54% 65% 32% 30%51% 54% 65% 32% 30%RegimenRegimen BPBP BPBP BPBP CF ErbituxCF Erbitux

The Rate of DM Was The Rate of DM Was NotNot Generally Significantly Reduced by CRT*Generally Significantly Reduced by CRT*

*Larynx Trial 91-11 Came Close Adelstein, JCO, 2003; Bernier, NEJM, 2005; Cooper, NEJM, 2005; Denis, JCO, 2005; Bonner, NEJM, 2006

Sequential Therapy for Head and Neck Cancer:Sequential Therapy for Head and Neck Cancer:

Induction ChemotherapyInduction Chemotherapy

ChemoradiotherapyChemoradiotherapy

SurgerySurgery

Sequential Combined Modality TherapySequential Combined Modality TherapyA Phase III Study: TAX 324A Phase III Study: TAX 324

TPF TPF vsvs PF Followed by ChemoradiotherapyPF Followed by Chemoradiotherapy

RANDOMIZE

P

P

F

F

Carboplatinum - AUC 1.5 Weekly

Daily Radiotherapy

EUA

T

Surgery

TPF: Docetaxel 75D1 + Cisplatin 100D1 + 5-FU 1000 CI- D1-4 Q 3 weeks x3 PF: Cisplatin 100 D1 + 5-FU 1000 CI-D1-5 Q 3 weeks x 3

Posner, NEJM, 2007

TAX324: Patients Characteristics (ITT)TAX324: Patients Characteristics (ITT)TPF (N=255)TPF (N=255) PF (N=246)PF (N=246)

Age (years): Median (Range)Age (years): Median (Range)≥≥ 65 years65 years

55 (38 to 82)55 (38 to 82)34 (13%)34 (13%)

56 (33 to 80)56 (33 to 80)36 (15%)36 (15%)

Gender MaleGender Male 215 (84%)215 (84%) 204 (83%)204 (83%)

PS (WHO) 0PS (WHO) 011

142 (56%)142 (56%)113 (44%)113 (44%)

126 (51%)126 (51%)117 (48%)117 (48%)

Anatomic site OropharynxAnatomic site OropharynxLarynxLarynxHypopharynxHypopharynxOral cavityOral cavity

132 (52%)132 (52%)48 (19%)48 (19%)42 (17%)42 (17%)33 (13%)33 (13%)

131 (53%)131 (53%)42 (17%)42 (17%)34 (14%)34 (14%)38 (15%)38 (15%)

Clinical Stage IIIClinical Stage IIIIVIV

41 (16%)41 (16%)214 (84%)214 (84%)

46 (18%)46 (18%)199 (81%)199 (81%)

Reason InoperabilityReason InoperabilityTechnical UnresectabilityTechnical UnresectabilityLow Surgical CurabilityLow Surgical CurabilityOrgan PreservationOrgan Preservation

92 (36%)92 (36%)78 (31%)78 (31%)85 (33%)85 (33%)

84 (34%)84 (34%)75 (31%)75 (31%)87 (35%)87 (35%)

Survival Time (months)

Surv

ival

Pro

babi

lity

(%)

0 6 12 18 24 30 36 42 48 54 60 66 72

0

10

20

30

40

50

60

70

80

90

100

TPF (n=255)

PF (n=246)

Number of patients at riskTPF: PF:

255 234 196 176 163 136 105 72 52 45 37 20 11246 223 169 146 130 107 85 57 36 32 28 10 7

TAX324 : SurvivalTAX324 : Survival

TPF 62%

PF 48%

Log-Rank P = 0.0058 Hazard Ratio = 0.70

TPF 67%

PF 54%

TAX324: Toxicity During ChemotherapyTAX324: Toxicity During Chemotherapy

Number of PatientsNumber of Patients TPF (N=251)TPF (N=251) PF (N=243)PF (N=243)

NCICNCIC--CTG ClassificationCTG Classification Grade 3/4Grade 3/4 Grade 3/4Grade 3/4Any EventAny Event 65%65% 62%62%StomatitisStomatitisNauseaNauseaLethargyLethargyVomitingVomitingDiarrheaDiarrheaAnorexiaAnorexiaDeaths within 30 daysDeaths within 30 days

NonNon--Tumor RelatedTumor Related

21%21%14% 14% 5% 5% 8%8%7%7%

12% 12% 1.6%1.6%

27%27%14% 14% 10% 10% 10%10%3%3%

12%12%4.5%4.5%

TAX 324: Delays During Induction TAX 324: Delays During Induction ChemotherapyChemotherapy

TPF TPF --251251 PFPF--243243 All All --494494

Treatment Delay*Treatment Delay* 73 (29%)73 (29%) 157 (65%)157 (65%) 230 (47%)230 (47%)

HematologicHematologic 11 (4%)11 (4%) 108 (44%)108 (44%) 119 ( (24%)119 ( (24%)

NeutropeniaNeutropenia 2 (1%)2 (1%) 95 (39%)95 (39%) 97 (20%)97 (20%)

NonNon--HematologicHematologic 25 (10%)25 (10%) 22 (9.1%)22 (9.1%) 47 (10%)47 (10%)

Other** Other** 38 (15%)38 (15%) 40 (17%)40 (17%) 78 (16%)78 (16%)

** Logistic, Personal, Vacation *P < .0001

TAX 324: Analysis of FailureTAX 324: Analysis of FailureTPF TPF --251251 PF PF --243243 All All --494494

Total Failures/TreatedTotal Failures/Treated## 88 (35%)88 (35%) 110 (45%)110 (45%) 198 (40%)198 (40%)LRF*LRF* 77 (31%)77 (31%) 93 (38%)93 (38%) 170 (34%)170 (34%)PrimaryPrimary 43 (17%)43 (17%) 49 (20%)49 (20%) 92 (19%)92 (19%)

NeckNeck 22 (9%)22 (9%) 33 (14%)33 (14%) 55 (11%)55 (11%)BothBoth 12 (5%)12 (5%) 11 (5%)11 (5%) 23 (5%)23 (5%)

Distant Metastases**Distant Metastases** 14 (5%)14 (5%) 21 (9%)21 (9%) 35 (7%)35 (7%)Distant OnlyDistant Only 11 (4%)11 (4%) 17 (7%)17 (7%) 28 (6%)28 (6%)

Distant and LRFDistant and LRF 3 (1%)3 (1%) 4 (2%)4 (2%) 7 (1%)7 (1%)

Second PrimariesSecond Primaries 9 (4%)9 (4%) 7 (3%)7 (3%) 16 (3%)16 (3%)

# # Hazard Ratio .70 (0.53Hazard Ratio .70 (0.53--0.920.92)), P = .01 , P = .01 *Hazard Ratio 0.73 (0.54*Hazard Ratio 0.73 (0.54--0.99), P = .030.99), P = .03**Hazard Ratio 0.60 (0.30**Hazard Ratio 0.60 (0.30--1.18), P = .181.18), P = .18

GORTEC Phase III Trial of TPF GORTEC Phase III Trial of TPF vsvs PF Followed by PF Followed by Radiotherapy for Radiotherapy for Organ PreservationOrgan Preservation in in

ResectableResectable Larynx and Hypopharynx CancerLarynx and Hypopharynx Cancer

RANDOMIZE

P

P

F

F Daily Radiotherapy: STD or ACB

Response

T

TPF: Docetaxel 75D1 + Cisplatin 75D1 + 5-FU 750 CI- D1-5 Q 3 weeks x 3 PF: Cisplatin 100 D1 + 5-FU 1000 CI-D1-5 Q 3 weeks x 3

Calais, ASCO, 2006

Surgery

No Response

TPF (n=108)PF (n=112)

P (Log-rank test) = 0.036

0 6 12 18 24 30 36 420

20

40

60

80

100

Per

cent

(%)

Laryngectomy Free Survival (European Definition) (Months)

GORTEC Phase III Larynx Preservation Trial: GORTEC Phase III Larynx Preservation Trial: TPF TPF vsvs PF Induction Therapy for Operable PF Induction Therapy for Operable

Hypopharynx and LarynxHypopharynx and Larynx

Calais et al. ASCO, 2006. Oral Presentation.Calais et al. ASCO, 2006. Oral Presentation.LFS = Improved LRC

TPFTPF PFPF PPNumberNumber 9090 7676HypopharynxHypopharynx 43 (48%)43 (48%) 34 (45%)34 (45%)LarynxLarynx 47 (52%)47 (52%) 42 (55%)42 (55%)Median Age (Range)Median Age (Range) 56 (3956 (39--82)82) 59 (3759 (37--80)80) P=.21P=.21Operability UnresectableOperability Unresectable

Low CurabilityLow CurabilityPreservationPreservation

““OperableOperable””

23 (26%) 23 (26%) 22 (24%)22 (24%)45 (50%)45 (50%)67 (74%)67 (74%)

20 (26%)20 (26%)16 (21%)16 (21%)40 (53%)40 (53%)56 (74%)56 (74%)

P=.90P=.90

T Stage T1,T2 T Stage T1,T2 T3 T3 T4 T4

15 (17%)15 (17%)35 (39%)35 (39%)40 (44%)40 (44%)

17 (22%)17 (22%)33 (43%)33 (43%)26 (34%)26 (34%)

P=.37P=.37

Nodal Stage N0,N1 Nodal Stage N0,N1 N2 N2 N3 N3

43 (47%)43 (47%)35 (39%)35 (39%)12 (13%)12 (13%)

33 (46%)33 (46%)31 (40%)31 (40%)12 (15%)12 (15%)

P=.81P=.81

Clinical Stage III Clinical Stage III IV IV

22 (24%)22 (24%)68 (76%)68 (76%)

22 (29%)22 (29%)54 (71%)54 (71%)

P= .60P= .60

Characteristics of Hypopharynx and Characteristics of Hypopharynx and Larynx Cases Treated On TAX324Larynx Cases Treated On TAX324

TPFTPF PFPF PPNumberNumber 9090 7676 166166Overall SurvivalOverall Survival

Median, mo (range)Median, mo (range)2 Year2 Year3 Year3 YearHazard ratioHazard ratio

59 (3159 (31--NR) NR) 64% (5464% (54--74%)74%)57% (4657% (46--68%)68%)

24 (1324 (13--42)42)50% (3850% (38--61%)61%)40% (2940% (29--52%)52%)

0.62 (0.410.62 (0.41--0.94)0.94) .024.024PFS ( Equivalent to LFS)PFS ( Equivalent to LFS)

Median, mo (range)Median, mo (range)2 Year2 Year3 Year3 YearHazard ratioHazard ratio

21 (1221 (12--59)59)48% (3748% (37--58%)58%)43% (3243% (32--54%)54%)

11 (811 (8--14)14)33% (2233% (22--43%)43%)29% (1929% (19--40%)40%)

.66 (0.45.66 (0.45--0.97)0.97) .032.032

Larynx and Hypopharynx Survival Larynx and Hypopharynx Survival and Progression Free Survival and Progression Free Survival

Hazard Ratio 0.62 (0.41-0.94) P = .024

Larynx and Hypopharynx Overall SurvivalLarynx and Hypopharynx Overall Survival

TPFTPF PFPF PPNumberNumber 6767 5656 123123Overall SurvivalOverall Survival

Median MonthsMedian Months2 Year2 Year3 Year3 YearHazard RatioHazard Ratio

71 (3271 (32--NR) NR) 67% (5667% (56--79%)79%)58% (4658% (46--71%)71%)

27 (1827 (18--NR)NR)53% (4053% (40--66%)66%)47% (3447% (34--60%)60%)

0.67 (0.410.67 (0.41--1.11)1.11) P=0.12P=0.12PFS ( Equivalent to LFS)PFS ( Equivalent to LFS)

Median MonthsMedian Months2 Year2 Year3 Year3 YearHazard RatioHazard Ratio

21 (1221 (12--NR)NR)50% (3750% (37--62%)62%)48% (3548% (35--60%)60%)

12 (812 (8--15)15)34% (2134% (21--46%)46%)32% (1932% (19--44%)44%)

0.61 (0.3950.61 (0.395--0.96)0.96) P = .033P = .033

Results in Results in ““OperableOperable”” Hypopharynx Hypopharynx and Larynx Patients and Larynx Patients –– OS and PFSOS and PFS

TPFTPF PFPF PPNumberNumber 6767 5656 123123Overall LFSOverall LFS

Median MonthsMedian Months2 Year2 Year3 Year3 YearHazard RatioHazard Ratio

39 (1739 (17--NR) NR) 58% (4658% (46--70%)70%)52% (3952% (39--65%)65%)

18 (1018 (10--24)24)37% (2437% (24--50%)50%)32% (1932% (19--45%)45%)

0.59 (0.370.59 (0.37--0.95)0.95) P=0.03P=0.03

Results in Results in ““OperableOperable”” Hypopharynx Hypopharynx and Larynx Patients and Larynx Patients –– LFS*LFS*

*Alive *Alive –– No Primary Site SurgeryNo Primary Site Surgery

LFS in the Operable Patient PopulationLFS in the Operable Patient Population

Hazard Ratio 0.59 (0.37-0.95) P = .03

Experience With DocetaxelExperience With Docetaxel--Based Based InductionInduction in Locally Advanced SCCHNin Locally Advanced SCCHN

StudyStudy N (Criteria)N (Criteria) Primary Primary EndpointEndpoint RegimensRegimens ResultResult

Vermorken 2007 Vermorken 2007 (EORTC 24791/ (EORTC 24791/ TAX 323)TAX 323)

358 358 (Inoperable)(Inoperable)

PFSPFS PF PF →→RT RT vsvsTPF TPF →→RT RT

TPF led to TPF led to higher PFS and higher PFS and

OS (P <.01)OS (P <.01)Posner, 2007Posner, 2007(TAX 324)(TAX 324)

501 501 (Advanced)(Advanced)

OSOS PF PF →→CRT CRT vsvs

TPF TPF →→CRT CRT

TPF improved TPF improved OS at 3OS at 3--yearsyears

P (<.01)P (<.01)Calais 2006* Calais 2006* (GORTEC 2000(GORTEC 2000--01)01)

213 213 (Resectable)(Resectable)

LxPLxP PF PF vsvsTPF TPF

TPF led to TPF led to higher LxP, CRhigher LxP, CR

*Preliminary results.

All Trials Showed That TPF Had All Trials Showed That TPF Had Less Significant Toxicity Less Significant Toxicity No Effect On Ability To Undergo Sequential CRT Or RT No Effect On Ability To Undergo Sequential CRT Or RT

Improved Local Regional Control Improved Local Regional Control

Sequential Therapy: The DataSequential Therapy: The Data

Sequential Therapy with TPF is a Standard of Care for Locally Sequential Therapy with TPF is a Standard of Care for Locally Advanced SCCHN Advanced SCCHN –– It is FDA ApprovedIt is FDA ApprovedTPF and Sequential TPF Significantly Improve Survival and TPF and Sequential TPF Significantly Improve Survival and Organ Preservation Compared to PF Organ Preservation Compared to PF

EvidenceEvidence From Randomized Trials Supports CRT and PFFrom Randomized Trials Supports CRT and PF--Induction Chemotherapy as at Least Equivalent for Survival and Induction Chemotherapy as at Least Equivalent for Survival and SafetySafety–– There is Evidence Suggesting that PF Induction Chemotherapy MighThere is Evidence Suggesting that PF Induction Chemotherapy Might t

be Safer than CRTbe Safer than CRT–– There is Evidence Suggesting TPFThere is Evidence Suggesting TPF--Based Sequential Therapy Might be Based Sequential Therapy Might be

Better and Safer than CRT aloneBetter and Safer than CRT alone–– Phase III Trials Will Compare TPFPhase III Trials Will Compare TPF--Based Sequential Therapy to Based Sequential Therapy to

ChemoradiotherapyChemoradiotherapy

Forastiere, 2006; Taylor, 1996Forastiere, 2006; Taylor, 1996

*Vermorken, 2007:Posner, 2007; Calais, 2006*Vermorken, 2007:Posner, 2007; Calais, 2006

Induction PF Induction PF vsvs PFPF--CRT for CRT for Unresectable Head and Neck Cancer Unresectable Head and Neck Cancer

PFPF PFPF--CRTCRTTotal TreatedTotal Treated 100100 9494Dead of DiseaseDead of Disease 5959 4444Died on TherapyDied on Therapy 66 1111Died of Toxicity*Died of Toxicity* 77 1515Total AliveTotal Alive 28 (28%)28 (28%) 24 (26%) 24 (26%)

*Pulmonary, Bleeding*Pulmonary, BleedingTaylor, JCO, 1996

PFPF--Based Concurrent CRT:Based Concurrent CRT:Duke Randomized Phase II PaliferminDuke Randomized Phase II Palifermin

PaliferminPalifermin Control Control TotalTotalNumber EnteredNumber Entered 6969 3232 101101Discontinued NonDiscontinued Non--ToxicToxic 1111 22 1313TreatedTreated 5858 3030 8888DeathsDeaths (20 wk Study Period) 4 (7%) 2 (7%)(20 wk Study Period) 4 (7%) 2 (7%) 6(7%)6(7%)ITT (%) ITT (%) (6%)(6%) (6%)(6%) (6%)(6%)

CisplatinCisplatin

RADIOTHERAPYRADIOTHERAPYQD or BIDQD or BID

++ PaliferminPalifermin

55--FUFU

Brizel, JCO, 2008

Induction Chemotherapy, Sequential Therapy Induction Chemotherapy, Sequential Therapy and Chemoradiotherapy and Chemoradiotherapy –– LogicLogic and Bioand BioLogicLogic

PFPF--Based Induction Chemotherapy and Chemoradiotherapy Based Induction Chemotherapy and Chemoradiotherapy SignificantlySignificantly Improve Survival and Organ Preservation Improve Survival and Organ Preservation Compared to Radiotherapy +/Compared to Radiotherapy +/-- SurgerySurgeryPFPF--Based Induction Chemotherapy and Chemoradiotherapy Based Induction Chemotherapy and Chemoradiotherapy are are EquivalentEquivalent for Survival and Organ Preservation (LFS)*for Survival and Organ Preservation (LFS)*TPFTPF--Based Induction Chemotherapy is Based Induction Chemotherapy is SignificantlySignificantly Better Better than PF for Survival and Organ Preservation (LFS)than PF for Survival and Organ Preservation (LFS)TPFTPF--Based Induction Chemotherapy Might be Better Based Induction Chemotherapy Might be Better ththananChemoradiotherapy for Survival and Organ PreservationChemoradiotherapy for Survival and Organ Preservation

*Taylor, 1996; Forastiere, 2006; Lefebvre, 2007

Sequential Therapy: The FutureSequential Therapy: The Future

Sequential Therapy with TPF and CRT is a Standard of Care for Sequential Therapy with TPF and CRT is a Standard of Care for Locally Advanced SCCHN in the USLocally Advanced SCCHN in the US–– Sequential Therapy With TPF is Tolerable and SafeSequential Therapy With TPF is Tolerable and Safe–– Sequential Therapy Makes Biological Sense and is Highly EffectivSequential Therapy Makes Biological Sense and is Highly Effective e –– Phase III Trials Will Compare TPFPhase III Trials Will Compare TPF--Based Sequential Therapy to Based Sequential Therapy to

ChemoradiotherapyChemoradiotherapy

TPFTPF--Based Sequential Therapy is Platform For Exploiting New Based Sequential Therapy is Platform For Exploiting New Targeted TherapiesTargeted Therapies–– Improving Induction Chemotherapy and ChemoradiotherapyImproving Induction Chemotherapy and Chemoradiotherapy–– Reducing Morbidity and MortalityReducing Morbidity and Mortality

Sequential Therapy: The FutureSequential Therapy: The Future

Induction ChemotherapyInduction Chemotherapy–– High Response Rates, Organ Preservation, Improved Survival, SystHigh Response Rates, Organ Preservation, Improved Survival, Systemic emic

TreatmentTreatment–– Reduced Tumor Volume, Better IMRT Planning, Improved FunctionReduced Tumor Volume, Better IMRT Planning, Improved Function–– An Intermediate Assessment of ResponseAn Intermediate Assessment of Response

ChemoradiotherapyChemoradiotherapy–– RiskRisk--Based Based -- Response to Induction Therapy/ Potential Response to Induction Therapy/ Potential

Toxicity/Prognostic Factors/Planned SurgeryToxicity/Prognostic Factors/Planned Surgery–– Increased/Decreased Dose Intensity, New Biologics, Improved IMRTIncreased/Decreased Dose Intensity, New Biologics, Improved IMRT

PlanningPlanningSurgerySurgery–– Remove Areas of Initial Bulk DiseaseRemove Areas of Initial Bulk Disease–– Preserve Primary SitePreserve Primary Site

Sequential Combined Modality TherapySequential Combined Modality TherapyA Phase III Study: TPF A Phase III Study: TPF vsvs PF Followed by PF Followed by

ChemoradiotherapyChemoradiotherapy vsvs CRTCRT

RANDOMIZE

P

P

F

F

Cisplatinum 100 mg/M2

Daily Radiotherapy

T

Salvage Surgery

TPF: Taxotere 75D1 + Cisplatin 75D1 + 5-FU 750 CI-D1-5 Q 3 weeks x3 PF: Cisplatin 100 D1 + 5-FU 1000 CI-D1-5 Q 3 weeks x 3

CRT: Cisplatin 100 D1,22,42; Hitt et al, ASCO, 2006

HearHear No InductionNo Induction

SeeSee No InductionNo Induction

SpeakSpeak No InductionNo Induction

HearHear About The Data About The Data

ThinkThink About The DataAbout The Data

SpeakSpeak About The DataAbout The Data

Evaluate the Data:Evaluate the Data:Form Your Own Form Your Own

OpinionOpinion

Question

Group ACetuximab 400 mg/m2 initial dose

then 250 mg/m2 weekly +EITHER carboplatin (AUC 5, d1) OR cisplatin (100 mg/m2 IV, d1)+ 5-FU (1000 mg/m2 IV, d1-4):

3-week cycles

Group BEITHER carboplatin (AUC 5, d1) OR cisplatin (100 mg/m2 IV, d1) + 5-FU (1000 mg/m2 IV, d1-4):

3-week cycles

No treatmentCetuximab

Randomized

Progressive disease or unacceptable toxicity

6 chemotherapy cycles maximum

The EXTREME TrialThe EXTREME Trial

Patients at Risk Survival Time [Months]CTX onlyCET + CTX

220 173 127 83 65 47 19 8 1222 184 153 118 82 57 30 15 3

HR (95%CI): 0.797 (0.644, 0.986)Strat. log-rank test: 0.0362

Overall SurvivalCTX onlyCET + CTX

Sur

viva

l Pro

babi

lity

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18 21 24

|| |

| |

| |

||| | || ||| || |||| | | |||| | | | | ||| | | | | | | ||

| |

| |

|

|

|

||

||| | | |||| ||| ||| || | | || | | || | ||| | | | | ||| | | ||| | |

10.1 momo

7.4 mo

~10%~10%

Induction Chemotherapy: Weekly Paclitaxel, Induction Chemotherapy: Weekly Paclitaxel, Carboplatin, and Cetuximab Carboplatin, and Cetuximab –– PCPC22

CarboplatinCarboplatin

Taxol Taxol

C225 C225

WEEKLY CHEMOTHERAPY:WEEKLY CHEMOTHERAPY:C225 400mg/m2 wk1 C225 400mg/m2 wk1 -- 250mg/m2 wk 2250mg/m2 wk 2--66

Paclitaxel 135 mg/m2 wk 1Paclitaxel 135 mg/m2 wk 1--66Carboplatin AUC 2.0 wk 1Carboplatin AUC 2.0 wk 1--66

Early Stage Early Stage –– RadiotherapyRadiotherapy

Advanced Stage Advanced Stage –– ChemoradiotherapyChemoradiotherapy

PRIMARY END POINT: PRIMARY END POINT:

Safety, Tolerability, Response Safety, Tolerability, Response

Kies et al, ASCO, 2006

The DFCI The DFCI TPFTPF--EE Phase I Trial:Phase I Trial:Sequential Therapy with Erbitux Sequential Therapy with Erbitux

P

F

PlatinumPlatinum--based based ChemoradiotherapyChemoradiotherapy

3 Cycles of 3 Cycles of ChemotherapyChemotherapy

T

E Primary End Points: MTD of 5Primary End Points: MTD of 5--FU, SafetyFU, SafetySecondary End Points: Response Rate, PFSSecondary End Points: Response Rate, PFS

Taxotere 75 mg/MTaxotere 75 mg/M22; Cisplatin 100 mg/M; Cisplatin 100 mg/M22; 5; 5--FU 700FU 700--1000 mg/M1000 mg/M22/day for 4 days/day for 4 days

Erbitux 400/250 mg/MErbitux 400/250 mg/M22 weeklyweekly

RTOG 0522: A Randomized Phase III Trial of RTOG 0522: A Randomized Phase III Trial of ACB Chemoradiotherapy With or Without ACB Chemoradiotherapy With or Without

CetuximabCetuximab

RANDOMIZE

P - 100 mg/M2

XRT

XRT

C225 400/250 mg

P - 100 mg/M2

Stratify: XRT as Standardor IMRT on DAHANCA

A Growing EpidemicA Growing EpidemicA Therapeutic TargetA Therapeutic Target

Human PapillomavirusHuman Papillomavirusand Oropharyngeal Cancer:and Oropharyngeal Cancer:

A Major Prognostic FactorA Major Prognostic Factor

Oropharynx Cancer and HPVOropharynx Cancer and HPV--20092009New Population At RiskNew Population At Risk–– Increasing NumbersIncreasing Numbers

»» 2525--50% Of New Cases50% Of New CasesOropharynx Oropharynx –– Base of Tongue and Tonsil, Unknown PrimaryBase of Tongue and Tonsil, Unknown PrimaryAdvanced Stage At DiagnosisAdvanced Stage At Diagnosis

–– Sexually TransmittedSexually Transmitted»» Younger, Less Alcohol, Less Tobacco, Both SexesYounger, Less Alcohol, Less Tobacco, Both Sexes

–– Vaccine Available Vaccine Available –– Preventive not TherapeuticPreventive not Therapeutic»» HPV 16, 18, 31, 33HPV 16, 18, 31, 33

–– Different Prognosis Different Prognosis (Responsive (Responsive vsvs Aggressive)Aggressive)»» More Responsive To Radiotherapy?, Chemotherapy?More Responsive To Radiotherapy?, Chemotherapy?»» Aggressive Behavior Aggressive Behavior –– High Rate of Distant High Rate of Distant

Metastases in Locally Advanced Disease Metastases in Locally Advanced Disease

HPV and Tonsillar Cancer HPV and Tonsillar Cancer –– Tonsillar Cancer Tonsillar Cancer Sweden and StockholmSweden and Stockholm

0

0,5

1

1,5

2

2,5

3

1970-1979 1980-1989 1990-1999 2000-2002Calender years

Inci

denc

e ra

te (1

/100

000

)

Men Women

2.8 Fold Increase2.8 Fold Increase2.0 Fold Increase2.0 Fold IncreaseDahlstrand ASCO, 2008Dahlstrand ASCO, 2008

Sexual Behaviors And Head And Sexual Behaviors And Head And Neck CancerNeck Cancer

BehaviorBehaviorDiagnosis Of Diagnosis Of HPVHPV--HNSCCHNSCC(Case(Case--case)case)

Risk Of Risk Of HPVHPV--HNSCC HNSCC

(Case(Case--control)control)Number Of Sexual PartnersNumber Of Sexual Partners ++ ++History Of OralHistory Of Oral--Genital SexGenital Sex ++ ++History Of Anal CancerHistory Of Anal Cancer ++ ++Spouse With Tonsil CancerSpouse With Tonsil Cancer ++ ++Cervical CIS or Cancer Cervical CIS or Cancer AssocAssoc AssocAssoc

Ritchie Int J Cancer 2003; Smith EM Int J Cancer 2004; Herrero R JNCI 2003; Rajkumar Eur J Cancer Prev 2003, D’Souza, NEJM, 2007, Hemminiki. IJC 2001

Sequential Therapy forSequential Therapy forLocally Advanced Oropharynx and Larynx Cancer Locally Advanced Oropharynx and Larynx Cancer

ECOG 2399ECOG 2399

Taxol Taxol Weekly Weekly

Cmelak, JCO, 2007

Taxol Taxol Carboplatin Carboplatin

Daily Daily Radiotherapy Radiotherapy

ECOG 2399: HPV ResultsECOG 2399: HPV Results

HPV +*HPV +* HPV HPV --

OPOP 3838 2424

LarynxLarynx 00 3434

TotalTotal 38 (40%)38 (40%) 58 (60%)58 (60%)

* Determined by in situ hybridization for HPV serotype 16, 31, 33, 35

60% of OP Cases Are HPV+ and Almost all are HPV 1660% of OP Cases Are HPV+ and Almost all are HPV 16Cmelak, JCO, 2007

Oropharynx Tumor HPV Status And Oropharynx Tumor HPV Status And SurvivalSurvival

Time in Months

Prob

abili

ty

0 10 20 30 40 50 60

0.0

0.2

0.4

0.6

0.8

1.0

NegativePositive

Log-rank test, p=0.004

Two-year Overall Survival

Fakhry, JNCI, 2008

ECOG 2399: HPV ResultsECOG 2399: HPV Results

HPV +HPV + HPV HPV --

NumberNumber 3838 2424

ProgressionProgressionLRFLRFDMDM

5 (13%)5 (13%)2 (5%)2 (5%)3 (8%)*3 (8%)*

9 (38%)9 (38%)8 (33%)8 (33%)1 (4%)*1 (4%)*

DeathsDeaths 7 (18%)7 (18%) 12 (50%)12 (50%)

Fakhry, JNCI, 2008

* 60% and 11% of Failures, Respectively* 60% and 11% of Failures, Respectively

Oropharynx Cancer and HPVOropharynx Cancer and HPV--20092009How Do We Treat HPV+ Oropharynx CancerHow Do We Treat HPV+ Oropharynx Cancer

HPV has Significant Prognostic Value HPV has Significant Prognostic Value –– HPV+ Oropharynx Cancer is More Responsive to TreatmentHPV+ Oropharynx Cancer is More Responsive to Treatment

»» Is HPV+ Oropharynx Cancer Less Aggressive?Is HPV+ Oropharynx Cancer Less Aggressive?–– In ECOG 2399 Survival in the HPV+ Population is >80%In ECOG 2399 Survival in the HPV+ Population is >80%

»» Early Follow upEarly Follow up»» Aggressive Sequential Therapy Aggressive Sequential Therapy »» Better PS, Age, CoBetter PS, Age, Co--MorbiditiesMorbidities

–– Retrospective/Prospective Analysis of Phase III Trials is OngoinRetrospective/Prospective Analysis of Phase III Trials is Ongoingg»» RTOG 01RTOG 01--29, Tax 324, RTOG 0529, Tax 324, RTOG 05--2222

Do Not Change Practice Yet!Do Not Change Practice Yet!–– Treat HPV Positive Oropharynx Cancer As You HaveTreat HPV Positive Oropharynx Cancer As You Have

»» Are We Happy With 80% Survival?Are We Happy With 80% Survival?»» Where Do People Fail?Where Do People Fail?»» What Can We Reduce What Can We Reduce –– Chemotherapy, Radiotherapy?Chemotherapy, Radiotherapy?

Head and Neck Cancer and HPVHead and Neck Cancer and HPVTough Questions Will Be Addressed To Tough Questions Will Be Addressed To CliniciansClinicians–– PatientPatient

»» Am I At Risk For A Second CancerAm I At Risk For A Second Cancer»» How Long Have I Had ThisHow Long Have I Had This»» How Did I Get ItHow Did I Get It

–– SpouseSpouse»» Should I Get VaccinatedShould I Get Vaccinated»» Do I Need SurveillanceDo I Need Surveillance»» What Is My RiskWhat Is My Risk

–– ChildrenChildren»» Are They At Risk?Are They At Risk?

Oropharynx Cancer and HPVOropharynx Cancer and HPV--20092009A Major Opportunity for Specific TherapyA Major Opportunity for Specific Therapy

HPVHPV is a Specific Tumor Target is a Specific Tumor Target –– E6 and E7 Viral Oncogenes Necessary for Tumor Cell SurvivalE6 and E7 Viral Oncogenes Necessary for Tumor Cell Survival–– Foreign Antigen or Genetic TargetForeign Antigen or Genetic Target–– Only Present in Infected CellsOnly Present in Infected Cells

This Disease Could be the Poster Child for Targeted This Disease Could be the Poster Child for Targeted Therapy and ImmunotherapyTherapy and Immunotherapy–– Prevention Prevention –– Risk Identification/VaccineRisk Identification/Vaccine–– Treatment Treatment –– Advanced/Incurable; New Diagnosis, AdjuvantAdvanced/Incurable; New Diagnosis, Adjuvant–– Targeting E6 and E7 Targeting E6 and E7 –– Necessary for Tumor Cell SurvivalNecessary for Tumor Cell Survival

»» Therapeutic Vaccines, siRNA, SMIs, AntiTherapeutic Vaccines, siRNA, SMIs, Anti--SenseSenseScientific OpportunitiesScientific Opportunities–– Pathogenesis, LatencyPathogenesis, Latency–– Susceptibility, Immunity, ImmunosuppressionSusceptibility, Immunity, Immunosuppression

This Disease Should be a Major Priority for NCI FundingThis Disease Should be a Major Priority for NCI Funding–– More Cases Than Advanced MelanomaMore Cases Than Advanced Melanoma

Oropharynx Cancer and HPVOropharynx Cancer and HPV--20092009A Major Opportunity for Specific TherapyA Major Opportunity for Specific Therapy

HPV HPV Positive Oropharyngeal Cancer Positive Oropharyngeal Cancer

–– Is Preventable in the Next GenerationIs Preventable in the Next Generation»» Should We Vaccinate All Adolescents and Young Adults Should We Vaccinate All Adolescents and Young Adults

(20(20--40 yrs)?40 yrs)?

–– Should be Curable Without Chemotherapy or Should be Curable Without Chemotherapy or Radiotherapy Within the Next 5 YearsRadiotherapy Within the Next 5 Years

»» We Need Research FundingWe Need Research Funding

The Role of the Surgical Oncologist in The Role of the Surgical Oncologist in Head and Neck Cancer Head and Neck Cancer

For years: the only optionFor years: the only option……

“The most radical operation, done as soon as possible, to eradicate the last living cancer cell in the surgical

field…”

- Sir William HalstedJohns Hopkins University

Modern Treatment Paradigm in HNSCCModern Treatment Paradigm in HNSCC•Virology

•Proteomics

•Genomics

•Chemosensitivity

•Mutations

•Chemotherapy

•Biologic therapy

•Surgery

•Radiotherapy

•Combination

•Reassess Response

•Surrogate Markers

•Symptoms

•Continue

•Maintenance

•Switch therapies

Question