Squamous Cell H&N CancerSquamous Cell H&N CancerHypopharynxHypopharynx

Therapeutic ApproachTherapeutic Approach

Ricardo Hitt MD, PhDHospital Universitario 12 Octubre

MADRID

STATEMENTS 2008

Squamous Cell H&N CancerSquamous Cell H&N CancerHypopharynxHypopharynx

The majority of hypopharyngeal lesions The majority of hypopharyngeal lesions

originate in the pyriform sinus.originate in the pyriform sinus.

On admission, 75% of the patients haveOn admission, 75% of the patients have

clinically positive nodes.clinically positive nodes.

There is no difference in the risk of neckThere is no difference in the risk of neck

metastases by T stage.metastases by T stage.

HN surgeon

Decisionmaking

Medical oncologist

Treatment of Head and Neck CancerTreatment of Head and Neck CancerMultidisciplinaryMultidisciplinary

Radiation oncologist

Decisionmaking

CLINICAL TRIAL

STANDARD TREATMENT

Treatment of Head and Neck CancerTreatment of Head and Neck CancerMultidisciplinaryMultidisciplinary

HYPOPHARYNGEAL CANCERHYPOPHARYNGEAL CANCER

HEAD AND NECK CANCERHEAD AND NECK CANCER

OROPHARYNXOROPHARYNX

ORAL CAVITYORAL CAVITY

LARYNXLARYNX

HIPOPHARYNXHIPOPHARYNX

HYPOPHARYNGEALHYPOPHARYNGEAL CANCERCANCER

OBJECTIVES

CURE CURE

ORGAN PRESERVATIONORGAN PRESERVATION

QUALITY OF LIFEQUALITY OF LIFE

HYPOPHARYNGEALHYPOPHARYNGEAL CANCERCANCER

TODAY ,WITH MEDICAL TREATMENTTODAY ,WITH MEDICAL TREATMENT

ORGAN PRESERVATIONORGAN PRESERVATION OVERALL SURVIVALOVERALL SURVIVAL

NEW OBJECTIVENEW OBJECTIVE: Increase Overall Survival and Organ PreservationIncrease Overall Survival and Organ Preservation

HOW???

J. L. Lefebvre, D. Chevalier, B. Luboinski, L. Traissac, G. Andry, D. De Raucourt, L. Collette, J. Bernier, EORTC Head and Neck Cancer Cooperative Group.

F R A N C E

Is Laryngeal Preservation (LP) With Induction Chemotherapy (ICT) Safe in the Treatment of Hypopharyngeal SCC? Final Results of the Phase III EORTC 24891 Trial.

Last Update: ASCO 2004

STUDY DESIGN STUDY DESIGN

Surgery + RT

LP: PF + RT

RR

•Primary endpoint: OS (non-inferiority of LP)

•Secondary endpoints: PFS, larynx preservation

Lefebvre JL, et al. JNCI 1996; 88:890-8; Lefebvre JL, et al. ASCO 2004: Abstract 5531.

N = 94

N = 100

Cycle 1

PD*

CR*PR*NC*

Cycle 2

NC/PD*

CR*

PR* Cycle 3 CR*

PR/NC/PD*

RXT 70 Gy± salvage surgery

Surgery + Postoperative RXT

Surgery (No CT)(N=94) (%)

Larynx Preservation(N=100)(%)

Stage

Stage II

6 7

Stage III

54 59

Stage IV

39 34

Site of primary

Pyriform sinus

79 78

Aryepiglottic fold

21 22

PATIENT CHARACTERISTICSPATIENT CHARACTERISTICS

Lefebvre JL, et al. ASCO 2004: Abstract 5531.

Lefebvre JL, et al. ASCO 2004: Abstract 5531.

(years)0 2 4 6 8 10 12 14 16

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk :81 94 49 36 26 14 9 5 3

83100 62 47 27 17 8 4 1

Surgery

LP

Overall survivalOverall survival

Larynx preservation

HR: 0.88 (95% CI: 0.65 - 1.19) HR: 0.88 (95% CI: 0.65 - 1.19)

P=0.0015 for non-inferiority of LPP=0.0015 for non-inferiority of LP

Surgery

Median, 44 mo Median, 25

mo (years)

0 2 4 6 8 10 12 14 160

10

2030

40

5060

7080

90100

O N Number of patients at risk :88 94 37 25 16 6 5 1 088100 47 32 19 10 5 2 1

SurgeryPreservation

Disease-free survival

Larynx Larynx preservationpreservationSurger

y

Hazard Ratio: 0.83 (95% CI: 0.62-1.12)

Lefebvre JL, et al. ASCO 2004: Abstract 5531.

OVERALL SURVIVAL AND DFSOVERALL SURVIVAL AND DFS

Devita. 7th

Edition

SURVIVALSURVIVAL PHARYNGEAL SCCPHARYNGEAL SCC

Devita. 7th

Edition

SURVIVAL PHARYNGEAL SCCSURVIVAL PHARYNGEAL SCC

Historical standard treatment (80') for locallyadvanced squamous cell carcinoma of the headand neck (SCCHN)Surgery radiation (RT)Surgery radiation (RT)

Inoperable diseaseInoperable disease

Operable diseaseOperable disease

BackgroundBackground

RT (5 yr surv. 10%-20%)RT (5 yr surv. 10%-20%)

Concomitant CT/RT standard for inop. Pts (90’)(5yr surv. 20%- 30% )

35 previously untreated pts: 3 cycles cisplatin-5FU (CF)Response > 50%Response > 50%

94%

Complete responseComplete response

63%Decker D et al. ASCO Annual Meeting.Saint Louis 1982, Abstract C-757

Decker DA et al. Cancer 1983;51:1353-5

60 tumors treated with platinum-based chemotherapy

Ensley J et al. ASCO Annual Meeting.Saint Louis 1982, Abstract C-767

Ensley JF et al. Cancer 1984;54:811-4

42 responses > 50%42 responses > 50%

97%

after RT

18 responses < 50%18 responses < 50%

6%

after RT

ASCO 1982: The Platinum Revolution

Induction CT: high RR ( 70%-80%); RC (5% - 30%)

1- 4 cycles prior to RT

Subsequent RT or surgery not compromised

Not clear if local control increased

Response to induction CT predicts response to RT

Part of a larynx preservation strategy

Rationale for induction CT -1-Rationale for induction CT -1-

Induction CT reduces incidence of distant metastases

Patient selection crucial (dist .met. 30%-40%)

T bulky ; N (bilateral, high number, capsula rupture),Site (hypopharynx), other markers

From meta-analysis: induction with PF 5% incr. OS5yr P=0.01

2 individual studies showed survival benefit with PF(GSTTC ; GETTEC)

Rationale for induction CT -2-Rationale for induction CT -2-

Improved Complete Response Rate and Survival in Advanced Head and Neck Cancer After Three-Course Induction Therapy With 120-Hour 5-FU Infusion and Cisplatin

MICHAEL ROONEY, MD,.t JULIE KISH, MD,JOHN JACOBS, MD.( JEANNIE KINZIE, MD,ARTHUR WEAVER, MD., JOHN CRISSMAN. MD. AND MUHYl AL-SARRAF. MD

Cancer 55: 1 1 23- I 1 28. 1985.

MACH-NC Collaborative Group:Effect of Chemotherapy on 5-Year Survival

Monnerat C, et al. Ann Oncol. 2002;13:995. [Review]Pignon JP, et al. Lancet. 2000;355:949.

Meta-analyses of individual patient data from randomized trial thatrecruited patients from 1965 to 1993

PF induction conferred a 5% survival gain at 5-years

CRT conferred an 8% survival improvement at 5-years

CRT=chemoradiotherapy; PF=cisplatin+5-FU.

Trial Category No. of Trials No. of Pts Difference,

% p-Value

All 65 10850 +4 <0.0001

Adjuvant 8 1854 +1 0.74

Induction 31 5269 +2 0.10

PFPF 1515 24872487 +5+5 0.010.01Other chemotherapy 16 2782 0 0.91

Concomitant Concomitant CRTCRT 2626 37273727 +8+8 <0.000<0.000

11

SCCHNCSCCHNC

HOW CAN WE IMPROVE HOW CAN WE IMPROVE THESE RESULTS?THESE RESULTS?

Change the schedule Change the schedule of ICTof ICT

Change the approach Change the approach of treatmentof treatment

Induction CT + Locoregional RT

Remenar E, et al. ASCO 2006, abstract 5516. Bernier J, et al. ASCO 2006, abstract 5522.

Vermorken JB, et al. ASCO 2004, abstract 5508.

EORTC 24971/TAX 323 - Study Design

Neck Dissectio

nInoperablInoperable e

SCCHNSCCHNStage 3-4.Stage 3-4.

StratificatioStratification:n:

1º tumor 1º tumor sitesite

InstitutionInstitution

TPF arm (n=177) Docetaxel (75

mg/m²) Cisplatin (75

mg/m²) 5-FU (750

mg/m²/dx5)Q 3 weeks x 4 cycles

PF arm (n=181) Cisplatin (100

mg/m²) 5-FU (1000

mg/m²/dx5)Q 3 weeks x 4 cycles

Radiotherapy(~70 Gy over

7 weeks)Follow up

Surgery for

Residual Disease

Treatment arms were well balanced in baseline

characteristics

Primary Objective: PFS

Overall Survival

EORTC 24971/TAX 323

(months)0

0

10

20

30

40

50

60

70

80

90

100

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

Treatment

PFTPF

Remenar E, et al. ASCO 2006, abstract 5516. Bernier J, et al. ASCO 2006, abstract 5522.

Vermorken JB, et al. ASCO 2004, abstract 5508.

PF TPF

Median OS, mo 14.2 18.6

Hazard ratio (95% CI)

0.71 (0.56, 0.90)

P-value 0.0055

Induction CT CRT Surgery

Posner RM, et al. ASCO 2006, abstract SPS24.

TAX 324 - Study Design

Treatment arms were well balanced in baseline demographic

and disease characteristics

Primary Objective:Primary Objective: OS

Radiotherapy(70Gy d1-5)+ Weekly

Carboplatin(AUC 1.5 7)

Surgery is

needed

PF arm (n=246) Cisplatin (100

mg/m²/d1) 5-FU (1000 mg/m²/d

5) Q 3 weeks x 3 cycles

TPF arm (n=255) Docetaxel (75

mg/m²) Cisplatin (100

mg/m²d1) 5-FU (1000

mg/m²/d 4)Q 3 weeks x 3 cycles

N=538Stage III/IVStage III/IVEpidermoidEpidermoidcarcinoma,carcinoma,

no prior no prior surgery,surgery,

no no hospitalizationhospitalizationfor COPD for COPD 1y1y

Stratification:Stratification:• CenterCenter• N statusN status• Primary sitePrimary site

Posner RM, et al. ASCO 2006, abstract SPS24.

TAX 324 - Study Design

Primary Endpoint: Overall Survival

0 6 12 18 24 30 36 42 48 54 60 66 720

3-Year OSTPF 62%PF 48%

2-Year OSTPF 67%PF 54%

Survival Time (months)

Log-Rank p = .0058Hazard ratio = 0.70

TPF (n=255)

PF (n=246)

TPF significantly improvedoverall survival vs PF30% reduction in mortality

Su

rviv

al P

rob

ab

ilit

y (

%)

10

20

30

40

50

60

70

80

90

100

HNSCC: Taxotere in Locally-Advanced Disease

Posner et al. ASCO 2006.Remenaer et al., ASCO 2006

Overall Survival

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

50

0

10

20

30

40

60

70

80

90

100

TPFTPF

PFPF

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

TPFTPF

PFPF

Survival Time (months)

Su

rviv

al P

rob

ab

ilit

y (

%)

Survival Time (months)

TAX 32430% reduction in risk of death

TAX 32329% reduction in risk of

death

Hitt R, et al. ASCO 2006, abstract 5515.Hitt R, et al. ASCO 2006, abstract 5515.

Phase III Trial PF ± Docetaxel CRT vs CRT

Study Design

Primary endpoint phase III: TTF

SCHNNStage III, IV

(locally advanced)Unresectable

PF 3 cycles q 21

days Cisplatin Infusional 5-

FU

(N=440)

TPF 3 cycles q 21

days Docetaxel Cisplatin Infusional 5-

FU CRT

CRT

Phase III Trial PF ± Docetaxel Phase III Trial PF ± Docetaxel CRT vs CRT CRT vs CRT

RESPONSE RATE BY RESPONSE RATE BY ARMARM

TPF/CRTTPF/CRT CRTCRT

CRCR (complete response)(complete response) 70 %70 % 49.48 %49.48 %p = 0.0080p = 0.0080

EFFICACYEFFICACY

Hitt R, et al. ASCO 2006, abstract 5515.Hitt R, et al. ASCO 2006, abstract 5515.

Al Sarraf Cancer 1985

Does the Complete Response to Induction Chemotherapy/CRT have the same benefit in

survival ?

CHEMORADIOTHERAPYCHEMORADIOTHERAPYHNCHNC

STANDARD TREATMENTSTANDARD TREATMENT

OLD STANDARD

CRTCRT

GOLD STANDARD

ICT/CRTICT/CRT

CONCLUSIONS (1)CONCLUSIONS (1)

Hypopharyngeal SCC has a bad prognostic with conventional Hypopharyngeal SCC has a bad prognostic with conventional

treatmenttreatment

The objective of treatment can be : cure-quality of life The objective of treatment can be : cure-quality of life

For Medical Oncologist Hypopharyngeal Cancer= SCCHNFor Medical Oncologist Hypopharyngeal Cancer= SCCHN

To day is possible Larynx Preservation without damage OSTo day is possible Larynx Preservation without damage OS

Induction chemotherapy is feasible in a set of the patientsInduction chemotherapy is feasible in a set of the patients

Chemoradiotherapy can be a Radical TreatmentChemoradiotherapy can be a Radical Treatment

CONCLUSIONS (2)CONCLUSIONS (2)

When is possible: Salvage Surgery is recommended When is possible: Salvage Surgery is recommended

Now we have data about the superiority of TPF as ICTNow we have data about the superiority of TPF as ICT

Complete Response to TPF/CRT might be a parameter as overall Complete Response to TPF/CRT might be a parameter as overall

survival survival

Induction TPF plus CRT might be the next standardInduction TPF plus CRT might be the next standard

Selection of patients is the key for treatment selectionSelection of patients is the key for treatment selection

• RESECTABLE////UNRESECTABLE TUMORS RESECTABLE////UNRESECTABLE TUMORS