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
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
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