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New Aspects in Oropharyngeal Cancer
Jan B. Vermorken, MD, PhD
Antwerp University Hospital
Edegem, Belgium
Statements on Head and Neck Cancer
Saturday, February 2, 2008
Oropharynx Cancer: Introduction
• Head and neck squamous cell carcinoma is the sixth most common cancer worldwide, with more than 300.000 cases occuring in the oral cavity and pharynx every year
• Despite a decreasing occurrence of most tumors of the upper aerodigestive tract in developed countries ( smoking, drinking), the incidence of oropharyngeal squamous cell carcinoma is on the rise
New Findings in the Last Five Years
• The role of HPV as a risk factor for OC
• Novel therapeutic agents (anti-EGFR)
• Expanding role for chemotherapy
• Impact of altered fractionation schedules (RT)
• New imaging techniques (PET)
• Survivorship issues
Human Papillomavirusand Oropharyngeal
Cancer
Incidence Trends for SCCHN in the US
• SEER program registries, NCI
• Incidence and survival of SCCHN in US from 1973-2004
• 45.769 oral (oral cavity and oropharynx) SCC cases
• Classified as potentially HPV-related vs unrelated based on primary site
Courtesy of Dr. Gillison
Incidence Trends for SCCHN in the USStudy methods
• 9 Surveillance, Epidemiology, and End Results (SEER) program registries (1973-2003)
• Squamous cell cancers classified based on anatomic site
HPV-related cancers HPV-unrelated cancers Excluded cancers
Base of tongue Tongue Lip
Lingual and palatine tonsil Gum Nasopharynx
Oropharynx Floor of mouth Salivary gland
Waldeyer ring Palate Hypopharynx
Other/unspecified mouth Ill-defined sites
• Incidence increasing for HPV-related
• Incidence decreasing for HPV-unrelated
• Equalization in 2004
1975 1980 1985 1990 1995 2000 20040.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
9.0
10.0
Year of diagnosis
Age-a
dju
ste
d r
ate
per
100,0
00 p
ers
on-y
ears
HPV-R, APC1= 2.06*
HPV-R, APC2= -0.05HPV-R, APC3= 5.22*
HPV-U, APC1= 0.82 HPV-U, APC2= -1.85*
Incidence Trends in the US
ActuarialActuarial Life-table Estimates of Survival Life-table Estimates of Survival
Chaturvedi A et al, JCO. In press
Period Two-year survival
HPV-R vs. HPV-U
P-value
1973-1982 46.6 vs. 47.2% 0.71
1983-1992 56.0 vs. 49.6% <0.01
1993-2004 69.7 vs. 50.3% <0.01
Treatment of Locoregionally Advanced SCCHN
Historically: Surgery (+ RT) or RT aloneOutcomes poor for OS and OP
Currently there are three multimodality treatment approaches:
1. Surgery adjuvant concurrent CRT
2. Definitive concurrent CRT, with surgery as an optional salvage or completion treatment
3. Induction CT definitive local therapy
Seiwert et al, 2007; OS = overall survival; OP = organ preservation
MACH-NC: Results - Overall Survival
Chemotherapy Risk P Absolute benefit
timing reduction value at 5 years
Adjuvant 2% NS 1%
Neoadjuvant* 5% NS 2%
Concomitant 19% < 0.0001 8%
Total 10% < 0.0001 4%
* 15 studies with PF 5%
Pignon et al, 2000 (63 trials / 10.741 patients)
IGR, June 2004IGR, June 2004
Survival, concomitant trials by SiteMeta-Analysis of Chemotherapy
in Head & Neck Cancer
MACH-NC
17% + 5
23% + 4
22% + 6
16% + 6
-3% + 11
R R
KK
ShcPI3K
Shc
Grb2
Grb2 Ras
Sos
Sos
Raf
MEK1/2
Akt
MAPK
Cell cycleprogression
survival proliferation
PTEN
GSK-3mTOR FKHR
Bad
Cyclin D1
p27
0
20
40
60
80
100
0 20 40 60 80 100
% E
GF
R
% Activated MAPK
p=0.037
Activated MAPK
SCCHN, an EGFR-dependent tumor• SCCHN express high levels of EGFR and its ligands
• SCCHN have EGFR-dependent signaling pathways activated
• Activated EGFR confers worse outcome
Albanell. Cancer Res. 61: 6500-10., 2001
Prognostic significance of EGFR Expression in SCCHN
High levels of EGFR and TGF result in reduced disease-free and overall survival
EGFR TGF
Low
Medium
High
p=0.0001
1.
0
0.
8
0.
6
0.
4
0.
2
0.
0
Pro
po
rtio
n s
urv
ivin
g w
ith
NE
D
0 1 2 3 4 5 6
Years after surgery
p=0.0001
Low
Medium
High
1.0
0.8
0.6
0.4
0.2
0.0
Pro
po
rtio
n s
urv
ivin
g w
ith
NE
D
0 1 2 3 4 5 6
Years after surgery
Grandis et al, 1998
EGFR: a marker for response to radiation (SCCHN)
0
25
50
75
100
0 1 2 3 4 5
Years from randomization
p=0.0006
Overall survival
n = 155EGFR > median
EGFR median
Locoregional relapse
Ang K, et al. Cancer Res 2002;62:7350–7356
% a
live
Years from randomization
0
25
50
75
100
0 1 2 3 4 5
EGFR > median
EGFR median
p=0.003
n = 155
% f
aile
d
Cetuximab + RT in Locally Advanced SCCHN Study design
Bonner et al. N Eng J Med 2006;354:567-578
RT as before +ERBITUX initial 400 mg/m2 2-h
infusion then 250 mg/m2 1-h infusion weekly for at least 7 doses
RTonce or twice daily or
concomitant boost for 7 – 8 weeks
Patients with measurable locally advanced SCCHN (stratified by KPS;node+/0;T1-3/4; RT regimen)
Randomization
Follow-up until disease progression or up to 5 years
The Cetuximab/Radiotherapy Phase III TrialThe Cetuximab/Radiotherapy Phase III Trial
RadiotherapyRadiotherapy BioRadiotherapyBioRadiotherapy P-valueP-value (n=213)(n=213) (n=211) (n=211)
ToxicityToxicity**MucositisMucositis 52%52% 56%56%Acneiform rashAcneiform rash 1%1% 17%17%< .001< .001Radiation dermatitisRadiation dermatitis 18%18% 23%23%Infusion reactionsInfusion reactions NANA 3%3%(Late Peg dependency(Late Peg dependency 17%17% 19%19%))
EfficacyEfficacy3-Yr Survival3-Yr Survival 45%45% 55%55%.03.032-yr PFS2-yr PFS 37%37% 46%46%.006.0062-Yr LRC2-Yr LRC 41%41% 50%50%.005.0052- Yr DM2- Yr DM 17%17% 16%16%
Bonner, NEJM 2006 (*Grade 3-5)Bonner, NEJM 2006 (*Grade 3-5)
The Cetuximab/Radiotherapy Phase III TrialSubgroup analyses
Variable RT alone
(N=213)
RT + CET
(N=211)
HR (95% CI)
Overall survival+ 29.3 49.0 0.74 (0.57-0.97)*
- oropharynx 30.3 > 66.0 0.62
- larynx 31.6 32.8 0.87
- hypopharynx 13.5 13.7 0.94
According to RT+
- once daily 15.3 18.9 1.01
- twice daily 53.3 58.9 0.74
- CB 31.0 > 66.0 0.64
+Median duration; *p=0.03 (Bonner et al, N Eng J Med 2006; 354: 567-578 )
Treatment of Locoregionally Advanced SCCHN
Historically: Surgery (+ RT) or RT aloneOutcomes poor for OS and OP
Currently there are three multimodality treatment approaches:
1. Surgery adjuvant concurrent CRT
2. Definitive concurrent CRT, with surgery as an optional salvage or completion treatment
3. Induction CT definitive local therapy
Seiwert et al, 2007; OS = overall survival; OP = organ preservation
ECOG 2399: Study Design
REGISTER
RESPONSE
Inductionchemotherapy
Paclitaxel (PTX)175 mg/m2 IV
Carboplatin AUC 6
q 21 days2 cycles
Concurrentchemoradiation
RT 70 Gy 35 fx / 7 wks
PTX 30 mg/m2/wk
Oropharynx vs
larynxCR
PR
Discontinue protocol therapy
stable
PD
Neck dissection*
FUP at CR
SS+ at PR, SD and PD
$
$
$ Epoetin alpha for patients with hgb ≤ 15g/dl for males and ≤ 14g/dl for females
* Neck dissection in N1-2 if incomplete response in nodes and all N3 (optional if CR in N1-2 patients)
+ SS = surgical salvage
Courtesy from Dr. Forastiere
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
61% of OP Cases Are HPV+ and Almost all are HPV 1661% of OP Cases Are HPV+ and Almost all are HPV 16HPV + tumors more regionally advanced and basaloid typeHPV + tumors more regionally advanced and basaloid type
ECOG 2399: Efficacy by HPV Status
HPV + HPV - P Value
Response• Induction• Protocol
82%
84%
55%
57%
.01
.07
2-Year PFS 86% 53% .02
2-Year OS 95% 62% .005
Survival, OP cancers• 2-Year PFS• 2-Year OS
85%
94%
50%
58%
.05
.004
Response rates in HPV-cases: 58% vs 52% during induction and 54% vs 59% final for oropharynx and larynx respectively
Oropharynx Tumor HPV Status And Survival
Time in Months
Pro
babi
lity
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
Oropharynx Tumor HPV Status And SurvivalOropharynx Tumor HPV Status And Survival
Time in Months
Pro
babi
lity
0 10 20 30 40 50
0.0
0.2
0.4
0.6
0.8
1.0
NegativePositive
Log- rank, p=0.05
Two-year Progression Free Survival By HPV
Int. J Cancer: 120, 1731-1738 (2007)
© 2007 Wiley-Liss, Inc.
Combined analysis of HPV-DNA, p16 and EGFR expression to predict prognosis in oropharyngeal cancer
Niklas Reimers1, Han U. Kasper2,3, Soenke J, Weissenborn4, Hartmut Stützer5, Simon F, Preuss1, Thomas K. Hoffmann6, Ernst Jan M. Speel7, Hans P. Dienes2, Herbert J. Pfister3,4, Orlando Guntinas-Lichius1 and Jens P. Klussman1*
1Department of Oto-Rhino-Laryngology, Head and Neck Surgery, University of Cologne, Germany
2Department of Pathology, University of Cologne, Germany
3Center for Molecular Medicine Cologne, University of Cologne, Germany
4Institute of Virology, University of Cologne, Germany
5Institute of Medicine Statistics, Informatics and Epidemiology, University of Cologne, Germany
6Department of Otorhinolaryngology, University of Duesseldorf, Germany
7Department of Molecular Cell Biology, Research Institute Growth Development, University of Maastricht, Netherlands
Correlation Between the Presence of P16 Expression and the Presence of HPV-DNA
and EGFR Expression in OSCC
P16+ (29/96) P16- (67/96)
HPV+ 25/29 (86) 2/67 (3)
HPV- 4/29 (14) 65/67 (97)
p value (HPV x P16) <0.001
EGFR+ 10/29 (34.5) 36/37 (54)
EGFR- 19/29 (65.5) 31/67 (46)
p value (EGFR x P16) 0.083
Reimers et al, Int J Cancer 2007; 120, 1731–1738 (OSCC = Oropharyngeal squamous cell carcinoma)
Reimers et al, Int J Cancer 2007; 120, 1731–1738
Univariate Survival Analysis by p16 Tumor Status and by the Combination of EGFR and p16 Expression. Disease-Free Survival (C) and Overall Survival (D).
Conclusion (1)
• Over the last 5 years it has become clear that a subset of OSCC is associated with oncogenic HPV
• These tumors differ from the PHV (-) tumors with respect to tumor differentiation, risk factors and genetic changes
• The presence of HPV has been associated with a more favorable outcome in most studies
Conclusion (2)
• A recent study from Germany indicated that p16 expression is the most reliable prognostic factor for OSCC and might be a surrogate marker for HPV + OSCC
• HPV + / p16 + tumors tended to have decreased EGFR expression
• It is still unclear what impact these markers have on therapeutic decision making