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