1. 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

2. 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

3. 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

4. Human Papillomavirus and Oropharyngeal Cancer

5. 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

6. Incidence Trends for SCCHN in the US Study methods 9 Surveillance, Epidemiology, and End Results (SEER) program registries (1973-2003) Squamous cell cancers classified based on anatomic site HPV-related cancersHPV-unrelated cancersExcluded cancers Base of tongueTongueLip Lingual and palatine tonsilGumNasopharynx OropharynxFloor of mouthSalivary gland Waldeyer ringPalateHypopharynx Other/unspecified mouthIll-defined sites

7. Incidence increasing for HPV-related Incidence decreasing for HPV-unrelated Equalization in 2004 Incidence Trends in the US

8. Actuarial Life-table Estimates of Survival Chaturvedi A et al, JCO. In press PeriodTwo-year survival HPV-R vs. HPV-U P-value 1973-198246.6 vs. 47.2%0.71 1983-199256.0 vs. 49.6%<0.01 1993-200469.7 vs. 50.3%<0.01

9. Treatment of Locoregionally Advanced SCCHN Historically:Surgery (+ RT) or RT alone Outcomes 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

10. MACH-NC: Results - Overall Survival ChemotherapyRiskPAbsolute benefit timingreductionvalueat 5 years Adjuvant2%NS1% Neoadjuvant*5%NS2% Concomitant19%< 0.00018% Total10%< 0.00014% * 15 studies with PF 5% Pignon et al, 2000 (63 trials / 10.741 patients)

11. IGR, June 2004 Survival, concomitant trials by Site 17% + 5 23% + 4 22% + 6 16% + 6 -3% + 11

12. R R K K Shc PI3K Shc Grb2 Ras Sos Raf MEK1/2 Akt MAPK Cell cycle progression survivalproliferation PTEN GSK-3 mTOR FKHR Bad Cyclin D1 p27 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

13. 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 Proportion surviving with NED 01234560123456 Years after surgery p=0.0001 Low Medium High 1.0 0.8 0.6 0.4 0.2 0.0 Proportion surviving with NED 01234560123456 Years after surgery Grandis et al, 1998

14. EGFR: a marker for response to radiation (SCCHN) 0 25 50 75 100 012345 Years from randomization p=0.0006 Overall survival n = 155 EGFR > median EGFR  median Locoregional relapse Ang K, et al. Cancer Res 2002;62:7350–7356 % alive Years from randomization 0 25 50 75 100 012345 EGFR > median EGFR  median p=0.003 n = 155 % failed

15. 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/m 2 2-h infusion then 250 mg/m 2 1-h infusion weekly for at least 7 doses RT once 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

16. The Cetuximab/Radiotherapy Phase III Trial RadiotherapyBioRadiotherapyP-value (n=213) (n=211) (n=213) (n=211) Toxicity* Mucositis52%56% Acneiform rash1%17%<.001 Radiation dermatitis18%23% Infusion reactionsNA3% (Late Peg dependency17%19%) Efficacy 3-Yr Survival45%55%.03 2-yr PFS37%46%.006 2-Yr LRC41%50%.005 2- Yr DM17%16% Bonner, NEJM 2006 (*Grade 3-5)

17. The Cetuximab/Radiotherapy Phase III Trial Subgroup analyses VariableRT alone (N=213) RT + CET (N=211) HR (95% CI) Overall survival + 29.349.00.74 (0.57-0.97)* - oropharynx30.3> 66.00.62 - larynx31.632.80.87 - hypopharynx13.513.70.94 According to RT + - once daily15.318.91.01 - twice daily53.358.90.74 - CB31.0> 66.00.64 + Median duration; *p=0.03 (Bonner et al, N Eng J Med 2006; 354: 567-578 )

18. Treatment of Locoregionally Advanced SCCHN Historically:Surgery (+ RT) or RT alone Outcomes 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

19. ECOG 2399: Study Design REGISTERREGISTER RESPONSERESPONSE Induction chemotherapy Paclitaxel (PTX) 175 mg/m 2 IV Carboplatin AUC 6 q 21 days 2 cycles Concurrent chemoradiation RT 70 Gy 35 fx / 7 wks PTX 30 mg/m 2 /wk Oropharynx vs larynx CR 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 N 1-2 if incomplete response in nodes and all N 3 (optional if CR in N 1-2 patients) + SS = surgical salvage Courtesy from Dr. Forastiere

20. ECOG 2399: HPV Results HPV +* HPV - OP3824 Larynx034 Total 38 (40%) 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 16 HPV + tumors more regionally advanced and basaloid type

21. ECOG 2399: Efficacy by HPV Status HPV +HPV -P Value Response Induction Protocol 82% 84% 55% 57%.01.07 2-Year PFS86%53%.02 2-Year OS95%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

22. Oropharynx Tumor HPV Status And Survival Two-year Overall Survival

23. Oropharynx Tumor HPV Status And Survival Two-year Progression Free Survival By HPV

24. 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 Reimers 1, Han U. Kasper 2,3, Soenke J, Weissenborn 4, Hartmut Stützer 5, Simon F, Preuss 1, Thomas K. Hoffmann 6, Ernst Jan M. Speel 7, Hans P. Dienes 2, Herbert J. Pfister 3,4, Orlando Guntinas-Lichius 1 and Jens P. Klussman 1* 1 Department of Oto-Rhino-Laryngology, Head and Neck Surgery, University of Cologne, Germany 2 Department of Pathology, University of Cologne, Germany 3 Center for Molecular Medicine Cologne, University of Cologne, Germany 4 Institute of Virology, University of Cologne, Germany 5 Institute of Medicine Statistics, Informatics and Epidemiology, University of Cologne, Germany 6 Department of Otorhinolaryngology, University of Duesseldorf, Germany 7 Department of Molecular Cell Biology, Research Institute Growth Development, University of Maastricht, Netherlands

25. 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)

26. 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).

27. 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

28. 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