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2014/04/23
1
Head and Neck Cancer Care in the
Era of Human Papillomavirus
SAC Conference
Ottawa, Ontario
May 8, 2014
Julie Theurer, PhD
Anthony Nichols, MD
Objectives
• Curative treatment landscape for Head and
Neck Cancer
• New entity of HPV-related Head and Neck
Cancer
• Future directions for treatment/management in
HPV era
Pre-Modern Era (1500-1900)
• Cancers of the head and neck were “rare”
• Primarily treated with surgery
• Very poor outcomes
• Lacked anesthesia
• Uncontrolled intraoperative bleeding
• Post-operative infection
Treatment Landscape
McGurk & Goodger, 2000
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Modern Era (1900-1990)
• Discovery of x-rays and radium - primarily treated with
radiation therapy
• Caustic skin reaction → IMRT
• Improved surgical techniques
• Cure rates rose from 5% to 30% for oral cancers
• Reconstructive surgery
• Cytotoxic chemotherapy
• Major initiative of 1970s and 1980s
Treatment Landscape
McGurk & Goodger, 2000
Shifting Paradigm in HNSCC:
Organ Preservation
Veteran’s Affairs (VA) Laryngeal Cancer Trial
Applied to other HNSCC sites:
Oropharynx, Hypopharynx
Treatment Landscape
Advanced HNSCC
TPF Carboplatin
+ XRT
PF Carboplatin
+ XRT
TPF = Docetaxel, Cisplatin, 5-Fluorouracil
PF = Cisplatin, 5-Fluorouracil
Contemporary Paradigm: Improving
Survival
Posner et al., 2007
3-yr OS
62%
48%
Treatment Landscape
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OPSCC: Open Surgery
Treatment Landscape
Shifting Paradigm in OPSCC:
Organ Preservation Surgery ± RT (%) RT ± ND (%) P value
5 year Survival
Base of Tongue 49 52 0.20
Tonsil 47 43 0.20
Severe Complications
Base of Tongue 32 3.8 < 0.001
Tonsil 23 3.2 < 0.001
Fatal Complications
Base of Tongue 3.5 0.4 < 0.001
Tonsil 6 0.8 < 0.001
Retrospective analysis of non-randomized cohort studies published 1970-2000 (Parsons et al., Cancer, 2002)
Treatment Landscape
Contemporary Paradigm: Improving
Survival
Calais et al., 1999
Treatment Landscape
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Oropharyngeal Cancer
T3-T4?
N+?
Yes Chemoradiation
No Radiation
Treatment Landscape
Management of OPSCC in 2014
Human Papillomavirus
• DNA virus with tropism for human epithelia
• HPV6, 11 - benign warts, papillomas
• HPV16, 18, 31, 33, 35 - oncogenic
• Etiologic agent in genital, anorectal, and head and
neck cancers
– Present in 20-25% of all HNSCCs; ~70% of OPSCCs
• Unlike cervical cancer, HPV16 is responsible for ~90%
of HPV-positive OPSCC
HPV-related Head and Neck Cancer
Chaturvedi et al., JCO, 2011
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1. Rising incidence of OPSCC
• < 20% of OPSCCs were HPV+ in 1980s
• > 80% of OPSCCs were HPV+ by 2000-2004
• Population-level incidence of HPV+ OPSCC
has increased by 225%
• Population-level incidence of HPV- OPSCC has decreased by 50%
HPV-related Head and Neck Cancer
Chaturvedi et al., JCO, 2011
2. Unique demographic cohort
• Younger, healthier
• Less tobacco and alcohol exposure
• > # of lifetime sexual partners, hx of genital warts,
marijuana use
• Advanced stage tumors at presentation, node-positive
regional disease
• Oropharyngeal tumors, or unknown primary
D’Souza et al., NEJM, 2007; Gillison et al., JNCI, 2008
HPV-related Head and Neck Cancer
3. Distinct disease entity
• HPV-negative disease
• Mutations in p53 protein (due to tobacco and alcohol
exposure) lead to decreased expression of genes involved in
tumor suppression
• Loss of p16
• HPV-positive disease
• Two oncoproteins (E6 and E7) inactivate and degradate p53
and pRb, resulting in cell proliferation
• Overexpression of p16
HPV-related Head and Neck Cancer
Gillison, Semin Oncol, 2004
2014/04/23
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• 3-year survival with radiation and
chemotherapy is > 80%
– For HPV- disease, 3-year survival is approx. 30-40%
HPV-related Head and Neck Cancer
4. Good/Excellent survival
Ang et al., 2010; Nichols et al., 2013
5. Distant disease
• Rate of distant metastases (DM) remains
equivalent between HPV-positive and HPV-
negative disease
• DM in HPV-positive disease = enigma
• Occur in unexpected sites, > 10 years post-tx
Ang et al., 2010; Huang et al., 2012
HPV-related Head and Neck Cancer
Current Clinical Picture
• Many younger, healthier patients with HPV-
positive OPSCC
• High overall survival and locoregional control
with standard care (CRT); distant control
similar to HPV-negative disease
• High risk of treatment-related toxicities
HPV-related Head and Neck Cancer
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1. Prevention
• Low risk types 6/11
• High risk 16/18
• Merck
Gardasil® Cervarix® • High risk 16/18
• GlaxoSmithKline
Future Directions
2. De-intensification of treatment
• Treatment has intensified over time
• CRT-associated toxicities are unsatisfactory
• Common acute and late treatment toxicities:
• Mucositis, xerostomia, fibrosis, dysphagia, ototoxicity, neurotoxicity, osteoradionecrosis
• Cautious consideration of de-intensification in
light of concern for DM
Future Directions
Antibody therapy
Future Directions
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Future Directions
Radiation alone
• Patients with HPV-positive disease at low-risk
for DM could be treated with radiation only
• T1-3N0-N2a, and <10 pack-years N2b have
minimal risk of DM, irrespective of treatment
Transoral Robotic Surgery (TORS)
Future Directions
Functional Outcomes of TORS
• Overall, oropharyngeal TORS data boasts
impressive functional outcomes
• However, outcomes are moderated by post-op
radiation
• No data examining physiologic impact, and its
relationship to function and QOL
• No direct comparison of TORS with gold
standard, RT
Future Directions
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9
A Phase II Randomized Trial for Early-Stage Squamous Cell Carcinoma of the Oropharynx:
Radiotherapy vs. Trans-Oral Robotic Surgery
(ORATOR)
Patients with early T-stage squamous cell carcinoma of the oropharynx, meeting
inclusion criteria
ARM 1: Radiotherapy
Chemotherapy With surgical treatment for salvage
of persistent disease
Follow-up for QOL and Survival
ARM 2: Transoral Robotic Surgery + Neck Dissection
With adjuvant radio(chemo)therapy based on
pathological findings
Follow-up for QOL and Survival
Randomize
3. Personalized Medicine
Treatment Factors in 2014:
• Tumor site, tumor size, lymph node involvement
Treatment Factors in 2020:
• Tumor site, tumor size, lymph node involvement
• HPV status
• Metastatic Risk – circulating tumor cells/DNA
• Tumor molecular profile – gene mutations, amplifications
Future Directions
4. What patients want to know
Cancer diagnosis + sexually transmitted infection
• What is HPV?
• How do I get an oral HPV infection?
• When did I get an oral HPV infection?
• Will I transmit this infection to others?
• Will the vaccine help me?
Future Directions
Fakhry & D’Souza, Oral Oncol, 2013
2014/04/23
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Summary
• Who?
• What?
• Where?
• When?
• Why?
• How do we treat, how do patients do?
Ang KK, Harris J, Wheeler R et al. (2010). Human papillomavirus and
survival of patients with oropharyngeal cancer. NEJM 363: 24-35.
Chaturvedi AK, Engels EA, Pfieffer RM et al. (2011). Human
papillomavirus and rising oropharyngeal cancer incidence in the United
States. JCO 29: 4294-4301.
D’Souza GA, Kriemer AR, Viscidi R et al. (2007). Case-control study of
human papillomavirus and oropharyngeal cancer. NEJM 356: 1944-
1956.
Gillison ML. (2004). Human papillomavirus-associated head and neck
cancer is a distinct epidemiologic, clinical, and molecular entity. Semin
Oncol 31: 744-754.
Huang SH, Perez-Ordonez B, Weinreb I et al. (2012). Natural course of
distant metastases following radiotherapy or chemotherapy in HPV-
related oropharyngeal cancer. Oral Oncol 49: 79-85.