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

2014/04/23

2

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

2014/04/23

3

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

2014/04/23

4

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

2014/04/23

5

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

6

• 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

2014/04/23

7

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

2014/04/23

8

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

2014/04/23

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

10

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.