The Changing Landscape of Oral Cancer: HPV-positive and HPV-negative SCC Nishant Agrawal, MD Chief of Otolaryngology-Head and Neck Surgery Director of Head and Neck Surgical Oncology Section of Otolaryngology-Head and Neck Surgery Department of Surgery
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The Changing Landscape of Oral Cancer: HPV-positive and HPV-negative SCCNishant Agrawal, MDChief of Otolaryngology-Head and Neck SurgeryDirector of Head and Neck Surgical OncologySection of Otolaryngology-Head and Neck SurgeryDepartment of Surgery
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Disclosure Information
• I have no relevant financial relationships to disclose.
• I will not discuss off label use or investigational use in my presentation.
Objectives
• Review the clinically relevant features of head and neck cancer.
– Demographics– Epidemiology– Survival
• Discuss the molecular classification of HPV-positive and HPV-negative SCC.
• Discuss management guidelines of oral cancer.
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Anatomy
• Oral cavity
• Pharynx
– Nasopharynx– Oropharynx– Hypopharynx
• Larynx
• Esophagus
• Nasal cavity/paranasal sinuses
• Salivary glands
• Thyroid/parathyroid
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
HNSCC
• > 600,000 cases of HNSCC
– 6th most common cancer worldwide
• 5 year survival of ~40-60%
• Cancer mortality rates continue to decline in the US
• Incidence of some HNSCC has increased
Siegel et al. CA: A Cancer Journal for Clinicians. 2012.
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Risk Factors• Environmental
– Smoking– Alcohol– Betel quid (betel leaf, areca
nut, slaked lime)• Virus
– HPV– EBV
• Immunosuppression
• Heredity/germline
• Bad luck
– Replicative random errors• Unknown
– Increasing incidence of oral/oral tongue SCC
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Smoking Prevalence
www.cdc.gov
The Changing Landscape of Oral Cancer: HPV-positive and
– Loose teeth– Tongue mobility– Trismus– V3 (mental nerve) numbness– Examination of the neck-30%
accuracy• LNs-size, shape, number,
mobility, and consistency• Thyroid
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Work-up
• Biopsy-Pathology/cytopathology• CT- bony cortex• MRI- marrow space, soft tissue• PET/CT- for staging for advanced stage
disease
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Treatment
– Early stage (stage I and II)• Surgery• Radiotherapy• HPV ?
– Advance stage (stage III and IV)• Surgery + radiotherapy +/- chemotherapy• Radiotherapy + chemotherapy
– New therapy• EGFR inhibitor (cetuximab)• Immunotherapy
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Two Diseases
• Oral cavity cancer– Early Stage
• Primarily surgical treatment– Advanced Stage
• Surgery followed by adjuvant therapy• Multi-modality clinical trial
• Oropharynx cancer– Historically large surgical approaches with disfiguring
treatments– New roles for minimally invasive (e.g. TORS)– Chemoradiation
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
National Comprehensive Cancer Network. 2015.
Oral Cavity
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Oral Cancer Surgical Approaches
• Surgical Approaches
– Transoral– Mandibulotomy– Cheek flap with lip split– Visor flap– Lateral rhinotomy with
lip split– Lingual mandibular
release
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Shah et al. Oral Oncology. 2009.
Surgical Approach
• Tumor size
• Tumor site
• Proximity to mandible or maxilla
• Need for reconstructive surgery
• (Lots of overlap)
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Oropharynx
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Oropharynx
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Oropharynx
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Oropharynx cancer in the HPV era
• Smaller primary
• Larger nodal disease burden
• Adult neck mass is cancer until proven otherwise!
• Fine needle aspiration, not incisional biopsy should be the first line of investigation
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Traditional approaches to the oropharyngeal cancers
Mandibulotomy Pharyngotomy
Jatin Shah, Head and Neck Surgical Oncology, 4th Edition 2010
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
OPSCC and TORS• Historically large surgical approaches
with disfiguring treatments
• Surgical option must offer limited morbidity with excellent function (organ-sparing) and oncologic outcomes
• New roles for minimally invasive approaches (e.g. TORS)
– FDA approval for transoral surgery in 2009
– T1-T2, N0-N2 SCC of the tonsil and BOT
– Concurrent neck dissection is performed at the time of TORS
– Appropriate staging and determination of appropriate adjuvant therapy
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
National Comprehensive Cancer Network. 2015.
TORS
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
TORS
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
TORS Radical Tonsillectomy
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
TORS Radical Tonsillectomy
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
HNSCC• 5 year survival
– Stage I-II• 70-90%• HPV positive
– Stage III-IV (HPV negative)• 30-60%
• Metastasis to cervical lymph nodes has markedly negative impact on prognosis
• HPV association has markedly positive impact on prognosis
• Failure
– Loco-regional recurrence– Metastasis– Second primary malignancy
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Ang et al. NEJM. 2010; Fakhry et al. JNCI. 2008.
HPV and Survival
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
3- year OS82.4 vs. 57.1%
3- year PFS73.7 vs. 43.4%
Ang et al. NEJM. 2010
HPV and Overall Survival
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
HPV and Overall Survival
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
O’Sullivan et al. Lancet Oncology. 2016
HPV and Smoking
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
3-year OS93.0% vs. 70.8% vs. 46.2%
Ang et al. NEJM. 2010
Treatment Failure
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Progression of Disease: Locoregional and Distant
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
3 year: 17.3% v 32.5% P<0.001
3 year: 6.5% v 17.0% p=0.005
Ang et al. JCO 2014;32:2940-2950
Time to Disease Progression
• Median follow-up post progression: 4 years
• Median time to disease progression: p16-positive vs. p16-negative
• 8.2 vs. 7.3 months, p=0.67
• Majority of disease progressions occurred year 1 for p16-positive and p16-negative (65 vs. 63%)
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Fakhry et al. JCO 2014
Patterns of Disease Progression
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Fakhry et al. JCO 2014
De-intensification/de-escalation impetus
• Quality of life
– Chronic dysphagia• At 24 months after XRT
– 15% of patients had grade >= 2 swallowing dysfunction– 8% had progressive dysphagia
– Chronic xerostomia– Psychosocial impact
• Patients accept marginal lower survival versus severe treatment to avoid toxicity
• 81% of patients indicated they preferred reduced treatment
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Brotherston et all. Head Neck. 2013; Maxwell et al. Laryngoscope. 2014; Christianem et al. Radiother Oncol. 2015; Samuels et al. Oral Oncol. 2016; Curran et al. JCO. 2007; Gold. Oto Clinics NA. 2012;
De-intensification/de-escalation approaches• Reducing intensity/dose of a given modality without compromising efficacy
– Chemotherapy• Induction chemotherapy
– If favorable response, radiation dose de-escalation (Cmelak et al. JCO. 2014)• Omit chemotherapy
– Patients at low risk of distant metastatic disease (T1-3, N0-2a) may be treated with XRT alone (O’Sullivan et al. JCO. 2013)
• Targeted therapy– Cetuximab
» Ongoing RTOG 1016 trial to evaluate cetuximab + XRT versus cisplatin + XRT in p16+ OPSCC
– Immunotherapy– Radiation therapy-toxicity is dose dependent
• Dysphagia increases with every 10 Gy above 55 Gy delivered to the constrictors• Reduce overall dose of radiation to < 60 Gy
– Surgery• TORS
– Pathologic staging– Surgery followed by risk-adapted adjuvant treatment (ECOG 3311)
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Genomic Carcinogenesis
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Leemans et al. Nature Reviews Cancer. 2018.
Signaling Pathways
The Changing Landscape of Oral Cancer: HPV-positive and