Contemporary Management of Oral Cancer

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Contemporary Management of Oral Cancer

• Andrew Salama MD DDS
• University of Maryland Medical Center
• Baltimore College of Dental Surgery
• Marlene and Stuart Greenebaum Cancer Center

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Outline

• Oral cancer
• Demographics
• Risk factors
• Clinical diversity
• Treatment
• Staging /Decision making
• Reconstruction
• Recent Advances

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Oral/Jaw Cancer 1991-2008University of Maryland
2554 patients
Cancer Oral Cavity/Jaws Epidermoid carcinoma
(scca) 1044 CIS 83 Salivary
(intra-oral) 147 Sarcomas 48 Lymphoma 35
Metastatic 29 Others 17
1363
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DemographicsOral and Pharynx cancer

• USA (oral pharyngeal scca)
• 2-6 of all cancers
• 30 of head and neck cancers
• 3000 cases diagnosed per year
• 2007 estimated (SEER)
• 34360
• 7555 deaths

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DemographicsOral and Pharynx cancer

• World
• Western Europe Australia ( 5)
• France India Brazil Eastern Europe

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DemographicsOral and Pharynx cancer
World wide incidence of cancers by site
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DemographicsOral and Pharynx cancer
Maryland -8th incidence -national death rate
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Oral Cancer-Maryland
Baltimore City Anne Arundel County Charles
County
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Oral Cancer-Maryland
Survival has not changed Dramatically in past 30
years
Blacks
Whites
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DemographicsOral and Pharynx cancer

• Age at diagnosis (SEER 2004)
• Median age 62
• lt20 0.5
• 20-34 2.4
• 35-44 7.1
• 45-54 20.6
• 55-64 24.7
• 65-74 22.3
• 75-84 16.7
• gt85 5.7

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Stage at Presentation

• Presentation stage Survival (5 yr OS)
• Local 35 81.1
• Regional 50 52.1
• Distant 10 26.5
• Unknown 5

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DemographicsOral and Pharynx cancer

• Survival (5-year)
• How long will I live
• 60 alive at 5 years

• White men 60.2
• White women 62.8
• Black men 35.5
• Black women 51.3

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Projected Estimates

• 1 in 98 men and women will be diagnosed with
  cancer of the oral cavity and pharynx during
  their lifetime
• 0.74 of men will develop cancer of the oral
  cavity and pharynx between their 50th and 70th
  birthdays compared to 0.25 for women

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Cancer Survival African Americans
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Non-traditional patients

• Women
• African Americans
• lt40 year
• Non-smokers

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Gender Trends

• Male Female
• 1930 10 1
• 1950 6 1
• 2000 3 2
• Women have an increased risk of developing cancer
  with the same level of exposure to environmental
  mutagens

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Why do African American do so much worse

• Treatment (non-operative)
• radiation
• More aggressive disease
• Nodal disease at presentation
• Extracapsular spread
• Risk factors
• Utilization of care/Access to care
• Insurance status had a significant effect on
  survival in black patients after controlling for
  other variables
• Laryngoscope. 116(7)1093-1106 July 2006

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Tongue Cancer lt40

• 60 increase in tongue cancer in patients lt40
• -1973-1984 versus 1985-1997
• SEER data

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Tongue Cancer lt40

• Finland 4 1960s 7 1980s
• Atula et al Arch OtoHNS 1221996
• USA 4 1971 18 1993
• Myers et al OtoHNS 1222000

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Tongue Cancer lt40

• Implicated causality
• Genetic predisposition
• Greater sensitivity to mutagens
• HPV

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Tongue Cancer lt40Genetics

• Are these different cancers than in older
  patients
• LOH at 39and 17 p chromosomes in young adults
  no different to those found in older patients.
• Jin Y-T Oral Oncology 351999
• No significant differences in the expression of
  p53 p21 Rb and MDM2 proteins from tongue SCC
  in patients lt35 years compared to patients gt75
  years.
• Regezi JA Oral Oncology 351999

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Tongue Cancer lt40Survival

• Historical trends
• Recent trends
• A Matched Control Study of Treatment Outcome in
  Young Patients with SCC of the Head and Neck
• Verschuur et al Laryngoscope 1091999
• No difference in 5 year cause specific survival
• Younger cases significantly better overall
  survival
• Performance status
• Comorbid disease

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Tongue Cancer lt40Survival and Outcomes

• Outcome predictors
• T stage
• N stage
• Perineural and lymphatic invasion
• Improved survival
• Patients who underwent neck dissection

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Non-Smokers

• Smoking status is related to anatomic subsites
• Non-smokers
• 54 tongue
• 3.7 Floor of mouth
• Koch et al Laryngoscope 1999
• Floor of mouth cancer
• Smokers 37.8
• Non-smokers 6.6
• Schmidt et al J Oral Maxillo Fac Surg 2004

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Non-Smokers
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Non-SmokersHPV

• HPV and scca
• Non-smokers gt 50 HPV (oral/pharynx)
• lt 33 of smokers HPV (oral/pharyx)
• Koch et al Laryngoscope 1999
• 187 cases HNSCC 10 nonsmokers
• Non-smokers 50 HPV
• Smokers 8.5 HPV
• Forest et al Arch Otolaryngol HNS 1997

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Non-SmokersGenetics

• Oral cancer in non-smokers is a different disease
• Elderly females (gt75) PVL
• Rate of p53 mutations
• LOH at 3p4q and 11q13
• Koch et al. Laryngoscope 1091999

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HPV associated Head and Neck Cancer

• HPV Prevalence (5046 cases)
• OSCC 23.5 HPV16 68.2
• HPV18 34.1
• OPSCC 35.6 HPV16 86.7
• HPV18 2.8
• Larynx 24.0 HPV16 69.2
• HPV18 17.0
• Kreimer et al Cancer Epidemiol Biomarkers Prev
  2005

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Oral Cancer Traditional Risk factors

• Smoking tobacco
• 300 carcinogens
• Aromatic hydrocarbons
• Benzpyrene
• Tobacco-specific nitrosamine (TSNs)
• Smoking is an independent risk factor 80-90
• Relative risk 6-8 fold

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Oral Cancer Traditional Risk factors

• So why bother quitting
• Morphologic changes are reversible
• Cessation associated with risk
• 30 1-9 years
• 50 gt9 years
• gt20 years relative risk 1.5 compared to
  non-smokers

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Oral Cancer Traditional Risk factors

• Smokeless tobacco (SLT)
• US/Swedish SLT
• RR developing oral cancer lower than previously
  expected
• Moist snuff RR 0.6-1.7
• Dry snuff RR 4-13
• Developing countries
• Tobacco mixed with Betel/staked lime
• Definitive increases in risk

Rodu et. al. OOOO 2002
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Oral Cancer Traditional Risk factors

• Cigars
• Not a safe alternative to cigarettes
• Relative risk
• 4-20
• 2 cigars/day 1 pack of cigarettes

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Oral Cancer Traditional Risk factors

• Alcohol
• 75-80 patients with oral cancer consumer alcohol
• Etiopathogenesis independent of tobacco
• Heavy drinkers (gt55 drinker/week) risk higher
  than for tobacco alone
• Synergistic effect
• RR smoking drinking 15X

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Oral Cancer Traditional Risk factors
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Oral CancerMolecular Pathogenesis
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Oral Cancer - Anatomy
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Oral Cancer Clinical presentation
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Oral Cancer Clinical presentation
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Oral Cancer Clinical presentation
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Oral Cancer Clinical presentation
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Oral Cancer Clinical presentation
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Oral Cancer Clinical presentation
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Physical Exam and Staging
Neck Oral Cavity
Staging
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Staging (AJCC)
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Staging (AJCC)
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Imaging

• Routine imaging
• CT scan of oral cavity and neck with IV contrast
• PET/CT imaging
• Alternative imaging
• MRI/US

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CT

• Cervical lymph nodes and blood vessels
• Bone invasion

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MRI

• Improved delineation of soft tissue
• Better for deeply invasive tumors
• Increased time and expense

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PET and PET/CT

• Utility
• Post Chemo RT ChemoRT
• Unknown primary
• Limitation of cervical lymph nodes
• Must be gt6mm
• Activity measured as metabolically active
• SUV gt2.5 chance of malignancy
• False positive
• Inflammation
• Salivary gland disease
• Small metabolic units (vocal cords)
• Sarcoidosis

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PET in the N0 Neck

• Not sufficiently accurate in the N0 neck to rule
  out nodal metastases.
• Menda and Graham Semin Nuc Med 2005

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PET and PET/CT

• Head and Neck Cancer Staging
• PET CT
• Sensitivity 87 62
• Specificity 89 73

Gambhir et al. J. of Nuclear Medicine Vol
42-Number 5 May 2001
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PET/CT Fusion
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Ultrasound

• High sensitivity for neck nodes
• Non-invasive
• Can be performed by surgeon in office
• US guided FNAB
• User dependant

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Decision making

• Surgery vs. Radiation
• Equivalent cure rates stage I/II oral cavity
  tumors
• Tumors 0-4 cm
• Exceptions
• Bone invasion
• Primary Chemoradiation
• Larynx
• Base of tongue
• Tonsil

Quality of Life Organ preservation
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Clinical Management

• Stage I/II disease
• Single modality
• Surgery
• Radiation
• The utility of elective neck dissection has led
  to increased upstaging of Stage I/II disease

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Clinical Management

• Stage III/IV
• Multimodality
• SurgeryRadiation
• SurgeryRadiation Chemo
• Neoadjuvant
• Unresectable disease
• Palliative surgery
• Palliative chemoradiation

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Surgical Treatment

• Resection of the tumor
• Access
• The Neck
• Reconstruction

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Surgical Margins (1.0-1.5cm)

• Per oral resection
• (T1 selected T2)

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Surgical accessParamedian Mandibular Osteotomy
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Surgical accessPull through
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Surgical accessmandibular osteotomy
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Surgical accessWeber-Furguson Approach
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Surgical Margins (1.0-1.5cm)

• Margins and survival
• 5-year survival median
• Clear margins 69 gt60mos
• Close margins 58 gt60mos
• Positive margins 38 31mos

Binahmed et al. Oral Oncol 2007
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Molecular Margins

• 53 of histologically negative margins may
  contain p53 mutations and of these 38 developed
  local recurrence
• Brennan et al New Eng J Med 1995

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The Neck

• Types of Neck dissection
• Elective neck dissection (N0)
• Selective neck dissection
• Levels (I-III or I-IV)
• Therapeutic neck dissection (N)
• Radical Neck dissection
• Modified radical neck dissection
• Selective neck dissection (selected cases)

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Who should have a ND

• N (RND/MRND)
• N0 (I-III I-IV)
• T3 T4
• Tongue FOM gingival buccal maxillary (bone
  invasive)
• Deep/thick tumor
• Other
• Entry into the neck for access or reconstruction

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The NeckLikelihood of occult metastasis related
to depth of invasion
-Risk increases at 3mm
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The Neck
Tumor Thickness Occult Cervical Metastasis lt2
mm 7.5 2-8 mm 25.7 gt8 mm 41.2
Spiro et al.1986
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The Old

• Radical Neck Dissection
• Formerly the standard ND for all patients
• N necks with bulky nodal disease

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The New

• Modified Radical Neck Dissection
• N necks
• Preservation of selected structures
• IJV
• SCM
• Spinal accessory nerve
• Selective Neck Dissection
• N0 necks
• Selected N1 necks

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Rationale for the Elective Neck Dissection
Level I 20 II 17 III 9 IV
3 V 0.5

• 192 patients resection Elective RND
• 34 had positive nodes

Shah et al. Cancer 1990
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The Neck

• Rationale
• Staging
• 30-35 patients clinical N0 actually have occult
  metastasis in levels I-III (IV)
• adjuvant therapy

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The dilemma

• Only 30-35 of patients have occult metastasis
• So 65-70 of patients have an unnecessary
  procedure
• BUT
• It allows us to stage the patient
• Can be therapeutic in early stage neck disease

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Alternatives to END

• No treatment (watch and wait)
• If they have occult metastases and develop a
  lymph node later
• Patient survival is NOT different
• But they require a MRND or RND
• Decrease in QOL!
• Elective radiation
• Equivalent regional control and survival
• Never know what stage the patient

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SOMND (I-III)

• Risks
• Nerve injury
• Facial
• Lingual
• Hypoglossal
• Great auricular
• Vagus
• Spinal accessory nerve

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The importance of NStatus of cervical node
single most important prognostic factor
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The importance of N

• N
• Rate of distant metastasis doubles
• 6.9 to 13.6
• Patients gt3 positive nodes
• Incidence of distant metastasis 46.8
• Patients with extra-nodal spread
• 3 times incidence of distant metastasis
• 6.7 to 19.1

Leemans et. al. 1993
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Prognosticators

• Type Squamous vs. Verrucous vs. Spindle cell
• Differentiation
• Mode of Invasion
• Perineural/Perivascular Spread
• Host Response

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Who benefits from adjuvant therapy

• Advanced stages
• T3/T4
• Any bone invasion
• Adverse histologic features
• gt1 cervical lymph node
• 1 cervical lymph node with
• Extracapsular spread
• Perineural/Perivascular invasion
• Poor margin status (lt4mm)

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Recent Advances

• Chemoradiotherapy
• Monoclonal antibody therapy
• HPV vaccine trial

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Post-operative Chemo/Radiotherapy

• Post-operative Radiotherapy and Chemotherapy for
  High Risk Squamous Cell Carcinoma of the Head and
  Neck
• Cooper J.S. et al RTOG 9501/
• Bernier J. et al EORTC 22931
• Local/Regional control
• Disease free survival
• Toxicity

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Monoclonal antibody

• Cetuximab (Erbitux)
• EGFR antibody
• Radiation versus Radiation Erbitux
• LR control 14.9 vs 29.3 months
• Overall survival 29.3 vs 49 months
• Improved progression free survival
• Limited toxicities (skin rash)

Bonner NEJM 2006
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HPV vaccine trial

• Portions of the HPV genome block p53 tumor
  suppressor
• Peptide vaccine aims to inactivate HPV proteins
  responsible for p53 inactivation
• Phase I trial at UMMC
• Recurrent unresectable patients with HPV tumors
• Tonsil/Base of tongue

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Developing Treatment Strategies

• Induction chemotherapy
• Sentinel lymph node biopsy
• Chemoprevention

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Reconstruction

• Goals
• Form
• Restoration/maintenance of orofacial structure
• Function
• QOL
• This is our primary outcome
• Unassisted public eating
• Speech
• Ability to handle secretions

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Reconstruction-considerations

• Patient factors
• What tissue will be removed
• Soft tissue (tongue floor of mouth palate)
• Bone (mandible maxilla)
• Suitability for surgery
• Dentate status
• Willingness to undergo lengthy reconstruction

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Reconstruction

• Soft tissue reconstruction
• Recruitment of tissue
• Regional flaps
• Pectoralis Major flap
• Latissimus dorsi flaps
• Free flaps
• Radial forearm flap
• Anterior lateral thigh
• Rectus abdominus flap

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Soft tissue reconstruction

• Obturation of defects
• Tongue
• Cheek
• Floor of mouth
• Maxilla
• Meaningful function

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Tongue reconstruction
Radial forearm flap
Anterior lateral thigh
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Dynamic tongue reconstruction
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Soft Tissue Maxillary Reconstruction
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Soft Tissue Maxillary Reconstruction
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Free Fibula Mandibular Reconstruction
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Free Fibula Mandibular Reconstruction
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Free Fibula Mandibular Reconstruction
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Free Fibula Mandibular Reconstruction
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Iliac Crest Bone Grafting
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Follow-up (www.nccn.org)
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Thank You