Contemporary Management of Oral Cancer

1
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

2
Outline

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

3
Oral/Jaw Cancer 1991-2008University of Maryland
2,554 patients
Cancer Oral Cavity/Jaws Epidermoid carcinoma
(scca) 1,044 CIS 83 Salivary
(intra-oral) 147 Sarcomas 48 Lymphoma 35
Metastatic 29 Others 17
1,363
76
4
DemographicsOral and Pharynx cancer

• USA (oral pharyngeal scca)
• 2-6 of all cancers
• 30 of head and neck cancers
• 30,00 cases diagnosed per year
• 2007 estimated (SEER)
• 34,360
• 7,555 deaths

5
DemographicsOral and Pharynx cancer

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

6
DemographicsOral and Pharynx cancer
World wide incidence of cancers by site
7
DemographicsOral and Pharynx cancer
Maryland -8th incidence -national death rate
8
Oral Cancer-Maryland
Baltimore City, Anne Arundel County, Charles
County
9
Oral Cancer-Maryland
Survival has not changed Dramatically in past 30
years
Blacks
Whites
10
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

65
11
Stage at Presentation

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

12
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

13
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

14
Cancer Survival African Americans
15
Non-traditional patients

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

16
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

17
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

18
Tongue Cancer lt40

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

19
Tongue Cancer lt40

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

20
Tongue Cancer lt40

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

21
Tongue Cancer lt40Genetics

• Are these different cancers than in older
  patients?
• LOH at 3,9,and 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

22
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

23
Tongue Cancer lt40Survival and Outcomes

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

24
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

25
Non-Smokers
26
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

27
Non-SmokersGenetics

• Oral cancer in non-smokers is a different disease
• Elderly females (gt75) PVL
• ? Rate of p53 mutations
• ? LOH at 3p,4q, and 11q13
• Koch et al. Laryngoscope 1091999

28
HPV associated Head and Neck Cancer

• HPV Prevalence (5,046 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

29
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 ?

30
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

31
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
32
Oral Cancer Traditional Risk factors

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

33
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

34
Oral Cancer Traditional Risk factors
35
Oral CancerMolecular Pathogenesis
36
Oral Cancer - Anatomy
37
Oral Cancer Clinical presentation
38
Oral Cancer Clinical presentation
39
Oral Cancer Clinical presentation
40
Oral Cancer Clinical presentation
41
Oral Cancer Clinical presentation
42
Oral Cancer Clinical presentation
43
Physical Exam and Staging
Neck Oral Cavity
Staging
44
Staging (AJCC)
45
Staging (AJCC)
46
Imaging

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

47
CT

• Cervical lymph nodes and blood vessels
• Bone invasion

48
(No Transcript)
49
MRI

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

50
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

51
PET in the N0 Neck

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

52
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
53
(No Transcript)
54
PET/CT Fusion
55
Ultrasound

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

56
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
57
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

58
Clinical Management

• Stage III/IV
• Multimodality
• Surgery?Radiation
• Surgery?Radiation Chemo
• Neoadjuvant ?
• Unresectable disease
• Palliative surgery
• Palliative chemoradiation

59
Surgical Treatment

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

60
Surgical Margins (1.0-1.5cm)

• Per oral resection
• (T1, selected T2)

61
Surgical accessParamedian Mandibular Osteotomy
62
Surgical accessPull through
63
Surgical accessmandibular osteotomy
64
Surgical accessWeber-Furguson Approach
65
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
66
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

67
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)

68
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

69
The NeckLikelihood of occult metastasis related
to depth of invasion
-Risk increases at 3mm
70
The Neck
Tumor Thickness Occult Cervical Metastasis lt2
mm 7.5 2-8 mm 25.7 gt8 mm 41.2
Spiro et al.1986
71
The Old

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

72
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

73
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
74
The Neck

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

75
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

76
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

77
SOMND (I-III)

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

78
The importance of NStatus of cervical node
single most important prognostic factor
79
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
80
Prognosticators

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

81
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)

82
Recent Advances

• Chemoradiotherapy
• Monoclonal antibody therapy
• HPV vaccine trial

83
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

84
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
85
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

86
Developing Treatment Strategies

• Induction chemotherapy
• Sentinel lymph node biopsy
• Chemoprevention

87
Reconstruction

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

88
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

89
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

90
Soft tissue reconstruction

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

91
Tongue reconstruction
Radial forearm flap
Anterior lateral thigh
92
(No Transcript)
93
Dynamic tongue reconstruction
94
Soft Tissue Maxillary Reconstruction
95
Soft Tissue Maxillary Reconstruction
96
Free Fibula Mandibular Reconstruction
97
Free Fibula Mandibular Reconstruction
98
Free Fibula Mandibular Reconstruction
99
Free Fibula Mandibular Reconstruction
100
(No Transcript)
101
Iliac Crest Bone Grafting
102
Follow-up (www.nccn.org)
103
(No Transcript)
104
Thank You