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Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging
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Medical Students 2011 - J.B. Vermorken - HEAD&NECK CANCER SESSION - Epidemiology, clinical presentation, diagnosis, staging

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  • 9. Head & Neck Cancer: Anatomy The most common sites for head and neck tumors are the oral cavity, pharynx, paranasal sinuses, and larynx. Approximately 50% of all cases are in the oral cavity and oropharynx, and one-third are in the larynx.
  • 10. Head & Neck Cancer: Lymph Node Regions Head and neck cancers of the oral cavity and/or nasopharyngeal regions may involve several major lymphatic chains. These chains contain nearly 200 lymph nodes that run parallel to the jugular veins, the spinal accessory nerve, and the facial artery, and into the submandibular triangle. .
  • 1. Head & Neck Cancer: Worldwide Incidence and Mortality (estimated) The most common cancers of the head and neck are those occurring in the mouth and/or pharynx. Worldwide, these cancers account for more than 360,000 new cases and nearly 200,000 deaths annually. Overall, the incidence of these cancers is approximately 2.5 times greater in men than women.
  • I particular pts with HPV positive tumors were recognised to have a better prognosis than HPV negative, irrespective of treatmenand site of origin of the tumor.
  • M225, a murine monoclonal antibody, competitively binds to the EGFR and inhibits EGFR pathways. Clinical trials using murine monoclonal antibodies have been complicated by the development of the human antimouse antibody (HAMA) immune response. The HAMA response not only carries the risk of serious allergic reactions but also increases the clearance of the murine proteins. Thus, the clinical utility of murine monoclonal antibodies has been limited. Cetuximab is a human:murine chimeric anti-EGFR IgG monoclonal antibody that binds exclusively to the EGFR. Chimeric antibodies are composed of the variable regions of murine antibody (the regions responsible for antigen binding) and the constant region of the human Fc fragment.[1] Chimeric monoclonal antibodies have demonstrated specificity and a diminished incidence of immunologic reactions.[2,3] Cetuximab binds to the EGFR with a binding affinity that is approximately one log higher than natural ligands.[4] Cetuximab prevents binding of endogenous ligands and induces receptor internalization, which ultimately blocks the activities of the EGFR pathway. Owens RJ, Young RJ. The genetic engineering of monoclonal antibodies. J Immunol Methods 1994; 168:149–165. Shitara K, Kuwana Y, Nakamura K, et al. A mouse/human chimeric anti-(ganglioside GD3) antibody with enhanced tumor activities. Cancer Immunol Immunother . 1993; 36:373–380. LoBuglio AF, Wheeler RH, Trang J, et al. Mouse/human chimeric monoclonal antibody in man: kinetics and immune response. Proc Natl Acad Sci U S A . 1989; 86:4220–4224. Goldstein NI, Prewett M, Zuklys K, et al. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res . 1995; 1:1311–1318.
  • Clavel M, et al. Ann Oncol 1994;5:521–526; Forastiere A, et al. J Clin Oncol 1992;10:1245–1251; Gibson MK, et al. J Clin Oncol 2005;23:3562–3567;Grose WE, et al. Cancer Treat Rep 1985;69:577–581; Vermorken JB, et al. N Engl J Med 2008;359:1116–1127; Wittes RE, et al. Cancer Treat Rep 1977;61359–61366.
  • Transcript

    • 1. Head and Neck Cancer Clinical Presentation, Diagnosis, Staging (1) Treatment (2) Jan B. Vermorken, MD, PhD Department of Medical Oncology University Hospital Antwerp Edegem, Belgium ESO student course, Ioannina, 2011
    • 2. HEAD & NECK CANCER Anatomy Paranasal sinuses Nasopharynx Oropharynx Pharynx Hypopharynx Larynx Esophagus Trachea Salivary glands Oral cavity Nasal cavity
    • 3. HEAD & NECK CANCER Lymph node regions Preauricular Facial Intraauricular Submandibular Submental Subdigastric Node Upper Jugular Mid-Jugular Lower Jugular Postauricular Upper Post. Cervical (Spinal Accessory Chain) Superf. Occipital Middle Post. Cervical (Spinal Accessory Chain) Lower Post. Cervical (Spinal Accessory Chain) Supraclavicular (Trans. Cervical Chain)
    • 4. Head and Neck Cancer (HNC) Malignant Tumors
      • Squamous cell carcinoma (SCC)
      • Most common primary cancer (> 90%)
      • Differentiation
      • (well-moderate-poor)
      • based on keratinization
      • Other carcinomas
      • Adenocarcinoma
      • Mucoepidermoid carcinoma
      • Lymphoepithelioma
      • Lymphomas
      • Non-Hodgkin’s
      • Hodgkin
      • Sarcomas
      • Metastatic cancers
      • Lung
      • GI tract
      • Breast
    • 5. Head and Neck Cancer Epidemiology
      • 5 - 6% of all cancer ( + 650.000 new cases/year)
      • 6th most frequent cancer worldwide
      • Parts of Southeast Asia: most frequent malignancy
      • Incidence increases with age (most cases > 45 years)
      • Average male to female ratio 3:1, but it differs for the various anatomical sites
      • High incidence of second primary tumors
    • 6. Head & Neck Cancer Worldwide incidence and mortality (estimated) 141 40 77 66 24 50 0 40 80 120 160 Mouth Nasopharynx Other Pharynx Cases (thousands) Incidence Mortality Males (thousands) Females (thousands) Parkin DM, et al. CA Cancer J Clin. 1999;49:33-64. 70 18 17 34 11 12 0 40 80 120 160 Mouth Nasopharynx Other Pharynx Cases (thousands) Incidence Mortality
    • 7. Epidemiology of SCCHN Squamous cell carcinoma of the head and neck (SCCHN): 95 000 new cases in Europe annually SCCHN: mortality in Europe is 43 000 annually SCCHN accounts for 6% of all malignancies Worldwide annual incidence of SCCHN: 644 000 new patients; 352 000 deaths Source: IARC, Globocan 2002
    • 8. Head and Neck Cancer in Europe, ASR (n/100.000), Males 0 5 10 15 20 25 30 35 40 45 Sweden Finland Iceland Norway Ireland United Kingdom The Nederlands Denmark Latvia Austria Switzerland Estonia Belgium Germany Lithuania Luxembourg France
    • 9. Most Frequently Occurring Invasive Tumors per Age Group and Gender, 2000-2001
    • 10. Head and Neck Cancer Risk factors
      • Tobacco
      • Alcohol
      • Betel nut chewing
      • Male gender
      • Genetic susceptibility
      • Occupational exposure
      • Malnutrition
      • Poor dental care
      • Mechanical irritation
      • Chronic viral infection
      • Stupp R, Vokes EE 1998 / Shaha AR, 2001
    • 11. Molecular and Epidemiological Evidence suggest that HPV is Associated with a Distinct Subset of SCCHN HPV+ oropharynx cancer
          • P53 WT
          • basaloid
          • favorable prognosis
          • correlation with HIV+ and anogenital HPV+ cancer
          • Gillison et al, 2000
    • 12. Gillison, et al., 2000
    • 13.
      • Incidence increasing for HPV-related
      • Incidence decreasing for HPV-unrelated
      • Equalization in 2004
      Incidence Trends in the US Chaturvedi A et al. JCO 2008
    • 14. Differences between HPV+ and HPV- SCCHN HPV-pos HPV-neg Anatomical Tonsil, base of tongue All sites Histology Non-keratinized Keratinized Age Younger cohorts Olders cohorts Sex ratio 3:1 men 3:1 men Stage Tx, T1-2 Variable Risk factors Sexual behaviour Alcohol, tobacco Incidence Increasing Decreasing Survival Improved Unchanging Marur et al, 2010
    • 15. HPV Oropharyngeal Cancer
      • HPV positive tumor
      • HPV negative tumor
      E6 inactivate p53 E7 inactivate pRb Wild-type p53 p16 not inactivated p53 mutations p16 alteration Normal mucosa HPV: oncoprotein E6/E7 Tobacco/C2H5OH
    • 16. Head and Neck Cancer Nasopharyngeal cancer and EBV
      • Endemic in regimens of Northern Africa and Asia
      • Etiology distinct from other head and neck cancers
      • Epstein-Barr viral proteins detectable in majority of NPCs
      • Associated with frequent consumption of salted fish or nitrosamines
      • Stupp R, Vokes EE, 1998
    • 17. Head and Neck Cancer Biology
      • Mucosal surfaces in the upper aerodigestive tract, lungs and esophagus are exposed to the same carcinogens
      • Therefore, multiple anatomical sites may be at risk for the simultaneous or sequential development of dysplasia and malignant lesions (the concept of “field cancerization”: Slaughter et al, 1953)
      • Braakhuis et al, 2003
    • 18. Models of genetic instability and progression in head and neck cancer. Haddad RI, Shin DM. N Engl J Med 2008; 359: 1143-54
    • 19. Head and Neck Cancer Prevention
      • Avoidance of tobacco and alcohol
      • Routine medical examination
      • Participaton in chemoprevention trials
      • Stupp R, Vokes EE, 1998
    • 20. Head and Neck Cancer Early detection in patients at risk
      • Annual physical examination
      • Special attention to upper aerodigestive tract and neck with digital examination of oral cavity
      • Referred for evaluation of unexplained symptoms
      • Biopsy / FUP for leukoplakia and erythroplakia
      • Stupp R, Vokes EE, 1998
    • 21. Leukoplakia (smoker’s keratosis)
    • 22. Erythroplasia
    • 23. Head and Neck Cancer Screening of at-risk patients
      • Not generally succesful due to:
      • Low level of participation of at-risk patients in screening programs
      • Prolonged subclinical disease state
      • Constraints on time and need for education in primary care setting
      • Schantz et al, 2001
    • 24. Head and Neck Cancer Typical symptoms by site (1) Site of origin Symptoms Nasopharynx Early: hearing loss, tinnitus, epistaxis nasal obstruction, single LN Late: headache, cranial nerve abnormalities, trismus, multipe LN, weight loss Oral cavity Early: superficial mucosal pain, denture malposition, mouth bleeding Late: pain from bone invasion, cranial nerve abnormalities, tongue tethering, trismus palpable LN, weight loss, skin infiltration O’Sullivan et al, 1999
    • 25. Head and Neck Cancer Typical symptoms by site (2) Site of origin Symptoms Glottic larynx Early: hoarseness (glottic) Late: dyspnea (airway obstruction), cartilage penetration (neck mass) Supraglottis/oropharynx Early: dysphagia or otalgia (supraglottic) Hypopharynx Late: dyspnea (airway obstruction), odynophagia, palpable LN, weight loss O’Sullivan et al, 1999
    • 26. Head and Neck Cancer Physical evaluation (1)
      • General physical examination
        • height, weight, performance status
        • PE of heart, lungs, abdomen
        • vital signs
      • Specified physical examination directed at the different disease sites in the head and neck area and possible second primary sites
    • 27. Head and Neck Cancer Physical evaluation (2)
      • Inspection of mucosa
      • Bimanual examination of oral cavity
      • Palpation of the neck
      • Biopsy of leukoplakia, erythroplakia, erythroleukoplakia
      • Indirect laryngoscopy
      • Endoscopic examination
        • Direct laryngscopy
        • Esophagoscopy
        • Bronchoscopy
      • Vokes et al, 1993
    • 28. Diagnostic Procedures Physical Examination
      • Oral cavity
    • 29. Diagnostic Procedures Physical Examination
      • Pharynx
    • 30. Diagnostic Procedures Physical Examination
      • Larynx
    • 31. Head and Neck Cancer Examination of the neck
      • Inspection
      • asymmetry, masses, atrophy
      • Palpation
      • level I to VI
        • Size, consistency, level and fixation
        • Submental region (level I)  bimanual transoral palpation
      • Thyroid gland
    • 32.  
    • 33.  
    • 34. wrong
    • 35. correct
    • 36.  
    • 37. Diagnostic Procedures Physical Examination
      • Neck
      • localization?
      • size?
      • consistency?
      • mobiity?
      • Pulsations?
    • 38. Diagnostic Procedures Physical Examination
      • Ear
    • 39. Diagnostic Procedures Physical Examination
      • Nose
    • 40. Diagnostic Procedures Examination under anesthesia
      • Natural extension of the clinical evaluation
      • Extent of the lesions
      • Histology
      • Additional primary tumors
        • Inspection
        • Palpation
        • Direct laryngoscopy
        • Esophagoscopy
        • Bronchoscopy
    • 41. Diagnostic Procedures Examination under anesthesia
      • Direct laryngoscopy
        • Different laryngoscopes: visualisation of tongue base, vallecula, pyriform sinus, post-cricoid area and the larynx
        • Excisional biopsy with the CO2 laser or with cold instruments  margins neg. = definitive treatment
        • Cytology, in vivo stains (Toluidin-Blue) and contact-endoscopy may guide the surgeon
    • 42. Diagnostic Procedures Examination under anesthesia
      • Direct laryngoscopy
    • 43. Diagnostic Procedures Examination under anesthesia
      • Esophagoscopy and bronchoscopy
        • 15% incidence of synchronous second primary tumors
        • Chest X-rays are more sensitive than rigid bronchoscopy in asymptomatic patients?
        • Is in the follow-up systematic panendoscopy to detect early second primaries useful?
    • 44. Diagnostic Procedures Examination under anaesthesia
      • Esophagoscopy and bronchoscopy
    • 45. Diagnostic Procedures Imaging Techniques
      • CT and/or MRI
        • Seldom necessary to make the diagnosis
        • Extension of the tumor
        • Cartilage and bone invasion,
        • Perivascular spread
        • Regional lymph nodes
        • Follow-up  recurrence or residual tumor  earlier salvage therapy
    • 46. Diagnostic Procedures Imaging Techniques
      • CT MRI
    • 47. Diagnostic Procedures CT vs MRI
      • CT-scan
      • Greater availability
      • Superior bone detail
      • Superior cervical LN
      • Shorter duration
      • Fewer limiting factors
        • Claustrophobia
        • Implanted metallic objects
      • MRI
      • Preferred in specific regions
        • Nasopharynx
        • Intracranial extension
        • Tumor spread / submucosal extension
        • DD tumor recurrence or scar tissue
    • 48. Diagnostic Procedures Other imaging techniques
      • Chest X-ray
        • distant metastasis
      • Ultra sound
        • distant metastasis
        • detecting small lymph-nodes
      • Radionuclides imaging
        • thyroid gland malignancy
        • bone metastasis.
      • PET and SPECT scan
    • 49. VdP: Progression after EXTREME (03.05.06) PET-scan: January 2006 PET-scan: May 2006
    • 50. VdP: Antitumor Effect of TPF + Cetuximab (2006)
    • 51. Head and Neck Cancer (lip, oral cavity) TNM summary T1 < 2 cm T2 > 2 to 4 cm T3 > 4 cm T4a lip : through cortical bone, inferior alveolar nerve, floor of mouth, skin oral cavity : through cortical bone, deep/extrinsic muscle of tonge, maxillary sinus, skin T4b masticator space, pterygoid plates, skull base, internal corticoid artery N1 Ipsilateral single < 3 cm N2 (a) ipsilateral single > 3 to 6 cm (b) ipsilateral multiple < 6 cm (c) bilateral or contralateral < 6 cm N3 > 6 cm TNM classification of malignant tumors, 7th Edition (2009 )
    • 52. TNM Staging 1 resectable; 2 unresectable; 3 advanced resectable; 4 advanced unresectable; 5 distant metastatic N0 N1 N2 N3 T1 I III IVa 3 , b 4 , c 5 T2 II T3 T4a 1 T4b 2
    • 53. Results of Present Therapies
      • Early stages (I and II)  single modality TRT
      •  5-yr S: 60-90%
      • Advanced stages (III and IV)  combined modality
      •  5-yr S: < 35%
        • Resectable: > 60% LRR, 20% DM, 10-40% SPT
        • Unresectable: 5-yr S < 20%, majority † < 18 months
      • Recurrent/metastatic disease  chemotherapy
      • Median survival 6-10 months, 1-year survival 20-40%
    • 54. Diagnostic Procedures Conclusions (1)
      • Accurate staging is very important in the decision making of head and neck tumors.
      • It makes more conservative treatments such as endoscopic laser resection and external partial laryngectomy possible, without affecting the recurrence rate and survival.
      • This contributes to the quality of live of the patients.
    • 55. Diagnostic Procedures Conclusions (2)
      • In the diagnostic work up of head and neck tumors clinical and endoscopical evaluations play the most important role.
      • Imaging techniques are very useful in refining the extent of the tumor, because on clinical basis the tumor is very often understaged.
      • Open biopsies of neck masses are reserved if all clinical and radiological studies cannot reveal the primary tumor.
    • 56. Head and Neck Cancer Treatment
    • 57. Treatment Modalities in SCCHN 2011
      • Surgery as single modality
      • Radiotherapy (RT) or in combination
      • Chemotherapy (CT)
        • combined modality treatment (CMT):
        • Induction CT (ICT); concomitant CT and RT (CCRT); sequential therapy (ICT  CCRT); adjuvant CCRT postoperative
        • Palliative therapy
      • Targeted therapy (TT)
        • Alone or combined with RT, CMT or palliative CT
    • 58. HN Surgeon Radiation Oncologist Medical Oncologist Anesthesiologist Internist GP Radiologist Social worker Psychologist Patient Guidelines Clinical trials Biologist Pathologist Dietician Speech Therapist
    • 59. Considerations in Decision Making
      • Pretreatment considerations 1
        • Comorbid chronic disease (pulmonary, CV, digest.)
        • Malnutrition (severe in > 25% of patients)
        • Oral health (periodontal disease, infections, caries)
      • Morbidity of treatment (radiotherapy, chemotherapy, targeted therapy, surgery) 1
      • What do patients want? (cure, long living, no pain) 2
      • 1 Schantz SP et al. Cancer: Principles & Practice of Oncology, 6th ed. 2001; 797-860
      • 2 List, Head and Neck, 2004
    • 60. Multimodality Treatment Approaches (MMTAs) in Locoregionally Advanced SCCHN
      • Historically: Surgery ( + RT) or RT alone
      • Outcomes poor for OS and OP
      • Currently there are three multimodality treatment approaches:
      • Surgery  adjuvant concurrent CRT
      • Definitive concurrent CRT, with surgery as an optional salvage or completion treatment
      • Induction CT  definitive local therapy
      • Seiwert et al, Nat Clin Pract Oncol 2007; 4 (3): 156-171; OS = overall survival; OP = organ preservation
    • 61. 63 randomized trials MACH-NC = Individual patients data base 7,307 deaths (68 %) 10,741 patients Lancet 2000;355:949-55 IGR 10.00 Meta-Analysis of Chemotherapy in Head & Neck Cancer MACH-NC
    • 62. MACH-NC: Results - Overall Survival Chemotherapy Risk P Absolute benefit timing reduction value at 5 years Adjuvant 2% NS 1% Neoadjuvant* 5% NS 2% Concomitant 19% < 0.0001 8% Total 10% < 0.0001 4% * 15 studies with PF 5% Pignon et al, 2000 (63 trials / 10.741 patients)
    • 63. Effects of Concomitant Chemoradiotherapy
      • Better local control than with RT alone
      • Better survival than with RT alone
      • Best results with cisplatin (based) CT
      • But,
      • Toxicity, bot acute and late, is enhanced
    • 64. CRT: Significant Increase in Acute Toxicity Acute adverse effects: Grade ≥ 3 p<0.05 ns Patients (%) p<0.01 Wendt TG, et al. J Clin Oncol 1998;16:1318–1324 0 10 20 30 40 50 60 Xerostomia Nausea/emesis Leukopenia Dermatitis Mucositis RT alone (n=140) CRT (n=130) ns, not significant CRT = CDDP + 5-FU + RT
    • 65. CRT: Late Toxicity
      • Analysis of 230 patients receiving CRT in 3 studies (RTOG 91-11, 97-03, 99-14)
      10% 12% 27% 13% 43% 0 10 20 30 40 50 Patients (%) Any severe late toxicity Feeding-tube dependence >2 yrs post-RT Pharyngeal dysfunction Laryngeal dysfunction Death Machtay M, et al. J Clin Oncol 2008; 26: 3582–3589
    • 66. How to Overcome the Limitations of Concurrent Chemoradiation (CRT)
      • Explore options to reduce toxicity of CRT
      • - in terms of RT techniques
      • - in terms of targets for response & sensitization (bioradiation)
      • Make a better selection of patients who might need more and who might need less treatment
    • 67. Planning Comparative Studies Standard IMRT versus swallowing sparing IMRT (SW-IMRT) Standard IMRT aiming at sparing parotid glands (PCM D mean = 60 Gy) Swallowing sparing IMRT aiming at sparing parotid glands and superior PCM (PCM D mean = 50 Gy) Van der Laan, et al. work in progress 2011
    • 68. IMRT SWIMRT Translating dose difference into clinical benefit Mean dose Radiotherapy alone Radiotherapy + concomitant chemotherapy Estimated Benefit SWIMRT Combining NTCP-model with planning comparison Van der Laan, et al. work in progress 2011 Tube feeding dependency (6 months)
    • 69. Enhancement of Radiation Effects Selective Targeting of Hypoxic Cells Induction of Pro-Apoptotic Mechanisms Anti- Angiogenesis Strategies Inhibition of Cox-2 Replacement of Mutated Tumor Suppressor Genes Inhibition of EGFR Several biological mechanisms that have potential to alter sensitization strategies (Choy and MacRae, 2003)
    • 70. EGFR-targeting Agents under Clinical Investigation in SCCHN Monoclonal antibodies Toxicity Cetuximab IMC225 chimeric human/murine IgG1 skin Matuzumab EMD72000 humanized mouse IgG1 skin Nimotuzumab h-R3 humanized mouse IgG1 systemic/hemodynamic Zalutumumab 2F8 human IgG1 skin Panitumumab ABX-EGF human IgG2 skin Tyrosine kinase inhibitors Gefitinib ZD1839 reversible EGFR skin/gastrointesinal (GI) Erlotinib OSI-774 reversible EGFR skin/GI Lapatinib GW-572016 reversible EGFR/erbB2 skin/GI/systemic Afatinib BIBW-2992 irreversible EGFR/erbB2 skin/GI/systemic Canertinib CI-0033 irreversible EGFR skin/oral/GI/systemic
    • 71. Cetuximab: Properties and Mechanism of Action
      • IgG 1 monoclonal antibody
      • Specifically binds to the EGFR with higher affinity than its natural ligands (TGFα, EGF), thus competitively inhibiting their binding
      • H igh affinity: K d = 0.39 nM
      • Induces apoptosis and ADCC1
      • Preclinical synergistic activity in combination with chemotherapy and radiotherapy
      ADCC = antibody-dependent cellular cytotoxicity
    • 72. Bonner et al. N Engl J Med 2006; 354: 567-578
    • 73. Cetuximab + RT in locally advanced SCCHN: Study design Bonner et al. N Engl J Med 2006; 354: 567-578 RT as before + ERBITUX initial 400 mg/m 2 2-h infusion then 250 mg/m 2 1-h infusion weekly for at least 7 doses RT once or twice daily or concomitant boost for 7 – 8 weeks Patients with measurable locally advanced SCCHN (stratified by KPS;node+/0;T1-3/4; RT regimen) Randomization Follow-up until disease progression or up to 5 years
    • 74. Results of the Cetuximab/Radiotherapy Trial
      • Better locoregional control than with RT
      • Better survival than with RT
      • No increase in severe mucositis
      • No significant increase in severe RT dematitis
      • No decrease in quality of life
      • Seemingly better compliance than with CRT
    • 75. Overall Conclusion No direct comparison *level I evidence; **level II evidence; + with mono Platin therapy Concurrent chemoradiation Bioradiation ( cetuximab ) 50 trials, 9615 pts (MA)* 1 trial, 424 pts (Bonner trial)** HR of death 0.74 (0.67-0.82) + HR of death 0.74 (0.57-0.97) Main effect on local failure Modest effect on DM Only effect on local failure No effect on DM Efficacy irrespective of site and of fractionation schedule Effect may be site and RT schedule specific Significant acute toxicity which may inflict on late toxicity, in particular swallowing dysfunction Skin reaction?? Late toxicity as RT Compliance of receiving cetuximab 90% in the Bonner trial
    • 76. Analysis of Failures in Phase III CCRT or BRT Trials Trials Group Year Published Locoregional failure (%) Distant metastases (%) % of failures due to DM INT 2003 22 23 51 EORTC 2005 18 21 54 RTOG 2005 16 20 65 GORTEC Bonner 2005 2006 57 53 18 17 32 30 Modified from Posner and Vermorken, 2008
    • 77. Rationale for Induction Chemotherapy (ICT)
      • Optimal drug delivery: high response rates: transient toxicity
      • Improves nutritional status and performance status
      • Has an established efficacy in organ preservation strategies
      • No compromise of subsequent RT or surgery
      • Response to ICT predicts response to RT
      • Is an early systemic treatment of occult disease
      • Most recent studies have indicated that the combination of docetaxel, cisplatin and 5-FU (TPF) is a new standard
    • 78. Randomized Trials of Sequential Therapy versus Concurrent Chemoradiation Only Group Regimen TPF (or PF) x 3  CRT (cisplatin) TTCC (Sp) CRT (cisplatin) TPF x 3  CRT (carboplatin) Boston (US) CRT (cisplatin) TPF x 2  THFX Chicago (US) THFX XRT (cetuximab) TPF x 3 XRT (PF) GCTCC (It) XRT (cetuximab) XRT (PF)
    • 79. Recurrent and/or metastatic SCCHN Introduction
      • Over 50% of newly diagnosed stage III/IV SCCHN cases are not cured and will relapse locally or at distant sites
      • 10% of newly diagnosed cases present with distant metastases
      • Treatment options: - Chemotherapy (CT) - Re-irradiation - Salvage surgery - Best supportive care (BSC)
      • Cisplatin-based CT: - Response rate: 30% - Overall survival: 6 – 9 months
    • 80. Development of Chemotherapy in R/M SCCHN 1977: cisplatin shows efficacy in 1 st -line SCCHN CABO, cisplatin, methotrexate, bleomycin, vincristine *significant Clavel et al. Ann Oncol 1994; Forastiere et al. JCO 1992; Gibson et al. JCO 2005; Grose et al. Cancer Treat Rep 1985; Vermorken et al. NEJM 2008; Wittes et al. Cancer Treat Rep 1977 N Regimen ORR (%) Median OS (months) Significant OS benefit Grose et al 1985 100 Methotrexate Cisplatin 16 8 5.0 4.5 No Forastiere et al 1992 277 Cisplatin + 5-FU Carboplatin + 5-FU Methotrexate 32* 21 10 6.6 5.0 5.6 No Clavel et al 1994 382 CABO Cisplatin + 5-FU Cisplatin 34* 31* 15 7.3 7.3 7.3 No Gibson et al 2005 218 Cisplatin + 5-FU Cisplatin + paclitaxel 27 26 8.7 8.1 No Vermorken et al 2008 442 Platinum + 5-FU Platinum + 5-FU + Cetuximab 20 36* 7.4 10.1* Yes
    • 81. Completed Randomized Trials in First-Line Recurrent/Metastatic SCCHN Study/Reference N Regimen RR (%) PFS (mo) OS (mo) ECOG 5397/ Burtness et al 2005 117 Cisplatin + cetuximab Cisplatin + placebo 26 a 10 4.2 2.7 9.2 8.0 EXTREME/ Vermorken et al 2008 442 PF 1 + cetuximab PF 1 36 a 20 5.6 b 3.3 10.1 c 7.4 SPECTRUM/ Vermorken et al 2010 657 PF 2 + panitumumab PF 2 36 a 25 5.8 b 4.6 11.1 9.0 PF 1 = cisplatin or carboplatin plus 5-FU; PF 2 = cisplatin plus 5-FU a, b, c : significant differences
    • 82. Other Novel Targeted Agents in SCCHN
      • Anti-angiogenesis
        • VEGF
        • VEGFR
      • Integrin inhibitors
      • Histone deacetylase inhibitors
      • SRC inhibitors
      • Proteasome inhibitors
      • IGFR inhibitors
      • No phase III data!
    • 83. Conclusions
      • Better understanding of the biology of SCCHN has led to change in treatment approaches, which may end up with improved outcome and less toxicity
      • Better selection of patients for specific treatment approach may become an important issue in future trials
      • Finally a breakthrough in R/M SCCHN after 30 years
    • 84.  
    • 85.  

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