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. 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. 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.
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
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
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
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
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
Most Frequently Occurring Invasive Tumors per Age Group and Gender, 2000-2001
Incidence Trends in the US Chaturvedi A et al. JCO 2008
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
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
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
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
Diagnostic Procedures Other imaging techniques
detecting small lymph-nodes
thyroid gland malignancy
PET and SPECT scan
VdP: Progression after EXTREME (03.05.06) PET-scan: January 2006 PET-scan: May 2006
VdP: Antitumor Effect of TPF + Cetuximab (2006)
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 )
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
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
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
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
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)
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)
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
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
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
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
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