Head and Neck Cancer. Mukund Seshadri DDS, PhD.!

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1 Head and Neck Cancer Mukund Seshadri DDS, PhD

2 Overview Epidemiology Etiology and Risk factors Disease Biology Management Conventional Novel Targeted Therapies Treatment- related complications Impact of HPV

3 Head and Neck Cancers rmgmed.com Sixth most common cancer world wide Annual global incidence ~600,000 cases Biologically heterogeneous group of cancers Weiss and Hayes, Expert Reviews 2014

4 Epidemiology Incidence of ~54,000 in the US (~3% of all cancers) ~12,000 deaths annually in the US Diagnosed more often in people over 50 but Epidemiology of the disease is changing Siegel et al, 2014

5 Epidemiology High incidence areas of central Asia and the Indian sub- continent Eastern Europe and the former Soviet republics have high mortality (low socio- economic status, limited treatment facilities) Papua New Guinea and surrounding melanesian islands of the Western Pacific are in the top quintile both in incidence and mortality Johnson and Amarasinghe, J Bernier Head and Neck Cancer: Multimodality Management

6 Clinical Significance Prognosis varies depending on site Stage of presentation varies (lip vs. hypopharynx) Vascularization, ease of surgical access Weiss and Hayes, Expert Reviews 2014

7 Etiology and Risk factors Tobacco Single most important risk factor Cigarettes, pipe, smokeless tobacco (chew, snuff, betel quid) Increased risk of HNC in smokers (5-20 fold> non- smokers) Warnakulasuriya et al. 2005

8 Alcohol Etiology and Risk factors Second most common risk factor Association is stronger for pharyngeal cancer Tobacco and alcohol - synergistic effects on risk of HNC ACS Atlas of the Head and Neck Jatin Shah

9 Viral infection Etiology and Risk factors EBV nasopharyngeal carcinoma HIV HPV Occupational exposure Radiation Diet Genetic factors Scully & Bagan, 2009

10 Changing Epidemiology of HNSCC Lifestyle changes (tobacco consumption has decreased) Incidence of larynx, oral cavity cancers are decreasing Tonsils/Oropharyngeal cancers are increasing Ang and Sturgis, Seminars in Rad Oncol. 2012

11 HPV- associated Head and Neck Cancers Oropharynx Increasing incidence in US, Canada, Australia and Japan A developed country phenomenon Rising incidence in young males Reason: Change in sexual behaviors Male predominance Efficiency of transmission through oral sex Marur et al., 2010 Chaturvedi et al., NCI

12 Head and Neck Carcinogenesis Forastiere et al., 2001

13 Premalignant or Potentially malignant lesions Leukoplakia Erythroplakia Lichenoid lesions Submucous fibrosis Oral epithelial dysplasia Diagnosis: Clinical + histopathologic assessment Hunter et al., 2005

14 Leukoplakia Homogeneous Non- homogeneous with ulceration A white plaque that does not conform clinically or histopathologically to any specific disease & cannot be attributed to reactive, frictional, or traumatic causes 9-37% represent dysplasia, carcinoma in situ or invasive carcinoma at the time of biopsy 16-36% of dysplasias develop invasive carcinoma Sook- Bin Woo, DMD, MMSc, Oral Pathology

15 Leukoerythroplakia Proliferative leukoplakia Proliferative leukoplakia is multifocal or extensively 60% to 100% of proliferative leukoplakias develop carcinoma Highest incidence of malignancy - ventral tongue, floor of mouth, and soft palate Sook- Bin Woo, DMD, MMSc, Oral Pathology

16 Erythroplakia Erythroplakia of the palate (histologically CIS) Velvety red plaque, usually painless, less common than leukoplakia >90% of the lesions are dysplastic or malignant at the time of diagnosis Sook- Bin Woo, DMD, MMSc, Oral Pathology

17 Histopathology of Oral lesions Speight, Head and Neck Pathol 2007

18 Histopathology of Oral lesions Mild dysplasia Moderate dysplasia Nuclear pleomorphism Hyperchromatism Cytologic atypia Basal cell hyperplasia Increased cell density Disordered maturation Speight, Head and Neck Pathol 2007

19 Histopathology of Oral lesions Severe dysplasia Carcinoma in situ Cell and nuclear pleomorphism Abnormal mitotic figures Hyperchromatic nuclei Full thickness changes Architectural disruption Loss of stratification Speight, Head and Neck Pathol 2007

20 Pathology of Head and Neck Cancers Majority (~75%) are squamous cell carcinomas Moderately diff SCC ACS Atlas of the Head and Neck Jatin Shah

21 Pathology of Head and Neck Cancers Salivary glands ACS Atlas of the Head and Neck Jatin Shah

22 Perineural Invasion in SGC Cancer cell invasion in, around and through nerves or the finding of tumor cells within any of the the layers (epineurium, perineurium, endoneurium) of the nerve sheath. ACCs and SDCs exhibit high degree of PNI; SCCs also exhibit PNI frequently. Indicator of aggressive behavior and independent prognostic factor in ACC Johnston et al 2012

23 Head and Neck Carcinogenesis Field cancerization and local relapse Presence of one or more mucosal areas consisting of epithelial cells that have cancer- associated genetic or epigenetic alterations Leemans et al., 2011

24 Clinical evaluation Evaluation of suspicious oral lesions Williams et al 2008

25 Clinical evaluation Appearances of oral premalignant and early cancer smooth, white, homogeneous red, diffuse, granular lesion; diffuse, red ulcerated lesion diffuse, raised,speckled, indurated lesion Williams et al 2008

26 Autofluorescence imaging Clinical evaluation Visualization of a diffuse, nodular erythro- leukoplakia at the right lateral ventral tongue Moderate-severe dysplasia Williams et al 2008

27 Diagnosis/Staging of HNC Biopsy Essential for diagnosis of malignancy FNA nodal disease, parotid, thyroid lesions, TNM classification Combination of histopathologic/radiologic assessment Standardized classification system

28 TNM Classification T tumor size, location, extent N lymph node involvement (size, side) M metastases American Joint Committee on Cancer, Cancer Staging

29 Diagnosis/Staging of HNC Lymph node distribution of the head and neck region Critical component of the clinical examination Marur et al, Mayo Clin Proc 2008

30 Staging of HNC Describes the severity of an individual's cancer based on the magnitude of the original (primary) tumor as well as on the extent cancer has spread in the body Clinical Staging - based on physical examination, imaging tests, and biopsies. Pathologic Staging - Combines the results of clinical staging with pathologic examination of surgical tissue Post- Therapy or Post- Neoadjuvant Therapy Staging - determines how much cancer remains after a patient is first treated with systemic (chemotherapy or hormone therapy) and/or radiation therapy prior to their surgery or where no surgery is performed. This can be assessed by clinical staging guidelines and/ or pathologic staging guidelines. Restaging is used to determine the extent of the disease if a cancer comes back after treatment. Restaging helps determine the and the best treatment options for cancer that has returned. American Joint Committee on Cancer, Cancer Staging

31 Staging of HNC TNM staging system allows clinicians to categorize tumors of the head and neck region in a specific manner to assist with the assessment of disease status, prognosis, and management. Deschler and Day, TNM Staging of Head and Neck Cancer

32 Radiologic assessment Plain X- ray Panorex bone invasion - mandible Chest small lesions CT bone involvement, cystic nodal metastasis (CT with contrast) MRI soft tissue (extent of tumor, bone invasion, vascular involvement) PET - metastatic survey

33 Management of Head and Neck Cancer NCCN Guidelines 2011

34 Management of Head and Neck Cancer SUPPORTIVE SERVICES NCCN Guidelines 2011

35 Primary Therapy Decision Making Surgery, Chemotherapy and Radiation (+/- Targeted Therapy) Patient status Age, debility, pulmonary status, medical co- morbidities psychological status, motivation, family support, rehab potential Primary Tumor Anatomic site, tumor volume, extent (PNI, bone invasion etc), field cancerization Anticipated cosmetic and functional sequelae QOL Prior therapy ACS Atlas of the Head and Neck Jatin Shah

36 Optimizing the Therapeutic Ratio in HNC Balance between disease control and toxicity Corry et al 2010

37 Management of Head and Neck Cancer Surgery Oral cavity Primary treatment Eliminates risk of ORN (complication of RT) Larynx Organ preservation/conservative laryngeal procedures can preserve voice Salivary gland tumors Surgery + post- operative RT for high- grade lesions Thyroid Total thyroidectomy NCCN Guidelines 2011

38 Management of Head and Neck Cancer Lymph nodes Surgery Drainage of oral cavity into extensive number of lymph nodes in the neck Neck is divided into 6 surgical levels Selective or radical neck dissection depending on stage (lymph node involvement) ACS Atlas of the Head and Neck Jatin Shah

39 Management of Head and Neck Cancer Radiation Therapy Can be pre- operative or post- operative Pre- operative RT Patients can undergo rigorous supportive therapy prior to surgery Control of sub- clinical disease at the primary site Typically given 5 days a week ( cgy; total of cgy) Post- operative RT Risk of locoregional recurrence - improved local control Advanced lesions Positive margins PNI/vascular invasion No delay in surgery, sterilization of residual microscopic disease

40 Management of Head and Neck Cancer Chemotherapy Platinum analogues Cisplatin, carboplatin Bind to DNA à s/ds breaks Taxanes Microtubule inhibitor cell cycle arrest 5- Fluorouracil Thymidylate synthase inhibition (DNA damage)

41 Management of Head and Neck Cancer The Concurrent ChemoRT paradigm Siewert et al., 2007

42 Management of Head and Neck Cancer The Concurrent ChemoRT paradigm Siewert et al., 2007

43 Molecular Pathogenesis of HNC EGFR pathway Leemans et al., 2011 Ciardiello & Tortora, 2008

44 Targeted Therapies for HNSCC EGFR inhibitors Cetuximab monoclonal antibody against EGFR First targeted agent to be approved for HNC Ciardiello & Tortora, 2008

45 Management of Head and Neck Cancer Anti- EGFR therapy + Radiation Treatment of locoregionally advanced head and neck cancer with concomitant high- dose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck. Bonner et al., 2006

46 Management of Head and Neck Cancer Anti- EGFR therapy + chemotherapy On November 7, 2011 the U.S.FDA approved cetuximab in combination with cisplatin or carboplatin and 5- fluorouracil for the first- line treatment of patients with recurrent locoregional or metastatic squamous cell head and neck cancer. The median overall survival was 10.1 months (95% CI: ) for the cetuximab/ chemotherapy arm compared to 7.4 months (6.4, 8.3) for the chemotherapy alone arm (stratified log- rank p.035). Cohen et al., 2013

47 Antiangiogenic Therapies in HNSCC Klein et al 2010

48 Treatment complications Scully/Bagan 2009

49 Treatment complications Mucositis (complication of RT) Inflammation and ulceration of the mucosal lining of the mouth, pharynx, esophagus and GI tract due to the direct cytotoxic effects on the epithelial cells - Painful, affects QOL - Management: Mouth rinses, anti- fungal agents Xerostomia (dry mouth) Effect of RT on salivary glands Management salivary substitutes, Dental management - prevention of caries, fluoride gels Osteoradionecrosis Non- vital bone in a site of radiation injury; related to radiation PreRT dental evaluation is imperative to minimize risk of ORN Supportive therapy, HBO therapy, microvascular reconstruction

50 Prognosis Clinical impact and Biological Mechanisms of HPV- associated HNSCC

51 HPV- associated Head and Neck Cancers Human papilloma virus DNA viruses with tropism for squamous epithelia High- risk oncogenic types: HPV16,- 18,- 31-,33,- 35 Rautava- Syrjanen, 2012

52 HPV & Carcinogenesis The E6 protein binds p53 and targets the protein for degradation, whereas the E7 protein binds and inactivates the Rb pocket proteins. The molecular consequence of the expression of these viral oncoproteins is cell cycle entry and inhibition of p53- mediated apoptosis, which allows the virus to replicate. Leemans et al., 2011

53 HPV+ Vs. HPV- HNSCC Marur et al., 2010 Leemans et al., 2011

54 HPV- associated Head and Neck Cancers HPV- positive HNSCC Typically well defined borders Axial contrast- enhanced CT image showing midline base of tongue mass with well- defined margins and nodal metastases Cantrell et al., 2013

55 HPV- associated Head and Neck Cancers HPV- negative HNSCC Deep muscular invasion involving the extrinsic muscles of the tongue with submucosal spread Axial contrast- enhanced CT image showing a large and deeply invasive T4 base of tongue lesion, extending anteriorly into the oral tongue. Cantrell et al., 2013

56 Prognostic Impact of HPV in HNSCC ECOG Phase II trial (Stage III or IV HNSCC) HNSCC HPV positive HPV negative OPC Patients with HPV- positive tumors had higher response rates compared to patients with HPV- negative tumors after induction chemotherapy (82% vs 55%) and after chemoradiation treatment (84% vs 57%) Fakhry et al., 2008

57 Prognostic Impact of HPV in HNSCC RTOG 0128 Strong and independent prognostic factor for survival among patients with oropharyngeal cancer Ang et al., 2010

58 Prognostic Impact of HPV in HNSCC Summary of Clinical Evidence For patients with HNSCC of the oropharynx, tumor HPV status is strongly associated with therapeutic response and survival Langer, 2012

59 Impact of HPV on Targeted Therapies p16 and HPV status have prognostic value in R/M SCCHN and survival benefits of chemotherapy plus cetuximab over chemotherapy alone are independent of tumor p16 and HPV status. Vermorken et al., 2014

60 HPV- associated Head and Neck Cancers Biological mechanisms Possible reasons for the improved survival Increased sensitivity to chemo/rad Immune surveillance to viral antigens Absence of field cancerization in these patients who tend to be nonsmokers HPV- positive tumors may have an intact apoptotic response to radiation and chemotherapy (functional inactivation may not be similar to p53 mutation). Fakhry et al., 2006 Marur et al., 2010

61 HPV- associated Head and Neck Cancers Biological mechanisms HPV+ cells exhibit enhanced sensitivity to radiation Low levels of normal functioning p53 in HPV+HNC could be activated by radiation Kimple et al., 2013

62 HPV- associated Head and Neck Cancers Biological mechanisms Kimple et al., 2013 Inactivation of the p53 and prb pathways is a common event in the molecular progression of HNSCC but occurs by different mechanisms in HPV+ and HPV- tumors. HPV- positive tumors Tend to have wild- type p53 because p53 is functionally inactivated by viral E6 oncoprotein HPV- negative tumors have specific p53 mutations demonstrated to be induced by carcinogens in tobacco Fakhry et al., 2006

63 HPV- associated Head and Neck Cancers Biological mechanisms Troy et al., 2013

64 HPV- associated Head and Neck Cancers Biological mechanisms Kostareli et al., 2012

65 Therapeutic Impact of HPV- related HNC - HPV+ and HPV- cancers are discrete cancers with differing biology. - Current HNSCC treatments have a severe impact on QOL - - Can treatment intensity be personalized by HPV status? Treatment de- intensification to reduce acute toxicity and improve patient recovery? - Selection of patients for organ preservation therapy Need to identify new approaches to treat HPV- negative HNSCC Chung and Schwartz, 2012

66 HPV- associated Head and Neck Cancers Implications for Prevention A male phenomenon No change in incidence of HPV- related cancers in women Growing burden of younger patients with good performance status and superior survival Male vaccination? Chaturvedi et al., NCI Marur et al., 2010

67 Concluding remarks Head and neck cancers Biologically heterogeneous group of cancers Management is complex and interdisciplinary Understand the role of HPV and its clinical implications The need for early detection and chemoprevention strategies Kostareli et al., 2012