Dr.

Supreet Singh Nayyar, AFMC

2012

Head and Neck Cancer Chemoprevention

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Def Use of synthetic or biologic agents to reverse or suppress carcinogenic progression Primary chemoprevention o Directed at patients with premalignant lesions o Pre malignant lesions in head neck include Leukoplakia Erythroplakia Secondary chemoprevention o Targeted at patients with cancer who have undergone potentially curative therapy o To prevent recurrent or metachronous disease o After successful treatment with surgery, radiation, and chemotherapy, patients with head and neck cancer are at an increased risk of metachronous primary tumor, which is estimated to occur at an annual rate of 3-10% Principles o The central idea that guides head and neck chemoprevention efforts is the concept of the diffuse injury of epithelium that results from widespread, chronic carcinogen exposure o The exposure to carcinogenic substances and carcinogenic promoters for e.g. in tobacco smoke leads to genetic changes, called sick mucosa syndrome, over large areas of the oral cavity and the airway epithelium o These changes result in a field cancerization with potential multifocal unsynchronized premalignant and malignant lesions o This may explain the high recurrence rate and the development of further primary tumors after successful treatment of early-stage (I or II) head and neck cancers. o Thus, novel approaches to controlling cancers of the head and neck region should include treatment of the surrounding condemned airway epithelium o Because these cancers develop over a prolonged period of exposure to carcinogens and promoters and because of the multistep nature of carcinogenesis, an opportunity exists to intervene in the process with chemical agents for prevention (ie, chemoprevention) o The reversal of this process is the goal of chemoprevention. o Type of agents used Antimutagenic agents Antiproliferative agents Chemoprevention proven success in familial adenomatous polyposis (FAP) and breast cancer Oral keratosis with atypia ideal model for study of head and neck cancer chemoprevention lesions are readily accessible to visual examination, diagnostic sampling, and evaluation of response to treatment

Chemoprevention Agents Agents used in head and neck cancer chemoprevention include the following: Retinoids and vitamin A (beta carotene) Vitamin E Biochemoprevention Selenium Cyclooxygenase-2 (COX-2) inhibitors
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Dr. Supreet Singh Nayyar, AFMC

2012

Tyrosine kinase inhibitors (TKIs) ONYX-015 Bowman birk inhibitor (soyabean) Green tea extracts Protease inhibitors (PIs)

Retinoids Possible mechanisms o Induce apoptosis o Suppress carcinogenesis o Decrease growth rate of epithelial cells o Reduce free radicals E.g. 13-cis -retinoic acid (13cRA)

Vitamin A Essential for the development and maintenance of normal epithelium Deficiency hyperplasia and squamous metaplasia in laboratory animals

Beta Carotene A naturally occurring, nontoxic carotenoid Found to inhibit the formation of oral squamous cell carcinoma (SCC) in animal models

Vitamin E Potent antioxidant Prevents free radical formation Chemical name alpha-tocopherol

Biochemoprevention Retinoids and interferons (IFNs) have synergistic combined effects in modulating cell proliferation, differentiation, and apoptosis

Selenium Study low levels of selenium increased head and neck cancers Another study Pt with HNSCC 200 mg of selenium daily significantly enhanced cell-mediated immune response destroy tumor cell Further level 1 studies required

Cyclooxygenase-2 Inhibitors Colorectal cancer proven that chronic inflammation & cancer development are related Celecoxib proven effective in prevention of colon adenomas in patients with familial adenomatous polyposis (FAP) Nearly 100-fold greater expression levels of COX-2 were found in HNSCC cells compared with normal oral mucosa Being tried in combination with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) leads to the inhibition of cell growth by simultaneously blocking EGFR and COX-2 pathways This combination holds great potential for HNSCC prevention, treatment, or both

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Dr. Supreet Singh Nayyar, AFMC

2012

Aspirin Nonselective cyclooxygenase (COX) inhibitor that blocks the action of COX-1 and COX-2, in turn inhibiting prostaglandin (PG) synthesis, particularly PGE2 HNSCC overexpression of COX-2 and PGE2

Targeted Therapy with ONYX-015 Target P53 tumor suppressor gene Altered P53 expression is found in up to 45% of dysplastic mucosal lesions of the head and neck ONYX-015 is an attenuated adenovirus designed to selectively replicate in and destroy p53 mutant cells Given as a mouthwash formulation held in the mouth for 30 minutes

Bowman-Birk Inhibitor Bowman-Birk inhibitor (BBI) found in soyabean Low incidence rates of several cancers in populations with a high soy intake

Green Tea Extracts Green teas contain the following 4 major polyphenols o Epicatechin (EC) o Epigallocatechin (EGC) o Epicatechin-3-gallate (ECG) o Epigallocatechin-3-gallate (EGCG) EGCG most abundant and most active constituent Biologic functions attributed to EGCG o Antioxidant o Inhibit cell proliferation o Inhibit invasiveness o Inhibits angiogenesis Mediated by signaling transduction pathways involving EGFR, nuclear kappa factor (NkF)- B, TNF-, p53, and others Prospective cohort data collected over 10 years suggest consumption of more than 10 cups of green tea a day results in decreased cancer incidence Studies are on going

Epidermal Growth Factor Receptor and Tyrosine Kinase Inhibitor Overexpression of EGFR receptors in HNSCC Lead to cell proliferation & angiogenesis EGFR inhibitors used to block them

Under Investigation

Pioglitazone Pomegranate Turmeric Erlotinib (an TKI EGFR inhibitor)

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