Table of ContentsList of Tables

Table 1: Comparison of SCCHN incidence in Canada and India (Globocan 2012)

Table 2: Selected physical characteristics of cigarettes, cigars, pipes and bidi

Table 3: Characteristics of SNPs involved in tobacco and alcohol metabolism

Table 6: Representation of joint effect ORs for SCCHN by strata of smoking and SNP

List of Figures

Figure 1: Pathways involving tobacco carcinogens, metabolizing enzymes and SCCHN

Figure 2: A depiction of copy number variants in human genome adopted from He et al, 2012

Figure 3: Hypothetical DAG 1

Figure 4: Hypothetical DAG 2

Figure 6 Minimal sufficient set of confounders identified from hypothetical DAGs 1 and 2 to estimate total causal effect of an exposure on the outcome

Figure 7: Causal graph representing time-varying confounders effected by prior exposure

Figure 8: Percentage of control participants recruited from participating clinics at Indian and Canadian site

Figure 9: Causal graph representing SEP in three periods of life, oral cancer and associated potential confounders

Figure 10:  Mediation model proposed by Baron and Kenny (1986)

Figure 11: Illustration of selection bias within a case-control study

Figure 12: Causal diagram illustrating information bias due to exposure misclassification

1         Introduction to be written

2         Literature review

The following sub-sections present current knowledge regarding the epidemiology of squamous cell carcinomas of the head and neck (SCCHN) with special reference to Canada and India, the role of risk factors such as tobacco, alcohol consumption and specific genetic polymorphisms involved in their metabolism, human papillomaviruses (HPV) and socioeconomic position (SEP), followed by a brief description of life-course epidemiology, case-control study design, counterfactual causal framework and directed acyclic graphs.

2.1       Squamous cell carcinomas of the head and neck (SCCHN) – Definition

Malignant tumours arising from the squamous cells that line the mucosal surface of the oral cavity, pharynx and larynx [C00‐C14, C32 under the International Classification of Diseases (ICD) 10 classification], are commonly referred to as squamous cell carcinomas of the head and neck (1). Histologically, more than 90% of cancers of the oral cavity, pharynx and larynx are of squamous cell origin (2).

2.2       Epidemiology of SCCHN

SCCHN are a heterogeneous group of cancers that differ in distribution, predisposing factors, diagnostic workup and management strategies. According to Globocan 2012 statistics, SCCHN accounted for approximately 599,500 incident cases worldwide, making them the 7^th most common cancers in incidence (3.8% of cases) (3). Most of these cancers affect males (70.8%) and are diagnosed above 60 years of age (4). The sub-site with the highest cancer incidence is the oral cavity (300,373), followed by the larynx (156,877) and pharynx (142,387) [Age standardized incidence rates (ASIR) per 100,000 population: oral cavity=4, pharynx=1.9, larynx=2.1]. Globally, these cancers were the 8^th most common causes of cancer mortality (3.6% of cases), and were responsible for 300,000 deaths in 2012 (3).

There is wide variation in the geographic distribution of SCCHN incidence across the globe (4, 5). Approximately two-thirds of the burden of incident SCCHN cases is borne by developing countries, with India accounting for 25% of new cases and 35% of deaths occurring worldwide (3). In 2012, approximately 142,000 new SCCHN cases were reported in India, accounting for 30% of all incident cancer cases in this country (6). There has been a rapid increase in the incidence of these cancers, specifically oral cancers, in India. A comparison of Globocan 2008 and 2012 reveals that oral cancer surpassed lung cancer in a span of four years to become the 3^rd most common cancer in this country after breast and cervical cancers (3, 7).

In developed countries such as Canada, SCCHN accounts for 3% of incident cancer cases (3). An increase in the incidence of SCCHN from 3,000 new cases in 1990 to an estimated 5,650 new cases in 2016 has been reported, accounting for 1,650 deaths in this country in 2016 (8). According to Canadian Cancer Statistics 2016, a significant decrease in the incidence rate of oral cavity cancers was noted in males between 1992 and 2003, after which the rates became relatively stable (8). Rates among females did not change significantly between 1992 and 2012. In contrast, the incidence rate of pharyngeal cancers has increased significantly in both males and females since the mid-1990s. In males, the incidence of pharyngeal cancers surpassed that of oral cavity cancers in 2001 while in females, the incidence of oral cavity cancers continues to be higher than that of pharyngeal cancers (8).

A comparison of SCCHN incidence between India and Canada (Table 1) based on Globocan 2012 estimates shows that the age standardised incidence rates (ASIR) for SCCHN overall and nearly all subsites for both males and females are higher in India than in Canada  (9).

Table 1: Comparison of SCCHN incidence in Canada and India (Globocan 2012)