Irene Possenti

Background and rationale Tobacco smoking remains one of the leading preventable causes of cancer worldwide and continues to represent a major public health challenge in Italy. Although the carcinogenicity of active smoking is well established, important gaps persist in the quantification of site specific risks, the role of secondhand smoke (SHS), and the specific estimation of the population burden attributable to tobacco exposure. In addition, stagnating trends in smoking prevalence, the emergence of novel nicotine products, and evolving public attitudes towards tobacco control policies highlight the need for updated and integrated evidence to inform prevention strategies in Italy. In response to this background, this PhD thesis aims to provide a comprehensive assessment of cancer risk and burden attributable to cigarette smoking and SHS exposure in Italy, combining updated epidemiological evidence, national data on exposure and attitudes, and methodological innovation in burden estimation. Association between tobacco exposure and cancer risk The thesis provides updated meta-analytical evidence confirming the strong association between active smoking and cancers of the upper aerodigestive tract. For nasopharyngeal cancer, pooled estimates presented in Chapter 2 showed a significantly increased risk among both current and former smokers, with clear dose-response relationships according to smoking intensity and duration. Similarly, Chapter 3 showed that smoking was associated with more than a twofold increased risk of oral and pharyngeal cancers among current smokers and a 60% increased risk for former smokers. Across sites, the analyses consistently demonstrated the cumulative and time dependent nature of tobacco related carcinogenesis, with progressive risk reduction following smoking cessation. Beyond active smoking, a major contribution of this thesis concerns involuntary exposure. A comprehensive systematic review and meta-analysis presented in Chapter 4 provided strong evidence of an association between SHS exposure and breast cancer risk among never smoking women. The synthesis demonstrated a significant excess risk together with linear dose-response relationships for duration, intensity, and cumulative exposure, addressing long standing discrepancies in the literature. These findings suggest that SHS is an important preventable carcinogenic exposure in women’s health. Tobacco use, secondhand smoke exposure, and public attitudes in Italy Using recent national data, Chapter 5 documents that tobacco use remains widespread in Italy despite decades of tobacco control efforts. Analyses conducted within this work indicate that approximately one quarter of Italian adults are current smokers, with a substantial average daily cigarette consumption. Exposure to SHS also remains common, with a meaningful proportion of non-smokers reporting daily indoor exposure, particularly in settings not fully covered by existing legislation, such as private homes, vehicles, and some workplaces. These patterns suggest persistent gaps in population protection. At the same time, Chapter 6 provides evidence of broad public support for strengthening tobacco control policies in Italy. A clear majority of adults expressed support for fiscal measures, age-based restrictions such as Tobacco 21 and Smoke Free Generation proposals, and the extension of smoke free environments to electronic cigarettes (e-cig) and heated tobacco products (HTP). This combination of high exposure and strong public support highlights an important context for future tobacco control efforts. Methodological innovation in burden estimation A key contribution of this thesis is the development and application of a novel methodological framework to estimate cancer burden attributable to tobacco smoking, presented in Chapter 7. Traditional burden estimates typically rely on average relative risks applied to broad exposure categories, which do not fully capture heterogeneity in smoking histories or the time dependent reduction in risk after cessation. In contrast, this thesis constructs individual level relative risks based on smoking status, intensity, duration, and time since cessation, calibrated using dose-response relationships from updated meta-analyses. Population attributable fractions (PAF) are then derived by aggregating individual excess risks, allowing the burden to reflect the true distribution of exposure in the population. This approach provides a realistic and flexible representation of risk and can be extended to SHS exposure and multiple cancer sites. Health and economic burden of tobacco smoking Applying this framework to national data, Chapter 8 quantifies a substantial burden of cancer attributable to tobacco smoking in Italy. High PAFs were observed for cancers of the digestive tract, including oral cavity and pharynx, oesophagus, stomach, and colorectum. Beyond cancer, the thesis documents a considerable impact of smoking on healthcare utilisation in Chapter 9. Approximately one third of hospitalisations for selected smoking related diseases were attributable to tobacco smoking, corresponding to direct hospital costs of about €1.64 billion in a single year. Public health and policy implications From a public health perspective, the findings underscore that tobacco use and SHS exposure remain central, preventable determinants of cancer burden in Italy. The identification of SHS as a breast cancer risk factor highlights the importance of protecting women from involuntary exposure and integrating SHS awareness into cancer prevention strategies alongside other lifestyle determinants such as alcohol consumption. The coexistence of high smoking and SHS prevalence with strong public support for tobacco control indicates that meaningful reductions in burden are achievable. Strengthening enforcement of existing measures, preventing initiation among younger generations, and reducing exposure through comprehensive approaches remain key priorities. Limitations The findings of this thesis should be interpreted in light of some limitations, including the reliance on observational and self-reported data and the assumptions underlying burden estimation. Consequently, the estimated risks and population burdens are likely conservative approximations of the true impact of tobacco exposure. Conclusions In summary, this thesis provides an integrated and updated assessment of tobacco attributable cancer risk and burden in Italy. By combining refined epidemiological evidence, contemporary national data, and methodological innovation, it moves beyond descriptive estimates to deliver decision relevant evidence. The results demonstrate that tobacco smoking and SHS exposure continue to generate a substantial and largely preventable burden on population health and the healthcare system, while also highlighting clear opportunities for prevention. The analytical framework and findings presented in this work can support more effective, equitable, and evidence based tobacco control strategies in Italy.