OBJECTIVES: This study aimed at re-evaluating the strength and shape of the dose-response relationship between the combined (or joint) effect of intensity and duration of cigarette smoking and the risk of head and neck cancer (HNC). We explored this issue considering bivariate spline models, where smoking intensity and duration were treated as interacting continuous exposures. MATERIALS AND METHODS: We pooled individual-level data from 33 case-control studies (18,260 HNC cases and 29,844 controls) participating in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. In bivariate regression spline models, exposures to cigarette smoking intensity and duration (compared with never smokers) were modeled as a linear piecewise function within a logistic regression also including potential confounders. We jointly estimated the optimal knot locations and regression parameters within the Bayesian framework. RESULTS: For oral-cavity/pharyngeal (OCP) cancers, an odds ratio (OR) >5 was reached after 30 years in current smokers of ∼20 or more cigarettes/day. Patterns of OCP cancer risk in current smokers differed across strata of alcohol intensity. For laryngeal cancer, ORs >20 were found for current smokers of ≥20 cigarettes/day for ≥30 years. In former smokers who quit ≥10 years ago, the ORs were approximately halved for OCP cancers, and ∼1/3 for laryngeal cancer, as compared to the same levels of intensity and duration in current smokers. CONCLUSION: Referring to bivariate spline models, this study better quantified the joint effect of intensity and duration of cigarette smoking on HNC risk, further stressing the need of smoking cessation policies.

Aichi Cancer Center Research Institute Nagoya Japan

Boston University School of Public Health Boston MA USA

Branch of Medical Statistics Biometry and Epidemiology G A Maccacaro Department of Clinical Sciences and Community Health Università degli Studi di Milano Milano Italy

Brown University Providence RI USA

Cancer Epidemiology Unit Centro di Riferimento Oncologico di Aviano IRCCS Aviano Italy

Cancer Registry of Norway Oslo Norway

Cancer Research Centre Moscow Russia

College of Public Health University of Iowa Iowa City IA USA

Department of Biomedical and Clinical Sciences Università degli Studi di Milano Milano Italy

Department of Cardiovascular and Thoracic Sciences and Public Health University of Padova Padova Italy

Department of Economics Business Mathematics and Statistics University of Trieste Trieste Italy

Department of Epidemiology Brown University School of Public Health Providence RI USA

Department of Head and Neck Surgery Division of Surgery The University of Texas MD Anderson Cancer Center Houston TX USA

Department of Hygiene Epidemiology and Medical Statistics School of Medicine National and Kapodistrian University of Athens Athens Greece

Department of Medical Sciences University of Turin Turin Italy

Department of Oncology Istituto di Ricerche Farmacologiche Mario Negri IRCCS Milan Italy

Department of Otorhinolaryngology School of Medicine and Surgery University of Milano Bicocca Monza Italy

Department of Statistics Padua University Padua Italy; Department of Economics Business Mathematics and Statistics University of Trieste Trieste Italy

Department of Woman and Child Health and Public Health Public Health Area Fondazione Policlinico Universitario A Gemelli IRCCS Roma Italy; Sezione di Igiene Istituto di Sanità Pubblica Università Cattolica del Sacro Cuore Roma Italy

Departments of Epidemiology and Environmental Health Sciences School of Public Health and Department of Urology Medical School University of Michigan Ann Arbor MI USA

Dipartimento di Scienze dell'Invecchiamento Neurologiche Ortopediche e della Testa Collo Fondazione Policlinico Universitario A Gemelli IRCCS Roma Italy; Istituto di Clinica Otorinolaringoiatrica Università Cattolica del Sacro Cuore Roma Italy

Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda MD USA

Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg Germany

Division of Epidemiology New York University School Of Medicine New York NY USA

Division of Head and Neck Surgical Oncology in the Department of Otolaryngology Head and Neck Surgery at Washington University School of Medicine USA

Division of Public Health Department of Family and Preventive Medicine and Huntsman Cancer Institute University of Utah School of Medicine Salt Lake City UT USA

Division of Public Health Department of Family and Preventive Medicine University of Utah School of Medicine Salt Lake City UT USA

Epidemiology CIPE ACCAMARGO Sao Paulo Brazil

Escola Nacional de Saude Publica Fundacao Oswaldo Cruz Rio de Janeiro Brazil

Hospital Moinhos de Vento Porto Alegre Brazil

Inserm Center for Research in Epidemiology and Population Health Cancer and Environment team Université Paris Sud Université Paris Saclay Villejuif France

Institut Catala Oncologia Barcelona Spain

Institut Universitaire de Medecine Sociale et Preventive Centre Hospitalier Universitaire Vaudois and University of Lausanne Lausanne Switzerland

Institute of Hygiene and Epidemiology 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Occupational Medicine Lodz Poland

Institute of Oncology and Radiobiology Havana Cuba

Institute of Oncology Angel H Roffo University of Buenos Aires Argentina

Institute of Population Health Sciences National Health Research Institutes Taiwan

International Agency for Research on Cancer Lyon France

Johns Hopkins Bloomberg School of Public Health Baltimore MD USA

Leibniz Institute for Prevention Research and Epidemiology BIPS Bremen Germany; University of Bremen Faculty of Mathematics and Computer Science Bremen Germany

Medical Informatics Center Peking University China

National Institute of Environmental Health to National Public Health Institute Budapest Hungary

National Institute of Public Health Bucharest Romania

New York Eye and Ear Infirmary New York NY USA

Penn State College of Medicine Hershey PA USA

Program in Epidemiology Division of Public Health Sciences Fred Hutchinson Cancer Research Center Seattle WA USA

Regional Authority of Public Health in Banska Bystrica Slovakia

Roswell Park Cancer Institute Buffalo NY USA

School of Medicine Dentistry and Nursing University of Glasgow Glasgow UK

School of Medicine Medical Sciences and Nutrition University of Aberdeen Aberdeen UK and School of Medicine University of Dundee Dundee UK

Sorbonne Université INSERM Institut Pierre Louis d'Epidémiologie et de Santé Publique IPLESP Department of Social Epidemiology F75012 Paris France

The M Skasodowska Curie Memorial Cancer Center and Institute of Oncology Dept of Cancer Epidemiology and Prevention Warsaw Poland

The Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York NY USA

Thoracic Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center TX USA

Trinity College School of Dental Science Dublin Ireland

UCLA School of Public Health Los Angeles CA USA

Universidade Federal de Pelotas Pelotas Brazil

Université de Rennes INSERM EHESP Irset UMR_S 1085 Pointe à Pitre France

University of Heidelberg Germany

University of Hong Kong Hong Kong China

University of North Carolina School of Public Health Chapel Hill NC USA

University of São Paulo School of Medicine São Paulo Brazil

University of São Paulo School of Public Health São Paulo Brazil

UT M D Anderson Cancer Center Houston TX USA

Washington State University College of Pharmacy and Pharmaceutical Sciences Spokane WA USA

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