BMJ Confidential: For Review Only Trends i n colorectal cancer mortality in Europe: an analysis of the WHO mortality database Journal: BMJ Manuscript ID: BMJ.2015.026370 Article Type: Research BMJ Journal: BMJ Date Submitted by the Author: 10-Apr-2015 Complete List of Authors: Ait Ouakrim, Driss; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Pizot, Cecile; International Prevention Research Institute (iPRI), Boniol, Magali; International Prevention Research Institute (iPRI), Malvezzi, Matteo; Universitá degli Studi di Milano, Department of Clinical Sciences and Community Health Boniol, Mathieu; International Prevention Research Institute (iPRI), ; University of Strathclyde Institute for Global Public Health at iPRI, Negri, Eva; IRCCS - Istituto di Ricerche Farmacologiche ‘Mario Negri’, Department of Epidemiology Bota, Maria; International Prevention Research Institute (iPRI), ; University of Strathclyde Institute for Global Public Health at iPRI, Jenkins, Mark; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Bleiberg, Harry; Jules Bordet Institute, Autier, Philippe; University of Strathclyde Institute of Global Public Health at iPRI, ; International Prevention Research Institute (iPRI), Keywords: colorectal cancer, mortality, screening, epidemiology https://mc.manuscriptcentral.com/bmj Page 1 of 33 BMJ 1 2 3 4 N = 3361 5 6 7 8 TrendsConfidential: in colorectal cancer mortality For in Review Europe: an analysis Only of the 9 10 WHO mortality database 11 12 13 14 1 2 15 Driss Ait Ouakrim Research Fellow , Cécile Pizot Research Officer , Magali Boniol Assistant 16 Statistician 2, Matteo Malvezzi Post Doctoral Fellow 3, Mathieu Boniol Vice-President 17 Biostatistics 2, 4, Eva Negri Head of laboratory 5, Maria Bota Research Officer 2, 4 , Mark A Jenkins 18 1 6 19 Professor and Director , Harry Bleiberg Professor Emeritus , Philippe Autier Vice-President 2, 4 20 Population Research . 21 22 23 1 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, 24 25 University of Melbourne, 3010, Australia 26 2 International Prevention Research Institute (iPRI), 69006 Lyon, France 27 28 3 Department of Clinical Sciences and Community Health, Universitá degli Studi di Milano, 29 30 20156 Milan, Italy 31 4 University of Strathclyde Institute for Global Public Health at iPRI, 69006 Lyon, France 32 33 5 Department of Epidemiology, IRCCS - Istituto di Ricerche Farmacologiche ‘Mario Negri’, 20156 34 Milan, Italy. 35 36 6 Jules Bordet Institute, 1000 Brussels, Belgium 37 38 39 40 Correspondence: Dr Philippe Autier, International Prevention Research Institute (iPRI), Cours 41 Lafayette 95, 69006 Lyon Cedex 08, France; E-mail: [email protected]; website : www.i- 42 pri.org. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 1 https://mc.manuscriptcentral.com/bmj BMJ Page 2 of 33 1 2 3 Abstract (n=297) 4 5 Objectives: To examine changes in colorectal cancer (CRC) mortality in 34 European countries 6 7 between 1989 and 2011 8 Confidential: For Review Only 9 Design: Retrospective trend analysis. 10 11 12 Data source: World Health Organisation mortality database. 13 14 Population: Female and male colorectal cancer deaths between 1989 and 2011. 15 16 17 Main outcomes measures: Time trends in colorectal cancer mortality rates using join point 18 19 regression analysis. Rates were age adjusted using the European Standard Population. 20 21 Results: From 1989 to 2011, declines in CRC mortality of more than 25% in men and 30% in 22 23 women occurred in Austria, Switzerland, Germany, the United Kingdom, Belgium, the Czech 24 25 Republic, Luxemburg and Ireland. In contrast, CRC mortality rates declined by less than 15% in 26 27 the Netherlands and Sweden for both sexes. Increases of 28 to 45% were observed in men in 28 Spain, Portugal and Greece that were not observed in women. Smaller or no declines occurred 29 30 in most Central European countries. Substantial mortality increases of 20 to 102% occurred in 31 32 Croatia, Macedonia, and Romania for both sexes and in most Eastern European countries for 33 34 men. In countries with declining CRC mortality, declines were generally more important for 35 36 women and people aged less than 65 years. Overall, from 1989 to 2011, CRC mortality in the 27 37 38 European member states has decreased by 13% for men and by 27% for women. As a 39 40 comparison, In the United States, CRC mortality declined by 40% for men and by 39% for 41 42 women. 43 44 Conclusions: There is considerable disparity in the level of CRC mortality between European 45 46 countries, as well as between men and women and between age categories. Countries with the 47 48 greatest declines in CRC mortality are characterised by greater accessibility to screening 49 50 services, especially endoscopic screening, and specialised care. In countries where rates are 51 52 sharply increasing, lifestyle factors such as poor diet and alcohol drinking also play a major role. 53 54 55 56 57 58 59 60 2 https://mc.manuscriptcentral.com/bmj Page 3 of 33 BMJ 1 2 3 Introduction 4 5 6 Colorectal cancer (CRC) is the second most commonly diagnosed cancer in the world and has 7 8 poorConfidential: prognosis when metastasised to lymph For nodes orReview distant organs. In 2012, Only it was estimated 9 1 10 that 241.6 thousand European men were diagnosed with CRC and 113.2 thousand died from it. 11 For European women, 205.2 thousand CRC cases and 101.5 thousand CRC deaths were 12 13 recorded that year.1 Estimations also indicated substantial differences in CRC mortality across 14 15 European countries.2 16 17 18 Over the last two decades in Europe, early detection of CRC has increased through screening 19 20 and easier access to endoscopic removal of adenomatous polyps (the commonest CRC 21 precursor lesion).3 At the same time, new CRC treatments have been developed and their 22 23 availability improved.4 Taken together, these factors would be expected to lead to a decrease in 24 25 CRC mortality over time; however, effectiveness and access to these mortality-reducing factors 26 27 may not be equal across age groups, sex, and nationality. Further, the prevalence of some of 28 29 the main risk factors for CRC has been increasing (e.g. adiposity and sedentary lifestyle) and is 30 5 31 unequally distributed between countries. 32 33 In order to better understand the possible reasons underlying the heterogeneity in CRC 34 35 mortality across European countries, we analysed age and sex-specific trends in CRC mortality 36 37 rates from 1970 to 2011 in 34 European countries. We were most interested in recent CRC 38 39 mortality trends (1989-2011) because the most profound changes in screening and treatment 40 41 efficiency took place after 1988. 42 43 Methods 44 45 46 Mortality data 47 48 Number of CRC deaths was obtained from the World Health Organisation (WHO) mortality 49 6 50 database for 34 European countries for the period 1970–2011. For the sake of comparison, we 51 52 also extracted data for the United States of America (USA). 53 54 Between 1970 and 2011, data on cause of death was classified using three versions of the 55 56 international Classification of Diseases (ICD). We defined CRC mortality as any death with an 57 58 ICD 8 code of A048-A049, an ICD 9 code of B093-B094, or an ICD 10 code of C18-C21. We also 59 60 3 https://mc.manuscriptcentral.com/bmj BMJ Page 4 of 33 1 2 3 included any death with an ICD code for cancers of the anus and/or anal canal because it was 4 5 unclear from the database how some countries used the different ICD coding schemes to 6 7 classify cancers into the various CRC sub-sites—“colon”, “recto-sigmoid junction”, “rectum”, 8 Confidential: For Review Only 9 “anus” and “anal canal”. 10 11 For a majority of Western European countries, data were available for most of or the period of 12 13 interest. Cyprus was not included because data were only available for four years (1999, 2000, 14 15 2004, 2006). For Switzerland, data were available until 2010. Furthermore, a change in coding 16 17 practice in 1994 resulted in an over-reporting of cancer mortality before 1994. We therefore 18 19 applied a correction factor of 0·94 to all mortality rates before 1995, as recommended by Lutz 20 7 21 et al. For most central and eastern European countries, data were available since the early-mid 22 23 1980s until 2009 – 10, with the exception of Bulgaria for which data were available for the 24 25 entire period. For Slovakia and the Republic of Macedonia data were available from 1991 and 26 27 1992 respectively, until 2010. Years for which data were missing are presented in 28 Supplementary Table 1. 29 30 31 Statistical analyses 32 33 We used the direct method and age-specific population estimates from the WHO mortality 34 35 database 6 to compute age-adjusted CRC mortality rates according to the age distribution of the 36 37 standard European population.8 Joinpoint regression analysis over the whole period was 38 39 performed to identify years where statistically significant changes in mortality trends occurred. 40 41 Annual percent changes (APCs) (relative change) were then computed for each country, by 42 43 fitting a regression line to the natural logarithm of the rates on the period 1989-2011 and over 44 45 the last five years of available data (2007-2011). Because of missing data, regression was fitted 46 over the period 1992 – 2010 for Slovakia and 1991 – 2010 for Macedonia.