Colorectal Cancer Mortality Across the American Continent: Temporal Trends

• Abstract
• Introduction
• Materials and Methods
• Study Design
• Data Source
• Data Collection
• Data Analysis
• Results
• Both Sexes
• Women
• Men
• Countries
• Discussion
• Conclusions
• References

Abstract

Introduction

Colorectal cancer (CRC) is a major global health concern and a leading cause of cancer-related mortality. Understanding temporal trends in CRC mortality is crucial for guiding public health policies and resource allocation.

Objective

To evaluate the temporal trends of CRC mortality rates across the American continent.

Materials and Methods

This retrospective, population-based study used data from the Pan American Health Organization for its development. Age-adjusted mortality rates per 100,000 individuals were collected for the period 2000–2019 and stratified by country and sex. Joinpoint regression analysis was conducted to estimate the annual percentage change (APC) and assess temporal trends.

Results

CRC mortality trends varied across regions and sexes. In South and Central America, mortality rates increased, particularly in the early 2000s, whereas North America experienced a general decline. Gender-specific trends showed significant increases in South and Central American women, while men exhibited rising trends except in North America, where rates steadily declined.

Conclusions

The study identified distinct trends in CRC mortality across the Americas, with increasing rates in some countries and declines in others. Socioeconomic factors, healthcare access, and sex-based differences appear to contribute to these variations. These findings underscore the need for targeted public health strategies to reduce colorectal cancer burden and address disparities in early detection and treatment.

Introduction

Colorectal cancer (CRC) is a malignant neoplasm arising from the epithelial cells of the colon or rectum, representing one of the most prevalent and lethal forms of cancer worldwide.[1] Histologically, many CRC cases are adenocarcinomas, originating from glandular epithelial cells. Less common subtypes include mucinous adenocarcinomas, characterized by abundant extracellular mucin production, and signet-ring cell carcinomas, an aggressive variant with poor prognosis.[1] Other rare histological subtypes, such as neuroendocrine tumors and squamous cell carcinomas, account for a small proportion of cases but often exhibit distinct biological behaviors and clinical outcomes.[1]

The development of CRC is influenced by a multifactorial interplay of genetic and environmental risk factors.[2] Familial syndromes, such as Lynch syndrome and familial adenomatous polyposis, significantly increase the lifetime risk of CRC due to inherited genetic mutations.[2] Lifestyle-related factors, including a diet high in red and processed meats, low fiber intake, obesity, physical inactivity, and excessive alcohol consumption, contribute to sporadic CRC cases.[2] Chronic inflammatory conditions, such as inflammatory bowel disease (ulcerative colitis and Crohn's disease), are also associated with an increased risk, highlighting the role of persistent inflammation in carcinogenesis.[2]

Clinically, CRC presents with a broad spectrum of symptoms, often depending on tumor location and disease stage.[3] Early-stage cases may remain asymptomatic or cause nonspecific gastrointestinal complaints, such as changes in bowel habits, mild abdominal discomfort, or intermittent rectal bleeding.[3] As the disease progresses, symptoms become more pronounced, including hematochezia or melena, iron-deficiency anemia, unintentional weight loss, and bowel obstruction in advanced cases.[3] The insidious nature of CRC underscores the critical importance of early detection through screening programs, which significantly improve prognosis and survival rates.[3]

The incidence of CRC has been rising globally, with variations across different geographic regions.[4] While high-income countries have observed a stabilization or decline in mortality rates due to improved screening and treatment strategies, low- and middle-income regions continue to experience an increasing burden.[4] This trend has significant social and economic implications, as CRC-related morbidity and mortality impose substantial healthcare costs and productivity losses.[4] The shifting epidemiology of CRC necessitates comprehensive public health interventions aimed at prevention, early diagnosis, and equitable access to treatment.[4]

Given the growing impact of CRC on public health, it is crucial to examine temporal trends in mortality rates to better understand the epidemiological dynamics of the disease.[1] [2] Investigating these trends across the Americas allows for the identification of regional disparities and the effectiveness of preventive and therapeutic strategies.[2] [3] Such studies provide valuable insights for policymakers and healthcare professionals, facilitating data-driven decision-making to enhance cancer control measures, optimize resource allocation, and ultimately reduce CRC-related mortality.[1] [2] [3] [4] So, this study was developed with the aim to evaluate the temporal trends of CRC mortality rates across the American continent.

Materials and Methods

Study Design

This research was designed as a retrospective, populational with quantitative approach study.

Data Source

All data used in this study were obtained from the Pan American Health Organization (PAHO), available at the following link: https://www.paho.org/en . In case, PAHO is the oldest international health organization in the world, acting as a regional agent of the World Health Organization (WHO) in the Americas. It specializes in health promotion, disease prevention, epidemiological analysis, among other actions in the location.

Data Collection

Data were collected from the PAHO's archive and published on January 15th, 2025, on the aforementioned website. The collection was performed manually by the author of this research by transposing the data into Excel ® spreadsheets. The Data were stratified by country's origin, reported year, individual's sex, and the reported age-adjusted mortality rates for 100,000 individuals. The study's time draft was chosen as the one between 2000 and 2019 since it was the unique time range disponible in the data.

Data Analysis

An annual percentage change (APC) was calculated with the Jointpoint software 5.0 ® to evaluate the temporal trends of CRC mortality rates.

The APC is calculated using a regression model where time is treated as an independent variable, and the natural logarithm of the observed rates is utilized as the dependent variable. This approach involves fitting the natural logarithm of each observation to a straight line, with the slope of this line representing the rate of change over time. The APC quantifies the average percentage change per year within the specified time frame, providing a standardized measure to evaluate trends.

The 95% confidence interval was calculated for the evaluated APCs. For statistically significant confidence intervals (p-values < 0.05), a positive APC suggests an increasing trend, while a negative APC indicates a decreasing trend; in parallel, a non-significant confidence interval (p-value ≥ 0.05) suggests a stationary trend.

Results

Both Sexes

In South America, between 2000 and 2012, mortality rates increased significantly (APC: 0.62; 95%CI: 0.51 - 1.07; p-value: < 0.01). From 2012 to 2019, the trend was not significant (APC: 0.17; 95%CI: −0.76 - 0.41; p-value: 0.43). In Central America, between 2000 and 2003, there was a marked increase (APC: 4.26; 95%CI: 3.42 - 5.53; p-value: < 0.01), followed by a decline from 2003 to 2006 (APC: −1.39; 95%CI: −2.05 - −0.12; p-value: 0.03). From 2006 to 2014, rates increased again (APC: 1.86; 95%CI: 1.60 - 2.35; p-value: < 0.01), but then decreased between 2014 and 2019 (APC: −0.63; 95%CI: −1.32 - −0.09; p-value: 0.02). In North America, mortality rates decreased significantly from 2000 to 2009 (APC: −1.51; 95%CI: −2.59 - −1.24; p-value: < 0.01). From 2009 to 2019, the decline was not statistically significant (APC: −1.01; 95%CI: −1.27 - 0.19; p-value: 0.07). From a whole American perspective, the period 2000–2003 saw an increase (APC: 2.28; 95%CI: 1.69 - 3.33; p-value: < 0.01), followed by a decline from 2003 to 2006 (APC: −0.83; 95%CI: −1.30 - 0.07; p-value: 0.08). From 2006 to 2014, there was an increase (APC: 1.13; 95%CI: 0.94 - 1.64; p-value: < 0.01), but rates decreased from 2014 to 2019 (APC: −0.45; 95%CI: −0.98 - −0.06; p-value: 0.02) - [Table 1] and [Fig. 1].

Women

In South America, between 2000 and 2019, mortality rates increased significantly (APC: 0.29; 95%CI: 0.13 - 0.45; p-value: < 0.01). In Central America, a sharp increase occurred between 2000 and 2003 (APC: 5.44; 95%CI: 3.81 - 7.45; p-value: < 0.01). The trend between 2003 and 2008 was not significant (APC: −0.52; 95%CI: −2.12 - 0.31; p-value: 0.16). From 2008 to 2014, mortality increased (APC: 2.25; 95%CI: 1.65 - 3.88; p-value: < 0.01), followed by a decrease from 2014 to 2019 (APC: −1.07; 95%CI: −2.08 - −0.34; p-value: < 0.01). In North America, there was a significant decrease from 2000 to 2009 (APC: −1.57; 95%CI: −2.67 - −1.28; p-value: < 0.01). The decline from 2009 to 2019 was not statistically significant (APC: −0.89; 95%CI: −1.16 - 0.29; p-value: 0.08). On the all-American continent point of view, between 2000 and 2003, mortality rates increased (APC: 3.17; 95%CI: 2.33 - 4.49; p-value: < 0.01), followed by a significant decline from 2003 to 2006 (APC: −1.48; 95%CI: −2.12 - −0.22; p-value: 0.01). The period 2006–2014 saw an increase (APC: 1.20; 95%CI: 0.95 - 2.06; p-value: < 0.01), but a decline was observed from 2014 to 2019 (APC: −0.66; 95%CI: −1.47 - −0.13; p-value: 0.01) - [Table 2] and [Fig. 2].

Men

In South America, between 2000 and 2010, there was a significant increase in mortality rates (APC: 1.12; 95%CI: 0.88 - 1.57; p-value: < 0.01). From 2010 to 2019, the trend was not significant (APC: 0.21; 95%CI: −0.32 - 0.48; p-value: 0.28). In Central America, mortality rates increased significantly from 2000 to 2019 (APC: 0.99; 95%CI: 0.71 - 1.28; p-value: < 0.01). In North America, there was a consistent decline from 2000 to 2019 (APC: −1.36; 95%CI: −1.51 - −1.21; p-value: < 0.01). Over the whole continent, between 2000 and 2003, rates increased (APC: 1.44; 95%CI: 0.48 - 2.83; p-value: < 0.01). The trend between 2003 and 2006 was not significant (APC: −0.57; 95%CI: −1.19 - 1.50; p-value: 0.23). From 2006 to 2011, a borderline increase was observed (APC: 1.59; 95%CI: −0.02 - 2.51; p-value: 0.05), followed by a non-significant trend from 2011 to 2019 (APC: 0.07; 95%CI: −0.22 - 0.36; p-value: 0.56) - [Table 3] and [Fig. 3].

Countries

An evaluation of CRC mortality trends by each American country analyzed can be assessed in the following link: https://docs.google.com/spreadsheets/d/1oYDkZUDw0P47aLWfnFWm72QIjDfJSr7gZEX6B2ZPuYE/edit?usp=sharing .

Discussion

For both sexes, colorectal cancer mortality rates have shown increasing trends in South and Central America, with fluctuations, while North America has experienced a general decline. Among women, South and Central America showed increasing trends, but North America exhibited a decreasing pattern. Among men, South and Central America saw rising mortality rates, whereas North America showed a consistent decline.

The observed trends in colorectal cancer (CRC) mortality across different regions highlight the complex interplay of social, economic, and healthcare-related factors in shaping the burden of this disease.[5] [6] In Latin America and the Caribbean, CRC mortality rates have increased significantly in several countries, while nations such as Argentina and Uruguay have experienced declines. These divergent patterns can be attributed to disparities in healthcare infrastructure, screening programs, and public health policies.[5] [6] Uruguay, for instance, has implemented robust CRC screening programs, which likely contributed to the reduction in mortality, particularly among women aged 50 to 74 years.[5] Conversely, in countries where mortality has increased, limited access to early diagnosis and treatment remains a critical challenge.[7]

Economic development and healthcare accessibility play crucial roles in CRC mortality trends.[8] [9] High-income countries have generally experienced stable or declining CRC mortality rates due to the widespread implementation of early detection strategies, improved treatments, and increased public awareness.[8] In contrast, middle- and low-income regions continue to face rising CRC mortality due to limited preventive measures and inadequate healthcare resources.[9] For example, in Mexico, mortality rates increased from 3.9 to 4.8 per 100,000 inhabitants between 2000 and 2012, with the highest rates observed in Baja California, Baja California Sur, and Sonora.[8] These trends likely reflect the unequal distribution of medical facilities, delays in diagnosis, and lifestyle changes associated with urbanization, including increased consumption of processed foods and decreased physical activity.[8] [9]

Sex-based differences in CRC mortality patterns suggest that biological and behavioral factors significantly influence outcomes.[10] [11] Women have historically exhibited lower CRC incidence and mortality rates compared with men, potentially due to the protective effects of estrogen, which modulates immune responses and reduces chronic inflammation.[10] Additionally, differences in dietary habits, smoking prevalence, and occupational exposures contribute to varying risks between sexes.[10] However, in some regions, female CRC mortality has increased more sharply than in men, as observed in Brazil, where CRC mortality rose from 5.60 to 7.98 per 100,000 inhabitants between 2005 and 2014, disproportionately affecting women in the South and Southeast regions.[11] This may reflect shifting dietary patterns, increased obesity rates, and delayed diagnosis in female patients.[11]

The role of inflammatory pathways, cytokine activity, and genetic predispositions further explains sex-based disparities in CRC mortality.[12] [13] Estrogen is known to regulate inflammatory cytokines such as IL-6 and TNF-α, which are implicated in colorectal carcinogenesis. In postmenopausal women, the decline in estrogen levels may lead to increased inflammation, contributing to higher CRC risk.[12] Conversely, men generally exhibit higher systemic inflammation and oxidative stress levels, factors that exacerbate tumor progression1.[3] The notable decline in CRC mortality in Uruguayan women aged 50–74 years suggests that gender-targeted screening programs and healthcare interventions may effectively reduce mortality, underscoring the need for similar strategies in other high-risk populations.[5]

Another crucial factor influencing CRC mortality trends is population aging.[14] As life expectancy increases, a larger proportion of the population enters age groups at higher risk for CRC, leading to an overall rise in mortality despite advances in treatment.[14] In Barranquilla, Colombia, CRC mortality nearly tripled between 1985 and 2020, with 59.6% of recorded deaths occurring in women.[14] This trend reflects not only an aging population but also delayed detection and suboptimal management of CRC cases in older adults.[14] Additionally, the study highlighting a relative decrease in CRC-related deaths alongside an increase in non-cancer causes of mortality among CRC patients suggests that cardiovascular disease and other comorbidities play an increasing role in long-term patient outcomes.[14]

Globally, regional disparities in CRC mortality emphasize the need for targeted public health initiatives.[15] [16] In 2012, the highest mortality rates were recorded in Central and Eastern Europe, while the lowest rates were observed in the Middle Division of Africa.[15] These discrepancies highlight the impact of socioeconomic factors, dietary patterns, and healthcare access.[15] European countries with high CRC mortality may be experiencing aging populations and lifestyle-related risk factors, whereas, in Africa, lower CRC mortality might be due to differences in diet, genetic predisposition, or underreporting due to inadequate cancer surveillance systems.[16]

Looking forward, the future trajectory of CRC mortality will be shaped by advancements in early detection, personalized treatment approaches, and population-level preventive measures.[17] Improved screening technologies, such as liquid biopsy and molecular biomarker-based tests, hold promise for enhancing early diagnosis and treatment precision.[17] Additionally, expanding access to screening in underserved regions will be essential for mitigating mortality disparities.[17] Public health campaigns promoting healthier diets, increased physical activity, and smoking cessation can further reduce CRC incidence and mortality in high-risk populations.[17]

Finally, ongoing epidemiological surveillance is crucial for understanding the evolving burden of CRC and informing evidence-based policy decisions.[18] Investigating temporal trends in CRC mortality across the Americas provides valuable insights into the effectiveness of national cancer control programs and healthcare investments.[18] By identifying successful strategies in countries with declining mortality and addressing barriers in regions with rising trends, policymakers can implement targeted interventions to reduce CRC-related deaths and improve cancer outcomes on a global scale.[18] As the burden of CRC continues to rise in certain regions, a coordinated, multi-sectoral approach will be necessary to bridge healthcare disparities and enhance survival rates for all populations.[18]

This study presents several strengths that enhance its reliability and significance. First, by utilizing mortality data from the Pan American Health Organization (PAHO), the research ensures a comprehensive and standardized dataset covering multiple countries across the Americas. The extended study period (2000–2019) allows for an in-depth evaluation of long-term trends, providing valuable insights into epidemiological shifts over time. Moreover, the application of the Joinpoint regression model ensures a robust and statistically rigorous analysis of temporal mortality trends, allowing for the precise identification of changes in mortality patterns. Finally, stratification by sex enables a more nuanced understanding of potential disparities, contributing to the growing body of knowledge on sex-related differences in colorectal cancer epidemiology.

Despite its strengths, this study has some limitations that should be acknowledged. First, the reliance on secondary data from PAHO means that the accuracy of the findings is dependent on the completeness and quality of the original data sources, which may vary between countries. Additionally, potential discrepancies in death certification practices and cancer registry coverage across different regions may introduce bias in the reported mortality rates. Another limitation is the inability to assess individual-level risk factors such as genetic predisposition, lifestyle habits, or access to healthcare, which could provide deeper insights into the observed trends. Lastly, the study does not account for potential improvements in diagnostic techniques or treatment strategies over time, which could influence mortality trends independently of epidemiological shifts.

Conclusions

This study provides a comprehensive analysis of colorectal cancer mortality trends in the Americas, highlighting both increasing and decreasing patterns in different countries. The observed trends are likely influenced by a combination of demographic, socioeconomic, and healthcare-related factors, emphasizing the importance of continued investments in screening programs, early detection initiatives, and equitable access to high-quality treatment. The findings also underscore notable sex-based disparities, suggesting potential biological and behavioral contributors to colorectal cancer outcomes. As colorectal cancer remains a significant public health concern, future research should focus on understanding the interplay between policy measures, healthcare access, and disease burden to develop more effective prevention and control strategies.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Declaration of the Use of Artificial Intelligence

None.

• References

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• 11 de Menezes CCS, Ferreira DBB, Faro FBdeA, Bomfim MS, Trindade LMDF. Câncer colorretal na população brasileira: taxa de mortalidade no período de 2005–2015. Rev Bras Promoc Saude 2016; 29 (02) 172-179
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• 12 Alcocer-Olaciregui A, Chamorro P, Niño S, Saucedo E, Vargas R. Mortalidad por cáncer de colon, recto y ano en Barranquilla entre 1985 y 2020. Rev Colomb Gastroenterol 2024; 39 (03) 260-266
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• 13 Medina Franco H, Suárez Bobadilla YL. Escrutinio y vigilancia del cáncer colorrectal. Rev Port Pneumol 2010; 75: 131-137 http://www.revistagastroenterologiamexico.org/es-escrutinio-vigilancia-del-cancer-colorrectal-articulo-X0375090610873741
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• 14 Algarra SCUM. Cáncer colorrectal: una epidemia silenciosa. Rev Med Univ Navarra 2017; 47 (01) 9 https://dadun.unav.edu/bitstream/10171/39678/1/editorial.pdf
  Search in Google Scholar
• 15 Araghi M, Soerjomataram I, Jenkins M. et al. Global trends in colorectal cancer mortality: projections to the year 2035. Int J Cancer 2019; 144 (12) 2992-3000
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• 16 Lu B, Li N, Luo C-Y. et al. Colorectal cancer incidence and mortality: the current status, temporal trends and their attributable risk factors in 60 countries in 2000-2019. Chin Med J (Engl) 2021; 134 (16) 1941-1951
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• 17 Sharma R. An examination of colorectal cancer burden by socioeconomic status: evidence from GLOBOCAN 2018. EPMA J 2019; 11 (01) 95-117
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• 18 Huguet JM, Ferrer-Barceló L, Suárez P. et al. Colorectal cancer screening and surveillance in patients with inflammatory bowel disease in 2021. World J Gastroenterol 2022; 28 (05) 502-516
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Address for correspondence

Publication History

Received: 06 March 2025

Accepted: 22 May 2025

Article published online:
30 June 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/)

Thieme Revinter Publicações Ltda.
Rua Rego Freitas, 175, loja 1, República, São Paulo, SP, CEP 01220-010, Brazil

• References

• 1 Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet 2019; 394 (10207): 1467-1480
  CrossrefPubMedSearch in Google Scholar
• 2 Li J, Ma X, Chakravarti D, Shalapour S, DePinho RA. Genetic and biological hallmarks of colorectal cancer. Genes Dev 2021; 35 (11-12): 787-820
  CrossrefPubMedSearch in Google Scholar
• 3 Baidoun F, Elshiwy K, Elkeraie Y. et al. Colorectal Cancer Epidemiology: Recent Trends and Impact on Outcomes. Curr Drug Targets 2021; 22 (09) 998-1009
  CrossrefPubMedSearch in Google Scholar
• 4 Kim BJ, Hanna MH. Colorectal cancer in young adults. J Surg Oncol 2023; 127 (08) 1247-1251
  CrossrefPubMedSearch in Google Scholar
• 5 Sánchez-Barriga JJ. Tendencias de mortalidad y riesgo de muerte por cáncer colorrectal en las 7 regiones socioeconómicas de México, 2000-2012. Rev Gastroenterol Mex 2017; 82 (03) 217-225
  CrossrefPubMedSearch in Google Scholar
• 6 Blas LM. (2024). Evolución de las tasas de mortalidad por cáncer colorrectal en América Latina y el Caribe: Un análisis basado en la población entre 1997 al 2020. https://doi-org.accesdistant.sorbonne-universite.fr/10.21142/tl.2024.3734
  Crossref
• 7 Gandomani HS. yousefi, seyed majid, Aghajani, M., Mohammadian-Hafshejani, A., Tarazoj, A. A., Pouyesh, V., & Salehiniya, H. Colorectal cancer in the world: incidence,mortality and risk factors. Biomed Res Ther 2017; 4 (10) 1656-1675
  CrossrefSearch in Google Scholar
• 8 Chen J, Zheng Y, Wang H. et al. Cause of death among patients with colorectal cancer: a population-based study in the United States. Aging (Albany NY) 2020; 12 (22) 22927-22948
  CrossrefPubMedSearch in Google Scholar
• 9 Santucci C, Mignozzi S, Alicandro G. et al. Trends in cancer mortality under age 50 in 15 upper-Middle and high-income countries. J Natl Cancer Inst 2025; 117 (04) 747-760
  CrossrefPubMedSearch in Google Scholar
• 10 Ardila Salcedo JO, González Ibáñez CF. (2009). Diferencias en las tendencias de mortalidad por cáncer colorrectal entre Bogotá y Colombia entre 1985 y 2004: análisis edad-periodo-cohorte. https://repository.urosario.edu.co/handle/10336/1303
• 11 de Menezes CCS, Ferreira DBB, Faro FBdeA, Bomfim MS, Trindade LMDF. Câncer colorretal na população brasileira: taxa de mortalidade no período de 2005–2015. Rev Bras Promoc Saude 2016; 29 (02) 172-179
  CrossrefSearch in Google Scholar
• 12 Alcocer-Olaciregui A, Chamorro P, Niño S, Saucedo E, Vargas R. Mortalidad por cáncer de colon, recto y ano en Barranquilla entre 1985 y 2020. Rev Colomb Gastroenterol 2024; 39 (03) 260-266
  CrossrefSearch in Google Scholar
• 13 Medina Franco H, Suárez Bobadilla YL. Escrutinio y vigilancia del cáncer colorrectal. Rev Port Pneumol 2010; 75: 131-137 http://www.revistagastroenterologiamexico.org/es-escrutinio-vigilancia-del-cancer-colorrectal-articulo-X0375090610873741
  Search in Google Scholar
• 14 Algarra SCUM. Cáncer colorrectal: una epidemia silenciosa. Rev Med Univ Navarra 2017; 47 (01) 9 https://dadun.unav.edu/bitstream/10171/39678/1/editorial.pdf
  Search in Google Scholar
• 15 Araghi M, Soerjomataram I, Jenkins M. et al. Global trends in colorectal cancer mortality: projections to the year 2035. Int J Cancer 2019; 144 (12) 2992-3000
  CrossrefPubMedSearch in Google Scholar
• 16 Lu B, Li N, Luo C-Y. et al. Colorectal cancer incidence and mortality: the current status, temporal trends and their attributable risk factors in 60 countries in 2000-2019. Chin Med J (Engl) 2021; 134 (16) 1941-1951
  CrossrefPubMedSearch in Google Scholar
• 17 Sharma R. An examination of colorectal cancer burden by socioeconomic status: evidence from GLOBOCAN 2018. EPMA J 2019; 11 (01) 95-117
  CrossrefPubMedSearch in Google Scholar
• 18 Huguet JM, Ferrer-Barceló L, Suárez P. et al. Colorectal cancer screening and surveillance in patients with inflammatory bowel disease in 2021. World J Gastroenterol 2022; 28 (05) 502-516
  CrossrefPubMedSearch in Google Scholar