The Rising Incidence of Early-Onset Colorectal Cancer

Background: The incidence of early-onset (diagnosis before age 50) colorectal cancer (EO-CRC) is increasing in some high-income countries. The present study analyzed this trend in Germany.

Methods: The epidemiological data on the incidence of colorectal cancer (ICD-10 C18–C20) in the federal states of Germany were obtained from the German Center for Cancer Registry Data (ZfKD). The regions included were those with adequate documentation, according to the ZfKD criteria, for the years 1999–2018. Cases identified from death certificates alone were excluded. The data on mortality were derived from the official cause of death statistics. Time trends for persons aged 20–49 years were expressed as the average annual percentage change (AAPC) with 95% confidence interval. The incidence was stratified by sex, site (proximal colon, distal colon, rectum), 10-year age group (20–29, 30–39, 40–49), and tumor size (T).

Results: EO-CRC accounted for 5.1% (9529 cases) of all colorectal cancers in the selected German regions. The EO-CRC incidence rose annually by 1.16% [0.51; 1.81] in men and 1.32% [0.80; 1.84] in women. The incidence of proximal colon cancer increased in both sexes (men: AAPC 3.26 [2.00; 4.53]; women: AAPC 2.99 [2.17; 3.83]), while the incidence of distal colon cancer remained unchanged.

Conclusion: The incidence of EO-CRC in Germany is rising. The reasons are probably multifactorial, reflecting the changing prevalence of risk and protective factors to which one is exposed in the early years of life.

Following the implementation of colonoscopy as part of a population-based screening program in Germany, the overall incidence of colorectal cancer decreased (1). Similar trends have been reported in other high-income countries (2, 3). These trends have been attributed mainly to the early detection and removal of adenomas through colorectal cancer screening (2). The incidence of early-onset colorectal cancer (EO-CRC) (diagnosis in people aged less than 50 years) shows a divergent trend. Recent studies—mostly analyzing data from high-income countries—have reported a pronounced upward trend for EO-CRC, especially among persons under 40 years of age (3, 4). In the USA, EO-CRC currently accounts for more than 12% of all cases of colorectal cancer (5). The American Cancer Society (6) and the US Preventive Services Task Force (7) have recently updated their colorectal cancer screening recommendations, lowering the age of first screening for average-risk individuals from 50 to 45 years. Previous studies analyzed data on EO-CRC incidence in Germany (4) or German regions (3) and reported increasing EO-CRC incidence for colon cancer and rectal cancer. However, the analyses were for the whole colon, not for the different colonic subsites. In this study, we assessed the time trends in EO-CRC in six regions of Germany, including analyses of tumor site.

Methods

Data on the incidence of colorectal cancer (ICD-10 C18–C20) for the period 1999 to 2018, last updated in December 2021, were provided on request by the Center for Cancer Registry Data (Zentrum für Krebsregisterdaten, ZfKD) at the Robert Koch Institute (RKI) (8, 9). Sufficiently complete data covering the whole analysis period stemmed from the cancer registries for Bremen, Hamburg, Münster, Rhineland–Palatinate, Saarland, and Schleswig–Holstein (selection comparable with the routine analyses of the ZfKD) (1). These registries cover 12.9 million inhabitants, approximately 16% of the German population (independent of age and sex). We included cases that were not documented by death certificate only (DCO cases). The reason for excluding DCO cases was the absence of the date of diagnosis. This exclusion of DCO cases did not affect the results (data not shown). The official colorectal cancer (ICD-10 C18–C20) mortality statistics from the Federal Statistical Office for the same period, the same regions, and the same reference populations were also evaluated. All rates were age-standardized to the world population using the direct method (11). All new cases in persons aged 20 years and older were included, but the main analyses were restricted to diagnoses in the age group 20–49 years, referred to here as EO-CRC. To assess time trends, we fitted joinpoint regression models. This method identifies shifts in trends and enables specific estimates of the annual percentage changes (APC) as well as the average annual percentage changes (AAPC) for the entire series. The AAPC were given with the corresponding 95% confidence intervals (95% CI). We considered trends statistically significant when the 95% CI did not include zero. The main analyses of incidence were stratified by sex, 10-year age group (20–29, 30–39, and 40–49 years), and site (colon [C18] and rectum [C19–C20]). Additionally, the colon cancers were classified by site:

• Proximal colon (C18.0–C18.4)
• Distal colon (C18.5–C18.7)
• Colon overlapping/unspecified (C18.8–C18.9)

Trend analyses by sex and tumor size T (TNM staging system) (12) were grouped into T1/T2 and ≥ T3. To assess the possible impact of inclusion of cases of malignant neoplasia of the appendix (appendiceal cancer) on our analysis, as described in previous studies (3), we conducted exploratory analyses excluding new cases of appendiceal cancer (C18.1). All analyses were conducted using the Joinpoint Regression Program (version 4.8.0.1, National Institute of Cancer) and the R package ggplot2 (version 3.1.1.1).

Results

Between 1999 and 2018, there were 185 994 cases of colorectal cancer among adults (over 20 years) in the selected German regions, of which 9529 (5.1%) were diagnosed in persons aged 20–49 (Table 1) (EO-CRC diagnoses). The median age at EO-CRC diagnosis was 45 years in men and 44 years in women. Most tumors (58.4%) arose in the colon. Appendiceal cancer accounted for half of all colon cancers in persons aged 20–29 years (eTable 1).

Table 1

New cases and age-standardized incidence rates (ASR) by age and sex for the diagnosis colon cancer or rectal cancer in Germany (Bremen, Hamburg, Münster, Rhineland–Palatinate, Saarland, and Schleswig–Holstein) from 1999 to 2018

eTable 1

Absolute number and distribution by age and sex for cancers of the appendix (ICD-10 C18.1) among early-onset colon cancers (C18) in Germany (Bremen, Hamburg, Münster, Rhineland–Palatinate, Saarland, and Schleswig–Holstein) from 1999 to 2018

Incidence and mortality of colorectal cancer

The incidence of EO-CRC increased yearly by 1.16% (95% CI [0.51; 1.81]) in men, from around seven to nine cases per 100 000, between 1999 and 2018. There was a similar annual increase of 1.32% [0.80; 1.84] in women, from around six to eight cases per 100 000 (Figure). When analyzing the 10-year age groups (eFigure 1), we found the highest increasing pattern for those aged 20–29 years, although colorectal cancer in this age group remained a rare event (< 50 cases per year): In men, with an average increase of 4.44% per annum, rates doubled from around one to two cases per 100 000. Among women, rates increased by 6.40% annually, thus more than tripling from around 1 to 3 cases per 100 000. In the age group 30–39 years, the rates rose to a lesser degree, though still significantly—by more than 2% in both sexes—while they remained stable among those aged 40–49 years. Mortality from EO-CRC, however, declined significantly, by 1.42% and 2.56% respectively, for males and females over all the age groups examined (Figure).

Figure

Trends in the incidence and mortality of early-onset colorectal cancer (20–49 years), by sex, in Germany (Bremen, Hamburg, Münster, Rhineland–Palatinate, Saarland, and Schleswig–Holstein) from 1999 to 2018

eFigure

Trends in the incidence and mortality of early-onset colorectal cancer (20–49 years), by 10-year age group and sex, in Germany (Bremen, Hamburg, Münster, Rhineland–Palatinate, Saarland, and Schleswig–Holstein) from 1999 to 2018

Incidence of colon cancer

An annual rise in colon cancer incidence of 1.62% in and 1.39% in women was observed (Table 2). In the 10-year age group analyses, increases were detected for ages 20–29 and 30–39 but were especially pronounced in the former (eTable 2).

Table 2

Trends in the incidence of early-onset colorectal cancer (20–49 years) by sex and diagnosis in different segments of the colon in Germany (Bremen, Hamburg, Münster, Rhineland–Palatinate, Saarland, and Schleswig–Holstein) from 1999 to 2018

eTable 2

Trends in the incidence of early-onset colorectal cancer (20–49 years) by 10-year age group, sex, and diagnosis in different subsites of the colon in Germany (Bremen, Hamburg, Münster, Rhineland–Palatinate, Saarland, and Schleswig–Holstein) from 1999 to 2018

Incidence of cancers in the proximal and distal colon

The incidence of proximal colon cancer increased across all age groups in both sexes (men: AAPC = 3.26; women: AAPC = 2.99) (Table 2). In contrast, the incidence of distal colon cancer remained constant. Diagnoses with overlapping sites and cases of colon cancer not otherwise specified declined with time.

Incidence of rectal cancer

The rise in the incidence of rectal cancer found in women (AAPC = 1.29) was not observed in men (Table 2). Analysis of the 10-year age groups, however, identified statistically significant increases in incidence among men aged 20–29 (AAPC = 5.08) and women aged 30–39 (AAPC = 2.47). Among persons aged 40–49 years, the incidence was constant (eTable 2).

Exploratory analyses excluding new appendiceal cancers

Exclusion of cases of appendiceal cancer in the exploratory analyses attenuated the percentage increase in incidence in both sexes (eTable 3). After the removal of appendiceal cancer cases from the group of colon cancers, no increasing incidence of colon cancer was seen for either sex. Moreover, exclusion of appendiceal cancer from the subgroup of cancers in the proximal colon canceled out the above-mentioned increasing trend in incidence among women. The incidence of the diagnosis of appendiceal cancer increased markedly in both sexes over the observation period (men: AAPC = 9.28; women: AAPC = 9.52) (eTable 3).

Table 3

TABLE 3 Trends in the incidence of early-onset colorectal cancer (20–49 years) by sex and tumor size/tumor extension in Germany (Bremen, Hamburg, Münster, Rhineland–Palatinate, Saarland, and Schleswig–Holstein) from 1999 to 2018

eTable 3

Exploratory analyses of the trends in the incidence of early-onset colon cancer (20–49 years), excluding appendiceal cancer, by sex and diagnosis in different subsites of the colon in Germany (Bremen, Hamburg, Münster, Rhineland–Palatinate, Saarland, and Schleswig–Holstein) from 1999 to 2018

Colorectal cancer incidence by T stage

Increasing trends were observed for the diagnosis of smaller tumors (T1–T2) in both sexes (men: AAPC = 2.96; women: AAPC = 4.84) (Table 3). As for larger tumors (T3+), increasing trends, albeit less pronounced than for smaller tumors, were seen in men (AAPC = 1.07) and in both sexes combined (AAPC = 0.67).

Discussion

This study described rising trends in new cases of EO-CRC in both men and women in Germany, driven mainly by rising incidence among people aged 20–39 years. Analysis of the diagnoses in different colonic subsites shows growth in the incidence of cancer particularly in the proximal colon in both sexes. Increasing incidence of EO-CRC has been identified in at least 19 high-income countries, with the greatest yearly changes seen in New Zealand (4.0%), the UK (3.3%), Canada, and Australia (2.8%) (3). The overall 1.2% overall annual increase found in Germany by this study is less pronounced, similar to the figures reported for Sweden (1.6%), Denmark (1.0%), and Slovenia (0.8%). The reasons for this rising EO-CRC burden have not been elucidated but are likely multifactorial, reflecting the changing prevalence of early life exposure to risk and protective factors in these countries (13). Excess body weight and other closely linked lifestyle factors, including diet and insufficient physical activity, have been hypothesized as drivers for these increasing patterns. These assumptions are based on convincing evidence that obesity in adults, most commonly defined as body mass index ≥ 30 kg/m², is a risk factor for colorectal cancer in general (14) and especially for late-onset colorectal cancer (15, 16). There is also growing evidence that excess weight at an early age elevates the risk of EO-CRC (17, 18).

Strengthening this hypothesis, obesity-related cancers such as multiple myeloma, kidney cancer, and uterine corpus cancer are increasing in high-income countries (19, 20), and upward trends in EO-CRC in several countries, including Germany, have been preceded by increased occurrence of excess weight in childhood and adolescence (3, 21). Recent birth cohorts show an increasing cumulative burden of excess body weight (22). In Germany, about 15% of girls and boys aged 3–17 years are overweight/obese (23). The proportions are even higher among young adults: overweight/obesity affects 36.5% of men and 26.2% of women aged 18–29 years and 60.0% of men and 41.5% of women aged 30–44 years (24). Regarding diet, there is convincing evidence linking the consumption of red and processed meats as well as alcohol consumption (≥2 drinks/ day) to an increased risk of developing colorectal cancer. On the other hand, there is probable evidence that the consumption of whole grains, dairy products, calcium supplements and dietary fiber is linked to a decreased risk of colorectal cancer (25). Most studies on diet and colorectal cancer are based on eating habits in the 1990s or earlier. Current dietary patterns have shifted towards a more westernized diet: high in saturated fat, rich in red meat, and low in fiber. This, in turn, produces gut microbiota imbalances and procarcinogenic advanced glycation end products that might contribute to the development of EO-CRC (26, 27).

Hereditary conditions and their associated management could have also contributed to the observed patterns in EO-CRC burden. A review reported that the prevalence of rare hereditary diseases ranges from 5% to 35% in EO-CRC, as opposed to 2–5% in late-onset colorectal cancer (28). First-degree relatives of persons with colorectal cancer are advised to initiate colorectal cancer screening at an age 10 years younger than that at which the index case was diagnosed and no later than age 45 years. Persons with Lynch syndrome, familial adenomatous polyposis. or MUTYH-associated polyposis should start with screening in the early decades of life and should be closely monitored thereafter (29).

Changes in diagnostic and clinical practices could may also play a role (13, 30). In the USA and Italy, the increase in EO-CRC rates coincided with the expansion of diagnostic procedures to age groups not eligible for colorectal cancer screening (13, 30), but this did not fully explain the increase in EO-CRC rates (30, 31). We found no data on trends in colonoscopy uptake by persons not in the age group eligible for colorectal cancer screening in the context of the organized cancer screening program in Germany. The increasing rate of smaller tumors (T1/T2) among persons aged 20–49 years may indicate that colonoscopy has been performed significantly more frequently also in this age group in recent years and may have contributed to this trend. Considering the high proportion of colorectal cancer cases with unknown T classification, however, this remains speculative.

Other possible factors include widespread exposure to broad-spectrum antibiotics, resulting in gut microbiota imbalances which in turn may favor carcinogenesis (32), and the increasing prevalence of inflammatory bowel diseases, i.e., Crohn’s disease and ulcerative colitis, which almost doubled between 1990 and 2017 in Germany (33).

Unlike in the USA, where mortality among younger adults reportedly rose by 1.3% annually between 2008 and 2017 (5), mortality from colorectal cancer among adults aged 20–49 years is still declining in Germany. The evidence on survival prospects is conflicting, with some studies reporting a poorer prognosis while other research describes similar or even better outcomes than for late-onset colorectal cancer (28, 34, 35). In Germany, the relative 5-year survival rate for EO-CRC was estimated at 72% in 2006 (35).

The present study has several limitations. The trend analyses were restricted to a relatively short period and to selected registries. Moreover, we did not conduct analyses for Union Internationale Contre le Cancer (UICC) stage because this information was often missing. Furthermore, the analyses were restricted to adult patients aged 20–49 years. However, the occurrence of colorectal cancer below the age of 20 years is extremely rare, so the exclusion of this age group probably had a negligible impact on our findings. Nevertheless, this should be considered when comparing our results with those of other studies.

The strengths of this study include the size of the population covered, which conferred relatively stable rates for most of the analyses and enabled stratification by sex, cancer diagnosis in different colonic subsites, and 10-year age group. As previously described and also shown by our exploratory analyses, inclusion or exclusion of appendiceal cancers from the group of EO-CRC had an impact on the trends (3, 36). Since new cases of appendiceal cancer account for 26% of all colon cancer diagnoses in persons aged 20–39 years, this needs to be considered. The increase in appendiceal cancer may be partially attributable to changes in registration practices: following the International Classification of Diseases for Oncology, third edition, until 2011 carcinoid tumors of the vermiform appendix (the most frequent tumor in this subcategory) were coded with uncertain behavior (8240/1), but since 2012 they have been registered as invasive (8240/3) (37). However, this would only affect the later part of the observation period (2012–2018). Therefore an actual increase cannot be ruled out, especially considering that the incidence of gastrointestinal carcinoid tumors has reportedly increased (38), which in turn has often been attributed to improvements in diagnostics (39). In contrast, little is known about the risk factors for these tumors.

Conclusion

Despite the increasing burden, EO-CRC accounts for about 5% of all colorectal cancers and mortality continues to decline. The rising EO-CRC has been attributed mainly to early life exposures, including obesity since the most pronounced increases were detected among young adults. This assumption is based on the current knowledge regarding the risk factors for colorectal cancer derived from epidemiological studies, which often do not distinguish onset and in which patients under the age of 50 years are under-represented. Moreover, several studies group colon and rectum, but emerging evidence shows that the risk factors across the colon continuum might differ (15, 26, 40). Thus, large epidemiological studies on risk factors for EO colon and rectal cancer are needed to improve our understanding of what is driving these changes. It is unclear how these trends will develop; therefore, monitoring them is essential. At the present time, lowering the age for colorectal cancer screening for persons without hereditary conditions would be premature. This would require an initial comprehensive assessment of the risks and benefits in the German setting.

Conflict of interest statement
The authors state that no conflict of interest exists.

Manuscript submitted on 29 November 2021, revised version accepted on 31 October 2022

Corresponding author
Dr. phil. Luana Fiengo Tanaka
Technical University of Munich

TUM Department of Sport and Health Sciences
Chair of Epidemiology,
Georg-Brauchle-Ring 60/62, 80992 München, Germany

Cite this as:
Tanaka LF, Hechenbichler Figueroa S, Popova V, Klug SJ, Buttmann-Schweiger N: The rising incidence of early-onset colorectal cancer. Dtsch Arztebl Int 2023; 120: 59–64. DOI: 10.3238/arztebl.m2022.0368

►Supplementary material

eTables, eFigure:
www.aerzteblatt-international.de/m2022.0368

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