| |

Received: 6 April 2021    Revised: 17 June 2021    Accepted: 8 July 2021

DOI: 10.1111/codi.15819

ORIGINAL ARTICLE

Rising incidence of colorectal cancer in individuals younger

than 50 years and increasing mortality from rectosigmoid
cancer in England

Oon-­Hui  Ng  | Raimundas Lunevicius  | James D. Arthur

Department of General Surgery, Liverpool Abstract

University Hospitals NHS Foundation
Trust, Liverpool, UK
Correspondence
James D. Arthur, Liverpool University
Hospitals NHS Foundation Trust, Aintree
Hospital, Lower Lane, Liverpool, L9 7AL,
UK.
Email: james.arthur@liverpoolft.nhs.uk
Funding information
The authors received no financial support
for the study, authorship and publication
of this article.
Aim: The aim was to describe changes in incidence and mortality from colorectal cancer
(CRC) in England by analysing data available from the National Cancer Registration and
Analysis Service (NCRAS, 2001–­2017).
Methods: Data analysis was undertaken to interpret trends and patterns in age-­
standardized incidence and death rates from CRC, including sub-­analyses by six age
groups (0–­24, 25–­49, 50–­59, 60–­69, 70–­79, 80+) and three sites of cancer—­colonic, rec-
tosigmoid and rectal.
Results: Overall CRC incidence remained relatively stable—­70.1 cases per 100  000 in-
dividuals (95% CI 69.3–­71.0) in 2001 and 68.8 cases (95% CI 68.0–­69.5) in 2017. Sub-­
analysis demonstrates a quarter fewer incidence of rectosigmoid cancer (−27%). This is
counterbalanced by a 3% rise in colon cancers. The age-­standardized incidence rate of
CRC increased by 59% in the 25–­49 age group. In the over 50s, CRC incidence remained
stable, with reductions seen in rectosigmoid cancer (50–­59 years, −19%; 60–­69, −26%;
70–­79, −39%; 80+, −27%). Overall, mortality improved (−18.7%), primarily as a result of
the reduction in deaths from colon (−31.6%) and rectal cancers (−25.1%). Deaths from
the small incident number of rectosigmoid cancers, however, demonstrated a significant
increase overall (+166.7%). Grouped age-­standardized death rate analyses showed in-
creasing death rates in the under 50s (+28.3%) compared to declining rates in the over
50s (−15.8%).
Conclusions: There is a clear trend in increased incidence and mortality in individuals
under 50 years old. There is also a trend to increased mortality from rectosigmoid cancer.
These findings should have implications for national screening programme extension to
under 50s and a call to arms for appropriate identification, staging and treatment of rec-
tosigmoid cancers.

KEYWORDS
colorectal cancer, England, epidemiology, incidence, mortality

© 2021 The Association of Coloproctology of Great Britain and Ireland

Colorectal Disease. 2021;23:2637–2646.  |

wileyonlinelibrary.com/journal/codi     2637
 |
2638      NG et al.
I NTRO D U C TI O N
Colorectal cancer (CRC) is the second leading cause of death from
cancer globally and in the UK and the seventh leading cause of death
among all diseases and injuries in England [1–­3]. Only half of the pa-
tients with a diagnosis of CRC, which is the fourth most common
cancer in the UK, survive for more than 5 years [4]. Understanding
trends and patterns in CRC incidence and mortality is critical for pri-
oritizing action such as screening age limits and evaluating cancer
control progress.
Recently published literature demonstrates an observed increase
in CRC among individuals under 50 in North America. This has led the
American Cancer Society to recommend a lowering of the screening
start age from 50 to 45 [5]. Studies that look at global and regional trends
also demonstrated that, in highly developed countries such as the UK,
rates still remain among the highest in the world. These countries con-
tinue to have a rising incidence of the disease, but with decreasing mor-
tality [6]. Vuik and colleagues, in a study of 20–­49-­year-­old European
individuals from a large cohort of 143.7 million people, found a ‘signifi-
cant’ CRC incidence increase among young adults in Europe particularly
in the 20–­39-­year group with no significant mortality change among the
youngest adults, but with few detailed UK-­specific data [7].
In 2018, a publication looking at trends of disease incidence in
40–­89-­year-­old individuals, utilizing data from The Health Improvement
Network (THIN) (2000–­2014), showed that CRC incidence has re-
mained relatively stable in the UK over the last decade [8], contrary to
other studies [6]. The THIN data, however, are derived from about 600
general practitioner practices and, while described as a fairly accurate
representative snapshot of UK CRC incidence, did not include data on
under 40s or on mortality, and we found this to be particularly relevant
if these studies are to guide screening start age and provide informa-
tion on outcome measures such as death from CRC [8] Exarchakou and
colleagues, analysing trends in CRC incidence among young adults in
England by anatomical sub-­site and deprivation (England cancer regis-
try data 1971–­2014), found that despite the magnitude of the increase
in incidence rates among young adults 20–­39  years, the number of
newly diagnosed cases remained far lower than in adults aged 50 years
or more [9]. The authors also demonstrated a smaller comparative an-
nual increase (1.5% per year) in adults aged 40–­49 years. In the over
50-­year-­old individuals, incidence rates remained stable or improved.
It is clear from the background published information that a low-
ering of the CRC screening onset age is required, but to what age? Are
there England-­ and UK-­specific mortality trends or sub-­site incidence
and mortality trends that would guide decision-­making? To help answer
these questions a review of current, up-­to-­date data from the National
Cancer Registration and Analysis Service (NCRAS) was undertaken.
M E TH O D S
This nationwide database study adheres to the Strengthening the
Reporting of Observational Studies in Epidemiology (STROBE) state-
ment and its checklist [10]. A comprehensive search was performed in
What does this paper add to the literature?
This paper shows an increase in the incidence of colorec-
tal cancer in individuals under 50 years old over the data
period. There is also a trend to increasing mortality from
cancer of the rectosigmoid junction in five age groups, but
especially in age groups 25–­49 and 80+. The results pre-
sent further evidence to advocate for extension of the na-
tional screening programme to individuals under 50 years
old, and provide food for thought about the management
of rectosigmoid cancers in particular.
the online data resource https://www.cance​rdata.nhs.uk, the National
Cancer Registration and Analysis Service, Public Health England [11,12].
Data corresponding to the following categories for CRC were retrieved
for each calendar year from 2001 to 2017: incident cases, number of
deaths, age-­standardized incidence and mortality rates. They were
further subdivided and grouped in standard Microsoft Excel Mac2011
worksheets by CRC sub-­site (colon, rectosigmoid, rectum) and six age
groups of patients (0–­24, 25–­49, 50–­59, 60–­69, 70–­79, 80+). These data
were used to generate CRC sub-­site and age-­group-­specific trends over
17 years and identify patterns within these trends.
Percentage changes from the means of age-­standardized inci-
dence and death rates were calculated using a standard formula to
identify the age groups for which a rapid change in incidence and
mortality rates has occurred. All visual material was generated using
GraphPad Prism version 9.0.0 (86) for macOS [13].
An incident case of CRC is a new cancer case, counted once when
the cancer is diagnosed. Incidence refers to the proportion or rate
of individuals who develop CRC per year. The age-­standardized inci-
dence rate is a weighted average of the age-­specific incidence rates
per 100  000 individuals, where the weights are the proportions of
individuals in the corresponding age groups. The same principle of
definition applies to the age-­standardized mortality (death) rate. The
percentage change between two mean values represents the degree
of change (percentage increase or decrease) at different points in time.
Ethical approval from the institutional research ethics commit-
tee was not required, as confirmed by the National Research Ethics
Service decision tool [14]. The institutional clinical audit manage-
ment board reviewed and approved the study's submitted protocol,
audit no. 9940. We confirm the authors had no access to identifying
patient information when collecting and analysing the data.
R E S U LT S
Incidence
In England, there were 550  697 patients with CRC in 2001–­2017
(Table 1). The total number of CRC cases increased by 25.3%, from
28 068 in 2001 to 35 157 cases in 2017. However, the incidence rate
NG et al.
per 100 000 population changed little between 2001 (70.1 cases per
100 000 individuals, 95% CI 69.3–­71.0) and 2017 (68.8 cases, 95%
CI 68.0–­69.5).
By site, colonic cancer accounted for 65.1% (n = 358 619), rectal
cancer 28.0% (n  =  153  923) and rectosigmoid cancer 6.9% of pa-
tients (n = 38 155). Colon cancer incidence increased by 32% (case
difference was 5664), and rectal cancer by 19% (case difference was
1558) (Figure 1A). Rectosigmoid cancer decreased from 2121 cases
in 2001 to 1988 cases in 2017, resulting in a significant fall in stan-
dardized incidence rate of 27.1% from 5.3 (95% CI 5.1–­5.6) in 2001
to 3.9 (95% CI 3.7–­4.1) in 2017 (Figure 1C).
Mortality
Between 2001 and 2017, CRC caused 221 633 deaths in England.
While there was a 4.4% increase in the number of cases of mortality
from CRC during this time (12 991 deaths in 2001 and 13 566 deaths
in 2017), when population size was accounted for, the standardized
incidence death rate fell by 18.7% (namely from 32.6% to 26.5%). By
site, the number of deaths from colon cancer (Figure 1B) and age-­
standardized death rate (Figure 1D) decreased by 12% and 32%, re-
spectively, from 2001 to 2017. A similar trend was observed in rectal
cancers—­the number of deaths and the age-­standardized death rate
decreased by 4% and 25%. However, the number of deaths and
age-­standardized death rate from rectosigmoid cancer rose sharply
in England, by 240% (from 732 to 2490 deaths) and 167% (from
1.83 to 4.88 cases per 100  000 individuals per year), as shown in
Figure 1B,D. Table 1 provides detailed information on the number of
deaths and age-­standardized death rates.
Incidence and mortality by age group
Figure 2  shows stable incidence rates (Figure 2A) and decreasing
death rates (Figure 2B) for colon cancer, especially in the age groups
60–­69 and 70–­79. A similar pattern is observed for rectal cancer
(Figure 2C,D). In contrast, mortality rates from rectosigmoid cancer
rose sharply in all age groups between 2001 and 2017 (Figure 2F).
This increase was particularly apparent in age groups 60–­69, 70–­79
and 80+. Paradoxically, rectosigmoid cancer incidence declined in all
age groups (Figure 2E).
Annual percentage change in incidence and mortality
Figure 3 highlights a gradual increase in the incidence of CRC in in-
dividuals under 50 years old with particular increase in colon cancer
in the age groups 0–­24 and 25–­49 (Figure 3A). The heat maps of
the figure highlight, via dark shades of colours, the same pattern for
the other two sites of CRC—­rectal and rectosigmoid (Figure 3B,C).
Figure 3F shows high levels of percentage changes in mortality rates
from rectosigmoid cancer in five age groups, but especially for adults
|
      2639
from the age groups 25–­49 and 80+, with a steady increase from
2003.
DISCUSSION
The results demonstrate that, overall, CRC incidence in England
across all combined age groups has remained stable. Delving deeper
into the data, they also show that, whilst there is declining incidence
in the over 50s, this is counterbalanced by a rise in incidence in the
under 50s. Further, there is a steady rise in mortality from rectosig-
moid cancers, particularly in the under 50s and over 80s.
Incidence
Possible reasons for this rise in the under 50s are myriad. Non-­
modifiable risk factors, including sex, race, inflammatory bowel
disease and family history of CRC, have been found to be associ-
ated with early-­onset CRC [15,16] but cannot explain the rise in
incidence. For example, hereditary CRC syndromes are attributed
as a cause in less than 20% of young-­onset CRCs [17,18]. This fac-
tor alone does not explain the rise in incidence of young-­onset
cancers. Clinicopathological differences between young-­ and
older-­onset CRC are also known (higher incidence of mucinous and
signet-­ring tumours, poor differentiation, greater incidence of left
colon and rectum cancers, higher rate of synchronous, metachro-
nous and metastatic disease at presentation) and these suggest a
different molecular pathway or influence for CRC in this age group
[19–­21]. Molecular genetics which influence these differences may
contribute in part to the rising incidence, and more investigation is
required. Wang and colleagues also suggested that attained height
showed a stronger association with higher risk of younger-­onset
CRC, especially rectal cancers [16]. Whilst we found no published
evidence to suggest that populations with increasing under-­50s
incidence of CRC had increasing height, height is a genetically
and early-­life nutritional and health related consequence, and it is
therefore a possibility that in utero and early-­life factors, as well as
a contribution from genetic and therefore hereditary factors, are
drivers of increasing incidence of young-­onset CRC. A ‘Western’
diet theory has also been proposed by authors and researchers
such as Zheng and colleagues [22], specifically a diet low in fibre
and seeds, low in calcium but high in saturated fats as found in pro-
cessed meats, and increasing alcohol intake. These dietary com-
ponents, amongst others, are ‘pro-­inflammatory’, according to the
Dietary Inflammatory Index, and are associated with an increased
risk of CRC [23,24]. Social deprivation, lack of exercise and obesity
may also be contributing to this increased incidence of CRC in the
young [25]. How much, if at all, any of these factors contribute
to a milieu that facilitates development of CRC in a young person
is unclear and it is most likely that there are complex interactive
pathways that result in the "perfect" environment for development
of CRC in a young person.
2640      | NG et al.

TA B L E 1  Incident cases, deaths, age-­standardized incidence and mortality rates per 100 000 individuals of both sexes combined in
England between 2001 and 2017, by colorectal cancer site and overall.

A. Incidence

Colon Rectum Rectosigmoid Colorectal

a a a
Cases Rate   Cases Rate   Cases Rate   Cases Ratea 

2001 17 837 44.4 (43.7–­45.0) 8111 20.4 (20.0–­20.9) 2121 5.3 (5.1–­5.6) 28 069 70.1 (69.3–­71.0)
2002 17 628 43.4 (42.7–­4 4.1) 8208 20.4 (20.0–­20.9) 2237 5.6 (5.4–­5.9) 28 073 69.4 (68.6–­70.3)
2003 17 825 43.6 (42.9–­4 4.3) 8277 20.5 (20.0–­20.9) 2300 5.7 (5.5–­5.9) 28 402 69.7 (68.9–­70.6)
2004 18 492 44.8 (44.2–­45.5) 8419 20.7 (20.2–­21.1) 2490 6.1 (5.9–­6.4) 29 401 71.6 (70.8–­72.5)
2005 18 844 45.2 (44.6–­45.9) 8561 20.8 (20.3–­21.2) 2547 6.2 (6.0–­6.4) 29 952 72.2 (71.3–­73.0)
2006 19 463 46.0 (45.3–­46.7) 8791 21.0 (20.6–­21.5) 2423 5.8 (5.6–­6.1) 30 677 72.8 (72.0–­73.7)
2007 20 104 46.8 (46.1–­47.5) 8850 20.8 (20.4–­21.3) 2409 5.6 (5.4–­5.9) 31 363 73.2 (72.4–­74.0)
2008 21 428 49.1 (48.4–­49.7) 8978 20.8 (20.3–­21.2) 2420 5.6 (5.3–­5.8) 32 826 75.4 (74.5–­76.2)
2009 21 662 48.8 (48.2–­49.5) 9233 21.0 (20.6–­21.4) 2471 5.6 (5.4–­5.8) 33 366 75.4 (74.6–­76.3)
2010 22 041 48.9 (48.2–­49.5) 9345 21.0 (20.5–­21.4) 2403 5.4 (5.1–­5.6) 33 789 75.1 (74.3–­76.0)
2011 22 835 49.8 (49.1–­50.4) 9633 21.2 (20.8–­21.7) 2307 5.1 (4.88–­5.30) 34 775 76.1 (75.3–­76.9)
2012 23 050 49.6 (48.9–­50.2) 10 004 21.7 (21.3–­22.2) 2238 4.9 (4.7–­5.1) 35 292 76.1 (75.3–­77.0)
2013 22 974 48.5 (47.8–­49.1) 9394 20.0 (19.6–­20.4) 1991 4.2 (4.1–­4.4) 34 359 72.7 (71.9–­73.5)
2014 23 191 47.8 (47.2–­48.5) 9344 19.5 (19.1–­19.9) 1875 3.9 (3.7–­4.1) 34 410 71.2 (70.5–­72.0)
2015 23 775 48.2 (47.6–­48.8) 9445 19.4 (19.0–­19.8) 1914 3.9 (3.7–­4.1) 35 134 71.5 (70.7–­72.2)
2016 23 719 47.2 (46.6–­47.8) 9572 19.3 (18.9–­19.7) 1994 4.0 (3.8–­4.2) 35 285 70.5 (69.8–­71.2)
2017 23 243 45.3 (44.7–­45.8) 9614 19.0 (18.7–­19.4) 1968 3.9 (3.7–­4.0) 34 825 68.1 (67.4–­68.9)

B. Mortality
Deaths Rate Deaths Rate Deaths Rate Deaths Rate
2001 8791 22.0 (21.5–­22.5) 3468 8.8 (8.5–­9.1) 732 1.8 (1.7–­2.0) 12 991 32.6 (32.0–­33.2)
2002 8889 22.0 (21.5–­22.5) 3484 8.8 (8.5–­9.1) 813 2.0 (1.9–­2.2) 13 186 32.8 (32.2–­33.4)
2003 8512 20.8 (20.4–­21.3) 3511 8.8 (8.5–­9.1) 879 2.2 (2.0–­2.3) 12 902 31.8 (31.3–­32.4)
2004 8486 20.7 (20.2–­21.1) 3426 8.5 (8.2–­8.8) 1066 2.6 (2.5–­2.8) 12 978 31.8 (31.2–­32.4)
2005 8447 20.4 (19.9–­20.8) 3462 8.5 (8.2–­8.8) 1015 2.5 (2.3–­2.6) 12 924 31.4 (30.8–­31.9)
2006 8329 19.7 (19.3–­20.2) 3395 8.2 (7.9–­8.5) 1144 2.8 (2.6–­2.9) 12 868 30.7 (30.1–­31.2)
2007 8179 19.0 (18.6–­19.4) 3351 7.9 (7.7–­8.2) 1311 3.1 (2.9–­3.2) 12 841 30.0 (29.5–­3 0.5)
2008 8314 19.1 (18.6–­19.5) 3389 7.9 (7.7–­8.2) 1364 3.2 (3.0–­3.3) 13 067 30.2 (29.6–­3 0.7)
2009 8095 18.3 (17.9–­18.7) 3267 7.5 (7.2–­7.8) 1329 3.0 (2.9–­3.2) 12 691 28.9 (28.3–­29.4)
2010 8118 18.0 (17.6–­18.4) 3319 7.5 (7.3–­7.8) 1468 3.3 (3.1–­3.5) 12 905 28.8 (28.9–­29.3)
2011 8037 17.5 (17.1–­17.9) 3238 7.2 (7.0–­7.5) 1596 3.5 (3.4–­3.7) 12 871 28.3 (27.8–­28.8)
2012 8151 17.5 (17.1–­17.9) 3268 7.1 (6.9–­7.4) 1814 3.9 (3.8–­4.1) 13 233 28.6 (28.1–­29.0)
2013 7832 16.5 (16.1–­16.9) 3260 7.0 (6.7–­7.2) 1907 4.1 (3.9–­4.2) 12 999 27.6 (27.1–­28.0)
2014 7833 16.1 (15.8–­16.5) 3210 6.7 (6.5–­7.0) 1993 4.2 (4.0–­4.4) 13 036 27.0 (26.6–­27.5)
2015 7753 15.7 (15.3–­16.0) 3213 6.6 (6.4–­6.8) 2194 4.5 (4.3–­4.7) 13 160 26.8 (26.3–­27.2)
2016 7726 15.4 (15.0–­15.7) 3238 6.5 (6.3–­6.7) 2451 4.9 (4.7–­5.1) 13 415 26.8 (26.3–­27.3)
2017 7751 15.1 (14.7–­15.4) 3325 6.6 (6.3–­6.8) 2490 4.9 (4.7–­5.1) 13 566 26.5 (26.1–­27.0)
a
Data in parentheses are the lower and upper limits of the 95% confidence interval. The estimates are shown as values after rounding.

The role of microbiota in colorectal carcinogenesis deserves
mention. There is no doubt that dysbiosis and decreased diversity of
the gut microbiome are linked to numerous diseases, including CRC
[26]. Western diets, particularly pro-­inflammatory diets as discussed
above, are thought to alter gut microbiomes that may lead to gut-­cell
proliferation, via cytokine release pathways, thus promoting an envi-
ronment for CRC development. It is also known that moderate to heavy
alcohol intake is a risk factor for CRC. Ethanol metabolism by compo-
nents of the microbiome, under the right conditions, generates carcino-
genic acetaldehyde in the colon and rectum [27,28]. These pathways
NG et al. |
      2641

(A) Incident cases (B) Deaths

25000 10000

20000 8000

Colon Colon
6000

Counts
15000
Counts

Rectal Rectal
10000 4000 Rectosigmoid
Rectosigmoid

5000 2000

0
0
2000 2005 2010 2015 2020 2000 2005 2010 2015 2020
Year Year

(C) Age-standardised incidence (D) Age-standardised mortality

25

Rate per 100,000 individuals

Rate per 100,000 individuals

50
20
40
Colon Colon
15
30
Rectal Rectal
20 10 Rectosigmoid
Rectosigmoid

10 5

0 0
2001 2005 2009 2013 2017 2001 2005 2009 2013 2017
Year Year

F I G U R E 1  Incidence and Mortality trends (Overall and Age-­standardised) by Tumour sub-­site [Colour figure can be viewed at
wileyonlinelibrary.com]

highlight the potential significance of microbiomes not only in the path-
way of genesis of CRC in all age groups but in that for incidence of CRC
in the young.
The falling incidence of CRC rates in the over 50s is again pos-
sibly multifactorial, with screening and the results of population
education on screening playing a probably significant role [29–­32].
The question to be addressed is whether to extend screening to
the under 50s, and if so to what lower age limit. Further, are more
sensitive and therefore more accurate tests with resultant minimiza-
tion of unnecessary invasive investigations the answer for screen-
ing in a younger and possibly more discerning but less engaging or
compliant population? In the USA, the Multi-­Society Task Force on
Colorectal Cancer recommends screening African American individ-
uals at age 45 years owing to the higher incidence of, and mortality
from, earlier-­onset disease [33]. Such targeted approaches may need
consideration in the UK. A screening program could utilise either a
Faecal Occult Blood Test (FOBT) or a Faecal Immunochemical Test
(FIT). Population uptake for FOBT test, is however suboptimal, re-
quiring two faecal samples on three separate occasions. In this cir-
cumstance, utilization of the FIT test may improve acceptance and
uptake, as publications suggest a third more people perceive FIT
to be easier and ‘less disgusting’ to complete, and therefore more
likely to be undertaken, completed and returned [34]. The Scottish
Bowel Screening Programme also showed that the FIT uptake by
the population is higher compared to the FOBT, with increased up-
take across gender, age groups and social deprivation, from 63.9%
compared with 56.4% for FOBT [35]. These studies suggest that
the introduction of the FIT is likely to result in a notable increase in
CRC screening uptake. FITs have also demonstrated accuracy; the
National Institute for Health and Care Excellence (NICE) FIT study
demonstrated that at the lowest cut-­off of 2 μg/g FIT sensitivity is
maximized to 97%. At that level a negative FIT can effectively rule
out CRC and was shown to be better than symptoms alone for se-
lection of patients for urgent investigations [36]. Another study into
the utilization of FIT demonstrated via modelling that a reduction
in colonoscopy of 30%–­50% could be achieved while missing very
few cancers, with cut-­off FIT levels at between 2 and 10 μg/g (NICE
DG30 recommended) [37]. This would alleviate the impact on en-
doscopy capacity associated with the extension of screening to a
younger population [38]. The value in freeing up capacity for bowel
cancer screening and the utilization of available urgent slot inves-
tigation of patients with non-­screening symptoms (iron deficiency
anaemia, weight loss, rectal bleeding, and palpable abdominal and
rectal mass) is invaluable. Extension of the FIT to the under 50s
should therefore be considered.
Mortality
Age-­standardized death rates fell by 18.7%. Absolute deaths from
colon cancer and age-­standardized death rate also decreased by
11.8% and 31.5%, respectively, over the study period. This trend
2642      | NG et al.

(A) Colon cancer, incidence (B) Colon cancer, mortality

350
350

Rate per 100,000 individuals

80+
Rate per 100,000 individuals

80+ 300
300 70-79
70-79 250
250 60-69
60-69
200 200
50-59 50-59
150 150
25-49 25-49
100 0-24 100 0-24
50 50
0 0
2001 2005 2009 2013 2017 2001 2005 2009 2013 2017
Year Year
(C) Rectal cancer, incidence (D) Rectal cancer, mortality
120

Rate per 100,000 individuals

80+
Rate per 100,000 individuals

120
80+ 70-79
90
90 70-79
60-69
60-69
60 50-59
60 50-59
25-49 25-49
30 0-24 30 0-24

0 0
2001 2005 2009 2013 2017 2001 2005 2009 2013 2017
Year Year

(E) Rectosigmoid cancer, incidence (F) Rectosigmoid cancer, mortality

40
Rate per 100,000 individuals

40 80+
Rate per 100,000 individuals

80+ 70-79
30
30 70-79
60-69
60-69
20 50-59
20 50-59
25-49
25-49
10 0-24 10 0-24

0 0
2001 2005 2009 2013 2017 2001 2005 2009 2013 2017
Year Year

F I G U R E 2  Trends in Incidence and Mortality Rates by age-­group and Tumour sub-­site [Colour figure can be viewed at wileyonlinelibrary.
com]

was also observed in rectal cancers—­absolute deaths and age-­
standardized death rates decreased by 4% and 25%. The overall
decrease could again be explained by the significant reduction in
mortality attributable to bowel cancer screening in the over 60 year
olds [39,40]. Mandel and colleagues, from as far back as 1993, dem-
onstrated a decrease in 13-­year cumulative mortality from CRC by
33% when studying a population of 45 000 aged 50–­8 0 years. This
significant benefit of screening, in addition to the reduction of inci-
dence, has been replicated and reported in other studies over time.
There are other notable contributors to improved survival.
Uptake and widespread adoption of surgical techniques such as
Heald's ‘holy plane’ mobilization of the rectum (total mesorectal ex-
cision plane) has been proven to reduce local recurrence after re-
section of rectal cancer to low rates. This has been demonstrated to
result in improved survival [41]. The benefits of complete mesocolic
excision with central vascular ligation as described by Hohenberger
[42] has been demonstrated in a recent systematic review that
showed an improved 3-­ and 5-­year survival compared to ‘standard
right colectomy’ for cancer [43]. Several randomized controlled trials
have demonstrated that preoperative radiotherapy and chemoradio-
therapy for non-­early rectal cancers and neoadjuvant chemotherapy
for both advanced rectal (as part of total neoadjuvant therapy or
alone) and colonic cancers result in less local recurrence and better
overall and disease-­free survival compared to people who did not
have preoperative treatment. These form the evidence for treat-
ment guidance for CRC in the UK published by NICE (NICE guidance
NG151) [44]. The role of total neoadjuvant therapy for rectal can-
cer in improving survival is still unclear but holds promise. Robotic
surgery also deserves mention; despite a retrospective cohort
study demonstrating survival benefit for robotic transoral surgery
NG et al. |
      2643

(A) (B) (C)

2017 2017 51 2017
2015 2015 2015
301
2013 2013 2013
51
2011 2011 1
2011
201
2009 2009 2009
2007 2007 2007
101
2005 2005 2005 1

2003 2003 2003

1
2001 2001 2001
Blue colour key Blue colour key Blue colour key

+
9

9
24

9
24
9

9
24

-6

-7

80
-4

-5

-6

-7

80

-4

-5
-4

-5

-6

-7

80
0-

0-
0-

60

70
25

50

60

70

25

50
25

50

60

70
Age groups, colon cancer: incidence Age groups, rectal cancer: incidence Age groups, rectosigmoid cancer: incidence

(D) (E) (F)

2017 2017 21 2017 261
241
2015 2015 2015
221
2013 2013 2013 201
181
2011 2011 1 2011 161
141
2009 2009 2009 121
1 101
2007 2007 2007 81
61
2005 2005 2005 41
2003 2003 2003 21
1
2001 2001 2001
Red colour key Red colour key Red colour key
9

9
24

24

24

+
-4

-5

-6

-7

-4

-5

-6

-7

-4

-5

-6

-7
80

80

80
0-

0-

0-
25

50

60

70

25

50

60

70

25

50

60

70
Age groups, colon cancer: mortality Age groups, rectal cancer: mortality Age groups, rectosigmoid cancer: mortality

F I G U R E 3  Heat maps demonstrating temporal trends and changes in degree of Incidence and Mortality by age group [Colour figure can
be viewed at wileyonlinelibrary.com]

compared to non-­robotic surgery in patients with early-­stage oro-
pharyngeal cancer, these benefits have not been consistently
demonstrated in randomized trials in CRC [45].
Rectosigmoid cancers
It is unclear why there is such a stark and sharp rise in mortality from
rectosigmoid cancers. There is evidence in the literature of particu-
larly poor outcome for cancers involving this segment [46,47]. One
suggsted reason is that they appear to have different patterns of
lymphatic spread with earlier or more frequent metastases to para-
rectal nodes [48], making them more likely to be advanced at pres-
entation. There is also the possibility that some of the rectosigmoid
cancers may be miscoded and could be upper rectal or distal sigmoid.
This wrong-­site allocation could even be endoscopic or radiological
[49]. Similar to lower third cancers of the rectum, the rectosigmoid
segment, anatomically, also occurs at a ‘waist’ and therefore, theo-
retically, smaller tumours could be more likely to involve surround-
ing structures earlier, creating an earlier T4  stage with a higher risk
of local relapse and earlier distant metastases even after potentially
curative treatment. The presence of a rectosigmoid ‘waist’ identified
radiologically and pathologically is undisputed and may also be uti-
lized to correctly identify, code and guide appropriate treatment [50].
We suggest that a first step in appropriate management of rec-
tosigmoid tumours is the accurate identification of that segment
of the colorectum, especially radiologically. To do so, a universally
accepted and reproducible identification parameter has to be uti-
lized. One such parameter could be the ‘rectosigmoid take-­off’ as
described by D’Souza and colleagues [51]. The call for universally
utilizable identification parameters must not go unheeded.
Treatment of rectosigmoid cancers, considering the ‘waist’ the-
ory and potential early nodal involvement and T4  status, may also
be generally suboptimal. There is a suggestion that cancers of this
area, particularly Stages II and III, may be undertreated, and perhaps
the same approach to tumours at the other ‘waist’ of the rectum,
the lower third of the rectum, must be considered [52]. In this area,
within the bony pelvis’s protection, such rectal cancers are more
readily treated with chemoradiation particularly because concerns
about radiation injury to surrounding tissue are less problematic.
While radiation may pose a risk of injury to the small bowel if de-
livered in the rectosigmoid region, there is now increasing evidence
of benefit from neoadjuvant chemotherapy with acceptable tumour
response, albeit lower complete pathological response [53]. Further
investigation into this area is required.
Potential sources of error
In this large cohort study, the NCRAS database could contain errors
of coding, particularly for rectosigmoid cancers. Distal sigmoid and
upper rectal cancers could have been coded as rectosigmoid before
submission to the NCRAS database. The large study population size,
however, would potentially eliminate this error.
 |
2644      NG et al.
CO N C LU S I O N S
This large sample analysis of national data confirms a rising incidence
of CRC in the under 50s, less so in the under 25s but obviously so
in the 25–­49 age group. It also shows an alarming rise in mortality
from rectosigmoid cancer. Efforts need to be directed either at tar-
geted identification of groups at risk for screening, using molecular
profile techniques, or extension of screening to lower ages—­a po-
tential mammoth health economics undertaking. In-­depth review of
rectosigmoid cancer management is needed, from staging through
optimal neoadjuvant techniques to surgical strategy.
C O N FL I C T O F I N T E R E S T
No conflicts of interest are declared.
AU T H O R C O N T R I B U T I O N S
Oon-­Hui Ng: data collection, analysis and interpretation, subse-
quent revisions, approval. Raimundas Lunevicius: methodology, data
analysis, processing and interpretation, figure production, manu-
script writing, subsequent revisions, approval. James D. Arthur: pro-
ject conceiver, data interpretation, manuscript writing, subsequent
revisions, approval.
E T H I C A L A P P R OVA L
Ethical approval from the institutional research ethics committee
was not required. The study was registered with the Trust's audit
department (audit registration number 9940).
PAT I E N T C O N S E N T S TAT E M E N T
The authors had no access to identifying patient information when
collecting and analysing the data. Therefore, patient consent was
not required.
P E R M I S S I O N TO R E P R O D U C E M AT E R I A L F R O M
OT H E R S O U R C E S
No material has been reproduced from external sources.
DATA AVA I L A B I L I T Y S TAT E M E N T
The data points on age-­specific incidence and mortality are available
from the corresponding author on reasonable request.
ORCID
Oon-­Hui Ng  https://orcid.org/0000-0003-0881-5645
Raimundas Lunevicius  https://orcid.org/0000-0003-3295-0142
James D. Arthur  https://orcid.org/0000-0003-3738-7264
REFERENCES
1. Newton JN, Briggs ADM, Murray CJL, Dicker D, Foreman KJ, Wang H,
et al. Changes in health in England, with analysis by English regions and
areas of deprivation, 1990–­2013: a systematic analysis for the Global
Burden of Disease Study 2013. Lancet. 2015;386(10010):2257–­74.
https://doi.org/10.1016/S0140​-­6736(15)00195​-­6
2. GBD 2017 Colorectal Cancer Collaborators. The global, regional,
and national burden of colorectal cancer and its attributable risk
factors in 195 countries and territories, 1990–­2017: a system-
atic analysis for the Global Burden of Disease Study 2017. Lancet
Gastroenterol Hepatol. 2017;4:913–­33. https://doi.org/10.1016/
S2468​-­1253(19)30345​- ­0
3. GBD 2017 Causes of Death Collaborators. Global, regional, and
national age-­sex-­specific mortality for 282 causes of death in
195 countries and territories, 1980–­2017: a systematic anal-
ysis for the Global Burden of Disease Study 2017. Lancet.
2018;392(10159):1736–­88. https://doi.org/10.1016/S0140​
-­6736(18)32203​-­7. Erratum. In: Lancet. 2019; 393: e44. Erratum in:
Lancet. 2018; 392: 2170.
4. George AT, Aggarwal S, Dharmavaram S, Menon A, Dube M,
Vogler M, et al. Regional variations in UK colorectal cancer screen-
ing and mortality. Lancet. 2018;392(10144):277–­8. https://doi.
org/10.1016/S0140​-­6736(18)31208​-­X
5. Wolf AMD, Fontham ETH, Church TR, Flowers CR, Guerra CE,
LaMonte SJ, et al. Colorectal cancer screening for average-­risk
adults: 2018 guideline update from the American Cancer Society.
CA Cancer J Clin. 2018;68:250–­81. https://doi.org/10.3322/
caac.21457
6. Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A,
Bray F. Global patterns and trends in colorectal cancer incidence
and mortality. Gut. 2017;66:683–­91. https://doi.org/10.1136/gutjn​
l-­2015-­310912
7. Vuik FER, Nieuwenburg SAV, Bardou M, Lansdorp-­Vogelaar I,
Dinis-­Ribeiro M, Bento MJ, et al. Increasing incidence of colorec-
tal cancer in young adults in Europe over the last 25 years. Gut.
2019;68:1820–­6. https://doi.org/10.1136/gutjn​l-­2018-­317592
8. Soriano LC, Soriano-­Gabarró M, García Rodríguez LA. Trends
in the contemporary incidence of colorectal cancer and patient
characteristics in the United Kingdom: a population-­based co-
hort study using the Health Improvement Network. BMC Cancer.
2018;18:402. https://doi.org/10.1186/s1288​5-­018-­4265-­1
9. Exarchakou A, Donaldson LJ, Girardi F, Coleman MP. Colorectal
cancer incidence among young adults in England: trends by ana-
tomical sub-­site and deprivation. PLoS One. 2019;14:e0225547.
https://doi.org/10.1371/journ​al.pone.0225547
10. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC,
Vandenbroucke JP. The Strengthening the Reporting of
Observational Studies in Epidemiology (STROBE) state-
ment: guidelines for reporting observational studies. Lancet.
2007;370(9596):1453–­7. https://doi.org/10.1016/S0140​
-­6736(07)61602​-­X
11. National Cancer Registration and Analysis Service. CancerData:
Incidence. [cited 2020 Dec 31]. Available from: https://www.cance​
rdata.nhs.uk/incid​ence
12. National Cancer Registration and Analysis Service. CancerData:
Mortality. [cited 2020 Dec 31]. Available from https://www.cance​
rdata.nhs.uk/morta​lity
13. GraphPad Software. GraphPad Software. San Diego; Available
from: http://www.graph​pad.com
14. Health Research Authority. Health Research Authority and the
UKRI MRC Regulatory Support Centre. Available from: http://
www.hra-­decis​ionto​ols.org.uk/research
15. Gausman V, Dornblaser D, Anand S, Hayes RB, O'Connell K, Du
M, et al. Risk factors associated with early-­onset colorectal cancer.
Clin Gastroenterol Hepatol. 2020;18:2752–­2759.e2. https://doi.
org/10.1016/j.cgh.2019.10.009
16. Wang L, Lo C-­H, He X, Hang D, Wang M, Wu K, et al. Risk fac-
tor profiles differ for cancers of different regions of the colorec-
tum. Gastroenterology. 2020;159:241–­256.e13. https://doi.
org/10.1053/j.gastro.2020.03.054
17. Siegel RL, Jemal A, Ward EM. Increase in incidence of colorec-
tal cancer among young men and women in the United States.
Cancer Epidemiol Biomarkers Prev. 2009;18:1695–­8. https://doi.
org/10.1158/1055-­9965.EPI-­09-­0186
NG et al.
18. Silla IO, Rueda D, Rodríguez Y, García JL, de la Cruz VF, Perea J.
Early-­onset colorectal cancer: a separate subset of colorectal
cancer. World J Gastroenterol. 2014;20:17288–­96. https://doi.
org/10.3748/wjg.v20.i46.17288
19. Perea J, García JL, Corchete L, Tapial S, Olmedillas-­López S, Vivas
A, et al. A clinico-­pathological and molecular analysis reveals differ-
ences between solitary (early and late-­onset) and synchronous rec-
tal cancer. Sci Rep. 2021;11:2202. https://doi.org/10.1038/s4159​
8-­020-­79118​-­z
20. Willauer AN, Liu Y, Pereira AAL, Lam M, Morris JS, Raghav KPS,
et al. Clinical and molecular characterization of early-­onset colorec-
tal cancer. Cancer. 2019;125:2002–­10. https://doi.org/10.1002/
cncr.31994
21. Akimoto N, Ugai T, Zhong R, Hamada T, Fujiyoshi K, Giannakis
M, et al. Rising incidence of early-­onset colorectal cancer—­a call
to action. Nat Rev Clin Oncol. 2021;18:230–­43. https://doi.
org/10.1038/s4157​1-­020-­0 0445​-­1
22. Zheng X, Hur J, Nguyen LH, Liu J, Song M, Wu K, et al. Comprehensive
assessment of diet quality and risk of precursors of early-­onset col-
orectal cancer. JNCI J Natl Cancer Inst. 2021;113:543–­52. https://
doi.org/10.1093/jnci/djaa164
23. Shivappa N, Steck SE, Hurley TG, Hussey JR, Hébert JR. Designing
and developing a literature-­derived, population-­based dietary in-
flammatory index. Public Health Nutr. 2014;17:1689–­96. https://
doi.org/10.1017/S1368​98001​3 002115
24. Shivappa N, Godos J, Hébert J, Wirth M, Piuri G, Speciani A, et al.
Dietary inflammatory index and colorectal cancer risk—­a meta-­
analysis. Nutrients. 2017;9:1043. https://doi.org/10.3390/nu909​
1043
25. Liu P-­H, Wu K, Ng K, Zauber AG, Nguyen LH, Song M,
et al. Association of obesity with risk of early-­onset colorectal
cancer among women. JAMA Oncol. 2019;5:37–­4 4. https://doi.
org/10.1001/jamao​ncol.2018.4280
26. Jahani-­Sherafat S, Alebouyeh M, Moghim S, Ahmadi Amoli H,
Ghasemian-­Safaei H. Role of gut microbiota in the pathogenesis
of colorectal cancer; a review article. Gastroenterol Hepatol Bed
Bench. 2018;11:101–­19.
27. Cho S, Shin A, Park SK, Shin H-­R , Chang S-­H, Yoo K-­Y. Alcohol
drinking, cigarette smoking and risk of colorectal cancer in the
Korean multi-­center cancer cohort. J Cancer Prev. 2015;20:147–­52.
https://doi.org/10.15430/​jcp.2015.20.2.147
28. Salaspuro M. Bacteriocolonic pathway for ethanol oxidation: char-
acteristics and implications. Ann Med. 1996;28:195–­200. https://
doi.org/10.3109/07853​89960​9033120
29. Mandel JS, Church TR, Bond JH, Ederer F, Geisser MS, Mongin SJ,
et al. The effect of fecal occult-­blood screening on the incidence
of colorectal cancer. N Engl J Med. 2000;343:1603–­7. https://doi.
org/10.1056/NEJM2​0 0011​3 0343​2203
3 0. Murphy CC, Sandler RS, Sanoff HK, Yang YC, Lund JL, Baron JA.
Decrease in incidence of colorectal cancer among individuals 50
years or older after recommendations for population-­based screen-
ing. Clin Gastroenterol Hepatol. 2017;15:903–­909.e6. https://doi.
org/10.1016/j.cgh.2016.08.037
31. McClements PL, Madurasinghe V, Thomson CS, Fraser CG, Carey
FA, Steele RJC, et al. Impact of the UK colorectal cancer screening
pilot studies on incidence, stage distribution and mortality trends.
Cancer Epidemiol. 2012;36:e232–­42. https://doi.org/10.1016/j.
canep.2012.02.006
32. Kaminski MF, Robertson DJ, Senore C, Rex DK. Optimizing the qual-
ity of colorectal cancer screening worldwide. Gastroenterology.
2020;158:404–­17. https://doi.org/10.1053/j.gastro.2019.11.026
33. Rex DK, Boland CR, Dominitz JA, Giardiello FM, Johnson DA,
Kaltenbach T, et al. Colorectal cancer screening: recommendations
for physicians and patients from the U.S. Multi-­Society Task Force
on colorectal cancer. Gastroenterology. 2017;153:307–­23. https://
doi.org/10.1038/ajg.2017.17434
|
      2645
3 4. Chambers JA, Callander AS, Grangeret R, O’Carroll RE. Attitudes
towards the Faecal Occult Blood Test (FOBT) versus the Faecal
Immunochemical Test (FIT) for colorectal cancer screening: per-
ceived ease of completion and disgust. BMC Cancer. 2016;16:96.
https://doi.org/10.1186/s1288​5-­016-­2133-­4
35. Clark G, Strachan JA, Carey FA, Godfrey T, Irvine A, McPherson A,
et al. Transition to quantitative faecal immunochemical testing from
guaiac faecal occult blood testing in a fully rolled-­out population-­
based national bowel screening programme. Gut. 2021;70:106–­13.
https://doi.org/10.1136/gutjn​l-­2019-­320297
36. D’Souza N, Georgiou Delisle T, Chen M, Benton S, Abulafi M.
Faecal immunochemical test is superior to symptoms in predicting
pathology in patients with suspected colorectal cancer symptoms
referred on a 2WW pathway: a diagnostic accuracy study. Gut.
2021;70:1130–­8. https://doi.org/10.1136/gutjn​l-­2020-­321956
37. National Institute for Health and Care Excellence. Quantitative
faecal immunochemical tests to guide referral for colorectal cancer
in primary care [DG30]. London: National Institute for Health and
Care Excellence; 2017. Available from https://www.nice.org.uk/
guida​nce/dg30
38. D’Souza N, Abulafi M. The faecal immunochemical test in low
risk patients with suspected bowel cancer. Br J Hosp Med (Lond).
2019;80:22–­6. https://doi.org/10.12968/​hmed.2019.80.1.22
39. Mandel JS, Bond JH, Church TR, Snover DC, Bradley GM, Schuman
LM, et al. Reducing mortality from colorectal cancer by screening
for fecal occult blood. Minnesota Colon Cancer Control Study. N
Engl J Med. 1993;328:1365–­71. https://doi.org/10.1056/NEJM1​
99305​13328​1901
4 0. Wiegering A, Ackermann S, Riegel J, Dietz UA, Götze O, Germer
C-­T, et al. Improved survival of patients with colon cancer detected
by screening colonoscopy. Int J Colorectal Dis. 2016;31:1039–­45.
https://doi.org/10.1007/s0038​4-­015-­2501-­6
41. Heald RJ, Ryall RD. Recurrence and survival after total mesorectal
excision for rectal cancer. Lancet. 1986;1(8496):1479–­82. https://
doi.org/10.1016/s0140​-­6736(86)91510​-­2
42. Siani LM, Garulli G. The importance of the mesofascial interface in
complete mesocolic excision. Surgeon. 2017;15:240–­9. https://doi.
org/10.1016/j.surge.2016.10.006
43. Crane J, Hamed M, Borucki JP, El-­Hadi A, Shaikh I, Stearns AT.
Complete mesocolic excision versus conventional surgery for colon
cancer: a systematic review and meta-­analysis. Colorectal Dis,
2021;23:1670–­86. https://doi.org/10.1111/codi.15644
4 4. Colorectal Cancer NICE guideline [NG151]. National Institute for
Health and Care Excellence. London: NICE; 2020.
45. Nguyen AT, Luu M, Mallen-­St Clair J, Mita AC, Scher KS, Lu DJ,
et al. Comparison of survival after transoral robotic surgery vs non-
robotic surgery in patients with early-­stage oropharyngeal squa-
mous cell carcinoma. JAMA Oncol. 2020;6:1555–­62. https://doi.
org/10.1001/jamao​ncol.2020.3172
46. Falch C, Mueller S, Braun M, Gani C, Fend F, Koenigsrainer A, et al.
Oncological outcome of carcinomas in the rectosigmoid junction
compared to the upper rectum or sigmoid colon—­a retrospective
cohort study. Eur J Surg Oncol. 2019;45:2037–­4 4. https://doi.
org/10.1016/j.ejso.2019.06.024
47. Bussotti C, Burattini MF, Ricci E, Giuliani N, Bufalari A, Servoli A,
et al. Rectosigmoid junction neoplasms: our experience. G Chir.
2003;24:409–­12.
48. Park IJ, Choi G-­S, Lim KH, Kang BM, Jun SH. Different patterns
of lymphatic spread of sigmoid, rectosigmoid, and rectal cancers.
Ann Surg Oncol. 2008;15:3478–­83. https://doi.org/10.1245/s1043​
4-­0 08-­0158-­x
49. Loffeld RJLF, Flens M, Fransen G, den Boer FC, van Bochove A.
The localisation of cancer in the sigmoid, rectum or rectosigmoid
junction using endoscopy or radiology—­what is the most accu-
rate method? J Gastrointest Oncol. 2014;5:469–­73. https://doi.
org/10.3978/j.issn.2078-­6891.2014.087
 |
2646      NG et al.

50. D’Souza N, Lord AC, Shaw A, Patel A, Balyasnikova S, Tudyka V, systematic review. Int J Clin Oncol. 2020;25:1570–­8 0. https://doi.
et al. Ex vivo specimen MRI and pathology confirm a rectosigmoid org/10.1007/s1014​7-­020-­01738​-­2
mesenteric waist at the junction of the mesorectum and mesocolon.
Colorectal Dis. 2020;22:212–­8. https://doi.org/10.1111/codi.14856
51. D'Souza N, de Neree tot Babberich M, Lord A, Shaw A, Abulafi M,
How to cite this article: Ng O-­H, Lunevicius R, Arthur JD.
Tekkis P, et al. The rectosigmoid problem. Surg Oncol. 2018;27:521–­
Rising incidence of colorectal cancer in individuals younger
5. https://doi.org/10.1016/j.suronc.2018.06.005
52. Sanford NN, Aguilera TA, Beg MS, Sanjeevaiah A, Hong TS, Wo than 50 years and increasing mortality from rectosigmoid
JY, et al. Patterns of care for stage II–­III rectosigmoid cancers in cancer in England. Colorectal Dis. 2021;23:2637–­2646.
the United States, 2004–­2015. Am J Clin Oncol. 2020;43:311–­8. https://doi.org/10.1111/codi.15819
https://doi.org/10.1097/COC.00000​0 0000​0 00674
53. Manatakis DK, Gouvas N, Souglakos J, Xynos E. Neo-­adjuvant
chemotherapy alone for the locally advanced rectal cancer: a