Young- onset colorectal cancer: Insights from an English population- based study

Aim: Young colorectal cancer (CRC) patients are reported to have more aggressive disease, an advanced stage at diagnosis and conflicting survival outcomes. The aim of this study was to analyse the demographics, clinicopathological features and prognosis of young CRC at a population- based level in England. Method: This is a retrospective review of all CRC patients using data from Public Health England collated from regional cancer registries in England between 2010 and 2014. Those aged 40 years and below were classified as young and those over 40 were classified as older. Results: Overall, 167,501 patients had CRC. Of these, 3757 patients (2.2%) were young. Right- sided cancers were more common in younger patients (48.2% vs. 32.9%, p < 0.001). Favourable histological grade (well or moderately differentiated) was present in 83.1% and 73.5% of young and older patients, respectively. The percentage of young and older patients being diagnosed at an early stage (Stages 1 and 2) was similar at 40.6% vs. 42.9%. The 5- year age- and gender- adjusted relative survival (cancer specific) was significantly better for young patients when compared with older patients diagnosed with CRC. Additionally, overall 5- year survival was better for younger patients (71.6% and 47.2%, p < 0.001 in young and older CRC patients respectively). Conclusion: The increased right- sided colon cancer in young CRC patients in England war-rants attention. Contrary to previous reports, they do not present at later stage. Young CRC patients have better overall and relative survival than older patients with CRC.

left-sided CRC in young patients [11]. In-depth population-based survival data for younger CRC patients from England are sparse, with data limited to hospital case series [12,13].
The aim of this population-wide study was to describe clinicopathological trends in a contemporary cohort of young CRC patients and to determine if cancer in these patients significantly differed from that in older patients in terms of anatomical location, histopathological characteristics, cancer stage at diagnosis and long-term survival.

Study design
In this population-based retrospective study, anonymized data from all patients diagnosed with CRC in England between 2010 and 2014 were analysed. The dataset was collated by Public Health England (PHE) and was derived from eight regional cancer registries. The National Cancer Registration and Analysis Service (NCRAS), which is run by PHE, is responsible for collecting, registering and analysing cancer data in England. There are robust mechanisms to ensure validity and completeness of the data. Fewer than 0.1% of available data have serious errors [14,15].
The diagnosis of CRC, treatment details and dates of diagnosis and death were based on the data entered into the cancer registries. Study approval was obtained from the University Hospitals Plymouth NHS Trust Audit, Research and Development Department (CA 2018-19-152). This study did not require ethical review or individual patient consent as only anonymized, noninterventional data were collected. The online National Research Ethics Service decision tool was used to confirm this [16].
Patients diagnosed with CRC at the age of 40 years or younger were classified as young CRC and those diagnosed above the age of 40 years were classified as older. An age cut-off of 40 years was used because the majority of indications for urgent suspected CRC referral in the UK national guidelines use 40 years as a cut-off [17].
All patients diagnosed with colorectal adenocarcinoma were included in the study. Patients with neuroendocrine tumours and other synchronous malignancies were excluded. The dataset comprised baseline demographics, stage of cancer at diagnosis, histopathological factors, socio-economic status and cancer registry region.
Socio-economic deprivation was assessed based on the income domain of the 2010 Index of Multiple Deprivation based on the patient's residential postcode [18]. Patients were scored on a scale of 1-5 with 1 being least deprived and 5 being most deprived. Cancer stage was based on the AJCC 7th edition TNM classification for CRC [19]. Cancers were grouped based on anatomical location: right-sided colon cancer (cancers of the appendix, caecum, ascending colon, Excellence guidelines [20].
The primary objective was to compare the survival outcomes between younger CRC and older CRC patients. The secondary objectives were to establish baseline demographic, clinicopathological, treatment and survival data and to identify factors that may affect outcomes in the young CRC cohort.

Statistical analysis
All percentages were calculated based only on the available data; with the missing responses displayed in the tables for each variable.
Chi-square tests were used to assess the association between age groups and each demographic and clinical variable. Survival time was calculated as the time between the date of diagnosis and the date of death. Censored observations were included for patients who were alive when the data were extracted from the database (January 2020). Kaplan-Meier curves were used to visualize the differences in survival times between the young and older groups for each stage of disease and each category of deprivation. Log-rank tests were used to test the differences between 5-year survival rates across the age groups. Odds ratios and their 95% confidence intervals were calculated to compare the odds of each treatment in the two groups; the odds from the older CRC group were used in the denominator of all odds ratios reported and older CRC patients were the reference group. Hazard ratios were obtained for all demographic and clinical variables in the younger CRC cohort from a multivariable Cox proportional hazards model, with survival time as the outcome variable.
Post hoc relative survival rates were calculated for the young group (aged 40 and under) and each 10-year age band from 41 to 90. As explained by Dickman and Adami [21], relative survival rates were calculated using an adjustment for the expected survival of each patient in the study according to their age and gender. The age-and gender-specific expected 5-year survival probabilities used to calculate relative survival were obtained from the InterPreT Cancer Survival website and they reflect the expected 5-year survival rate of the general population in

What does this paper add to the literature?
This is the largest in-depth analysis of young-onset colorectal cancer (CRC) in England in a contemporary timeframe. Young patients with CRC in England do not present at later stages or have worse histopathological features, as has been previously reported, and have good long-term survival outcomes.
England. Data from the reference population were only available for ages 40-90 years; anyone under the age of 40 years was assigned the expected survival probability of a 40-year-old to allow the calculation of conservative estimates. [22].
Statistical analyses and data cleaning were carried out with the statistical programming software R (version 4.0.2; The R Foundation for Statistical Computing Platform).  Table 1). Young CRC patients were more likely to be from ethnic minority groups compared with older CRC patients ( Table 1). The proportion of older patients diagnosed with CRC increased with increasing affluence (Table 1). However, this trend was reversed in young patients, with a higher proportion of patients being diagnosed with higher levels of deprivation ( Figure S1).

Anatomical location, stage at diagnosis and histopathological features
Compared with older CRC patients, young patients were more likely to be diagnosed with right-sided colon cancer ( Figure 3). The proportion of patients diagnosed with early stage (Stages 1 and 2) and late stage (Stages 3 and 4) cancers is depicted in Table 2.
Young CRC patients were more likely to have well or moderately differentiated CRC than older patients (83.1% vs. 73.5%, p < 0.001) ( Table 2). Younger patients were also more likely to have signet ring and mucinous cancers.

Treatment patterns in young and older patients with CRC
Significant variations in the use of surgery and chemotherapy were noted between young and older patients. Young patients with Stage 2 and 3 CRC were significantly more likely to undergo chemotherapy. In Stage 4 (metastatic) cancer, young patients were significantly more likely to undergo surgery and chemotherapy compared with older patients (Table 3).

Survival from diagnosis
The median follow-up for patients was 4.3 years (interquartile range 0.8-7.1 years).
Relative survival rates (a measure of studying disease-specific survival) were calculated for the young age group (≤40 years) and in 10-year age bands up to age 90 (Table 4) Young patients with CRC were more likely to achieve 5-year overall survival than older patients (71.6% vs. 47.2%, p < 0.001) ( Table 5).
Stage-stratified survival analysis revealed that young patients with  considerably lower than historical cohorts where these histological subtypes accounted for up to 20% of young CRC patients [8,28,29].
In the older age group, there were fewer CRC patients from more deprived areas compared with the least deprived areas; Interestingly, this trend is reversed in young patients, with higher deprivation indices having a higher number of cases of CRC. Despite deprivation being associated with an increased incidence of CRC in young patients the effect of deprivation on 5-year survival was markedly less than in older patients. It is possible that deprivation affects all-cause mortality rather than CRC-specific mortality, which may explain why deprivation had a greater effect on 5-year survival in older patients.
The relative (cancer-specific survival based on age and gender), overall and stage-stratified survival of young CRC patients in England is good; especially if diagnosed early (5-year overall survival 98.2% in Stage 1 and 89.1% in Stage 2). This is in keeping with populationbased data from Canada and Australia [24,30]. American studies have shown varied results in terms of survival, ranging from worse to equivocal and better overall survival compared with older patients.
The worse overall (all stages combined) survival in a few American studies has largely been attributed to later stage at diagnosis; nevertheless, the stage-stratified survival of young CRC in America has consistently shown favourable results [8,31]. On the other hand, a few studies from Asia have tended to show worse overall and stagestratified survival in younger patients [9,28]. The relative survival analysis in this paper suggests that, even after adjusting for the reference life expectancy between the groups, younger patients had better survival figures.
A potential explanation for the improved outcomes of younger CRC patients in this contemporary dataset is that younger patients received more treatment than older patients (Table 3). This was especially evident in those with metastatic cancer: young patients had a significantly higher chance of receiving all forms of therapy than older patients. In addition, young CRC patients with Stage 2 and 3 disease had twice the odds of receiving chemotherapy [32]. This finding is consistent with a recent American population-based study, in which younger patients with Stage 1 and 2 CRC received significantly more chemotherapy than older patients [31]. However, more treatment does not necessarily translate to better survival; comparable stage of diagnosis, overall patient fitness and the better grade of cancers in this cohort probably play a role in explaining the overall better survival outcomes.
There are several study limitations. As with all retrospective registry-based studies, missing data can result in information and selection bias [33]. However, the English cancer registries are amongst the most complete and therefore provide robust data.
Due to the large numbers in population studies, there is a known trend of the statistical tests producing highly significant results (as observed in our study). However, statistical significance is not always equivalent to clinical significance.

CO N FLI C T O F I NTE R E S T
MC and SS have served on the board of the funding charity; however, they declare no conflict of interest and the charity was not involved in the study design, data analysis or manuscript preparation in any way.

E TH I C A L A PPROVA L
This study did not require ethical review or individual patient consent as only anonymised, non-interventional data was collected. The online National Research Ethics Service decision tool was used to confirm this.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.