Trend analysis of CRC

The joinpoint regression analysis has significant analytic advantages for disease surveillance and, therefore, is valuable to portray trends in CRC incidence over time. This approach has been widely used in many CRC trend reports from several world regions, including North America (e.g., USA54 and Canada55), Latin America (e.g., Brazil56 and Mexico57), Europe (e.g., England58 and Netherland59), East Asia (e.g., China60 and South Korea61), the Middle East (e.g., Iran62 and Lebanon63), and Southeast Asia (e.g., Vietnam64 and Thailand65). Using this method, our first Indonesian study also successfully identified short-term CRC trend patterns that differed between young and old patients. CRC incidence rates were modestly elevated in all and young patients with APC+2.23% and +1.98%, respectively with p>0.05. Meanwhile, the CRC cases among subjects aged ≥50 were mounting more dramatically, with an APC of +2.38% (p=0.041). A similar conclusion was reached by Pham et al64 in the elderly Vietnamese population (APC+5.3%; 95% CI 2.8% to 7.9%). Hypothetically, this might happen because older patients were more likely to be included in screening programmes than young patients.64 Since the population-based CRC screening programme has not been implemented in routine clinical practice in Indonesia, the actual rate of early-onset CRC might have been undervalued. The estimated cost of treatment for patients with CRC in Indonesia is US$116 083.37,66 representing 0.000011% of the gross domestic product (GDP) in 2020.67 The cost burden of treatment increases significantly as the disease progresses. In terms of screening costs, colonoscopy, and faecal testing range from US$207 to US$765 and US$2.75 to US$11, respectively. Given the rising CRC incidence and high cost of treatment, but the comparatively low cost of screening, our research implies that Indonesia should adopt a population-based CRC screening programme for high-risk populations, particularly those born after 1980. This early detection will benefit the public health sector and may further reduce the economic burden.

According to WHO, the prediction of CRC incidence in Indonesia from 2020 to 2025 was higher than the APC of trend analyses done in our study (CRC: +17.7% vs. +2.23%; colon cancer: +18.1% vs. +6.38%; and rectal cancer: +17.3% vs. –0.09%).68 Further evidence showed that the trend of CRC cases among all Indonesian patients was lower in this study than in a study of patients with CRC in Tunisia from 1994 to 2009 (+2.23% vs.+3.90%).69 We also discovered a smaller APC for CRC cases among young patients compared to a study among young Thai patients between 1989 and 2012 (+1.98% vs.+5.70%).65 Trend analysis in figure 2 reveals a sharp rise in colon cancer annually among young patients with a higher APC than in old and overall patients (+9.24% vs. +5.11% and +6.38%, respectively). In the last few decades, the incidence of CRC has been increasing in Asia, particularly in Southeast Asian countries, including Indonesia and Malaysia.70 If this trend continues, the number of CRC cases may suddenly overwhelm the healthcare system. Thus, better health policies should be constructed by the government.

The rise of CRC in young patients has not yet been fully elucidated. Early life exposure to the deleterious effects of risk factors, such as frequent smoking, alcohol consumption, obesity, a Western diet, reduced physical activity, and early-life antibiotic exposure, has been thought to increase susceptibility to CRC. The first contributor is smoking, associated with hypermethylation, microsatellite instability, and BRAF mutations in CRC carcinogenesis.71 Early-life smoking may contribute to the rising incidence of CRC in young individuals.71 Concerning that fact, 13.4% of Indonesian teenagers (95% CI 12.9% to 13.9%) and 27.3% of young adults (95% CI 26.8% to 27.8%) were found to be daily smokers, respectively.72 The risk of CRC is also increased by alcohol consumption, which is positively associated with the risk of cancer of distal colon and rectum among the Asian population.73 74 In Indonesia, alcohol consumption rose strikingly from 2000 to 2020, with the current proportion of alcohol consumption in teenagers and young adults being 4.0% (95%CI 3.8% to 4.3%) and 6.4% (95%CI 6.1% to 6.6%), respectively.72 Third attributed factor should be obesity, which has been linked with a higher risk of colon cancer in Asians. In Indonesia, obese and overweight individuals comprised roughly 4–8.8% of people aged 13–18 and nearly 21% of those over 18.72 75 It is not surprising that the obesity epidemic and the rise in colon cancer happen simultaneously. Many behaviours that are thought to cause weight gain, for instance, unhealthy eating habits and sedentary lifestyles, also raise the risk of CRC. Obesity can promote cancer formation through metabolic abnormalities, hyperinsulinaemia, systemic inflammation, and alteration of the gut microbiota.76 An upward trend in CRC in Indonesia is also probably due to the acquisition of the Western diet as the fourth contributor.77 This lifestyle trend has been seen in Indonesian teenagers who consume inadequate amounts of protein, fruits, and vegetables, but excessive amounts of sodium and fast food.78 A recent study found that the de novo introduction of a Western-style high-fat, low-fibre diet induces inflammation and proliferation in the colonic mucosa within 2 weeks.79 Increasing obesity is concurrent with reductions in physical activity levels.80 A study in Japan revealed an inverse association between physical activity and CRC, and this association was stronger for colon cancer than rectal cancer.81 This fact agrees with a survey in Indonesia that found 33.5% (95% CI 33.3% to 33.8%) of the population lacked physical activity in terms of time and frequency standards.72 Another related risk factor for CRC among Indonesians is early life and improper antibiotic use.82 These two risk factors could change the gut microbiota and metabolic profile, making a person more likely to have obesity later in life.83

What stands out in the trend analysis of this study, is that the incidence rate of colon and rectal cancer was differed remarkably. In contrast with colon cancer which gradually increase (+5.11% to +9.24%), rectal cancer incidence has generally declined in all and young patients (–0.09% and –0.97%, respectively). Rectal cancer also remains stable in the old patients group (+0.58%). These findings could result from the rectum being more easily examined clinically during screening procedures than the colon, making precancerous lesions or suspected tumours easier to detect and removed during clinical examination of the rectum in screening. The negative trend of rectal cancer in this study was contradictory to the WHO’s prediction,68 but consistent with the trend in Canada.84 After 1985, rectal cancer incidence slightly declined, with an APC of –0.38% among Canadians.84 It also has been observed that the trend of CRC subsite distribution progressively shifted to the proximal colon in various countries, such as the USA (1970–2000)85, Japan (1974–1994)86, and Norway (1962–2006).87

Our findings emphasise that colon cancer incidence rose faster than rectal cancer in young patients (APC+9.24% vs. –0.97%), similar to results among Canadian young patients from 1969 to 2010 (APC+6.2% vs. +1.5%).88 The APC of colon cancer in our population was higher than in Tunisia (+6.38% vs. +4.5%).69 Some well-known risk factors do not exactly give a similar susceptibility towards colon and rectal cancer. The carcinogenic process may be different depending on where it happens.84 Diet patterns, physical inactivity, and high body mass index have been linked to a higher risk of colon cancer, but not rectal cancer.73 89 Meanwhile, smoking and alcohol consumption have been linked to a higher risk of rectal cancer.90 91 Obesity, insulin resistance, and high blood glucose levels are connected with a higher risk of colon cancer because the colon is more insulin-sensitive than the rectum.92 93 We also hypothesised that women may have benefited from the preventive effect of hormones against cancer of distal colon and rectum. Endogenous hormones may have protected some women from developing cancer of distal colon and rectum. Increased use of exogenous hormones, such as hormone replacement therapy or oral contraceptives, might also have resulted in further reductions in these cancers.42 Respecting to that evidence, 61% of Indonesian women used contraceptive management between 2005 and 2012,94 but this preventive effect has not been investigated for proximal (right-sided) colon tumours.84

In contrast to earlier findings and the widely held belief that RSCRC is more common in young patients, this study revealed that RSCRC was more frequent in old patients, similar to a study from Germany.95 Our results showed that most young patients had lesions in the left colon, in agreement with a hospital-based study in the Memorial Sloan Kettering Cancer Center, in the USA, where their young patients were more likely to have LSCRC.96 A study also claimed that LSCRC is more prevalent in men and younger individuals, whereas RSCRC is more common in women and older people.20 Accordingly, although genetic alterations might spread more in young patients and are typically related to the cause of RSCRC, it is still possible that LSCRC predominated in this group.

The trend analyses in figure 2 show that the APC of RSCRC rose statistically significantly among all patients (+6.52%) and old patients (+6.57%) over the study’s 11-year period, with the largest APC being noticed in young patients (+6.59%). The causes of these patterns remain unclear; they might be due to inconsistent plotting of several incidences each year to follow a particular joined line to figure out a trend. The rising trend of RSCRC from 2009 to 2019 could be influenced by a lack of genetic counselling addressing age, specific syndromes, and family history in Indonesia, as RSCRC is usually associated with a genetic predisposition.97 It is also challenging to detect nonpolypoid (flat or depressed) tumours, more common in the right colon. These lesions are more likely to include carcinoma but are more difficult to detect and occur more frequently in high-risk individuals.98 Higher colonoscopy miss rates may impede screening and identification of precancer and cancer lesions in the right colon, contributing to the rising trend of RSCRC.99–101 ,102 The presented study found that LSCRC had a positive steady trend among all (APC+1.41%), young (APC+1.37%), and old patients (APC+1.46%); all p-values were >0.05, similar to a report from Siegel et al103 in the USA. The clinical implications of different proportion of side involvement between young and old patients was to the aggressiveness of the disease. RSCRCs are typically bulky, exophytic, polypoid lesions projecting into the lumen and causing significant anaemia. LSCRCs are infiltrating, constricting lesions encircling the lumen, often leading to obstruction.104 A study implied that LSCRCs are genetically more unstable and phenotypically more aggressive due to distinct molecular biology patterns between RSCRC and LSCRC in DNA euploidy status, KRAS and p53 mutation rates.95

Observing more specifically the trend of colon cancer based on its subsites, what can be seen in figure 3 is the significant growth of four of five colon subsites during the study period. The APC of ascending colon rose more quickly than APC in China from 2000 to 2004 (+10.60% vs. +2.25%).91 The transverse and descending colon had opposite results (+9.88% vs. –1.95% and +10.04% vs. –1.02%, respectively), while the sigmoid colon had a more positive trend (+5.84% vs. +4.19%).105 Surprisingly, no differences in APC were found in the caecum (–0.98%), which had a slow and steady decline in cases. These trends aligned with the right-sided dominance during 11 years of study. Different parts of the colon may be more or less vulnerable to carcinogens because of biological differences in the intestine.106 For example, genetic factors may play a significant role in developing proximal colon cancer, but factors like diet, exercise, and hormone use are more likely linked to distal colon cancer.106

The trend analysis in this study enlightens us to narrow down patients in danger. Given the rapid economic transition and urbanisation occurring in Indonesia, it is possible to generalise the upward CRC incidence trend in a single centre in Jakarta to all of Indonesia,107 108 similar to what a study in Vietnam suggested.64 However, as this is a single-centre study, the data presented may not be fully representative of other centres. Further research is needed to see if the trend can be reversed, for example, by evaluating current CRC screening standards and lowering the age at which people should begin screening. To reduce the upward trend, more studies are also required to investigate CRC risk factors in Indonesia. Our current study did not record data on risk factors of CRC that might help explain the trend of CRC found in the study. Furthermore, the cross-sectional design of this study did not allow us to establish any causal relationship.

Forecasting the CRC burden

In figure 4, we forecasted the future burden of CRC by performing a fit-model regression analysis to predict colon and rectal cancer incidences along with RSCRC and LSCRC. The model with a significant slope was found in all and old patients with colon cancer and RSCRC. Meanwhile, in young patients, the model with a significant slope was found only for colon cancer. Projection models for CRC, colon cancer, and rectal cancer follow the exponential growth curve pattern in all patients and young patient group. While, in the old patient group, colon cancer and CRC forecasting models use the quadratic model. In contrast, the projection model for rectal cancer follows the linear model in the old patient group. Compared with RSCRC, which follows the quadratic model, LSCRC was more varied, with the overall occurrences following the exponential growth curve, the young patients’ incidences following the quadratic model, and the old patients’ cases following the S-shaped model (sigmoid) curve.

The best-fitted model for forecasting CRC cases had different clinical implications based on curve shape. Addressing the interpretation of each curve was challenging since little robust research explains forecasting cancer incidence.109 A linear trend is a forecasting model that develops a linear relationship between time and the response variable (incidence of disease). The linear model observed in rectal cancer among old patients means that cases increase gradually and linearly at a constant rate over time. This model assumption was based on forecast accuracy metrics and was supported by what has been pictured in trend analysis of rectal cancer with stable APC.110 What should be highlighted in this paper is that although the rectum was the most prevalent tumour site, we identified a negative trend or stable growth for this site in both joinpoint analysis and fit-model regression analysis for forecasting, similar to what was predicted in Japan.86

Six of 15 scenarios were fitted into the quadratic curve model, a forecasting method that developed a non-linear relationship between time series and the response variable. The quadratic trend resembles a polynomial regression model that accurately captures the data trend.110 Following a quadratic model, the number of RSCRC cases was expected to steeply grow after 2019, particularly among all patients (p<0.05) and old patients (p<0.01). The literature corroborates that RSCRC is associated with several adverse prognostic factors: older age, advanced stage, and mucinous histological subtype.20 111 112 On the other hand, the incidence of RSCRC among young patients was projected to plummet until 2029 (p>0.05). The future trend among young patients differs from the past between 2009 and 2019, which exhibited a steady movement. This pattern was similar to a study in the USA, which found that RSCRC increased initially, experienced stagnation, and was projected to fall by 2.3–2.6% annually.97 The reasons for different past and future trends of RSCRC might be explained hypothetically by the increased use of colonoscopy in the early 21st century.¹¹⁴ Along with this direction, improved techniques and training for conducting colonoscopy in the right colon to screen, detect and diagnose may contribute to reducing RSCRC lesions among subclinical diseases.113 Another possible explanation for this result is that in the previous 11-year period, our young patients were dominated by a high proportion of patients with genetic factors, thus resulting in a higher trend of RSCRC cases in the young patients’ group.8–10 In the next 10 years, the trend is predicted to shift to increasing rates of LSCRCs and RSCRCs otherwise due to greater exposure to specific cancer-related risk factors at the distal subsites.64 106 114 It is linked to the increasing adoption of a Westernised lifestyle in Indonesia, as also growing in other Asian countries, is a reasonable ground for this shift.84 115 The reasons for conflicting forecasts between young and old patients for CRC in overall and specifically RSCRC cases remain unclear. It might be explained by the complex attributions of risk factors associated with age and side of tumour involvement which has not been scrutinized in this study. Accordingly, further studies are urgently required in Indonesia to identify the contributing factors for the occurence of CRC in each subsite, thus explaining the different trends based on subsite and side involvement.

Seven cases were forecasted following the exponential growth curve as the best-fitted model. Among these forecast models, two colon cancer cases elucidated significant progression slopes; they were in all patients (p<0.001) and in young patients (p<0.01). Their future trends were identical to past trends in the previous period, even were expected to be skyrocketing. Exponential growth curve has a J-shape, reflecting a growth whose rate is proportional to the size of the population over a specific period. Exponential growth curve modelling is a regression-based method for analysing longitudinal data (i.e., tracking the same sample at different points in time), suited to the projection of trends in one disease entity into a different period. The advantage of growth curve modelling over other methods is that this technique permits the testing of several types of trajectories until the one with the best fit to the data is found, and an output is far more precise than other statistical means.116 117 Exponential growth is distinguished by its slow start and, at some point, accelerating growth rate. The exponential growth curve has the fastest growth compared with the S-shaped, quadratic, and linear curves. This pattern causes an explosion of cases, relatively more than the S-shaped, which causes a relatively constant growth rate in the population.

One scenario of LSCRC among old patients following the sigmoid (S-shaped) curve trend model refers to a case whose growth rate decreases with the increasing number of individuals.110 An S-shaped curve is symmetric around the inflection point, which means that the case increases rapidly initially, followed by a slower rate after the inflection point than the rate postulated by the curve. Following this pattern, of movement of LSCRC cases have initial slow growth, reach a growth explosion, then at their upper limit, cases will be gradually steady, consistent with insignificant slope progression (p>0.05). The S-curve trend model is best for time series that follow a logistic manner.110However, this model drawback may lead to underestimation and overestimation of the actual disease risk at the lower and upper tails of projected line.118

Projected CRC cases in Indonesia for the next 10 years confirm the future global burden of CRC, which is expected to increase by 60%, to over 2.2 million new cases in 2030.119 Looking specifically at online supplemental file 7, regarding cases predicted for 2020–2029, the burden of CRC remained high in our institution.

Distinct clinical and pathological features in young patients

Young individuals may be more susceptible to CRC due to genetic alterations and dietary changes; hence molecular profiles of young Indonesian patients with CRC have been identified to understand better the specific pathway involved in this group.8 Our young cases, mainly found in distal locations for CRC, are not in line with the characteristics of hereditary CRC, primarily found in proximal sites. They also did not follow the conventional pathways of sporadic CRC (the CIN pathway).8 Instead, carcinogenesis in these patients seems to have originated with MSI and inflammatory pathways, including cyclooxygenase-2 (COX-2) and nucleus factor κB (NF-κB). Also, lower mutation rates of the pro-oncogene KRAS are found among young Indonesian patients.8 Sudoyo et al120 found that 56.5% of CRC cases were positively stained for MSH2 and 16.5% stained for MLH1. Moreover, signet-ring cell carcinoma—an aggressive subtype of CRC that spreads rapidly and is characterised by late symptom manifestations—disproportionately affects young individuals.121 It is also possible that the differences in the immune systems of young patients could play a role in age-related immunosenescence, T-cell dysfunction, and systemic inflammation.122

Age is crucial due to its impact on prognosis. However, this idea is still debatable; some suggest worse outcomes at a young age,123 124 whereas others imply an equal prognosis between young and old age125 depending on the staging reported.43 124 Contrary to other studies,46 126 127 where stage III–IV cancer predominates in the young age group, we found that more than half of our young patients with stage I–II cancer. However, no statistically significant difference in cancer staging between the two age groups was evident, similar to a prior report.128 This might reflect increased awareness of the disease among young patients and primary care physicians, better access to colonoscopy, and more widespread use of CT with improved quality. Also, the introduction of national health insurance in the middle of the study period (2014) made access to healthcare more accessible, increasing people’s concern for their health. Providing better facilities for cancer diagnosis may result in an inflation of the number of CRC and earlier detection of CRC through screening.129 Patients with cancer found through screening show up at a much earlier stage of the disease than those not found through screening. Our study found no distinct clinical characteristics between young and old patients regarding sex, side involvement, location, site or specimen type. There is no tendency for proximalisation of colon cancer in young patients compared with old patients in our study. Overall, the proximal and distal colon had an equal proportion of all CRC cases. However, if we included rectal cancer in the calculation of distal CRC, the proportion was in line with an extensive colonoscopy survey in Asia, which found that more patients had distal than proximal CRC.130

Single institution and population-based studies have found that young patients with CRC have unique tumour locations, stages at presentation and histological features. Our findings were similar to those of these studies.131–134 The proportion of rectal cancer among young patients was significantly higher than in their old counterparts; as previously mentioned in an American study, 32% of CRC occurred in the rectum.134 Looking more specifically at colon subsites, young patients with CRC mainly have lesions originating from the ascending and descending colon. Meanwhile, the caecum, transverse colon, and sigmoid colon were the most affected sites among old populations. Lesions with poorly defined histological features, such as mucinous and signet ring features, are more likely associated with poor outcomes.123 They are also more resistant to chemotherapy.128 Our results showed that the proportion of adenocarcinoma NOS in young patients was less frequent than in old patients, agreeing with a study by Chan et al52 and Gheju et al135 . The mucinous histological variant was significantly higher in young than in old patients. Signet-ring cell cancer was only observed in young patients, accounting for only 0.6–1.0% of all CRC cases globally.135 Our single patient who has signet-ring cell cancer has the following characteristics: 48 years, female, located in the caecum, right-sided, size 5.5 cm, brown-coloured surface, exophytic, adequate LNR 5/13, pT3N2aM0 (IIIB), no LVI, no PNI, and with poor tumour differentiation. Likewise, only one patient with signet-ring cell carcinoma was also identified in a Romanian study, but that patient was elderly (>50 years).135 Signet-ring cancers have intracellular mucin pushing the nucleus to one side and are associated with a more advanced stage at diagnosis, a higher incidence of LVI, LNM, and liver metastases, a higher rate of recurrence, and higher aggression.136 137 The literature stated that mucinous histopathology was a significant predictor of poor outcomes and more advanced node stage.138

The average number of dissected LNs in our study was lower than that in a recent Romanian study (mean: 9.96±5.46 vs. median: 35.7 LNs removed), indicating that optimal LN sampling was a challenge in our institution.135 Meanwhile, the average number of positive LNs per patient was lower than positive cases in Romania (mean: 1.54±2.73 vs. median: 3.7 (1–62)).135 The interpretation of LNM is thus more complicated because the number of dissected LNs was not ideal, but the positive number was favourable, which might be masking. More insufficiently removed LNs might result in a higher probability of positive LNs in actual conditions due to unsuccessful LNs sampling, which could harm the detection of cancer spread. This issue may have an impact on patient staging. In contrast, increasing the number of dissected LNs leads to more accurate information about node status and more effective patient care. In a recent Dutch nationwide study,139 authors found that with an increasing number of evaluated nodes, the risk of mortality is decreased, related to a better quality of surgical resection (yielding more LN for the pathologist to assess).

A closer inspection of the dissected LNs in table 2 shows significant differences between the two age groups. The number of adequate LNs dissected in young patients was higher than in old patients, a favourable finding in young patients. Old patients are more likely to receive inadequate LN dissection during operative therapy, given their higher surgical risk for various postoperative complications and comorbid diseases. This concern possibly makes surgeons weigh the risks and benefits of a more thorough LN dissection.140 Other contributing factors to the number of LNs dissected from resection include the surgeon’s technique, bowel resection length, and tumour location.141 Complying with a minimum LN count of 12 is sometimes problematic, challenging, and less applicable. Thus, a novel measurement has been proposed to be used in clinical practice: LNR, a ratio of positive LNs to total dissected LNs. The mean score of LNR in our patients was was lower than a median value of LNR in a study in Romania (mean: 0.18±0.29 vs. median: 0.221 (0.139–1)).135 This value was in line with the highest proportion of lower-category LNR (LNR1 was 57.5%) in the study analysis, implying favoured results. LNR provides a superior prognostic value than the number of positive nodes alone. A higher LNR is also significantly associated with poorer survival of CRC.142 Given no statistical difference in the LNR measurement between young and old patients in this study, it might be potential for LNR to be included as a predictive indicator in CRC staging systems for all patients.

This study found a lesser proportion of PNI in all CRC patients than in Elsamany et al143 (11.3% vs. 24.4%). Nonetheless, we documented a significantly higher proportion of PNI in young patients than in old patients (p<0.001), similar to findings in Zahir et al,45 showing that 22% of their young CRC patients had positive PNI. PNI is associated with a higher rate of metastatic disease, a greater likelihood of recurrence, and poorer survival.144 Several studies have also recognised it as a notable independent prognostic factor in CRC multivariate analysis.144

Although some pathological features exhibited significant differences between the two age groups, no evidence was found for significant differences in tumour size, growth pattern, tumour grade, pT, pN, LNR, LNM, distant metastasis, and LVI. Two-thirds of patients had tumour size ≥5 cm, the most significant size being 18 cm. Although some authors believe that tumour size does not affect prognosis, others believe that tumour size partially affects prognosis.145 146 Increasing tumour size is associated with decreased loco-regional control, resulting in an increased risk of malignant potential.147 More extensive tumours are more likely to be more invasive and invade adjacent organs.148 Local recurrence was significantly higher in patients with tumours measuring ≥5 cm in size, poorly differentiated adenocarcinoma, pT4 stage, and having adjuvant radiotherapy. Moreover, the 5-year overall survival rates in patients with tumours ≥5 cm were lower than those with a size <5 cm (log-rank, p=0.001).149

According to our findings, the proportion of growth patterns (from highest to lowest, in both age groups) was exophytic, endophytic, ulcerative, and linitis plastica. These findings agree with a previous study in Thailand, which found that fungating and polyp mass (exophytic) were more common compared to ulcerative masses.149 Our research revealed that exophytic growth patterns were prevalent in all patients and were distributed equally between the two age groups. Ulcerative growth and linitis plastica were much less common, which is favourable since both growth modes entail a worse prognosis. Linitis plastica suggests de novo origin, associated with a reduced proportion of KRAS mutations. Clinically, de novo tumours may represent a more aggressive subtype of CRC with a worse prognosis, poorer disease progression, and higher aggressiveness.104 These results call for more awareness and persistence in detecting non-polypoid lesions, more intensive monitoring of colonoscopically treated cases, and surgery for selected patients.

Concerning tumour grading, most tumours in both age categories were well differentiated, similar to the results of a study from India.138 These findings differed from those of a study by Chan et al,52 who discovered that both age groups were primarily affected by cases of moderately differentiated tumours. We identified that young patients were more likely to have poorly differentiated CRC than old patients. This finding shows how young patients have predilections for more aggressive tumour biology and implies a poorer prognosis regarding distinct tumour grade and histological subtypes distribution.124 150 However, although we found notable differences in the histological subtypes of young and old patients, no evidence was found for a significant association between tumour grade and age.

LVI was detected in almost two-fifths of individuals in this study. This proportion was fewer than in a previous report on Saudi patients (49.5%).143 However, it was noticed that positive LVI cases were higher in our young patients than in old ones (41.7% vs. 36.7%). These findings suggest that LVI is a critical histopathological feature that needs to be assessed in every young patient with CRC, since literature mentioned its presence links to worse survival.143

In short, all empirical findings related to clinicopathological characteristics of CRC in this study have provided a new understanding of this disease entity in Indonesia. Our study collected CRC data archived in one of Indonesia’s national referral hospitals for cancer with a lengthy study period and is therefore the most robust data accessible in our nation. Its coverage could represent CRC epidemiology on a regional scale since primary data for the entire country is not readily available. Another strength of this study was that we applied an efficient and noteworthy statistical method called joinpoint regression analysis to study the in-depth dynamics of CRC cases in Indonesia.31 151 152 This approach has allowed estimation of the magnitude of incidences, testing the movement of cases statistically, and clearly illustrating the direction of CRC trends.24 25 153 This study also provided several best-fitted models and computed forecasts that predict future trend patterns statistically.

However, our study should be interpreted with caution in light of the following limitations related to research methodologies. As a retrospective study, the quality of our database depends on the patient records and is subjective to record bias. We also excluded patients from our study due to retention of medical records or microscopic slide deterioration. This research may also have missed some old, frail patients with symptoms of CRC who were treated at home or in nursing homes without further investigation. Furthermore, several drawbacks might also arise concerning joinpoint regression analysis to measure the trend of cases. This method’s common impediment was that it only offered a description of the time series based solely on yearly aggregated data154; thus, it could not draw a causal relationship between possible risk factors that contributed to the findings.155 As such, we could only hypothesise associations between CRC trends changes highlighted by our data and their possible influential factors supported by existing scientific evidence. Also, relying on the length of the study period, the software could only measure a certain number of year segments at a time.153 A longer research term would have offered more freedom to measure the APC in several segmented sequences.153 As a result, we could not compare several joinpoint segments to gain additional clarity regarding the impact of a specific intervention or event. The analysis could only be limited to 1 joinpoint because our samples only had 11 data points (i.e., 2009–2019).153 To exemplify, given that Indonesia initially implemented universal health coverage in 2014, this limitation might restrict the analysis to distinguish different APCs between 2009–2013 and 2014–2019.

In addition, the projections of future CRC incidence discussed in this study should be carefully interpreted.109 Predictions of future cancer incidence inherently depend on several uncertain factors, could be part of a larger cycle and may not persist into the future. Our projection of CRC in 2020–2029 was assumed to have similar clinicopathological characteristics as the circumstances observed from 2009 to 2019. Any changes affecting future cancer incidence rates beyond those included in the model’s base years could not be statistically calculated by the forecasting models.156 Dynamic evolutions in the population (e.g., advancing obesity or smoking rates and introducing new screening programmes with more cutting-edge technologies), governmental policy adjustments, and emerging public health threats (e.g., pandemics) may influence the record of a predictive number of cases.156 Trends and projections are volatile, and thus we could only forecast cases over a short period (e.g., 10 years in our study) to maintain forecasting accuracy. Moreover, this work did not include population-level data, and the mathematical prediction of cases in this study should be further validated using multicentre datasets.157 Therefore, population and multicentre epidemiological studies are highly suggested to further predict trends in this disease entity

Despite all methodology-related limitations, our data showed a similar trend to other countries worldwide, primarily Asian countries. The incidence rates fit well into forecasting models, allowing clinicians and policy-makers to predict and anticipate future disease burdens of CRC.