There is a huge incidence gap of CRC across countries and world regions whereby incidence is associated with the level of socioeconomic development. Regions higher on the Human Development Index (HDI) have higher incidence, and regions that are lower on the HDI have a lower incidence . The higher incidence of CRC in Brunei (a high HDI region)  may be a reflection of the quality of our healthcare infrastructure and surveillance system. There is a disproportionate (2.42-fold or 141.5%) increase in the number of CRC patients diagnosed in 2010–2019 (732 individuals) compared to 2002–2009 (303 individuals) (the population has increased by only 1.08 fold or 8.6% [6, 21, 22] between the two periods). The introduction of Brunei Darussalam Healthcare Information and Management System (Bru-HIMS), a national and centralised electronic medical health database in late 2012 may have improved medical surveillance and better capture all CRC patients, partially accounting for the spike in numbers in the latter period. The substantial rise in CRC cases from 2002–2009 to 2010–2017 may be also due to other factors. Dietary patterns have been strongly implicated in CRC development. Diet can modulate the gut microbiota and their metabolites, epigenetics, inflammation and immune function, and trigger metabolic or hormonal disruption to influence cancer risk . With modernization, the global nutrition transition has rapidly shifted dietary behaviours to heavy reliance on processed foods, increased away-from-home food intake and excessive consumption of edible oils and sugar-sweetened beverages, leading to adverse outcomes . A recent systematic review and meta-analysis reported an association between a Westernized diet and higher risk of CRC , with plant-based diets conferring protective effects against CRC [25, 26]. It is noted that a high proportion (91.7%) of the Bruneian adult population do not meet the required consumption of fruits and vegetables . Tobacco smoking has been shown to cause CRC, especially among long-term smokers through formation of polyps in the intestine [28–30]. Although the percentage of smokers in this population remains unknown, a study has reported that 20% of adults in Brunei smoke . Physical inactivity may increase the risk of CRC , although the reason behind it is still unclear . It has been stated in a Bruneian study that physical inactivity is prevalent among older people. Another risk factor is obesity, which may be related to physical inactivity and dietary behaviors. Brunei has the highest prevalence of obesity (28.2%) compared to other Southeast Asian countries .
Comparing the two periods, there is an increasing proportion of younger CRC patients (< 40 years old, and 40–59 years old) from 46.8–51.3%; specifically, the percentage increase of patients < 40 years old is 20.3% from 2002–2009 to 2010–2017, and the percentage increase of patients 40–59 years old patients is 7.8% from 2002–2009 to 2010–2017). Meanwhile, the proportion of elderly CRC patients ≥ 60 years old has decreased from 53.1% in 2002–2009 to 48.6% in 2010–2017, a percentage decline of 8.5% (for comparison, the percentage proportion of ageing population in Brunei in the latter period has expanded by 72.5% where the proportion of ≥ 55 year olds increased from 6.2% [21, 22] (2002–2009) to 10.7% (2010–2017)) . The rise in young CRC patients (< 40 years old) (20.3% increase in proportion of CRC cases; from 6.9% in 2002–2009 to 8.3% in 2010–2017) calls for awareness on the existence of CRC in younger individuals. Some studies have recommended a lower screening age, with non-invasive techniques such as the FOBT for high-risk groups < 50 years . With the advent of precision medicine, personalized screening approaches such as genetic profiling of high-risk patients to reveal specific molecular alterations to determine genetic susceptibility and to guide targeted therapy [34, 35], may also benefit survival outcomes. A novel, US FDA (United States Food and Drug Administration)-approved non-invasive stool-DNA test, Cologuard (also known as a multitargeted stool DNA test [MT-sDNA] or FIT-DNA) which tests for both abnormal cancer-associated DNA changes (from CRC or polyp cells that often enters the stool) and blood in the stool without requiring any dietary or drug restrictions may also be considered, as it comes with the flexibility of self-sampling from home  for patients’ convenience and preserves privacy.
Advanced stage CRC (Stage 3 or 4) was noted in 68.5% (regional: 35.0%, distal: 33.5%) of our patients in 2010–2017, up from 60.2% in 2002–2009. This may be attributed to several factors such as low awareness of early signs and symptoms of CRC (54.1% of the population are unaware of the signs and symptoms of CRC) , fears and denial in the context of Brunei (the free healthcare coverage for citizens and permanent residents (84.6% of the population) in Brunei negates the effects of healthcare expenses as a barrier to seeking diagnosis/treatment). In addition, those experiencing non-specific CRC symptoms such as weight loss and fatigue tend to normalize these symptoms and disregard them as indications of cancer, which may prevent them from seeking timely medical attention. The 'private nature' of CRC symptoms also suggests that it is crucial to reduce stigma on conversations around bowel movements with others including healthcare professionals . It will also be useful to characterize patients’ experience, from symptoms’ (bleeding, obstruction, and abdominal/rectal pain ) onset to diagnosis, to identify potential barriers and promptly guide future interventions .
No significant difference in survival rates between genders were observed in this study, although female CRC patients are significantly younger (< 40 years) than male CRC patients (p = 0.002) (data not shown), consistent with a previous 29-year national epidemiological study . However, males account for more than half of the total CRC cases (56.8%) in 2002–2009 and (56.6%) in 2010–2017, concurrent with findings from previous reports of higher incidence of CRCs among males [42, 43]. A recent systematic analysis of global CRC trends from 1990 to 2017 across 195 countries and territories reported high numbers of incidence and deaths among males than females up to the ages of 80–84 years, with the highest rates observed in the oldest age group (≥ 95 years) for both sexes . It has been reported that female CRC patients have a survival advantage compared to male CRC patients, particularly in young and middle-aged patients and patients with localized disease . Factors such as differences in diet and lifestyle , and the protective effect of estrogens in females against CRC [45, 46], may explain the male predominance in CRC. Meanwhile, other studies observed no differences in 5-year survival between the sexes [reviewed in ]. The association between gender and CRC survival therefore remains to be validated as study findings remain inconsistent , due to variations in study design/analysis and differences in CRC subgroupings. Standardizing and harmonizing study designs with large, multi-center, population-based data may be the way forward.
The global heterogeneity in survival rates of CRC patients may be due to the varied lifestyles, environmental, and genetic factors. The 1, 3- and 5-year survival rates of CRC patients from 2002 to 2017 in this study are 78.6%, 62.5%, and 56.0% respectively. The overall 5-year survival rate for CRC patients in this study (56.0%) is slightly below the average (60%) for Asia . Meanwhile, a study of CRC patients diagnosed between 1996–1998 in the USA and Europe revealed age-standardised 5-year net survival rates at 58% (the USA), 54–56% (Northern and Western Europe), and 42% in Eastern Europe . A more recent population-based retrospective cohort study of all CRC patients diagnosed between 1989 and 2014 in the Netherlands reported significant increase in 5‐year relative survival from 53 to 62% for colon cancer and from 51 to 65% for rectal cancer . This study also demonstrates that the 5-year survival rate of CRC patients is significantly lower in 2010–2017 (51.3%) compared to 2002–2009 (64.7%). This may be attributed to a larger number of unrecorded mortalities in 2002–2009 (pre-Bru-HIMs in late 2012), leading to an overestimation of surviving patients. In addition, Bru-HIMS-facilitated alterations in the coding mechanism for causes of deaths may also contribute to improved/accurate case registration in the latter period (2010–2017). Epidemiological studies have shown an increased risk of CRC in patients with inflammatory bowel disease (IBD) . The incidence of IBD in Brunei has increased from 0.28 per 100,000 population in 2004 to 3.08 per 100,000 population in 2016 . However, the proportion of patients with IBD who transition to CRC remains to be determined. A poorer prognosis in the latter period may also be attributed to treatment refusal or high dropout rates among patients. Advanced-stage cancer, feeling discouraged or depressed from the cancer worsening, and pre-existing catastrophic illnesses make patients more likely to refuse treatment .
This study shows that CRC patients < 40 years old have a higher 5-year survival rate than those aged ≥ 60 years old (69.4% versus 51.2% respectively). Adj. HRs indicate that patients ≥ 60 years old have the highest risk of mortality, followed by the 40 to 59 years old group. This is contrary to a previous report, which shows that age does not impact survival rates of CRC patients significantly . The average life expectancy (males and females) in Brunei has increased from 76.6 years between 2002 and 2009  to 77.6 years between 2010 and 2017 , suggesting that the increased mortality risk among the elderly group is not attributed to a general reduction in life expectancy. The increasing proportion of ageing population nationally [6, 21, 22] and globally  calls for concern to address ways to reduce mortality among the elderly CRC patients. The presence of more advanced comorbidities in elderly CRC patients [56, 57], may also explain their lower survival rate. Malnutrition, a frequent physical manifestation of gastrointestinal cancers which is particularly common in older adults, have potential negative repercussions on quality of life, functional status, treatment tolerance, and prognosis . However, nutrition post-cancer diagnosis especially in elderly patients remains understudied  and knowledge gaps remain to be closed.
Malaysian and Bruneian studies have reported a higher incidence of CRC among the Chinese [47, 60, 61]. As mentioned earlier, the burden of colorectal cancer has been attributed to dietary risks, and lifestyle factors including alcohol consumption, and smoking . Cultural and lifestyle differences among different ethnicities may contribute to the etiology of CRC. Previous studies show strong evidence of an association between alcohol consumption and colorectal cancer risk [62–64]. It remains to be determined whether alcohol consumption is associated with the increasing incidence of CRC among Bruneian-Chinese (alcohol consumption is forbidden amongst Muslims (predominantly Malays), by the Islamic law in this country). The unequal CRC risk between different ethnic groups within the same region may also be explained by genetic factors that may alter the effects of the environment on disease predisposition . Despite the higher incidence of CRC among the Chinese population in Brunei, they have significantly higher 1-year, 3-year and 5-year survival rates, and a significantly lower risk of death after adjusting for variables, compared to the Malays. In addition, Bruneian-Chinese tend to develop CRC at a slightly later age (60.4 ± 12.7 years) compared to the Malays (59.9 ± 15.2 years) . The disparity in survival rates between CRC patients of differing ethnicities in Brunei are in agreement with findings in Singaporean studies [66, 67] but differs from the findings in Malaysia . It is important to consider that the number of Bruneian-Chinese patients may be underestimated in our study, as they may seek diagnosis and/or treatment overseas , thus may not be enrolled in the cancer registry. Another study reported that the reluctance to seek aggressive therapies among the Malay CRC patients may contribute to their low survival rates [66, 67]. Local clinicians also report the tendency of patients to opt for mostly traditional medicine before considering, and therefore delaying conventional treatment (personal communication). It is integral that healthcare professionals in Brunei work to increase targeted awareness in the community regarding CRC symptoms and the importance of early screening and early intervention.
This study shows that distant CRC is associated with the highest risk of death, followed by regional cancer, and localised cancer, consistent with previous reports [9, 31]. Surgical removal of advanced staged tumors with metastatic lesions is challenging , therefore, minimizing the number of CRC patients who present with advanced stage diagnosis needs to be emphasised. It is also crucial for physicians and the relevant multidisciplinary team to construct an effective treatment and clinical management plan with supportive care for the patients to improve their quality of life.
This study shows that tumor location impacts survival outcome of CRC patients. The definition of right-sided colorectal cancer (RCRC) and left-sided colorectal cancer (LCRC) varies across different studies with respect to tumors in the transverse colon (some studies consider the cecum, ascending colon, hepatic flexure and transverse colon as RCRC; LCRC includes the splenic flexure, descending colon, sigmoid colon and rectosigmoid cancers [69–71]) whereas other studies only include the proximal two-thirds of the transverse colon (alongside cecum, ascending colon and hepatic flexure) as RCRC, with the distal third of the transverse colon (alongside splenic flexure, descending colon, sigmoid colon and rectosigmoid cancers) categorized as LCRC [72, 73]. The effect of CRC tumor subsite on CRC patients’ survival rate of our study differs from previous reports [74–78]. Majority of the patients in this study (89.2%) present with LCRC (tumour sites from splenic flexure to the rectum), which tends to associate with lowered 5-year survival rates and higher risk of death. CRC patients with tumors in the first part of the proximal/right-sided colon (cecum until hepatic flexure) have a significantly higher 5-year CRC survival rate (77.8%), compared to patients with tumors in the transverse colon and splenic flexure (5-year survival: 52.2%), patients with tumors in the descending colon, sigmoid colon, overlapping lesion colon and colon (NOS) (5-year survival: 55.2%) and patients with tumors in the rectosigmoid junction until rectum (5-year survival: 51.0%). Patients with tumors in the transverse colon and splenic flexure [Adj. HR = 2.44 (1.25, 4.76); p = 0.009], descending colon, sigmoid colon, overlapping lesion colon and colon (NOS) [Adj. HR = 2.01 (1.26, 3.30); p = 0.003]) followed by those with tumors in the rectosigmoid junction until rectum (NOS) [Adj. HR = 2.00 (1.24, 3.24); p = 0.005]) have significantly higher risk of mortality compared to patients with tumors located from the caecum to the hepatic flexure of colon. RCRC and LCRC have differing embryological origins (right-sided colon arises from the embryologic midgut whereas left-sided colon is derived from the embryologic hindgut) , molecular etiologies  and significant epidemiological, clinical and histological differences [81, 82]. Microsatellite instability (MSI) is more common in RCRCs. Although tumors showing MSI have an improved prognosis, the good prognosis may be counteracted by the fact that they tend to present at a later stage. In contrast, LCRCs tend to involve p53 mutations, and overexpression of vascular endothelial growth factor which are associated with an adverse prognosis and poor response to fluorouracil-based chemotherapy . RCRC has been associated with poorer survival outcomes as RCRC patients tend to be older [72, 82, 83], and typically present with more advanced, poorly differentiated tumor, with flat morphology, thus more challenging to detect, compared to LCRC patients [74, 79, 80]. Although CRC patients with tumors in the cecum until the hepatic flexure have the highest survival rate compared to CRC patients with other cancer sites, the sample size is significantly smaller (8.1% of total CRC patients) than that of other cancer sites. Therefore, these findings remain to be validated with a larger sample size. The small number of RCRC patients (10.8% of total CRC patients) in this study may also be due to reporting bias, due to challenges in detection as mentioned earlier. As CRC presents differently depending on tumor location and sidedness, screening and awareness efforts should emphasize the different presentations . Screening modality choice may also be affected by the anatomic location of CRC presentation; for instance FOBT is more sensitive for detecting left-sided lesions compared with right-sided lesions . Overall, the survival rate of CRC patients with LCRC and RCRC remain conflicting, and there is insufficient evidence to support the use of tumor location in making decisions about therapy. Therefore, a deeper understanding of the interaction between tumor sub-site and molecular profile may enable a more personalised therapy to improve management of CRC patients .
A strength of our study is the use of a population-based national cancer registry where data is centralized and cross-verified from the pathology laboratory, clinical reports, electronic medical records and death registry. However, like any data registry, there are several limitations such as coding inaccuracies due to heavy manual data-recording especially in the early period (2002 to 2009) prior to the introduction of the electronic medical record system, Bru-HIMS. This may result in an underestimation and/or overestimation of CRC patients’ survival rates. In addition, CRC patients who chose to seek diagnosis and/or treatment overseas may not be enrolled in the registry (although this number is likely to be small due to the availability of free universal healthcare services in Brunei). In addition, in-situ cases were not included in the analysis as the data obtained from the cancer registry using CanReg5 was designed primarily for reporting of malignant cancers. The presence of unknown variables in the cancer registry may also lead to ambiguity in the results. Information such as patients’ family health history, comorbidities, diet, lifestyle factors, treatment(s) received and their responses to treatments were not available, thus were not evaluated. A larger data set including those from pre-2002 would provide a longer period of assessment of the survival rates of CRC patients in Brunei Darussalam (BDCR was only established in 2002, therefore prior data were not analysed).
In conclusion, this study evaluated the 1-, 3- and 5-year survival rates of CRC patients in Brunei, compared the survival rates between age groups, ethnicities, cancer stages, and sites of cancer, as well as compared CRC patients’ survival rates between two different study periods. Although the overall survival rates were similar to data from other countries/population, our study observed a significant increase in the number of new CRC cases from the period 2002–2009 to 2010–2017, increase in the proportion of younger CRC patients and a high proportion of CRC diagnosed at advanced stages. These findings highlight the importance of public health policies and programmes to enhance cancer prevention strategies and improve awareness on CRC including screening, symptom recognition among younger population, healthy lifestyle practices, and the significance of early diagnosis and early intervention, to reduce CRC-associated mortality.