With an estimated 1.8 million new cases and 881,000 deaths worldwide in 2018, colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause in cancer-related death (1). Both incidence and mortality are growing rapidly worldwide and are expected to increase to up to 2.2 million new cases and 1.1 million deaths by 2030 (2). Reasons for this increase are multifactorial and include aging, changing diet, and growth of the population, as well as changes in the prevalence and distribution of the main risk factors for colorectal cancer, several of which are associated with socioeconomic development (1, 3, 4).

These risk factors for CRC comprise both endogenous factors, such as (inherited) genetic predisposition, and exogenous factors such as lifestyle and environmental exposure (5). The influence of environmental factors on the incidence of CRC has been investigated extensively. Multiple studies have shown a positive association between both CRC incidence and mortality and smoking, alcohol consumption, obesity, and diabetes mellitus (DM) (6–15). In line with global trends in incidence and mortality rates in well-developed countries over the past few decades, incidence rates in the Netherlands increased from nearly 7,000 new colorectal cancer cases in 1990 to more than 15,000 new cases in 2014, while mortality rates in the same time period have decreased (16–18). After implementation of the national screening programme in 2014, incidence rates increased a little further to almost 16,000 new cases in 2015. Thereafter, a decrease was noted to nearly 14,000 new cases in 2018, with a further decrease expected to approximately 12,500 new cases in 2019 (18). Previous Dutch cohort studies, with data obtained from national registries, suggested that the decrease in mortality might be attributed to improvements in both early detection and treatment (2, 19–22). However, since they were unable to adjust for potential confounders, the influence of patient characteristics such as socioeconomic status (SES), presence of overweight, alcohol usage, smoking status, or presence of comorbidity on survival of CRC remains unknown.

Therefore, the aim of the present study was to describe changes in treatment and its effect on survival in patients with CRC in the Netherlands between 1990 and 2014. The secondary aim was to assess which patient-related and tumor-related factors were associated with survival.

In total, 396 individuals with an incident diagnosis of a histopathological proven primary CRC were divided into a colon cancer cohort (n = 272, with a tumor in either caecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, and sigmoid colon) and a rectal cancer cohort (n = 124, with a tumor in either rectosigmoid or rectum, see Supplementary Figure S1). As previously described, analyses were split for cases with a date of diagnosis between January 1, 1990 and December 31, 2002 and cases with a date of diagnosis between January 1, 2003 and December 31, 2014 (26).

We observed a decreased risk of mortality in rectal cancer subjects diagnosed after January 1, 2003 compared with those diagnosed before this date, whereas in colon cancer subjects, no change over time was observed. Kaplan–Meier estimates of survival showed no differences in both rectal and colon cancer subjects. While resection rates remained stable and high, over time procedures were more often performed laparoscopically and both colon and rectal cancer patients were more often treated chemotherapeutically.

In diagnosing colorectal cancer cases, information on possible lymph node and distant metastases was obtained and reported significantly more often over time, illustrated by the decrease in the proportion of patients in whom information on lymph node metastasis (22.6% vs. 16.9% in the colon cancer cohort and 16.3% vs. 14.3% in our rectal cancer cohort) and distant metastasis (46.0% vs. 21.0% in colon cancer and 48.9% vs. 18.7% in rectal cancer, respectively) was not available, which is in line with a previous nationwide Dutch study (27). During our study period, advancements in imaging techniques, such as more widespread use of CT and MRI scanning, have emerged, leading to detection of smaller metastases, which would otherwise have remained undetected (28, 29). Nonetheless, no evidence was found that more recently diagnosed patients as a result were diagnosed at an earlier stage yet. In 2014, a nationwide screening program was implemented in the Netherlands. Studies conducted in the other parts of Western Europe and the United States observed a trend towards an earlier stage and less advanced disease at diagnosis, leading to a significant decrease in mortality rates (30–32). Nationwide mortality rates in the Netherlands have decreased modestly over the last decades and are, partly due to the screening program, expected to decrease further (27, 33). The number of cases from the national screening program included in our cohort was too low to address this question.

Our findings of stable resection rates over time in stages I–III patients were also demonstrated in a French population-based study, and also our findings with regard to changes in both detection and treatment in both colon and rectal cancer, are in line with a previous Dutch study (17, 34). As shown by multiple studies, the proportion of patients receiving adjuvant chemotherapy (both curative and palliative) increased, with the increase being steeper in stage III patients and smaller in older patients (aged >75 years) (17, 34). This is similar to our findings. In colon cancer, chemotherapy was mainly administered as adjuvant therapy, whereas rectal cancer cases mainly received chemotherapy as neoadjuvant treatment. In our cohort, none of the ten stage III patients aged >85 years received adjuvant treatment with either chemotherapy or radiotherapy. Previous, mainly retrospective, studies have shown conflicting results in benefits of adjuvant therapy in elderly patients, ranging from no benefit and increased toxicity to similar benefits from adjuvant chemotherapy in elderly patients as compared with younger patients, without a significant increase in toxicity (35). The Dutch Colorectal cancer guideline recommends an individual approach in elderly patients to carefully weigh harms against benefits, taking performance status and comorbidities into account instead of age.

Overall survival in our colon cancer cases did not improve over time. This might, at least partly, be explained by changes in diet and lifestyle over time, as subjects diagnosed after 2003 were more often overweight, (former) smokers and (current) alcohol users. Previous studies have shown an increased mortality (both overall mortality and cancer-specific mortality) for current and former smokers, alcohol users, and obese CRC patients (6–14). Another, and maybe more likely, explanation might be the age distribution of our study population. A previous Dutch cohort study found improved 5-year survival rates from 51% in 1975–1984 to 58% in 2000–2004 in colon cancer patients, and survival rates in rectal cancer patients improved from 44% to 59% in that period (17). In younger patients (aged <70 years), these survival rates increased throughout the whole study period, while in elderly patients, this increase was only seen up to 1995–1999 (17). In their study, over 30% of all patients were younger than 65 years old, while in our study almost 90% of all subjects were aged 65 years and over and almost 75% were aged >70 years.

Other studies reported relative survival and disease-specific survival, while we report absolute all-cause mortality numbers. We therefore obtained age-specific national data on absolute overall survival in both colon and rectal cancer. The proportion of younger patients (<75 years) in both our colon cancer and rectal cancer cohort were smaller than nationwide. This might be explained by the age limit in our cohort of 55 years and older for the first two included cohorts (1990-2005) and 45 years and over for the third cohort. Nationwide, the proportion of colon cancer patients aged <75 years remained stable around 60% (95% CI, 60–62), whereas in our cohort, these percentages were 41.9% (95% CI, 33–51) in those diagnosed before January 1, 2003 and 37.1% (95% CI, 29–45) in those diagnosed after January 1, 2003 (p < 0.001). In our rectal cancer cohort, 49.0% (95% CI, 35–63) of the patients diagnosed before January 1, 2003 and 57.3% (95% CI, 46–69) of those diagnosed after January 1, 2003 were aged <75 years. This was significantly smaller than nationwide, where this proportion remained stable around 70% (95% CI, 68–71; p = 0.005). As mentioned before, previous studies have shown that the improvement in survival was much more prominent in younger patients.

Our Cox proportional hazards model showed a lower risk of mortality in rectal cancer patients after adjustment for patient-related factors, tumor characteristics, and treatment strategy, suggesting a significant contribution in the improvement of survival. Resection rates in our cohort were consistently high over 80% in all stages in both colon and rectal cancer, while the proportion of laparoscopic procedures significantly increased over time. Median overall survival in laparoscopically operated patients was significantly higher than those who underwent an open procedure when stratified for diagnose before or after January 1, 2003 (p = 0.008 in colon cancer patients and p = 0.04 in rectal cancer patients, data not shown). This, however, can be explained by the stage distribution, as laparoscopically operated patients were more often diagnosed with stage I or II cancer (p = 0.02 in our colon cancer cohort and p = 0.001 in our rectal cancer cohort, data not shown). The European Multicenter Colon Cancer Laparoscopic or Open Resection (COLOR) trial, a large, prospective, randomized controlled trial conducted in 29 participating hospitals in Europe, demonstrated no differences in both disease-free and overall survival at 3 and 10 years follow-up between laparoscopic and open surgery for colon cancer with tumor stages being equally distributed among both types of procedures (36, 37). Similar results were found in rectal cancer patients (38). In addition, treatment of rectal cancer has changed drastically during our study, with implementation of the total mesorectal excision (TME) approach and increased neoadjuvant administration of chemo- and radiotherapy, leading to an increased survival as shown in previous studies (22, 39, 40). In metastasized patients, a shift was observed from resection of the primary tumor towards systemic therapy with chemotherapy. In our cohort however, no improvement in absolute overall survival or conditional survival was observed.

With its long follow-up and detailed information on important risk factors and comorbidities, a large population-based cohort study, such as the Rotterdam study, enables evaluation of changes in patient characteristics, diagnostics, and implemented care. However, an important limitation of our study is the relatively small number of included cases, causing overfitting in some of our multivariate Cox proportional hazard models.

In conclusion, between 1990 and 2014, resections in colorectal cancer patients were performed laparoscopically more often and patients were treated chemotherapeutically more frequently. Absolute overall survival in rectal cancer patients improved, while absolute overall survival in colon cancer patients remained stable. Lack of improvement of survival in our cohort may be explained by the large proportion of elderly, compared with the general population and the difference in survival benefit of treatment between younger and elderly patients.

Because of restrictions based on privacy regulations and informed consent of the participants, data cannot be made freely available in a public repository. Requests to access these datasets should be directed to the management team of the Rotterdam study (datamanagement.ergo@erasmusmc.nl), which has a protocol for approving data requests.

The studies involving human participants were reviewed and approved by the Medical Ethics Committee of the Erasmus MC (registration number MEC 02.1015) and by the Dutch Ministry of Health, Welfare and Sport (Population Screening Act WBO, license number 1071272-159521-PG). The Rotterdam Study Personal Registration Data collection is filed with the Erasmus MC Data Protection Officer under registration number EMC1712001. The Rotterdam study has been entered into the Netherlands National Trial Register (NTR; www.trialregister.nl) and into the WHO International Clinical Trials Registry Platform (ICTRP; https://apps.who.int/trialsearch/) under shared catalogue number NL6645/NTR6831. All participants provided written informed consent to participate in the study and to have their information obtained from treating physicians. The patients/participants provided their written informed consent to participate in this study.

Conception and study design: BL, JF, TR, BS, and CE. Data collection: all. Data analysis: BL, JF, and TR. Supervision: TR, BS, and CE. Writing original draft: BL and TR. Editing and final approval: all. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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