Our analysis shows, to our knowledge for the first time that both the incidence and mortality rates over the last 35 years have developed differently for LCRC and RCC. While the rates of LCRC have been steadily declining over time, the rates for RCC remained largely unchanged. The lack of progress in outcome of RCC might be due to several factors. Several trials since 1992 suggested a major protective effect of colonoscopy and sigmoidoscopy against colorectal cancer by detecting and removing precancerous lesions, which resulted in an increased screening activity in many countries (Selby et al. 1992; Newcomb et al. 1992; Winawer et al. 1993; Stock et al. 2011; Shapiro et al. 2012; Issa and NouredDine 2017). This might be one of the major reasons for the decline of incidence rates since then. However, the detection rate of proximal neoplasms is significantly lower than the detection rate of distal neoplasms (Bressler et al. 2004, 2007; Singh et al. 2006; Brenner et al. 2014). Another reason might be found in well-known differences in the appearance of premalignant neoplasms, including flat lesions in the proximal colon, which are rather overseen compared to the typical polypous lesions in the left colon (Iacopetta 2002; Nawa et al. 2008; Arain et al. 2010). This might be reasonable, if sigmoidoscopy, inspecting parts of the left colorectum only, were the predominant method used in these publications. However, the same difference in detection rates is found if total colonoscopy is used (Baxter et al. 2009; Mulder et al. 2010; Ostenfeld et al. 2013). It has even been shown, that the reduction in CRC-related mortality in a colonoscopy-screened population seems to be restricted to LCRC without affecting mortality from RCC (Singh et al. 2010). This observation is in line with our findings that the mortality rate for RCC remains unchanged over time, while the same rate for LCRC is constantly declining over the last centuries.
Incidence-rates according to stage at diagnosis showed that the occurrence of disseminated RCCs have been declining to some extent. Here again the effect is much more pronounced for LCRC and non-overlapping CI-ranges of the two slopes suggest a significant difference. This difference in incidence-rates was not found for localized disease, implying a stage-migration from disseminated disease to locoregional disease that potentially is gained by screening also for RCC. One could hypothesize that the main effect of screening is earlier detection, but not preventing RCC. However, the mortality rate for disseminated RCC has not changed to the same extent as the respective incidence rate. This might reflect the reduced benefit that RCC gains from oncological treatment based on the biological differences between RCC and LCRC, especially, if the RAS-mutation status is considered in oncological treatment decisions (Benedix et al. 2010; Weiss et al. 2011; Modest et al. 2014; Von Einem et al. 2014; Missiaglia et al. 2014; Loupakis et al. 2015; Zhang et al. 2015; Guinney et al. 2015; Venook et al. 2016; Arnold et al. 2017). Both less effective screening and less effective treatment aspects contribute to an unfavorable development in mortality of RCC, especially in disseminated stages.
In published observations reporting on differences in the clinical outcome in LCRC and RCC the relative 5-year survival rates are applied for comparing oncological outcome between distinct time intervals (Brouwer et al. 2018; Dulskas et al. 2020). The risk of a lead-time bias in such approaches is problematic, especially in CRC, which is a screening sensitive disease. This potential bias in that context has been addressed by several authors (Welch et al. 2000; Gigerenzer and Wegwarth 2013). Comparing time intervals before and after the millennium is particularly problematic, as screening was introduced around the turn of the millennium leading to earlier diagnosis of CRC, which implies the risk of prolonged overall survival times. This might explain to some extent why not all of the published results are conclusive. For example, in one study the relative increase in clinical benefit from 1998-2008 compared to 2008-2012 was 11% less for LCRC than for RCC (Dulskas et al. 2020). This length bias can be avoided by using mortality rates rather than survival times or survival rates (Welch et al. 2000; Gigerenzer and Wegwarth 2013).
Several factors underline the reliability of our results. In addition to the high numbers of cases included, the information on the location of primary tumor was available in 81.2% of the cases for calculating incidence rates. The distribution of LCRC and RCC within this population can be well compared to the literature, as it reflects PTL at diagnosis. We found 73.3% LCRC and 26.6% RCC, which is a well comparable distribution also found by others and supports, that our dataset is not biased by documentation issues (Benedix et al. 2010; Holch et al. 2017b). Furthermore, our data on 22.6% disseminated disease at time of diagnosis align with those reported from a dataset of the Netherland Cancer Registry (Brouwer et al. 2018).
Variations in the prognostic impact of PTL on survival were also found in our study. This stage-specific difference is well known and broadly reported and the accordance of our results with the literature indicates the validity of our dataset (Weiss et al. 2011; Tejpar et al. 2017b). Information on PTL at time of death derived from death certificates was available for half of the cases; due to the lack of reports describing the distribution of PTL at this time point, it is difficult to compare these numbers with the literature.
This study provides a nationally representative perspective in trends of colon cancer outcomes. We report an evolving disparity in outcomes for patients suffering from RCC compared to oncological progress in patients with LCRC in both incidence and mortality. These findings underline the necessity to consider RCC as a distinct disease, which requires more efficient prevention-, treatment- and specific future research strategies.