Page 42 - SRPSKO DRUŠTVO ISTRAŽIVAČA RAKA

Serbian Association for Cancer Research SDIRSACR

the age of 50 years and the average age at the time of the diagnosis is around 64 years (18, 19). The incidence of CRC
is higher in highly developed countries, which is explained by the fact that the modernization of society and increased
living standards also affect the development of health care (18). As a result, the life expectancy of citizens is increased,
and thus the frequency of CRC cases in the population (20). The rise in the number of cases in Eastern Europe appears
to be due to westernization and an unhealthy lifestyles that includes poor diet and reduced physical activity (14).
In the analyzed 14-year period, the number of late-onset CRC cases increased over the years and there was also a
slight increase in the incidence of early onset cases, reflecting the global trend observed during the past couple of
decades (21). This is in line with the increasing number of all CRC cases globally, and may be partly due to the improved
detection of the disease. Several studies point to the increase in incidence of early-onset cases (12, 18, 22). On the
other hand, the frequency of early-onset disease slightly declined during the final years of the observation period, and
the average value of 15% is lower than in the majority of other similar studies where early-onset patients represented
20% or more of the analyzed group (23, 24). In general, younger patients appear to have more distal or rectal disease,
a more advanced stage of disease at presentation, and more unfavorable histological features, and the results of our
study align with these findings (24-26).
Until 2014, the patients were more frequently diagnosed at the advanced stage of CRC. Since then, the slight decrease
has been observed, which can be explained by the introduction of the national screening program. Serbia joined the
majority of European countries conducting national CRC screening programs in 2013 by extending the local programs
that had been active in three municipalities since 2005 (27, 28). The program is based on the immunochemical faecal
occult blood test (iFOBT) and it is offered to 50-74 year olds without evidence of CRC. The rate of participation is around
60%.
The disease was observed to affect the rectum more frequently than colon, with the incidence of the right colon
disease of 14%, which was overrepresented in younger patients. The colon being affected in less than half of the cases
is a different pattern than in most developed countries, where the declining frequency of rectal cancer was observed
(2, 29). The disproportionately high proportion of rectal cancers in this cohort (54%) compared to the expected ~35%
in general CRC populations could be explained by referral bias, since this study was conducted at a tertiary care center,
patients with rectal cancers, which often require more complex management and have different treatment protocols
(e.g., neoadjuvant chemoradiotherapy), may have been more likely to be referred to this specialized facility, and colon
cancer surgeries can be performed in secondary centers, while rectal cancer surgeries are usually centralized at tertiary
institutions. This could lead to a higher representation of rectal cancer cases in our cohort.
Fluctuations in the ratio between right-sided and left-sided lesions in different populations may be due to the diagnostic
improvements, namely the application of the complete colonoscopy instead of the earlier most commonly applied
rigid rectoscopy (29). The frequency of the right colon lesions was significantly lower in our study in comparison to the
results that came out of the national screening program in 2016, when 29.6% of polyps and 22.7% of the carcinomas
were found in the proximal parts of the colon of subjects with the positive diagnosis on colonoscopy (30). The results
of the national screening program correspond to the findings from other countries (31). This discrepancy could be due
to the fact that subjects in the national screening program are recruited directly from the general population, while
surgical cases included in our study are those referred to the tertiary care center from the local healthcare institutions.
In the subgroup of patients who underwent nCRT, there was an unexpectedly low rate of complete pathological response
(3%) when compared to the data collected from other populations (over 10%) (32). These patients are candidates for
the watch-and-wait approach, an evolving alternative to radical surgery aiming for organ preservation and improved
quality of life (5). The other group of interest is patients with no response (TRG5), as they are candidates for other
therapeutic modalities since nCRT appears to be non-beneficial for them. In our study, 6% of patients were classified
as non-responders. Overall, patients with good response were slightly younger, and there were slightly more women
among them.

This study has several limitations that should be acknowledged. As a retrospective, single-center analysis, it may not
fully represent the broader CRC population in Serbia or other regions, thereby limiting the generalizability of the
findings. Patients referred to a tertiary care center are more likely to have advanced or complex disease, which may
skew the distribution of tumor stages and treatment outcomes. Another limitation of our study was the unavailability
of follow-up data, which was due to the fact that most patients who underwent surgery at the clinic where the study
was conducted do not return for control examinations. The absence of structured follow-up data prevents evaluation
of long-term outcomes such as recurrence or survival, which are essential for assessing the prognostic significance of
pathological findings and treatment responses. The study also lacked molecular profiling, which is increasingly relevant
in CRC classification and personalized treatment planning. These limitations highlight the need for prospective,
multicenter studies incorporating comprehensive clinical, pathological, and molecular data, as well as robust follow-up
protocols, to better inform CRC management and outcomes in diverse populations.

27