Keywords
colorectal cancer - risk factors - tumor stage
What Does this Paper Add to The Literature?
What Does this Paper Add to The Literature?
This study explores aspects of the CRC profile over 37 years within a specified geographical
population, ascertaining specific changes in its manifestation and at diagnosis.
Cover Letter
For the attention of the Drafting Committee of the journal Colorectal Disease, we—the
authors—provide this manuscript “Colorectal cancer: comparative analysis between patient
groups separated by three decades” wherein all content is entirely original and has
not been previously posted or considered for any other publications.
The authors do not present any conflict of interests in the presentation of this work.
The authorship requirements have been fulfilled: All authors have read and approved
the study, and they have all actively and relevantly participated in the article's
design and development, assuming full responsibility for the contents and affirming
their agreement with this final and definitive version of the article.
Likewise, we have received study approval, as evaluated by the Clinical Research Ethics
Committee of the Ramón y Cajal University Hospital for Health Research, IRYCIS, Madrid,
in Madrid, on July 3, 2015. We declare that we have followed the established protocols
in accessing clinical records data in order to enable publication for the scientific
community in compliance with the Organic Law of Protection of Personal Data (LO 15/1999).
Introduction
Colorectal cancer (CRC) is one of the most common neoplasms affecting Western populations.
In Spain, 90,000 people suffer from CRC, two out of every thousand at all ages. Approximately
32,240 new patients are diagnosed each year, but more than 90% can be cured if the
disease is detected early.[1]
[2] It is the second most common cancer in women, after the mammary tumor, and the third
in men, after lung and prostate tumors.[1]
[2]
[3] In both genders, it has the highest incidence, at 15% of all diagnosed cancers.[4]
[5] The majority of cases appear between 65 and 75 years, though some are registered
under 40, generally associated with genetic predisposition.[6]
The risk factors that predispose development of this neoplasm are age,[7] neoplastic polyps,[8] oncologic family history,[9] history of other tumors, especially gynecological, or several digestive pathologies
such as inflammatory bowel diseases,[10] and biliary pathology.[11]
Symptoms usually prevail in advanced stages. Because of this, guidelines focus on
preventive programs and identification of risk groups.[12] The main screening tests are fecal occult blood test (FOBT)[13] and colonoscopy,[14] which are the most effective methods for early detection and reduction of mortality
and incidence.[15] There are several screening modalities, depending on the risk of developing sporadic
or hereditary CRC due to familial adenomatous polyposis (FAP) and Lynch syndrome,
and the control of preventable environmental factors.[16]
Surgical treatment is often curative for localized disease. However, once metastases
have occurred, the prognosis is poor with palliation often being the sole option.
Although recent therapeutic advances have changed the course of CRC,[17]
[18] the chances of improving survival lie mainly in early detection.
The aim of this study is to explore the biology and risk factors of this neoplasm,
specifically through comparing the data longitudinally through three decades to determine
and analyze any changes.
Method
A retrospective analysis was performed on a database with a consecutive series of
adult patients diagnosed with colorectal adenocarcinoma and admitted for surgery at
the University Hospital Ramon and Cajal. The catchment area served by this hospital
is densely urban, and hence the largest population assigned to a single health center
in the greater Madrid area.
The sample was divided into two cohorts. The current group, comprised of 185 patients
recruited between January 2014 and February 2015 (G1); and the historical group, comprised
of 106 patients recruited between September 1977 and January 1979 (G2).
The following sociodemographic epidemiological variables were recorded: age and gender,
habits involving toxicity, personal history, family history of cancer, tumor location,
clinical, diagnosis time, anatomical pathology, and treatment.
This study's weaknesses lie in data differences between the two groups: currently,
there are resources and therapeutic modalities that did not exist 37 years ago. Thus,
the samples were not comparable across all items. This affected gauging the degree
of tumor extension because, despite registering on the TNM staging system and using
a modified Astler-Coller classification in G1, the Dukes stage was the common method
used across both groups.
Nevertheless, this work's strength lies in the two series not having patient selection
bridges, having been studied correlatively according to their entry into the Service,
since its inception at the Ramon y Cajal University Hospital. This ensures an authentic
depiction of how things were at that moment, before starting activities that could
modify them.
Statistical and data analysis was performed using the Stata (StataCorp LLC., College
Station, TX, US) 2013 software. Categorical variables were compared using the chi2 test (Fisher exact test) and continuous tests with the Student t-test or analysis
of variance (ANOVA). For cases in which we were unable to assume normality or homoscedasticity,
the contrast between groups was performed with the Mann-Whitney U test or the Kruskal-Wallis
H test. A p-value of < 0.05 was considered to be statistically significant.
Results
In G1, 55.1% of the patients were men and 44.9% women, while in G2 the rates were
54.7% and 45.3%, respectively. The mean age of G1 patients was 71.4 years (95% confidence
interval, CI: 69.8–73.1), with a median of 74 (range: 41–96). In G2, the mean age
was 64.5 (95% CI: 63–66.7), with a median of 67 (range: 20–84) (p-value < 0.001) ([Fig. 1]). In G1, 25.9% of the patients were smokers and 7% consume alcohol; in G2, the figures
were 21.7% and 7.3%, respectively.
Fig. 1 Distribution of patients by age in both groups.
In terms of those with a personal history of adenomatous polyps, there was a 48.1%
incidence in G1 patients, and 19.8% in G2, with significant differences. [Table 1] compares the number of patients with a personal history by category. There were
significant differences in the histological type of polyps (p = 0.001), with a greater number of tubular adenomas registered in G1, 50.6 versus
12.5%, and a greater number of villous adenomas in G2, 37.5 versus 6.7% ([Fig. 2]).
Fig. 2 Patients with a history of adenomatous polyps of both groups and their histological
type.
Table 1
Personal history
|
Personal history
|
Group 1
|
Group 2
|
p-value
|
|
Adenomatous polyps
|
89
|
21
|
0.001
|
|
Hepatobiliary disease
|
32
|
11
|
0.109
|
|
Previous colorectal cancer
|
13
|
2
|
0.448
|
|
Other previous cancers
|
11
|
3
|
0.214
|
|
Gynecological cancer
|
6
|
2
|
0.758
|
|
Non-affiliated gynecological cancer
|
5
|
3
|
0.949
|
|
HNPCC
|
3
|
1
|
0.964
|
|
Ulcerative colitis
|
N/R
|
1
|
0.78
|
Abbreviations: Hepato-biliary disease, hepatopathy and/or cholecystectomy and/or cholelithiasis;
NPHCRC, hereditary non-polyposis colorectal cancer; N/R, not reported.
In G1, 24.3% of the patients had one or more family history of cancer, in G2, the
number is 35.8%, showing significant differences (p = 0.036).
The most frequent locations of tumors for both groups were in the rectum and rectosigmoid
junction, with 36.9% in G1 and 49.5% in G2. Significant differences were found in
relation to tumors in the rectum and ascending colon: the percentage of tumors in
the rectum was higher in G2, 37.8 versus 26.2% (p = 0.033), and tumors in the ascending colon had higher rates in G1, 14.4 versus 5.4%
(p = 0.017), as shown in [Table 2].
Table 2
Tumor location
|
Locations
|
Group 1, n = 195 (%)
|
Group 2, n = 111 (%)
|
p-value
|
|
Rectum
|
51 (26.2)
|
42 (37.8)
|
0.033
|
|
Sigmoid colon
|
43 (22.1)
|
23 (20.7)
|
0.786
|
|
Ascending colon
|
28 (14.4)
|
6 (5.4)
|
0.017
|
|
Cecal colon
|
23 (11.8)
|
7 (6.3)
|
0.121
|
|
Rectosigmoid junction
|
21 (10.8)
|
13 (11.7)
|
0.801
|
|
Transverse colon
|
10 (5.1)
|
8 (7.2)
|
0.457
|
|
Splenic flexure
|
7 (3.6)
|
5 (5)
|
0.801
|
|
Hepatic flexure
|
6 (3.1)
|
3 (2.7)
|
0.868
|
|
Descending colon
|
6 (3.1)
|
3 (2.7)
|
0.868
|
|
Appendix
|
N/R
|
1 (0.9)
|
0.775
|
Abbreviation: N/R, not reported.
Establishing the classic locations of the digestive tract and using the Bonferroni
correction to obtain the p-values, right colon cancers were significantly higher in G1, 26.1 versus 12.6% (p = 0.02).
In men, there were more colon tumors in G1, 75.7 versus 57.4% (p = 0.013). Comparing gender and tumor location, excluding synchronous cancers, colon
cancer was more frequent in G1 males, at 78.4%, and rectal cancer in G2, 44.8% (p = 0.002).
Clinically, 82.7% of G1 patients, and 78.3% of G2 had symptoms. As shown in [Tables 3]
[4]
[5], the first and most frequent symptom was lower gastrointestinal bleeding (LGIB)
in G1 and change in bowel habits (CBH) in G2. There is a significant difference in
CBH as the first symptom, which is higher in G2 at 38.6 versus 20.9%; p = 0.003. The most frequent main symptom was LGIB in both groups, higher in G2 at
43.4 versus 39.2%, although the only significant difference was CBH, which was higher
in G2 at 28.9 versus 7.8%; p <0.001. Significant differences were found in the associated symptoms such as constitutional
syndrome, CBH and abdominal pain, more frequent in G2, whereas perforation was only
recorded in G1.
Table 3
Most common first, main, and associated symptoms: First symptom
|
First symptom
|
Group 1, n = 153 (%)
|
Group 2, n = 83 (%)
|
p-value
|
|
Lower gastrointestinal bleeding
|
43 (28.1)
|
28 (33.7)
|
0.379
|
|
Change in bowel habits
|
32 (20.9)
|
32 (38.6)
|
0.014
|
|
Abdominal pain
|
23 (15.0)
|
20 (24.1)
|
0.085
|
|
Incomplete intestinal obstruction
|
3 (2.0)
|
3 (3.6)
|
0.735
|
|
Asthenia and other symptoms
|
52 (34.0)
|
N/R
|
0.001
|
Abbreviation: N/R, not reported.
Table 4
Most common first, main, and associated symptoms: Main symptom
|
Main symptom
|
Group 1, n = 115 (%)
|
Group 2, n = 83 (%)
|
p-value
|
|
Lower gastrointestinal bleeding
|
60 (52.2)
|
36 (43.4)
|
0.221
|
|
Abdominal pain
|
30 (26.1)
|
18 (21.7)
|
0.476
|
|
Incomplete intestinal obstruction
|
16 (13.9)
|
5 (6.0)
|
0.075
|
|
Change in bowel habits
|
9 (7.8)
|
24 (28.9)
|
0.001
|
Table 5
Most common first, main, and associated symptoms: Other associated symptoms
|
Other associated symptoms
|
Group 1
|
Group 2
|
p-value
|
|
Weight-loss
|
29 (15.7)
|
41 (38.7)
|
0.001
|
|
Asthenia
|
27 (14.6)
|
25 (23.6)
|
0.054
|
|
Perforation
|
16 (8.6)
|
N/R
|
0.002
|
|
Anorexia
|
15 (8.1)
|
17 (16)
|
0.037
|
|
Lower gastrointestinal bleeding
|
10 (5.4)
|
6 (5.7)
|
0.927
|
|
Change in bowel habits
|
2 (1.1)
|
22 (20.8)
|
0.001
|
|
Abdominal pain
|
1 (0.5)
|
12 (11.3)
|
0.001
|
Abbreviation: N/R, not reported.
The time elapsed from the first symptom to the diagnosis was 2 months of average in
G1, with a standard deviation (SD) = 82.4, and 6.5 months in G2, SD = 208.1. Although
the study showed significant differences, it was not suitable due to the variation
of sample sizes.
Regarding to Dukes staging system, we found significant differences in all stages.
In G1 the most frequent was the stage A with 34.1% and the less frequent was the stage
D with 5.9%. In G2 the most frequent was the stage D with 30.2% and the less frequent
was stage A with 6.6% ([Table 6]). On average, 18.7 lymph nodes (95% CI: 17.3 - 20.2) were examined in G1 and 12.6
in G2 (p = 0.008).
Table 6
The Dukes staging system
|
Tumor staging
|
Group 1, n = 185 (%)
|
Group 2, n = 106 (%)
|
p-value
|
|
Dukes stage A
|
63 (34.1)
|
7 (6.6)
|
< 0.001
|
|
Dukes stage B
|
57 (30.8)
|
30 (28.3)
|
< 0.001
|
|
Dukes stage C
|
53 (28.6)
|
25 (23.6)
|
< 0.001
|
|
Dukes stage D
|
11 (5.9)
|
32 (30.2)
|
< 0.001
|
|
Non-affiliated
|
1 (0.5)
|
12 (11.3)
|
< 0.001
|
In G1, 99.4% of the patients were operated on and in G2 the 94.8%. The percentage
of operability did not show significant differences but there was the percentage of
resectability: in G1, 80.4% of the surgery was performed with resection R0 with only
58.2% in G2 ([Table 7]).
Table 7
The residual tumor (R) classification in 1987 by the Union for International Cancer
Control (UICC)
|
Resectability
|
Group 1 n = 184 (%)
|
Group 2 n = 98 (%)
|
p-value
|
|
R0
|
148 (80.4)
|
57 (58.2)
|
< 0.001
|
|
R1/R2
|
17 (9.2)
|
29 (29.6)
|
< 0.001
|
|
Non-affiliated
|
19 (10.3)
|
12 (12.2)
|
< 0.001
|
Abbreviations: R0, resection, tumor negative, “clean”, “negative margin”, resection for cure or
complete remission; R1, tumor positive, microscopic residual tumor; R2, tumor positive
macroscopic residual tumor.
Discussion
This comparative study did not reveal significant differences in the diagnosis of
CRC and gender, predominating in both groups in men, but the mean age did increase
significantly to 71.4 years in G1, when compared with 64.5 in G2, as published by
Devesa et al.[9] This change could be related to a greater longevity and delay in the appearance
of this disease, although it is logical to consider the involvement of other factors.
We also found that in G1 the mean age was higher in men (p < 0.001), and in G2 it was higher in women (p = 0.02). Both series remained in the established age line of development of this
neoplasia in developed countries, such as across Europe.[1]
[2]
[3] As reported by the literature, CRC is more frequent in men and in patients over
70 years old.[7]
[19]
In relation to smoking[20] and alcohol consumption,[21] there were no significant differences between groups, and although health campaigns
probably translate their impact on smokers, the reduction of a toxic habit as casual
in disease incidence takes years occur.[22]
Regarding medical history, there were differences in the numbers affected by adenomatous
polyps,[8] G1 being higher. Although welcome, we have no conclusive data to link it to the
increase in colonoscopies.[6] This early screening test for precancerous lesions continues to be the most appropriate
for a significant reduction in CRC incidence and mortality.[23]
[24] In turn, tubular adenomas evolve towards villous adenomas over time, in the adenoma-cancer
sequence[8], which would also explain the percentage of tubular adenomas being significantly
higher in G1 and villous adenomas in G2, since they are currently diagnosed more efficiently
than before.
There were more patients with a history of CRC in G1. This is attributable to a greater
survival to the first tumor,[25] better diagnosis of the second cancer thanks to the follow-up programs,[26]
[27] and to a more advanced age, associated with increased life expectancy. These same
considerations can be applied for the history of other cancers, especially gynecological,[28] because their prevention and early diagnosis are subject to campaigns in health
catchment areas such as the University Hospital Ramon and Cajal.
Regarding the detection of patients with relatives who had cancer, which established
them as an intermediate high-risk population, the rates were superior in G2. We could
attribute this to the greater implication in the anamnesis thirty years ago, before
the technological improvements. It may be paradoxical, since there is a constant oncological
significance in that subjects with relatives with a history of cancer are more likely
to develop CRC than the average population.[29]
Recently, the advance of science has uncovered certain hereditary factors, the so-called
population groups with high incidence of CRC, from 10% to 15% and a spectrum that
can reach 100% in individuals with genetic mutations, such as familial adenomatous
polyposis (FAP).[30] However, if the early screening tests were only limited to these subjects, most
CRC would be over-looked.[31]
The localization of cancer in the ascending colon was higher in G1, and in the rectum
in G2, which is in accord with the tendency towards an increase in neoplasms in the
right colon,[19] to the detriment of the rectum, a fact that can be linked not only with a possible
change in the tumor biology per se, but with the fact that rectal tumors prevention
is simpler and more effective. Also, when performing an endoscopy, the rectal examination
is guaranteed while examinations of the right colon may be unsuccessful, being incomplete
in approximately 10% of cases. In Spain, there are 1.56 times more cancers of the
colon than the rectum.[6]
Colon cancer was more common in men in G1 than in G2. We do not have an explanation
for this. It might be linked with the broader epidemiology of colon and rectal cancer.[9]
Clinically, a change in bowel habits (CBH) was significantly more frequent in G2,
both as the first and main symptom, and also as the paraneoplastic syndrome. We do
not believe that this has a special exegesis, except for the result of more advanced
tumor stages in G2. Perhaps the frequency of these symptoms as the first and principal
also supports the claim that, in the historical series, the most commonly used initial
diagnostic test was fecal occult blood test (FOBT)[9]
[13] because it was more comfortable and faster back then.
What is noteworthy is the difference in the reduction of the mean time to CRC diagnosis
in G1, when compared with G2, since the appearance of the first symptoms, 2 versus
6.5 months, respectively. Although, due to the sample size, no statical significance
can be established. Regarding the tumor location, in G1 this interval was greater
for tumors in the transverse and right colon, at 3.1 and 2.2, respectively, which
may justify patient non-compliance with the CBH, whose diagnostic time interval was
also greater, such as the first symptoms in G1 at 2.3 and G2 at 8.6 months. In this
regard, it is important that awareness programs not only talk about lower gastrointestinal
bleeding (LGIB), but also about CBH without apparent cause, and asthenia with anemia,
which are symptoms of a neoplastic pathology of the colon requiring medical consultation.
In G2, the diagnostic time was longer for rectal tumors and transverse colon tumors,
at 8.3 and 6 months, respectively. This delay, especially when the first and main
symptom was rectal bleeding, could explain doctors' common misinterpretation of the
diagnosis as hemorrhoids, with a rectal examination being discounted without further
study. Therefore, bleeding or other symptoms were added.[9] Likewise, the age in both groups was higher as the decades advanced.
In the extension of the disease, according to the Dukes classification,[32]
[33] in G1 the most frequent stage was Dukes A and in G2 it was D. That is to say, in
more than three decades, the figures for local disease and metastasized disease have
been inverted. Although part of this result can be ascribed to the use of neoadjuvant
therapy[17]
[18] in rectal cancers of G1, and the frequencies according to location, as rectum cancer
was more frequent in G2, it does not sufficiently clarify this difference, and it
remains a fact that the percentage of local disease is associated with an earlier
diagnosis,[15] and to the advances in medical practice itself. This fact corroborates the Dukes
stage D percentages in each group, as they are not adulterated by any previous procedure.
Regarding the anatomical-pathological quality, the number of nodes examined was significantly
higher in G1, although in G2 it was above 12, which is the minimum number for optimal
staging.[19]
[34]
Finally, the surgical treatment revealed that, although the percentage of operability
showed no differences, the percentage of resectability with negative margin (R0) was
significantly higher in G1.
In conclusion, this is a study of CRC, a malignant disease with high prevalence and
mortality in Spain, comparing two series of patients from the same catchment area
and separated by more than three decades, revealing interesting differences that favor
the current period. Regarding the identification of risk groups for this neoplasm,
in order to establish prevention programs, this study reveals that it is necessary
to implant prevention programs because of diagnosis in earlier stages of disease,
to increase the percentage of surgical treatment with a curative intent and subsequent
improvement in prognosis.
