Vol.2, No.8, 842-849 (2010)
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/NS/
Changing trends in colorectal cancer: possible cause
and clinical implications
Mikhail Fisher1, Leon Fisher2, Bruce Waxman1, Alexander A. Fisher3*
1Academic Surgical Unit, Monash University, Dandenong Hospital, Southern Health, Melbourne, Australia
2Department of Gastroenterology, Peninsula Health, Frankston, Australia
3Division of Medicine, The Canberra Hospital and Australian National University Medical School, Canberra, Australia;
*Corresponding Author: alex.fisher@act.gov.au
Received 18 April 2010; revised 4 May 2010; accepted 6 May 2010.
OBJECTIVES: The aims of this study were to
determine whether pattern of patients present-
ing with colorectal cancer (CRC) in the last few
years differs significantly from that previously
reported in Australia, and to relate the trends, if
present, to use of hormone replacement therapy
(HRT). METHODS: We examined demographic
and pathological characteristics of 145 con-
secutive CRC patients (65 females) treated in
our institution in calendar years 2006-2007.
Comparisons were made with data on 12536
CRC patients obtained from the Australian As-
sociation on Cancer Registries (AACR) for the
year 2003, most recent available. Prescribing
data for HRT were obtained from the Australian
Commonwealth Department of Health and Age-
ing. RESULTS: The distribution of colon, sig-
moid and rectal cancers in our series was 40%,
24.8% and 35.2%, respectively, which differs
significantly from 65%, 8.1% and 26.9% in the
AACR data (p < 0.01). Our cohort was signifi-
cantly younger (65.4 ± 12.1 vs. 69.5 ± 12.3 years),
especially females (63.0 ± 12.7 vs. 70.3 ± 13.0
years; p < 0.001). The proportion of female pa-
tients aged < 55 and < 60 years was significantly
higher (30.8% vs. 13.8% and 41.5% vs. 21.4%,
respectively). Younger patients have more ag-
gressive and advanced cancers. In Australia
HRT use declined since 2001 and fell by a half in
2006. CONCLUSIONS: In the changing CRC pat-
tern of greatest concern is a significantly higher
proportion of younger patients, especially fe-
males, with higher prevalence of more ad-
vanced and aggressive cancers, coincident with
decreased prescribing of HRT. These findings
may have important implications for refining
screening and preventive strategies and on
demand for radiotherapy services.
Keywords: Colorectal Cancer; Age; Gender;
Hormone Replacement Therapy; Trends
Colorectal cancer (CRC) is the most prevalent non-skin
malignancy and second highest cause of cancer-related
death in Australia [1] as in other industrialized countries.
The incidence and mortality increase with age and the
risk of being diagnosed with CRC by age 85 years is one
in 10 for males and one in 14 for females [1]. In the last
two decades a decline in incidence and mortality rates
for CRC has been observed in most developed countries
including Australia [2-9]. The reasons for this trend may
include risk factors modification, introduction of scree-
ning and improvements in medical intervention.
The characteristics of CRC vary significantly with age,
gender, race/ethnicity and region of residence [7,10-12].
The causes for these differences, genetic, environmental
or acquired, are not fully understood. Numerous epide-
miological studies have suggested a protective effect of
estrogens (alone or in combination with progestins) against
CRC [13-18]. A meta-analysis of 18 observational stud-
ies of CRC and use of hormone replacement therapy
(HRT) indicated a 34% reduction among current users
and a 20% reduction among ever users [19]. Similar data
were reported in a large randomised controlled trial [20].
However, since the Women’s Health Initiative (WHI)
hormone trial demonstrated the risks of HRT (coronary
heart disease, stroke, breast cancer, venous thromboem-
bolism, cholecystitis), a sharp decline in the use of HRT
has been seen over the last few years [21]. No study to
date has addressed possible effects of reduced HRT use
on CRC trends.
M. Fisher et al. / HEALTH 2 (2010) 842-849
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In Australia, following a pilot program, national CRC
screening program for people between 55 and 74 years
of age is currently being phased in. However, the evi-
dence in relation to target age is insufficient.
Better understanding of risk factors and regional
trends, especially in relation to age, gender and ana-
tomical site may prove invaluable in fine-tuning screen-
ing, providing better services and, perhaps, contribute to
development of new preventative strategies. The pur-
poses of the present study were 1) to determine whether
pattern of patients presented with CRC to our institution
in the last 2 years differs significantly from that previ-
ously reported in Australia in regard to age, gender, ana-
tomical site, histopathology and TNM stage, and 2) to
relate the trends, if present, to use of HRT.
Study population consisted of 145 consecutive CRC
patients (age ranged from 34 to 85 years, mean 65.4 ±
12.13 years) treated in calendar years 2006 and 2007 in
the Dandenong Hospital, a major public teaching hospi-
tal. The patients were admitted from a catchment area of
approximately 360,000 inhabitants. The information
collected included patient demographics, stage, grade
and anatomical site of the cancer. The sites of CRC were
determined from the surgical description and the pa-
thology report and classified according to the Interna-
tional Statistical Classification of Diseases (ICD) 10th
revision. In order to compare results with previous re-
ports three subsites were defined and analyzed: colon
(the caecum, ascending colon, hepatic flexure, transverse
colon, splenic flexure and descending colon), sigmoid
colon (sigmoid and rectosigmoid junction) and rectum.
We used a broad definition to categorize the proximal
(descending colon and above), and distal segments of
colon because current data indicate that subsites within
sigmoid colon have characteristics similar to rectal-type
cancers rather than proximal-colon cancers.
TNM staging was based on the operative findings and
the histopathological report. Histological grade was re-
corded as well, moderately, or poorly differentiated.
Comparison data for Australia-wide patterns of CRC
were obtained from the Australian Association of Cancer
Registries (AACR) for the year 2003, most recent avail-
able. These included data on 12,536 CRC patients ana-
lyzed on the same lines as ours. Unfortunately, AACR
does not provide data concerning TNM staging. There-
fore, such analysis was performed for our study popula-
tion only.
To examine trends in HRT use data were obtained
from the Pharmaceutical Benefits Scheme and Repatria-
tion Pharmaceutical Benefits Scheme databases (Medi-
care Australia PBS Statistics), as well as from the annual
Australian statistics on medicines reports. The latter use
a combination of PBS data and survey data from a sam-
ple of community pharmacies.
For statistical evaluation data were presented as a
number of cases and percentages with 95% confidence
intervals (CI), chi-square and Fisher exact test were used
for statistical analysis of these. Quantitative normally
distributed data were expressed as means and standard
deviation (SD) and Student’s t-test was used for com-
paring mean values. Two-tailed P value was considered
significantly at < 0.05 level.
Of 145 patients with CRC admitted to our hospital in the
2 year period there were 65 (44.8%) females with a
mean age of 63.0 ± 12.7 years and 80 (55.2%) males
with a mean age of 67.3 ± 11.4 years. Colon cancer was
diagnosed in 58 patients (32 females), sigmoid in 36 (16
females) and rectal in 51 (17 females). In our series there
was a more distal distribution of CRC comparing with
that seen previously in the Australian population: the
proportion of rectal (35.2% vs 26.9%, p = 0.032) and
sigmoid cancers (24.8% vs 8.1%; p = 0.003) was sig-
nificantly higher and the proportion of colon cancers
(40% vs 65%, p = 0.001) was significantly lower. The
distal colon (sigmoid and rectal) was the most common
site of carcinomas contributing 55.9% of all cases
(50.8% in females and 67.5% in males). The ratio of
proximal to distal cancers was 0.67 in our series and
1.85 in the previous report.
The age-distribution pattern was similar in both stud-
ied periods with CRC rare before the age of 30, signifi-
cant increase after the age of 45 until 75-79 and decline
thereafter. But the 2006-2007 data revealed a marked
shift to the younger age most pronounced in females.
Our cohort overall was on average 4 years younger (p =
0.001), and the females were 7.3 years younger than
previously reported (p < 0.001) (Table 1). The difference
was statistically significant in females with colon and
rectal cancers, while no differences were observed in
males for any cancer site. In our series females with rec-
tal cancer were the youngest, they were on average 7.9
years younger than previously reported and 3.8 years
younger than males with rectal cancer.
The total male/female (M/F) ratio in our series was
the same as reported previously (1.23 and 1.21, respec-
tively). As indicated in Table 1, in both studied periods
the M/F ratio increased markedly from colon through the
rectum site. However, our series demonstrated that,
comparing with the previously described, the M/F ratio
was significantly lower in colon cancer patients (0.81 vs
M. Fisher et al. / HEALTH 2 (2010) 842-849
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Table 1. Comparison of mean age (years SD) of CRC patients in two studied periods by gender and site distribution of carcinomas.
Cancer Site
Period Gender All Patients
Colon Sigmoid Rectal
2003 70.3 13.01 71.4 12.56 67.7 13.09 67.8 13.83
2006-2007 Females 63.0 12.68*** 63.9 14.16***64.4 12.63 59.9 9.54***
2003-2004 68.8 11.56 69.9 11.27 67.7 10.92 66.9 11.42
2006-2007 Males 67.3 11.38 72.1 9.37 67.3 9.24 63.7 12.74
2003 69.5 12.26 70.6 11.97 67.7 11.91 67.2 12.68
Genders 65.4 12.13*** 67.6 12.82* 66.0 10.81 62.4 11.81***
2003 1.21 1.06 1.30 1.64
Ratio 1.23 0.81 1.25 2.00
*** p < 0.001, * p < 0.05
1.06) and higher in rectal cancer patients (2.00 vs 1.64),
indicating that the proportion of males with distal can-
cers is increasing. The ratio of proximal to distal cancers
in females was 0.97 in our series and 2.30 in the previ-
ous report and in males 0.48 and 1.57 respectively, again
suggesting a pronounced shift to distal cancer sites espe-
cially in males.
In our cohort, patients < 50 years of age comprised
12.4% (18.5% females and 7.5% males), < 55 years of
age 20.0% (30.8% and 11.3% respectively), < 60 years
of age 33.1% (41.5% and 26.3% respectively). In 2003
the corresponding figures were 6.9% (7.8% and 6.2%),
12.9% (13.8% and 12.3%) and 21.4% (21.2% and
21.7%). The proportions of younger patients with CRC
by gender and cancer site are given in Figure 1. In the
recent series the proportion of patients with CRC
younger than 50, 55 or 60 years of age was significantly
higher than previously reported due to a 2-fold increase
in the proportion of younger females with cancers at all
sites except sigmoid. In our cohort, among females with
colon cancer 31.3% were aged < 55 years and 37.5%
were aged < 60 years. Corresponding figures in the pre-
vious report were 11.6% and 17.9%. Similarly in our
series, among females with rectal cancer 35.3% were <
55 years of age and 64.7% were < 60 years of age, while
previously this has been observed only on 19.1% and
28.9, respectively.
The prevalence of advanced clinicopathological fea-
tures of CRC in our younger patients is presented in Ta-
ble 2. A significant proportion of patients with locally
advanced T3 and T4 cancers were younger than 55 years
of age (25% females and 13.3% males). Importantly,
most of patients < 55 years of age were in T3 and T4
categories (12 of 20 females and 8 of 9 men). This age
group contributed to 1/3 of all females and 1/5 of all
males with lymph nodes metastasis and/or poor differen-
tiation. The frequency of node metastasis was signifi-
cantly higher in females than in males. (p = 0.018). Sub-
jects younger than 60 years of age comprised from 1/3 to
about 1/2 of all patients with advanced and/or unfavor-
able CRC.
Figure 2 presents the proportion of females with CRC
in 5 year age groups in the recent series and in Australia
in 2000 and 2003. The age-distribution patterns in 2000
and 2003 were similar, while in 2006-2007 there was a
significant increase in proportion of females aged 45 to
59. This age group comprises the majority of women
who use HRT.
Figure 3 displays the combined number of prescrip-
tions for Premarin and Depo-premarin (most frequently
prescribed HRT drugs) in Australia and Victoria over a
10-year period (financial years 1997/8-2006/7). The
number of prescriptions peaked in 1999 and has declined
since 2001. In Australia the total number of prescriptions
for these drugs dropped in 2002 by 30.7% compared
with the previous year and by 54.1% in 2006; in Victoria
the corresponding figures were 32.4% and 55.4% re-
spectively. These data are comparable with 40% drop
in the number of total HRT prescriptions among conces-
Table 2. Proportion (%, 95% confidence interval) of younger
subjects among patients with advanced CRC (2006-2007).
(years) Total Females Males
T3/T4 stage
< 55 18.5
< 60 32.4
< 55 25.0
< 60 35.7
Poor Differentiation
< 55 29.0
< 60 38.7
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ColonSigmoid RectumTotalColonSigmoid RectumTotalAll
Females Males
<60years ofage
*** ***
Figure 1. Proportion (%) of younger patients with CRC in two study periods by
gender and cancer site. *** p < 0.001, ** p < 0.01.
Age (years)
Figure 2. Age-distribution patterns of CRC in females in Aus-
tralia in 2000 and 2003 and in our series 2006-2007.
Vi ctori a
Figure 3. Prescriptions for Premarin and Depo-provera (com-
bined data) in Australia and Victoria, 1997-2006.
M. Fisher et al. / HEALTH 2 (2010) 842-849
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sion cardholders in Australia from 2001 to 2003. In this
period a similar decline was observed in prescriptions for
estrogen-only preparations (39% decrease), and combined
estrogen-progestogen preparations (–41%) [22].
Our study indicates a change in pattern of CRC occur-
rence in 2006-2007. Compared with Australian data for
2003 our experience is of more distal cancers, greater
proportion of younger patients, especially females, with
high prevalence of more advanced and aggressive tu-
mors. Several potential explanations for the changes in
CRC characteristics observed in our study should be
Cancers of proximal and distal colon might differ in
their genetic nature, oncofetal antigen expression and
evolve through different pathways and may be associ-
ated with distinct risk factors [6,23-29]. Proximal tumors
compared to distal ones have a higher proportion of
DNA microsatellite instability cancers, are more com-
mon in women and older patients. Risk factors for these
include high intake of red meat and animal fat, low con-
sumption of vegetables and fiber, sedentary life style,
obesity and lower socioeconomic status. Alcohol con-
sumption and smoking [30-32], use of aspirin and non-
steroidal anti-inflammatory drugs (NSAID) [33-35] and
especially postmenopausal HRT use [15,19,20,36-40]
have also an important influence on CRC risk. Although
we cannot fully evaluate the possible effects of all the
mentioned risk factors for CRC, it seems unlikely that
considerable changes in dietary and lifestyle habits oc-
curred in our population between 2003 and 2006-2007.
However, one variable which may be relevant, namely, a
substantial reduction in HRT use, is obvious. In Australia
and Victoria after 2001 prescriptions of Premarin and
Depo-provera fell by a third in 2002 and by a half in
2006. A similar rapid and substantial drop in total HRT
prescriptions from 2001 to 2003 was reported in Austra-
lia and New Zealand [22]. Age and gender-related
changes in anatomical subsite CRC distribution observed
in our study may be attributed, at least in part, to reduced
HRT use after 2001. If hormonal factors protect against
CRC then the reduced use of HRT should be accompa-
nied by an increase in colon cancers in women during
early postmenopausal period, as HRT use is associated
mainly with reduced risk of colon cancer [14,15,20,
37,41]. Our experience is consistent with such expecta-
This study comparing with previous Australian data
clearly demonstrated three points: only females with
CRC were significantly younger (on average 7.5 years),
there was a substantial increase in proportion of females
aged 45 to 59 years who comprise the majority of HRT
users and the male predominance in colon cancer was
reversed (M/F ratio for colon cancer was 0.81 in 2006-
2007 whereas 1.06 in 2003). Notably, the majority of our
younger patients had aggressive and advanced CRC.
Previous studies indicated that decrease in estrogen level
after menopause increases the risk of a colon cancer with
poorer differentiation [11,42]. Our findings are in line
with the assumption of an approximate 3-5 year time lag
between decrease in HRT use and its impact on CRC
incidence rate [21,43,44]. In the Women’s Health Initia-
tive (WHI) trial the 38% lower risk of CRC observed in
women prescribed HRT during the trial phase disap-
peared within 3 years of discontinuing HRT [43].
Numerous epidemiological and experimental studies
suggested a favorable influence of HRT on CRC risk. It
was estimated that estrogens alone or in combination
with progestins reduce colon risk by 20-44% in post-
menopausal women, and the duration of HRT did not
influence risk estimates [19-21]. In the present study a
sharp drop in the HRT use after 2001 was associated
with 20.1% increase in the proportion of females < 60
years of age with CRC compared to the 2003 data. If this
association is causal a further increase in CRC female
patients should be expected. Of interest, the substantial
decrease in HRT use was associated with a decline of
breast cancer incidence in Australia, US and other coun-
tries [22,45,46]. The protective effects of estrogen on
colonic carcinogenesis are mediated predominately
through estrogen receptor β (ER-β) involving both ge-
nomic and non-genomic mechanisms [40]. ER-β-knock-
out mice demonstrate hyperproliferation, loss of differ-
entiation and disordered apoptosis of colonic mucosa, as
well as disorganization of mucin localization, reduction
in the number of hemidesmosomes and loss of tight
junctions of colonic epithelium [47], indicating that ER-
β plays a pivotal role in maintenance of cellular homeo-
stasis in the colon. ER-β is the dominant receptor in hu-
man colonic mucosa and seems to be essential for pre-
venting malignant transformation of colonic epithelial
cells. A significant reduction of ER-β expression has
been shown in colon adenocarcinoma cells and this cor-
related with tumor dedifferentiation, stage and grade
[42,48,49]. Moreover, in the pre-malignant phase of co-
lon carcinogenesis ER-β expression is also reduced and
inversely correlates with increase of proliferative activity
in the adenomatous tissue [50]. It has been shown pre-
viously that methylation associated inactivation of es-
trogen receptor gene in ageing colorectal mucosa is one
of the earliest events predisposing to cancerogenesis [51].
Other postulated mechanisms by which HRT use might
reduce CRC risk include the influence of estrogens on
bile acids [52,53], insulin and glucose control [54].
M. Fisher et al. / HEALTH 2 (2010) 842-849
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Openly accessible at
Our findings may have important practical implica-
tions for present and future screening strategies, treat-
ment and prevention of CRC. Early diagnosis of CRC
could improve survival. Currently CRC screening in
Australia is advocated for people aged 55 and older.
However, in our series patients younger than 55 years
comprise 20% (females 31%, males 11%), suggesting
that the optimal cut-off age for screening needs to be
reviewed. Although we observed a distal shift of CRCs,
in 40% of our patients (in 49.8% of females and in
30.6% of males) the cancers were located above the
sigmoid colon. These tumors will be missed if sigmoi-
doscopy (not total colonoscopy) is chosen as the screen-
ing technique. The significant and rising number of rec-
tal cancers (35.2% in total, 26.2% in females and 42.5%
in males) is likely to increase demand for radiotherapy
services. The observed association between the changing
age and subsite patterns of CRC in females and the drop
in HRT use in the context of current data on estrogen
effects on growth, differentiation and functioning of
epithelial cells in the colon and the protective role of
estrogen in CRC may stimulate research of novel pre-
ventive and therapeutic approaches such as development
of selective ER-β agonists. At present, the well estab-
lished risks of traditional HRT [21] preclude its use to
reduce the CRC in postmenopausal women [20]. How-
ever consumption of soy products and dietary fiber
which are high in phyto-estrogens demonstrate a protec-
tive effect in CRC [55,56] and are not associated with
breast cancer [57]. Of note, the re-analysis of the WHI
data showed that women who started estrogen therapy at
the age of 50-59 years and continued it for 6-7 years did
not have an increased risk of coronary heart disease
[58],and have a decreased risk of early-stage breast can-
cer and a decreased risk of ductal carcinomas when com-
pared with placebo treated women, although the risk of
stroke in the estrogen group was non-significantly ele-
vated [59]. These data together with significantly de-
creased incidence of colon cancer and fractures with
long-term HRT use indicate the potential benefits of HRT.
However, additional large controlled studies are needed to
find definitive criteria for HRT usetime of initiation (?
menopause) and duration (? 5-6 years) of therapyto
have beneficial effects on women’s health, including pro-
tection against CRC and to avoid adverse effect.
Some limitations of this study warrant consideration.
Our study was a single hospital-based. We were not able
to calculate true incidence rates and therefore the com-
parisons with previous report were performed using
proportions of CRC patients in age and subsite catego-
ries. The observation that sharp decrease in HRT use was
followed by changes in CRC patterns in females does
not establish causal relationship between the two, but
provides a logical explanation and is of importance to
public health.
Our series of CRCs in 2006-2007 show important age-,
gender- and subsite-related changed in CRC patterns
compared with those seen in the Australian population
previously (2003). Of greatest concern is a significantly
higher proportion of patients aged < 55 and < 60 years of
age (20% and 33% respectively), especially females
(31% and 41.5%). Furthermore, there were more female
patients with colon cancer and younger patients were
more likely to have more advanced and aggressive can-
cers. These findings seem to be temporally, and possibly
causatively, related to decrease in HRT use and may
have significant implications for effective screening
strategies, provision of radiotherapy services and further
research in CRC pathogenesis and prevention.
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