Changing trends in colorectal cancer: possible cause and clinical implications

doi:10.4236/health.2010.28127

Paper Menu >>

Journal Menu >>

Vol.2, No.8, 842-849 (2010)

doi:10.4236/health.2010.28127

HEALTH

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.

ABSTRACT

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

1. INTRODUCTION

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

843

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.

2. METHODS

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.

3. RESULTS

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

844

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

2006-2007

Both

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

2006-2007

Male/Female

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).

Age

(years) Total Females Males

T3/T4 stage

< 55 18.5

(11.7-27.1)

25.0

(13.6-39.6)

13.3

(5.9-24.6)

< 60 32.4

(23.7-42.1)

35.4

(22.2-50.5)

30.0

(18.8-43.2)

N1/N2

< 55 25.0

(14.4-38.4)

34.6

(17.2-55.7)

16.7

(5.6-34.7)

< 60 35.7

(23.4-49.6)

42.3

(23.4-63.1)

30.0

(14.7-49.4)

Poor Differentiation

< 55 29.0

(14.2-48.0)

33.3

(13.3-59.0)

23.1

(5.0-53.8)

< 60 38.7

(21.8-57.8)

44.4

(21.5-69.2)

30.8

(9.1-61.4)

M. Fisher et al. / HEALTH 2 (2010) 842-849

845

Openly accessible at

ColonSigmoid RectumTotalColonSigmoid RectumTotalAll

Patients

Females Males

<60years ofage

***

*** ***

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)

2000

2003

2006/7

Figure 2. Age-distribution patterns of CRC in females in Aus-

tralia in 2000 and 2003 and in our series 2006-2007.

200

400

600

800

1000

1200

Numberofprescriptions

Australia

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

846

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].

4. DISCUSSION

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

considered.

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-

tions.

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

847

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 use－time of initiation (?

menopause) and duration (? 5-6 years) of therapy－to

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.

5. CONCLUSIONS

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.

REFERENCES

[1] Australian Institute of Health and Welfare (AIHW) and

Australasian Association of Cancer Registries (AACR).

(2007) Cancer in Australia: An overview 2006. Cancer

Series, AIHW, Canberra, 2007, 37.

[2] Chu, K.C., Tarone, R.E., Chow, W.H., Hankey, B.F. and

Ries, L.A. (1994) Temporal patterns in colorectal cancer

incidence, survival and mortality from 1950 through

1990. Journal of the National Cancer Institute, 86(13),

997-1006.

[3] Nelson, R.L., Persky, V. and Turyk, M. (1999) Determi-

nation of factors responsible for the declining incidence

of colorectal cancer. Diseases of the Colon & Rectum,

42(6), 741-752.

[4] Boyle, P. and Leon, M.E. (2002) Epidemiology of colo-

rectal cancer. British Medical Bulletin, 64, 1-25.

[5] Rabeneck, L., El-Serag, H.B., Davila, J.A. and Sandler, R.

S. (2003) Outcomes of colorectal cancer in the United

States: no change in survival (1986-1997). American

Journal of Gastroenterology, 98(2), 471-477.

[6] Gupta, A. K., Melton, L.J., Petersen, G.M., Timmons, L.

J., Vege, S.S., Harmsen, W.S., Diehl, N.N., Zinsmeister,

A.R. and Ahlquist, D.A. (2005) Changing trends in the

incidence, stage, survival, and screen-detection of colo-

rectal cancer: A population-based study. Clinical Gas-

troenterology and Hepatology, 3(2), 150-158.

[7] Cress, R.D., Morris, C., Ellison, G.L. and Goodman, M. T.

(2006) Secular changes in colorectal cancer incidence by

subsite, stage at diagnosis, and race/ethnicity, 1992- 2001.

Cancer, 107(5), 1142-1152.

[8] Koo, J. H., Jalaludin, B., Wong, S.K., Kneebone, A.,

Connor, S.J. and Leong, R.W. (2008) Improved survival

in young women with colorectal cancer. American Jour-

nal of Gastroenterology, 103(6), 1488-1495.

[9] Singh, H., Demers, A.A., Xue, L., Turner, D. and Bern-

stein, C.N. (2008) Time trends in colon cancer incidence

and distribution and lower gastrointestinal endoscopy

M. Fisher et al. / HEALTH 2 (2010) 842-849

848

utilization in Manitoba. American Journal of Gastroen-

terology, 103(5), 1249-1256.

[10] Wu, X., Cokkinides, V., Chen, V.W., Nadel, M., Ren, Y.,

Martin, J. and Ellison, G.L. (2006) Associations of sub-

site-specific colorectal cancer incidence rates and stage

of disease at diagnosis with county-level poverty, by race

and sex. Cancer, 107(5), 1121-1127.

[11] Liang, W. (2007) Age, sex and the risk of grade-specific

second primary colorectal cancer: Evidence for the pro-

tective effect of female hormone. European Journal of

Cancer, 43(12), 1856-1861.

[12] Ferlay, J., Autier, P., Boniol, M., Heanue, M., Colombet,

M. and Boyle, P. (2007) Estimates of the cancer inci-

dence and mortality in Europe in 2006. Annals of On-

cology, 18(3), 581-592.

[13] Crandall, C.J. (1999) Estrogen replacement therapy and

colon cancer: A clinical review. Journal of Women's

Health and Gender-Based Medicine, 8(9), 1155-1166.

[14] Paganini-Hill, A. (1999) Estrogen replacement therapy

and colorectal cancer risk in elderly women. Diseases of

the Colon & Rectum, 42(10), 1300-1305.

[15] Nanda, K., Bastian, L.A., Hasselblad, V. and Simel, D.L.

(1999) Hormone replacement therapy and the risk of co-

lorectal cancer: A meta-analysis. Obstetrics & Gynecol-

ogy, 93(5), 880-888.

[16] Di Leo, A., Messa, C., Cavallini, A. and Linsalata, M.

(2001) Estrogens and colorectal cancer. Current Drug

Targets

－

Immune, Endocrine & Metabolic Disorders,

1(1), 1-12.

[17] Gambacciani, M., Monteleone, P., Sacco, A. and Genaz-

zani, A.R. (2003) Hormone replacement therapy and en-

dometrial, ovarian and colorectal cancer. Best Practice &

Research Clinical Endocrinology & Metabolism, 17(1),

139-147.

[18] Hoffmeister, M., Raum, E., Krtschil, A., Chang-Claude, J.

and Brenner, H. (2009) No evidence for variation in co-

lorectal cancer risk associated with different types of

postmenopausal hormone therapy. Clinical Pharmacol-

ogy & Therapeutics, 86(4), 416-424.

[19] Grodstein, F., Newcomb, P.A. and Stampfer, M.J. (1999)

Postmenopausal hormone therapy and the risk of colo-

rectal cancer: A review and meta-analysis. American

Journal of Medicine, 106(5), 574-582.

[20] Chlebowski, R.T., Wactawski-Wende, J., Ritenbaugh, C.,

Hubbell, F.A., Ascensao, J., Rodabough, R.J., Rosenberg,

C.A., Taylor, V.M., Harris, R., Chen, C., Adams-Campbell,

L.L. and White, E. (2004) Estrogen plus progestin and

colorectal cancer in postmenopausal women. The New

England Journal of Medicine, 350(10), 991-1004.

[21] Nelson, H.D., Humphrey, L.L., Nygren, P., Teutsch, S.M.

and Allan, J.D. (2002) Postmenopausal hormone re-

placement therapy: Scientific review. JAMA, 288(7),

872-881.

[22] Canfell, K., Banks, E., Moa, A.M. and Beral, V. (2008)

Decrease in breast cancer incidence following a rapid fall

in use of hormone replacement therapy in Australia.

Medical Journal of Australia, 188(11), 641-644.

[23] Lindblom, A. (2001) Different mechanisms in the tu-

morigenesis of proximal and distal colon cancers. Cur-

rent Opinion in Oncology, 13(1), 63-69.

[24] Cheng, X., Chen, V.W., Steele, B., Ruiz, B., Fulton, J.,

Liu, L., Carozza, S.E. and Greenlee, R. (2001) Sub-

site-specific incidence rate and stage of disease in colo-

rectal cancer by race, gender, and age group in the United

States, 1992-1997. Cancer, 92(10), 2547-2554.

[25] Iacopetta, B. (2002) Are there two sides to colorectal

cancer? International Journal of Cancer, 101(5), 403-

408.

[26] Giovannucci, E., Pollak, M., Liu, Y., Platz, E.A., Majeed,

N., Rimm, E.B. and Willett, W.C. (2003) Nutritional pre-

dictors of insulin-like growth factor I and their relation-

ships to cancer in men. Cancer Epidemiology, Bio-

markers & Prevention, 12(2), 84-89.

[27] Matanoski, G., Tao, X.G., Almon, L., Adade, A.A. and

Davies-Cole, J.O. (2006) Demographics and tumor char-

acteristics of colorectal cancers in the United States,

1998-2001. Cancer, 107(5), 1112-1120.

[28] Azzoni, C., Bottarelli, L., Campanini, N., Di Cola, G.,

Bader, G., Mazzeo, A., Salvemini, C., Morari, S., Di

Mauro, D., Donadei, E., Roncoroni, L., Bordi, C., and Sarli,

L. (2007) Distinct molecular patterns based on proximal

and distal sporadic colorectal cancer: Arguments for dif-

ferent mechanisms in the tumorigenesis. International

Journal of Colorectal Disease, 22(2), 115-126.

[29] Leopoldo, S., Lorena, B., Cinzia, A., Gabriella, D.C.,

Angela Luciana, B., Renato, C., Antonio, M., Carlo, S.,

Cristina, P., Stefano, C., Maurizio, T., Luigi, R., and Ce-

sare, B. (2008) Two subtypes of mucinous adenocarci-

noma of the colorectum: clinicopathological and genetic

features. Annals Of Surgical Oncology, 15(5), 1429-

1439.

[30] Cho, E., Smith-Warner, S.A., Ritz, J., van den Brandt,

P.A., Colditz, G.A., Folsom, A.R., Freudenheim, J.L.,

Giovannucci, E., Goldbohm, R.A., Graham, S., Holm-

berg, L., Kim, D.H., Malila, N., Miller, A.B., Pietinen, P.,

Rohan, T.E., Sellers, T.A., Speizer, F.E., Willett, W.C.,

Wolk, A., and Hunter, D.J. (2004) Alcohol intake and

colorectal cancer: a pooled analysis of 8 cohort studies.

Annals of Internal Medicine, 140(8), 603-613.

[31] Moskal, A., Norat, T., Ferrari, P. and Riboli, E. (2007)

Alcohol intake and colorectal cancer risk: A dose-

response meta-analysis of published cohort studies. In-

ternational Journal of Cancer, 120(3), 664-671.

[32] Shrubsole, M.J., Wu, H., Ness, R.M., Shyr, Y., Smalley,

W.E. and Zheng, W. (2008) Alcohol drinking, cigarette

smoking, and risk of colorectal adenomatous and hyper-

plastic polyps. American Journal of Epidemiology,

167(9), 1050-1058.

[33] Smalley, W., Ray, W.A., Daugherty, J. and Griffin, M.R.

(1999) Use of nonsteroidal anti-inflammatory drugs and

incidence of colorectal cancer: A population-based study.

Archives of Internal Medicine, 159(2), 161-166.

[34] Rostom, A., Dube, C., Lewin, G., Tsertsvadze, A., Bar-

rowman, N., Code, C., Sampson, M. and Moher, D.

(2007) Nonsteroidal anti-inflammatory drugs and cyclo-

oxygenase-2 inhibitors for primary prevention of colo-

rectal cancer: A systematic review prepared for the U.S.

Preventive Services Task Force. Annals of Internal

Medicine, 146(5), 376-389.

[35] Dube, C., Rostom, A., Lewin, G., Tsertsvadze, A., Bar-

rowman, N., Code, C., Sampson, M. and Moher, D.

(2007) The use of aspirin for primary prevention of co-

lorectal cancer: a systematic review prepared for the U.S.

Preventive Services Task Force. Annals of Internal

M. Fisher et al. / HEALTH 2 (2010) 842-849

849

Medicine, 146(5), 365-375.

[36] Hebert-Croteau, N. (1998) A meta-analysis of hormone

replacement therapy and colon cancer in women. Cancer

Epidemiology, Biomarkers & Prevention, 7(8), 653-659.

[37] Prihartono, N., Palmer, J.R., Louik, C., Shapiro, S. and

Rosenberg, L. (2000) A case-control study of use of

postmenopausal female hormone supplements in relation

to the risk of large bowel cancer. Cancer Epidemiology,

Biomarkers & Prevention, 9(4), 443-447.

[38] Nichols, H.B., Trentham-Dietz, A., Hampton, J.M. and

Newcomb, P.A. (2005) Oral contraceptive use, reproduc-

tive factors, and colorectal cancer risk: Findings from

Wisconsin. Cancer Epidemiology, Biomarkers & Preven-

tion, 14(5), 1212-1218.

[39] Murff, H.J., Shrubsole, M.J., Smalley, W.E., Wu, H.,

Shyr, Y., Ness, R.M. and Zheng, W. (2007) The interac-

tion of age and hormone replacement therapy on colon

adenoma risk. Cancer Detection and Prevention, 31(2),

161-165.

[40] Kennelly, R., Kavanagh, D.O., Hogan, A.M. and Winter,

D.C. (2008) Oestrogen and the colon: Potential mecha-

nisms for cancer prevention. Lancet Oncology, 9(4), 385-

391.

[41] Rizk, D.E., Helal, T.E., Mason, N. and Berg, B. (1998)

Non-evidence of estrogen receptors in the rectal mucosa.

International Urogynecology Journal and Pelvic Floor

Dysfunction, 9(3), 136-139.

[42] Konstantinopoulos, P.A., Kominea, A., Vandoros, G.,

Sykiotis, G.P., Andricopoulos, P., Varakis, I., Sotiropou-

lou-Bonikou, G. and Papavassiliou, A.G. (2003) Oestro-

gen receptor beta (ERbeta) is abundantly expressed in

normal colonic mucosa, but declines in colon adenocar-

cinoma paralleling the tumour's dedifferentiation. Euro-

pean Journal of Cancer, 39(9), 1251-1258.

[43] Heiss, G., Wallace, R., Anderson, G.L., Aragaki, A., Bere-

sford, S.A., Brzyski, R., Chlebowski, R.T., Gass, M.,

LaCroix, A., Manson, J.E., Prentice, R.L., Rossouw, J.

and Stefanick, M.L. (2008) Health risks and benefits 3

years after stopping randomized treatment with estrogen

and progestin. JAMA, 299(9), 1036-1045.

[44] Chan, J.A., Meyerhardt, J.A., Chan, A.T., Giovannucci, E.

L., Colditz, G.A. and Fuchs, C.S. (2006) Hormone re-

placement therapy and survival after colorectal cancer

diagnosis. Journal of Clinical Oncology, 24(36), 5680-

5686.

[45] Clarke, C.A. and Glaser, S.L. (2007) Declines in breast

cancer after the WHI: Apparent impact of hormone ther-

apy. Cancer Causes Control, 18(8), 847-852.

[46] Ravdin, P.M., Cronin, K.A., Howlader, N., Berg, C.D.,

Chlebowski, R.T., Feuer, E.J., Edwards, B.K. and Berry,

D.A. (2007) The decrease in breast-cancer incidence in

2003 in the United States. The New England Journal of

Medicine, 356(16), 1670-1674.

[47] Wada-Hiraike, O., Warner, M. and Gustafsson, J.A. (2006)

New developments in oestrogen signalling in colonic

epithelium. Biochemical Society Transactions, 34(6),

1114-1116.

[48] Foley, E.F., Jazaeri, A.A., Shupnik, M.A., Jazaeri, O. and

Rice, L.W. (2000) Selective loss of estrogen receptor beta

in malignant human colon. Cancer Research, 60(2), 245-

248.

[49] Jassam, N., Bell, S.M., Speirs, V. and Quirke, P. (2005)

Loss of expression of oestrogen receptor beta in colon

cancer and its association with Dukes' staging. Oncology

Reports, 14(1), 17-21.

[50] Di Leo, A., Barone, M., Maiorano, E., Tanzi, S., Piscitelli,

D., Marangi, S., Lofano, K., Ierardi, E., Principi, M. and

Francavilla, A. (2008) ER-beta expression in large bowel

adenomas: implications in colon carcinogenesis. Diges-

tive and Liver Disease, 40(4), 260-266.

[51] Issa, J.P., Ottaviano, Y.L., Celano, P., Hamilton, S.R.,

Davidson, N.E. and Baylin, S.B. (1994) Methylation of

the oestrogen receptor CpG island links ageing and neo-

plasia in human colon. Nature Genetics, 7(4), 536-540.

[52] McMichael, A.J. and Potter, J.D. (1980) Reproduction,

endogenous and exogenous sex hormones, and colon

cancer: A review and hypothesis. Journal of the National

Cancer Institute, 65(6), 1201-1207.

[53] Alberts, D. S., Martinez, M.E., Hess, L.M., Einspahr, J.G.,

Green, S. B., Bhattacharyya, A. K., Guillen, J., Krutzsch,

M., Batta, A. K., Salen, G., Fales, L., Koonce, K., Parish,

D., Clouser, M., Roe, D., and Lance, P. (2005) Phase III

trial of ursodeoxycholic acid to prevent colorectal ade-

noma recurrence. Journal of the National Cancer Insti-

tute, 97(11), 846-853.

[54] Saydah, S.H., Platz, E.A., Rifai, N., Pollak, M.N., Bran-

cati, F.L. and Helzlsouer, K.J. (2003) Association of

markers of insulin and glucose control with subsequent

colorectal cancer risk. Cancer Epidemiology, Biomarkers

& Prevention, 12(5), 412-418.

[55] Adlercreutz, H. (2002) Phyto-oestrogens and cancer. Lan-

cet Oncology, 3(6), 364-373.

[56] Hogan, A.M., Collins, D., Sheehan, K., Zierau, O., Baird,

A.W. and Winter, D.C. (2010) Rapid effects of phytoes-

trogens on human colonic smooth muscle are mediated

by oestrogen receptor beta. Molecular and Cellular En-

docrinology, 320(1-2), 106-110.

[57] Hedelin, M., Lof, M., Olsson, M., Adlercreutz, H., Sandin,

S. and Weiderpass, E. (2008) Dietary phytoestrogens are

not associated with risk of overall breast cancer but diets

rich in coumestrol are inversely associated with risk of

estrogen receptor and progesterone receptor negative

breast tumors in Swedish women. Journal of Nutrition,

138(5), 938-945.

[58] Rossouw, J.E., Prentice, R.L., Manson, J.E., Wu, L.,

Barad, D., Barnabei, V.M., Ko, M., LaCroix, A.Z., Mar-

golis, K.L. and Stefanick, M.L. (2007) Postmenopausal

hormone therapy and risk of cardiovascular disease by

age and years since menopause. JAMA, 297(13), 1465-

1477.

[59] Stefanick, M.L., Anderson, G.L., Margolis, K.L., Hendrix,

S.L., Rodabough, R.J., Paskett, E.D., Lane, D.S., Hubbell,

F.A., Assaf, A.R., Sarto, G.E., Schenken, R.S., Yasmeen,

S., Lessin, L. and Chlebowski, R.T. (2006) Effects of

conjugated equine estrogens on breast cancer and mam-

mography screening in postmenopausal women with

hysterectomy. JAMA, 295(14), 1647-1657.