I. Introduction

Colorectal cancer is the second malignancy in frequency among Uruguayan population (Parkin et al, 2002). Age-standardized incidence rates (ASIR) are of 36.1 per 100,000 men and 25.7 per 100,000 women (Parkin et al, 1997). Moreover, in international comparisons among Latin American registries, Uruguayan rates occupy the first place, both in men and women (Parkin et al, 2002).

According to several reviews (Potter, 1996; World Cancer Research Fund, 1997), diet is probably the major risk factor in colorectal cancer. In particular, high consumption of red meat and fat and low intake of vegetables and fruits are strongly associated with high risk of colorectal cancer (Potter, 1996; World Cancer Research Fund, 1997). Uruguayan population is characterized by high consumption of red meat and low consumption of plant foods (Comisi½n Honoraria de Lucha contra el C΅ncer, 1993; Matos and Brandani, 2002). This dietary pattern is probably responsible for the high rates observed in Uruguay. Thus, Uruguay is a rather convenient country to perform observational studies.

Most case-control studies reported an increased risk of colorectal cancer associated with high consumption of meat, particularly red meat (Manousos et al, 1983; Marchand et al, 1997; La Vecchia et al, 1988; Tuyns et al, 1988; Benito et al, 1990; Gerhardsson de Verdier et al, 1991). Nevertheless, some prospective studies failed to confirm this effect (Phillips and Snowdon, 1985; Bostick et al, 1994; Goldbohm et al, 1994; Knekt et al, 1994). It has been suggested that recall bias could be responsible for this discrepancy between retrospective and prospective studies (Goldbohm et al, 1994). On the other hand, Potter has suggested that case-control studies have the advantage over prospective ones of a larger age range (Potter, 2000). This age range allowed both genetically and non-genetically participants in retrospective studies (Potter, 2000).

Taking into account this discrepancy and the dietary pattern observed in Uruguay, we decided to conduct a case-control study on the relationship between meat consumption and colorectal cancer risk in this high-risk area.

II. Material and methods

A. Selection of cases

In the time period 1996-2003, all newly diagnosed and microscopically confirmed adenocarcinomas of the colon and rectum were considered eligible for this study. Five thousand and sixty five patients so diagnosed were identified in the four major hospitals of Montevideo, Uruguay. Nine patients refused the interview, leaving a final total of 556 cases of colorectal carcinomas (response rate 98.4 %). Cases were distributed by sex as follows: men (330, 59.3 %) and women (226, 40.7 %). Concerning subsite, 69 patients presented lesions of the right colon (12.4 %), 222 showed tumors of the left colon (39.9 %) and 265 patients presented carcinomas of the rectum (47.7 %).

B. Selection of controls

In the same time period and in the same hospitals, 1375 patients hospitalized for non-neoplastic diseases were considered eligible for the study. These patients presented diseases not related with tobacco smoking, alcohol drinking and without recent changes in their diets. Nineteen patients refused the interview, leaving a final number of 1356 (response rate 98.6 %). From this pool of potential controls, 1112 patients were frequency matched to the cases on age (in ten-years intervals), sex and residence (Montevideo, other counties). These patients presented the following diseases: eye disorders (317 patients, 28.5 %), abdominal hernia (235, 21.1 %), skin diseases (95, 8.5 %), acute appendicitis (75, 6.7 %), varicose veins (82, 7.4 %), urinary stones (62, 5.6 %), injuries (81, 7.3 %), blood disorders (55, 4.9 %), hydatid cyst (57, 5.1 %), fractures (36, 3.2 %) and bone diseases (17, 1.5 %).

C. Questionnaire

All participants were interviewed face-to-face in the hospitals by two trained social workers. They were administered a questionnaire which included the following sections: sociodemographics, a complete occupational history based in jobs and their duration, self-reported height and weight five years before the date of the interview, family history of cancer in first-degree relatives, a complete tobacco smoking history, a complete alcohol drinking history, a complete maté drinking history (maté is the folk name of a herbal tea which is drunk every hot), menstrual and reproductive events and a food frequency questionnaire (FFQ) on 64 food items.This FFQ allowed the calculation of total energy intake and is considered as representative of the usual Uruguayan diet. Although it was not validated, it was tested for reproducibility with good results.

D. Definition of food groups

The following food groups were created: red meat (beef, lamb), white meat (poultry, fish), processed meat (bacon, sausage, blood pudding, mortadella, salami, saucisson, hot dog, ham, salted meat), total meat (red meat, white meat, processed meat, liver), dairy foods (cheese, butter, whole milk, ice cream), eggs (boiled eggs, fried eggs, mayonnaise), desserts (milk with sugar, rice pudding, custard, marmalade, cake), grains (white rice, maize, polenta, pasta, white bread), high-fat foods (red meat, processed meat, dairy foods, eggs, desserts), raw vegetables (carrot, tomato, lettuce, onion), cooked vegetables (garlic, swiss chard, spinach, potato, sweet potato, beetroot, winter squash, cabbage, cauliflower, zucchini, red pepper), total vegetables (raw vegetables, cooked vegetables), citrus fruits (orange, tangerine), other fruits (apple, pear, grape, peach, banana, plum, fig, fruit cocktail), total fruits (citrus fruits, other fruits), total vegetables and fruits (total vegetables, total fruits), all tubers (potato, sweet potato), legumes (chickpea, kidney bean, lentil). Also red meat was analyzed by the cooking method: fried, barbecued and boiled (stewed) red meat. Finally, estimation of heterocyclic amines exposure was calculated according to the method of Sinha and Rothman (1997).

D. Statistical analysis

Relative risks of colorectal cancer, approximated by the odds ratios (OR’s) and its corresponding ninety five per cent confidence intervals (95 % CI), were estimated by multiple unconditional logistic regression (Breslow and Day, 1980). Comparisons between colonic and rectal carcinomas were carried out by polytomous (multinomial) logistic regression (Hosmer and and Lemeshow, 1989). The basic model included terms for age (categorical, 6 strata), sex (ordinal), residence (ordinal), urban/rural status (ordinal), education (categorical, 3 strata), body mass index (categorical, 4 strata), tobacco smoking (categorical, 5 strata), alcohol drinking (categorical, 5 strata), total energy intake (continuous), total vegetables and fruits (categorical, 4 strata) and total fat intake (categorical). Tests for trend were performed after entering categorical variables as ordinal (continuous) in the same model. Departure from the multiplicative model was determined by assessing the likelihood ratio test statistic. An alpha of 0.05 was used as the indicator of statistical significance and, accordingly 95 % CI’s were reported. All p-values were derived from two-sided statistical tests. All the calculations were done with the STATA programme (1999).

III. Results

The distribution of cases and controls by sociodemographic variables and selected risk factors is shown in Table 1. As expected from the frequency matched design, age, sex and residence were rather similar. Also the percentage of cases living in rural areas was similar to the percentage of rural controls. Education and income were similar in both series of patients. The proportion of cases with family history of colon cancer was significantly higher compared with controls (OR 4.7, 95 % CI 2.1-10.6). The estimates were similar for each tumor subsite (results not shown). Body mass index was similar in both series of patients and total energy intake was slightly higher among controls compared with cases, but the differences were not significant. Finally, cases and controls smoked and drank alcohol in similar amounts.

Odds ratios of colorectal cancer for meat consumption in men are shown in Table 2. Beef consumption was positively associated with colon cancer risk (OR 3.4, 95 % CI 1.8-6.4). Similar estimates were observed for rectal cancer and for both tumor sites together (p-value for trend <0.0001). On the contrary, lamb intake was not associated with colorectal cancer risk. Red meat (beef plus lamb) was significantly associated with increased risk of colorectal adenocarcinoma (OR 3.1, 95 % CI 1.8-5.3, p-value for trend <0.0001). Poultry consumption was directly associated with rectal cancer risk, but the trend was only marginally significant (OR 1.5, 0.9-2.3, p-value for trend=0.07). Both colon cancer and colorectal cancer were not associated with poultry intake. Fish consumption, an uncommon item in the Uruguayan diet, was not associated with colorectal cancer risk. The same was observed for white meat consumption (poultry plus fish). Unexpectedly processed meat displayed an inverse association with colorectal

Table 1. Distribution of cases and controls by sociodemographic variables and selected risk factors.

			Cases			Controls
Variable	Category	NΦ		%	NΦ		%
Age (in years)	30-39	10		1.8	20		1.8
	40-49	47		8.4	94		8.4
	50-59	92		16.5	185		16.6
	60-69	179		32.2	358		32.2
	70-79	187		33.6	374		33.6
	80-89	41		7.4	81		7.3
Sex	Males	330		59.4	660		59.4
	Females	226		40.6	452		40.6
Residence	Montevideo	285		51.3	565		50.8
	Other counties	271		48.7	547		49.2
Urban/rural status	Urban	461		82.9	903		81.2
	Rural	95		17.1	209		18.8
Education (years)	0-2	141		25.4	307		27.6
	3-5	232		41.7	386		34.7
	6+	183		32.9	419		37.7
Income (US dollars)	<=140	220		39.6	449		40.4
	141+	228		41.0	442		39.7
	Missing	108		19.4	221		19.9
Family history of colon cancer	No	517		93.0	1090		98.0
	Yes	39		7.0	22		2.0
Body mass index	<=23.0	141		25.4	278		25.0
	23.1-25.3	142		25.5	288		25.9
	25.4-27.9	137		24.6	269		24.2
	28.0+	136		24.5	277		24.9
Total calories	<=1857	124		22.3	278		25.0
	1858-2283	144		25.9	278		25.0
	2284-2688	127		22.8	278		25.0
	2689+	167		29.0	278		25.0
Cigarettes per day	Never smokers	124		40.5	251		42.7
	1-9	30		9.8	56		9.5
	10-19	38		12.4	108		18.4
	20-29	59		19.3	92		15.6
	30+	55		18.0	81		13.8
Alcohol drinking	Never drinkers	163		53.3	319		54.2
	1-60	65		21.2	110		18.7
	61-120	37		12.1	71		12.1
	121-240	30		9.8	51		8.7
	241+	11		3.6	37		6.3
NΦ patients		556		100.0	1112		100.0

Table 2. Odds ratios of colorectal cancer for meat consumption in men¹.

			Colon			Rectum			Both sites
Meat variable (cutpoints)²	Colon/Rectum/Controls³	OR		95 % CI	OR		95 % CI	OR		95 % CI
Beef	24/34/199	1.0			1.0			1.0
208	51/61/212	2.1		1.2-3.8	1.8		1.3-2.9	1.9		1.3-2.9
365	76/84/249	3.4		1.5-4.5	2.6		1.9-4.6	2.9		1.9-4.6
	p-value trend	0.0001			0.001			<0.0001
Lamb	54/59/201	1.0			1.0			1.0
0	46/46/213	0.8		0.5-1.3	0.7		0.5-1.2	0.8		0.5-1.1
12	51/74/246	0.9		0.5-1.4	0.9		0.6-1.5	0.9		0.7-1.3
	p-value trend	0.59			0.94			0.52
Red meat	28/33/182	1.0			1.0			1.0
260	52/63/220	2.0		1.1-3.6	2.1		1.2-3.7	2.0		1.3-3.2
377	71/83/258	3.1		1.6-6.2	3.1		1.6-6.0	3.1		1.8-5.3
	p-value trend	0.001			0.001			<0.0001
Poultry	54/58/262	1.0			1.0			1.0
24	63/66/204	1.5		0.9-2.2	1.5		1.0-2.3	1.5		1.1-2.1
52	34/55/194	0.8		0.5-1.3	1.5		0.9-2.3	1.1		0.8-1.6
	p-value trend	0.60			0.07			0.35
Fish	50/56/254	1.0			1.0			1.0
12	57/67/211	1.2		0.8-1.9	1.4		0.9-2.2	1.3		0.9-1.9
52	44/56/195	1.0		0.6-1.6	1.3		0.8-1.9	1.1		0.8-1.6
	p-value trend	0.96			0.28			0.44
White meat	58/65/263	1.0			1.0			1.0
52	53/64/203	1.1		0.7-1.7	1.3		0.9-2.0	1.2		0.9-1.7
104	40/50/194	0.9		0.5-1.4	1.2		0.8-1.9	1.1		0.7-1.5
	p-value trend	0.71			0.31			0.63
Processed meat	50/62/199	1.0			1.0			1.0
70	51/56/219	0.8		0.5-1.2	0.8		0.5-1.2	0.8		0.6-1.1
182	50/61/242	0.7		0.4-1.1	0.7		0.5-1.1	0.7		0.5-1.0
	p-value trend	0.13			0.16			0.06
Total meat	34/48/197	1.0			1.0			1.0
481	51/48/218	1.4		0.8-2.4	0.9		0.5-1.5	1.1		0.7-1.7
682	66/83/245	1.7		0.9-3.0	1.5		0.9-2.6	1.6		1.0-2.4
	p-value trend	0.10			0.07			0.03

¹Adjusted for age, residence, urban/rural status, education, family history of colon cancer in first-degree relatives, body mass index, tobacco smoking, alcohol drinking, total energy intake, total fat and total vegetables and fruits.

²Cut-off points in servings per year.

³Number of cases of colon, rectum and number of controls.

Table 3. Odds ratios of colorectal cancer for meat consumption in women¹.

		Colon		Rectum		Both sites
Meat variable (cutpoints)²	Colon/Rectum/ Controls³	OR	95 % CI	OR	% CI	OR95	% CI
Beef	41/24/171	1.0		1.0		1.0
208	55/30/159	1.3	0.8-2.2	1.2	0.6-2.4	1.3	0.8-2.0
365	45/31/122	1.6	0.8-2.9	1.9	0.9-3.9	1.7	0.9-2.8
	p-value trend	0.15		0.06	0.05
Lamb	49/28/169	1.0		1.0		1.0
0	58/35/158	1.5	0.9-2.6	1.6	0.8-2.8	1.5	1.0-2.4
12	34/22/125	1.0	0.6-1.8	0.9	0.5-1.7	0.9	0.6-1.5
	p-value trend	0.98		0.76		0.85
Red meat	45/24/188	1.0		1.0		1.0
260	54/32/151	1.5	0.8-2.5	1.6	0.8-3.2	1.5	0.9-2.4
377	42/29/113	1.8	0.9-3.6	2.3	1.0-5.3	2.0	1.1-3.6
	p-value trend	0.13		0.03		0.01
Poultry	27/26/108	1.0		1.0		1.0
24	45/25/167	1.1	0.6-1.9	0.6	0.3-1.1	0.8	0.5-1.3
52	69/34/177	1.7	0.9-2.9	0.8	0.4-1.5	1.2	0.8-1.9
	p-value trend	0.03		0.65		0.21
Fish	41/29/116	1.0		1.0		1.0
12	55/26/160	1.1	0.7-1.9	0.7	0.4-1.3	0.9	0.6-1.5
52	45/30/176	0.8	0.5-1.4	0.7	0.4-1.3	0.8	0.5-1.2
	p-value trend	0.40		0.30		0.28
White meat	31/26/108	1.0		1.0		1.0
52	52/25/167	1.1	0.6-1.9	0.5	0.3-1.0	0.8	0.5-1.3
104	58/34/177	1.3	0.8-2.2	0.8	0.4-1.4	1.1	0.7-1.6
	p-value trend	0.29		0.69		0.63
Processed meat	46/30/171	1.0		1.0		1.0
70	45/23/152	0.9	0.6-1.6	0.8	0.4-1.4	0.9	0.6-1.4
182	50/32/129	1.4	0.9-2.4	1.3	0.7-2.4	1.4	0.9-2.1
	p-value trend	0.15		0.15		0.11
Total meat	40/23/173	1.0		1.0		1.0
481	57/33/153	1.7	1.0-2.8	1.5	0.8-2.9	1.6	1.1-2.5
682	44/29/126	1.8	0.9-3.3	1.7	0.8-3.5	1.7	1.1-2.9
	p-value trend	0.09		0.06		0.03

²Cut-off points in servings per year.

³Number of cases of colon, rectum and number of controls.

Table 4. Odds ratios of colorectal carcinoma for cooking method of red meat¹.

Males		Colon		Rectum		Both sites
Method (cutpoints)	Colon/Rectum/ Controls	OR	95 % CI	OR	95 % CI	OR	95 % CI
Fried ²	36/67/223	1.0		1.0		1.0
78	40/56/226	1.0	0.6-1.7	0.7	0.5-1.1	0.8	0.6-1.2
130	75/56/211	2.1	1.5-3.4	0.8	0.5-1.2	-
	p-value trend	0.001		0.28		-³
Barbecued	42/46/191	1.0		1.0		1.0
24	57/62/211	1.2	0.7-1.9	1.2	0.7-1.8	1.2	0.8-1.7
64	52/71/371	0.9	0.5-1.4	1.1	0.7-1.8	1.0	0.7-1.5
	p-value trend	0.47		0.59		0.93
Boiled	52/58/205	1.0		1.0		1.0
104	50/66/224	0.9	0.6-1.4	1.0	0.7-1.6	0.9	0.7-1.4
208	49/55/231	1.0	0.6-1.6	0.9	0.6-1.5	0.9	0.7-1.4
	p-value trend	0.96		0.93		0.98
Females		Colon		Rectum		Both sites
Method (cutpoints)²	Colon/Rectum /Controls	OR	95 % CI	OR	95 % CI	OR	95 % CI
Fried	43/34/147	1.0		1.0		1.0
78	48/25/145	0.9	0.6-1.5	0.6	0.3-1.1	0.8	0.5-1.2
130	50/26/160	0.9	0.5-1.5	0.6	0.3-1.0	0.8	0.5-1.2
	p-value trend	0.85		0.09		0.29
Barbecued	44/20/179	1.0		1.0		1.0
24	57/36/160	1.5	0.9-2.4	2.2	1.2-4.1	1.7	1.1-2.6
64	40/29/113	1.5	0.9-2.7	2.5	1.3-5.0	1.9	1.2-2.9
	p-value trend	0.008		0.006		0.005
Boiled	34/35/166	1.0		1.0		1.0
104	59/28/146	1.7	1.0-2.9	0.7	0.4-1.3	-
208	48/22/140	1.5	0.9-2.6	0.6	0.3-1.2	-
	p-value trend	0.14		0.17		^{- 4}

¹Adjusted for age, residence, urban/rural status, education, family history of colon cancer among first-degree relatives, tobacco smoking, alcohol drinking, total energy intake, total vegetables and fruits, total fat intake and for each other.

2-In servings per year.

³p-value for heterogeneity 0.0005

⁴p-value for heterogeneity 0.03

Table 5. Odds ratios of colorectal cancer for estimated intake of heterocyclic amines¹.

		Colon		Rectum		Both sites
Males	Colon/Rectum/ Controls	OR	95 % CI	OR	95 % CI	OR	95 % CI
Cutpoints	68/203	1.0		1.0		1.0
160.5 ²	112/216	1.5	0.9-2.6	1.4	0.8-2.3	1.5	0.9-2.2
258.6	150/241	1.8	0.9-3.4	2.0	1.2-3.6	1.9	1.2-3.0
	p-value trend	0.06		0.009		0.004
		Colon		Rectum		Both sites
Females	Colon/Rectum /Controls	OR	95 % CI	OR	95 % CI	OR	95 % CI
Cutpoints	59/168	1.0		1.0		1.0
160.5 ²	81/154	1.7	0.9-2.9	1.7	0.9-3.1	1.7	1.1-2.6
258.6	86/130	2.3	1.2-4.3	1.7	0.8-3.5	2.0	1.2-3.4
	p-value trend	0.01		0.17		0.01

²Nanograms/day.

V. Discussion

According to the results of our study, beef and red meat were associated with a significant increase in risk for colorectal cancer in men and women. These results were rather similar in colon and rectal cancer. These findings are in accordance with most of the previous case-control and prospective studies (Manousos et al, 1983; Tuyns et al, 1988; La Vecchia et al, 1988; Benito et al, 1990; Gerhardsson de Verdier et al, 1991; Potter, 1996; Le Marchand et al, 1997; World Cancer Research Fund, 1997; Potter, 2000). Moreover, we included a term for total fat intake in all models and, whereas fat displayed a null effect, red meat increased its risk.

Aside from its content in fat, red meat is a rich source of iron and protein. Adjustment for these variables left the OR’s for red meat without any change, Thus, other components of red meat should be responsible for the deleterious effect of this food item. Strong candidates for explaining the carcinogenic effect of red meat in colorectal cancer risk are the heterocyclic amines (HCA). These chemicals are formed in muscle meat cooked by frying or barbecuing (Weisburger, 2002). More precisely, the presence of creatine is required in the formation of HCA’s. The carcinogenicity was discovered by Sugimura and Sato in experimental animal studies (Sugimura 2000). Since then, numerous experimental and epidemiological studies have increased the consistence of the noxious effect of HCA’s in colorectal cancer (De Stefani et al, 1997; Sinha et al, 1999, 2001; Le Marchand et al, 2002; Nowell et al, 2002). Moreover, HCA’s have been suggested as carcinogens for several cancer sites, like breast and lung (De Stefani et al, 1997; Sinha et al, 1998). In fact, some case-control studies have found an increased risk for colorectal cancer and breast cancer, after using an estimated variable for PhIP (25, 28). Other studies have employed proxy variables like type of cooking and doneness of meat consumed (Gerhardsson de Verdier et al, 1991; Sinha et al, 1998, 1999). Most of these studies consistently showed a significant increase in risk of colorectal and breast carcinomas.

In the present study fried meat was associated with an increased risk of colon cancer, whereas rectal carcinoma displayed a null effect. On the other hand, barbecued meat was a strong risk factor for female rectal carcinoma, whereas the effect on colon cancer was rather small. This discrepancy between fried and barbecued meat, two proxy variables of HCA’s exposure, could be due to unknown factors or, taking into account the numerous comparisons made, be a chance finding. In fact, doneness of red meat is a better proxy variable of HCA’s exposure than cooking methods (Sinha et al, 1998). We also employed an estimated amount of total heterocyclic amines (HCA’s). High exposure to HCA’s was associated with a two-fold increase in risk. This finding, albeit subject to misclassification, replicates findings in the recent review of Sinha (2002).

Like other case-control studies, our report has limitations. Selection bias is almost impossible to eliminate. In order to minimize its effect, we frequency matched cases and controls on age, sex and residence. Recall bias is always a potential problem in retrospective studies on diet and cancer. Since cases and controls were hospitalized it is probable that both series of participants were subjected to similar forces of recall. Furthermore, cases and controls were drawn from a low socioeconomic strata of the Uruguayan population. This segment of the population is mostly unawere of the potential danger of high consumption of red meat. Also, both interviewers were participating in a large multisite case-control study on environmental factors and several cancer sites. Therefore, it is unlikely that the interviewers have a precise knowledge of the role of diet in colorectal cancer. Our study has also strengths. Perhaps the most important strength is the high response rate observed both in cases and controls.

In summary, the present study gives further support to the noxious effect of red meat in colorectal carcinoma. This strong association was observed for high consumption of beef and red meat. The positive association was observed in colon and rectal cancers and in men and women. Also, the cooking method, that is the exposure to fried and barbecued meat, was associated with increased risks for colorectal cancer. Nevertheless, these associations were inconsistent by tumor site and by gender, suggesting that doneness is a better proxy variable of HCA’s than cooking method. Finally, estimated exposure to total HCA’s was consistently associated with high OR’s for colorectal cancer. Further studies on effect modifiers of the carcinogenic risk of red meat and HCA’s are needed.

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Research Article

Received: 29 March 2005; Accepted: 06 April 2005; electronically published: April 2005

I. Introduction

II. Material and methods

III. Results

V. Discussion

References