Fibra y cancer colorectalI Jornada Universitaria UCM-CLAS Mayo 2012 H.G.U.Gregorio Marañón. Cátedra UCM- CLAS Dra. Pilar Riobó Serván Endocrinologia y Nutrición www.doctorariobo.com
Denis Parsons Burkitt (1911-1993)Burkitt DP. Epidemiology of cancer of the colon and rectum. Cancer. 1971 Jul;28(1):3-13.
Burkitts observation was followed by numerous case-control studies.• A combined analysis of 13 case-control studies as well as a meta-analysis of 16 case-control studies indicated an inverse association between fiber intake and colorectal cancer.• 10 prospective studies, which avoid the potential for recall and control selection bias, have largely failed to support this association.
Associations between consumption of dietary fibre and risk of CRC: Studies are level II evidence.Terry et al,2001 Prospective cohort study of 61 Very low consumption of fruit and 463 women vegetables raises risk of CRCAsano and Meta-analysis (5 randomized Increase in dietary fibre intake does notMcLeod, 2002 controlled trials) reduce incidence or recurrence of adenomatous polypsLevi et al, 2001 Case-control study: 286 cases Vegetable fibre appears to be more vs. 550 controls protective against CRC than either fruit or grain fibreBingham et al, Prospective cohort study of 19 Intake of fibre was inversely related to2003 978 patients incidence of large-bowel cancerMai et al, 2003 Prospective cohort study No association between fibre intake and CRCPeters et al,21 Cancer screening trial High dietary fibre lowers risk of adenomas2003
Meat???• countries that consume a lot of meat and animal fat have the highest rates of CCR• this inversely correlates with the consumption of dietary fiber• The protection that fibre offers could be dependent on the type of fibre – cereals type fibre – Vegetable fibre – Fruit fiber
Colorectal cancer incidence lower in AfricaIncidence rates : USA: 35.8 cases/ 100,000/year UK: 12/100,000/y (40-44 y); 24/100,000/y (45–49y) Nigeria: 3.4/100,000/year, but increasing incidence: (by the last decade, carcinoma of the colon and rectum moved from the tenth to the fourth position) Relative absence of premalignant conditions like adenomatous polyps in West African
Body Mass Index Increases Risk forColorectal Adenomas (Meta-analysis)36 independent studies, 29,860 incident cases of CRA.A 5-unit increase in BMI, increased the risk for CRA (relative risk = 1.19)increased risk of CRA in obese was independent of race, sex, adenoma progression, and confounders.The association between increased BMI and risk for CRA was stronger for colon than rectal adenoma.A 5-unit increase in BMI was associated with a 19% increased risk for colorectal adenoma Ben Q. Gastroenterology. 2012 Apr;142(4):762-72.
• 34,467 women, who had undergone colonoscopy• Fruits and vegetables intake was assessed/2 years, FFQ• 1,720 cases of adenoma were diagnosed (1980 – 1998).• Fruit consumption was inversely related to the risk of polyps, but little association was found for vegetable consumption. – five or more servings of fruit a day had OR: 0.60 for developing colorectal adenomas (P = 0.001). – OR for vegetable consumption was 0.82 (P = 0.1). – four or more servings of legumes per week had a lower incidence of colorectal adenomas (OR, 0.67. P = 0.005).
• 2818 persons who had undergone colonoscopy.• Self-administered questionnaire from AHS-1, 1976• outcome was assessed from AHS-2 data (2002 - 2005)• Results: – A total of 441 cases of colon polyps were identified. – total fiber intake was inversely associated with the risk of colon polyps (OR for highest vs lowest quartile 0.71, 95% CI 0.51–0.99). – Vegetables &legumes (OR for highest vs lowest quartile 0.65; p .02). – This association showed a dose-response effect (p .04).
Total dietary fiber intake, specifically from vegetables, was inverselyassociated with colon polyps, with a clear dose-response effect. Fiber intake from fruits and grains did not show a significant effecton colon polyps
• Prospective cohort: 59000 African American women• 155,414 person-years of follow-up (1997 to 2007) women who had had at least one colonoscopy• Two dietary patterns, Western and prudent, were utilized – 620 incident cases of colorectal adenomas were identified. Cancer Epidemiol Biomarkers Prev; 20(5); 818–25
The highest quintile of prudent diet, relative to thelowest quintile, was significantly associated with 34% lowercolorectal adenoma risk (IRR = 0.66; P< 0.01). Higher scores on the Western pattern were associated with a higher risk of developing colorectal adenoma (IRR = 1.42; 95% CI, 1.09–1.85 for the highest quintile relative to the lowest; P = 0.01).
Tennessee Colorectal Polyp Study. Participants (40–75 y) colonoscopy from 2003 to 2005. Dietary intake was assessed 764 cases and 1517 controlsincreased intakes of total fruits, berries, fruit juice, and green leafyvegetables were associated with reduced adenoma risk
Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) (1993–2001) 3057 cases with 1 adenoma 29 413 control subjects. FFQ to quantify intake of fruit and vegetables in the 12 mo before screeningDiets rich in fruit and deep-yellow vegetables, dark-greenvegetables, and onions and garlic are modestly associated with reduced risk of colorectal adenoma
dietary fiber intake was inversely associatedwith risk of colorectal cancer in age-adjusted analyses.However, after accounting for other dietary risk factors, high dietary fiber intake was not associated with a reduced risk of colorectal cancer.
• Prospectively assess the association between the Alternate Mediterranean Diet (aMed) and the DASH-style diet scores and risk of colorectal cancer• A total of 87,256 women and 45,490 men , followed for 26 y.• The aMed and DASH scores were calculated for each participant by using dietary information that was assessed ≤7 times during follow-up.Results:• 1432 cases of incident colorectal cancer among women and 1032 cases in men.• Comparing top with bottom quintiles of the DASH score, the pooled RR for total colorectal cancer was 0.80 (P for trend = 0.0001).• No association was observed with aMed score.• Conclusion: Adherence to the DASH diet (higher intakes of whole grains, fruit, and vegetables; moderate amounts of low-fat dairy; and lower amounts of red or processed meats, desserts, and sweetened beverages) was associated with a lower risk of colorectal cancer.
1.8 million person-years and 1,596 cases of CRC little association with fiber intake
European Prospective into Cancer (EPIC)• 519 978 individuals; FFQ in 1992—98• Follow-up consisted of 1 939 011 person-years,• 1065 reported cases of colorectal cancer• Dietary fibre in foods was inversely related to incidence of CRC• RR for the highest versus lowest quintile of fibre intake was 0·58• No food source of fibre was more protective than others• Critics: – included various populations, ranging from Scandinavia to the Mediterranean, with diverse dietary habits. – Folate intake was not controlled In populations with low average intake of fibre, an approximate doubling of total fibre intake from foods could reduce the risk of colorectal cancer by 40%.
• 45 491 women in the Breast Cancer Detection Demonstration Project (BCDDP) follow-up cohort.• A 62-item FFQ was administered in 1987-89 and follow-up questionnaires (in 1992–95 and 1995–98)• follow-up time of 8.5 years,• 487 CRC cases• No evidence that dietary fibre intake lowers CRC risk• Critics: cohort of older women characterized by a relatively low fibre intake
Fibra de frutas Aune D et al BMJ 2011;343:d6617
Fibra de vegetales Aune D et al BMJ 2011;343:d6617
Fibra de legumbres Aune D et al BMJ 2011;343:d6617
Fibra de cereales Aune D et al BMJ 2011;343:d6617
Grano integral Aune D et al BMJ 2011;343:d6617
The relative risk of colorectal cancer for each 10 g/day intake was: 0.90 for total fibre 0.93 for fruit fibre 0.98 for vegetable fibre 0.62 for legume fibre 0.90 for cereal fibreIn addition to a high total dietary fibre , cereal fibre and whole grains may reduce the risk of CRC The relative risk for an increment of three servings daily of whole grains was 0.83
Mechanisms for a reduced risk of colorectal cancer with high fiber intake• high stool bulk, dilution, absorption, and removal of carcinogens, cocarcinogens, and/or tumor promoters• reduces stool transit time ->lowers exposure to potential carcinogens.• bind to bile acids potentially lessening their toxic effects.• Cereal fibre and whole grains are rich in inositol hexaphosphate (IP6) that has been proven to reduce experimental cancers, not just of the CRC but of other organs• fibre is fermented to volatile fatty acids , – protective in experimental models of carcinogenesis. – lowers the pH, which prevents the conversion of primary to secondary bile acids
Efectos del butirato sobre el colon • inhibition of inflammation and carcinogenesis, • reinforcing various components of the colonic defence barrier • decreasing oxidative stress. • may promote satiety. • inhibition of nuclear factor kappa B activation • histone deacetylation.Hamer HM. the role of butyrate on colonic function.Aliment Pharmacol Ther. 2008 15;27(2):104-19
elevated luminal butyrate as delivered by HAMSB increased the rate of apoptosis but not colonocyte proliferation in the distal colon of rats in acute response toAOM-induced genotoxicity• Proapoptotic function of butyrate plays a major role reducing tumour formation in the AOM-treated rat Carcinogenesis. 2012 January; 33(1): 197–202.
Otros factores carcinogenos/ anticarcinogenos
Spices and Phytonutrients• Turmeric (curcumin, curry) has anticancer properties – it targets multiple signalling pathways that may protect the colon by decreasing the activity of beta-glucuronidase and mucinase – Other anticancer properties : • inhibition of lipooxygenase activity, specific inhibition of cyclooxygenase 2 expression, and the promotion/progression stages of carcinogenesis [55, 56].• Garlic and onions, contain diallyl sulphide and flavonoids – suppress cell division in human colon tumor cells – high antioxidant property (due to their wide content of) ;• Red pepper (chili ) has been shown to protect against colorectal carcinoma – The main ingredient of pepper is capsaicin, and this is known to cause death of colon cancer cells.
Dietary constituent which may decrease tumor risk in colon and rectum Correa Lima , Nutr Hosp 2005
• The EPIC study is a prospective cohort to investigate the associations between dietary, lifestyle, genetic, and environmental factors and risk of specific cancers.• 366,521 women and 153,457 men enrolled between 1992 and 1998 in 10 European countries There is convincing evidence that physical activity reduces colon cancer risk
Actividad fisica y cancer de colonKaiser Permanente Medical Care Program (1997 - 2002)Vigorous physical activity was associated with reduced risk ofrectal cancer (OR = 0.60) Participation in vigorous activity over thepast 20 years conferred the greatest protection (OR = 0.55, 95% CI:0.39, 0.78 for men; OR = 0.44, 95% CI: 0.30, 0.67 for women).
•Lifestyle index: physical activity, waist, smoking, alcohol, anddiet (fibre, fat, red and processed meat, fruits and vegetables)•Follow-up: 9.9 years, 678 persons had CRC diagnosed.• 13% (95% CI 4% to 22%) of CRC were attributable to lack ofadherence to one additional recommendation•If all participants had followed the 5 recommendations, 23% (9%to 37%) of CRC might have been prevented.
• 37,112 persons from Australia, recruited from 1990 to 1994• 9 years of follow-up• Diet was measured with a FFQ• 283 colon cancers and 169 rectal cancersConsumption of fresh red meat and processed meat seemed to be associated with an increased risk of rectal cancer.Consumption of chicken and fish did not increase risk. Dietary heme injures surface epithelium, hyperproliferation, inhibition of apoptosis and crypt hyperplasia in rat colon Cancer Epidemiol Biomarkers Prev 2004;13(9):1509–14)
Daily increase of 100 g of all meat or red meat is associated with a significant 12–17% increased risk of CRC A significant 49% increased risk was found for a daily increase of 25 g of processed meat
Heterocyclic amines (HCAs)• Meat cooked at high temperatures contains HCA• Produced when meat is heated above 180°C for long periods, and these HCAs have consistently been identified in well-done meat• Meat grilled or barbecued contains the highest amount of polycyclic aromatic hydrocarbons (PAHs) because of the exposure to smoke formed from the pyrolysis of fatty juices that drip down onto the heat source• The poor electricity supply in most rural and urban areas in Africa does not allow proper refrigeration of meat, thus many households deep-fry meat for preservation and consumption.
Netherlands Cohort Study on diet and cancer 2,323 CRC cases, after 13.3 years of follow-up. • Compared to abstaining, alcohol consumption of ≥30.0 g/day (∼3 alcoholic drinks) was positively associated with the risk of CRC (HR: 1.32,). • Cancer risk seemed to increase from proximal colon through rectum; – HR: 1.29, for proximal colon cancer, – HR: 1.41, for distal colon cancer, – HR: 2.07, for rectosigmoid cancer
• CRC risk for beer (HR 1.38) was higher than wine (HR 5 1.21)• Higher HRs for baseline alcohol with low levels of folate intake
Folate and CRC risk• epidemiologic studies have found an inverse relationship between high intake of folate & CRC risk, but not consistentely• Reduction of 30%-40% in CRC risk for persons with high levels of folate intake compared to those with low levels• The risk of CRC decreases 11% for every 400 μg of folate ingested.• BUT…• Animal studies have suggested that high-dose folic acid might promote colorectal tumorigenesis• A large, placebo-controlled multicenter trial has shown that high- dose folate might increase the risk of neoplastic transformation• A multicenter, randomized, double-blind trial has shown that folate supplementation was found to have no effect on adenoma recurrence [relative risk (RR) = 1.07, 95% CI: 0.85-1.34
Folate and CRC riskdietary folate supplementation protection against colonic carcinogenesis might depend on the stage of colorectal carcinogenesis, and would protect against carcinogenesis in normal colorectal tissue, but that folate might enhance pre-existing lesions
Vitamina DActividad anticancer de la vit D? en animales y en líneas celulares durante años.1,25(OH)2D estimula la expresión de inhibidores delciclo celular p21 y p27 y de E-cadherina e inhibe laactividad de β-catenina1,25(OH)2D repara el DNA dañado por UVRHay evidencias epidemiológicas que apoyan el papelde la vitamina D para la prevención de ciertos canceres,sobre todo mama, colon y prostata.
Premature mortality due to cancer in white females, andmales as determined on the basis of the July 1992 DNA-weighted ultraviolet B (UV-B) radiation by use of a totalozone mapping spectrometer Holick, M. F Am J Clin Nutr 2004;79:362-371
Multivariable relative risks for an increment of 25nmol/L in predicted plasma 25-hydroxy-vitamin Dlevel for individual cancers in the HealthProfessionals Follow-up Study (1986-2000) Low levels of vitamin D may be associated with increased cancer incidence and mortality in men, particularly for digestive-system cancers. Giovannucci, E. et al. J. Natl. Cancer Inst. 2006 98:451-459; doi:10.1093/jnci/djj101
Los individuos con ingesta ≥1000 IU/día de Vitamina D o con niveles séricos ≥33 ng/ml (82 nmol/l) de 25-hydroxyvitamin D tenían una incidencia 50% más bajas de cancer colorectal cancerSon necesarias acciones para aumentar la ingesta de D3 a 1000 IU/díaGorham ED. Vitamin D and prevention of colorectal cancer. J SteroidBiochem Mol Biol 2005;97:179-194.
Professionals Health Study179 casos de cancer Acociacion inversa entre vitamina D y Cancer colorectal
74.000 japoneses No asociacion con vitamina D Pero si con calcio. Ishihara, M. Inoue, M. Iwasaki, S. Sasazuki, and S. TsuganeDietary calcium, vitamin D, and the risk of colorectal cancerAm. J. Clinical Nutrition, December 1, 2008; 88(6): 1576 - 1583.
Interrelationship among risk factors for colon cancer Davis, C. D. et al. J. Natl. Cancer Inst. 2007 99:1563-1565;
Cancer PCRT, n 1178 1100 IU vit D y 1500 mg ca Reducción 77% en colon y mamaaumento de 25OH de 28 a 38.4 ng/ml Lappe, J. M et al. Am J Clin Nutr 2007;85:1586-1591
Riesgo de cancer Colorectal Cancer invasivo consuplemento de Calcio y vitamina D (1000/800) vs Placebo WHI N=36,000 mujeres 1000 mg de calcio 400 IU vit D 7 años NO reduccionProblemas: dosis baja, mal cumplimiento, no control de niveles de25OHD al final del estudio Wactawski-Wende J. Calcium plus Vitamin D Supplementation and the Risk of Colorectal Cancer. NEJM 354:684
Conclusions I• Colorectal cancer is the third most common cancer worldwide, with 1.2 million new cases annually• Intake of dietary fibre and whole grains has been established as protective• It is unclear whether only specific types of fibre or sources of fibre are associated with the risk of colorectal cancer• Intakes of dietary fibre, cereal fibre, and whole grains are associated with linear decreases in the risk of colorectal cancer• Evidence of an association between intake of fruit, vegetable, or legume fibre and risk of colorectal cancer was lacking• Intake of dietary fibre, particularly cereal fibre and whole grains, was associated with a small reduction in the risk of colorectal cancer
Conclusions I• Epidemiology indicates an inverse correlation between high fiber consumption and lower colon cancer rates.• Cereal fiber sources show the most consistent negative correlation.• However, human case-control studies in general fail to confirm any protective effect due to dietary fiber.• Experimental data have in general shown a protective effect with supplements of poorly fermentable fibers such as wheat bran or cellulose.
Conclusions II• Because dietary fibers differ in their physiochemical properties it has been difficult to identify a single mechanism by which fibers modify colon carcinogenesis.• More metabolic and physiological studies are needed to fully define the mechanisms by which certain fibers inhibit experimental colon carcinogenesis.