1. Several studies have found an inverse association between fiber intake, particularly cereal fiber and fiber from vegetables and legumes, and risk of colorectal cancer and adenomas. 2. Physical activity is also associated with reduced colorectal cancer risk, with greater reductions seen with more vigorous activity. 3. Red and processed meat intake is positively associated with colorectal cancer risk, while poultry and fish intake have not been found to increase risk.

1. Fibra y cancer colorectal
I Jornada Universitaria UCM-CLAS
Mayo 2012
H.G.U.Gregorio Marañón.
Cátedra UCM- CLAS
Dra. Pilar Riobó Serván
Endocrinologia y Nutrición
www.doctorariobo.com

2. Denis Parsons Burkitt (1911-1993)
Burkitt DP. Epidemiology of cancer of the colon
and rectum. Cancer. 1971 Jul;28(1):3-13.

3. Burkitt's 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.

4. 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 CRC
Asano and Meta-analysis (5 randomized Increase in dietary fibre intake does not
McLeod, 2002 controlled trials) reduce incidence or recurrence of
adenomatous polyps
Levi 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 fibre
Bingham et al, Prospective cohort study of 19 Intake of fibre was inversely related to
2003 978 patients incidence of large-bowel cancer
Mai et al, 2003 Prospective cohort study No association between fibre intake and
CRC
Peters et al,21 Cancer screening trial High dietary fibre lowers risk of adenomas
2003

5. 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

6. Colorectal cancer incidence lower in Africa
Incidence 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

7. Body Mass Index Increases Risk for
Colorectal 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.

8. • 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).

9. • 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).

11. Total dietary fiber intake, specifically from vegetables, was inversely
associated with colon polyps, with a clear dose-response effect.
Fiber intake from fruits and grains did not show a significant effect
on colon polyps

12. • 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

13. The highest quintile of prudent diet, relative to the
lowest quintile, was significantly associated with 34% lower
colorectal 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).

14. Tennessee Colorectal Polyp Study.
Participants (40–75 y)
colonoscopy from
2003 to 2005.
Dietary intake was
assessed
764 cases and
1517 controls
increased intakes of total fruits, berries, fruit juice, and green leafy
vegetables were associated with reduced adenoma risk

15. 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 screening
Diets rich in fruit and deep-yellow vegetables, dark-green
vegetables, and onions and garlic are modestly associated
with reduced risk of colorectal adenoma

16. dietary fiber intake was inversely associated
with 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.

17. • 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.

18. 1.8 million person-years and 1,596 cases of CRC
little association with fiber intake

19. 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%.

20. • 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

22. Fibra de frutas
Aune D et al BMJ 2011;343:d6617

23. Fibra de vegetales
Aune D et al BMJ 2011;343:d6617

24. Fibra de legumbres
Aune D et al BMJ 2011;343:d6617

25. Fibra de cereales
Aune D et al BMJ 2011;343:d6617

26. Grano integral
Aune D et al BMJ 2011;343:d6617

27. 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 fibre
In 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

28. 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

29. 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

30. 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.

31. Otros factores carcinogenos/
anticarcinogenos

32. 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.

33. Dietary constituent which may decrease
tumor risk in colon and rectum
Correa Lima , Nutr Hosp 2005

34. • 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

35. Actividad fisica y cancer de colon
Kaiser Permanente Medical Care Program (1997 - 2002)
Vigorous physical activity was associated with reduced risk of
rectal cancer (OR = 0.60) Participation in vigorous activity over the
past 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).

36. •Lifestyle index: physical activity, waist, smoking, alcohol, and
diet (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 of
adherence to one additional recommendation
•If all participants had followed the 5 recommendations, 23% (9%
to 37%) of CRC might have been prevented.

37. • 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 cancers
Consumption 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)

38. 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

39. 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.

40. 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

41. • 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

42. 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

43. Folate and CRC risk
dietary 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

44. Vitamina D
Actividad anticancer de la vit D?
en animales y en líneas celulares durante años.
1,25(OH)2D estimula la expresión de inhibidores del
ciclo celular p21 y p27 y de E-cadherina e inhibe la
actividad de β-catenina
1,25(OH)2D repara el DNA dañado por UVR
Hay evidencias epidemiológicas que apoyan el papel
de la vitamina D para la prevención de ciertos canceres,
sobre todo mama, colon y prostata.

45. Premature mortality due to cancer in white females, and
males as determined on the basis of the July 1992 DNA-
weighted ultraviolet B (UV-B) radiation by use of a total
ozone mapping spectrometer
Holick, M. F Am J Clin Nutr 2004;79:362-371

46. Multivariable relative risks for an increment of 25
nmol/L in predicted plasma 25-hydroxy-vitamin D
level for individual cancers in the Health
Professionals 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

47. 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 cancer
Son necesarias acciones para aumentar la ingesta de D3 a
1000 IU/día
Gorham ED. Vitamin D and prevention of colorectal cancer. J Steroid
Biochem Mol Biol 2005;97:179-194.

48. Professionals Health
Study
179 casos de cancer
Acociacion inversa
entre vitamina D y
Cancer colorectal

49. 74.000 japoneses
No asociacion con
vitamina D
Pero si con calcio
. Ishihara, M. Inoue, M. Iwasaki, S. Sasazuki, and S. Tsugane
Dietary calcium, vitamin D, and the risk of colorectal cancer
Am. J. Clinical Nutrition, December 1, 2008; 88(6): 1576 - 1583.

50. Interrelationship among risk factors for colon cancer
Davis, C. D. et al. J. Natl. Cancer Inst. 2007 99:1563-1565;

51. Cancer
PCRT, n 1178
1100 IU vit D y 1500 mg ca
Reducción 77% en colon y mama
aumento de 25OH de 28 a 38.4 ng/ml
Lappe, J. M et al. Am J Clin Nutr 2007;85:1586-1591

52. Riesgo de cancer Colorectal Cancer invasivo con
suplemento 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 reduccion
Problemas: dosis baja, mal cumplimiento, no control de niveles de
25OHD al final del estudio
Wactawski-Wende J. Calcium plus Vitamin D Supplementation and the Risk of
Colorectal Cancer. NEJM 354:684

54. 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

55. 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.

56. 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.

57. Thank you very much for
your attention