EJINME-03023; No of Pages 5 European Journal of Internal Medicine xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Review Article
Prevention of colorectal cancer: How many tools do we have in our basket? Luca Roncucci ⁎, Francesco Mariani Department of Diagnostic and Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Policlinico, Via Del Pozzo 71, Modena 41124, Italy
a r t i c l e
i n f o
Article history: Received 27 March 2015 Received in revised form 16 July 2015 Accepted 7 August 2015 Available online xxxx Keywords: Colorectal cancer prevention Chemoprevention Screening Hereditary colorectal cancer Inflammatory bowel diseases
a b s t r a c t Prevention is the main strategy in order to reduce colorectal cancer incidence and mortality. It can be accomplished through primary prevention, using measures affecting factors known to confer higher risk of colorectal cancer, or through secondary prevention, aimed at early diagnosis of cancer or preneoplastic lesions in groups of subjects at increased risk of cancer. Although primary prevention should be the goal for future years, because it acts on the probable causes of colorectal cancer, at present it seems that secondary prevention is more effective on colorectal cancer survival, and the approaches which have yielded the most satisfying results, in terms of reduced mortality for cancer, are those aimed at detecting preneoplastic lesions, or cancer at an early stage in selected groups of subjects at average or increased risk of colorectal cancer. These groups are subjects aged 50 years or older, affected individuals (gene carriers) or family members of hereditary colorectal cancer syndromes (i.e., Lynch syndrome and familial adenomatous polyposis), and patients with inflammatory bowel diseases. The most effective procedures used, though with some drawbacks, are fecal occult blood tests and colonoscopy. Future research should be addressed to find new approaches that will render preventive strategies more acceptable for the population, and more cost-effective. © 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Introduction Colorectal cancer (CRC) is a major cause of incidence and mortality in many countries, especially in more developed ones, though in very recent years its incidence is increasing also in developing areas of the world [1]. There is a wide epidemiological and observational evidence that the risk of colorectal cancer is strictly related to lifestyle, especially to diet and physical activity [2]. In analytical case–control and cohort studies, risk is directly associated with the consumption of red and processed meat, and with abdominal fatness, and inversely related to physical activity. Somewhat at a lesser extent, dietary fiber seems to reduce the risk. For many years researchers have taken advantage of the fact that colorectal carcinogenesis is a stepwise process, lasting several years, since its beginning as a single mutational event in a cell, until detectable malignancy. Meanwhile, it is supposed that several actions might be taken or planned, or almost thought to be tested in several models, in order to change the course of the process, either stopping or slowing it. At present, two main preventive strategies for colorectal cancer are being in action: primary prevention affecting risk factors, and secondary prevention aimed at the early detection of preneoplastic or neoplastic lesions in the large bowel, in populations at average or increased risk, mainly because of age, hereditary colorectal cancer syndromes, or inflammatory bowel diseases. Only some of them have reached strong ⁎ Corresponding author. Tel.: +39 59 4224052; fax +39 59 4222958. E-mail address: [email protected] (L. Roncucci).
and sound results in terms of decreasing incidence and mortality for CRC. We will discuss the effectiveness of these strategies, taking into account only solid evidence coming from randomized clinical trials or guidelines of scientific societies. Articles have been selected using the following keywords: prevention of colorectal cancer, chemoprevention of colorectal cancer, colorectal cancer screening, Lynch syndrome, familial adenomatous polyposis, inflammatory bowel diseases, and the time period of the search was October–December 2014. 1. Primary prevention through measures affecting risk factors: Lessons from chemopreventive studies The available evidence indicates that primary prevention of colorectal cancer is feasible. At least 70% of colon cancers may be – at least in theory – preventable by changes in diet and lifestyle [3]. The target of primary prevention is the general population at large. The perspective of reducing colorectal cancer incidence and mortality through multiple dietary modifications or adding substances to the diet is very attractive. However, we need studies on high colorectal cancer risk patients to gather information useful for the general population. The main problem of this approach is that actions are based only on hypotheses or epidemiological evidence linking lifestyle and colorectal cancer [4–6]. Another issue is the long time a randomized clinical trial would last in order to see any effect of an intervention, having cancer mortality as an end point [7]. To overcome that problem researchers have adopted “surrogate” end points for colorectal cancer mortality so far, either very early in carcinogenesis (“tumor markers”) or later, i.e., aberrant
http://dx.doi.org/10.1016/j.ejim.2015.08.019 0953-6205/© 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Please cite this article as: Roncucci L, Mariani F, Prevention of colorectal cancer: How many tools do we have in our basket?, Eur J Intern Med (2015), http://dx.doi.org/10.1016/j.ejim.2015.08.019
2
L. Roncucci, F. Mariani / European Journal of Internal Medicine xxx (2015) xxx–xxx
crypt foci or microadenomas [8], adenomas, and colorectal cancer incidence. Earlier markers have the drawback to be linked too loosely with cancer. Indeed, despite interesting observations in animal studies [9, 10], and in human short-term biochemical risk marker trials [11], major human intervention studies of dietary manipulations on patients at increased risk of colorectal cancer have largely failed to demonstrate any robust effect, or results were not consistent [12–14]. Similarly, chemoprevention with dietary supplementation with fiber, antioxidant vitamins, and minerals (mainly calcium) provided negative or inconsistent results on adenoma recurrence [15–20]. On the other hand, when considering chemoprevention with drugs, those more frequently investigated are non-steroid anti-inflammatory drugs (NSAIDs), and, among them, 5-aminosalicylic acid, sulindac, and cyclooxygenase 2 inhibitors (celecoxib and rofecoxib). Supplementations with these drugs were consistently effective in preventing adenoma onset or recurrence [21–23], but their gastrointestinal and/or cardiovascular toxicity render them not suitable for prevention. Taken together, results of prospective human randomized chemopreventive trials were not in line with those of observational studies, for different reasons [24]. In addition, primary prevention does not eliminate the need of follow-up or surveillance for the disease. Thus, at present, any dietary, lifestyle or chemopreventive recommendations aimed at reducing colorectal cancer mortality, is premature for the general population. The real problem is that we do not have completely unraveled the complex network of the causes of CRC. This fact reinforces the need for studies on risk factors, and it does not mean that active research on prevention based on lifestyle modifications should be stopped. The available epidemiological evidence for colon and rectal cancers suggests that physical activity decreases the risk, whereas body (especially abdominal) fatness, and the consumption of red and processed meat, and of alcoholic beverages increase the risk. Thus, from a practical point of view, recommendations should be given to the general population, in order to encourage a healthy lifestyle. At present, the “milestones” recommendations for colorectal cancer are: be as lean as possible within the normal range of body weight, be physically active as part of everyday life, eat mostly foods of plant origin (especially foods containing dietary fiber), limit intake of red meat and avoid processed meat, and limit alcoholic drinks [2]. 2. Secondary prevention Secondary prevention of colorectal cancer is targeted at populations at average or increased risk of colorectal cancer. At present, they are: general population at increased risk because of age, subjects belonging to families with hereditary colorectal cancer syndromes, and patients with longstanding and widespread inflammatory bowel diseases. 2.1. General population Screening programs are mostly targeted at adults older than 50–55 years, a population at increased risk of developing adenomas and cancer [25]. These programs have been implemented at regional and national levels all over the world, though they differ considerably across countries. At present screening is based on some methods with different advantages and drawbacks, and different economic impact. The most employed are fecal occult blood tests (FOBT) or, more recently, fecal immunological tests (FIT), flexible sigmoidoscopy (FS) and colonoscopy (C). FOBT and FIT are based on the assumption that a colorectal adenoma or cancer bleeds, but this is not always the case. FS and C may allow to remove adenomas and to detect a malignancy at an early stage. Adenoma removal reduces long term colorectal cancer mortality [26]. The effectiveness of screening policies in reducing cancerrelated mortality has been evaluated with randomized clinical trials and systematic reviews of their results, or indirectly by observational studies based on incidence and mortality data from cancer registries at the population level. Indeed, colorectal cancer screening with FOBT,
flexible sigmoidoscopy or colonoscopy has been shown to reduce incidence of colorectal cancer and cancer-related mortality [27–34], though for screening colonoscopy randomized clinical trials are still lacking. Cancer registries are particularly useful in order to evaluate the impact of prevention strategies [35]. However, caution should be used when interpreting mortality data from cancer registries, because of wide differences in stage distribution among countries [36]. It is necessary to develop new screening approaches, for example using new innovative technologies such as computed tomographic colonography and stool screening for molecular markers [37,38]. Where available, a screening program for colorectal cancer is probably the best way to prevent colorectal cancer. This would provide the most benefit for the population, though the participation rates for the various screening programs should be improved. A valid alternative for us could be performing a once-in a lifetime colonoscopy at the age of 50–55, in line with the age-specific incidence of colorectal cancer at the population level [25]. 2.2. Hereditary colorectal cancer (HCRC) The most frequent forms of HCRC are Lynch syndrome (LS) and familial adenomatous polyposis (FAP). The genetic bases of both diseases have been clarified in the early 1990s. Prevention of CRC in gene carriers (i.e., patient carriers of a deleterious mutation in a DNA mismatch-repair [MMR] gene, and in adenomatous polyposis coli [APC] or MUTYH genes, respectively) can be accomplished through follow-up colonoscopies with removal of adenomas (when feasible), or prophylactic colectomy (in selected cases) (Table 1). 2.2.1. Lynch syndrome LS is the most frequent autosomal dominant hereditary colorectal cancer syndrome. It accounts for approximately 1%–2% of the whole colorectal cancer burden in the population, at least in western countries, considering only MMR gene carriers [39]. Our approach used to identify DNA MMR gene carriers is based on a careful evaluation of the nuclear family pedigree (limited to first-degree relatives of the proband affected by colorectal cancer), in order to find out the clinical feature of a Lynch syndrome, according to some criteria which, if present, prompt us to expand the pedigree to second and third-degree relatives [40]. Then, in this expanded pedigree, we evaluate whether the international validated criteria for the clinical diagnosis of Lynch syndrome (the so-called Amsterdam II criteria [41]) are satisfied. The molecular genetic test for the identification of the deleterious mutation in a DNA MMR gene is offered to the proband and then to all the family members at risk. DNA MMR gene carriers have a high life-time risk of developing cancer in the large bowel [42], and in other organs. Surveillance colonoscopies have been shown to reduce CRC-related mortality [43]. At present, prevention of CRC through colonoscopies every 1–2 years in gene carriers, starting at ages 20 to 25 years, is the recommended schedule of colorectal follow-up [44]. Indeed, it is mandatory for the MMR gene mutation carriers to perform a full colonoscopy every 1–2 years for the whole life, because of the high penetrance of the diseases. It should be also offered to selected patients the option of a prophylactic colectomy, though there are still few data to recommend it in all gene mutation carriers. Furthermore, in some families an increased risk of endometrial and ovarian cancers has been observed, and they must undergo screening also for gynecological cancers through transvaginal ultrasound starting from 25–30 years, and then every 2–3 years, though this approach has not yet proven to be effective in reducing cancer mortality. 2.2.2. Familial adenomatous polyposis FAP is the most frequent hereditary colorectal polyposis syndrome. Data from cancer registries show that classical FAP (at least 100 adenomas in the colorectum of affected patients) accounts for less than 1% of
Please cite this article as: Roncucci L, Mariani F, Prevention of colorectal cancer: How many tools do we have in our basket?, Eur J Intern Med (2015), http://dx.doi.org/10.1016/j.ejim.2015.08.019
L. Roncucci, F. Mariani / European Journal of Internal Medicine xxx (2015) xxx–xxx
3
Table 1 Genetic transmission, molecular defects, screening and preventive strategies for colorectal cancer in the most common hereditary colorectal cancer syndromes (HCRC). HCRC
Phenotype
Genetic transmission
Molecular defects
Screening and prevention
Lynch syndrome
Cancer at an early age
Autosomal dominant
Familial adenomatous polyposis (classical) Familial adenomatous polyposis (attenuated)
100 or more colorectal adenomas. Extracolonic manifestations Less than 100 colorectal adenomas. Extracolonic manifestations
Autosomal dominant (APC) or recessive (MUTYH) Autosomal recessive (MUTYH) or dominant (APC)
Mutation in a DNA mismatch-repair gene Mutation in APC or MUTYH Mutation in MUTYH or APC
Colonoscopy at 20–25 years, and then every 1–2 years Colonoscopy and then prophylactic colectomy
all CRC cancer [45]. The syndrome is caused by mutations in the APC gene, or, in a minority of patients, by mutations in the base excision repair MUTYH gene (Table 1). In the former case it is inherited as an autosomal dominant trait, in the latter as an autosomal recessive trait. Whatever the cause, careful surveillance colonoscopies and prophylactic colectomy result in reduction of mortality in FAP patients [46], though the evidence is based on observational studies, and the cause of death is often attributable to extracolonic manifestations of the disease [47–49]. However, total colectomy with ileorectal or ileo-anal anastomosis with ileal reservoir is mandatory in patients with classical FAP, otherwise they develop a CRC, usually at 10–20 years since the onset of the full-blown FAP phenotype [50]. After colectomy, our follow-up schedule provides that patients will be followed with an annual endoscopic evaluation of the residual rectal stump, or every 3 years for the ileal reservoir. It should be borne in mind that patients with classical FAP should undergo also a careful examination of the upper digestive system (stomach duodenum) with endoscopy every 1–3 years, and where available, of the small bowel with endoscopic videocapsule. This surveillance is necessary because of the high prevalence of adenomas of the upper digestive tract. As a matter of fact, carcinoma of the ampulla of Vater is the second cause of death in these patients [50]. Attenuated FAP (AFAP) can be defined as the presence of less than 100 adenomas in the large bowel (usually 10–99). This disease has a milder phenotype when compared with classical FAP, if not treated CRC develops later (usually at 40–60 yrs). Genetically, it is caused more frequently by mutations in the MUTYH gene, thus it has a recessive pattern of transmission, or, less frequently by mutations in the APC gene, and in this case it is inherited as a dominant trait, as for the classical FAP. From a practical point of view, we recommend the endoscopic removal of polyps, when they are less than 30–40, or according to the local endoscopic skills; when polyps are more numerous total colectomy is usually necessary. The surveillance program after colectomy is the same as for the classical FAP. 2.3. Inflammatory bowel diseases (IBD) Patients with inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), have an increased risk of developing CRC, and other intestinal neoplasms, especially in the youngest [51], though the magnitude of risk was somewhat overestimated in
Colonoscopy and endoscopic polypectomies, or prophylactic colectomy
the past [52]. IBD-associated CRC has a worse prognosis than non IBDassociated ones [53,54], and it accounts for 10%–15% of deaths in IBD, though other causes of death in patients with IBD seem to have gained more weight in recent years [55]. The risk increases with longer duration, extent and degree of colitis, and coexistent primary sclerosing cholangitis. Colonoscopy with multiple biopsies to detect dysplasia is the procedure of choice, because it reduces mortality [56], though surveillance guidelines are not based on solid evidence, but on findings of retrospective or case–control studies [57], and the endoscopic recommendations differ among countries [58]. Guidelines suggest surveillance colonoscopy for patients with colitis 8 to 10 years after diagnosis [59]. Recently new endoscopic techniques have been introduced in order to ease the evaluation of dysplasia in the colonic mucosa [60]. Colectomy is suggested to patients whose biopsy findings are indicative of increased cancer risk based on interpretation by pathologists [61]. We suggest patients to undergo surveillance colonoscopy after 10 years of inflammation of the colonic mucosa. Biopsies should be taken on every abnormal/suspected area of the mucosa, and the subsequent follow-up (including surgery) must be driven by pathological results. 3. Targeted prevention As a summary of the evidence presented above, we suggest a scheme of prevention based on the level of risk of colorectal cancer of a given individual (Table 2). During the whole life-span a healthy lifestyle should be recommended, in the light of judgments based on the best scientific evidence available. The recommendations are more justified in countries and regions at high incidence of colorectal cancer. Between 50–55 and 70 years, a screening program should be offered to people, taking into account the level of the risk and the attitude toward screening of the population, the economic impact, and the skills of the personnel involved in the program. When an inherited colorectal cancer syndrome of colorectal cancer is diagnosed or strongly suspected a targeted follow-up should be designed for the proband and the whole family, along with the results of genetic testing. For inflammatory bowel diseases, we think that colonoscopic surveillance should be started after 10 years since the diagnosis, with the
Table 2 Targeted prevention. Preventive measures and goals based upon the level of risk of a given individual. Population
Levels of risk
Prevention
Measures
Goals
Population at large
All
Primary prevention
Promotion of a healthy lifestyle
Individuals aged 50/55–70 yrs
Average
Secondary prevention
Hereditary colorectal cancer syndromes (HCRC)
High
Secondary prevention
Screening with: FOBT Sigmoidoscopy Colonoscopy Colonoscopy, targeted examinations Genetic testing
Body fatness Physical activity Plant and animal foods Alcoholic drinks Early colorectal cancer detection Adenoma detection and removal
Inflammatory bowel diseases (IBD)
High
Secondary prevention
Colonoscopy Pathological examination of mucosal biopsies
Early colorectal cancer detection Adenoma detection and removal Prophylactic colectomy Early colorectal cancer detection
Please cite this article as: Roncucci L, Mariani F, Prevention of colorectal cancer: How many tools do we have in our basket?, Eur J Intern Med (2015), http://dx.doi.org/10.1016/j.ejim.2015.08.019
4
L. Roncucci, F. Mariani / European Journal of Internal Medicine xxx (2015) xxx–xxx
subsequent follow-up scheduled on the basis of the surface of the colonic mucosa involved by inflammation, and the results of the pathological examination of mucosal biopsies in suspected areas. Conclusions Prevention of colorectal cancer is the main approach to reduce colorectal cancer mortality. It may be pursued through different ways. Although primary prevention should be the goal for future years, because it acts on the probable causes of CRC, at present it seems that secondary prevention is more effective on colorectal cancer survival, and the strategies which have yielded the most solid results in terms of reduced mortality for cancer are those aimed at detecting preneoplastic lesions, or cancer at an early stage in selected groups of subjects at average or increased risk of CRC. These groups are subjects aged 50 years or older, family members of hereditary colorectal cancer syndromes, and patients with inflammatory bowel diseases. Indeed, the more widespread implementation of CRC screening may in part explain the decrease of colorectal cancer mortality at the population level, observed in many countries. Future research should be addressed to find new approaches that will render preventive strategies more acceptable for the general populations, and more cost-effective. Any effort should also be taken in order to keep testing these preventive approaches, both in experimental models and in randomized clinical trials in humans. Conflict of interests The authors state that they have no conflicts of interest. Acknowledgments We wish to thank the Associazione per la Ricerca sui Tumori Intestinali (ARTI) for its valuable support. References [1] Ferlay I, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359–86. http://dx.doi.org/10.1002/ ijc.29210. [2] World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective. Washington DC: AICR; 2007. p. 280–8. [3] Giovannucci E. Modifiable risk factors for colon cancer. Gastroenterol Clin N Am 2002;31:925–43. [4] Ames BN, Gold LS, Willett WC. The causes and prevention of cancer. Proc Natl Acad Sci U S A 1995;92:5258–65. [5] Potter JD. Colorectal cancer: molecules and populations. J Natl Cancer Inst 1999;91: 916–32. [6] Bruce WR, Giacca A, Medline A. Possible mechanisms relating diet and risk of colon cancer. Cancer Epidemiol Biomarkers Prev 2000;9:1271–9. [7] Bruce WR, Eyssen GM, Ciampi A, Dion PW, Boyd N. Strategies for dietary intervention studies in colon cancer. Cancer 1981;47(Suppl. 5):1121–5. [8] Roncucci L, Stamp D, Medline A, Cullen JB, Bruce WR. Identification and quantification of aberrant crypt foci and microadenomas in the human colon. Hum Pathol 1991;22:287–94. [9] Rijken PJ, Timmer WG, van de Kooij AJ, van Benschop IM, Wiseman SA, Meijers M, et al. Effect of vegetable and carotenoid consumption on aberrant crypt multiplicity, a surrogate end-point marker for colorectal cancer in azoxymethane-induced rats. Carcinogenesis 1999;20:2267–72. [10] Corpet DE, Pierre F. How good are rodent models of carcinogenesis in predicting efficacy in humans? A systematic review and meta-analysis of colon chemoprevention in rats, mice and men. Eur J Cancer 2005;41:1911–22. [11] Holt PR, Wolper C, Moss SF, Yang K, Lipkin M. Comparison of calcium supplementation or low-fat dairy foods on epithelial cell proliferation and differentiation. Nutr Cancer 2001;41:150–5. [12] McKeown-Eyssen GE, Bright-See E, Bruce WR, Jazmaji V, Cohen LB, Pappas SC, et al. A randomized trial of a low fat high fibre diet in the recurrence of colorectal polyps. Toronto Polyp Prevention Group. J Clin Epidemiol 1994;47:525–36. [13] Beresford SA, Johnson KC, Ritenbaugh C, Lasser NL, Snetselaar LG, Black HR, et al. Low-fat dietary pattern and risk of colorectal cancer: the Women's Health Initiative randomized controlled dietary modification trial. JAMA 2006;295:643–54.
[14] Lanza E, Yu B, Murphy G, Alberts PS, Caan B, Marshall JR, et al. The polyp prevention trial continued follow-up study: no effect of a low-fat, high-fiber, high-fruit, and -vegetable diet on adenoma recurrence eight years after randomization. Cancer Epidemiol Biomarkers Prev 2007;16:1745–52. [15] Greenberg ER, Baron JA, Tosteson TD, Freeman Jr DH, Beck GJ, Bond JH, et al. A clinical trial of antioxidant vitamins to prevent colorectal adenoma. N Engl J Med 1994;331:141–7. [16] MacLennan R, Macrae F, Bain C, Battistutta D, Chapuis P, Gratten H, et al. Randomized trial of intake of fat, fiber, and beta carotene to prevent colorectal adenomas. J Natl Cancer Inst 1995;87:1760–6. [17] Hofstad B, Almendingen K, Vatn M, Andersen SN, Owen RW, Larsen S, et al. Growth and recurrence of colorectal polyps: a double-blind 3-year intervention with calcium and antioxidants. Digestion 1998;59:148–56. [18] Baron JA, Beach M, Mandel JS, van Stolk RU, Haile RW, Sandler RS, et al. Calcium supplements and colorectal adenomas. Ann N Y Acad Sci 1999;889:138–45. [19] Bonithon-Kopp C, Kronborg O, Giacosa A, Räth U, Faivre J, European Cancer Prevention Organisation Study Group. Calcium and fibre supplementation in prevention of colorectal adenoma recurrence: a randomised intervention trial. Lancet 2000;356: 1300–6. [20] Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR, Brunner RL, O’Sullivan MJ, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684–96. [21] Sandler RS, Halabi S, Baron JA, Budinger S, Paskett E, Keresztes R, et al. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med 2003;348:883–90. [22] Bertagnolli MM, Eagle CJ, Zauber AG, Redston M, Solomon SD, Kim KM, et al. Celecoxib for the prevention of sporadic colorectal adenoma. N Engl J Med 2006; 355:873–84. [23] Baron JA, Sandler RS, Bresalier RS, Quan H, Riddell R, Lanas A, et al. A randomized trial of rofecoxib for the chemoprevention of colorectaladenomas. Gastroenterology 2006;131:1674–82. [24] Bresalier RS. Chemoprevention of colorectal cancer: why all the confusion? Curr Opin Gastroenterol 2008;24:48–50. [25] Ponz de Leon M, Benatti P, Goldoni CA, Domati F, Kaleci S, Maffei S, et al. Epidemiology of tumors of the colon and rectum. Incidence, mortality, familiality and survival in the health care district of Modena, 1984–2004. University of Modena and Reggio Emilia; 2011. [26] Løberg M, Kalager M, Holme Ø, Hoff G, Adami HO, Bretthauer M. Long-term colorectal-cancer mortality after adenoma removal. N Engl J Med 2014;371: 799–807. [27] Hewitson P, Glasziou P, Watson E, Towler B, Irwig L. Cochrane systematic review of colorectal cancer screening using the fecal occult blood test (hemoccult): an update. Am J Gastroenterol 2008;103:1541–9. [28] Zorzi M, Fedeli U, Schievano E, Bovo E, Guzzinati S, Baracco S, et al. Impact on colorectal cancer mortality of screening programmes based on the faecal immunochemical test. Gut Sep 1 2014. http://dx.doi.org/10.1136/gutjnl-2014-307508 [pii: gutjnl-2014-307508, Epub ahead of print]. [29] Selby JV, Friedman GD, Quesenberry Jr CP, Weiss NS. A case–control study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med 1992;326: 653–7. [30] Atkin WS, Edwards R, Kralj-Hans I, Wooldrage K, Hart AR, Northover JM, et al. Onceonly flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial. Lancet 2010;375:1624–33. [31] Manser CN, Bachmann LM, Brunner J, Hunold F, Bauerfeind P, Marbet UA. Colonoscopy screening markedly reduces the occurrence of colon carcinomas and carcinoma-related death: a closed cohort study. Gastrointest Endosc 2012;76:110–7. [32] Brenner H, Chang-Claude J, Jansen L, Knebel P, Stock C, Hoffmeister M. Reduced risk of colorectal cancer up to 10 years after screening, surveillance, or diagnostic colonoscopy. Gastroenterology 2014;146:709–17. [33] Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin 2014; 64:104–17. [34] Rutter CM, Johnson EA, Feuer EJ, Knudsen AB, Kuntz KM, Schrag D. Secular trends in colon and rectal cancer relative survival. J Natl Cancer Inst 2013;105:1806–13. [35] Rossi S, Crocetti E, Capocaccia R, Gatta G, A.I.R.T.U.M. Working Group. Estimates of cancer burden in Italy. Tumori 2013;99:416–24. [36] Maringe C, Walters S, Rachet B, Butler J, Fields T, Finan P, et al. Stage at diagnosis and colorectal cancer survival in six high-income countries: a population-based study of patients diagnosed during 2000–2007. Acta Oncol 2013;52:919–32. [37] Atkin W. Options for screening for colorectal cancer. Scand J Gastroenterol Suppl 2003;237:13–6. [38] Sonoda H, Kohnoe S, Yamazato T, Satoh Y, Morizono G, Shikata K, et al. Colorectal cancer screening with odour material by canine scent detection. Gut 2011; 60:814–9. [39] Ponz de Leon M, Benatti P, Pezzi A, Roncucci L, Di Gregorio C, Losi L, et al. Hereditary colorectal cancer (Lynch syndrome). The Experience of the Study Group on Colorectal Tumors of the University of Modena and Reggio Emilia and of the University Hospital of Modena. University of Modena and Reggio Emilia; 2007. [40] Ponz de Leon M, Sassatelli R, Benatti P, Roncucci L. Identification of hereditary nonpolyposis colorectal cancer in the general population. Cancer 1993;71: 3493–501. [41] Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology 1999;116:1453–6. [42] Bailey-Wilson JE, Elston RC, Schuelke GS, Kimberling W, Albano W, Lynch JF, et al. Segregation analysis of hereditary nonpolyposis colorectal cancer. Genet Epidemiol 1986;3:27–38.
Please cite this article as: Roncucci L, Mariani F, Prevention of colorectal cancer: How many tools do we have in our basket?, Eur J Intern Med (2015), http://dx.doi.org/10.1016/j.ejim.2015.08.019
L. Roncucci, F. Mariani / European Journal of Internal Medicine xxx (2015) xxx–xxx [43] Jarvinen HJ, Aarnio M, Mustonen H, Aktan-Collan K, Aaltonen LA, Peltomäki P, et al. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 2000;118:829–34. [44] Vasen HFA, Blanco I, Aktan-Collan K, Gopie JP, Alonso A, Aretz S, et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut 2013;62:812–23. [45] Ponz de Leon M, Di Gregorio C, Roncucci L, Benatti P, Fante R, Rossi G, et al. Epidemiology of Tumors of the Colon and Rectum. Incidence, Mortality, Familiality, and Survival in the Health Care District of Modena, 1984–1995; June 1998(University of Modena). [46] Vasen HF, Möslein G, Alonso A, Aretz S, Bernstein I, Bertario L, et al. Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut 2008;57: 704–13. [47] Arvanitis ML, Jagelman DG, Fazio VW, Lavery IC, McGannon E. Mortality in patients with familial adenomatous polyposis. Dis Colon Rectum 1990;33:639–42. [48] Nugent KP, Spigelman AD, Phillips RK. Life expectancy after colectomy and ileorectal anastomosis for familial adenomatous polyposis. Dis Colon Rectum 1993;36: 1059–62. [49] Belchetz LA, Berk T, Bapat BV, Cohen Z, Gallinger S. Changing causes of mortality in patients with familial adenomatous polyposis. Dis Colon Rectum 1996;39:384–7. [50] Utsunomiya J, Murata M, Tanimura M. An analysis of the age distribution of colon cancer in adenomatosis coli. Cancer 1980;45:198–205. [51] Jussila A, Virta LJ, Pukkala E, Färkkilä MA. Malignancies in patients with inflammatory bowel disease: a nationwide register study in Finland. Scand J Gastroenterol 2013;48: 1405–13. [52] Baars JE, Looman CW, Steyerberg EW, Beukers R, Tan AC, Weusten BL, et al. The risk of inflammatory bowel disease-related colorectal carcinoma is limited: results from a nationwide nested case–control study. Am J Gastroenterol 2011; 106:319–28.
5
[53] Adams SV, Ahnen DJ, Baron JA, Campbell PT, Gallinger S, Grady WM, et al. Survival after inflammatory bowel disease-associated colorectal cancer in the Colon Cancer Family Registry. World J Gastroenterol 2013;19:3241–8. [54] Hrabe JE, Byrn JC, Button AM, Zamba GK, Kapadia MR, Mezhir JJ. A matched case– control study of IBD-associated colorectal cancer: IBD portends worse outcome. J Surg Oncol 2014;109:117–21. [55] Kassam Z, Belga S, Roifman I, Hirota S, Jijon H, Kaplan GG, et al. Inflammatory bowel disease cause-specific mortality: a primer for clinicians. Inflamm Bowel Dis 2014;20: 2483–92. [56] Choi PM, Nugent FW, Schoetz Jr DJ, Silverman ML, Haggitt RC. Colonoscopic surveillance reduces mortality from colorectal cancer in ulcerative colitis. Gastroenterology 1993;105:418–24. [57] Ananthakrishnan AN, Cagan A, Cai T, Gainer VS, Shaw SY, Churchill S, et al. Colonoscopy is associated with a reduced risk for colon cancer and mortality in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol 2014, Jul 17. http://dx.doi. org/10.1016/j.cgh.2014.07.018 [pii: S1542-3565(14)01047-7, Epub ahead of print]. [58] Shergill AK, Farraye FA. Toward a consensus on endoscopic surveillance of patients with colonic inflammatory bowel disease. Gastrointest Endosc Clin N Am 2014;24: 469–81. [59] Dyson JK, Rutter MD. Colorectal cancer in inflammatory bowel disease: what is the real magnitude of the risk? World J Gastroenterol 2012;18:3839–48. [60] Iacucci M, Uraoka T, Fort Gasia M, Yahagi N. Novel diagnostic and therapeutic techniques for surveillance of dysplasia in patients with inflammatory bowel disease. Can J Gastroenterol Hepato 2014;28:361–70. [61] Itzkowitz SH, Present DH, Crohn's and Colitis Foundation of America Colon Cancer in IBD Study Group. Consensus conference: colorectal cancer screening and surveillance in inflammatory bowel disease. Inflamm Bowel Dis 2005;11:314–21.
Please cite this article as: Roncucci L, Mariani F, Prevention of colorectal cancer: How many tools do we have in our basket?, Eur J Intern Med (2015), http://dx.doi.org/10.1016/j.ejim.2015.08.019
Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Review Article
Prevention of colorectal cancer: How many tools do we have in our basket? Luca Roncucci ⁎, Francesco Mariani Department of Diagnostic and Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Policlinico, Via Del Pozzo 71, Modena 41124, Italy
a r t i c l e
i n f o
Article history: Received 27 March 2015 Received in revised form 16 July 2015 Accepted 7 August 2015 Available online xxxx Keywords: Colorectal cancer prevention Chemoprevention Screening Hereditary colorectal cancer Inflammatory bowel diseases
a b s t r a c t Prevention is the main strategy in order to reduce colorectal cancer incidence and mortality. It can be accomplished through primary prevention, using measures affecting factors known to confer higher risk of colorectal cancer, or through secondary prevention, aimed at early diagnosis of cancer or preneoplastic lesions in groups of subjects at increased risk of cancer. Although primary prevention should be the goal for future years, because it acts on the probable causes of colorectal cancer, at present it seems that secondary prevention is more effective on colorectal cancer survival, and the approaches which have yielded the most satisfying results, in terms of reduced mortality for cancer, are those aimed at detecting preneoplastic lesions, or cancer at an early stage in selected groups of subjects at average or increased risk of colorectal cancer. These groups are subjects aged 50 years or older, affected individuals (gene carriers) or family members of hereditary colorectal cancer syndromes (i.e., Lynch syndrome and familial adenomatous polyposis), and patients with inflammatory bowel diseases. The most effective procedures used, though with some drawbacks, are fecal occult blood tests and colonoscopy. Future research should be addressed to find new approaches that will render preventive strategies more acceptable for the population, and more cost-effective. © 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Introduction Colorectal cancer (CRC) is a major cause of incidence and mortality in many countries, especially in more developed ones, though in very recent years its incidence is increasing also in developing areas of the world [1]. There is a wide epidemiological and observational evidence that the risk of colorectal cancer is strictly related to lifestyle, especially to diet and physical activity [2]. In analytical case–control and cohort studies, risk is directly associated with the consumption of red and processed meat, and with abdominal fatness, and inversely related to physical activity. Somewhat at a lesser extent, dietary fiber seems to reduce the risk. For many years researchers have taken advantage of the fact that colorectal carcinogenesis is a stepwise process, lasting several years, since its beginning as a single mutational event in a cell, until detectable malignancy. Meanwhile, it is supposed that several actions might be taken or planned, or almost thought to be tested in several models, in order to change the course of the process, either stopping or slowing it. At present, two main preventive strategies for colorectal cancer are being in action: primary prevention affecting risk factors, and secondary prevention aimed at the early detection of preneoplastic or neoplastic lesions in the large bowel, in populations at average or increased risk, mainly because of age, hereditary colorectal cancer syndromes, or inflammatory bowel diseases. Only some of them have reached strong ⁎ Corresponding author. Tel.: +39 59 4224052; fax +39 59 4222958. E-mail address: [email protected] (L. Roncucci).
and sound results in terms of decreasing incidence and mortality for CRC. We will discuss the effectiveness of these strategies, taking into account only solid evidence coming from randomized clinical trials or guidelines of scientific societies. Articles have been selected using the following keywords: prevention of colorectal cancer, chemoprevention of colorectal cancer, colorectal cancer screening, Lynch syndrome, familial adenomatous polyposis, inflammatory bowel diseases, and the time period of the search was October–December 2014. 1. Primary prevention through measures affecting risk factors: Lessons from chemopreventive studies The available evidence indicates that primary prevention of colorectal cancer is feasible. At least 70% of colon cancers may be – at least in theory – preventable by changes in diet and lifestyle [3]. The target of primary prevention is the general population at large. The perspective of reducing colorectal cancer incidence and mortality through multiple dietary modifications or adding substances to the diet is very attractive. However, we need studies on high colorectal cancer risk patients to gather information useful for the general population. The main problem of this approach is that actions are based only on hypotheses or epidemiological evidence linking lifestyle and colorectal cancer [4–6]. Another issue is the long time a randomized clinical trial would last in order to see any effect of an intervention, having cancer mortality as an end point [7]. To overcome that problem researchers have adopted “surrogate” end points for colorectal cancer mortality so far, either very early in carcinogenesis (“tumor markers”) or later, i.e., aberrant
http://dx.doi.org/10.1016/j.ejim.2015.08.019 0953-6205/© 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Please cite this article as: Roncucci L, Mariani F, Prevention of colorectal cancer: How many tools do we have in our basket?, Eur J Intern Med (2015), http://dx.doi.org/10.1016/j.ejim.2015.08.019
2
L. Roncucci, F. Mariani / European Journal of Internal Medicine xxx (2015) xxx–xxx
crypt foci or microadenomas [8], adenomas, and colorectal cancer incidence. Earlier markers have the drawback to be linked too loosely with cancer. Indeed, despite interesting observations in animal studies [9, 10], and in human short-term biochemical risk marker trials [11], major human intervention studies of dietary manipulations on patients at increased risk of colorectal cancer have largely failed to demonstrate any robust effect, or results were not consistent [12–14]. Similarly, chemoprevention with dietary supplementation with fiber, antioxidant vitamins, and minerals (mainly calcium) provided negative or inconsistent results on adenoma recurrence [15–20]. On the other hand, when considering chemoprevention with drugs, those more frequently investigated are non-steroid anti-inflammatory drugs (NSAIDs), and, among them, 5-aminosalicylic acid, sulindac, and cyclooxygenase 2 inhibitors (celecoxib and rofecoxib). Supplementations with these drugs were consistently effective in preventing adenoma onset or recurrence [21–23], but their gastrointestinal and/or cardiovascular toxicity render them not suitable for prevention. Taken together, results of prospective human randomized chemopreventive trials were not in line with those of observational studies, for different reasons [24]. In addition, primary prevention does not eliminate the need of follow-up or surveillance for the disease. Thus, at present, any dietary, lifestyle or chemopreventive recommendations aimed at reducing colorectal cancer mortality, is premature for the general population. The real problem is that we do not have completely unraveled the complex network of the causes of CRC. This fact reinforces the need for studies on risk factors, and it does not mean that active research on prevention based on lifestyle modifications should be stopped. The available epidemiological evidence for colon and rectal cancers suggests that physical activity decreases the risk, whereas body (especially abdominal) fatness, and the consumption of red and processed meat, and of alcoholic beverages increase the risk. Thus, from a practical point of view, recommendations should be given to the general population, in order to encourage a healthy lifestyle. At present, the “milestones” recommendations for colorectal cancer are: be as lean as possible within the normal range of body weight, be physically active as part of everyday life, eat mostly foods of plant origin (especially foods containing dietary fiber), limit intake of red meat and avoid processed meat, and limit alcoholic drinks [2]. 2. Secondary prevention Secondary prevention of colorectal cancer is targeted at populations at average or increased risk of colorectal cancer. At present, they are: general population at increased risk because of age, subjects belonging to families with hereditary colorectal cancer syndromes, and patients with longstanding and widespread inflammatory bowel diseases. 2.1. General population Screening programs are mostly targeted at adults older than 50–55 years, a population at increased risk of developing adenomas and cancer [25]. These programs have been implemented at regional and national levels all over the world, though they differ considerably across countries. At present screening is based on some methods with different advantages and drawbacks, and different economic impact. The most employed are fecal occult blood tests (FOBT) or, more recently, fecal immunological tests (FIT), flexible sigmoidoscopy (FS) and colonoscopy (C). FOBT and FIT are based on the assumption that a colorectal adenoma or cancer bleeds, but this is not always the case. FS and C may allow to remove adenomas and to detect a malignancy at an early stage. Adenoma removal reduces long term colorectal cancer mortality [26]. The effectiveness of screening policies in reducing cancerrelated mortality has been evaluated with randomized clinical trials and systematic reviews of their results, or indirectly by observational studies based on incidence and mortality data from cancer registries at the population level. Indeed, colorectal cancer screening with FOBT,
flexible sigmoidoscopy or colonoscopy has been shown to reduce incidence of colorectal cancer and cancer-related mortality [27–34], though for screening colonoscopy randomized clinical trials are still lacking. Cancer registries are particularly useful in order to evaluate the impact of prevention strategies [35]. However, caution should be used when interpreting mortality data from cancer registries, because of wide differences in stage distribution among countries [36]. It is necessary to develop new screening approaches, for example using new innovative technologies such as computed tomographic colonography and stool screening for molecular markers [37,38]. Where available, a screening program for colorectal cancer is probably the best way to prevent colorectal cancer. This would provide the most benefit for the population, though the participation rates for the various screening programs should be improved. A valid alternative for us could be performing a once-in a lifetime colonoscopy at the age of 50–55, in line with the age-specific incidence of colorectal cancer at the population level [25]. 2.2. Hereditary colorectal cancer (HCRC) The most frequent forms of HCRC are Lynch syndrome (LS) and familial adenomatous polyposis (FAP). The genetic bases of both diseases have been clarified in the early 1990s. Prevention of CRC in gene carriers (i.e., patient carriers of a deleterious mutation in a DNA mismatch-repair [MMR] gene, and in adenomatous polyposis coli [APC] or MUTYH genes, respectively) can be accomplished through follow-up colonoscopies with removal of adenomas (when feasible), or prophylactic colectomy (in selected cases) (Table 1). 2.2.1. Lynch syndrome LS is the most frequent autosomal dominant hereditary colorectal cancer syndrome. It accounts for approximately 1%–2% of the whole colorectal cancer burden in the population, at least in western countries, considering only MMR gene carriers [39]. Our approach used to identify DNA MMR gene carriers is based on a careful evaluation of the nuclear family pedigree (limited to first-degree relatives of the proband affected by colorectal cancer), in order to find out the clinical feature of a Lynch syndrome, according to some criteria which, if present, prompt us to expand the pedigree to second and third-degree relatives [40]. Then, in this expanded pedigree, we evaluate whether the international validated criteria for the clinical diagnosis of Lynch syndrome (the so-called Amsterdam II criteria [41]) are satisfied. The molecular genetic test for the identification of the deleterious mutation in a DNA MMR gene is offered to the proband and then to all the family members at risk. DNA MMR gene carriers have a high life-time risk of developing cancer in the large bowel [42], and in other organs. Surveillance colonoscopies have been shown to reduce CRC-related mortality [43]. At present, prevention of CRC through colonoscopies every 1–2 years in gene carriers, starting at ages 20 to 25 years, is the recommended schedule of colorectal follow-up [44]. Indeed, it is mandatory for the MMR gene mutation carriers to perform a full colonoscopy every 1–2 years for the whole life, because of the high penetrance of the diseases. It should be also offered to selected patients the option of a prophylactic colectomy, though there are still few data to recommend it in all gene mutation carriers. Furthermore, in some families an increased risk of endometrial and ovarian cancers has been observed, and they must undergo screening also for gynecological cancers through transvaginal ultrasound starting from 25–30 years, and then every 2–3 years, though this approach has not yet proven to be effective in reducing cancer mortality. 2.2.2. Familial adenomatous polyposis FAP is the most frequent hereditary colorectal polyposis syndrome. Data from cancer registries show that classical FAP (at least 100 adenomas in the colorectum of affected patients) accounts for less than 1% of
Please cite this article as: Roncucci L, Mariani F, Prevention of colorectal cancer: How many tools do we have in our basket?, Eur J Intern Med (2015), http://dx.doi.org/10.1016/j.ejim.2015.08.019
L. Roncucci, F. Mariani / European Journal of Internal Medicine xxx (2015) xxx–xxx
3
Table 1 Genetic transmission, molecular defects, screening and preventive strategies for colorectal cancer in the most common hereditary colorectal cancer syndromes (HCRC). HCRC
Phenotype
Genetic transmission
Molecular defects
Screening and prevention
Lynch syndrome
Cancer at an early age
Autosomal dominant
Familial adenomatous polyposis (classical) Familial adenomatous polyposis (attenuated)
100 or more colorectal adenomas. Extracolonic manifestations Less than 100 colorectal adenomas. Extracolonic manifestations
Autosomal dominant (APC) or recessive (MUTYH) Autosomal recessive (MUTYH) or dominant (APC)
Mutation in a DNA mismatch-repair gene Mutation in APC or MUTYH Mutation in MUTYH or APC
Colonoscopy at 20–25 years, and then every 1–2 years Colonoscopy and then prophylactic colectomy
all CRC cancer [45]. The syndrome is caused by mutations in the APC gene, or, in a minority of patients, by mutations in the base excision repair MUTYH gene (Table 1). In the former case it is inherited as an autosomal dominant trait, in the latter as an autosomal recessive trait. Whatever the cause, careful surveillance colonoscopies and prophylactic colectomy result in reduction of mortality in FAP patients [46], though the evidence is based on observational studies, and the cause of death is often attributable to extracolonic manifestations of the disease [47–49]. However, total colectomy with ileorectal or ileo-anal anastomosis with ileal reservoir is mandatory in patients with classical FAP, otherwise they develop a CRC, usually at 10–20 years since the onset of the full-blown FAP phenotype [50]. After colectomy, our follow-up schedule provides that patients will be followed with an annual endoscopic evaluation of the residual rectal stump, or every 3 years for the ileal reservoir. It should be borne in mind that patients with classical FAP should undergo also a careful examination of the upper digestive system (stomach duodenum) with endoscopy every 1–3 years, and where available, of the small bowel with endoscopic videocapsule. This surveillance is necessary because of the high prevalence of adenomas of the upper digestive tract. As a matter of fact, carcinoma of the ampulla of Vater is the second cause of death in these patients [50]. Attenuated FAP (AFAP) can be defined as the presence of less than 100 adenomas in the large bowel (usually 10–99). This disease has a milder phenotype when compared with classical FAP, if not treated CRC develops later (usually at 40–60 yrs). Genetically, it is caused more frequently by mutations in the MUTYH gene, thus it has a recessive pattern of transmission, or, less frequently by mutations in the APC gene, and in this case it is inherited as a dominant trait, as for the classical FAP. From a practical point of view, we recommend the endoscopic removal of polyps, when they are less than 30–40, or according to the local endoscopic skills; when polyps are more numerous total colectomy is usually necessary. The surveillance program after colectomy is the same as for the classical FAP. 2.3. Inflammatory bowel diseases (IBD) Patients with inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), have an increased risk of developing CRC, and other intestinal neoplasms, especially in the youngest [51], though the magnitude of risk was somewhat overestimated in
Colonoscopy and endoscopic polypectomies, or prophylactic colectomy
the past [52]. IBD-associated CRC has a worse prognosis than non IBDassociated ones [53,54], and it accounts for 10%–15% of deaths in IBD, though other causes of death in patients with IBD seem to have gained more weight in recent years [55]. The risk increases with longer duration, extent and degree of colitis, and coexistent primary sclerosing cholangitis. Colonoscopy with multiple biopsies to detect dysplasia is the procedure of choice, because it reduces mortality [56], though surveillance guidelines are not based on solid evidence, but on findings of retrospective or case–control studies [57], and the endoscopic recommendations differ among countries [58]. Guidelines suggest surveillance colonoscopy for patients with colitis 8 to 10 years after diagnosis [59]. Recently new endoscopic techniques have been introduced in order to ease the evaluation of dysplasia in the colonic mucosa [60]. Colectomy is suggested to patients whose biopsy findings are indicative of increased cancer risk based on interpretation by pathologists [61]. We suggest patients to undergo surveillance colonoscopy after 10 years of inflammation of the colonic mucosa. Biopsies should be taken on every abnormal/suspected area of the mucosa, and the subsequent follow-up (including surgery) must be driven by pathological results. 3. Targeted prevention As a summary of the evidence presented above, we suggest a scheme of prevention based on the level of risk of colorectal cancer of a given individual (Table 2). During the whole life-span a healthy lifestyle should be recommended, in the light of judgments based on the best scientific evidence available. The recommendations are more justified in countries and regions at high incidence of colorectal cancer. Between 50–55 and 70 years, a screening program should be offered to people, taking into account the level of the risk and the attitude toward screening of the population, the economic impact, and the skills of the personnel involved in the program. When an inherited colorectal cancer syndrome of colorectal cancer is diagnosed or strongly suspected a targeted follow-up should be designed for the proband and the whole family, along with the results of genetic testing. For inflammatory bowel diseases, we think that colonoscopic surveillance should be started after 10 years since the diagnosis, with the
Table 2 Targeted prevention. Preventive measures and goals based upon the level of risk of a given individual. Population
Levels of risk
Prevention
Measures
Goals
Population at large
All
Primary prevention
Promotion of a healthy lifestyle
Individuals aged 50/55–70 yrs
Average
Secondary prevention
Hereditary colorectal cancer syndromes (HCRC)
High
Secondary prevention
Screening with: FOBT Sigmoidoscopy Colonoscopy Colonoscopy, targeted examinations Genetic testing
Body fatness Physical activity Plant and animal foods Alcoholic drinks Early colorectal cancer detection Adenoma detection and removal
Inflammatory bowel diseases (IBD)
High
Secondary prevention
Colonoscopy Pathological examination of mucosal biopsies
Early colorectal cancer detection Adenoma detection and removal Prophylactic colectomy Early colorectal cancer detection
Please cite this article as: Roncucci L, Mariani F, Prevention of colorectal cancer: How many tools do we have in our basket?, Eur J Intern Med (2015), http://dx.doi.org/10.1016/j.ejim.2015.08.019
4
L. Roncucci, F. Mariani / European Journal of Internal Medicine xxx (2015) xxx–xxx
subsequent follow-up scheduled on the basis of the surface of the colonic mucosa involved by inflammation, and the results of the pathological examination of mucosal biopsies in suspected areas. Conclusions Prevention of colorectal cancer is the main approach to reduce colorectal cancer mortality. It may be pursued through different ways. Although primary prevention should be the goal for future years, because it acts on the probable causes of CRC, at present it seems that secondary prevention is more effective on colorectal cancer survival, and the strategies which have yielded the most solid results in terms of reduced mortality for cancer are those aimed at detecting preneoplastic lesions, or cancer at an early stage in selected groups of subjects at average or increased risk of CRC. These groups are subjects aged 50 years or older, family members of hereditary colorectal cancer syndromes, and patients with inflammatory bowel diseases. Indeed, the more widespread implementation of CRC screening may in part explain the decrease of colorectal cancer mortality at the population level, observed in many countries. Future research should be addressed to find new approaches that will render preventive strategies more acceptable for the general populations, and more cost-effective. Any effort should also be taken in order to keep testing these preventive approaches, both in experimental models and in randomized clinical trials in humans. Conflict of interests The authors state that they have no conflicts of interest. Acknowledgments We wish to thank the Associazione per la Ricerca sui Tumori Intestinali (ARTI) for its valuable support. References [1] Ferlay I, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359–86. http://dx.doi.org/10.1002/ ijc.29210. [2] World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective. Washington DC: AICR; 2007. p. 280–8. [3] Giovannucci E. Modifiable risk factors for colon cancer. Gastroenterol Clin N Am 2002;31:925–43. [4] Ames BN, Gold LS, Willett WC. The causes and prevention of cancer. Proc Natl Acad Sci U S A 1995;92:5258–65. [5] Potter JD. Colorectal cancer: molecules and populations. J Natl Cancer Inst 1999;91: 916–32. [6] Bruce WR, Giacca A, Medline A. Possible mechanisms relating diet and risk of colon cancer. Cancer Epidemiol Biomarkers Prev 2000;9:1271–9. [7] Bruce WR, Eyssen GM, Ciampi A, Dion PW, Boyd N. Strategies for dietary intervention studies in colon cancer. Cancer 1981;47(Suppl. 5):1121–5. [8] Roncucci L, Stamp D, Medline A, Cullen JB, Bruce WR. Identification and quantification of aberrant crypt foci and microadenomas in the human colon. Hum Pathol 1991;22:287–94. [9] Rijken PJ, Timmer WG, van de Kooij AJ, van Benschop IM, Wiseman SA, Meijers M, et al. Effect of vegetable and carotenoid consumption on aberrant crypt multiplicity, a surrogate end-point marker for colorectal cancer in azoxymethane-induced rats. Carcinogenesis 1999;20:2267–72. [10] Corpet DE, Pierre F. How good are rodent models of carcinogenesis in predicting efficacy in humans? A systematic review and meta-analysis of colon chemoprevention in rats, mice and men. Eur J Cancer 2005;41:1911–22. [11] Holt PR, Wolper C, Moss SF, Yang K, Lipkin M. Comparison of calcium supplementation or low-fat dairy foods on epithelial cell proliferation and differentiation. Nutr Cancer 2001;41:150–5. [12] McKeown-Eyssen GE, Bright-See E, Bruce WR, Jazmaji V, Cohen LB, Pappas SC, et al. A randomized trial of a low fat high fibre diet in the recurrence of colorectal polyps. Toronto Polyp Prevention Group. J Clin Epidemiol 1994;47:525–36. [13] Beresford SA, Johnson KC, Ritenbaugh C, Lasser NL, Snetselaar LG, Black HR, et al. Low-fat dietary pattern and risk of colorectal cancer: the Women's Health Initiative randomized controlled dietary modification trial. JAMA 2006;295:643–54.
[14] Lanza E, Yu B, Murphy G, Alberts PS, Caan B, Marshall JR, et al. The polyp prevention trial continued follow-up study: no effect of a low-fat, high-fiber, high-fruit, and -vegetable diet on adenoma recurrence eight years after randomization. Cancer Epidemiol Biomarkers Prev 2007;16:1745–52. [15] Greenberg ER, Baron JA, Tosteson TD, Freeman Jr DH, Beck GJ, Bond JH, et al. A clinical trial of antioxidant vitamins to prevent colorectal adenoma. N Engl J Med 1994;331:141–7. [16] MacLennan R, Macrae F, Bain C, Battistutta D, Chapuis P, Gratten H, et al. Randomized trial of intake of fat, fiber, and beta carotene to prevent colorectal adenomas. J Natl Cancer Inst 1995;87:1760–6. [17] Hofstad B, Almendingen K, Vatn M, Andersen SN, Owen RW, Larsen S, et al. Growth and recurrence of colorectal polyps: a double-blind 3-year intervention with calcium and antioxidants. Digestion 1998;59:148–56. [18] Baron JA, Beach M, Mandel JS, van Stolk RU, Haile RW, Sandler RS, et al. Calcium supplements and colorectal adenomas. Ann N Y Acad Sci 1999;889:138–45. [19] Bonithon-Kopp C, Kronborg O, Giacosa A, Räth U, Faivre J, European Cancer Prevention Organisation Study Group. Calcium and fibre supplementation in prevention of colorectal adenoma recurrence: a randomised intervention trial. Lancet 2000;356: 1300–6. [20] Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR, Brunner RL, O’Sullivan MJ, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684–96. [21] Sandler RS, Halabi S, Baron JA, Budinger S, Paskett E, Keresztes R, et al. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med 2003;348:883–90. [22] Bertagnolli MM, Eagle CJ, Zauber AG, Redston M, Solomon SD, Kim KM, et al. Celecoxib for the prevention of sporadic colorectal adenoma. N Engl J Med 2006; 355:873–84. [23] Baron JA, Sandler RS, Bresalier RS, Quan H, Riddell R, Lanas A, et al. A randomized trial of rofecoxib for the chemoprevention of colorectaladenomas. Gastroenterology 2006;131:1674–82. [24] Bresalier RS. Chemoprevention of colorectal cancer: why all the confusion? Curr Opin Gastroenterol 2008;24:48–50. [25] Ponz de Leon M, Benatti P, Goldoni CA, Domati F, Kaleci S, Maffei S, et al. Epidemiology of tumors of the colon and rectum. Incidence, mortality, familiality and survival in the health care district of Modena, 1984–2004. University of Modena and Reggio Emilia; 2011. [26] Løberg M, Kalager M, Holme Ø, Hoff G, Adami HO, Bretthauer M. Long-term colorectal-cancer mortality after adenoma removal. N Engl J Med 2014;371: 799–807. [27] Hewitson P, Glasziou P, Watson E, Towler B, Irwig L. Cochrane systematic review of colorectal cancer screening using the fecal occult blood test (hemoccult): an update. Am J Gastroenterol 2008;103:1541–9. [28] Zorzi M, Fedeli U, Schievano E, Bovo E, Guzzinati S, Baracco S, et al. Impact on colorectal cancer mortality of screening programmes based on the faecal immunochemical test. Gut Sep 1 2014. http://dx.doi.org/10.1136/gutjnl-2014-307508 [pii: gutjnl-2014-307508, Epub ahead of print]. [29] Selby JV, Friedman GD, Quesenberry Jr CP, Weiss NS. A case–control study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med 1992;326: 653–7. [30] Atkin WS, Edwards R, Kralj-Hans I, Wooldrage K, Hart AR, Northover JM, et al. Onceonly flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial. Lancet 2010;375:1624–33. [31] Manser CN, Bachmann LM, Brunner J, Hunold F, Bauerfeind P, Marbet UA. Colonoscopy screening markedly reduces the occurrence of colon carcinomas and carcinoma-related death: a closed cohort study. Gastrointest Endosc 2012;76:110–7. [32] Brenner H, Chang-Claude J, Jansen L, Knebel P, Stock C, Hoffmeister M. Reduced risk of colorectal cancer up to 10 years after screening, surveillance, or diagnostic colonoscopy. Gastroenterology 2014;146:709–17. [33] Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin 2014; 64:104–17. [34] Rutter CM, Johnson EA, Feuer EJ, Knudsen AB, Kuntz KM, Schrag D. Secular trends in colon and rectal cancer relative survival. J Natl Cancer Inst 2013;105:1806–13. [35] Rossi S, Crocetti E, Capocaccia R, Gatta G, A.I.R.T.U.M. Working Group. Estimates of cancer burden in Italy. Tumori 2013;99:416–24. [36] Maringe C, Walters S, Rachet B, Butler J, Fields T, Finan P, et al. Stage at diagnosis and colorectal cancer survival in six high-income countries: a population-based study of patients diagnosed during 2000–2007. Acta Oncol 2013;52:919–32. [37] Atkin W. Options for screening for colorectal cancer. Scand J Gastroenterol Suppl 2003;237:13–6. [38] Sonoda H, Kohnoe S, Yamazato T, Satoh Y, Morizono G, Shikata K, et al. Colorectal cancer screening with odour material by canine scent detection. Gut 2011; 60:814–9. [39] Ponz de Leon M, Benatti P, Pezzi A, Roncucci L, Di Gregorio C, Losi L, et al. Hereditary colorectal cancer (Lynch syndrome). The Experience of the Study Group on Colorectal Tumors of the University of Modena and Reggio Emilia and of the University Hospital of Modena. University of Modena and Reggio Emilia; 2007. [40] Ponz de Leon M, Sassatelli R, Benatti P, Roncucci L. Identification of hereditary nonpolyposis colorectal cancer in the general population. Cancer 1993;71: 3493–501. [41] Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology 1999;116:1453–6. [42] Bailey-Wilson JE, Elston RC, Schuelke GS, Kimberling W, Albano W, Lynch JF, et al. Segregation analysis of hereditary nonpolyposis colorectal cancer. Genet Epidemiol 1986;3:27–38.
Please cite this article as: Roncucci L, Mariani F, Prevention of colorectal cancer: How many tools do we have in our basket?, Eur J Intern Med (2015), http://dx.doi.org/10.1016/j.ejim.2015.08.019
L. Roncucci, F. Mariani / European Journal of Internal Medicine xxx (2015) xxx–xxx [43] Jarvinen HJ, Aarnio M, Mustonen H, Aktan-Collan K, Aaltonen LA, Peltomäki P, et al. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 2000;118:829–34. [44] Vasen HFA, Blanco I, Aktan-Collan K, Gopie JP, Alonso A, Aretz S, et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut 2013;62:812–23. [45] Ponz de Leon M, Di Gregorio C, Roncucci L, Benatti P, Fante R, Rossi G, et al. Epidemiology of Tumors of the Colon and Rectum. Incidence, Mortality, Familiality, and Survival in the Health Care District of Modena, 1984–1995; June 1998(University of Modena). [46] Vasen HF, Möslein G, Alonso A, Aretz S, Bernstein I, Bertario L, et al. Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut 2008;57: 704–13. [47] Arvanitis ML, Jagelman DG, Fazio VW, Lavery IC, McGannon E. Mortality in patients with familial adenomatous polyposis. Dis Colon Rectum 1990;33:639–42. [48] Nugent KP, Spigelman AD, Phillips RK. Life expectancy after colectomy and ileorectal anastomosis for familial adenomatous polyposis. Dis Colon Rectum 1993;36: 1059–62. [49] Belchetz LA, Berk T, Bapat BV, Cohen Z, Gallinger S. Changing causes of mortality in patients with familial adenomatous polyposis. Dis Colon Rectum 1996;39:384–7. [50] Utsunomiya J, Murata M, Tanimura M. An analysis of the age distribution of colon cancer in adenomatosis coli. Cancer 1980;45:198–205. [51] Jussila A, Virta LJ, Pukkala E, Färkkilä MA. Malignancies in patients with inflammatory bowel disease: a nationwide register study in Finland. Scand J Gastroenterol 2013;48: 1405–13. [52] Baars JE, Looman CW, Steyerberg EW, Beukers R, Tan AC, Weusten BL, et al. The risk of inflammatory bowel disease-related colorectal carcinoma is limited: results from a nationwide nested case–control study. Am J Gastroenterol 2011; 106:319–28.
5
[53] Adams SV, Ahnen DJ, Baron JA, Campbell PT, Gallinger S, Grady WM, et al. Survival after inflammatory bowel disease-associated colorectal cancer in the Colon Cancer Family Registry. World J Gastroenterol 2013;19:3241–8. [54] Hrabe JE, Byrn JC, Button AM, Zamba GK, Kapadia MR, Mezhir JJ. A matched case– control study of IBD-associated colorectal cancer: IBD portends worse outcome. J Surg Oncol 2014;109:117–21. [55] Kassam Z, Belga S, Roifman I, Hirota S, Jijon H, Kaplan GG, et al. Inflammatory bowel disease cause-specific mortality: a primer for clinicians. Inflamm Bowel Dis 2014;20: 2483–92. [56] Choi PM, Nugent FW, Schoetz Jr DJ, Silverman ML, Haggitt RC. Colonoscopic surveillance reduces mortality from colorectal cancer in ulcerative colitis. Gastroenterology 1993;105:418–24. [57] Ananthakrishnan AN, Cagan A, Cai T, Gainer VS, Shaw SY, Churchill S, et al. Colonoscopy is associated with a reduced risk for colon cancer and mortality in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol 2014, Jul 17. http://dx.doi. org/10.1016/j.cgh.2014.07.018 [pii: S1542-3565(14)01047-7, Epub ahead of print]. [58] Shergill AK, Farraye FA. Toward a consensus on endoscopic surveillance of patients with colonic inflammatory bowel disease. Gastrointest Endosc Clin N Am 2014;24: 469–81. [59] Dyson JK, Rutter MD. Colorectal cancer in inflammatory bowel disease: what is the real magnitude of the risk? World J Gastroenterol 2012;18:3839–48. [60] Iacucci M, Uraoka T, Fort Gasia M, Yahagi N. Novel diagnostic and therapeutic techniques for surveillance of dysplasia in patients with inflammatory bowel disease. Can J Gastroenterol Hepato 2014;28:361–70. [61] Itzkowitz SH, Present DH, Crohn's and Colitis Foundation of America Colon Cancer in IBD Study Group. Consensus conference: colorectal cancer screening and surveillance in inflammatory bowel disease. Inflamm Bowel Dis 2005;11:314–21.
Please cite this article as: Roncucci L, Mariani F, Prevention of colorectal cancer: How many tools do we have in our basket?, Eur J Intern Med (2015), http://dx.doi.org/10.1016/j.ejim.2015.08.019
