Hi Lerardi,

we are working on a preventive vaccine - at least for HNPCC. But, honestly, it will take several years to prove the concept. However, clinical studies using the so-called frameshift peptides (FSP) are ongoing.

Concerning chemoprevention, the best or better the best-proven substance is aspirine. There are even clinical long-term data available. John Burn is the one most famous for this strategy. Recently, he and his coworkers pubished a review: doi: 10.1007/978-3-642-30331-9_9.

Best

Michael

There is evidence that aspirin prevents polyp and colorecta neoplasm development in Lynch syndrome. Some studies are ongoing to study effect of aspirin in preventing these lesions in general population.

doi: 10.1016/S0140-6736(11)61049-0

There have been several studies suggesting NSAIDs such as Aspirin may be protective but of course there are potential side effects. A recent study by West et al. (PMID: 20348368 ) has suggested a protective effect of fish oils. These authors gave 2g/d eicosapentaenoic acid as the free fatty acid and showed a reduction in polyps recurrence.

While chemoprevention to prevent adenomas can work, most agents studied to date are not adequately protective to avoid the need for standard colonoscopy surveillance. This paper demostrates that: Can calcium chemoprevention of adenoma recurrence substitute or serve as an adjunct for colonoscopic surveillance?INTERNATIONAL JOURNAL OF TECHNOLOGY ASSESSMENT IN HEALTH CARE Shaukat, A., Parekh, M., Lipscomb, J., Ladabaum, U.2009; 25 (2): 222-231

If you are looking for some agent to reccomend, calcium carbonate has been shown to reduce adenoma recurrence by about 20% N Engl J Med 1999; 340:101-107January

DFMO showed promise in this study (Cancer Prev Res June 2008 1; 32 ) however side effect (ototoxicity) make it not a great chemopreventive agent.

Botanicals such as flavonoids could help to reduce the recurrence rate of adenomas in the colon. Apigenin and epigallocatechin gallate are promising agents and can be used as nutritional supplement. For tertiary prevention of colonic neoplasia we have shown this in the Word J Gastroenterology 2008. Hoensch et al. World J Gastroenterol 2008 14: 2187-2193

I agree with Dr. Robertson. There are certainly data to support the chemopreventive effects of calcium as well as aspirin, even at low doses. Peter Rothwell's recently published series in the the Lancet and Lancet Oncology show promising results regarding decreased rates of colonic (and other) adenocarcinomas both in incidence and mortality. All the effects are relatively mild, and it is highly unlikely that a single "magic bullet" for prevention exists.

On going studies will explain eventual role for vaccines; at the moment the only useful drug in Lybch Syndrome, are salicilates

A scientific answer to this question will be probably never possible - you would need huge cohorts and the role of confounding factors will be never clearly eliminated, despite of side effects. In the moment there are good screening options for colorectal cancer, which are much more effective than any chemoprevention in this disease. Nevertheless, it will be extremly problematic to get good and conclusive data...

Some reports for the prevention of CRC with Aspirin and other NSAIDs have been published. There seems to be a trend of decrease with the use of these drugs.

We as gastroenterologists are concerned with the upper GI complications of these group of drugs very well and do have endogenous fear of them. But it seems that if the risk benefit ratio of these drugs in the prevention of GI cancers has been shown definitely, we should prescribe them in the proper setting.

Aspirin is found to have some preventive effect. The explanation is that it reduces inflammation which leads to polyps and then CRC. But Aspirin may have side effects and hence it is always better to combine with Ranitidine.

I should like to raise another related problem. Since aspirin has been voted as the most effective chemopreventive agent, what do you think about mesalazine?

Mesalazine in non-IBD cases? Is there any evidence for that available?

Indded, few studies have examined the possibility of using 5ASA molecules for colorectal cancer prevention even outside inflammatory bowel diseases:

Aliment Pharmacol Ther. 2010 Jan 15;31(2):202-9. Systematic review: molecular chemoprevention of colorectal malignancy by mesalazine. Lyakhovich A, Gasche C.

Dig Dis Sci. 2009 Nov;54(11):2488-96. Chemoprevention of colonic polyps with balsalazide: an exploratory, double-blind, placebo-controlled study. Terdiman JP, Johnson LK, Kim YS, Sleisenger MH, Gum JR, Hayes A, Weinberg VK, McQuaid KR.

Mesalazine has the advantage of avoiding side effects of aspirin on upper and lower gastrointestinal tract and its use has been extended to colon inflammatory condition other than Crohn's and colitis, i. e. diverticular disease. Its chemopreventive effects is a debated problem in literature even if mainly confined to ulceratve colitis. However, basic science studies support its anti-carcinogenetic effect. So it will be possible that mesalzine may be useful for intestinal cancer prevention also in selected populations outside inflammatory bowel diseases.

I would say that there is pretty much overwhelming evidence that aspirin should be used as a primary chemoprevention agent. Look at the CAPP2 study:

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61049-0/abstract

If you note there was no difference in the adverse incident rate between aspirin and placebo, so I am not sure that safety is as great an issue as you think.

There's plenty of population evidence too that it is effective, and there are probably other drugs that act either as anti-inflammatories (statins) or as epigenetic modifiers (valproate, lithium) that should be studied as well.

On the item about mesalazine and chemo prevention of CRC, one should think of cost effectiveness as well. Aspirin is a cheap and available drug, but at least in my country mesalazine is not as cheap.

So if we want to recommend it in a population based protocol, the cost versus benefit ratio should be considered critically.

That's a very good point.

Indeed, the cost/effectiveness ratio of a chemprebetion with mesalazine is an excellent discussion point. However, I should like to raise some problems regarding NSAID adverse events on the digestive tract. I red with interest the reference reported by Andrew Beggs and the dose of aspirin and the time of assumption require to consider some guidelines for a safe long term use of these drugs. The first point concerns the need of eradicating H. pylori if present in the stomach, the second the possibility of prevent gastric lesions with the association of PPIs. Unfortunately, this second option may reduce upper injuries and increase lower ones. I should like to emphasize that lower gastrointestinal tract is the site of different NSAID induced injuries, which is often underestimated when compared to that observed in the upper area for both less marked clinical manifestations and more difficult possibility of detection. I had the possibility to red only the abstract of the clinical trial suggested by dr. Beggs and I could not know how the adverse events of aspirin and placebo were detected. Was only a clinical evaluation performed or was at least blood in the stools evaluated in the two groups? Often, expecially lower lesions, require expansive and not largely available investigations such as video capsule endoscopy to be detected and the studies in this topic reveal a high percentage of mucosal damages. In the study the dose of asprin was almost higher compared to that used for the prevention of cardio-vascular disorders. Opinios on this aspect are wellcome.

IMHO it could be a song for the future, but not at this stage. Too many confounding factors, side-effects of chemoprevention etc. For colorectal cancer we have very effective screening options with very good strategies how to proceed with the findings. So yes, may be chemoprevention will be availaible in the future, the task for the moment is advancing the acceptance rates for colonoscopy and

increase the quality of these procedures.

Chemoprevention could be a valuable goal, but due to adverse events of "chemicals" bioprevention with natural compounds (flavonoids) seems to be more promising.

DEBIRI is superior to sistemic treatment (FOLFIRI) after failure of praevious chemotherapy.

Do you think that DEBIRI could be combined with sistemic treatment?

DEBIRI induces shrinkage of the liver metastases but also hypoxia and the following stimulation of pro angiogenic factors.

Do you think that a combination with cetuximab, panitumumab, aflibercept, regorafenib ( given after DEBIRI) could increase PFS and OS?

I don't suppose that chemotherapy is a chemoprevention :-)

Dear Pawel, i agree with you that "The task for the moment is advancing the acceptance rates for colonoscopy and increase the quality of these procedures". This sentence is unquestionable in every procedure of screening and follow-up of colo-rectal cancer prevention. However, despite gastrointestinal disorders are very frequent, I have the impression that we need to follow the example of other specialists (eg cardiologists) who have made the chemoprevention of coronary heart disease a relevant objective as important as that of the operating maneuvers, such as the placement of stents in the course of coronary angiography. In my country gastroenterologists always reach a goal 10 years after cardiologists. For this reason, Publlc Health Institutions invest significantly more resources in the prevention and treatment of cardiovascular disease than in gastroenterology.

Dr Andre Gernez was a famous French Doctor and he developed his own controversial method for the prevention and the treatment of cancers. He suggested Fasting with a caloric restriction on food which he called it phase one. Then, attaching the cancerous cells with anti tibules drugs like Colchicin and Mebendazole.

Dear Yahia, prof. Hoensch and you proposed a dietary intervention. Diet and lifestyle may exert a preventive effect on colo-rectal cancer.Some more details may be found in the attached paper of our group where a review of literature may be found about this problem. Colchicin has been the first anti-blastic drug and a spontaneous question arise from your answer: did dr. Gomez used this chemical in patients with or without cancer?

NSAIDS and calcium have been approved by FDA for treatment of recurrent adenomas (significant adenomas:>3 larger than 3mm or any 1 cm or greater). The side effects of major GI bleed can be balanced by the length of treatment on NSAIDs according to your next colonoscopy. If the frequency of colonoscopy can be decreased, that in itself will decreased the significant morbidity of perforation (1 in 500). More exciting research are in the area of markers using miRNA and monitoring nutrition by miRNA.

I think before we look to chemoprevention with "artificial" compounds, we should focus on chemoprevention with products that promote growth of healthy microbiota in the colon that can generate anti-cancer compunds. The cheapest and most efficient way of doing this is by studying the effect of diet on colorectal cancer in rodent models and human intervention trials. Why not use what we already have as a defence mechanism (ie the huge mass of microbiota) in the lumen rather than trying to avoid all the effort by taking a pill? I agree when it comes to treatment of CRC itself drugs have an important role to play. However, our group has been studying the effects food products such as resistant starch on reducing CRC and early markers, and now we are focussing on inflammation as well. I think the idea of chemoprevention is an excellent one, but I think the way it is implemented needs careful consideration.

Dear Jean,

I fullly agree with your statements. Bioprevention with botanicals such as phytochemicals (e.g. flavonoids) is the way to go. Epigallocathechin gallate and apigenin positively infuence the microbiota and depress the inflammatory changes of the gut mucosa. See our paper : Emerging role of bioflavonoids in gastroenterology: Especially their effects on intertinal neoplasia. Hoensch H, Oertel R World J Gastrointestinal Oncology 2011,

In sporadic colorectal cancer(CRC) cases substantial evidence has shown that non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors can reduce the incidence of CRC. Aspirin and calcium also have been shown to be chemopreventive. Significant risk reduction is reported after folate supplementation in folate-depleted patients. Ursodeoxycholic acid has been shown to decrease the incidence of colonic dysplasia in patients with ulcerative colitis and primary sclerosing cholangitis. RCT are not available and the evidence is stil contriversial. The issue that needs to be further investigated is the potential role of hormones as a chemopreventive agents in CRC. It is reported an increase in CRC in women with an eary menopause. In patients with inflammatory bowel disease surveillance colonoscopy shown to be inadequate for decreasing interval cancer rates. 5-aminosalicylates and thiopurine analogues are the most promised chemopreventives agents in IBD patients.

It is well known from old epidemiological data that estrogen replacement therapy in the menopausal period drammatically reduces the risk of colo-rectal cancer. On the other hand, estrogen receptors, which are largely present in the colonic mucosa are able to interfere with the proliferation/apoptosis balance of the epithelium.

As mentioned by another respondent, NSAIDs (including those with some selectivity for COX-2) do appear to be effective, but their untoward gastrointestinal and cardiovascular adverse effects prevent their widespread use for chemoprevention. However, new NSAIDs are in development that spare the GI tract of injury and may also be more cardiovascular safe (Conflict Disclosure: my own company is working on such compounds). At least in animal models, these compounds, which are NSAIDs that release small amounts of hydrogen sulfide, are significantly more effective than conventional NSAIDs, and much safer.

A question in the question: limits and benefits of dietary (natural) versus chemical prevention. Where do you think the future will be addressed?

I think that dietary would definitely be the best way to go (less animal fat, for example), but will people be willing to do that? Perhaps people with a strong genetic predisposition to cancer will be motivated enough to make significant changes to their diet, but I suspect that most people will be resistant without there being some "selection pressure" to encourage them. It would take an aggressive public health campaign to get this done (but consider how long it has taken to get people to quit smoking?). In the meantime, if a safe, effective and affordable drug could be available, perhaps people would be more likely to accept that, particularly if it meant that they didn't have to make changes to the diet that they prefer.

I agree with this point of view. However, will it be possiible in the future to obtain with dietary supplements results similar to chemicals?

Dr. Harald Hoensch proposed the use of some phychemicals such as flavonoids. At the best of my knowledge, flavonoids contain phytoestrogens whose effectiveness in chemoprevention of colorectal cancer has been largely demonstrated by some groups in animal models. On the other hand, it is well knowm the dramatic decrease of colorectal cancer incidence in women assuming estrogens in pre-menopausal period. A diet rich in phytoesrogens (soy) decreases also the incidence of this neoplasm in Asian countries. Recently, a dietary supplementation with phytoestrogens had an impressive effect on duodenal polyp number and size in subjects with FAP (Calabrese et al, World J Gastroenterol 2013 September 14; 19(34): 5671-5677) as well as in small bowel polyps in Lynch syndrome in a case treated by our group (Bringiotti et al, J Gastroenterol Hepatol, in press). In conclusion, is a new road being plotted for the chemoprevention of colorectal cancer with the use of dietary supplements of vegetable origin?

I think SIBO can be a trigger of colon cancer. Fixing the SIBO issue can solve many health problems. New study found a correlation between SIBO and breast cancer in women.

Certainly human nature is very "reactive" and not so "proactive", particularly when it comes to diet. I think it will take many many more years (possibly not in my lifetime) for a "high risk diet" to be identified on teh same level as cigarette smoking.

Chemoprevention should be replaced by bioprevention. This is possible with phytochemicals from botanical agents like flavonoids. This way the side effects of chemicals can be avoided. and the longterm use is possible..

There have been studies that showed beneficial effects of statins on prevention of colorectal cancer. Although statins are very popular nowadays regarding their preventive effect both of cardiovascular and malignant diseases it remains to be seen whether the attributable effect is due to the statins or other factors such as change of lifestyle and healthier diet,

Some studies shown benefit of aspirin even in low doses, but other studies did not demonstrate the protective effect.

It seems many times that we have a new contender for chemoprevention, and then come randomized controlled trials and refute the supposed protective effect we see,

As you all remember the COX2 inhibitors colon adenoma prevention trials resulted in excess cardiovascular events, leading to withdrawal of Vioxx.

ATBC and CARET RCT's among smokers have shown no benefit of beta carotene and or retinol, resulting in excess risk of lung cancer and cardiovascular events.

My research group conducted a case control study which has shown that dietary intake of 9 cis beta carotene has been associated with a lower risk of colorectal cancer among non smokers, whereas among smokers it had no protective effect.

As we dig more we find that there is probably no one chemopreventive agent that is good for all. As a population we are comprised of different groups carrying various polymorphisms resulting in different metabolism of all kinds of substances, therefore what suits one subgroup could have no effect on the other subgroup or even have a hazardous effect. Therefore, as we progress in personalized medicine, creating the necessary mosaic of our genotype and our resulting metabolic phenotype, we will learn that different agents will work in a different way on individuals. Meanwhile, we can conclude that healthy diet of Meditteranean type rich with vegetables and fruit can be beneficial, as well as physical activity, eating less red meat and fat.

This question has been going on for over 20/30 years See the excellent epideamiology study by Kane and kane many years ago to illustrate the point. Both calcium and vitamin D protect against CRC, Vit D more powerfully due to its well documented cytokinteic effects on colorectal epithelium but it is to toxic to use commercially even with Viamin D analogues. The is powerful and increasing evidence for NSAI aggents and we and many other have published on this. Diet is notoriously diffucult to prove and fraught with poor quality research methodology to justify some claims so must be viewed with caution but is clearly important

I believe that chemoprevention could be done with products that promote growth of healthy microbiota in the colon that can generate anti-cancer compunds.

Also some drugs can help in chemoprevention : both calcium and vitamin D protect against CRC, Vit D more powerfully due to its well known cytokinteic effects on colorectal epithelium but there is a risk of toxicity even with Viamin D analogues.

We are studying the effect of  dietary flavonoids on the recurrence rate of adenomatous colon polyps in patients. I hope that  this prospective cohort study will give us a clue as to the antineoplastic activities of flavonoids. The flavonoids are supplied as dietary supplements containing apigenin and epigallocatechin gallat (EGCG) as compared to untreated controls. .

EGCG can be used as nanoparticles for improved bioavailability. Enclosed an article which may help. 

There are several phase III studies showing the efficacy of NSAIDs, low dose aspirin and calcium carbonate in decreasing the frequency of the intermediate marker adenomas in sporadic and metachronous adenomas to treated colorectal cancers. In addition, these individuals should be surveilled with colonoscopies and the chemopreventive agents can then decrease the frequency of surveillance endoscopies. (Chu,D: Colorectal chemoprevention pilot study... Clin Colorectal Cancer 2011)

These five proteins could tell you how long will you survive if diagnosed with cancer:

https://www.researchgate.net/publication/335714418_Prediction_of_risk_scores_for_colorectal_cancer_patients_from_the_concentration_of_proteins_involved_in_mitochondrial_apoptotic_pathway