Colonoscopy in prevention of colorectal carcinoma

Continuing from my previous post on colorectal carcinoma, I just came across a study by Hermann Brenner et al. showing the effectiveness of colonoscopy in preventing colorectal carcinoma. They had conducted a population based case-control study in Germany to quantify the effectiveness of colonoscopy. 1688 cases and 1932 controls aged over 50 years participated in the study. The selection criteria for the cases were - a first diagnosis of invasive colorectal carcinoma (>30 years), physically and mentally fit to participate and ability to communicate in German. The study used randomly selected population based controls without history of colorectal carcinoma and were age, sex and country matched. The use of population based control prevents selection bias in recruiting controls and Berkson's bias, so this can be counted as a strength of the study.

Colon and rectum. Modified screenshot from Google body browser.

The cases were interviewed by trained interviewers in hospital setting while the controls were examined at their home. It would have been better if the interviewers were blinded to remove interviewer bias. The data on endoscopies during the last 10 years were corroborated with medical records which were available in 84% of the cases; hence there isn't much chance of recall bias. The authors excluded from statistical analysis cases less than 50 years old as screening colonoscopy is not recommended in them, cases with history of inflammatory bowel disease as they undergo surveillance colonoscopy due increased risk of colorectal carcinoma, missing information regarding colonoscopy, had undergone any other endoscopic procedure or if the last colonoscopy was done less than 1 year or more than 10 years ago.

Flow diagram of the study.

The confounding factors accounted for were age, sex, and education level, family history of colorectal carcinoma, smoking, body mass index, non-steroidal anti-inflammatory drug use, hormone replacement therapy use and participation in health screening examinations. The risk of colorectal cancer was estimated by calculating Odds ratio (OR).

The findings of the study clearly show the benefit of colonoscopy in preventing colorectal carcinoma. It should be noted that colonoscopy by itself is not preventive, colonoscopy identifies the early adenomas which are removed. As development of colon cancer follows adenoma-carcinoma sequence, colonoscopy becomes protective by early detection and removal of adenomas. The study found that colonoscopy reduces the overall risk of colorectal carcinoma by 77%. This is substantial. The greatest risk reduction was seen in case of cancers located in the sigmoid colon (adjusted OR=0.14). The least risk reduction was for cancers located in the ascending colon. In general the risk reduction was more for left colon cancers than for right colon cancers.

Adjusted odds ratio according to the site of colorectal cancer (less OR means more protection by colonoscopy).

The beneficial effect of colonoscopy did not vary with sex or with family history of colorectal carcinoma. The risk reducing effect of colonoscopy increased with increasing age in case of right sided colon cancer but such an effect was not observed in case of left sided colon cancers.

The study has few limitations like unaccounted confounders, possible differential rate of participation in the study. Also the authors did not account for the dietary habits of the participants. Increased intake of dietary fiber has a protective effect in development of colorectal cancer while intake of red meat and animal fat has a deleterious effect. It can be argued that BMI is a measure of the diet but I don’t think it can replace dietary history. This is one major point that I think the authors should have addressed.

Brenner H, Chang-Claude J, Seiler CM, Rickert A, & Hoffmeister M (2011). Protection from colorectal cancer after colonoscopy: a population-based, case-control study. Annals of internal medicine, 154 (1), 22-30 PMID: 21200035

How aspirin might prevent colorectal cancer?

I must confess that I am fascinated by the potential of aspirin in colorectal carcinoma prevention. It is worthwhile to look into this in some detail. Before we delve into the mechanism of colorectal carcinoma prevention by aspirin we must examine how colorectal carcinoma develops.

Colorectal carcinogenesis is characterized by a set of genetic alterations. The Fearon and Vogelstein model is a well accepted model explaining the sequence of colorectal cancer development. Their model is based on adenoma-carcinoma sequence. This suggests that colorectal carcinoma is preceded by adenomatous changes. Where adenomatous changes can not be identified, it is considered that the carcinoma directly arose from a dysplastic lesion. The development of colorectal carcinogenesis is taken to occur through through two distinct pathways –

• APC/β-catenin pathway.
• Microsatellite instability pathway.

In both the pathways there is step-wise accumulation of mutations but the genes involved and mutations occurring are different.

The APC/ β-catenin pathway is characterized by the loss of Adenomatous polyposis coli (APC) gene. The APC gene is located in the long arm of the 5^th chromosome (5q21). APC is a dual-function tumor suppressor gene coding for a protein that binds to bundles of microtubules and promotes cell adhesion and migration. The level of β-catenin is also regulated by APC. β-catenin is a mediator in the Wnt/ β-catenin signaling pathway which plays a significant role in normal development of the intestinal epithelium. It is also involved in colorectal carcinoma development. Inactivated APC can be found in more than 80% cases of colorectal cases and 50% of the cases that don’t have APC mutation have β-catenin mutation.

β-catenin, a member of the cadherin based cell adhesive complex, acts as a transcription factor when translocated to the nucleus. In case of APC gene mutation, β-catenin accumulates in the cytoplasm and is subsequently translocated to the nucleus. When inside the nucleus it binds with a family of transcription factors called T-cell factor or lymphoid enhancer factor (TCF or LEF). β-catenin –TCF complex is considered to activate genes associated with regulation of cellular proliferation and apoptosis like c-MYC and CYCLIN D1. Thus mutation in APC gene leads to increased cellular proliferation and decreased cell adhesion.

Mutation of the oncogene K-RAS is thought to occur next. This is the most commonly activated oncogene seen in adenomas and colorectal carcinomas. Allelic loss at chromosome 18q21 occurs and it is suggested to be SMAD2 and SMAD4 which are involved in TGF β signaling. p53 gene mutations occur late in colorectal carcinogenesis and are seen in 70 to 80% cases of colon cancer. Increased telomerase activity has also been found in colorectal cancers.

The microsatellite instability pathway is characterized by genetic lesions in the DNA mismatch repair genes. These lesions are found in the HNPCC (Hereditary Nonpolyposis Colorectal cancer) syndrome and in 10 to 15% of sporadic cases. Inactivation of the DNA mismatch repair genes results in defective DNA repair. Any of the human mismatch repair genes hMSH2, hMLH1, MSH6, hPMS1, hPMS2 may be involved in HNPCC syndrome.

Mutations in mismatch repair genes cause alterations in microsatellites (fragments of repeat sequences in human genome that are prone to misalignment during DNA replication). This leads to microsatellite instability. Some microsatellites are located in the coding or promoter regions of genes like type II TGF – β receptor and BAX. TGF – β signaling is involved in inhibiting the growth of colonic epithelial cells and BAX genes cause apoptosis. Microsatellite instability thus leads to their nonfunctioning and colorectal carcinogenesis.

Now where does aspirin come in all these? Aspirin belongs to a group of drugs called NSAIDs (Non Steroidal Anti Inflammatory Drugs) that inhibit cyclooxygenase (COX) enzymes resulting in decreased prostaglandin synthesis. There are two isoforms of COX, COX-1 which is constitutively expressed and COX-2 which is inducible.

In colorectal carcinogenesis there is overexpression of COX-2 enzyme, there by giving aspirin the chance to bite. However the exact step where aspirin might act is unclear.

Multistep progression of colon cancer and sites of NSAID action. From Postgrad Med J 2005;81:223-227 doi:10.1136/pgmj.2003.008227

Aspirin and other NSAIDs might also act through COX independent pathways to prevent colon cancer. High doses of aspirin have been shown to oppose the survival signaling pathway mediated by the transcription factor NF-kB. This is considered to occur through the inactivation of IkB kinase β. IkB kinase β is responsible for the activation of NF-kB cycle by phosphorylation of the inhibitory subunit of NF-kB. Hence aspirin inhibits the NF-kB pathway and interferes with cell survival.

Molecular mechanisms that mediate the effects of NSAIDs and anticancer drugs on survival and apoptosis in colon cancer cells. Schematic representation of cytokine, EGF-related growth factors and TRAIL ligand-dependent signal transduction pathways for survival and apoptosis. Stimulatory and inhibitory effects are indicated by arrows and bars, respectively. Abbreviations: MAPK=mitogen-activated protein kinase, MAPKK=mitogen-activated protein kinase kinase, JNK=jun kinase, IkB=inhibitor kinase B, NF-kB=nuclear factor kappa B, COX=cyclooxygenase, PI3K=phosphatidylinositol 3 kinase. From:Br J Cancer. 2003 March 24; 88(6): 803–807.

Synergistic effect of NSAIDs with conventional chemotherapeutic drugs has also been observed. The effect of NSAIDs in preventing neoangiogenesis is also important. Neoangiogenesis is a vital event in tumor growth and metastasis and tumor cells need adequate blood supply to derive nutrients. Prostaglandins are thought to be involved in angiogenesis by regulating proangiogenic factor synthesis like vascular endothelial growth factor (VEGF). Both COX-1 and COX-2 are considered to be involved in this.

Relative levels of Bcl-2 proteins regulate eukaryotic cell survival and apoptosis. SC-58125 and NS-398, COX-2 selective inhibitors, downregulates anti-apoptotic protein bcl-1 and sensitizes colorectal and proastate cancer cels to apoptosis. Aspirin upregulates bax and bak (proapoptotic proteins) and activates caspase 3 resulting in apoptosis. AKT, an anti-apoptotic protein kinase and the Fas-associated death domain has also been implicated in NSIAD induced apoptosis.

What remains to be seen is whether the advantages of aspirin will be sufficient considering the risk of GI adverse effects and how much benefit aspirin or any other NSAID provides. I want to remain hopeful.

Reference:

Sangha, S. (2005). Non-steroidal anti-inflammatory drugs and colorectal cancer prevention Postgraduate Medical Journal, 81 (954), 223-227 DOI: 10.1136/pgmj.2003.008227

Ricchi, P., Zarrilli, R., di Palma, A., & Acquaviva, A. (2003). Minireview: Nonsteroidal anti-inflammatory drugs in colorectal cancer: from prevention to therapy British Journal of Cancer, 88 (6), 803-807 DOI: 10.1038/sj.bjc.6600829

KINZLER, K. (1996). Lessons from Hereditary Colorectal Cancer Cell, 87 (2), 159-170 DOI: 10.1016/S0092-8674(00)81333-1

A new aspirin preparation: Possibility in prevention of colorectal cancer?

A recently published study in The Lancet has shown that low dose aspirin (acetylsalicylic acid) intake reduces the incidence and mortality of colorectal cancer. The study followed participants of four randomized controlled trials of aspirin against control and one trial of different doses of aspirin with a median follow-up period of 18.3 years. The risk reduction was greatest in case of proximal colon cancers and this is important as they are difficult to detect by screening colonoscopy. It may be possible to formulate a screening and prevention program consisting of aspirin intake and regular screening to cover both proximal and distal colon. However, it appears that the aspirin intake needs to be continued for five years to have an effect.

Aspirin - new role? From wikimedia commons

The main concern about the risk of aspirin intake is the risk of GI ulceration and subsequent bleeding. The question is if the risk of GI side effects from aspirin outweighs the benefit of colon cancer prevention. In an ongoing poll at the doc2doc community of the BMJ group, the opinion seems to be divided. When I last checked, 27.38% of the respondents said that aspirin should be prescribed daily to prevent colon cancer, 42.85% of the responders said it shouldn’t be prescribed while 29.77% were unsure. Enteric coated aspirin may provide an answer. Evidence from healthy volunteers shows reduced incidence of ulceration in short term cases but long term data on aged patients is not there.

A new preparation of aspirin, aspirin-phosphatidylcholine complex (PL2200) was tested by Byron Cryer et al. in an industry supported phase II trial. The participants were healthy subjects and received either aspirin or PL2200 for 7 days. The incidence of gastroduodenal ulcers were significantly more in the aspirin group than the PL2200 group. But, this was a study on healthy population and for short duration, will the gastroprotective effect persist in long term cases as required for colorectal cancer prevention? This remains to be seen.

Update: The poll at doc2doc has concluded, 32.6% of the responders were in favor of prescribing aspirin, 40% said it shouldn't be prescribed and 27.4% were unsure.

Reference: 

Rothwell, P., Wilson, M., Elwin, C., Norrving, B., Algra, A., Warlow, C., & Meade, T. (2010). Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials The Lancet, 376 (9754), 1741-1750 DOI: 10.1016/S0140-6736(10)61543-7


Cryer, B., Bhatt, D., Lanza, F., Dong, J., Lichtenberger, L., & Marathi, U. (2010). Low-Dose Aspirin-Induced Ulceration Is Attenuated by Aspirin–Phosphatidylcholine: A Randomized Clinical Trial The American Journal of Gastroenterology DOI: 10.1038/ajg.2010.436


Walker, J., Robinson, J., Stewart, J., & Jacob, S. (2007). Does enteric-coated aspirin result in a lower incidence of gastrointestinal complications compared to normal aspirin? Interactive CardioVascular and Thoracic Surgery, 6 (4), 519-522 DOI: 10.1510/icvts.2007.155788