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Article: Aspirin Use as Treatment in Colorectal Cancer: Teaching an Old Dog New Tricks Back to article | View all comments

Author: Jeffrey A. Gordon, M.D. | September 12, 2009

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October 01, 2009 08:33 AM
Tamer M. Fouad, M.D.'s avatar

Thanks Dr. Gordon for your reply and Dr. Kamath for your insight regarding aspirin’s role in inhibiting angiogenesis. I’d like to share a great reference that I found about the anticancer mechanisms of NSAIDs.

Thun MJ, Henley SJ, Patrono C. Nonsteroidal Anti-inflammatory Drugs as Anticancer Agents: Mechanistic, Pharmacologic, and Clinical Issues. J Natl Cancer Inst. 2002 Feb 20;94(4):252-66.

Free Full Article online: http://jnci.oxfordjournals.org/cgi/content/full/94/4/252

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September 30, 2009 08:29 PM
Jeffrey A. Gordon, M.D.'s avatar

Drs. Mahmoud and Fouad,

Thank you for posting your comments about my article.  Both of you raise some interesting questions and thoughts.

Aspirin use among the people in the cohort studies analyzed was for headaches, arthritis and other musculoskeletal reasons, heart disease prevention, and other non-listed reasons.  Chan and colleagues in their analysis determined that there was benefit in from aspirin use by the reduction in both all-cause mortality and colorectal cancer-specific mortality.  Likewise, their analysis did find benefit in people who received and did not receive chemotherapy.  The percentage of people who received or did not receive chemotherapy was found to be balanced in the aspirin use and aspirin non-use groups.  This is interesting given that during the time that the cohort study populations were queried of their aspirin use, major changes in the the types of adjuvant chemotherapy used to treat colorectal cancer had developed, which has caused an improvement in overall survival.

The median follow-up of people analyzed was 11.8 years.

Chan and colleagues did look at prediagnosis and postdiagnosis aspirin use vis-avis COX-2 expression.  For people who did not use aspirin prediagnosis but did use aspirin postdiagnosis and whose cancers were COX-2-positive, there was a significant reduction in colorectal cancer-specific mortality.  For people who used aspirin both pre- and post-diagnosis and whose tumors were COX-2-positive, there was not a significant risk reduction.  Whether or not there was some change in the degree of COX-2 expression in patients who took aspirin pre-diagnosis or some other change in the COX-2 pathway because of prediagnosis aspirin use, the authors do not mention. Certainly interesting to think about for those people whose use of aspirin did not prevent COX-2-positive colorectal cancers.

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September 30, 2009 11:42 AM
M. Jagesh Kamath, M.D.'s avatar

Very interesting. Asprin, is known to act on the vascular angiogenisis could prevent tumour growth and with a dual action on cox2 might well be the preferred drug than selective cox2 inhibitors.Thanks Dr.Gordon for the thought stimulating article.

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September 24, 2009 12:05 PM
Tamer M. Fouad, M.D.'s avatar

Thank you Dr. Gordon for your article and thank you Dr. Safaa for sharing your thoughts.

I just wanted to add my thoughts regarding the long term use of selective COX-2 inhibitors. While the study results do emphasize the potential importance of the COX-2 pathway in those that benefit from aspirin, this doesn’t necessarily mean that selective COX-2 inhibitors will fair better than aspirin in prevention trials. Do selective COX-2 inhibitors produce stronger inhibition of the COX-2 pathway than aspirin or other NSAIDs? To my knowledge the anti-inflammatory effects are similar, suggesting that this may also be the case with regards to their effects in COX-2 overexpression.

Were selective COX-2 inhibitors used in Chan et al’s study? The authors mention that only 17 participants from both cohorts used selective COX-2 inhibitors and therefore, as Dr. Gordon, mentioned follow up data was not reported.

Selective COX-2 inhibitos are associated with reduced prostacyclin production by vascular endothelium with little inhibition of platelet thromboxane A2 production a pro-thrombotic agent. COX-2 inhibitors are associated with elevated blood pressure which could predispose to endothelial injury and explain the link with fatal cardiovascular ischemia.

Interestingly two of the main trials that incriminated selective COX-2 inhibitors (two from six trials) were the adenomatous polyp prevention trial (APC trial) and the previous spontaneous colonic polyps (PreSAP trial).[1] The data-safety monitoring board discontinued the APC trial after observing a dose (800 mg vs 400 mg daily) related increased rate of cardiovascular events and a reported increase in the risk of death from cardiovascular causes. Later, a combined analysis of these two adenoma prevention trials confirmed a dose related risk of serious cardiovascular events.[2]

In addition an indistinct subset of colorectal cancer patients have evidence of hypercoagulability. Effective identification of those at risk should be crucial before selective COX-2 inhibitors are used in colorectal prevention trials.

All this makes COX-2 less attractive and aspirin more attractive in the subset of individuals that are considered at risk of colorectal cancer or those with a history of colorectal cancer.

Another idea is the concomitant use of aspirin and selective COX-2 inhibitors, one drug could potentially offset the adverse effects of the other. So far there has been no data to support any benefit from the concomitant use.

References:
=========
1. FDA. Celecoxib (marketed as Celebrex) - Healthcare Professional Sheet text version. Accessed at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124655.htm. Accessed on September 24, 2009.
2. Solomon SD, Pfeffer MA, McMurray JJ et al. Effect of Celecoxib on Cardiovascular Events and Blood Pressure in Two Trials for the Prevention of Colorectal Adenomas. Circulation. 2006 Sep 5;114(10):1028-1035. Epub 2006 Aug 30.

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September 22, 2009 03:01 PM
Dr. Safaa Mahmoud's avatar

Thank you Dr. Gordon for your review of this interesting study. I wanted to share a few comments and questions about this study.

Since the long term use of NSAIDs especially selective COX2 inhibitors have raised safety concerns about their potentially fatal side effects, which you have mentioned, the benefit/risk ratio is to be assessed. The total mortality as well as colorectal cancer-specific mortality rates between participants who did or did not use aspirin is important to be mentioned.
What were the main reasons for the use of aspirin in this cohort? Can the benefit seen from aspirin be related to its effect in reducing mortality from non cancer causes? Also aas the effect of aspirin the same regardless of the type of treatment for colon cancer and its stage, or patient characteristics especially risk factors for other diseases like cardiovascular or cerebrovascular diseases?

This is a group of patients who received adjuvant CT, so I think it’s important to note whether the type of chemotherapy used was the same or not and whether the different regimens would have resulted in a difference in DFS or OS in the different study groups?  Was the difference in any in disease free and overall survival maintained on 5 years and 10 years follow up?

Was there any information about the expression pattern of COX2 in the different group of patients and specially patients who failed primary prevention with aspirin? Whether this might propose an answer for why the favorable difference in cancer specific and overall mortality was significant in the patients initiated aspirin after diagnosis and not in the overall groups received regular aspirin at any time before or after diagnosis due to e.g. resistance gained during treatment or more COX2 negative tumors.

Are there any information about the recurrence rates and pattern or disease free survival, since one of the proposed mechanisms is the effect of aspirin on the micrometastatic disease and hence its effect on adjuvant use?

Best regards.
Dr. Safaa

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