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Aspirin Use as Treatment in Colorectal Cancer: Teaching an Old Dog New Tricks

Author: Jeffrey A. Gordon, M.D. | Submitted: September 12, 2009. Updated: September 30, 2009.

Jeffrey A. Gordon, M.D.'s avatar

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

 

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ABSTRACT:

Aspirin use can decrease the risk of colorectal adenomas.  Full-dose, but not low-dose, aspirin may decrease the risk of developing colorectal cancer.  Whether or not aspirin use can favorably augment survival in patients diagnosed with colorectal cancer is uncertain.  Data to date in the literature raises intriguing concepts that targeting cyclooxygensae-2 (COX-2), which is overexpressed in up to 80-85% of colorectal cancers, may improve cancer-specific survival.  Aspirin, COX-2 selective inhibitors (such as celecoxib), and nonselective NSAIDs are possible therapeutic agents.  Prospective, randomized trials are needed to more definitively answer the questions of efficacy and safety.

Colorectal cancer is estimated to account for approximately 147,000 new cancer cases and approximately 50,000 cancer deaths in the U.S. this year.1 Newer chemotherapy treatment regimens have lead to significant improvements in the number of people who can be cured after surgical resection of early stages of the disease.  Likewise, newer chemotherapy regimens and biologic agents have improved the survival and quality of life of people who have advanced stage disease.  The public awareness of screening opportunities, such as colonoscopy, has lead to more pre-cancerous colorectal lesions being found and removed.  Colonoscopy remains one of the best available colorectal cancer primary prevention modalities.  Since the best form of treatment is prevention, other preventative modalities have been and are being researched.

Chan and colleagues have reported on the results of two prospective cohort studies of 1,279 people diagnosed with stages I-III (non-metastatic) colorectal cancer. 2 The use and effect of aspirin was assessed.  Study participants were enrolled in either the Nurses’ Health Study or the Health Professionals Follow-up Study.  Questionnaires about aspirin use since 1980 and 1986, respectively for the two studies, were compiled.  Cancer diagnoses were between 1980 and 2002 in the Nurses’ Health Study and between 1986 and 2002 in the Health Professionals Follow-up Study.  Patients had follow-up through 2008.

This study was able to assess 76% of colorectal cancer specimens for COX-2 expression – approximately 68% were found to overexpress COX-2.  COX-2 overexpression has been reported to occur in 80-85% of colorectal cancers.3-5

COX-2 has been noted to promote cell proliferation and inflammation.6 There have been mixed reports in the literature about the prognostic importance of COX-2 overexpression.3,5,7-10 Because of its overexpression in a majority of colorectal cancers, it is a likely target of prevention and treatment strategies.

For the prevention of colorectal adenomas, several trials have shown a decreased incidence of such with the use of aspirin.11-13 For the primary prevention of colorectal cancer, the long-term use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) may decrease the risk of colorectal cancers.  Chan and colleagues previously reported that the use of at least 2 full-dose (325 milligrams) aspirin tablets weekly resulted in a 23% risk reduction for the development of colorectal cancer.14 The fullest benefit was seen with the use of upwards of 14 aspirin tablets each week.  In contrast, trials of low-dose aspirin have not shown benefit.15,16 For example, Cook and colleagues did not show a statistically significant benefit from the use of low-dose (100 milligrams) aspirin given every other day.15 For people who actually have developed colorectal cancer, the Intergroup CALGB trial 89803 showed that the use of aspirin by patients who were randomized for adjuvant chemotherapy after surgery to treat stage III colorectal cancer resulted in a 55% improvement in recurrence-free survival (statistically significant) and a 51% improvement in overall survival (not statistically significant).17 For people with advanced stage disease, the BIC-C trial studied the use of the  COX-2-selective inhibitor celecoxib while also studying several chemotherapy regimens.18 Due to cardiac safety concerns of celecoxib raised by the Food and Drug Administration (FDA), the use of celecoxib in the BIC-C trial was discontinued.  Initial (not complete) results did not demonstrate a benefit from celecoxib.

What did the authors show in this study of aspirin use by people diagnosed with colorectal cancer?  The median time of follow-up from the diagnosis of colorectal cancer was 11.8 years.  Of the 1,279 people with colorectal cancer, 42% of people did not use aspirin at all (non-use), 29% did before and after diagnosis (primary prevention failure but secondary prevention use), 15% did before but discontinued after diagnosis (primary prevention failure), and 14% started after diagnosis (secondary prevention use).  In total, there were 560 people who used aspirin before diagnosis (44%) and 549 who used aspirin after diagnosis (43%).  The regular use of aspirin after colorectal cancer diagnosis was associated with a lower risk of cancer-specific death: 81 deaths among 549 people who took aspirin (15%) compared with 141 deaths among 730 people who did not (19%).  The use of aspirin after diagnosis was identified as a statistically significant factor, but not aspirin use before diagnosis.  For all aspirin users after cancer diagnosis, the hazard ratio for colorectal cancer-specific mortality was statistically significant at 0.71 (95% confidence interval, 0.53-0.95; P = 0.008).  For all aspirin users before cancer diagnosis, the hazard ratio for colorectal cancer-specific mortality was not statistically significant at 1.05 (95% confidence interval, 0.80-1.37; P = 0.14).  For people who did not use aspirin pre-diagnosis but did use aspirin post-diagnosis, the hazard ratio for cancer-specific mortality was statistically significant at 0.53 (95% confidence interval, 0.33-0.86), whereas for people who used aspirin pre- and post-diagnosis, the hazard ratio was not statistically significant at 0.89 (95% confidence interval, 0.59-1.35).  There was a reported trend (P = 0.04) for improved colorectal cancer-specific mortality hazard ratios with increased use each week of aspirin compared with no use: 0.57 (95% confidence interval, 0.32-0.99) for ½ to 5 full-dose aspirin tablets each week; 0.49 (95% confidence interval, 0.18-1.35) for 6 or more tablets each week.

Among people whose colorectal cancers overexpressed COX-2, there was benefit seen: hazard ratio of 0.39 (95% confidence interval, 0.20-0.76).  However, for colorectal cancers that did not overexpress COX-2, no statistically significant benefit was seen: hazard ratio of 1.22 (95% confidence interval, 0.36-4.18).  Previously, Chan and colleagues have reported that the regular use of aspirin in people without known colorectal cancer was associated with a lower incidence of subsequent colorectal cancers overexpressing COX-2 (but not COX-2-negative tumors).19 For aspirin users (43,006) and non-aspirin users (87,268), there were 152 and 271 COX-2-positive cancers, respectively, with a hazard ratio of 0.64 (95% confidence interval, 0.52-0.78).  In contrast, for aspirin and non-aspirin users, there were 98 and 115 COX-2-negative cancers, respectively, with a hazard ratio of 0.96 (95% confidence interval, 0.73-1.26).  There was an association seen with the dose of aspirin used each week and a decreased risk of COX-2-positive tumors: statistical significance was reached once at least 5 full-dose tablets were used and there was a trend for benefit with increasing doses of aspirin each week.  An association was also identified between the duration of aspirin use and a decreased risk of COX-2-positive tumors: statistical significance was achieved with >10 years of regular aspirin use.

The results presented by this recent study are very intriguing, especially when taken in the context of prior reported data on the use of aspirin and that the use of chemotherapy to treat colorectal cancer (which did undergo a lot of revolutionary improvements during the time that people were diagnosed and treated in the 80’s, 90’s and 00’s on the cohort studies) did not appear to affect the reported benefits of aspirin use after colorectal cancer diagnosis.  As the authors state, “these results suggest that aspirin may influence the biology of established colorectal tumors in addition to preventing their occurrence” and that these results “highlight the potential for using COX-2 or related markers to tailor aspirin use among patients with newly diagnosed colorectal cancer”.2

However, there is always a caveat with new findings.  There is a known down side to aspirin use: gastrointestinal hemorrhage.  The trial reported an increased risk of such bleeding events that required either blood component transfusion or hospitalization.14 For women, the incidence rose from 0.77/1000 person-years for no aspirin use up to 1.57/1000 person-years for >14 aspirin doses each week.  For men, the incidence rose from 0.92/1000 person-years for no aspirin use up to 1.84/1000 person-years for >6 aspirin doses each week.  Although the gastrointestinal bleeding risk for the non-aspirin COX-2-selective inhibitor celecoxib may be lower than the risk from nonselective NSAIDs (if concurrent aspirin is not used with either of the drugs), there is a potential increased risk of cardiovascular events from the COX-2-selective inhibitors.20-24 Thus, even if one were to not use aspirin but use instead a nonselective NSAID or a COX-2-selective inhibitor, serious side effects are still possible.  In the study by Chan and colleagues, the use of NSAIDs or COX-2-selective inhibitors was not reported.

As the authors state, “because our data are observational, routine use of aspirin or related agents as cancer therapy cannot be recommended, especially in light of concerns over their related toxicities, such as gastrointestinal bleeding”.2 There are no current guidelines published that recommend the use of aspirin, NSAIDs or COX-2-selective inhibitors for the purposes of colorectal cancer prevention or treatment.25 Thus, although tempting to use aspirin in patients diagnosed with colorectal cancer that overexpresses COX-2, the routine use of aspirin in such situations cannot as of yet be considered a standard of care.

Prospective randomized trials comparing aspirin to placebo will be needed to help answer important questions.  It is not clear at this time that randomized trials of the COX-2-selective inhibitors will be conducted given the current medical, regulatory and legal issues surrounding these drugs.

Conflict of interest statement

None to report.

CITE THIS ARTICLE:
Jeffrey A. Gordon, M.D.. Aspirin Use as Treatment in Colorectal Cancer: Teaching an Old Dog New Tricks. Doctors Lounge Website. Available at: http://www.doctorslounge.com/index.php/articles/page/298. Accessed November 23 2014.

References



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October 01, 2009 08:33 AM

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

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

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

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

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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