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

BACKGROUND: 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. Available at: https://www.doctorslounge.com/index.php/articles/page/298. Accessed February 21 2019.

References

1. American Cancer Society. Cancer statistics 2009 presentation. Available at http://www.cancer.org/docroot/PRO/content/PRO_1_1_Cancer_Statistics_2009_Presentation.asp.  Accessed September 10, 2009.
2. Chan AT, Ogino S, Fuchs CS.  Aspirin use and survival after diagnosis of colorectal cancer. JAMA 2009;302(6):649-659.
3. Ogino S, Kirkner GK, Nosho K, et al. Cyclooxygenase-2 expression is an independent predictor of poor prognosis in colon cancer. Clin Cancer res. 2008;14(24):8221-8227.
4. Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN. Up-regulation of cyclooxygenase-2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology. 1994;107(4):1183-1188.
5. Soumaoro LT, Uetake H, Higuchi T, Takagi Y, Enomoto M, Sugihara K. Cyclooxygenase-2 expression: a significant prognostic indicator for patients with colorectal cancer. Clin Cancer Res. 2004;10(24):8465-8471.
6. Brown JR, DuBois RN. COX-2: a molecular target for colorectal cancer prevention. J Clin Oncol. 2005;23(12):2840-2855.
7. Sheehan KM, Sheahan K, O’Donoghue DP, et al. The relationship between cyclooxygenase-2 expression and colorectal cancer. JAMA. 1999;282(13):1254-1257.
8. Uchida K, Schneider S, Yochim JM, et al. Intratunoral COX-2 gene expression is a predictive factor for colorectal cancer response to fluoropyrimidine-based chemotherapy. Clin Cancer Res. 2005;11(9):3363-3368.
9. Zhang H, Sun XF. Overexpression of cyclooxygenase-2 correlates with advanced stages of colorectal cancer. Am J Gastroenterol. 2002;97(4):1037-1041.
10. Fux R, Schwab M. Thon KP, Gleiter CH, Fritz P. Cyclooxygenase-2 expression in human colorectal cancer is unrelated to overall patient survival. Clin Cancer Res. 2005;11(13):4754-4760.
11. Baron JA, Cole BF, Sandler Rs, et al. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med. 2003;348:891-899.
12. Sandler RS, Halabi S, Baron JA, et al. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med. 2003;348:883-890.
13. Benamouzig R, Deyra J, Martin A, et al. Daily soluble aspirin and prevention of colorectal adenoma recurrence: one-year results of the APACC trial. Gastroenterology. 2003;125:328-336.
14. Chan AT, Giovanucci EL, Meyehardt JA, Schernhammer ES, Curhan GC, Fuchs CS. Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer. JAMA. 2005;294 (8):914-923.
15. Cook NR, Lee IM, Gaziano JM, et al. Low-dose aspirin in the primary prevention of cancer. The women’s health study: a randomized controlled trial. JAMA. 2005;294(1):47-55.
16. Gann PH, Manson JE, Glynn RJ, Buring JE, Henekens CH. Low-dose aspirin and incidence of colorectal tumors in a randomized trial. J Natl Cancer Inst. 1993;85:1220-1224.
17. Fuchs C, Meyehardt JA, Heseltine DL, et al. Influence of regular aspirin use on survival for patients with stage III colon cancer: findings from intergroup trial CALGB 89803 [abstract]. J Clin Oncol. 2005;23(suppl16):3530.
18. Fuchs C, Marshall J, Mitchell E, et al. Updated results of BICC-C study comparing first-line irnotecan/fluoropyrimidine combinations with or without celecoxib in mCRC: updated efficacy data. J Clin Oncol. 2007;25(18S):4027.
19. Chan AT, Ogino S, Fuchs CS. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med. 2007;356(21):2131-2142.
20. Solomon SD, Wittes J, Finn PV, et al. Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials: the cross trial safety analysis. Circulation. 2008;117(16):2104-2113.
21. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA. 2000 Sep 13;284(10):1247-1255.
22. Juni P, Nartey L, Reichenbach S, et al. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 2004 Dec 4;364(9450):2021-2029.
23. Singh G, Fort JG, Goldstein JL, et al. Celecoxib versus naproxen and diclofenac in osteoarthritis patients: SUCCESS-I Study. Am J Med. 2006 Mar;119(3):255-266.
24. FDA Public Health Advisory: FDA Announces Important Changes and Additional Warnings for COX-2 Selective and Non-Selective Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). Available at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm150314.htm. Accessed on September 10, 2009.
25. Preventive Services Task Force. Screening for colorectal cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2008;149:627-637.

Submit your opinion:

• You must be logged in to post a comment. Please log-in.
• Not a member? Please register.
• Have you forgotten your password?

---