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Aspirin for the Prevention of Colorectal Cancer

Wednesday, August 8, 2018  
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Rachel Hatch, PharmD Candidate 2019, Philadelphia College of Pharmacy
Natalie Greco, PharmD Candidate 2019, Philadelphia College of Pharmacy
Advisor: Keith R. Warshany, PharmD, BCPS, NCPS-PP

Colorectal cancer, also known as CRC, is a common and fatal disease affecting a large number of patients in the United States.1 The American Cancer Society estimates that in 2018 about 97,000 people would be diagnosed with colon cancer and about 43,000 with rectal cancer making it the third most diagnosed cancer in the U.S.1,2 Furthermore, it was predicted that about 50,000 people would die from CRC in 2018 making it the third leading cause of deaths attributed to cancer.1,2 These statistics support the need for research regarding prevention options for CRC.

 

Colorectal cancer begins as a noncancerous growth, also called a polyp or adenoma, originating from a glandular cell on the inner lining of the colon or rectum and grows over many years with the possibility of becoming cancerous. As the adenoma grows, it invades the wall of the colon or rectum and then can enter lymph or blood vessels causing distant spread, or metastasis.2 A portion of colorectal adenocarcinomas overexpress specific molecular subtypes including the cyclooxygenase-2 (COX-2) enzyme, which metabolizes arachidonic acid to produce prostaglandins involved in signaling and inflammation.3-5 Colorectal adenocarcinomas can also express mutant forms of the phosphoinositide 3-kinase (PI3K) gene, which is responsible for regulating cancer cell proliferation and survival.3

 

Aspirin has generated considerable research interest in recent years as a possible pharmacological prevention option for CRC due to its unique mechanism of action. Aspirin is a non-steroidal anti-inflammatory drug (NSAID) that irreversibly inactivates COX-1 and COX-2 resulting in physiological effects that include decreased inflammation, analgesia, and anti-platelet activity. Several mechanisms by which aspirin might possess anti-cancer properties have been proposed.3-5 First, the inactivation of COX-2 can reduce PI3K and, in turn, prevent proliferation and survival of the cancer cells.3 Second, the anti-platelet action may reduce the interaction of platelets with cancer cells, preventing metastasis and cancer progression.4

 

Over the past few decades, research has been focusing on aspirin’s role in both primary and secondary prevention of CRC. Meta-analyses including cohort and case-control studies, show that daily aspirin use reduces the relative risk of CRC by 15 to 40%.6,7 However, the results of randomized controlled trials offer conflicting results. Baron et al conducted a randomized, double-blind, placebo-controlled trial in a population of 1,121 individuals with a recent history of adenomas to analyze the effects of aspirin 81 mg and aspirin 325 mg in the primary prevention of CRC. The trial concluded that daily aspirin use for approximately three years non-significantly reduced the risk of CRC, particularly in the 81 mg group for reasons not understood (RR, 0.81 in the aspirin 81mg group; 95% CI, 0.69-0.96; P= 0.06).8 Another controlled trial known as the Women’s Health Study (WHS), concluded that aspirin 100 mg every other day for 10 years was ineffective in preventing the first occurrence of CRC in healthy women (RR, 0.97; 95% CI, 0.77-1.24; P=0.83).9 In a more recent study published in 2012 by Benamouzig et al, known as the APACC trial, 272 patients with previous colorectal adenomas were given either aspirin 160 mg daily, aspirin 300 mg daily, or placebo with follow-up and results pubished at year one, and then again at year four.10,11 Results at one year showed a significant reduction in the proportion of patients with at least one adenoma for those receiving any dose of aspirin therapy (RR, 0.73; 95% CI, 0.52-1.04; P=0.01); however, the results at the four year follow-up did not show a significant decrease in the proportion of patients with at least one adenoma in either aspirin group (RR, 0.96; 95% CI, 0.75-1.22; P=NS).10,11 As for secondary prevention, the data is more limited. A trial published by Sandler et al in 2003 studied the use of aspirin 325 mg daily for about five years and saw a significant reduction in CRC patients with recurrent adenomas.12

 

The duration of aspirin therapy is not well-established, however, based on current literature, the general recommendation is at least 5-10 years of therapy due to the adenocarcinoma preventive effect of aspirin.3,4,13 The optimal dose of aspirin is also unclear and research is currently evaluating whether low-dose aspirin (75-162.5 mg) is sufficient or if a higher dose (162.5-325 mg) is needed.3 In addition, the role of aspirin in secondary prevention and/or as adjuvant treatment in CRC remains under investigation in the ongoing trials: ADD-ASPIRIN and ASCOLT.14,15 ADD-ASPIRIN is a placebo-controlled trial that will investigate the effect of 100 mg and 300 mg daily doses of aspirin on disease-free survival and overall survival in patients who have previously undergone potentially curative treatment for different cancers including breast, colorectal, gastro-esophageal, or prostate cancer. ADD-ASPIRIN is currently recruiting patients and is expected to complete in 2026.14 Second, ASCOLT is a randomized, placebo-controlled trial evaluating aspirin as adjuvant treatment in patients with specific sub-types of CRC. Modified dukes classifications are used to describe the severity of bowel cancers, with stage A meaning the tumor is confined to the inner lining of the mucosa and stage D meaning distant metastases are present.16 Patients in the ASCOLT trial have dukes C or high-risk dukes B colorectal cancer. The endpoints include disease free survival and five-year overall survival with eligible participants receiving aspirin 200 mg or placebo for a duration of three years with follow-up planned through five years. The ASCOLT trial is planned to be completed in 2023.15

 

As of now, the United States Preventative Services Task Force (USPSTF), in particular, recommends low-dose aspirin therapy as primary prevention in conjunction with colonoscopies in patients who will also benefit from the cardiovascular benefits of aspirin. This specifically includes patients 50 to 59 years old who have a greater than or equal to 10% ten-year cardiovascular disease risk (Grade B recommendation). Currently, the USPSTF recommends low-dose aspirin, as a lower dose will warrant less adverse effects.  In regards to other groups, the American Academy of Family Physicians produces recommendations that are consistent with those of the USPSTF. The American Gastroenterological Association and the National Comprehensive Care Network recommend aspirin only for patients who are at an increased risk of CRC including those with a family history of CRC or genetic susceptibilities. Lastly, the American Cancer Society recognizes the possible risk reductions in acquiring CRC, but has not reviewed the evidence and does not currently make any recommendations.13

 

Despite the potential anti-cancer benefits, it is important to keep in mind aspirin’s adverse effect (AE) profile when considering it for long-term use in the prevention of CRC.3-5,13 The main AEs associated with aspirin include gastrointestinal (GI) bleeding, GI ulcer formation, and hemorrhagic stroke.4,13 GI bleeding, although minor, is the most common AE experienced and the risk is increased in patients greater than 60 years old, patients taking concomitant NSAIDs, and those with previous GI ulcers.13 Therefore, it is important to carefully weigh the risks and benefits when considering long-term aspirin use.

 

In conclusion, numerous studies lend support to a potential role for aspirin in preventing CRC. However, there is still a great deal of unknown information regarding the optimal dose and duration, and identification of the specific target patient population. The decision to start aspirin as a preventive measure should be patient-specific and weigh the risks and benefits of long-term therapy.13


References:

1.     Benson AB, Venook AP, Al-Hawary MM et al. Colon Cancer, Version 2. 2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018 Mar; Available from: https://www.nccn.org/professionals/physician_gls/default.aspx

2.     American Cancer Society. Colorectal Cancer Facts & Figures 2018. Atlanta: American Cancer Society; 2018.

3.     Tougeron D, Sha D, Manthravadi S et al. Aspirin and colorectal cancer: back to the future. Clin Cancer Res. 2014 Mar 1;20(5):1087-94.

4.     Thorat MA, Cuzick J. Role of aspirin in cancer prevention. Curr Oncol Rep. 2013 Dec;15(6):533-40.

5.     Singh Ranger G. The role of aspirin in colorectal cancer chemoprevention. Crit Rev Oncol Hematol. 2016 Aug;104:87-90.

6.     Flossmann E, Rothwell PM; British Doctors Aspirin Trial and the UK-TIA Aspirin Trial. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet. 2007 May 12;369(9573):1603-13.

7.     Cuzick J, Otto F, Baron JA et al. Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement. Lancet Oncol. 2009 May;10(5):501-7.

8.     Baron JA, Cole BF, Sandler RS et al. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med. 2003 Mar 6;348(10):891-9.

9.     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 Jul 6;294(1):47-55.

10.  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 Aug;125(2):328-36.

11.  Benamouzig R, Uzzan B, Deyra J et al; Association pour la Prévention par l'Aspirine du Cancer Colorectal Study Group (APACC). Prevention by daily soluble aspirin of colorectal adenoma recurrence: 4-year results of the APACC randomised trial. Gut. 2012 Feb;61(2):255-61.

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 Mar 6;348(10):883-90.

13.  Bibbins-Domingo K. Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: Recommendations From the U.S. Preventive Services Task Force. Ann Intern Med. 2016 Jun 21;164(12).

14.  Coyle C, Cafferty FH, Rowley S et al; Add-Aspirin investigators. ADD-ASPIRIN: A phase III, double-blind, placebo controlled, randomised trial assessing the effects of aspirin on disease recurrence and survival after primary therapy in common non-metastatic solid tumours. Contemp Clin Trials. 2016 Nov;51:56-64.

15.  Ali R, Toh HC, Chia WK; ASCOLT Trial Investigators. The utility of Aspirin in Dukes C and High Risk Dukes B Colorectal cancer--the ASCOLT study: study protocol for a randomized controlled trial. Trials. 2011 Dec 14;12:261.

16.  Akkoca AN, Yanık S, Ozdemir ZT et al. TNM and Modified Dukes staging along with the demographic characteristics of patients with colorectal carcinoma. Int J Clin Exp Med. 2014 Sep 15;7(9):2828-35.

 


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