It is ever so important for us doctors who are treating patients with rare diseases that carry a poor prognosis to remember the anxiety and anguish that our patients feel; the burden of knowing that your options are limited with regards to an illness is simply unimaginable.
Medical researchers often carry with them a sense of urgency when conducting studies to discover new therapies that can potentially make a difference in these patients’ lives. Every new piece of information contributes towards the ultimate prize of finding a cure; meanwhile, small wins along the way also offer these patients hope.
There are generally 2 ways in which medical research is carried out: by looking forward and by looking backward. Looking forward, researchers aim to discover novel therapies that have new mechanisms of action. Increasingly, this means looking at gene-altering therapies. Looking backward, researchers aim to take a closer look at drugs that are already in use to see if there are any new ways in which they can be applied. In this article, we will be looking at a case of the latter.
Aspirin is one of the most common and instantly recognizable drugs on the market. It has become common advice to “take an aspirin” when someone experiences a headache. However, aspirin also has a chemoprotective role in a number of common cancers. Researchers conducted a literature review on the potential role of aspirin in the prevention and treatment of cholangiocarcinoma (CCA) and published their findings in the International Journal of Cancer. We will take a look at some of their findings in this article.
The Anticancer Effects of Aspirin
Let’s start with the basics. We all know aspirin inhibits cyclooxygenase (COX) enzymes, with a preference for COX-1 in lower doses and COX-2 in higher doses.
The overexpression of COX-2 is observed in CCA. This results in the dysregulated proliferation and reduction in apoptosis of cholangiocytes. In addition, studies have shown that the overexpression of COX-2 promotes tumor growth, while its inhibition attenuates tumor growth. This demonstrates how the inhibition of COX-2 by aspirin can achieve anticancer effects in CCA.
What about COX-1? COX-1 promotes pathways that lead to platelet aggregation and thrombus formation. Studies have shown that platelet function is a hallmark of occult cancer due to its role in carcinogenesis, angiogenesis, and metastasis. Daily low-dose aspirin likely works by inactivating platelets at epithelial injury sites and impeding their role in cancer growth.
Read more about CCA etiology
In addition, research has shown that cancer cells are disseminated by evading immune responses through the promotion of platelet aggregation around cancer cells; when platelet aggregation was inhibited by aspirin, the immune system was then able to target the tumor cells and eliminate them.
In vivo studies have shown that aspirin inhibits the release of the tumor growth factor sphingosine-1-phosphate from platelets. By engaging with platelet function, aspirin thus reduces metastatic cell growth and spread.
Evidence in CCA
Aspirin has been identified as potentially having a role in both the prevention and treatment of CCA. A study on patients with biliary tract cancer showed that patients who were on aspirin postdiagnosis demonstrated a significantly reduced mortality rate, with the greatest reduction observed in patients with CCA.
As for the prevention of CCA, the authors of this review cited 2 meta-analyses. The first examined 9 observational studies and found a 31% reduction in the risk of developing CCA in aspirin users. Another study examined 5 observational studies and found an inverse relationship between the use of aspirin and the risk of developing CCA.
What is the proposed dose of aspirin in which its anticancer properties can take effect? A UK study predictably demonstrated an inverse relationship between aspirin use and the incidence of CCA (odds ratio, 0.45), and the dose in that study was specified as 75 mg. However, given that only a single dose was used, dose-response analysis was not performed in that study.
Read more about CCA prognosis
A retrospective study classified daily aspirin use into 2 categories: low-dose (81–162 mg/day) and high-dose (≥325 mg/day). As with previous studies, this study found that aspirin use significantly reduced the risk of developing all 3 subtypes of CCA. The adjusted odds ratios were 0.29 for the low-dose group and 0.39 for the high-dose group, suggesting that the actual dosage of aspirin did not make a huge difference in CCA risk as long as the drug was taken daily.
However, these studies are not without their limitations. For us to draw a firmer line between aspirin use and CCA, future clinical trials need to be better designed. The authors of the review wrote, “We recommend that studies investigate patients with definitive risk factors for CCA (eg, [primary sclerosing cholangitis]) — and stratify the patients by CCA subtypes, sex, and body weight, and dose, duration, and frequency of aspirin use.” They added, “Dose-response and time-response analysis are also needed.”
Further Study Warranted
From the studies cited in this article, it is clear that aspirin has a positive role in reducing the risk of developing CCA and reducing mortality in patients with CCA postdiagnosis. However, as the authors of the study rightly pointed out, “Results might be distorted by healthy-user bias as healthy individuals tend to maintain a beneficial lifestyle, including taking aspirin regularly, and genetic variations in aspirin metabolism should also be considered.”
However, it is at least clear at a preliminary level that aspirin is an affordable, multipurpose drug that deserves further study in the area of cancer research.
Shen X, Shen X. A potential role for aspirin in the prevention and treatment of cholangiocarcinoma. Int J Cancer. 2021;148(6):1323-1330. doi:10.1002/ijc.33323
Choi J, Ghoz HM, Peeraphatdit T, et al. Aspirin use and the risk of cholangiocarcinoma. Hepatology. 2016;64(3):785-796. doi:10.1002/hep.28529