This article is based on a publication published in Open Biology that details the impact of aspirin on the biochemical processes involved in cancer and provides supporting clinical data.

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On September 14, 2022, Open Biology published a review article titled " Aspirin and cancer: biological mechanisms and clinical outcomes" by a team of researchers from the UK led by Professor Peter Elwood, Division of population medicine, University of Cardiff, Cardiff, Wales, UK.

The paper describes the effect of aspirin on biological mechanisms in cancer, and clinical studies of patients with cancer, some of whom take aspirin. The authors review systematically the relevant papers covering these two areas, from which evidence on aspirin and cancer emerges.

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Cancer: The grim realities

The researchers highlighted the following grim realities:

1. Cancer causes one in every six deaths worldwide; total deaths in 2018 were estimated to be 9.6 million. Sadly, around 70% of these deaths occur in low- and middle[1]income countries.
2. Most cancers in poorer countries are diagnosed very late, when most treatments are no longer effective, even if treatments were available.
3. Actually, cancer treatments are not available in many countries.

These limitations are leading to the testing of many approved drugs in the hope of extending the range of therapies in oncology. The value of "drug repurposing" is obvious. The researchers realised that the use of natural products has been a successful strategy in the discovery of medicines of possible value in the treatment of cancer. That is why they got interested in acetylsalicylic acid (aspirin); it is widely used as a painkiller and is highly active.

They noted that scientists have many decades of research experience in establishing salicylates as a potent hormone, governing various responses to abiotic and biotic stress, a major phytohormone influencing defence in plants against many varieties of pathogens and a regulator of apoptosis ( programmed cell death) —activities which may be of clinical relevance in patients.

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What is cancer?

Living beings are made of cells. Cells form tissues and tissues form organs. The cellular growth and its multiplication are precisely controlled. At times, some cells grow/multiply uncontrollably without obeying normal rules. They may even turn out to be anarchic and follow their own rules! The National Cancer Institute considers that cancer is a disease in which some of the body’s cells grow uncontrollably and spread to other parts of the body in a process called metastasis.

They highlight the evidence of survival in clinical studies of aspirin-taking subjects in randomised trials and observational studies, and the effect of aspirin on metastatic cancer spread and on thromboembolic complications of cancer. Finally, they address the most crucial aspect, namely the safety aspects of aspirin use about the risks of an increase in gastrointestinal and intracranial bleeding attributable to the drug. They emphasise the need to identify the seriousness of bleeds attributable to aspirin, and not just their frequency; they plead that specialists should evaluate these against the benefits, which may be attributable to its use.

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Aspirin and biological mechanisms relevant to cancer

Researchers thus summarised the biological mechanisms of aspirin, relevant to cancer pathogenesis:

Aspirin disrupts the cyclooxygenase (COX) enzyme responsible for forming the key signalling lipids known as prostanoids. This is a primary mechanism. Recent evidence highlights additional targets for aspirin in tackling cancer progression.

1. Using human breast and ovarian cancer cell lines, researchers have shown that aspirin beneficially interferes with energy metabolism by targeting key enzymes involved in the proliferation of cancer cells both directly and through COX inhibition.
2. Using in-vitro enzymatic assays and human cancer cell line studies, researchers showed that aspirin inhibited cancer.
3. In studies on human colon cancer and lymphoma cell lines, researchers noted that aspirin appeared to have a direct impact on angiogenesis(the process by which new blood vessels form, allowing the delivery of oxygen and nutrients to the body's tissues).

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Aspirin in metastatic spread

The authors found that almost 60 years ago, scientists demonstrated a reduction in metastatic cancer spread in animal models in vivo which was related to the anti-platelet effect of aspirin. This was famously the first evidence of the benefit of aspirin in cancer. Many authors have since confirmed the association in many cancers. In studies using in vivo animal models of metastasis, and in vitro models of cell invasion with human cell lines, researchers showed that platelets play a significant role in metastasis via several mechanisms that include secretion of growth factors, which enable metastatic migration. They logically concluded that inhibiting platelet function would serve as an effective anti-metastatic treatment.

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Evidence for aspirin in cancer-related thrombosis

Thrombosis occurs when blood clots block veins or arteries. The UK researchers noted that cancer patients appear to be in a hypercoagulable state with marked increases in vascular and thromboembolic disease events. Scientists do not consider aspirin an anti-coagulant; however, they showed that aspirin reduces thrombo-embolism including in patients with cancer.

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Lynch syndrome and aspirin

Work on Lynch syndrome (a rare dominant genetic error associated with a high risk of colon and other cancers) shows the mismatch repair of DNA to be the mechanism protective against cancer. Relying on some elegant studies the researchers concluded that the beneficial effect of aspirin in cancer might be through enhancement of DNA repair mechanisms.

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Clinical effects associated with aspirin

After reviewing the available randomised trials and observational studies of aspirin and mortality.

1. The researchers identified four early ad hoc randomised trials of aspirin and cancer treatment. The pooling of the results of these gives a suggestive reduction of 9% in cancer deaths in the 722 patients with cancer who had been randomised to aspirin.
2. During the US Physicians Health Study of aspirin and cancer prevention, researchers conducted an opportunistic trial in 502 subjects who having been randomised to take aspirin, developed cancer of the prostate. The follow-up study of these subjects revealed that a 30% relative reduction was attributable to aspirin.
3. Researchers included a recent report in which 3021 patients with HER2-negative breast cancer had been randomised to 300 mg aspirin daily. During a median follow-up of 20 months 191 invasive events had occurred (84 on aspirin and 107 on placebo: HR 1.27).

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Observational studies of aspirin and mortality

The authors found that most of the evidence on aspirin as an adjunct treatment comes from observational cohort and case-control studies of patients with cancer; usually, about 25% of them were taking aspirin, most often to prevent vascular disease. These studies inspired the researchers to test the hypothesis that aspirin reduces mortality across a range of different cancers.

Aspirin and metastatic cancer spread

This study was important because metastases are responsible for much of the pain and the complications of cancer, and many of the deaths are attributable to the metastases rather than to the primary tumour itself. A few studies described by researchers gave encouraging results.

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Aspirin and thromboembolic complications of cancer

The authors stated that aspirin is known to be of relevance to thromboembolism, a serious complication of cancer. The Surveillance, Epidemiology and End Results (SEER) programme on mortality in cancer patients reported that 11% of deaths amongst 20 cancer types had been certified as due to vascular disease, most of which (76%) was heart disease.

From the records of 108 000 survivors of a range of cancers, the researchers found that the risk of venous thromboembolism was substantially elevated in patients with almost all cancers.

Though the risk fell over time, it remained elevated more than five years after the diagnosis of cancer. Coronary artery disease and stroke were increased as well as heart failure, cardiomyopathy and other vascular disease events.

The researchers found that venous thromboembolic disease is one of the leading causes of death in cancer and is reduced by aspirin.

Though recently developed drugs for vascular protection have to some extent superseded the use of aspirin, specialists have shown that aspirin is effective against vascular and venous thrombosis.

The authors concluded:

"Putting all the above together, aspirin appears to affect some of the biological mechanisms relevant to cancer favourably, and, taken together, the clinical evidence appears to be supportive of an increase in cancer survival, a reduction in the metastatic spread and a reduction in cancer-related vascular mortality."

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Adverse effects of aspirin

"A bleed, either gastrointestinal or intra-cerebral, is a crisis for a patient and especially for patients who are already seriously ill. Yet the seriousness of bleeds attributable to aspirin, and not just their frequency, should be evaluated against the benefits which may be attributable to its use", the authors cautioned.

Based on relevant papers, the researchers asserted that low-dose aspirin is associated with additional gastrointestinal(GI) bleeds in between 0.8 and 5.0 patients per 1000 person-years aged 50–84 years in the general population. This represents an increase above spontaneous GI bleeding of between about 50% and 90%.

The authors clarified:

"It is important to note that these increases imply that only one in every two or every three bleeds that occur in patients taking low-dose aspirin is likely to be truly attributable to the aspirin, the other bleeds being spontaneous and not directly due to aspirin."

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General comments from the authors

The authors concede that uncertainties on aspirin arise from major trials, such as the US Women’s Health Study and the Australian ASPREE trial, neither of which detected benefit from aspirin.

The authors argued:

"One wonders if there are powerful, but as yet unidentified factors confounding relationships with aspirin. Further work on this should be fruitful. The lack of adequate ad hoc randomised trials on aspirin treatment of a wide range of cancers is a serious limitation in the available evidence."

"Further, almost all the current research appears to focus upon common cancers: colon, breast, prostate and lung cancer. The three cancers account for only about 30% of the worldwide cancer burden and studies focused on them will add little to the problem of the less common cancers, including the ‘rare’ cancers (usually defined as those with an incidence of less than 6 per 1 000,000), which account for about 22% of all cancers and have a worse survival (47%) than the common cancers (65%)", they highlighted a glaring limitation.

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Experts' comments

1. Dr Mangesh Thorat, Deputy Director (Clinical) of the Cancer Prevention Trials Unit at King’s College London, and Honorary Senior Lecturer, Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London (QMUL):

In a press release from Science Media Centre, London, Dr Thorat said: “This is a qualitative review combined with authors’ views, many of which I concur with. However, the paper does not report any new research data. Several important trials, for example, ADD-aspirin in breast, colorectal, prostate and gastro-oesophagal cancer patients and CaPP3 trials in individuals with Lynch syndrome are ongoing to investigate aspirin’s potential in reducing cancer incidence and mortality. Individuals should continue their participation in such trials.”

2. Dr Michael Jones, a Senior Staff Scientist in genetics and epidemiology at the Institute of Cancer Research, London: "The paper reports on some biological reasons why there may be beneficial effects of aspirin on cancer, and on published studies that have looked at the occurrence of, and survival after, a cancer diagnosis." Dr Jones said.

“The conclusions the authors reach about the possible beneficial effects of aspirin are generally accepted by health agencies like the US National Cancer Institute. The authors are aware of the limitations of many of the original research studies, but point out the generally consistent pattern of a beneficial effect, in particular for colorectal cancer and possibly for other cancers too." He added.

“Aspirin has been used for over 100 years by many millions of people for its pain and fever relieving properties, and more recently for heart and blood vessel problems. With such widespread use, the side effects and risks of aspirin are well known – for example, gastrointestinal bleeding. However, there are still questions that need to be answered about cancer – in particular on the biological mechanism and the effect in specific types of cancer and different age groups.” he clarified.

3. The UK researchers concluded that they need further evidence before the suggestion by the present evidence of about a 20% increase in survival of cancer is accepted, as it is to be hoped that research will eventually explain some of the large heterogeneity in the present evidence.

"Fortunately, research on aspirin taken by cancer patients can be conducted with a high degree of confidence that aspirin is a relatively safe drug", they clarified.

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An earlier review

A paper titled "Estimates of benefits and harms of prophylactic use of aspirin in the general population" was published online over eight years ago ( on 5 August 2014) in Annals of Oncology by an international group of researchers led by J Cuzick, Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK, claimed that accumulating evidence supports an effect of aspirin in reducing overall cancer incidence and mortality in the general population.

"The effects of aspirin on cancer are not apparent until at least 3 years after the start of use, and some benefits are sustained for several years after cessation in long-term users. No differences between low and standard doses of aspirin are observed, but there were no direct comparisons. Higher doses do not appear to confer additional benefit but increase toxicities." they added.

"Prophylactic aspirin use for a minimum of 5 years at doses between 75 and 325 mg/day appears to have favourable benefit–harm profile; longer use is likely to have greater benefits." they clarified.

"Further research is needed to determine the optimum dose and duration of use, to identify individuals at increased risk of bleeding, and to test the effectiveness of Helicobacter pylori screening–eradication before starting aspirin prophylaxis," they cautioned.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India. 

About the author of this article: Dr K S Parthasarathy is a former Secretary of the Atomic Energy Regulatory Board and is a medical physicist with a specialisation in radiation safety and regulatory matters.