Elsevier

The Lancet

Volume 379, Issue 9826, 28 April–4 May 2012, Pages 1591-1601
The Lancet

Articles
Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials

https://doi.org/10.1016/S0140-6736(12)60209-8Get rights and content

Summary

Background

Daily aspirin reduces the long-term incidence of some adenocarcinomas, but effects on mortality due to some cancers appear after only a few years, suggesting that it might also reduce growth or metastasis. We established the frequency of distant metastasis in patients who developed cancer during trials of daily aspirin versus control.

Methods

Our analysis included all five large randomised trials of daily aspirin (≥75 mg daily) versus control for the prevention of vascular events in the UK. Electronic and paper records were reviewed for all patients with incident cancer. The effect of aspirin on risk of metastases at presentation or on subsequent follow-up (including post-trial follow-up of in-trial cancers) was stratified by tumour histology (adenocarcinoma vs other) and clinical characteristics.

Findings

Of 17 285 trial participants, 987 had a new solid cancer diagnosed during mean in-trial follow-up of 6·5 years (SD 2·0). Allocation to aspirin reduced risk of cancer with distant metastasis (all cancers, hazard ratio [HR] 0·64, 95% CI 0·48–0·84, p=0·001; adenocarcinoma, HR 0·54, 95% CI 0·38–0·77, p=0·0007; other solid cancers, HR 0·82, 95% CI 0·53–1·28, p=0·39), due mainly to a reduction in proportion of adenocarcinomas that had metastatic versus local disease (odds ratio 0·52, 95% CI 0·35–0·75, p=0·0006). Aspirin reduced risk of adenocarcinoma with metastasis at initial diagnosis (HR 0·69, 95% CI 0·50–0·95, p=0·02) and risk of metastasis on subsequent follow-up in patients without metastasis initially (HR 0·45, 95% CI 0·28–0·72, p=0·0009), particularly in patients with colorectal cancer (HR 0·26, 95% CI 0·11–0·57, p=0·0008) and in patients who remained on trial treatment up to or after diagnosis (HR 0·31, 95% CI 0·15–0·62, p=0·0009). Allocation to aspirin reduced death due to cancer in patients who developed adenocarcinoma, particularly in those without metastasis at diagnosis (HR 0·50, 95% CI 0·34–0·74, p=0·0006). Consequently, aspirin reduced the overall risk of fatal adenocarcinoma in the trial populations (HR 0·65, 95% CI 0·53–0·82, p=0·0002), but not the risk of other fatal cancers (HR 1·06, 95% CI 0·84–1·32, p=0·64; difference, p=0·003). Effects were independent of age and sex, but absolute benefit was greatest in smokers. A low-dose, slow-release formulation of aspirin designed to inhibit platelets but to have little systemic bioavailability was as effective as higher doses.

Interpretation

That aspirin prevents distant metastasis could account for the early reduction in cancer deaths in trials of daily aspirin versus control. This finding suggests that aspirin might help in treatment of some cancers and provides proof of principle for pharmacological intervention specifically to prevent distant metastasis.

Funding

None.

Introduction

Cancer is the second most common cause of death worldwide and 5 million new cases are diagnosed each year in Europe and the USA alone.1, 2, 3 There has been evidence from animal studies and from observational studies in humans that daily aspirin might be effective in preventing several common cancers,4, 5, 6, 7, 8 which has recently been confirmed by follow-up of patients originally included in randomised trials of daily aspirin versus control in the prevention of vascular events.9, 10, 11, 12 Allocation to aspirin in these trials resulted in a 40% reduction in cancer deaths from 5 years onwards,12 with sustained reductions in deaths due to certain cancers at 20-year follow-up.9, 10, 11

These recent reports of randomised trials suggest that aspirin might also have short-term effects on outcome in patients who develop cancer while on treatment. First, the effect of aspirin on death due to cancer was greater than the apparent effect on incidence of cancer.12 Second, the reduction in mortality due to some cancers occurred within 2–3 years after randomisation and seemed too quick to be accounted for by an effect only on carcinogenesis or early cancer growth.12 Third, there was a reduction in deaths due to metastatic cancer with unknown primary.12 We therefore hypothesised that these shorter-term effects of aspirin could be due to the prevention of distant metastasis, consistent with experimental evidence in animals that platelets play an important part in blood-borne metastases,13, 14, 15, 16 which are reduced by aspirin,15, 16, 17, 18, 19 and with observational studies in humans that showed that aspirin use is associated with reduced distant metastasis and with decreased rates of recurrence in patients with common adenocarcinomas.7, 20, 21, 22, 23, 24 Since the results in animal studies might not apply to humans and because the observational studies are subject to several potential biases, we studied metastasis at initial diagnosis and during subsequent follow-up in all participants with a new diagnosis of cancer in all five large completed randomised trials of aspirin versus control in prevention of vascular events in the UK.25, 26, 27, 28, 29

Section snippets

Trials

Recent literature searches identified all randomised trials of aspirin (any dose) versus no aspirin in the absence of another antiplatelet agent, or aspirin (any dose) versus no aspirin in the presence of another antithrombotic agent (if balanced in the aspirin and no aspirin groups) in prevention of vascular events.11, 12 We restricted inclusion to trials done in the UK because of the availability of reliable and well validated centralised death certification and cancer registration to ensure

Trials

Of the five eligible randomised trials of aspirin versus control (appendix p 1), two had been done in primary prevention of vascular disease,25, 27 one in secondary prevention after recent vascular events,26 and two in groups with asymptomatic peripheral arterial disease (one in patients with diabetes;28 one in individuals with low ankle brachial index on screening29). Among the 17 285 participants in the five trials, there were 1101 incident cancers and 563 deaths due to incident cancer during

Discussion

Daily aspirin reduces the incidence of colorectal cancer after a delay of 8–10 years9, 10 and reduces mortality due to several other adenocarcinomas after a similar delay,11 consistent with the latency expected before the clinical manifestation of an effect on early carcinogenesis. However, the accompanying analysis of data from 51 trials of aspirin versus control showed that aspirin reduced mortality from all cancer after only 5 years, with even earlier reductions in deaths due to colorectal

References (41)

  • A Jemal et al.

    Global patterns of cancer incidence and mortality rates and trends

    Cancer Epidemiol Biomarkers Prev

    (2010)
  • Preventable cancer in the USA

    Lancet

    (2010)
  • MJ Thun et al.

    Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues

    J Natl Cancer Inst

    (2002)
  • C Bosetti et al.

    Aspirin and cancer risk: a summary review to 2007

    Recent Results Cancer Res

    (2009)
  • PM Rothwell et al.

    Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials

    Lancet

    (2012)
  • GJ Gasic et al.

    Antimetastatic effects associated with platelet reduction

    Proc Natl Acad Sci USA

    (1968)
  • GJ Gasic et al.

    Platelet-tumor-cell interactions in mice. The role of platelets in the spread of malignant disease

    Int J Cancer

    (1973)
  • LJ Gay et al.

    Contribution of platelets to tumour metastasis

    Nature Rev Cancer

    (2011)
  • UK Henschke et al.

    Aspirin for reducing cancer metastasis?

    J Nat Med Assoc

    (1977)
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