Aspirin and the treatment of cancer

A news item by Professor Peter Elwood, Honorary Professor, Cardiff University.

9 October 2018 

Against a background of controversy about the value of aspirin as a preventive in healthy subjects, a rather different use of the drug has recently been highlighted.

Fifty years ago evidence suggestive of benefit from aspirin beyond the reduction of pain and fever, was reported. In two remarkable papers published in 1968 and 1973 Gabriel Gasic and colleagues described the role of platelets in the metastatic spread of cancer. They showed that a deficiency of platelets is associated with a reduction in the risk of cancer,(1) and that experimentally-induced metastasis are reduced by aspirin.(2)  They concluded that these findings ‘strongly support the role of platelet aggregation and the platelet release reaction in metastasis’. 

During the following fifty years extensive experimental evidence has accumulated on how platelets protect tumour cells in the circulation from immune elimination, enable cancer cells to adhere to vascular endothelium and enhance the growth of metastases.(3) With this knowledge, benefit from aspirin in patients with cancer is a highly reasonable expectation.

A reduction in metastatic spread is important because metastases are a frequent source of pain, serious complications and death(4), but a number of studies which examined the prophylactic action of aspirin commented that a reduction in metastatic spread suggests that aspirin might help in the treatment of some cancers.(5,6)

The therapeutic use of aspirin in cancer has been examined in only a very few randomised controlled trials, and those that have been reported have been either unrealistically small, or randomisation was compromised.(7) The bulk of clinical evidence on aspirin taken by patients with cancer is therefore limited at present to observational studies

A systematic review of observational studies has now been published in an open access journal.(8) A search of the literature identified seventy-one studies and together these included over 120 thousand patients with cancer who took aspirin, usually for cardiovascular protection, and these are compared with over four hundred thousand patients who took no aspirin. The patients in the different studies had been followed for between about three and fifteen years.

Aspirin taking was found to be associated with an overall reduction in cancer mortality of about 25% (95% range 18-44%). That is: at any time following the diagnosis of cancer, about 25% more of the patients who had been taking aspirin had survived, compared with patients not taking aspirin.

Twenty-nine observational studies describe colorectal cancer and pooling the estimates of reduction associated with aspirin indicates an average reduction in cancer deaths of about 28%; thirteen observational studies reported on aspirin and breast cancer mortality and pooling these shows about a 31% reduction in cancer mortality, and fifteen studies suggest a pooled reduction by aspirin of about 13% in deaths from prostate cancer. 

A number of studies in the review give evidence which together indicate a reduction of about 70% in metastatic spread attributable to aspirin. A further reason to consider low-dose aspirin is that many patients with cancer, and particularly those with metastatic spread, appear to be in a hypercoagulable state and show marked increases in the incidence and the mortality of venous thromboembolism. The American Society of Clinical Oncology has therefore recommended that prophylactic anticoagulants be considered for all hospitalized cancer patients,(10) and aspirin has been shown to be effective in the reduction of thromboembolism.(11)

One of the studies included in the review used detailed data from forty thousand patients with colon cancer to generate a predictive formula which gives an estimate of the likely average duration of survival of patients, and the use of the formula was validated in another fifteen thousand patients.(12) Many factors, including aspirin taking, were found to be predictive of survival and are included in the formula.  Entering the details for a typical patient who has been given a diagnosis of colon cancer into the formula twice – first, not on aspirin and then on aspirin - indicates that the effect of aspirin is to give a non-diabetic man of about 65 years, a survival similar to that of a man five years his junior. For a woman of similar age etc. given a diagnosis of colon cancer, the addition of aspirin leads to a match with a woman four years younger.

The issue of bleeding was examined carefully in the review. Information on bleeding was sought from an author of each of the reports and 31 replies were received. Very few patients were reported as having had serious bleeding and amongst those who had, the proportion of patients taking aspirin who had had a ‘serious’ bleed was no greater than the proportion of patients not taking aspirin who had experienced a serious spontaneous stomach bleed due to causes other than aspirin.  In two of the 71 reports reviewed a very small number of fatal stomach bleeds had occurred, but again the proportion was no greater in the patients on aspirin than spontaneous bleed in those not taking aspirin.

Elsewhere, authors of this review have reported an extensive examination of the published evidence on ‘serious’ bleeds attributable to aspirin which led to death.(13)  Eleven randomised trials were found that had that reported fatal bleeds. In the fifty-four thousand subjects who had been randomised to receive aspirin eight in every thousand had a ‘serious’ bleed, while in the fifty-two subjects randomised not to receive aspirin five in every thousand had a ‘serious’ bleed. Fatal bleeds occurred in 3.7 in every 10,000 subjects on aspirin, and in 4.7 in every 10,000 subjects randomised not to receive aspirin. 

It must be emphasised that the evidence on aspirin and the treatment of cancer is limited, in particular because all the studies reviewed had been observational, and allocation of aspirin had not been randomised. There are therefore opportunities for bias(14) and these may explain much of the heterogeneity which is shown between the results of the various studies in the review. The heterogeneity is in fact considerable, a few studies failing to detect benefit attributable to aspirin. 

More evidence is urgently needed, and a number of ad hoc randomised trials are being set up,(15) but these are unlikely to report for quite a few years. In addition to testing the effect of aspirin on mortality and on metastatic spread, some of the new trials will examine predictive factors, including certain genetic mutations which may define the patients with cancers most likely to show a response to aspirin.(16) 

While awaiting results from randomised trials the authors of the review(8) judge that it is ethical and reasonable for patients with cancer to be given the evidence on aspirin now available, and to be helped to make their own assessment of the balance between the risks and benefits of low dose aspirin (100 mg or less salicylic acid daily). The reviewers also suggest that patients given a diagnosis of cancer should be strongly encouraged to participate in appropriate research studies. 

The research ‘Systematic review update of observational studies further supports aspirin role in cancer treatment: time to share evidence and decision-making with patients?’ is published in Plos One Medicine.
 

References

  1. Gasic G, Gasic T, Stewart CC. Antimetastatic effects associated with platelet reduction. Proc nat Acad Sci (Wash) 1968; 61:46-52.
  2. Gasic GJ, Gasic TB, Galanti N, Johnson T, Murphy S. Platelet-tumor-cell interactions in mice. The role of platelets in the spread of malignant disease. Int J Cancer. 1973; 11:704-718.
  3. Gay LJ, Felding-Habermann B. (2011) Contribution of platelets to tumour metastasis. Nature Reviews Cancer 11: 123-134.
  4. Mehlen P, Puisieux A. Metastasis: a question of life or death. Nature Rev Cancer 2006;6: 449-458.
  5. Chan AT, Ogino S, Fuchs CS, Meklin GP, Moeslein G, Olschwang et al. Aspirin use and survival after diagnosis of colorectal cancer. JAMA 2009; 302: 649-659.
  6. Rothwell PM, Wilson M, Price JF, Belch JFF, Meade TW, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. 2012. 379: 1591-1601.
  7. Langley RW, Burdett S, Tierney JF, Caferty F, Parmar MK, Venning G. Aspirin and cancer: has aspirin been overlooked as an adjuvant therapy. Brit J Cancer 2011;105:1107-1113.
  8. Elwood PC, Pickering JE, Morgan G, Galante J, Weightman AL, Morris D, Longley M, Mason M, Adams R, Dolwani S, Chia JWK, Lanas A. Systematic review update of observational studies further supports aspirin role in cancer treatment: time to share evidence and decision-making with patients? Public Library of Science Published: Sept. 25, 2018. https://doi.org/10.1371/journal.pone.0203957
  9. Liebman HA, O’Connell C. Incidental venous thromboembolismevents in cancer patients : what do we know in 2016? Thromb Res 2016;140; Suppl 1; S18-S20
  10. Lyman GH, Khorana AA, Falanga A, Clarke-Pearson D, Flowers C, Jahanzeb M, et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007;25: 5490-5505.
  11. Brighton TA, Ekelboom TA, Mann KMister R, Gallus A, Ockelford P. Low-Dose Aspirin for Preventing Recurrent Venous Thromboembolism. New Engl J Med 2012;367: 1979-1987.
  12. Hippisley-Cox J, Coupland C. Development and validation of risk prediction equations to estimate survival in patients with colorectal cancer: cohort study. British Medical Journal 2017; 357(j2497).
  13. Elwood PC, Morgan G, Galante J, Chia JW, Dolwani S, Graziano JM, et al. Systematic review and meta-analysis of randomised trials to ascertain fatal gastrointestinal bleeding events attributable to preventive low-dose aspirin: no evidence of increased risk. PLoS One 2016;11: e0166166.
  14. Frouws M, van Herk-Sukel MPP, Maas HA et al. The mortality reducing effect of aspirin in colorectal cancer patients: Interpreting the evidence. Cancer Treat Rev 2016;55: 120-127.
  15. Baigent C. Aspirin for disease prevention: public policy or personal choice? Ann Int Med 2016;164: 846-847.
  16. Coyle C, Cafferty FH, Langley RE. Aspirin and Colorectal Cancer Prevention and Treatment: Is It for Everyone? Curr Colorectal Cancer Rep 2016;12:27-34.

Professor Peter Elwood OBE, DSc, MD, FRCP, FFPHM

Division of Population Medicine,
Cardiff University, UK
ElwoodPC@cardiff.ac.uk