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Editorial

Aspirin and cancer prevention

BMJ 2012; 344 doi: http://dx.doi.org/10.1136/bmj.e2480 (Published 3 April 2012)
Cite this as: BMJ 2012;344:e2480

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Re: Aspirin and cancer prevention

16 July 2012

Reply to BMJ Editorial of 7.4.2012

ASPIRIN AND CANCER PREVENTION

Has the Medical profession accidentally stumbled onto a relatively inocuous cure for cancer?

Long term use of Aspirin, Metformin and the non selective BETA adrenergic receptor blocker Propranolol are all associated with lower cancer incidence, metastases and death.
Ref 1,2,3,4 and 5.

I believe the main mechanism linking thee drugs in inhibition of tumour Glycolysis.

You said in your Editorial of 7.4.12

“The study’s findings suggest low dose Aspirin should be considered in the treatment of some patients with cancer” and “the findings of 2 recent studies suggest daily low dose Aspirin could reduce cancer related outcomes”.

Otto Warburg found in the 1920s that cancer cells used 10 times more glucose because they get their energy from aerobic glycolysis rather than mitochondrial respiration. Switching off aerobic glycolysis and switching on mitochondrial respiration will lead to apoptosis : cancer cell death.

In your editorial you wrote that cancer metastases were reduced and that low dose Aspirin should be considered as a treatment for some cancers.

Aspirin was shown to block 5 enzymes of the glycolytic pathway.
Ref 6.

Aspirin reduced risk of adenocarcinoma with metastases at initial diagnosis and risk of metastasis on subsequent follow up of patients initially without metastases.
Ref 7

Empirically Metformin therapy gives a 31% to 37% reduction in relative risk of cancer, and improved prognosis in those found to have cancer.
Ref 8. Ref 2.

Metformin activates the AMP activated protein kinase pathway, a major sensor of the energetic status of the cell, which has been proposed as a promising therapeutic target in cancer treatment.

Metformin also inhibits the ability of Mitochondria to burn lactate and other products of glycolysis. New Scientist 17.9.2011.

Metformin delays uptake of glucose from the intestinal tract, decreases insulin resistance and inhibits hepatic and renal gluconeogenesis (Glucomet Data Sheet).

Propranolol users were significantly less likely to present with a T4 (odds ratio 0.24) or N2/N3/M1 (odds ratio 0.20). Cumulative probability of breast cancer specific mortality was significantly lower (hazard ratio = 0.19).

These results provide evidence in humans suggesting inhibiting the beta adrenergic pathway can reduce breast cancer progression and mortality.

Glycolysis is mediated through Beta 2 adrenergic receptor sites.
Ref 9

These drugs almost certainly act against cancer in other ways too, but the raw empirical data call for urgent trials of these drugs to be used together in randomised controlled trials as a cancer treatment at the very least in people otherwise offered only palliative chemotherapy.

My second question is can the medical profession do this when these drugs cost only pennies, and nearly all research is paid for by the Pharmaceutical Companies that expect to make large profits on expensive drugs.

REFERENCES

Reference 1 BMJ Editorial 7.4.2012
Aspirin & Cancer Prevention
Quote in studies Aspirin reduced the risk of cancer with distant metastases, hazard ratio 0.64.

“The study’s findings suggest low dose Aspirin should be considered in the treatment of some patients with cancer” and “the findings of 2 recent studies suggest daily low dose Aspirin could reduce cancer related outcomes”.

Reference 2
Metformin, cancer alphabet soup, and the role of epidemiology in Etiologic Research Diabetes care September 2009.

Reference 3
Metformin and Cancer Risk in Diabetic patients : A systematic review and Meta analysis Cancer Prevention and research 12th October 2010.

Reference 4
The influence of antidiabetic medications on the development and progression of prostate cancer. Cancer Epidemiology March 2012.

Reference 5
Betablockers and breast cancer mortality : a population and based study.
Journal of Clinical Oncology 2011 1st July

Reference 6
Aspirin acetylates multiple cellular proteins in HCT-116 colon cancer cells. Identification of novel targets, International Journal of Oncology 39; 1273-1283, 2011.

Reference 7
Effect of daily Aspirin on risk of cancer metastasis a study of incident cancers during randomised controlled trials. Lancet 20th March, 2012

Reference 8
Metformin in Cancer Therapy: a new perspective for an old diabetic drug published Molecular Cancer Therapy 2010 May.

Reference 9
Increased aerobic glycolysis through Beta 2 stimulation is a common mechanism involved in lactate formation during shock states. Shock October 2008 .

Competing interests: None declared

Martyn Phipps, GP

Old Hall Surgery, Ellesmere Port, 26 Stanney Lane, Ellesmere Port

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Re: Aspirin and cancer prevention

23 May 2012

Dear Sir, While Kurth urges caution in recommending aspirin as a chemopreventive for the general population, one must also note that he accepts that there is a compelling case for aspirin as a prophylactic for specific subgroups [1]. One such subgroup ought to be those suffering from Li Fraumeni Syndrome (LFS) and other TP53-related conditions. LFS is a rare hereditary cancer syndrome characterised by germline mutations in the TP53 tumour suppressor gene. The syndrome is associated with a range of cancers, particularly sarcomas, leukemias, adrenocortical carcinomas and other malignancies, particularly during childhood and early adulthood. Among women with LFS, the most common disease is breast cancer, with a 49% risk of developing the disease by age 60 [2]. Clearly people with LFS are in urgent need of cancer-preventative options. Recent work suggests that aspirin has some anti-cancer activity against a range of cancer types in addition to its action against colorectal cancer [3, 4]. We note that the CaPP2 trial results showed a protective effect in the case of sufferers of Lynch Syndrome, a syndrome that predisposes to the development of colorectal cancer, but also showed some evidence of a protective effect in other cancers [5]. Given the high risk of developing cancer and the relatively low risk of adverse aspirin-related events, it is time to actively consider clinical trials in LFS patients to establish whether aspirin has a protective effect in this rare and life-threatening condition. [1] Kurth K. Aspirin and cancer prevention, BMJ 2012;344:e2480 doi: 10.1136/bmj.e2480. [2] Masciari et al. Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort, Breast Cancer Res Treat 2012, doi: 10.1007/s10549-012-1993-9 [3] Mills et al. Low-dose Aspirin and Cancer Mortality: A Meta-analysis of Randomized Trials, Am J Med doi:10.1016/j.amjmed.2012.01.017 [4] Algra AM, Rothwell PM. Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncology 2012, DOI:10.1016/S1470-2045(12)70112-2. [5] Burn et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 2012, doi:10.1016/S0140-6736(11)61049-0

Competing interests: None declared

Pan Pantziarka, Patient Advocate

The George Pantziarka TP53 Trust, 7 Surbiton Crescent, KT1 2JP

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Re: Aspirin and cancer prevention

26 April 2012

RESPONSE TO AN EDITORIAL IN THE BMJ: Kurth T. Aspirin and cancer prevention. BMJ 2012;344.

Dear Sir,

An editorial on 7th April urges caution on prophylactic aspirin and calls for further targeted research before aspirin is ‘prescribed’ to ‘treat’ all adults.1 The use of the words quoted indicate what is surely an inappropriate concept of prophylaxis.
There is a fundamental difference between ‘therapy’ and ‘prophylaxis’. The treatment of disease has been delegated to health care practitioners working within the NHS. The prevention of disease is a subjects’ own responsibility. It is my choice, and my responsibility whether or not I smoke, what diet I consume, what exercise I take….. and whether or not I take a protective drug. In fact, it is estimated that around one third of adults aged over 40 take statins, and surveys in Wales2 show that 38% of subjects aged over 50 take aspirin regularly.

The decision whether or not to take prophylactic aspirin rests largely on the balance between the risks and the benefits of the drug. The evidence from trials is that deaths from stomach bleed attributable to aspirin are no more frequent than deaths from spontaneous bleeds,3,4 and further evidence from the recent trials,5 acknowledged in the Editorial, is that the rate of extracranial bleeds decrease over time.

The balance between risks and benefits of a prophylactic measure is crucial, but who should make the evaluation? Is colorectal screening for cancer to be withdrawn because of undesirable side-effect – bleeding in 2.4 per 1,000 subjects, and 9.7 perforations in those screened?6 One presumes that subjects invited to attend for screening are told these risks, encouraged to make their own evaluation and their own decision whether or not to be screened?

In the UK, the recent Department of Health White Paper ‘Healthy Lives, Healthy People’7 states “individuals should feel they are true partners..so decisions are shared as far as possible, based on the right information and genuine dialogue with health practitioners”. The voice of the public is seldom heard in such situations, yet in a Citizens’ Jury8 held to examine prophylaxis and the use of low-dose aspirin, the ‘jurors’ agreed that the preservation of health is their own responsibility and the role of government, doctors and health care professionals is to provide adequate evidence on risks and benefits to enable healthy subjects to make informed decisions about the preservation of their own health ‘….even before there is agreement amongst doctors’. Furthermore, the jurors urged the involvement of the public together with professionals in thinking these issues through and epitomised the sentiment, “Nothing about me without me.”9

1. Kurth T. Aspirin and cancer prevention. BMJ 2012;344.
2. Elwood P., Hughes J., Morgan G., Brown G., Longley M. A survey of aspirin use for vascular prophylaxis in Wales. Quality in Primary Care 2005;119:734-737.
3. Morgan G. Aspirin for the primary prevention of vascular events? Public Health 2009;123:787-8
4. Antithrombotic Trialists’ Collaboration. Collective meta-analysis of randomised trial of antiplatelet therapy for prevention of death, myocardial infarction and stroke in high risk patients. Brit Med J 2002;324:71-86.
5. R Rothwell PM, Price JF, Fowkes FGR 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 trials. Lancet March 21, 2012 DOI:10.1016/s0140-6736(11)61720-0
6. Logan RFA, Patnick J, Nickerson C et al. Outcomes of the bowel cancer screening programme (BCSP) in England after the first 1 million tests. Gut: Dec. 7th. 10.1136/gutinl-2011-300843
7. Department of Health. Healthy lives, healthy people White Paper: Our strategy for public health in England. London: 2010.
8. Elwood PC White J, Fone D, Dunstan F, Morgan G, Pickering J, Mitchell C. Aspirin taking in the community: a cross-sectional survey. Brit J Cardiol. 2011;18:238-230
9. Valerie Billingham, Through the Patient's Eyes, Salzburg Seminar Session 356, 1998.

Competing interests: Peter Elwood has taken part in a number of discussions on aspirin prophylaxis and has received several honoraria for his contributions to meetings.

Peter Elwood, Professor, Medical Epidemiologist

Mohammed Mustafa

Cochrane Institute of Primary Care and Public Health,Cardiff University School of Medicine, Neuadd Meirionnydd,Cardiff,CF14 4XN

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Re: Aspirin and cancer prevention

13 April 2012

Kurth’s editorial is timely.(1) As a general practitioner and a principal investigator in a large-scale randomised controlled trial of aspirin in the elderly (N = 19,000, ASPirin in the Reduction of Events in the Elderly [ASPREE](2)), I regularly deal with patients and trial participants who are in a quandary because of study results that week by week suggest aspirin as a cancer preventer,(3) a stroke promoter,(4) and a cause of blindness.(5) The best way to settle the question of whether it is advantageous to recommend routine preventive aspirin therapy to patients without an established evidence-based indication for it use is by a sufficiently powered community-based randomised controlled trial. We need to complete the ASPREE study rather than use associations and public perception as our guide for evidence based practice.

(1) Kurth K. Aspirin and cancer prevention BMJ 2012;344:e2480 doi: 10.1136/bmj.e2480.
(2) www.aspree.org
(3) Rothwell PM, Price FP, Fowkes FGR, Zanchetti A, Roncaglioni MC, Tognoni G, 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; published online 20 March.
(4) Seshasai SRK, Wijesuriya S, Sivakumaran R, Nethercott S, Erqou S, Sattar N, et al. Effect of Aspirin on Vascular and Nonvascular Outcomes Meta-analysis of Randomized Controlled Trials. Arch Intern Med. 2012;172(3):209-216. doi:10.1001/archinternmed.2011.628
(5) de Jong PT, Chakravarthy U, Rahu M, Seland J, Soubrane G, Topouzis F, et al. Associations between aspirin use and aging macula disorder: the European Eye Study. Ophthalmology. 2012 Jan;119(1):112-8.

Competing interests: Bayer has provided trial drug for ASPREE and travel funds for myself.

Mark R Nelson, General practitioner

Nil

University of Tasmania, 17 Liverpool St, Hobart, Tasmania, AUSTRALIA

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