{"id":8706,"date":"2021-09-06T11:28:50","date_gmt":"2021-09-06T10:28:50","guid":{"rendered":"https:\/\/www.zoeharcombe.com\/?p=8706"},"modified":"2022-10-14T09:15:36","modified_gmt":"2022-10-14T08:15:36","slug":"aspirin-cancer-survival","status":"publish","type":"post","link":"https:\/\/www.zoeharcombe.com\/2021\/09\/aspirin-cancer-survival\/","title":{"rendered":"Aspirin & cancer survival"},"content":{"rendered":"
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Executive summary<\/strong>\n <\/p>\n * Low dose aspirin has been the subject of much research in the fields of cancer and cardiovascular disease. It has been studied for potential prevention and help post diagnosis. \n <\/p>\n * This week’s note examines a very large systematic review and meta-analysis of 118 studies, which reviewed aspirin for cancer post diagnosis.\n <\/p>\n * Significant reductions (approximately 20%) in mortality were found in patients taking aspirin for some of the most common cancers and other cancers when grouped together. \n <\/p>\n * The paper summarised some findings on extension of median survival following cancer diagnosis, which is the way in which cancer data are presented. Some of the numbers on possible life extension among patients taking aspirin were impressive.\n <\/p>\n * The mechanisms were not explored in this paper but were explored in another paper by the lead author. The mechanisms are plentiful and plausible.\n <\/p>\n * The one downside of taking aspirin is the risk of bleeding. This note reviews the evidence for the risk of bleeding and tries to put possible benefit and risk in context with each other.\n <\/p>\n * There is no evidence that aspirin will increase the risk of fatal bleeds and so the concern that possible life extension may be offset by a fatal bleed is not warranted.\n <\/p>\n * The authors concluded that the evidence should be shared with patients and their carers so that they can make an informed choice about whether to add aspirin to their cancer treatment. I agree with this conclusion.\n <\/p>\n <\/p>\n Introduction<\/strong>\n <\/p>\n This is the third week in a row where I’ll declare an interest. I have met four of the authors on this week’s paper. The lead author, Professor Peter Elwood, was an examiner when I defended my PhD. Professor Elwood presided over one of the most well-known epidemiological studies \u2013 the Caerphilly Cohort study, which started in 1979 (Ref 1). I thought I was doomed with my findings that there was no evidence against total or saturated fat but he had found the same at the time. We both concluded that dietary fat guidelines had been introduced without evidence. \n <\/p>\n I met Janet Pickering with Peter once when we jointly explored the Caerphilly data to see if any other dietary associations could be observed. We concluded at the time that they couldn’t. I have met John Watkins a couple of times, as he and his wife are close friends of our neighbours. I also contacted John early in the epidemiology part of my PhD for advice, as he has worked in this field all his life. I met Christine Delon at the Public Health Collaboration conference in 2019 and we have emailed each other about research a few times since.\n <\/p>\n Peter has had many interests over many years, culminating in over 700 publications with his name on. He officially retired in 1995 but he was granted an honorary chair at Cardiff University, where he still goes to work. Peter quotes Archie Cochrane (founder of the Cochrane institute and his predecessor as Director of the MRC epidemiology unit) as saying “To treat a disease is an admission of failure, Prevention is the ultimate aim of medicine.<\/em>” For over 50 years Peter’s research has been focused on the prevention of disease.\n <\/p>\n Alongside dietary fat and heart disease, another of Peter’s great interests has been aspirin. The summary description issued for a talk which Peter gave in March 2018 explained “Forty years ago a randomised controlled trial of aspirin in the prevention of heart attacks showed a 25% reduction in deaths and brought aspirin to the notice of cardiologists. Ten years later benefit was confirmed in one of the first ‘overviews’ conducted in medicine. In 2011 a series of follow-up studies of randomised trials showed a 40% reduction in cancer deaths and brought aspirin to the notice of oncologists. A reduction by aspirin in deaths and in the spread of cancer has been confirmed in numerous overviews<\/em>.\n <\/p>\n But, aspirin is highly controversial. Its benefits in both vascular disease and cancer are widely acknowledged, but its dangers in increasing stomach bleeds are held by many to outweigh the benefits<\/em>” (Ref 2).\n <\/p>\n Peter is an enthusiastic recipient of the Monday note and he invited me to review one of his recent publications (July 2021) entitled “Aspirin and cancer survival: a systematic review and meta-analysis of 118 observational studies of aspirin and 18 cancers<\/em>” (Ref 3).<\/strong>\n <\/p>\n The title tells us so much already \u2013 it’s a huge study. It’s the best kind of evidence \u2013 a systematic review to find all the studies and then pooling them together in meta-analysis. It’s also looking at survival \u2013 which is what I would want to know had I had a cancer diagnosis. With the bizarre sense of evaluating the evaluator \u2013 here goes.\n <\/p>\n<\/p>\n <\/a><\/p>\n \n The study<\/strong>\n <\/p>\n The study opened with an explanation of the background and why this review was undertaken. "Despite the accumulation of research papers on aspirin and cancer, there is doubt as to whether or not aspirin is an acceptable and effective adjunct treatment of cancer<\/em>." The debate is as the summary accompanying the talk set out above \u2013 there is evidence of benefit, but there is concern that harm may outweigh this.\n <\/p>\n Elwood et al<\/em> conducted a systematic review of studies of patients with cancer some of whom took aspirin having received their cancer diagnosis. There were 118 observational studies relevant to the search. Eighty-one studies reported on aspirin and cancer mortality and 63 studies reported on all-cause mortality (some reported on both). Approximately 20-25% of patients reported taking aspirin, which totalled about a quarter of a million people. \n <\/p>\n The study found aspirin to be associated with a reduction of approximately 20% in cancer deaths (pooled hazard ratio (HR): 0.79; 95% confidence intervals: 0.73, 0.84 in 70 reports) with similar reductions in all-cause mortality (HR: 0.80; 0.74, 0.86 in 56 studies). The corresponding author of every paper was written to asking for information on bleeding. The frequency of bleeding increased in the patients taking aspirin "but fatal bleeding was rare and no author reported a significant excess in fatal bleeds associated with aspirin. No author mentioned cerebral bleeding in the patients they had followed<\/em>." We’ll come back to bleeding.\n <\/p>\n Most of the 118 studies examined three of the most common cancers \u2013 colon, breast and prostate. Supplementary File 4 set out the meta-analyses of aspirin and cancer mortality for each of these three cancers separately. The first two achieved significant differences: colon (HR: 0.72; 0.63, 0.82); and breast cancer (HR: 0.84; 0.72, 0.98). The prostate cancer result was not statistically significant (HR: 0.89; 0.78, 1.02). Pooling together evidence for aspirin and mortality in other cancers (e.g., lung, ovarian, liver, bladder, melanoma etc) also achieved a significant reduction (HR: 0.79; 0.70, 0.88).\n <\/p>\n When all-cause mortality was reviewed, aspirin continued to be associated with a significant difference for those with colon cancer (HR: 0.83; 0.75, 0.92), but not for those with breast cancer or prostate cancer. There was a significant difference for those who took aspirin with other cancers for all-cause mortality (HR: 0.67; 0.60, 0.75). \n <\/p>\n The rigor of the paper was the best I’ve seen. Pages and pages in the supplemental file were devoted to various tests that can be undertaken with meta-analysis to confirm whether results are robust or if any bias has been detected. Let’s use publication bias, as an example. Publication bias is the tendency to decide to publish a study based on the results of the study, rather than on the basis of its theoretical or methodological quality. In the absence of publication bias, studies are distributed symmetrically about the effect (HR) found. There is a diagram called a funnel plot, which can show asymmetry in the presence of bias. Other tests can also be done to detect publication bias and other potential bias in the pool of research.\n <\/p>\n The researchers found that the result for colon cancer mortality was robust, but not the result for colon cancer and deaths from any cause. The breast cancer mortality result was not robust. The findings for other cancers as a group \u2013 for death from cancer and death from any cause \u2013 were both robust.\n <\/p>\n Additional survival<\/strong>\n <\/p>\n The most powerful part of the paper for me was where median survival data were presented. Cancer has always been a field where I think data are presented in the ‘right’ way and by this I mean the way in which patients can understand what they want to understand. Cancer drugs invariably have their outcomes presented in terms of median survival. If you remember the three averages \u2013 mean is the sum of all the data divided by the number of data points, mode is the most common data point and median is the middle in an ordered list. Cancer drugs are presented as \u2013 Drug X resulted in a median survival of (say) 24 months vs a placebo median survival of (say) 12 months. The patient can then decide if the side effects of Drug X are worth the predicted 12 additional months. In contrast, cardiovascular disease interventions are presented as \u2013 take this drug for 5 years and you have a 20% (relative) reduced chance of having an event, which might turn out to be a 1 in 150 absolute risk of that event and then you might have that event on day 1 of year 6. I like how cancer does data.\n <\/p>\n Elwood et al<\/em> reported that a number of the papers they examined provided estimates of the association with aspirin in terms of the additional expected survival. Several examples were given (all references are in the paper, p6). Albandar et al<\/em> followed 174 US veterans with colorectal cancer to death and reported that the median survival of patients taking aspirin was 941 versus 384 days in those not taking aspirin. “Several papers record an increased survival associated with aspirin taken by patients with liver cancer: in one 18 months additional survival; in another 6% more patients survived 10 years with aspirin after diagnosis, and the median overall survival period after embolisation was longer for patients taking aspirin (57 versus 23 months). In a study of endometrial cancer, 91% of patients taking aspirin survived 10 years compared with 81% of patients not on aspirin. In a study of patients with lung cancer, patients on aspirin survived 1.69 and only 1.02 years if not on aspirin. In a study of pancreatic cancer, the 3-year survival was reported to be 61% in patients taking aspirin versus 26% in patients not taking aspirin, and finally, the 3-year survival of US veterans with head and neck cancer was 79% in those taking aspirin, compared with only 56% of those not taking aspirin.”<\/em> \n <\/p>\n I’ve cited much of that section verbatim as it was so powerful. Those are large differences for someone given months to live. Thanks to Peter’s work, I was aware of some of these differences as I researched them when my brother was diagnosed with cancer in May 2017. He has taken low dose aspirin daily since diagnosis and I’m delighted to say that he remains in excellent health, as fit and active as he was over four years ago. That could be nothing to do with aspirin of course. \n <\/p>\n Mechanism<\/strong>\n <\/p>\n This particular paper didn’t go into the mechanism by which aspirin can help with cancer. I asked Peter for this, and I did some research. The research I did elicited inflammation as an important plausible mechanism. The University of Texas cancer centre quoted their professor of Gastroenterology, Hepatology and Nutrition, Dr Robert Bresalier, “Aspirin reduces the risk of cancer by fighting inflammation<\/em>.” Inflammation is a double edged sword \u2013 it is a key part of our immune system’s response to sickness, injury or disease “But chronic or prolonged inflammation can create an environment in which cancer thrives<\/em>,” Bresalier said. He continued “Aspirin blocks the production of the enzymes that increase inflammation in your body and speed or assist the growth of cancer cells<\/em>” (Ref 4). \n <\/p>\n Peter shared with me a story based on the fact that years of botanical research have shown salicylates to be highly active in plants. “Early in my setting up the first RCT of aspirin and vascular disease mortality in 1974, I visited a dear old man in a research botanical unit \u2013 Prof Stan Pierpoint, said at that time to be the world expert on salicylates. I told him about my RCT on vascular disease and he said: ‘Skip vascular disease, go for cancer!’ I had to explain to him that we had enough resources for a vascular trial with adequate power to detect a small reduction in vascular disease. Had we wanted to test aspirin in cancer we would have needed about ten times the numbers and ten times the time! But how right he was<\/em>!”\n <\/p>\n Peter also shared an advance copy of another paper of his, which is awaiting decision on publication. This not-yet-published paper contains substantial evidence about the biological mechanisms relevant to cancer \u2013 both prevention and help post diagnosis. The paper discusses how aspirin can disrupt enzymes and interfere with pathways in a beneficial way. Aspirin can also inhibit other harmful pathways. The paper reports that almost 60 years ago there was evidence that aspirin could reduce metastatic spread of cancer \u2013 spread, of course, is what can make some manageable cancers fatal.\n <\/p>\n The observation in the Elwood et al<\/em> ‘118 studies paper’ that aspirin is associated with a significant reduced risk of death from any cause, and not just death from cancer, could be explained by the paper undergoing peer review. It reports that "Patients with cancer appear to be in a hypercoagulable state with marked increases in vascular and thromboembolic disease events<\/em>." In the field of cardiovascular disease, aspirin has been shown to have an anti-coagulant (anti-clotting) effect.\n <\/p>\n<\/p>\n <\/a><\/p>\n \n Bleeding<\/strong>\n <\/p>\n The evidence for benefit and the plausible mechanism are there. Yes, the risk ratios of approximately 20% are not Bradford Hill causation territory, but I would be interested in a possible extension of life span with an easy intervention if I had been diagnosed with cancer. The ‘but’ is the bleeding with which aspirin is also associated. \n <\/p>\n Bleeding was not extensively addressed in the paper we’re reviewing this week since “Many of the studies however had been based on recorded data, with no direct contact with the patients involved, and authors of such reports had little or no knowledge about bleeding in the patients they described<\/em>.”\n <\/p>\n The paper in peer review addresses bleeding more extensively. It did what I would do \u2013 a review of systematic reviews\/meta-analyses examining low dose aspirin and bleeding. It also split the review into bleeding generally and fatal bleeding, the latter, of course, being the ‘side-effect’ of most concern. However, arguably, as we are weighing up the benefit vs harm of low dose aspirin for cancer post diagnosis, we should only look at data examining bleeds in cancer post diagnosis. If we take benefit for cancer and harm for every possible circumstance in which someone takes aspirin (cardiovascular disease, post-surgery to avoid clotting, when flying to avoid DVT etc), we are not comparing like with like. Plus, there may be something related to cancer whereby aspirin increases or reduces the risk of bleeding.\n <\/p>\n With that caveat, I’m going to summarise the evidence for bleeds generally and then fatal ones before trying to hone in on bleeding just in the cancer post diagnosis circumstance. \n <\/p>\n