The authors have declared that no competing interests exist.
Conceived and designed the experiments: PCE GM SD. Analyzed the data: JEP JG AW DM MK SD. Wrote the paper: PCE JEP JG GM MK SD. Was involved throughout the study, in analysis, conducting literature searches, identifying studies for inclusion, and in writing the manuscript: AW.
‡ PCE was the senior author on this work.
Low-dose aspirin has been shown to reduce the incidence of cancer, but its role in the treatment of cancer is uncertain.
We conducted a systematic search of the scientific literature on aspirin taken by patients following a diagnosis of cancer, together with appropriate meta-analyses.
Searches were completed in Medline and Embase in December 2015 using a pre-defined search strategy. References and abstracts of all the selected papers were scanned and expert colleagues were contacted for additional studies. Two reviewers applied pre-determined eligibility criteria (cross-sectional, cohort and controlled studies, and aspirin taken after a diagnosis of cancer), assessed study quality and extracted data on cancer cause-specific deaths, overall mortality and incidence of metastases. Random effects meta-analyses and planned sub-group analyses were completed separately for observational and experimental studies. Heterogeneity and publication bias were assessed in sensitivity analyses and appropriate omissions made. Papers were examined for any reference to bleeding and authors of the papers were contacted and questioned.
Five reports of randomised trials were identified, together with forty two observational studies: sixteen on colorectal cancer, ten on breast and ten on prostate cancer mortality. Pooling of eleven observational reports of the effect of aspirin on cause-specific mortality from colon cancer, after the omission of one report identified on the basis of sensitivity analyses, gave a hazard ratio (HR) of 0.76 (95% CI 0.66, 0.88) with reduced heterogeneity (P = 0.04). The cause specific mortality in five reports of patients with breast cancer showed significant heterogeneity (P<0.0005) but the omission of one outlying study reduced heterogeneity (P = 0.19) and led to an HR = 0.87 (95% CI 0.69, 1.09). Heterogeneity between nine studies of prostate cancer was significant, but again, the omission of one study led to acceptable homogeneity (P = 0.26) and an overall HR = 0.89 (95% CI 0.79–0.99). Six single studies of other cancers suggested reductions in cause specific mortality by aspirin, and in five the effect is statistically significant. There were no significant differences between the pooled HRs for the three main cancers and after the omission of three reports already identified in sensitivity analyses heterogeneity was removed and revealed an overall HR of 0.83 (95% CI 0.76–0.90). A mutation of PIK3CA was present in about 20% of patients, and appeared to explain most of the reduction in colon cancer mortality by aspirin. Data were not adequate to examine the importance of this or any other marker in the effect of aspirin in the other cancers. On bleeding attributable to aspirin two reports stated that there had been no side effect or bleeding attributable to aspirin. Authors on the other reports were written to and 21 replied stating that no data on bleeding were available.
The study highlights the need for randomised trials of aspirin treatment in a variety of cancers. While these are awaited there is an urgent need for evidence from observational studies of aspirin and the less common cancers, and for more evidence of the relevance of possible bio-markers of the aspirin effect on a wide variety of cancers. In the meantime it is urged that patients in whom a cancer is diagnosed should be given details of this research, together with its limitations, to enable each to make an informed decision as to whether or not to take low-dose aspirin.
CRD42015014145
Despite significant advances in diagnosis and treatment in recent decades, cancer is still one of the main causes of morbidity and mortality worldwide. It claims more than 81,000 males and 74,000 females every year in the UK alone, the crude annual mortality rate being about 250 deaths in every 100,000 people [
There is convincing evidence that regular low-dose aspirin not only reduces vascular disease incidence and mortality [
Chan et al (2009) [
Our aim in what follows is to provide a comprehensive systematic review and meta-analysis of the available evidence on the effects of aspirin used as an adjunct treatment of cancer in the reduction of mortality and metastatic spread.
The review protocol was registered in PROSPERO (registration number CRD42015014145). In reporting we have followed the PRISMA guidelines [
In December 2015 observational and interventional studies in Medline and Embase were searched using a pre-defined strategy with indexed descriptors and keywords including “aspirin”, “acetylsalicylic acid”, “cancer” “tumour”, “neoplasm”, “mortality”, “death”, “adverse effect”, “bleed”. The search was limited to human studies in peer-reviewed journals and conference abstracts. Reference lists of the included studies were also searched and recent conference proceedings scanned and topic experts contacted for additional studies.
Studies were selected for inclusion in meta-analyses if (a) the studied population comprised patients diagnosed with cancer; (b) aspirin was taken regularly after cancer diagnosis independently of whether it had been taken before diagnosis; (c) they were case-control studies, cohort studies or controlled trials; and (d) cause-specific mortality was available. All-cause cancer mortality, incidence of metastases and adverse effects were noted but were not criteria for selection.
Two reviewers independently excluded reports that did not meet inclusion criteria based on title and abstract. Full published reports were obtained for the remainder, and inclusion criteria were applied.
The origin of the patient group and other details in each report were examined, and if there appeared to be two reports based on the same patients, if the evidence required for the meta-analyses was not clear, or if important items were missing, the author(s) was contacted and asked for clarification. Authors of all the papers were also asked whether they had data on gastrointestinal or other bleeding, and if this had been a concern at any time. All these processes were conducted by one of the authors and were checked as appropriate by another author.
The methodological quality of the included studies was assessed and graded independently by two authors using the Newcastle-Ottawa Scale [
Meta-analyses were conducted grouping the studies according to study design: intervention and observational studies. Subgroup analyses were conducted according to cancer types, key mutations and whether or not patients had taken aspirin only after diagnosis.
The summary statistics derived in the meta-analyses were either a hazard ratio or a risk ratio each with 95% confidence intervals. The analyses were carried out using the statistical package STATA. The inverse-variance method was used to weight the individual studies and provide the pooled estimate of effects. A 'random effects' model was used throughout to incorporate an estimate of between-study variation into the calculation of common effects. Funnel plots were created to highlight outlying studies and look at publication bias. Publication bias was assessed using Egger's test [
The literature search identified 373 reports and following omissions of duplicates and irrelevant reports, 42 were found to be relevant and gave sufficient data to be included in meta-analyses. We present a summary diagram in
Authors | Source | Design | Number of aspirin users and non-users. Duration of follow-up | Deaths in aspirin users and all-cause deaths | Comment | Grade |
---|---|---|---|---|---|---|
Rothwell et al. [ |
Five early vascular trials | Randomised for vascular reduction | 17,285 subjects randomised | 385 deaths on aspirin, 402 deaths on placebo | RCT | |
Lipton et al. [ |
Series of patients | Ad hoc randomisation | 57 patients randomised, F-U 24 months | Life table analysis, Numbers N.A. | RCT | |
LeBeau et al. [ |
Series of patients | Ad hoc randomisation | 303 patients randomised, F-U 18 months | 152 deaths on aspirin, 147 deaths on placebo | RCT | |
Cregan et al. [ |
Series of patients | Ad-hoc randomisation of patients with renal cancer | 176 patients randomised, F-U 8.8 months | 52 total deaths on aspirin, 56 deaths on placebo | RCT | |
Liu et al. [ |
Sequence of patients | Randomised by admission to ward | 445 users, 1153 non-users, F-U 5 years | 217 deaths in users, 685 deaths in non-users | RCT | |
Bastiaannet et al. [ |
Eindhoven Cancer Registry | Cohort of 4481 patients with cancer | 3305 users, 1176 non-users, F-U N.A. | 114 CRC deaths in users, 610 deaths in non-users | Most appear to have had aspirin, not other NSAIDs | |
Bains et al [ |
Cancer Registry of Norway | Cohort of 25644 patients with cancer | 6109 users, Non users N.A. | 1172 CRC deaths in users, 6356 CRC deaths in non-users, 2088 total deaths in users, 7595 total deaths in non-users | Conference presentation | |
Cardwell et al. [ |
UK Clinical Practice Research Datalink | Nested case-control in a cohort of 4794 patients with cancer | Numbers N.A. Mean F-U 7.2 years | 395 CRC deaths in users, 1164 deaths in non-users, 700 total deaths in users, 1514 total deaths in non-users | ||
Chan et al. [ |
US Nurses and Health Professionals Cohorts | Cohort of patients with cancer | 549 users, 730 non-users. Median F-U 11.8 years | 81 CRC deaths in users, 141 CRC deaths in non-users, 193 total deaths in users, 287 total deaths in non-users | Varied dose of aspirin judged by frequency | |
Coghill et al. [ |
Seattle Cancer Family Register | Cohort of patients with cancer | 234 users, 293 non-users. Mean F-U 8 years | 37 events in users, 72 events in non-users | ||
Din et al [ |
Series of cases of cancer | Case-control selected patients from a trial cohort | 354 users, 526 non-users. F-U 1 years | 125 deaths in users, 761 in non-users | NSAIDS, but data for aspirin given | |
Domingo et al. [ |
Series of patients | Cohort study | 125 users, 771 non-users. F-U N.A. | 22 deaths in users, 174 in non-users | Incidence and all-cause mortality in relation to PIK3CA state | |
Fuchs et al. [ |
Series of patients | Cohort study | 72 users, 830 users. Mean F-U 2.4 years | Numbers of deaths N.A. | ||
Goh et al. [ |
Series of patients | Cohort study | 92 users, 634 non-users. F-U ‘long term’ | 21 CRC deaths in users, 160 CRC deaths in non-users | ||
Liao et al. [ |
Nurses HS and Health Professionals Cohorts | Selected cohort of patients | 337 users, 627 non-users. Mean F-U 5 years | 68 CRC deaths in users, 122 CRC deaths in non-users | ||
McCowan et al. [ |
Database of residents | Cohort of selected new patients | 1340 users, 1650 non-users, F-U 11 years | 420 CRC deaths in users, 601 CRC deaths in non-users, 897 total deaths in users, 1101 total deaths in non-users | ||
Ng et al. [ |
Series of patients | Cohort study | 75 users, 725 non-users. F-U 5 years | 19 CRC recurrence in users, 21, CRC recurrence in non-users., 14 total deaths in users, 146 total deaths in non-users | ||
Reimers et al [ |
Cohort of study of cancer patients | 178 users, 784 non-users. F-U N.A. | 68 deaths in users, 380 deaths in non-users | HLA class 1 antigen groups amalgamated | ||
Sun et al. [ |
US Nurses and Health Professionals cohorts | cohort of selected cancer patients | 931 subjects. Other details N.A. F-U 28 years | 931 incident cases. Detailed numbers N.A. | ||
Walker et al. [ |
UK GP Research Database | Cohort of selected patients | 476 users, 10141 non-users. Median F-U 1.7 years | 192 total deaths in users, 3910 total deaths in non-users | ||
Zanders et al [ |
Eindhoven Cancer Registry | Cohort of selected patients with diabetes | 490 users, 156 non-users. F-U 1.5 years | Numbers N.A. | Diabetic patients | |
Barron et al [ |
Ireland National Cancer Registry | Cohort of 12507 patients with cancer | 764users, 4540 non-users. F-U 7.4 years | 50 breast cancer deaths in users, 311 breast cancer deaths in non-users, 311 total deaths in users, 459 total deaths in non-users | ||
Blair et al [ |
Iowa Women’s Health Study | Cohort of 591 women with cancer | 472 users, 120 non-users, F-U 15 years | 26 breast cancer deaths in users, 22 breast cancer deaths in non-users, 57 total deaths in users, 44 total deaths in non-users | ||
Bowers et al [ |
A Centre for Cancer Care | Cohort of 440 women with cancer | 159 users, 281 non-users. F-U N.A. | Number of deaths not available | NSAIDs. 81% were aspirin | |
Cronon-Fenton [ |
Population based cohort in Denmark | Cohort study of 34188 patients | Median F-U 7.1 years | Numbers N.A. | Conference report | |
Frazer et al. [ |
Database of residents | Cohort of 4627 women | 1244 users, 3383 non-users. F-U 16 years | 252 breast cancer deaths in users, 563 breast cancer deaths in non-users, 577 total cancer deaths in users, 1225 total cancer in non-users | ||
Holmes et al. [ |
US Nurses Health Study | Cohort of 4164 women | Number of users N.A. 5521 non-users. F-U n.a. | 109 breast cancer deaths in users, 56 breast cancer deaths in non-users | ||
Holmes et al. [ |
National Cancer Registry | Nested case-control within 27426 women | 1661 users, 3322 non-users. F-U up to 5 years | 395 breast cancer deaths in users, 750 breast cancer deaths in non-users | ||
Kwan et al. [ |
Cohort of cancer patients | Cohort of 2292 women | Total 2292 women. Mean F-U 2.5 years | 41 recurrent cancers in users, 209 recurrent cancers in non-users | NSAIDs | |
Murray et al. [ |
UK Clinical Practice Research Datalink | Nested case-control study | 1173 users, 1173 non-users. Mean F-U 6.9 years | 262/1435 cancer deaths in users, 1056/5697 cancer deaths in non-users | ||
Wernli et al. [ |
Cohort of cancer survivors | Cohort of 3058 selected patients with breast cancer | 541 users of NSAIDs, 2517 non-users of NSAIDs. F-U 6 years approx. | 7 breast cancer deaths in users, 141 breast cancer deaths in non-users, 37 total deaths in users, 383 total deaths in non-users | NSAIDs | |
Assayaq et al [ |
UK National Cancer Data Repository | Cohort of 11779 newly diagnosed patients | Numbers in users N.A. F-U 5.4 years | 801 cancer deaths in users, 992 cancer deaths in non-users, 1816 total deaths in users, 1686 deaths in non-users | ||
Caon et al. [ |
Patient series | Cohort of newly 3851 diagnosed patients | 509 users, 2428 non-users, F-U 7 years | 194 cancer deaths in users, 904 cancer deaths in non-users | ||
Choe et al. [ |
Patient registry | Cohort of 5955 patients | 1817 users, 1736 no relevant drugs. Medium F-U 70 months | 36 cancer deaths in users, 298 cancer ca deaths in non-users | ||
Daugherty et al. [ |
Screened cohort | Cohort of patients with cancer | Numbers N.A. Medium F-U 5 years | 136 cancer deaths | ||
Dhillon et al. [ |
US Health Professionals cohort | Cohort study | 1579 users, 1926 non-users, F-U up to 18 years | 177 cancer deaths. Details N.A. | ||
Flahavan [ |
Irish National Cancer Registry | Cohort study of 2936 | 1131 users, 1805 non-users. Median F-U 5.5 years | Numbers of deaths N.A. | ||
Grytli et al. [ |
Cancer Registry of Norway | Cohort of selected patients | 1279 users, 3515 non-users. Mean F-U 39 months | 504 cancer deaths in users | ||
Jacobs, Chun et al. [ |
Series of patients | Cohort study | 45 users, 29 non-users. Mean F-U 56.6 months | 6 cancer deaths in users, 8 cancer deaths in non-users | ||
Jacobs, Newton et al. [ |
Prospective cohort of subjects | New cancer patients. Also ‘High-risk’ patients | 3600 users, 3058 non-users, F-U up to 9 years | 134 cancer deaths in users, 112 cancer deaths in non-users | ||
Stock et al. [ |
Cancer Registry | cohort of selected cancer patients | 419 users, 1200 non-users. Maximum F-U 120 months | 115 cancer deaths in users, 338 cancer deaths in non-users | NSAIDs | |
Nagle et al [ |
Series of women with ovarian cancer | Cohort study of 1305 women with ovarian cancer | Numbers N.A., F-U 4.9 years | 834 deaths | ||
Fontaine et al. [ |
Series of patients with lung cancer | Cohort study of women with lung cancer | 412 users, 1353 non-users, F-U 7.5 years | Numbers of deaths N.A. | ||
Pastore et al. [ |
Series of patients with bladder cancer | Cohort of 574 patients with bladder cancer | 98 users, 56 non users F-U 2 years | Numbers of deaths N.A. | ||
Chae et al. [ |
536 patients with mixed cancers | Cohort of 536 women with mixed cancers | 54 users, 482 non-users. Median F-U 8.8 months | Numbers of deaths N.A. | ||
Chae et al [ |
Patients with relapsed/refractory chronic lymphocytic leukaemia | Retrospective study of 280 patients with chronic lymphocytic leukaemia | 37 users, 17 non-users. Median F-U 4 years | Numbers of deaths N.A. | ||
MacFarlane et al [ |
Series of 2392 patients with head and neck and oesophageal cancers | Cohort study of 2392 patients with oesophagus cancer; 1195 with head & neck cancer | 1197 oesophagus, F-U 9 months, 1195 head & neck, F-U 35 months | 965 oesophagus cancer deaths, 509 head & neck deaths cancer. Details N.A. | ||
Algra & Rothwell [ |
Based on a literature search | Overviews of 6 RCTs; 150 case-control studies, and 45 cohort studies | In case-control studies. Followed for up to 20 years | 245 in RCTs; 141,577 in case-control studies, 41,575 in cohort studies | Details on metastatic spread in RCTs and in 5 observational studies | |
Ljung et al. [ |
National Cancer Registry | Selected patient cohort | 3424users, 23104 non-users, F-U 5 years | Numbers with lymph node metastases. Numbers N.A. | ||
Kothari et al. [ |
Two cancer centres | Series of selected 999 patients with colon cancer | 49 users, 136 non-users. Mean F-U 54 months | Detail of deaths N.A. |
CI: confidence interval; CRC: Colorectal cancer;; F-U: Follow-up; N.A.: not available; NSAID: non-steroidal anti-inflammatory drug; RCT: randomised controlled trial; RR: risk ratio.
In the tables that follow we summarise the individual papers and report the results of meta-analyses and when available we give data for both cause-specific mortality and all-cause mortality.
Our search identified four reports of randomised trials, together with a report of pooled trials [
Study | Design | Cancer | Aspirin/none | Outcome | Numbers of outcome events aspirin/placebo | Effect of aspirin (95% CI) |
---|---|---|---|---|---|---|
Rothwell Wilson [ |
Pooled analysis of five RCTs | All solid cancers | 385.402 | Cancer deaths | 385,402 | HR 0.71 (0.57,0.90) |
All deaths | N.A. | HR 0.81 (0.65, 1.00) | ||||
Lipton [ |
RCT | Colorectal | 35,22 | Cause-specific mortality | N.A. | HR 0.65 (0.02–18.06) |
Lebeau [ |
RCT | Lung | 153/150 | Cause-specific mortality | 152,147 | HR 1.01 (0.81–1.27) |
Cregan [ |
RCT | Renal | 89/87 | Cause-specific mortality | 56,57 | HR 0.91 (0.63–1.31) |
Liu et al [ |
RCT |
Oesophagus | 445/658 | Cause-specific mortality | 217,388 | HR 0.83 (0.68, 1.01) |
Cause specific mortality: |
||||||
All-cause mortality: |
CI: confidence interval; HR Hazard Ratio; HR: hazard ratio; RCT: randomised controlled trial.
aHazard ratios taken from Langley [
bRandomisation was achieved by admitting patients to two different wards in which aspirin and placebo were given.
In
Study | Aspirin/none | Mortality | Deaths (aspirin, no aspirin) | Results (95% CI) | Comment |
---|---|---|---|---|---|
Bastiaannet et al [ |
275/ 1176 | All-cause | 114, 610 | HR 0.77 (0.63, 0.95) | Frequent use HR 0.70 (0.57, 0.88) |
Bains et al [ |
6109/19535 | Specific | 1172, 6356 | HR 0.53 (0.50, 0.57) | |
All-cause | 2088, 7595 | HR 0.71 (0.68, 0.75) | |||
Cardwell et al [ |
1005/ 2365 | Specific | 395, 1164 | HR 0.99 (0.86, 1.15) | |
Chan et al [ |
549/1279 | Specific mort | 81, 141 | HR 0.71 (0.53, 0.95) | Specific: Only post diagnosis: RR 0.53 (0.33, 0.86). Pre and post: RR 0.89 (0.59, 1.35) |
All-cause | 193, 287 | HR 0.79 (0.65, 0.97) | All-cause: Only post diagnosis RR 0.68 (0.61, 0.92). Pre and post RR 0.95 (0.71, 1.28) | ||
Coghill et al [ |
56/346 | Cause specific | 37, 72 | HR 0.76 (0.61, 0.95) | |
Din et al [ |
354/526 | Cause specific | 125, 761 | OR 0.78 (0.65, 0.92) | Aspirin result; also data on NSAIDs |
Domingo et al [ |
125/761 | Recurrence | 22, 174 | HR 0.86 (0.55–1.35) | Wild and mutated combined |
All-cause | HR 0.88 (0.53, 1.47) | ||||
Fuchs et al [ |
72/830 | Recurrence or death | N.A. | HR 0.48 (0.24, 0.99) | Compared with non-consistent use. Consistent users: HR 0.45 (0.21, 0.97) for disease recurrence |
All-cause | HR 0.52 (0.19, 1.46) | ||||
Goh et al [ |
92/726 | Specific | 21, 160 | HR 0.71 (0.43, 1.16) | Death or recurrence 0.38 (0.17, 0.84). Benefit only after 5 years) |
Liao et al [ |
155/395 | Specific | 68, 122 | HR 0.83(0.61–1.23) | Wild and mutated combined |
403/964 | All-cause | HR 0.87 (0.71, 1.06) | |||
McCowan et al [ |
894/2980 | Specific | 420, 601 | HR 0.58 (0.45, 0.75) | |
All-cause | 897, 1101 | HR 0.67 (0.57, 0.79) | |||
Ng et al [ |
75/724 | Recurrence or death | 19, 214 | HR0.68 (0.42, 1.11) | Consistent aspirin HR 0.51 (0.28, 0.95) |
Overall mortality | 14, 146 | HR 0.63 (0.35, 1.12) | |||
Reimers et al [ |
178/784 | Overall mortality | 68, 380 | RR 0.67 (0.52, 0.88) |
HLA class 1 antigen groups amalgamated |
Sun et al [ |
?/931 | Cancer specific survival | 931 total events | HR 0.77 (0.52, 1.14) | CTNNBI mutated and non- mutated groups combined |
Walker et al [ |
2619/13,994 | All-cause | 192, 3910 | HR 0.91 (0.82, 1.00) | No aspirin pre diagnosis: HR 0.99 (0.84, 1.16); aspirin pre diagnosis: HR 0.86 (0.76, 0.98) |
Zanders et al [ |
490/ | All-cause | N.A. | HR 0.98 (0.93, 1.03) | Diabetic patients |
Barron et al [ |
764/4540 | Specific | 50, 311 | HR 0.98 (0.74, 1.30) | Selected de-novo aspirin users |
Total | 311,495 | HR 1.11 (0.83, 1.50) | |||
Blair et al [ |
254/591 | Specific | 26, 22 | HR 0.53 (0.30,-0.93) | Selected overweight women |
All-cause | 57, 44 | HR 0.53 (0.36–0.79) | |||
Bowers et al [ |
159/440 | Recurrence | N.A. | OR 0.48 (0.22, 0.98) | NSAIDs, 81% of which are stated to be aspirin |
Cronin-Fenton et al [ |
Recurrence | N.A. | HR 1.0 (0.90, 1.1) | Conference report | |
Frazer et al [ |
815/1802 | Specific | 252, 563 | HR 0.42 (0.31–0.55) | |
All-cause | 577, 1225 | HR 0.53 (0.45–0.63) | |||
Holmes et al. [ |
?4164/11416 person/years | Specific | 109, 56 | RR 0.36 (0.24–0.54) | |
All-cause | RR 0.54 (0.41–0.70) | ||||
Holmes et al [ |
1661 cases 3322 controls | Specific | 395, 750 | HR 0.96 (0.80, 1.16) | |
Kwan et al [ |
270/2292 | Recurrence | 41, 209 | RR 1.09 (0.74, 1.61) | |
Murray et al [ |
262/1435 | Specific | 262, 1435 | OR 1.00 (0.71, 1.41) | ‘High’ dose aspirin 0.94 (0.48, 1.84), but dose imprecise |
Wernli et al [ |
7 breast cancer deaths | Specific | 7, 141 | HR 0.64 (0.27, 1.37) | |
37 total deaths | All-cause | 37, 383 | HR 0.91 (0.65, 1.29) | ||
Assayag et al [ |
801/1793 | Specific | 801, 992 | 1.46 (1.29, 1.65) | Aspirin only after diagnosis: HR 1.84 (1.59, 2.12) cause specific; HR 1.70 (1.53, 1.88) all-cause. Aspirin also before diagnosis: HR 0.97 (0.81. 1.16) cause specific; HR 0.98 (0.87, 1.18) all-cause |
1686/3502 | All-cause | 1816, 1686 | 1.37 (1.26, 1.50) | ||
Caon et al [ |
917/3851 | Cause specific | 194, 904 | HR 0.91 (0.65, 1.28) | |
Choe et al [ |
1817/5552 | Cause-specific | 36, 298 | HR 0.43 (0.21–0.87) | |
Daugherty et al [ |
136 | Cause specific | 136 total | HR 0.77 (0.48, 1.25) | Advanced disease: HR 0.37 (0.15, 0.92). Localised disease: HR 0.86 (0.47, 1.58) |
Dhillon et al [ |
N.A. | Cause specific | 177 total | HR 1.08 (0.76–1.54) | |
Flahavan et al [ |
1131/2936 | Cause-specific | N.A. | HR 0.88 (0.67, 1.15) | High aspirin: HR 0.73 (0.51, 1.05) |
Gryll et al [ |
504/3165 | Cause-specific | 504, N.A. | HR 0.94 (0.78, 1.14) | |
Jacobs Chun et al [ |
41/74 | All-cause | 6, 8 | HR 0.44 (0.15–1.28) | High risk patients selected |
Jacobs, Newton et al [ |
301/7118 | Cause specific | 134, 112 | HR 0.98 (0.74, 1.29) | In high risk patients: HR 0.60 (0.37, 0.97) |
Stock et al [ |
453/1,619 | Cause specific | 115, 338 | HR 1.03 (0.79, 1.34) | Survival after 5yrs of NSAIDs: HR 0.54 (0.26, 1.13) |
Nagle et al [ |
N.A. (Ovarian) | Overall survival | 115,338 | HR 0.92 (0.81. 1.06) | Aspirin plus NSAIDs |
Fontaine et al [ |
412/1,765 (Lung) | Survival | N.A. | HR 0.84 | |
Pastore et al [ |
574 (Bladder) | Recurrence | 42,98 | OR 0.75 (0.45, 1.24) | Effect of aspirin negated by statins |
Chae et al [ |
536 (Mix of female cancers) | Survival | N.A. | HR 0.82 (0.57, 1.18) | PIK mutation: HR 0.59 (0.35, 0.98).Wild type: HR 1.80 (1.01, 3.23) |
Chae et al [ |
280 (chronic lymphocytic leukaemia) | Survival | N.A. | HR 0.40 (0.21, 0.79). | Aspirin + statins together |
MacFarlane et al [ |
416/779 (head & neck) | Survival | 178/331 all-cause deaths | HR 0.56 (0.44, 0.71) | Post-diagnostic aspirin |
387/810 (Oesophagus) | Survival | 209/756 all-cause deaths | HR 0.54 (0.45. 0.64) |
CI: confidence interval; HR: hazard Ratio; N.A.: not available; NSAID: non-steroidal anti-inflammatory drug; OR: odds ratio; RCT: randomised controlled trial; RR: risk ratio.
aThe inclusion of NSAIDs other than aspirin posed difficulties but we assumed that aspirin was the major drug used, and evidence for this is given in one of the studies [
bThe examination of heterogeneity by the omission of papers was based on sensitivity analyses. The Newcastle-Ottawa grade of Frazer et al [
cReimers [
The sixteen reports of patients with colorectal cancer [
Data for ten breast cancer studies [
Amongst ten studies of aspirin and prostate cancer [
Six studies of other cancers [
A few of the reports give details of grade or stage of the cancer, but these were too few to enable any relevant analyses in relation to the effect of aspirin. Later however we quote a few comments on aspirin and ‘advanced’ cancer. Figs
It is possible to examine the pooling of the HRs for the three main cancers, and it seems not unreasonable to do this because the various pairs of HRs do not differ significantly (thus: for colon and breast cancer P = 0.90; for colon and prostate cancer P = 0.06 and for breast and prostate cancers P = 0.18). An overall meta-analysis for cause-specific mortality from these three cancers is 0.78 (95% CI 0.66, 0.92). Naturally, this has to be accepted with great caution, particularly as there is significant heterogeneity (P<0.0005), even though the omission of the three papers already identified as ‘outliers’ by sensitivity analysis [
An effect of aspirin on metastatic spread is clearly an evidence of treatment and the data in
Study | Cohort | Numbers (aspirin, no aspirin) | Cancer | Reduction (95% CI) | Comment |
---|---|---|---|---|---|
Algra & Rothwell [ |
150 Case-control and 45 cohort studies | 141577 in case-control 41575 in cohorts | All cancers | RR 0.71 (0.60, 0.84) | No reduction in localised spread: OR 0.98 (0.88–1.09) |
Choe et al [ |
Selected patients from a cancer centre | 2175, 3780 | Prostate | RR 0.50 (0.37–0.68) | |
Jacobs, Chun et al [ |
Series of patients | 45, 29 | Prostate | RR 0.42 (0.12, 1.45) | Reported as 12.2% vs. 26.7%, P = 0.039 at 5 years |
Barron et al [ |
Ireland National Cancer Register | 740, 2056 | Breast | RR 0.89 (0.81. 0.97) | Spread to lymph nodes: RR 0.81 (0.68, 0.96) in quarter women with highest aspirin dose |
Ljung et al [ |
Nationwide Swedish cohort | N.A. | Breast | RR 0.94 (0.87–1.03) | Anticoagulants; 96% were aspirin |
RR 0.80, (0.50–1.29) | In younger women | ||||
HR 0.84 (0.64, 1.11) | Reduced spread to lymph nodes | ||||
CI: confidence interval; HR: hazard Ratio; N.A.: not available; OR: odds ratio; RR: risk ratio.
A mutation in PIK3CA, a gene which produces a protein that increases Cox-2 and prostaglandin activity, has been shown to enhance the response of the tumour to aspirin. The prevalence of this mutation is stated in several of the present studies as around 15–20% [
Authors | Cancer | Wild (95% CI) | Mutation/overexposure (95% CI) |
---|---|---|---|
Chan et al [ |
Colorectal | HR 1.22 (0.36, 4.18) | HR 0.39 (0.20, 0.76) |
Domingo et al [ |
Colorectal | HR 0.94 (0.59, 1.49) | HR 0.11 (0.01, 0.83) |
Liao et al [ |
Colorectal | HR 0.90 (0.53, 1.54) | HR 0.28 (0.04, 2.10) |
Kothari et al [ |
Colorectal | No patients | HR 0.66 (0.31, 1,38) |
Chan et al [ |
Colorectal | HR 1.05 (0.55, 2.02) | HR 0.62 (0.42, 0.93) |
Domingo et al [ |
Colorectal | HR 0.95 (0.56, 1.61) | HR 0.29 (0.04, 2.33) |
Liao et al [ |
Colorectal | HR 0.97 (0.68, 1.37) | HR 0.59 (0.24, 1.41) |
Kothari et al [ |
Colorectal | No patients | HR 0.95 (0.55, 1.63) |
Chae et al [ |
Several cancers | HR 1.80 (1.01, 3.23) | HR 0.75 (0.17, 3.20) |
CI: confidence interval; HR: hazard ratio.
Evidence on these or other mutations appears not to be available in the present studies of breast or prostate cancers.
Does aspirin treatment affect cancers which have developed while aspirin has been taken? It may be that cancers which develop while aspirin is being taken are less responsive to the effect of aspirin.
Author | Cancer | Aspirin only after diagnosis, not before (95% CI) | Aspirin after and before diagnosis (95% CI) |
---|---|---|---|
Chan et al [ |
Colorectal | HR 0.53 (0.33, 0.86) | HR 0.89 (0.59, 1.35) |
Coghill et al [ |
Colorectal | HR 0.77 (0.58, 1.00) | HR 0.75 (0.56, 1.00) |
Goh et al [ |
Colorectal | HR 0.81 (0.51, 1.28) | HR 1.06 (0.71, 1.58) |
Cardwell et al [ |
Colorectal | HR 1.08 (0.71, 1.63) | HR 0.75 (0.43, 1.29) |
Liao et al [ |
Colorectal | HR 0.83 (0.50–1.39) | HR 0.79 (0.49–1.27) |
Barron et al [ |
Breast | HR 0.99 (0.68, 1.46) | HR 0.80 (0.62, 1.04) |
Kwan et al [ |
Breast | RR 1.23 (0.72, 2.11) | RR 0.99 (0.60, 1.64) |
Assayag et al [ |
Prostate | HR 1.84 (1.59, 2.12) | HR 0.97 (0.81. 1.16) |
Jacobs/Newton et al [ |
Prostate | HR 0.97 (0.65, 1.45) | HR 1.04 (0.73, 1.47) |
Bastiaannet et al [ |
Colorectal | HR 0.70 (0.57, 0.88) | HR 0.88 (0.83, 0.94) |
Chan et al [ |
Colorectal | HR 0.68 (0.51, 0.92) | HR 0.96 (0.71, 1.28) |
Walker et al [ |
Colorectal | HR 0.99 (0.84, 1.16) | HR 0.86 (0.76, 0.98) |
Goh et al [ |
Colorectal | HR 0.86 (0.58, 1.27) | HR 1.04 (0.72, 1.48) |
Liao et al [ |
Colorectal | HR 0.91 (0.66–1.26) | HR 0.81 (0.58–1.12) |
Barron et al [ |
Breast | HR 1.11 (0.83, 1.50) | HR 0.81 (0.66, 0.99) |
Assayag et al [ |
Prostate | HR 1.69 (1.53, 1.88) | HR 0.99 (0.87, 1.18) |
Macfarlane et al [ |
Oesophagus | HR 0.84 (0.97, 1.26) | HR 1.11(0.97, 1.26) |
CI: confidence interval; HR: hazard ratio.
Data in three reports of prostate cancer suggest that the effect of aspirin may be greater in advanced disease. Thus Daugherty et al [
Many of the reports state, or imply that aspirin at a dose appropriate for vascular protection had been used and only a very few reports comment further. Several studies report greater effects with ‘high’ dose aspirin [
Several authors refer to the consistency of aspirin taking. Chan et al [
Several authors state that an effect of aspirin because apparent only after 3–5 years of therapy. Goh et al [
An excess of bleeding attributable to aspirin has been well studied in short-term vascular trials [
The corresponding authors of the other reports in this series were written to. Replies received from twenty-one authors stated that no data on bleeding had been recorded.
The evidence we present from a systematic overview of the literature gives support to the use of aspirin as an additional treatment of cancer. The evidence is limited, and while it is encouraging in the case of bowel cancer, there is insufficient evidence to dismiss a role for aspirin as an adjunct treatment of cancers other than colorectal. In fact, its use can be justified on the basis of its likely benefit on outcomes other than death, including its probable reduction in metastatic spread and its reduction in vascular disease events, including venous thromboembolism.
Differences between individual studies leading to significant heterogeneity is to be expected in any collection of observational studies such as those we present, and it does limit confidence in the results. However, if, for each of the three cancers, an out-lying study identified by detailed sensitivity analyses is omitted, heterogeneity is reduced to an acceptable level and for each cancer there is evidence suggestive of reductions in mortality and in metastatic spread.
In colon cancer there is evidence of a reduction in colorectal deaths of about 25%, and perhaps about 20% in All-cause mortality. If one report [
With the present level of evidence, the pooling of data for the three cancers would seem to be not unreasonable and following omissions of three outliers, unacceptable heterogeneity is resolved. A meta-analysis then suggests a possible overall reduction by aspirin of about 15% (pooled HR 0.83; 95% CI 0.76–0.90). The evidence of a reduction in metastatic spread (RR 0.77; 95% CI 0.65–0.92) gives further encouragement to the use of therapeutic aspirin in cancer while awaiting evidence from
It would be unreasonable to attempt to draw firm conclusions from the single studies on lung cancer [
The evidence we present on the biomarker PIK3CA has been confirmed in an overviews by other authors [
All this suggests that the reduction by aspirin may be restricted to patients whose tumours show mutation in PIK3CA, HLA class I antigen, or show COX-2 over-expression. In colorectal cancer these subgroups represent approximately 17%, 54% and 50% of all patients, and our data suggest a reduction of about 50% in colorectal mortality, though another overview [
And yet any selection of patients for treatment with aspirin on the basis of a mutation or any other marker of cancer risk would be totally unwarranted on present evidence. Metastases are a major source of pain and other undesirable effects in solid cancers [
A major uncertainty in what we report arises from the possible omission of relevant reports, together with publication bias, and the test we performed suggests that this last may have occurred (Egger's test [
On the other hand certain time biases could be present in some of the studies, and especially in retrospective case-control studies [
All the reports in the present series were examined and while immortal time bias cannot be dismissed with certainty, an important effect upon the overall estimates of the effect of aspirin seems most unlikely. In fact, there is little difference in the overall mortality of the patients who had taken aspirin before diagnosis, and (presumably) continued to take it after diagnosis (HR 0.92), and the patients who had not taken aspirin before diagnosis (HR 0.90), in whom there could have been a time lag and thus, an ‘immortal time bias’ (see
While a serious limitation in the present evidence is that little comes from randomised trials, yet evidence from further observational studies is urgently needed to evaluate more fully how patients likely to benefit from aspirin can be identified. In particular evidence on PIK3CA, other mutations and other possible markers should be collected as a matter of urgency in cancers of breast, prostate and other organs. The results of such studies should be made available for the encouragement and guidance of colleagues setting up randomised trials, and, in fact, the further question arises whether or not these mutations are of relevance to aspirin used in prophylaxis.
The possible benefits of aspirin must of course be evaluated against it side effects. Shortly after aspirin taking commences the risk of a gastrointestinal (GI) bleed is high but the risk falls rapidly thereafter [
The most serious bleeds are those that lead to death, and despite frequent references to fatal bleeds attributed to aspirin, there appears to be no valid evidence that deaths from GI bleeds are increased by low-dose aspirin [
Cerebral bleeds attributable to aspirin are rare, about one or two per 10,000 patient-years. Hypertension is the major factor in such bleeds [
An early overview of studies of aspirin and cancer was based on three small randomised trials and two observational trials, and this led to the conclusion: ‘aspirin may have a role in the adjuvant setting… and should not be overlooked [
Li et al [
Huang et al [
It appears likely that low-dose aspirin has a beneficial role as an adjunct treatment of cancer. Reductions in mortality are shown in colon cancer, probably in prostate cancer and possibly in breast and individual studies of several other cancers also suggest benefit. Aspirin benefit in colorectal cancers, and possible other cancers, may be restricted to patients with tumours expressing certain genetic mutations. However, other benefits of low-dose aspirin, including reductions in metastatic spread and in vascular events, including venous thromboembolism appear to be independent of these biomarkers, and so information on aspirin should be given to patients whatever the state of the possible biomarkers.
The heterogeneity within the currently available studies–both between different cancers, and within the different studies of each cancer, together with evidence suggesting some publication bias, are such that further evidence from a number of adequately powered randomised, placebo controlled trials is urgently required, including trials of less common cancers. Evidence on the possible role of aspirin in uncommon cancers, and the possible enhancement of its effect if mutation and other markers of increased sensitivity to the actions of aspirin, are also urgently needed. Much of this evidence could some from further observational studies.
Nevertheless, despite the need for randomised trials, we believe the evidence of benefit from aspirin is sufficiently persuasive that physicians should engage with patients in a presentation and discussion of aspirin as an additional treatment. Furthermore, we hold that patients should be given this evidence within the context of a healthy lifestyle [
(DOC)
We are grateful to Ruth Langley who reviewed an early draft.