Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials

The term “evidence-based medicine” was first coined by Sackett and colleagues as “the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients.”[1][1] The key to practising evidence-based medicine is applying the best

Daily treatment with aspirin for longer than 5 years reduces the long-term risk of colorectal cancer. A number of studies have suggested that long-term aspirin use may reduce the risk of several noncolorectal solid cancers, but clear evidence for a preventive effect is lacking. This study investigated the possible effect of aspirin on reducing the risk of fatal cancer among patients with gastrointestinal and nongastrointestinal cancers. Data were obtained from randomized trials with aspirin, originally conducted on prevention of vascular events. Eligible trials with median duration of scheduled trial treatment of at least 4 years were identified in the medical literature. Pooled results comparing the effect of aspirin and controls on deaths due to cancer showed 674 deaths due to cancer among 25,570 patients; aspirin significantly reduced the risk of cancer deaths (odds ratio, 0.79; 95% confidence interval [CI], 0.68–0.92; P = 0.003). Analysis of data on time of death available from 7 trials (23,535 patients, 657 cancer deaths) showed that a reduction in risk of death was apparent only after 5 years' follow-up for all cancers (hazard ratio [HR], 0.66; 95% CI, 0.50–0.87) and gastrointestinal cancers (HR, 0.46; 0.27–0.77; P values for both = 0.003). Three posttrial follow-up studies on the 20-year risk of death due to cancer (1634 deaths in 12,659 patients) showed that the reduction in risk by aspirin treatment compared with controls remained lower for all solid cancers (HR, 0.80; 95% CI, 0.72–0.88; P < 0.0001) and gastrointestinal cancer (HR, 0.65; 95% CI, 0.54–0.78; P < 0.0001). The greatest benefit was found with scheduled duration of trial treatment of ≥7.5 years for solid cancers (P = 0.003) and gastrointestinal cancers (P = 0.0001). Reductions in risk of death due to esophageal, pancreatic, brain, and lung cancer were evident only after a latent period of 5 years, whereas reductions in deaths due to stomach, colorectal, and prostate cancer were not observed until about 10 years. The benefit on the 20-year risk of death was limited to certain cancers, especially adenocarcinomas of lung (P = 0.04) and esophagus (P = 0.0001). The absolute reduction in risk of death due to cancer at 20 years increased with age, reaching 7.08% (95% CI, 2.42–11.74) at age 65 years or more. No increased benefit was found for aspirin doses greater than 75 mg daily and the effect was unrelated to gender or smoking. These findings provide evidence that daily aspirin reduces the risk of death due to several common noncolorectal cancers during and after the trials, with consistent effects across different populations and benefit increasing with duration of treatment.

Lung cancer, the leading cause of cancer deaths globally, has better survival rates with early detection. Annual low-dose CT (LDCT) screenings are recommended for high-risk individuals due to age and smoking. These individuals are also at risk for other cancers. Our study explores gastrointestinal (GI) cancer mortality in lung cancer screening participants and the potential of LDCT screenings to detect pancreatic cancer. We utilized data from a prospective multi-institutional cohort study, the International Early Lung Cancer Action Project (I-ELCAP). We analyzed GI cancer deaths among participants in New York State (1992–2010), exploring demographics and GI cancer distribution. Radiologists retrospectively reviewed pancreatic cancer cases within 24 months post-LDCT, comparing findings with original reports. Among 10,150 participants, 189 died from GI cancers; mean age 75, mostly male smokers. Pancreatic cancer (41.8%) led, followed by esophageal (17.5%) and colon cancer (16.9%). Median time between baseline LDCT and death was 116 months (9.7 years). 82/189 (43.4%) participants died within 5 years of their last LDCT screening, with pancreatic cancer again prominent (45.1%). In 79 pancreatic cancer deaths, 17.7% occurred within 24 months post-LDCT. A re-review identified previously undetected pancreatic findings, with 4 out of 14 participants (28.6%) showing abnormalities. This underscores the potential of lung cancer screening programs to provide insights beyond lung health. This study of over 10,000 participants in a lung cancer screening program reveals that they are at risk for GI cancer deaths, particularly pancreatic cancer. Re-reviews of LDCT scans revealed previously undocumented pancreatic findings in a third of participants who died from pancreatic cancer, underscoring the need to identify, document, and follow up on these findings.

BackgroundIn the developed world, the lifetime risk of cancer is about40% [1] but, by contrast with treatment of cancer, there hasbeen little progress in the use of drugs for prevention. Somegrades of evidence suggest an association between a long-term use of aspirin and a reduction in the risk of somecancers, in particular gastrointestinal tumours [2–7].However, as most of them derive from observationalstudies, it is important to note that these type of data haveoften been shown to be unreliable [8].SummaryRothwell and colleagues [9] studied the effect of aspirin onrisk of fatal cancer and on overall all-cause mortality, usingdata extracted from other randomised trials that had a meanor median scheduled trial treatment of aspirin versus con-trol of at least 4 years and a range extending beyond5 years. Searching in Pubmed, Embase and CochraneLibrary and using the data from the ATT collaborationsearch of 2002 [10], they found eight randomised clinicaltrials (published between 1998 and 2010) that assessed theefficacy of aspirin (any dose) given for at least 4 yearsversus no aspirin, in the absence or in the presence ofanother antiplatelet or antithrombotic drug for the primaryor secondary prevention of cardiovascular events. Theycontacted the original investigators to determine whetherthe data about the number of deaths for cancer as the maincause, the time from randomisation to death and the pri-mary site of cancer were obtainable. If available, they usedthese individual patient data and assessed, with Kaplan–Meier curves and Cox proportional hazards model, theeffect of aspirin on death due to cancer, stratified for thesite of cancer (cancers of the gastrointestinal tract versusother solid cancers versus haematological cancers), for thelength of the follow-up (more or less than 5 years fromrandomisation) and for the type of solid cancer (site andhistological type). They also estimated pooled effect ofaspirin on risk of cancer death and all-cause mortality usingfixed-effects meta-analysis. All analyses were made byintention-to-treat.The analysis of individual patient data, available fromseven of the eight included trials (23,535 patients, 657cancer deaths), reveals that aspirin significantly reducesdeaths due to cancer (HR 0.82, 95% CI 0.70–0.95,p = 0.01), the benefit appears just after 5 years’ follow-up(HR 0.66, 95% CI 0.50–0.87, p = 0.003). The analysis ofpooled data from all the eight included trials (counting25,570 patients and 674 cancer deaths) reveals that allo-cation to aspirin reduces death due to cancer [pooled oddsratio (OR) 0.79, 95% CI 0.68–0.92, p = 0.003], but thedrug does not significantly decrease all-cause mortality(OR 0.92, 95% CI 0.85–1.00, p = 0.047). Moreover,Rothwell and colleagues present data obtained from threetrials performed in UK (12,659 patients; 1,634 deaths) witha follow-up of 20 years: the risk of cancer death remains

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Highlights from Recent Cancer Literature

830 Background: Aspirin has been shown to reduce the risk of various gastrointestinal (GI) and non-GI cancers 1,2 . However, little was known about at what age aspirin should be started for maximal chemoprotective better on GI cancer. Furthermore, the randomised controlled trial on aspirin for primary prevention use in healthy elderly (ASPREE) showed no association between aspirin and cancer incidence despite the limitation of short follow-up duration 3 . The current study aims to investigate the 20-year risk of cancer using aspirin in a territory-wide Hong Kong population cohort. Methods: The study included all aspirin users from 2000 to 2019, and non-aspirin users matched by age and sex at a ratio of 1:2. Enrolled subjects with a history of cancer at enrolment, cancer incidence or death within 6 months were excluded. The incidence of individual GI and non-GI cancer was presented as the primary outcome. Baseline characteristics between aspirin and non-aspirin users were adjusted in the survival analysis by inverse probability of treatment weighting (IPTW). The fine-grey model has been used to address bias from competing risk of death. The sub-distribution hazard ratio was presented for the association of aspirin use and risk of GI and non-GI cancers. Results: The current study included 538,147 aspirin users and 968,378 non-users with a mean age of 64.8 years. A total number of 36,683 cases of GI cancer (2.4%) and 47,196 cases of non-GI cancers (3.1%) were observed. Aspirin was associated with a lower risk of several common individual GI cancers, including colorectal cancer (SHR 0.78, 95% CI 0.76-0.81), liver cancer (SHR 0.67, 95% CI 0.64-0.70), stomach cancer (SHR 0.79, 95% CI 0.75-0.84) and pancreatic cancer (SHR 0.85, 95% CI 0.79-0.91), but not oesophageal cancer. On the other hand, aspirin was associated with a lower risk of prostate cancer (SHR 0.95, 95% CI 0.91-1.00) and breast cancer (SHR 0.76, 95% CI 0.73-0.79), but not lung cancer and kidney cancer. In overall, aspirin was associated with a 24% lower risk of GI cancers (SHR 0.76, 95% CI 0.74-0.78) and a 3% lower risk of non-GI cancers (SHR 0.97, 95% CI 0.95-0.99). Conclusions: Aspirin was associated with a lower risk of most GI cancers, including colorectal cancer, liver cancer, stomach cancer and pancreatic cancer, but not most non-GI cancers. In general, results on the effect of aspirin on GI cancer prevention were consistent with the previously presented 10-year cohort. 1. Bosetti C, Santucci C, Gallus S, Martinetti M, La Vecchia C. Aspirin and the Risk of Colorectal and Other Digestive Tract Cancers: An Updated Meta-analysis through 2019. Ann Oncol. 2020;31(5):558-568. 2. Santucci C, Gallus S, Martinetti M, La Vecchia C, Bosetti C. Aspirin and the risk of nondigestive tract cancers: An updated meta-analysis to 2019. Int J Cancer. 2021;148(6):1372-1382. 3. McNeil JJ, Gibbs P, Orchard SG, et al. Effect of Aspirin on Cancer Incidence and Mortality in Older Adults. J Natl Cancer Inst. 2021;113(3):258-265.

SummaryBackgroundA one-dose-fits-all approach to use of aspirin has yielded only modest benefits in long-term prevention of cardiovascular events, possibly due to underdosing in patients of large body size and excess dosing in patients of small body size, which might also affect other outcomes.MethodsUsing individual patient data, we analysed the modifying effects of bodyweight (10 kg bands) and height (10 cm bands) on the effects of low doses (≤100 mg) and higher doses (300–325 mg or ≥500 mg) of aspirin in randomised trials of aspirin in primary prevention of cardiovascular events. We stratified the findings by age, sex, and vascular risk factors, and validated them in trials of aspirin in secondary prevention of stroke. Additionally, we assessed whether any weight or height dependence was evident for the effect of aspirin on 20-year risk of colorectal cancer or any in-trial cancer.ResultsAmong ten eligible trials of aspirin in primary prevention (including 117 279 participants), bodyweight varied four-fold and trial median weight ranged from 60·0 kg to 81·2 kg (p<0·0001). The ability of 75–100 mg aspirin to reduce cardiovascular events decreased with increasing weight (pinteraction=0·0072), with benefit seen in people weighing 50–69 kg (hazard ratio [HR] 0·75 [95% CI 0·65–0·85]) but not in those weighing 70 kg or more (0·95 [0·86–1·04]; 1·09 [0·93–1·29] for vascular death). Furthermore, the case fatality of a first cardiovascular event was increased by low-dose aspirin in people weighing 70 kg or more (odds ratio 1·33 [95% CI 1·08–1·64], p=0·0082). Higher doses of aspirin (≥325 mg) had the opposite interaction with bodyweight (difference pinteraction=0·0013), reducing cardiovascular events only at higher weight (pinteraction=0·017). Findings were similar in men and women, in people with diabetes, in trials of aspirin in secondary prevention, and in relation to height (pinteraction=0·0025 for cardiovascular events). Aspirin-mediated reductions in long-term risk of colorectal cancer were also weight dependent (pinteraction=0·038). Stratification by body size also revealed harms due to excess dosing: risk of sudden death was increased by aspirin in people at low weight for dose (pinteraction=0·0018) and risk of all-cause death was increased in people weighing less than 50 kg who were receiving 75–100 mg aspirin (HR 1·52 [95% CI 1·04–2·21], p=0·031). In participants aged 70 years or older, the 3-year risk of cancer was also increased by aspirin (1·20 [1·03–1·47], p=0·02), particularly in those weighing less than 70 kg (1·31 [1·07–1·61], p=0·009) and consequently in women (1·44 [1·11–1·87], p=0·0069).InterpretationLow doses of aspirin (75–100 mg) were only effective in preventing vascular events in patients weighing less than 70 kg, and had no benefit in the 80% of men and nearly 50% of all women weighing 70 kg or more. By contrast, higher doses of aspirin were only effective in patients weighing 70 kg or more. Given that aspirin's effects on other outcomes, including cancer, also showed interactions with body size, a one-dose-fits-all approach to aspirin is unlikely to be optimal, and a more tailored strategy is required.FundingWellcome Trust and National Institute for Health Research Oxford Biomedical Research Centre.

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

Angiotensin-Converting Enzyme Inhibitors and Risk of Esophageal and Gastric Cancer: A Nested Case-Control Study

Recent studies have reached conflicting conclusions regarding the risk of esophageal cancer with oral bisphosphonates. Prior studies did not record the number of cancer deaths or endoscopy rates, which could be higher in bisphosphonate users and lead to more cancers being diagnosed at a stage when their esophageal or gastric location could be accurately distinguished. We conducted a register-based, open cohort study using national healthcare data for Denmark. Upper endoscopy frequency, cancer incidence and mortality was examined in 30,606 alendronate users (female, age 50+) and 122,424 matched controls. Primary outcomes were esophageal cancer incidence and death because of esophageal cancer. The analysis showed that alendronate users were more likely to have undergone recent upper endoscopy (4.1 versus 1.7%, p < 0.001). Alendronate users had a lower risk of incident gastric cancer [odds ratio (OR) 0.61; 95% confidence interval (CI): 0.39-0.97) and no increased risk of esophageal cancer (OR 0.71; 95% CI: 0.43-1.19). Risk reductions were greater in users with 10+ prescriptions. The risk of dying of esophageal cancer was significantly reduced in alendronate users after 3 years OR 0.45 (95% CI: 0.22-0.92) but not after 9 years (OR 1.01; 95% CI: 0.52-1.95). An additional comparison with etidronate users revealed no statistically significant difference in outcomes. In conclusion, we found no excess in esophageal cancer deaths or incidence. The early decrease in esophageal cancer rates may relate to the greater use of endoscopy before starting alendronate. Longer term observations also indicated no excess risk of esophageal cancer death and a significantly decreased risk of gastric cancer death.

Aspirin in the prevention of cancer

This study evaluated recurrence-free survival (RFS) as a surrogate endpoint for overall survival (OS) in esophageal cancer. OS is regarded as the gold-standard efficacy endpoint of oncological treatments but requires long follow-up. An integrated analysis of individual patient data (IPD) from phase III trials comparing perioperative therapies for resectable esophageal and gastroesophageal junction cancer was conducted. Surrogacy between RFS and OS was assessed at the individual level using the Kendall rank correlation coefficient (τ) and at the trial level using the coefficient of determination (R²). A τ of 0.8 and an R² of 0.65 were considered thresholds for a good surrogate. Twenty-two eligible trials were identified, and IPD were available from 10 randomized trials, including 2,145 patients who underwent R0 resection. The 5-year OS and RFS rates were 53.2% and 46.2%, with median OS of 6.2 and RFS of 3.6 years. For individual-level surrogacy, Kendall's τ was 0.823 (95% confidence interval [CI]: 0.807-0.839). Subgroup analysis by treatment modality revealed τ values of 0.830 (95% CI: 0.800-0.861) for neoadjuvant chemotherapy (NAC; n=586), and 0.827 (95% CI: 0.803-0.850) for neoadjuvant chemoradiotherapy (NACRT; n=982). Trial-level surrogacy analysis across all 22 trials demonstrated an R2 of 0.735 (95% CI: 0.512-0.939). The surrogate threshold effect was 0.929. This study demonstrated strong individual- and trial-level surrogacy between RFS and OS in resectable esophageal cancer across all perioperative treatments. These findings may accelerate perioperative treatment development by shortening follow-up in esophageal cancer trials.

Purpose: Daily aspirin use has been associated with a 10-20% reduced risk of ovarian cancer in case-control and cohort studies. However, it is unknown whether certain subgroups of women are more likely to benefit from potential chemoprevention through daily aspirin. We determined whether the association between aspirin use and ovarian cancer varies by other ovarian cancer risk factors, including age, body mass index (BMI), duration of oral contraceptive use, and duration of menopausal hormone use. Methods: This study included women from the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial. Women were enrolled between 1993-2001 and followed for cancer outcomes through 2009. Aspirin use and ovarian cancer risk factors were reported at baseline. Cox proportional hazards regression was used to examine associations between daily aspirin use and ovarian cancer risk. Analyses were conducted overall and stratified by baseline age (50-59, 60-69, ≥70), BMI (&amp;lt;25, 25-29, ≥30 kg/m2), duration of oral contraceptive use (none, ≤5 years, &amp;gt;5 years of use), and duration of menopausal hormone use (none, ≤5 years, &amp;gt;5 years of use). All models were adjusted for these risk factors, as well as race (white, non-white), study arm (intervention, control), and number of live births (0, 1, 2, 3, ≥4). Statistical interaction was tested via likelihood ratio tests. Results: There were 60,713 women included in this study, of whom 364 developed epithelial ovarian cancer. Overall, compared to nonuse or infrequent use, a reduced risk of ovarian cancer was suggested with daily aspirin use (hazard ratio [HR]: 0.79, 95% confidence interval [CI]: 0.61-1.03). The association appeared stronger among women with BMI ≥30 kg/m2 (HR: 0.61, 95% CI: 0.36-1.13) compared to women with BMI &amp;lt;25 kg/m2 (HR: 0.95, 95% CI: 0.64-1.41) or 25-29 kg/m2 (HR: 0.87, 95% CI: 0.55-1.38, p-interaction=0.48). The association remained inverse and did not vary quantitatively or statistically by baseline age (p-interaction=0.96), duration of oral contraceptive use (p-interaction=0.85), or duration of menopausal hormone use (p-interaction=0.95). Conclusion: Consistent with prior studies, women who used daily aspirin had a lower risk of developing ovarian cancer. The association was not modified by other ovarian cancer risk factors, with the possible exception of BMI. We plan to similarly evaluate modification of the associations between aspirin use and risk of other cancers with potential inflammatory etiologies (e.g., colorectal) and will evaluate this in multiple cohorts. To determine whether aspirin is an effective form of chemoprevention in certain subgroups, ongoing research will likely need to pool data across studies or leverage other large-scale resources. Citation Format: Lauren M. Hurwitz, Kara A. Michels, Britton Trabert. Modification of the association between daily aspirin use and ovarian cancer risk by potentially modifiable risk factors [abstract]. In: Proceedings of the AACR Special Conference on Modernizing Population Sciences in the Digital Age; 2019 Feb 19-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(9 Suppl):Abstract nr A02.

BackgroundTislelizumab, an anti-programmed cell death protein 1 monoclonal antibody, has demonstrated efficacy and safety in solid tumors. This analysis evaluates its long-term safety.Patients and MethodsA retrospective analysis was performed on data from 8 randomized phase III clinical trials involving patients with advanced gastrointestinal (GI) or lung cancers who received tislelizumab. Endpoints included immune-mediated adverse events (imAEs) by tumor type, race, and treatment duration, including early (within 1 year) and delayed (>1 year) imAEs.ResultsIn all, 2636 patients (1415 with GI cancer, 1221 with lung cancer) were included in the analysis, with a median follow-up of 15.4 months. Most imAEs were low-grade. In GI cancers, 32.5% of patients experienced any-grade imAEs (7.3% grade ≥ 3). In lung cancers, 39.6% reported any-grade imAEs (8.2% grade ≥ 3). The most frequently reported imAEs were skin toxicity, hypothyroidism, pneumonitis, and hyperthyroidism. The incidence of imAEs was slightly higher in Asian patients compared with non-Asian patients (34.3% vs 26.9% in GI cancer and 35.5% vs 29.7% in lung cancer, respectively), but the incidence of grade ≥ 3 imAEs remained similar (7.5% vs 6.9% in GI cancer and 6.1% vs 7.2% in lung cancer, respectively). Most imAEs occurred within 6 months of treatment initiation. Delayed imAEs were infrequent and predominantly occurred while patients were still receiving tislelizumab therapy.ConclusionsTislelizumab’s safety profile, as monotherapy or combined with chemotherapy, remains consistent with previous reports across tumor types. Delayed imAEs were relatively infrequent, with no new signals identified in this long-term safety analysis.