Results from a recent clinical trial indicate that for older adults with advanced cancer, initiating aspirin may increase their risk of disease progression and early death.
The study, which was conducted by a binational team led by researchers at Massachusetts General Hospital (MGH), the Berman Center in Minnesota, and Monash University in Australia, is published in the Journal of the National Cancer Institute.
Compelling evidence from clinical trials that included predominantly middle-aged adults demonstrates that aspirin may reduce the risk of developing cancer, especially colorectal cancer. Information is lacking for older adults, however.
To provide insights, investigators designed and initiated the ASPirin in Reducing Events in the Elderly (ASPREE) trial, the first randomized double-blind placebo-controlled trial of daily low-dose aspirin (100 mg) in otherwise healthy older adults.
The study included 19,114 Australian and U.S. community-dwelling participants aged 70+ years (U.S. minorities 65+ years) without cardiovascular disease, dementia, or physical disability at the start of the study.
Participants were randomized to aspirin or placebo and followed for a median of 4.7 years.
In October 2018, the investigators published a very surprising and concerning report showing an association between aspirin use and an elevated risk of death, primarily due to cancer.
The current report now provides a more comprehensive analysis of the cancer-related effects of aspirin in the ASPREE participants.
“We conducted this study as a more detailed examination of the effect of aspirin on the development of cancer as well as death from cancer,” explained senior author Andrew T. Chan, MD, MPH, Chief of the Clinical and Translational Epidemiology Unit at MGH, Director of Epidemiology at the MGH Cancer Center, and a Professor of Medicine at Harvard Medical School.
Dr. Chan and his colleagues reported that 981 participants who were taking aspirin and 952 who were taking placebo developed cancer.
There was no statistically significant difference between the groups for developing cancer overall or for developing specific types of cancer.
Aspirin was associated with a 19% higher risk of being diagnosed with cancer that had spread (or metastasized) and a 22% higher risk of being diagnosed with stage 4, or advanced, cancer, however.
Also, among participants who were diagnosed with advanced cancer, those taking aspirin had a higher risk of dying during follow-up than those taking placebo.
“Deaths were particularly high among those on aspirin who were diagnosed with advanced solid cancers, suggesting a possible adverse effect of aspirin on the growth of cancers once they have already developed in older adults,” said Dr. Chan.
He added that the findings suggest the possibility that aspirin might act differently, at the cellular or molecular level, in older people, which requires further study.
Notably, the vast majority of the study participants did not previously take aspirin before age 70.
“Although these results suggest that we should be cautious about starting aspirin therapy in otherwise healthy older adults, this does not mean that individuals who are already taking aspirin -particularly if they began taking it at a younger age – should stop their aspirin regimen,” Dr. Chan added.
Aspirin is a widely used anti‐platelet drug. Numerous studies have demonstrated the effects of aspirin on the secondary prevention of arterial thrombosis1 and several studies have investigated the effects of aspirin use for the primary prevention of atherosclerotic diseases.2, 3, 4, 5, 6, 7
Long‐term follow‐up of these studies established that regular daily aspirin use reduces the incidence, distant metastasis, and mortality of some cancers after approximately 5 years.8, 9, 10, 11 Several case‐control studies and cohort studies also revealed similar long‐term effects of aspirin.12, 13, 14, 15, 16, 17, 18
The evidence for the long‐term inhibitory effects of aspirin on cancer incidence and cancer‐related death is most prominent for gastrointestinal cancer, including colorectal cancer (CRC),19 and recently the US Preventive Services Task Force recommended initiating low‐dose aspirin use for the primary prevention of cardiovascular disease and CRC in adults aged 50 to 59 years who have a 10% or greater 10‐year cardiovascular disease risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low‐dose aspirin for at least 10 years.20
However, cancer incidence and mortality increases with advancing age, and the incidence and mortality of cancer is 10 times and 16 times greater in older adults, respectively, than in those younger than 65.21
Cancer is the leading cause of death in Japan, and according to the Japanese Cancer Institute registry data, 1 014 000 patients were estimated to be newly diagnosed with cancer, and 378 000 patients were estimated to die from cancer in 2017.22
Approximately half of Japanese people suffer from cancer during their lifetime, and one‐third die from cancer.
Therefore, it is crucial to assess the effects of aspirin on cancer incidence and mortality in the elderly Japanese, and the current evidence is insufficient.
We previously reported the results of the Japanese Primary Prevention Project (JPPP), which examined the inhibitory effects of aspirin on vascular events in the elderly Japanese population (age 60‐85 years, mean ± SD, 70.6 ± 6.2 years) with no previous history of arterial thrombosis.23
We performed a subanalysis of the JPPP to explore the effects of aspirin on cancer incidence and mortality in older Japanese by analyzing the in‐trial cancer incidence and mortality of patients participating in the JPPP.
Cancer incidence and mortality
Cancer was newly diagnosed in 332 (aspirin group) and 271 (no‐aspirin group) patients.
The cumulative incidence of newly diagnosed cancer was 5.60% (4.65‐6.64%) in the aspirin group and 4.14% (3.67‐4.66%) in the no‐aspirin group.
In the aspirin group, the HR for newly diagnosed cancer was 1.24 (1.06‐1.46) compared to the no‐aspirin group, and the incidence of newly diagnosed cancer was significantly higher than that in the no‐aspirin group (P = .008) (Figure 2).
CRC (66 [aspirin] and 50 [no‐aspirin]) was most often diagnosed in the study population, followed by gastric (55 [aspirin] and 49 [no‐aspirin]) and lung (56 [aspirin] and 37 [no‐aspirin]) cancer (Table 2).
The number of individual cancers was small, therefore we combined some cancers and divided into two categories: gastrointestinal (GI) cancer and non‐GI cancer.
GI cancer was newly diagnosed in 176 (aspirin group) and 151 (no‐aspirin group) patients, and the cumulative incidence of GI cancer was 2.62% (2.25‐3.03%) in the aspirin group and 2.31% (1.96‐2.70%) in the no‐aspirin group, respectively (Figure 3A).
Non‐GI cancer was newly diagnosed in 163 (aspirin group) and 123 (no‐aspirin group), and the cumulative incidence of non‐GI cancer was 3.12% (2.28‐4.15%) in the aspirin and 1.92% (1.59‐2.29%) in the no‐aspirin group, respectively (Figure 3B).
The HRs for GI cancer and non‐GI cancer in the aspirin group compared to the no‐aspirin group were 1.18 (0.95‐1.46), and 1.34 (1.06‐1.69), respectively. No statistically significant difference in the HR for GI cancer was detected between the aspirin group and no‐aspirin group (P = .138), while the incidence of non‐GI cancer in the aspirin group was significantly higher than that in the no‐aspirin group (P = .014).
Cumulative incidence of cancer in the aspirin and the no‐aspirin group. The P value was determined using the log‐rank test. CI, confidence interval; HR, hazard ratio. CI indicates confidence interval
Table 2
Organ site of newly diagnosed any cancer
| Aspirin | No‐Aspirin | |
|---|---|---|
| Head and Neck | 7 | 6 |
| Lung | 56 | 37 |
| Breast | 12 | 9 |
| Esophageal | 9 | 6 |
| Gastric | 55 | 49 |
| Colon | 66 | 50 |
| Hepato, Biliary, Pancreatic | 54 | 50 |
| Urinary | 16 | 13 |
| Prostate | 22 | 21 |
| Uterus | 8 | 5 |
| Hematologic | 26 | 23 |
| Others | 23 | 14 |
Cumulative incidence of gastrointestinal (GI) cancer (A) and non‐GI cancer (B) in the aspirin and the no‐aspirin group. The P value was determined using the log‐rank test. CI, confidence interval; GI, gastrointestinal; HR, hazard ratio
Total death and death related to newly diagnosed cancer occurred in 303 and 134 (aspirin group), and 308 and 125 (no‐aspirin group), and the cumulative mortality related to newly diagnosed cancer was 1.96% (1.65‐2.31%) in the aspirin group and 1.87% (1.56‐2.22%) in the no‐aspirin group, respectively.
In the aspirin group, the HR for cancer related death was 1.08 (0.85‐1.38) compared to the no‐aspirin group, and the risk of cancer‐related death did not differ significantly between the two groups (P = .527) (Figure 4).
Furthermore, the Fine and Gray model suggested that the difference in the incidence of newly diagnosed cancer between the two groups decreased year by year (Figure 5).
The number of deaths due to cancer after 5 years of follow‐up was relatively small, but there was a trend toward fewer deaths in the aspirin group (5 [aspirin] vs 16 [no–aspirin]; data not shown).
Cumulative incidence of cancer related death in the aspirin and the no‐aspirin group. The P value was determined using the log‐rank test. CI, confidence interval; HR, hazard ratio
Log‐log plot of newly diagnosed cancer in the aspirin group vs the no‐aspirin group
Journal information: Journal of the National Cancer Institute
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