아스피린 정기적으로 복용한 노인그룹에서 진행성 암 진단, 사망률 더 높게 나와

일반적으로 건강한 70세 이상 노인들에게 매일 저용량 아스피린을 복용하게 하면 진행암 발생율과 사망율의 위험이 커진다는 임상시험 결과가 나왔다.

그동안 많은 연구, 대부분 일반인을 대상으로 한 연구에서 보고된 적은 양의 아스피린을 규칙적으로 복용하는 사람들이 암으로 진단받거나 사망할 위험을 줄일 수 있다는 연구결과와는 배치되는 결과다. 

이 연구는 약 19,000명의 70세 이상의 건강한 사람들을 대상으로 진행됐다. 매일 100mg의 아스피린을 복용한 사람들은 위약을 복용한 사람들보다 진행성 암의 진단을 받고 암으로 사망할 가능성이 더 높다고 ASPREE 연구팀이 2020년 8월 11일 국립암연구소 저널에서 발표했다.

암 사망 위험 증가의 발견은 대장암에서도 유효했다. 대부분의 연구들이 아스피린 사용을 대장암 진단이나 사망 위험 감소와 연관시켰기 때문에 많은 암 예방 연구자들에게 충격을 주는 결과다. 

이른 나이에 복용한 사람과 특정질환 사람들은 약 중단 안돼 
ASPREE 시험의 참가자는 중위수 약 5년 동안 추적관찰을 받아왔다. 이 연구를 이끈 앤드류 챈(Andrew T. Chan) 박사는 이번 연구에 참여한 사람들은 젊었을 때부터 아스피린을 복용한 사람들이 아니라고 밝혔다. 

그렇기에 더 이른 나이에 정기적으로 아스피린을 복용한 사람들에게는 이 결과가 적용이 되지 않는다고 강조했다. 또한 찬 박사는 의사가 특정한 질환에 대해 아스피린을 처방한 사람들은 아스피린을 복용하는 것을 중단해서는 안 된다고 경고했다.

그러나 보다 넓은 관점에서 ASPREE 시험의 결과는 아스피린에 대한 최근의 다른 연구와 결합되어 임상 의사들이 '노인에 의한 아스피린의 임상적 사용'을 다시 논의해야 한다고 MD 앤더슨 암센터의 어네스트 호크 박사는 주장했다.

초기 연구의 발자취 추적하기
아스피린처럼 값이 싸고 상대적으로 안전한 약이 암 위험을 줄이는 데 도움이 될 수 있다는 전망이 수십 년 동안 연구자들을 유혹해 왔다. 저용량 또는 아기 아스피린은 이미 심장 질환이 있거나 그렇지 않으면 심장 질환의 위험이 높은 사람들에게 심장 관련 질환(심장마비 등)의 발생 가능성을 낮추기 위해 널리 사용되고 있다.

이러한 아스피린의 광범위한 사용은 아스피린 사용을 암의 진단과 그로 인한 사망 가능성이 줄어든 것과 연관시킨 수많은 관찰 연구를 가능하게 했다. 그러한 연구들은 결국 암을 포함한 아스피린의 질병 예방 가능성을 확인하기 위한 임상실험으로 이어졌다.

그 실험들 중에는 몇몇 암, 특히 대장암에 걸릴 가능성을 크게 높이는 조건인 린치 증후군을 앓고 있는 사람들이 포함되어 있었다. 그런 한 실험에서, 적어도 2년 동안 매일 고용량 아스피린(600mg)을 규칙적으로 복용한 린치 증후군 환자들은 그들의 대장암 위험을 1/3 이상 줄였다. 아스피린이 전 암 상태의 대장 용종 발병의 위험을 감소시킨다는 것도 여러 실험에서 밝혀졌다.

다른 임상 실험에서도 아스피린을 복용하면 대장암에 대해 지속적으로 가장 큰 감소가 관찰되면서 암 위험을 줄일 수 있다고 밝혔다. 그러나 이러한 다른 실험의 대부분은 아스피린이 암에 미치는 영향을 측정하기 위해 특별히 고안된 것이 아니었기 때문에 연구자들은 그러한 결과를 주의 깊게 보는 경향이 있다.

진행성 암으로 인한 사망 위험 증가
ASPREE 시험은 2010년부터 참가자를 등록하기 시작해 2014년까지 계속 등록을 받았다. 참가자들은 시험이 끝날 때까지 아스피린이나 위약 중 하나를 복용하도록 무작위로 배정되었고, 대부분은 실험에 들어가기 전에 정기적으로 아스피린을 복용하지 않았다. 실험은 2017년 6월 초에 중단되었다.

약 1,900명의 ASPREE 시험의 참가자들이 이 연구 기간 동안에 암 진단을 받았다. 전체적으로 약 3분의 2가 국소암이었다. 즉 원래 위치에서 퍼지거나 전이되지 않았다.

연구 기간 동안 암 진단을 받은 사람들 중 약 4분의 1이 결국 암으로 사망했다. 아스피린의 사용은 어떤 종류의 암의 진단과도 관련이 없었다.  그러나 매일 아스피린을 복용한 그룹은 위약에 비해 전이성 암 위험이 19% 더 높고 진행성 암 진단을 받을 위험은 22%, 진행성 암으로 사망 할 위험은 약 30 % 더 높았다. 

나이가 중요한 요소인가?
왜 아스피린 사용은 노인들에게 암의 발병 위험을 조금이라도 증가시킬까? 아스피린 사용과 암의 위험 감소, 사망율 연구는 그동안 주로 젊은 층에서 이루어졌다.

이 문제에 대해 연구팀은 노인들과 젊은층과의 생체조건이 다르기 때문이라고 전망했다. 노인들은 면역력이 약하기 때문에 아스피린이 노인들에게 있어서 암의 성장과 확산을 통제하는 면역체계 반응을 방해했을 수도 있다고 설명했다. 

ASPREE 시험의 일부 참가자들로부터 수집한 혈액과 종양 샘플 덕분에, 연구원들은 아스피린이 영향을 미칠 수 있는 면역 관련 또는 다른 잠재적인 분자 요인에 대해 좀 더 주의 깊게 연구할 수 있게 됐다. 그들은 또한 시간이 지남에 따라 암과 암 사망의 위험이 변화하는지 알아보기 위해 참가자들을 계속 추적관찰 것이라 밝혔다. 

아스피린 인식에 대한 관점 변화 오나  
호크 박사와 마레소 공중위생 석사는 다른 최근 실험의 결과도 아스피린이 해로울 수 있다는 우려를 낳고 있다고 설명했다. 예를 들어, 심장 질환의 위험이 높은 당뇨병 환자에게 저용량 아스피린을 검사한 ANSE 실험에서 아스피린을 복용한 참가자는 위약을 복용한 참가자에 비해 위장 출혈 위험이 상당히 높다는 점에 주목했다.

그럼에도 포드 박사는 ASPREE 연구결과로 인해 고용량 아스피린이 중요한 이점을 가지고 있는 것으로 입증된 린치 증후군과 같은 암 위험 조건이 높은 사람들에게 영향을 주어서는 안 된다고 말했다.

마지막으로 찬 박사는 "이 결과는 암 예방이 각 개인에 맞게 이루어져야 한다는 생각을 뒷받침해 준다"며 "예전의 사고방식은 한 가지 형식의 예방법이 모든 사람에게 동등하게 작용한다는 것이었다"고 말했다. 이어 "이것은 우리가 그 사고방식을 재고해야 한다는 것을 분명히 보여준다. 노년층에서 암이 발병하는 방식이나 예방약제에 대응하는 방식에는 생물학적으로 젊은 사람들과 다른 점이 있을 가능성이 분명히 있다"고 말했다.

2020년 8월 18일 : 국립암연구소 제공

Regular Aspirin Use May Increase Older People’s Risk of Dying from Cancer

August 18, 2020, by NCI Staff

In generally healthy people aged 70 and older, taking a daily low-dose aspirin increased their risk of being diagnosed with advanced cancer and dying from cancer, a large clinical trial found.

Numerous studies have suggested that people who regularly take low doses of aspirin may have reduced risks of being diagnosed with or dying from cancer. But new findings from a randomized clinical trial, called ASPREE, suggest that the same may not hold true for older adults.

The study included approximately 19,000 generally healthy people who were 70 years of age or older. Those who took 100 mg of aspirin daily were no more likely than those who took a placebo to be diagnosed with cancer. They did, however, have a greater likelihood of being diagnosed with an advanced cancer and of dying from cancerExit Disclaimer, the ASPREE research team reported August 11 in JNCI.

The finding of increased cancer death risk held true even for colorectal cancer. That may come as a surprise to many cancer prevention researchers, because most studies have linked aspirin use with a decreased risk for being diagnosed with or dying from colorectal cancer.

Data from those studies were considered strong enough that, in 2016, the US Preventive Services Task Force (USPSTF), an influential health panel of prevention experts, recommended the use of daily low-dose aspirin for certain people to reduce their risk of heart disease and colorectal cancer.

“These results are clearly unexpected,” said Andrew Chan, M.D., M.P.H., a professor of medicine at Massachusetts General Hospital and a senior researcher on the trial, which was funded primarily by the National Institute on Aging, and with support from NCI and others.

Participants in ASPREE have been followed for a median of approximately 5 years. Dr. Chan noted that they need to be followed for a longer period, to better understand the potential effect of aspirin on cancer diagnoses and deaths.

This was a group of people starting to take aspirin when they were older. It’s unclear if the findings apply to people who begin taking aspirin regularly at an earlier age, he said. Dr. Chan also cautioned that people whose doctors have prescribed aspirin for specific medical issues (e.g., reduce heart attack risk) shouldn’t stop taking it.

“They shouldn’t discontinue [aspirin] based on these results,” he said. “But if they’re concerned, they should consult with their doctor.”

But from a broader perspective, the ASPREE results, combined with other recent research on aspirin, should cause clinicians to revisit “the clinical use of aspirin by the elderly,” argued Ernest Hawk, M.D., and Karen Colbert Maresso, M.P.H., of the Division of Cancer Prevention and Population Sciences at MD Anderson Cancer Center, in an editorial in JNCI that accompanied the trial results.

The impact of specific treatments on older people is often not clear, because so few studies focus on them, said Leslie Ford, M.D., associate director for clinical research in NCI’s Division of Cancer Prevention and part of the ASPREE team. That’s part of what makes this trial so important, Dr. Ford continued.

“We … have to pay particular attention to studies done specifically in this age group,” she said.

Following the Trail of Earlier Research

The prospect that a cheap and relatively safe drug like aspirin could help reduce cancer risk has enticed researchers for decades. Low-dose, or baby, aspirin is already widely used to lower the chances of heart-related events (such as heart attacks) in people who have heart disease or who are otherwise at high risk of cardiac events.

This widespread use of aspirin allowed for the numerous observational studies that linked aspirin use with decreased chances of being diagnosed with cancer and dying from it. Those studies eventually led to clinical trials to confirm aspirin’s disease prevention potential, including for cancer.

Included among those trials were those in people with Lynch syndrome, a condition that greatly heightens the likelihood of developing some cancers, particularly colorectal cancer. In one such trial, people with Lynch syndrome who regularly took high-dose aspirin (600 mg) daily for at least 2 years cut their colorectal cancer risk by more than a thirdExit Disclaimer. Several trials have also shown that aspirin reduces the risk of developing precancerous colon polyps.

Other clinical trials have also indicated that taking aspirin could reduce cancer risk, with the largest reductions consistently seen for colorectal cancer. Most of these other trials, however, were not specifically designed to measure aspirin’s impact on cancer, so researchers tend to view those results with caution.

Largely conducted in Australia, but also with US participants, ASPREE is what is known as a primary prevention trial. It was launched to better understand the impact of low-dose aspirin on the risk of developing dementia or permanent physical disability among generally healthy older individuals. Whether aspirin affected cancer risk and cancer deaths was a planned, but secondary, goal of the study.

Initial results from ASPREE, published 2 years ago, showed that participants who had been randomly assigned to take daily low-dose aspirin had a modestly increased risk of dying from any cause compared with those who took a placebo. The increased risk was due almost entirely to a higher number of cancer-related deaths among those who took aspirin.

Increased Risk of Dying from Advanced Cancer

ASPREE began enrolling participants in 2010 and continued doing so until 2014. Participants were randomly assigned to take either aspirin or a placebo until the trial ended, and most had not taken aspirin regularly before entering the trial. The trial was stopped early in June 2017, when it was determined that there wouldn’t be an improvement in the study’s primary endpoint among those in the group taking aspirin.

Approximately 1,900 ASPREE participants were diagnosed with cancer during the study. Overall, about two-thirds of those were localized cancers—that is, they had not spread, or metastasized, from their original location.

About one-quarter of those diagnosed with cancer during the study ultimately died from it.

The use of aspirin wasn’t associated with the diagnosis of any single type of cancer. However, participants in the aspirin group had a nearly 20% higher risk of being diagnosed with advanced cancer and about a 30% higher risk of dying from advanced cancer.

The increased risk of being diagnosed with and dying from advanced cancer raise important questions, according to Dr. Hawk and Maresso.

“The unexpected and unexplained results of ASPREE suggest that we may still be missing a critical piece of the puzzle in our understanding of aspirin’s biologic effects on cancer development and evolution within and across individuals of differing ages,” they wrote.

Chyke Doubeni, M.D., director of the Center for Health Equity and Community Engagement Research at the Mayo Clinic, agreed that the results were unanticipated, particularly given the findings from earlier studies.

That participants in the aspirin group had a 77% higher risk of dying from colorectal cancer than those in the placebo group is particularly notable, continued Dr. Doubeni, who is a USPSTF member and was not involved in ASPREE. “I do think that what this is telling us is that we need more studies” on aspirin’s impact on colorectal cancer, he said.

Is Age the Critical Factor?

The findings raise a critical question, Dr. Ford said: Why would aspirin use lead to even a small increase in the risk of advanced cancer in older people? Studies linking aspirin use to decreased risks of cancer and dying from cancer were, she noted, largely done in younger populations.

It could be because older people’s biology is different than that of younger people, the study team proposed. For example, older people often already have weaker immune systems. And aspirin, they wrote, may be disrupting the immune system response that is “critical to controlling later stage [tumor] growth and spread.”

Dr. Ford agreed. “Maybe aspirin does have a different effect on people as they age,” she said. “And, similar to what we’ve seen with COVID-19, does it affect the immune system differently in an older population than it does in a younger, healthier one with a stronger immune system? It’s definitely a plausible explanation.”

Thanks in part to blood and tumor samples collected from participants as part of ASPREE, Dr. Chan said, the researchers are planning studies to look more carefully at immune-related or other potential molecular factors that aspirin may influence. They will also continue to follow participants to see if the risk of cancer and cancer death change over time.

Looking Ahead: Changes in Practice?

Dr. Doubeni said that the task force will consider the ASPREE results during its update of the 2016 recommendations, which is underway.

Results from other recent trials, Dr. Hawk and Maresso explained, have also raised concerns about the possible harms of aspirin. They noted, for example, that in the ASCEND trial, which tested low-dose aspirin in people with diabetes who were at increased risk of heart problems, participants who took aspirin had a substantially higher risk of gastrointestinal bleeding than those who took a placebo.

“Together, these findings alter the calculus of aspirin’s risks and benefits such that its use as a cancer [prevention] agent in the general population looks less likely,” they wrote.

Dr. Ford stressed that the ASPREE findings are relevant to older people and the use of aspirin as a means of primary prevention of cancer. They should not affect those with high cancer risk conditions like Lynch syndrome, she said, for which high-dose aspirin has been proven to have an important benefit.

In many other studies, Dr. Doubeni explained, the beneficial effects on cancer linked to aspirin use didn’t become apparent until long after people started using the drug, a decade or more in some cases. So the longer-term follow-up of trial participants will be critical, he said.

The results also support the notion that cancer prevention should be tailored to each person, Dr. Chan said.

“The old thinking was that one mode of prevention would work for everybody equally,” he said. “This clearly shows that we have to rethink that mindset. There’s a clear possibility that there’s something biologically different about the way cancers develop in older adults or how they respond to preventive agents.”