Health Benefits of Aspirin: Colorectal Cancer

 

Aspirin use improves survival in all gastrointestinal cancers

Aspirin improves survival in patients with tumours situated throughout the gastrointestinal (GI) tract, results from a large study in The Netherlands show. This is the first time that survival data from patients with tumours in different GI locations have been analysed at the same time; previously, only one type of cancer, usually colorectal, was studied. The results of the study, involving nearly 14,000 patients, may lead to new insights regarding the use of aspirin in GI cancer say the researchers.

Presenting the results to the 2015 European Cancer Congress [1], the trial co-ordinator Martine Frouws, MD, from Leiden University Medical Centre, Leiden, The Netherlands, will describe how her team analysed data from 13,715 patients who had been diagnosed with a GI cancer between 1998 and 2011. By linking the data to drug dispensing information from PHARMO, the Institute for Drug Outcomes Research based in Utrecht, the team was able to show an association between aspirin use after a cancer diagnosis and overall survival (OS); they found there was a significant increase in OS among patients who did take aspirin compared to those who did not.

In total, 30.5% of patients used aspirin pre-diagnosis, 8.3% were solely post-diagnosis users, and 61.1% had not taken aspirin at all. The commonest sites for tumours were colon (42.8% of patients), rectum (25.4%), and esophagus (10.2%). Median follow-up time for all patients was 48.6 months, with 28% of patients surviving for at least five years. Patients using aspirin after their diagnosis had a chance of survival twice as high than that of those who did not use it in the same circumstances. The beneficial effect of aspirin use on survival was seen in patients with GI tumours after adjusting for potential confounding factors such as sex, age, stage of cancer, surgery, radiotherapy, chemotherapy and other medical conditions or disorders. [

"In most observational studies an 'intention to treat' method (once an aspirin user, always an aspirin user) is used for analysing aspirin's effect. In this study we analysed each separate prescription per patient, and therefore we were able to achieve a more exact estimate of the effect of aspirin on cancer survival. Now we would like to analyse tumour material from these patients to try and discover which ones would benefit from aspirin treatment. Through studying the characteristics of tumours in patients where aspirin was beneficial, we should be able to identify patients who could profit from such treatment in the future," Dr Frouws will say

At present, a multicentre, randomised, placebo-controlled trial is investigating the effect of a daily dose of 80 mg aspirin on OS of elderly patients with colon cancer in The Netherlands. The researchers hope that they will then be able to expand the trial to include further sites in the GI tract, and provide convincing proof that more patients will benefit from aspirin treatment. "Given that aspirin is a cheap, off-patent drug with relatively few side-effects, this will have a great impact on healthcare systems as well as patients," says Dr Frouws.

The scientists believe that the beneficial effect of aspirin in cancer is due to its antiplatelet effect. Platelets are a blood component whose function is to stop bleeding by clumping and clogging blood vessel injuries. Circulating tumour cells (CTCs) are thought to hide themselves from the immune system with the help of the clothing of platelets that surround them. Aspirin inhibits platelet function and therefore allows the immune system to recognise CTCs and eliminate them.
"Medical research is focusing more and more on personalised medicine," Dr Frouws will say, "but many personalised treatments are expensive and only useful in small populations. We believe that our research shows quite the opposite -- it demonstrates the considerable benefit of a cheap, well-established and easily obtainable drug in a larger group of patients, while still targeting the treatment to a specific individual."

Professor Peter Naredi, the ECCO scientific co-chair of the Congress, who was not involved in the research, commented: "We have good evidence that the frequent use of aspirin in the population can prevent some cases of colorectal cancer. Now, Dr Frouws and colleagues show that in over 13,000 patients who were diagnosed with a gastrointestinal cancer, aspirin also improved survival compared with those who did not use it. With more and more data to support the beneficial role of aspirin, we must consider whether we should recommend it to a wider public."

ESMO spokesperson, Professor Nadir Arber, MD, Head of the Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, Israel, who was not involved in the research, said: "Aspirin may serve as the magic bullet because it can target and prevent ischaemic heart disease, cancer and Alzheimer's disease, the three major health catastrophes in the third millennium.

"Dr Frouws and her colleagues tell us that not only can aspirin prevent disease, but low dose aspirin is important as an adjunct therapy for gastrointestinal cancers. The appropriate dosage and duration of aspirin use and risk/benefit ratios of aspirin use remain to be determined but, in the area of precision medicine, genetic information and blood and/or urinary biomarkers may help in tailoring treatment to those who will benefit most, while limiting adverse effects."



How aspirin fights colorectal cancer

Taking aspirin reduces a person's risk of colorectal cancer, but the molecular mechanisms involved have remained unknown until a recent discovery by The Hormel Institute, University of Minnesota.

Researchers led by The Hormel Institute's Executive Director Dr. Zigang Dong and Associate Director Dr. Ann M. Bode, who co-lead the Cellular & Molecular Biology section, discovered that aspirin might exert its chemopreventive activity against colorectal cancer, at least partially, by normalizing the expression of epidermal growth factor receptor (EGFR) in gastrointestinal precancerous lesions. EGFR is overexpressed in about 80 percent of cases involving colorectal cancer, the third-leading cause of cancer-related death in the United States.

Recently published in the open-access journal EBioMedicine, the Hormel Institute's study revealed a previously unknown functional association between EGFR and COX-2 -- an enzyme associated with pain and inflammation -- during the development of colorectal cancer. The study also provides an explanation as to how taking aspirin can lower the risk of colorectal cancer in patients with familial adenomatous polyposis (FAP), a rare, inherited condition that causes extra tissue, or polyps, to form in the large intestine. Polyps left untreated almost always become cancerous by age 40.

For this study, The Hormel Institute partnered with Mayo Clinic researchers who provided tissue sections from recruited FAP patients who were classified as regular aspirin users or nonusers. Consistent clinical trial data strongly suggests that regular use of aspirin and other non-steroidal, anti-inflammatory drugs lowers a person's lifetime risk of developing colorectal cancer.

Institute researchers found that COX-2 might drive the formation of tumors, at least in part, through the upregulation of EGFR. Given that, researchers believe EGFR might be a novel target for preventing colorectal cancer.

"We found that EGFR overexpression is an early event in the formation of colorectal cancer that can be greatly reduced by regular use of aspirin," Dr. Zigang Dong said. "Our findings are highly interesting, but more research is needed."

A short commentary also published on EBioMedicine by Dr. Paola Patrignani of Italy's "G. d'Annunzio" University of Chieti, highlighting The Hormel Institute's latest paper while discussing the potential use of aspirin for cancer prevention.

"The accumulating data from randomized clinical trials provide the rationale to consider the potential role of daily aspirin use in colorectal cancer prevention and possibly other types of cancer," Patrignani wrote in her commentary titled "COX-2 and EGFR: partners in crime split by aspirin."

Some questions, however, need to be addressed, Patrignani wrote, before recommending the prophylactic use of aspirin for cancer prevention, such as whether the chemopreventive effect is dose-dependent and whether daily, low-dose aspirin affect other types of cancers in addition to colorectal cancer. Clinical studies should be performed, she added, to verify whether the coadministration of low-dose aspirin and possibly other antiplatelet agents may lead to overcoming the resistance to EGFR inhibitors in cancer treatment.

This latest research follows another paper published December 2014 in EBioMedicine by The Hormel Institute's Dong/Bode team related to colorectal cancer that provided a promising strategy for preventing and treating the disease. That study showed evidence that the TXA2 pathway also plays an important role in the processes leading to colorectal cancer, and laid the groundwork for introducing a strategy to target TXA2 for colorectal cancer prevention, early detection and management.

While reliable biomarkers remain a serious issue for the early detection of colorectal cancer, The Hormel Institute's findings in that study suggest that circulating TXA2 levels might have a potential prognostic or predictive value for detecting colorectal cancer early. Work is underway to further confirm the biomarker's clinical performance.

This month, Dr. Zigang Dong also received a grant for more than $1.7 million over five years from the National Cancer Institute to continue his team's supercomputer-assisted development of agents that are more effective and less toxic in preventing and treating colorectal cancer.

Through the use of The Hormel Institute's two IBM supercomputers, Drs. Dong and Bode have discovered three small molecules highly effective at suppressing colon cancer cell growth by inhibiting β-catenin, an enzyme strongly expressed in many cancer cell types that promotes growth and tumor formation.

---

Regular aspirin reduces the risk to develop colorectal cancer by an average of 40%.

The risk of developing cancer increases with age. Factors like smoking and regular aspirin use also affect the risk of cancer – although in the opposite sense. Researchers from the University of Basel were now able to show that aspirin use and smoking both influence aging processes of the female genome that are connected to colorectal cancer. The Journal of the National Cancer Institute has published their results.

Regular aspirin use is said to reduce the risk to develop colorectal cancer by an average of 40%. However, it is unknown how exactly the drug influences the cancer risk.

A research group led by Prof. Primo Schär, molecular geneticists at the Department of Biomedicine from the University of Basel and gastrointestinal specialist PD Dr. Kaspar Truninger, has now discovered a possible mechanism of how aspirin decreases the risk of cancer: It slows down certain aging processes of the genome - namely modifications that also play an important role in the development of tumors.

In order to analyze the relationships between lifestyle and genome aging, the researchers examined intestinal tissue samples of 546 healthy women over 50 years of age. They compared age-specific changes of gene markers, so-called DNA methylations, with the women's lifestyle factors regarding aspirin use, smoking, body mass index and hormonal replacement therapy. The most significant effects were measured for aspirin use and smoking. 

Aging Markers

“Each cell's genome resembles a library that is full of bookmarks”, explains Schär. Thanks to these bookmarks, the cells know which genes to read, so that they can fulfill their specialized tasks as skin, muscle or intestinal cells. “But these markers are not very stable and change during the course of age. If, at certain parts of the genome, the change is to drastic, tumors can develop”, says Schär.

In this study, the researchers were able to show for the first time that this age-related decay of gene markers can be slowed down by the regular use of aspirin.  Smoking on the other hand, accelerates the aging process. “Especially affected are genes that also play a role in the development of cancer”, says Dr. Faiza Noreen, research associate at the Department of Biomedicine from the University of Basel and first author of the study. 

Truninger emphasizes that it would be premature to start taking aspirin solely for cancer prevention without consulting a doctor first – especially when regarding the potential side effects such as gastrointestinal bleeding.

Aspirin blocks tumor growth in some colorectal cancer

Aspirin has the potential to block tumor growth in certain patients with colorectal cancer, according to an editorial in the Oct. 25, 2012 issue of the New England Journal of Medicine by a University of Alabama at Birmingham oncologist. In a study that appears in the same issue, researchers examined the use of aspirin in the treatment outcomes of patients with colorectal cancer.

Researchers collected experimental data from 964 patients with colorectal cancer, separating them into two groups based on the presence or absence of a mutation within the PIK3CA gene. The authors found that the use of aspirin after diagnosis in patients with the gene mutation was associated with a 46 percent reduction in overall mortality and an 82 percent reduction in colorectal cancer-specific mortality. In contrast, aspirin use in patients without the mutation did not affect either overall or colorectal-specific mortality.

“Approximately 17 percent of patients with colorectal cancer have a tumor that carries a mutated PIK3CA gene,” says Boris Pasche, M.D., Ph.D., director of the UAB Division of Hematology and Oncology. “Hence, more than one in every six patients with locally advanced colorectal cancer may benefit from this therapy.”

Every year, more than 140,000 Americans are diagnosed with colorectal cancer, and more than 50,000 people die from the disease. Colorectal cancer is the third most common cause of death from cancer in the United States and the fourth worldwide.

Over the past decade, little progress has been made in the treatment of locally advanced colorectal cancer, which is defined as cancer that has spread to nearby tissue or lymph nodes but has not metastasized, or spread to other organs. “While several new drugs have proven useful in the treatment of metastatic colorectal cancer, only one of them has demonstrated efficacy in locally advanced colorectal cancer,” Pasche says.

Pasche notes that the sample size for the current study was small. Only 66 patients with the PIK3CA mutation used aspirin after being diagnosed with colorectal cancer and only three of them died of colorectal cancer during the follow-up. “Although we are intrigued about these findings, they are still preliminary, and larger prospective studies need to be conducted,” says Pasche.

One cause of concern is that aspirin is known to increase the risk of gastrointestinal bleeding and hemorrhagic strokes, Pasche notes. Although many Americans use baby aspirin daily to reduce their risk of heart disease, patients are generally only advised to do so when their cardiac risk is presumed to outweigh the risk of taking aspirin.

“We haven’t reached the point where we can make a big leap and advise patients to take aspirin to prevent cancer recurrence after surgery, but we are accumulating more information that helps us understand the role that aspirin can potentially play in cancer,” says Pasche. “As it is with any type of cancer treatment, we need to examine the benefits against the risks, but aspirin may well become one of the oldest drugs to be used as a 21st-century targeted therapy.

Aspirin can reduce colorectal cancer risks for those with specific gene

The humble aspirin may have just added another beneficial effect beyond its ability to ameliorate headaches and reduce the risk of heart attacks: lowering colon cancer risk among people with high levels of a specific type of gene.

The extraordinary finding comes from a multi-institutional team that analyzed data and other material from two long-term studies involving nearly 128,000 participants. The researchers found that individuals whose colons have high levels of a specific gene product — 15-hydroxyprostaglandin dehydrogenase (15-PGDH) RNA — dramatically reduce their chances of developing colorectal cancer by taking aspirin. In contrast, the analgesic provides no benefit to individuals whose colons show low levels of 15-PGDH.

The findings appear in Science Translational Medicine.

While previous trials and prospective studies had indicated that aspirin could reduce colorectal cancer risk, this retrospective study provides the first evidence to help explain why aspirin benefits some people, but not others.

The research team included researchers from Case Western Reserve University School of Medicine, Dana Farber Cancer Institute, Harvard University, Massachusetts General Hospital, and University Hospitals Case Medical Center.

"If you looked at the folks from the study who had high 15-PGDH levels and took aspirin, they cut their risk of colon cancer by half," said senior author Sanford Markowitz, MD, PhD, Ingalls Professor of Cancer Genetics at Case Western Reserve School of Medicine. "If you looked at the folks from the study that were low for 15-PGDH, they did not benefit at all from taking aspirin. These findings represent a clean Yes-No about who would benefit from aspirin."

Funded in part by the Entertainment Industry Foundation's National Colorectal Cancer Research Alliance (NCCRA), the discovery represents precisely the kind of advancement that Katie Couric and her colleagues sought when they founded the initiative in 2000. She lost her 42-year-old husband, Jay Monahan, to colon cancer in 1998 and has been a steadfast advocate for colon cancer prevention efforts in the years since.

"Prevention, early detection and effective treatments are key to conquering cancer," Couric said. "This finding that aspirin can prevent colon cancer in certain individuals is an easy and cost-effective addition to our arsenal in the fight against the second-leading cancer killer. I am proud to see this valuable research advancing patient care for those at risk of colon cancer resulting from NCCRA support."

According to the American Cancer Society, colorectal cancer is the second leading cause of cancer-related deaths in the United States, with predictions that 137,000 Americans will develop the disease and 50,000 will die from it in 2014. Thanks to regular screenings, the death rate from colorectal cancer has dropped in the past 20 years, and members of this research team have been dedicated to finding additional measures to help reduce risk and ultimately eradicate the disease.

In this latest effort, the scientists sought to build on earlier research that indicated that regular use of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, reduces the chances of developing colon cancer for some individuals, but not in all. Their question: Why? What is different between those helped by aspirin, and those who saw no effects?

Markowitz, also the head of the Cancer Genetics Program at the Case Comprehensive Cancer Center and a medical oncologist at University Hospitals Case Medical Center joined lead co-senior author Andrew T. Chan, MD, PhD, of Massachusetts General to explore whether the presence of 15-PGDH led to different outcomes in terms of which individuals developed colon cancer.

Their goal: to see whether it is possible to develop a test that would help guide physicians and patients in determining whether an aspirin regimen would be of benefit.

The team examined tissues of 270 colon cancer patients culled from 127,865 participants followed for over three decades in the Harvard-based Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS).

Previous reports from the Massachusetts General/Dana-Farber team indicated that participants in these studies who regularly took aspirin had a lower risk of colorectal cancer. In earlier research, the Case Western Reserve investigators, along with Monica Bertagnolli, MD, of Brigham and Women's Hospital, had found that the presence of 15-PGDH appeared to enhance the ability of celecoxib, an anti-inflammatory medication commonly known as Celebrex, to prevent colon tumors in mice and in 16 humans tested. But when 15-PGDH was low or not present, celecoxib did not prevent colon tumors in mice or humans.

In this latest study, the investigators combined forces in a much larger study to examine whether 15-PGDH levels might also be associated with the colon cancer-preventing benefits of aspirin, which is already taken by many individuals and does not have the cardiovascular side effects of celecoxib .

The Massachusetts General and Dana-Farber team dissected normal colon tissue from the pathology specimens of NHS/HPFS participants who developed colon cancer over the studies' follow-up period. The team at Case Western Reserve then analyzed these colon tissues to identify which among them had high or low levels of colon 15-PGDH. The investigators at Massachusetts General and Dana-Farber examined how the data on participants' aspirin use and levels of 15-PGDH related to the risk of colorectal cancer to address the question the larger group had set out to answer: Were individuals who developed colorectal cancer while taking aspirin more likely to have low or high levels of colonic 15-PGDH?

The study is among the first examples of the type of test that could allow more personalized decisions about treatment to prevent colorectal cancer. It also allows those whose 15-PGDH levels indicate aspirin would have little impact to avoid the potential gastrointestinal challenges — such as stomach ulcers — that can accompany aspirin use.

The researchers' next steps are two-fold: first, the development of a cost-effective and accessible test for measuring 15-PGDH in the colon, and second, a prospective clinical trial to further confirm these findings.

Chan and Markowitz both consider the first step well within reach current medical practice.

"During a colonoscopy, a gastroenterologist could easily and safely take an additional biopsy from the colon in individuals for whom preventive aspirin treatment might be appropriate," Chan said. Added Markowitz, "There would be no reason why a good hospital pathology laboratory could not establish the test for 15-PGDH."

The study authors are also hopeful that publication of these findings will draw the interest from funders and other researchers in developing a confirmatory randomized, prospective clinical trial in which high-risk patients would be identified, treated with aspirin or a placebo, depending on their 15-PGDH levels, and monitored for development of colorectal tumors.

The mechanisms of action in the 15-PGDH gene and in aspirin make them key players in the colon cancer discussion. Prostaglandins promote development of colon cancer, and aspirin helps prevent colon cancer development by preventing prostaglandins from being generated. 15-PGDH also helps prevent colon cancer development by catalyzing the reaction that "chews up" prostaglandins. Markowitz refers to 15-PGDH as the body's genetic form of aspirin. The study shows that both aspirin and 15-PGDH must work together to effectively prevent colon cancer, with aspirin benefitting most individuals who also have high levels of 15-PGDH.

"This study highlights the benefits of the relatively new practice of molecular pathological epidemiology, or MPE," said co-senior author Ogino of Dana-Farber, an Associate Professor of Pathology at Harvard Medical School. "The molecular pathology part relates to analysis of 15-PGDH gene expression level in normal colon to classify cancer based on molecular pathogenesis, while the epidemiology part relates to collection and analysis of aspirin use data in population. MPE is an integration of these analyses."

Aspirin reduces the risk of colorectal cancer

A study of Medicare patients with osteoarthritis provides additional evidence that non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin reduce the risk of colorectal cancer. Earlier investigations of the drugs’ impact on tumor development could not rule out the possibility that an observed protective effect was caused by other preventive health care measures. The current study, led by a Massachusetts General Hospital (MGH) physician, appears in the August 2007 Journal of General Internal Medicine.

“This is good news for people who take NSAIDs regularly for osteoarthritis,” says Elizabeth Lamont, MD, MS, of the MGH Cancer Center, the study’s lead author. “Although patients face risks such as bleeding or kidney damage from this therapy, they probably are at a lower risk of developing colorectal cancer.” Because of the risks posed by the dosage used to treat osteoarthritis, she and her co-authors stress that currently available NSAIDs should not be used solely to prevent cancer.

Earlier randomized trials clearly showed that NSAID treatment can prevent the development of precancerous colorectal polyps, but whether or not such therapy also reduces the risk of invasive colorectal cancer has not yet been confirmed. Those trials used relatively low doses of aspirin and showed no significant differences in colorectal cancer rates between the aspirin and placebo groups. While many observational studies have shown a protective effect of NSAIDs against colorectal cancer, interpretation of some of those results may have been clouded by other healthy behaviors of the participants.

“It would be ideal to conduct a randomized clinical trial – in which half the patients receive NSAIDs at doses higher than those used in prior trials and half receive placebos – and follow both groups for many years for evidence of cancer. But such trials are expensive, time consuming, and could present real health risks to participants. Therefore, we took advantage of a natural ‘experiment’ by comparing data from patients known to regularly take higher amounts of NSAIDs with that from those taking lower doses in order to evaluate any effect on colorectal cancer risk.”

First the researchers reviewed data from the 1993-94 National Ambulatory Medical Care Survey, in which physicians report on the diagnoses of and treatments prescribed to patients seen during a randomly selected week. Those results verified that older patients with osteoarthritis were more than four times as likely to take NSAIDs as were those without osteoarthritis. They then analyzed information from the Survival Epidemiology and End-Results (SEER)-Medicare program, studying groups of elderly Medicare patients with and without colorectal cancer, to search for associations with NSAID use.

Comparing information on 4,600 individuals with colorectal cancer to data from 100,000 controls, they found that a history of osteoarthritis was associated with a 15 percent reduction in the likelihood of a colorectal cancer diagnosis. A similar association was seen when total knee replacement was used as a marker for NSAID treatment.

“The magnitude of colorectal cancer risk reduction between patients with and without osteoarthritis is completely consistent with the risk reduction for pre-cancerous polyps reported in clinical trials of NSAIDs,” Lamont says. “Confirming this association supports the need for further research to identify NSAID agents safe enough to be used for regular, preventive therapy by the general population.”

Benefits of aspirin to prevent colon cancer

A colon cancer researcher at the Ireland Cancer Center of University Hospitals Case Medical Center (UHCMC) has laid out the roadmap for how medical science should employ aspirin and new aspirin-like drugs for use in preventing colon cancer in certain high-risk individuals.

In the New England Journal of Medicine, (May, 2007) Sanford Markowitz, MD, PhD, writes an editorial accompanying research from Dr. Charles Fuchs' team at Harvard Medical School that lays out the hypothesized mechanism by which the use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), also called COX-2 inhibitors, act to decrease the risk of developing colon cancer.

"The compelling evidence that chronic use of aspirin or certain NSAIDS can substantially lower the risk of colon cancer has important implications, especially because colon cancer is the second leading cause of cancer death," writes Dr. Markowitz, the Francis Wragg Ingalls Professor of Cancer Genetics at UHCMC and Case Western Reserve University School of Medicine.

In the Journal article, the Harvard researchers' findings demonstrated that two-thirds of colon cancers have high levels of expression of the COX-2 enzyme, which is blocked by aspirin. Individuals who regularly used aspirin over a course of several years demonstrated a 36% decrease in the risk of developing one of these high COX-2 expressing colon cancers. These results again demonstrated that drugs that block COX-2 can decrease the risk of colon cancer, and demonstrated that such drugs specifically target those individuals whose tumor development is encouraged by the action of the COX-2 enzyme.

Dr. Markowitz' accompanying editorial maps out those studies which will be required to determine the potential use of aspirin in prevention of colon cancer and to determine which individuals might benefit most from taking aspirin or aspirin-like drugs (NSAIDS) such as ibuprofen and Celebrex. Finally, the editorial outlines potential targets for development of drugs that might provide similar protection as aspirin or COX-2 inhibitor drugs for developing colon cancer but with a lesser risk of adverse side effects.

"Interventional trials have shown a decreased risk of the development of colon cancer in high-risk subjects who were given aspirin or COX-2 selective NSAID inhibitors and observational trials have associated a decreased risk of colon cancer with aspirin use," writes Dr. Markowitz in the editorial. "The researchers' findings provide powerful support for the role of COX-2 as a key mediator in the development of colon cancer and now pose questions about the biologic basis and clinical applications of discovering differences that express high or low levels of COX-2."

Dr. Markowitz has done seminal research in the field of colon cancer genetics and prevention. Among his numerous research articles, he published a study on the findings of a new "Celebrex-like" gene that suppresses the grown of colon cancer in the July 2006 issue of Proceedings of the National Academy of Sciences. Dr. Markowitz likens the gene, called 15-PGDH, to a naturally occurring Cox-2 inhibitor such as Celebrex. These findings may lead to the development of a new drug for colon cancer prevention.

"Sandy and his research team have made great strides in colon cancer prevention," says Stanton Gerson, MD, Director of the Ireland Cancer Center at University Hospitals Case Medical Center as well as the Case Comprehensive Cancer Center. "This editorial and all of his proceeding work may have great impact on individuals at high risk for developing this deadly disease."

Aspirin Every Other Day May Lower Women's Colon Cancer Risk

Taking a low-dose aspirin every other day may reduce the risk of colorectal cancer, according to a study that focused on nearly 40,000 women aged 45 and older.

The protection does seem to take some time to surface, said researcher Nancy Cook, a professor of medicine at Brigham and Women's Hospital and Harvard Medical School. "After 10 years, we started to see an effect," she noted.

"After 18 years of follow-up, we saw a 20 percent reduction in colon cancer over the whole time period," she said. When they looked at the 10-to-18 year mark, the reduction was 42 percent, she said.

However, risks linked with aspirin, such as gastrointestinal bleeding, must be considered, Cook said.

The study, funded by the U.S. National Cancer Institute and U.S. National Heart, Lung, and Blood Institute, was published July 16, 2013 in the Annals of Internal Medicine.

Aspirin has been long known for its protective effects on heart health, but the protective effect of aspirin on colon and rectal cancer has only been found more recently. "In the past three years, analyses of trials conducted for cardiovascular health have begun to show an effect on colon cancer as well," Cook said.

Cook and her team followed women enrolled in the Women's Health Study, a trial that evaluated the benefits and risks of low-dose aspirin and vitamin E in preventing both cardiovascular disease and cancers.

The study began in 1993 and ended in 2004. The women had no history of cancer (except nonmelanoma skin cancer), cardiovascular disease or other major chronic illness when they enrolled.

The women assigned to the aspirin group were told to take a low dose -- 100 milligrams -- of aspirin every other day. The comparison group took placebo pills on alternate days.

After the study ended, the researchers continued to follow more than 33,000 women through March 2012. The women were told to continue the regimen, although the researchers no longer provided the pills.

The researchers tracked colorectal cancer, along with other cancers. They found the 20 percent lower colorectal cancer incidence over the entire 18-year follow-up.

They did not find a difference with cancer deaths between groups, but Cook said there may not have been enough women to show a comparative difference from a statistical point of view.

Cook found no difference in colorectal polyps between groups. Polyps are removed when they are found on colonoscopy as they can progress to cancer.

The aspirin group had more gastrointestinal bleeding, a known side effect, and more peptic ulcers. While 8.3 percent of the aspirin group had GI bleeding, 7.3 percent of the placebo group did. Peptic ulcers affected 7.3 percent of the aspirin group but only 6.2 percent of the placebo group.

While the study included only women, Cook said the results would probably apply to men, too. Other aspirin studies that looked at the effects of the drug, she said, have included mainly men.

Even with the double benefit of heart and colon protection, Cook said, "You really need to balance risks and benefits."

Dr. Anthony Starpoli, a gastroenterologist at Lenox Hill Hospital in New York City, agreed that patients should be carefully selected for aspirin therapy.

Before a doctor suggests aspirin for the colon protection, Starpoli said, the important question is: "Am I really reducing their risk of colon cancer or am I increasing their risk of GI bleeding?"

The strength of the study, he said, is the large number of women. However, he does not think the findings translate to a global recommendation that everyone over 45 take alternate day aspirin for colon cancer risk reduction. "There may be a subgroup of patients at higher risk who could benefit."

Those with a family history of colon cancer or who have had polyps have a higher than average risk.

The side effect of GI bleeding needs to be taken seriously, Starpoli said. "The nature of GI bleeding from nonsteroidal anti-inflammatories [NSAIDs] or aspirin is somewhat unpredictable," he said. And it can be serious and even fatal.

For those hoping to take an aspirin for the double benefit of heart and colon health, would alternate day protect their heart enough?

Generally, daily aspirin is recommended for heart disease risk reduction, Cook said. However, "the Physicians' Health Study showed a benefit for alternate day, but the dose was 325 milligrams of regular aspirin," she added.

Certain Colon Cancer Patients Might Benefit From Aspirin

           

Recent research has raised the possibility that low-dose aspirin could add extra years to the lives of colon cancer patients. Now, a new study suggests that only certain patients may gain a survival benefit by taking aspirin after diagnosis.

The study of about 1,000 patients found that people whose tumor cells give off a specific antigen, or defense mechanism, gained most from adding aspirin to their regular treatment.

The findings, published online March 31, 2014 in JAMA Internal Medicine, aren't conclusive, and patients who develop colon cancer while already taking aspirin may not get any benefit. Also, aspirin, while inexpensive, comes with its own risks.

Experts asked if colon cancer patients should begin taking aspirin as a result of these findings were divided.

"Absolutely not," said study lead author Dr. Marlies Reimers, a doctoral student at Leiden University Medical Center in the Netherlands. She believes more research is necessary.

But the author of a commentary accompanying the study, Dr. Alfred Neugut, said he now plans to recommend aspirin therapy for specific patients.

The study adds to growing evidence that aspirin is helpful for certain colon cancer patients, said Neugut, an oncologist and epidemiologist at Columbia University Medical Center in New York City.

In his commentary, Neugut writes he himself would add aspirin to his chemotherapy treatment regimen if he had a stage III colon cancer tumor, and he's ready to recommend that patients do, too. Stage III means the cancer has spread to nearby lymph nodes, but has not yet spread to other parts of the body.

Together, this research and other recent studies "paint a very sound picture that warrants a change in standard of care -- that aspirin can and should be recommended for use for stage III patients," he said in an interview.

But what about aspirin's well-known risks, especially the possibility of bleeding in the digestive system?

"Stage III patients have a 40 percent to 70 percent chance of dying. I don't think the possibility that 1 percent to 2 percent will have some significant bleeding should deter aspirin's use, given a potential 20 percent to 30 percent improvement in survival," Neugut said.

Aspirin is a "much easier and safer drug than chemotherapy, which we use without reservation," he added.Neugut said, however, that he doesn't recommend aspirin as a way to prevent colon cancer.

The study examined tissue samples of 999 patients in the Netherlands who had surgery for colon cancer, mostly stage III or lower. Researchers then compared death rates for patients who were prescribed low-dose aspirin after diagnosis to those without the prescription, which is required in the Netherlands.

The death rate was 38 percent among those who took low (80-milligram) doses of aspirin after diagnosis compared to 49 percent among the non-aspirin users, the study found.

Survival rates were notably higher among aspirin-taking patients whose tumor cells gave off what's called HLA class I antigen -- a type of substance that alerts the immune system to defend the body. About two-thirds of 963 patients whose tumors were analyzed fell into this category.

Aspirin had no apparent effect on the other patients who took it, the researchers said.

Colon Cancer Survival Improves With Aspirin

Colon cancer patients who take aspirin regularly shortly after diagnosis tend to live longer, researchers from Leiden University Medical Centre, the Netherlands, reported in the British Journal of Cancer. (April 2012)

The authors explain that NSAIDs (non-steroid anti-inflammatory drugs) have been known to have a preventive role with regards to colorectal cancer, and in particular, aspirin. Recently, some studies and experts have suggested that regular aspirin may have a therapeutic role too. However, studies so far have not been conclusive.

Dr Gerrit-Jan Liefers and team set out to determine what the therapeutic effect of aspirin/NSAIDs as adjuvant treatment might be on colorectal cancer patients after diagnosis. They carried out an observational population-based study.

They gathered prescription data from the PHARMA linkage systems, focusing on patients who had been diagnosed with colorectal cancer (1998-2007). They selected people from the Eindhoven Cancer Registry, a population-based cancer registry.

Patients were classified into:

* Pre-diagnosis and post-diagnosis - aspirin/NSAID users

* Pre-diagnosis and post-diagnosis - non-aspirin/NSAID users

* Just post-diagnosis - aspirin/NSAID users

* Just post-diagnosis - non-aspirin/NSAID users

Out of 4,481 participants:

* 26% (1,1176) of them were non-aspirin/NSAID users

* 47% (2,086) of them were pre- and post-diagnosis aspirin/NSAID users

* 27% (1,219) of them were just post-diagnosis aspirin/NSAID users

Those taking a daily dose of aspirin for nine months or more after diagnosis had a 30% lower risk of cancer-related death compared to non-users. Even taking aspirin regularly for any length of time reduced the risk of death (by 23%).