1. Susman, Ed

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SAN FRANCISCO-Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) appear to be associated with fatal cases of renal cell carcinoma, researchers cautioned here at the 2016 Genitourinary Cancers Symposium (Abstract 588).

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The NSAIDs-often over-the-counter treatments such as ibuprofen, but not aspirin-were linked to poorer outcomes that begin to be seen after four years of use, said Mark Preston, MD, a urologist on staff at Brigham and Women's Hospital and Dana-Farber Cancer Institute, and an instructor in Medicine at Harvard Medical School, Boston.


"Prospective data suggest that non-aspirin NSAID use is associated with an increased incidence of fatal renal cell carcinoma after at least four years of use," he and colleagues reported.


"It is not entirely clear why there would be a difference in outcome between the NSAIDs and aspirin," Preston told OT at his poster presentation. "One theory is that there may be some kind of interplay between prostaglandins, which causes chronic kidney injury, changes in DNA, and increased carcinogenesis."


The researchers also scrutinized the use of acetaminophen (Tylenol and other products) and "found that acetaminophen looks very much like aspirin," Preston said. The pooled multivariate relative risks for total renal cell cancer were 1.13 (95% CI: 0.91-1.39) for aspirin use; 1.34 (95% CI: 1.03-1.75) for non-aspirin NSAID use; and 1.07 (95% CI: 0.80-1.44) for acetaminophen use. Only the non-aspirin NSAID use was statistically significant.


"We think that the NSAIDs cause some kind of impact to the kidney itself," he said, noting that in other cancers there did not seem to be a difference between NSAIDs and aspirin.


Study Statistics

In the pooled multivariate analysis, the risk of fatal renal cell carcinoma among people who take aspirin regularly does not appear to budge over the course of 10 years or more. But that is not the case with the NSAIDs, Preston said.


There is no increase in fatal renal cell carcinoma at the four-year mark, but in the four to 10-year period, the risk rises significantly (relative risk 1.91 [95% CI: 1.04-3.49]). And among persons taking NSAIDs for more than 10 years, the risk is even greater (RR 3.97 [95% CI: 1.46-10.93]). Regular use of the analgesics was defined as taking the pills two or more times a week.


Preston and his colleagues examined the outcomes data in two large prospective cohorts: The Nurses' Health Study (1990) and the Health Professionals Follow-up Study (1986). Information was collected from the participants every two years.


During the 22 years of follow-up among 77,527 women and 26 years of follow-up among 45,913 men, the researchers documented 438 cases of renal cell carcinoma-230 in women and 208 in men. Of those cases, 56 that occurred among women and 40 that occurred among men were fatal, the researchers reported.


Gender Differences

When the researchers looked at outcomes among men and women separately, they observed that the increase in fatal renal cell carcinoma cases was driven by incidence of the disease among women. Women taking NSAIDs for four to 10 years were twice as likely to develop kidney cancer as women who took the analgesics for less than four years. And if women were taking the analgesics for longer than 10 years, their risk of kidney cancer jumped to nearly five times that of women taking NSAIDs for less than four years.


Among men, the risks were higher the longer they took the NSAIDs, but that increase did not achieve statistical significance at the four to 10-year period or at the greater than 10-year period.


"I don't think our study firmly establishes this relationship as being causal," Preston said. "It is certainly intriguing; there is a clear association, there is a dose response. There is something there that is not seen with aspirin or acetaminophen.


"We need further study of the biology to determine what is happening within the kidney that is sparking that difference," he added. "We have tissue samples of about 300 of these patients, so we are planning to do further analysis."

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Preston admitted, however, that he will sometimes switch from an NSAID to another analgesic because of the findings of his study.


'Compelling' Results

Xinhua Zhu, MD, Attending Physician in Genitourinary Medical Oncology at Northwell Health Cancer Center in Lake Success, New York, told OT that he found the results compelling. "This evidence could be practice changing, not only for oncologists, but for primary care physicians as well.


"In particular, the patients who have been exposed to non-aspirin NSAIDs for over 10 years should be counseled to discontinue this type of analgesics given the strong association between the use and the risk of developing renal cell cancer," he said.


"What is the underlying carcinogenesis?" he asked. "Given the wide use of this type of analgesic for mild and moderate pain control, we should focus on characterizing the mechanism of long-term non-aspirin analgesic use, through its metabolites as carcinogens or as inflammation inducers, to reduce or prevent the risk of developing renal cell carcinoma."


Preston said that when the researchers checked outcomes in patients diagnosed with clear cell kidney cancer, seen in 330 cases, the results with similar to the findings for the entire group.