Use Of Non-COX-2-specific NSAIDs Halves Odds For Oral Cancer: Doubles Cardiovascular Death Risk

However, use of these pain relievers (with the exception ofaspirin) for 6 months or more also doubled users' risks forcardiovascular death, according to collaborative research publishedonline Oct. 7 by The Lancet.

The study was conducted byresearchers at the Norwegian Radium Hospital and The National Hospitalin Oslo; University of Science and Technology, Trondheim, Norway;NewYork-Presbyterian Hospital/Weill Cornell Medical Center in New YorkCity; The University of Texas M. D. Anderson Cancer Center in Houston;and the University of Helsinki.

"Our findings highlight how acommonly used drug can have a benefit from the standpoint of cancerprevention but can also have side effects - in this case, an increasedrisk for cardiovascular death," said co-researcher Dr. AndrewDannenberg, the Henry R. Erle, M.D., Professor of Medicine at WeillMedical College of Cornell University and Director of Cancer Preventionat NewYork-Presbyterian/Weill Cornell.

The findings "also supportmoves by the U.S. Food and Drug Administration, which recently mandatedspecial 'black box' warning labels on all NSAID pain relievers exceptaspirin, warning consumers of potential cardiovascular side effectslinked to long-term use," added lead researcher Dr. Jon Sudbø, a seniorconsultant in the Department of Medical Oncology and Radiotherapy atNorwegian Radium Hospital.

The new FDA-mandated labeling appliesto both the over-the-counter and prescription versions of these drugs.The agency's decision followed earlier moves in 2004 and 2005, when twoCOX-2 enzyme-specific NSAIDs were withdrawn from the market - firstVioxx was voluntarily recalled by Merck in September 2004, and then theFDA ordered the recall of Bextra earlier this spring.

The findings were presented earlier this year at the annual meeting of the American Association for Cancer Research.

Theresearch team took a retrospective look at data collected prospectivelyfrom 1975 to 1995 on more than 123,000 adults participating in theNorwegian Health Survey. The survey tracks participant lifestyles,habits, and long-term health outcomes, and is one of the richest suchdatabases in the world.

Dr. Sudbø and colleagues narrowed theirfocus to 454 people with oral cancer and 454 others without suchmalignancies matched for age and sex. All of the individuals had ahistory of heavy smoking.

"Specifically, we were looking forassociations between the long-term use of traditional,non-COX-2-specific NSAIDs and the risk of oral cancer, since previouswork has suggested that these drugs can lower risks for othermalignancies, such as colon cancer," explained co-researcher Dr. ScottM. Lippman, Ellen F. Knisely Distinguished Chair and Chairman of theDepartment of Clinical Cancer Prevention at M. D. Anderson CancerCenter.

In fact, the researchers did find a correlation: Adultswho were prescribed NSAIDs such as aspirin, ibuprofen, naproxen,indomethacin, piroxicam, and ketoprofen for 6 months or more (most ofthem for much longer periods, with 88 percent taking NSAIDs for 5 yearsor more) were at a 53 percent lowered risk for oral malignanciescompared with those who did not take the drugs over the long-term.

"Butthere was a puzzling finding," Dr. Sudbø said. "Even though the drugsappeared to protect users from oral cancer, we saw no added benefitoverall in terms of prolongation of life or reduced mortality. Sosomething was potentially tipping the balance the other way."

Diggingdeeper, they identified that "something" as cardiovascular disease:According to the study, long-term use of traditional NSAIDs, except forcardiovascular-dose aspirin, doubled users' risk for cardiovasculardeath.

This type of elevated heart risk had already been notedwith a subclass of NSAIDs called COX-2 inhibitors, drugs like thenow-recalled Vioxx and Bextra and a third (still available) painkiller,Celebrex, which target a specific enzyme linked to inflammation.

"Butour data support the recent FDA move to put a warning label on theentire class of NSAID medications, except for aspirin - labeling thatalerts consumers that long-term use of these drugs might raise theircardiovascular risk," Dr. Lippman said.

The investigatorsstressed that the study does have its limitations. First, the NSAIDsused in the study were available to Norwegians via prescription only,and it's not clear whether dosages used by the survey participants weresimilar in strength to popular American over-the-counter products likeAleve (naproxen), Motrin (ibuprofen), or Advil (ibuprofen).

Inaddition, Dr. Dannenberg and co-author Dr. J. Jack Lee, Professor ofBiostatistics at the M. D. Anderson Cancer Center, stressed thatalthough the data themselves were collected prospectively, the studyremains a relatively small, retrospective effort. "It's tough to makesweeping generalizations until the results are confirmed by muchlarger, prospective trials," they said.

So, might long-term useof traditional NSAIDs still be right for some people - According to thestudy investigators, a careful risk-benefit assessment is required, andthat's a question best left to a patient and his or her doctor.

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Thestudy was funded by grants from the U.S. National Cancer Institute, theCenter for Cancer Prevention Research, the Norwegian Cancer Society,the Research Foundation of the Norwegian Radium Hospital, Astrid andBirger Torsteds Legat, and the Research Council of Norway.

Co-researchersinclude Dr. Jan Folkvard Evensen, Wanja Kildal, MSc, Prof. AlbrechtReith, and Dr. Nina Flatner, of Norwegian Radium Hospital, Oslo; SimoneSagen, MPH, of The Research Foundation of the Norwegian RadiumHospital, Oslo; Dr. Jon Mork, of The National Hospital and TheNorwegian Cancer Registry, Oslo; Dr. Li Mao and X. Zhou, MSc, of theUniversity of Texas M. D. Anderson Cancer Center, Houston; Prof. A.Sudbø, of the University of Science and Technology, Trondheim, Norway;and Dr. A. Ristmäki, of the University of Helsinki.