Studies on Painkillers In Jeopardy

[Guest guest]

Some researchers feel that what they are calling the Vioxx/Celebrex/Aleve

" hysteria " is overblown and is preventing researchers from investigating

promising cancer uses for these drugs............

By Rob Stein

The spate of bad news about painkillers has dealt a major setback to what

had been a highly promising effort to use the drugs to prevent a host of

leading killers, including many types of cancer, Alzheimer's and other forms

of dementia.

Since concerns emerged that drugs such as Vioxx and Celebrex might cause

heart attacks and strokes, researchers testing the drugs in dozens of

studies have been frantically scouring whatever data they have gathered so

far for signs of danger, urgently debating whether the trials should

continue, and quickly informing participants of possible risks.

Several large studies have shut down fully or partially, including trials

for preventing colon cancer, prostate cancer, Alzheimer's and, just last

week, two large international studies evaluating Celebrex to cut the risk of

getting breast cancer or suffering a recurrence. Other studies have been

temporarily suspended until all participants could be warned of the possible

danger.

Overall, the startling new concerns about the drugs' safety have cast a

pall over what had been one of the most exciting fields of biomedical

research, which was trying to harness important new insights into the

underlying cause of a wide spectrum of illnesses.

" It's definitely been a big setback, " said N. DuBois of Vanderbilt

University School of Medicine in Nashville. " It's really disappointing

because there had been a lot of enthusiasm in this area, and a lot of trials

were underway. I think this is going to slow things down considerably. It's

really unfortunate. "

The developments are particularly distressing because a large body of

evidence indicates the drugs could provide significant benefits aside from

relieving pain. Even the studies that revealed the possible heart disease

and stroke risks produced evidence that the approach could be highly

effective for reducing the risk for cancer.

" We have produced evidence for the proof-of-principle that agents like

these could be effective for preventing cancer, " said Bresalier of

the University of Texas M.D. Cancer Center in Houston, who led the

study that raised the first alarm. " There's a great deal of data suggesting

that these drugs might be beneficial in terms of preventing or treating a

large number of cancers. It would be a major mistake not to go forward with

this line of research. "

Several researchers said they believed the response to revelations of what

are potential risks was an overreaction. It may turn out that Celebrex and

similar drugs pose less of a danger than initially suspected, or that the

drugs could prove useful at lower doses or for certain patients, they said.

" I think we have created a situation of mass hysteria that's completely

unwarranted, " said Carol Fabian, director of breast cancer prevention at the

University of Kansas Medical Center in Kansas City, who decided to continue

two breast cancer studies after warning participants of the possible risk.

" I don't think we have all the data yet, and we may be prematurely drawing

conclusions. "

The drugs were developed to relieve pain with fewer side effects than

existing painkillers, but researchers began testing them to treat or prevent

a variety of diseases because of their ability to reduce inflammation, limit

cell growth, inhibit the growth of blood vessels that nourish tumors and, in

the case of breast cancer, lower estrogen levels.

A cascade of panic began in September when Merck & Co. pulled its

blockbuster arthritis drug Vioxx from the market because Bresalier's study

indicated the drug doubled the risk for heart attacks and strokes. Bresalier

was testing whether Vioxx reduced the risk for colon polyps, which can lead

to cancer. Merck then shut down another colorectal cancer-prevention trial,

as well as one for prostate cancer prevention.

That prompted the National Institutes of Health to begin scrutinizing other

trials using similar drugs, especially Pfizer Inc.'s popular Celebrex. On

Dec. 17, the NIH announced that another cancer prevention trial had found

evidence of a similarly increased risk for heart problems for Celebrex, and

shut down that trial.

Although another study contradicted that finding, the announcement caused

patients in many studies testing Celebrex to stop taking their drugs,

including those in a large Alzheimer's prevention trial. That trial also

raised concern about the over-the-counter pain reliever naproxen, sold as

Aleve.

Breitner of the University of Washington in Seattle, who led the

Alzheimer's trial, said the hint of risk for naproxen was far from clear

from his data, and the main reason his trial shut down was because so many

participants were worried about Celebrex.

" The reasons we had to suspend the treatments had less to with the

perception of danger . . . than with other purely practical considerations, "

Breitner said. " It's all very unfortunate. "

Other Alzheimer's researchers expressed similar disappointment, saying they

feared the developments would unnecessarily derail a promising line of

research.

" We should not give up on this, " said Van Eldik of the Northwestern

University Feinberg School of Medicine in Chicago. " Inflammation is a key

player in the damage in Alzheimer's. I would hate to have something like

these initial results make people stop this whole area of research, because

I think it's really important. "

Similarly, researchers leading the two large breast cancer trials decided

to discontinue parts involving Celebrex in part because of the health

concerns, but primarily because they felt the rising alarm made it

impractical to continue.

" We were concerned that, because of the widespread media attention around

this class of agents, the reaction of ethics review committees around the

country, and the volume of telephone contacts we were having from study

participants, that the entire machinery of our clinical research program

would unravel if we tried to persist, " said Goss of the Massachusetts

General Hospital in Boston, who is leading the studies.

The researchers are proceeding with the primary part of both studies, which

will test another type of drug known as an aromatase inhibitor in thousands

of patients in the United States, Canada and Spain.

" We felt we were being caught up in the eye of the storm, and it would be

even more harmful to us if this decision had to be made further down the

road, " Goss said. " I'm very disappointed. In my heart, I don't believe that

blanket withdrawal of this scientific endeavor is the most productive

decision to be made. "

Goss and others said that even if it turns out Celebrex and similar drugs

do increase the risk of heart attacks and strokes, many patients may be

willing to take that risk to cut their chances of getting cancer, especially

if it runs in their families.

" For women with a very high risk of breast cancer, if there is an

opportunity for them to benefit, it may strongly outweigh a cardiovascular

risk, " Goss said.

Other researchers agreed, saying what might emerge is a more targeted use

of these drugs only for those at low risk for heart disease and high risk

for other diseases.

" I hope what's going to emerge from this is that we're going to understand

risk and benefits more clearly and quantify them more explicitly, " said

Bernard Levin of the M.D. Cancer Center.

Elias A. Zerhouni, director of the NIH, defended the agency's actions,

saying even a hint of risk warranted discontinuing the Alzheimer's trial

because it involved healthy people. " You have to err on the side of doing no

harm, " he said.

But Zerhouni agreed that once the risk is better understood, it could turn

out that the drugs or others like them could still be useful, either for

selected patients or by taking countermeasures.

" We shouldn't shy away from this class of drugs because of Vioxx. If you

can demonstrate a benefit that is non-zero, then you have to evaluate risk

versus benefit, " Zerhouni said. " The inflammation theory is a very valid and

strong mechanistic approach. "

Several researchers noted that evidence has continued to mount that

cholesterol-lowering statin drugs cut the risk for heart attacks in part

through their anti-inflammatory effects. Some evidence has suggested they,

too, may reduce the risk for cancer.

Part of the problem for drugs such as Vioxx and Celebrex is that companies

are focused on developing drugs that can be marketed to large numbers of

patients, said Carl F. of the Weill Medical College of Cornell

University in Ithaca, N.Y.

" We have to stop demanding that every drug be a blockbuster, " said.

" What we have to go back to is smaller markets for individual drugs. We have

to take good drugs and market them conservatively and increase our knowledge

of the settings where the risk-benefit ratio is best. "

Other researchers said they were pessimistic that drugs such as Celebrex

would ever reemerge as major players for disease prevention, but the

underlying concept remains highly promising. As a result, the focus is

likely to shift to developing drugs without the negative side effects.

" I'm really cautious now. Anything we come up with, we'll have to evaluate

carefully after this, " DuBois said. " There are other ways to attack this

pathway, and there are other agents in early development. I think now they

could be moved up now. We'll have to see what new drugs might pop out from

people looking at this in a different way. "