My Most Difficult Choice

By Bill Saporito

Heart attack, stroke or cancer. Take your pick. That was the choice I was being offered, or so it seemed. I'm one of hundreds of patients who were participating in clinical trials to investigate whether COX-2 inhibitors such as Celebrex and Vioxx, commonly used as anti-inflammatory drugs, are also effective in fighting or preventing cancer. But the trials were halted last year after reports that the risk of heart attack or stroke doubled among a group of Vioxx users. Vioxx was summarily yanked from the market and the tort lawyers immediately canceled lunch. Celebrex was also implicated because it's in the same drug class. It's still available, but the FDA has called for a black-box warning about the added danger.

The Vioxx news was disappointing and upsetting, because it sidetracked what scientists believed--and I had come to hope-- was a promising avenue of research. That promise was underscored by several papers presented at the annual meeting of the American Society of Clinical Oncology (ASCO) last week, including one out of UCLA Medical School that showed that Celebrex, used in combination with newer cancer drugs, was successful in treating patients with late-stage lung cancer. In 9 out of 15 patients whose prior treatments had failed, the Celebrex cocktail either stopped the disease from progressing or shrank their tumors. In cancer circles, that is an impressive result.

Although most of the COX-2 cancer trials eventually resumed, some of the original subjects dropped out, and you can't blame them. There's something screwy about the way the whole COX-2 debacle unfolded. Drugs linked to a relatively small risk of heart attack got pulled off the shelves without apparent concern for the cancer patients whose lives the same drugs might save.

Ironically, the trial that exposed the heart risks of COX-2 inhibitors was a cancer experiment, designed to test whether Vioxx or Celebrex could prevent the recurrence of colon cancer. It was halted before any conclusion could be reached. The situation was even more frustrating for patients in a second trial. There, scientists did indeed find a lower recurrence of colon tumors in patients taking Vioxx. "There was a reduction in adenoma recurrence," notes the study's lead author, Dr. Robert Bresalier of MD Anderson Cancer Center. "How that balances with the potential risk remains to be seen."

How indeed. The news from last week's ASCO meeting reassured me that I made the right decision when I rejoined the Celebrex study. Joining the trial in the first place seemed utterly logical--I had cancer of the esophagus, and I was going to go after every advantage I could. My surgeon, Dr. Nasser Altorki, chief of thoracic surgery at Weill Cornell Medical Center in New York City, is both a top esophageal specialist and a researcher. He has been investigating--along with my oncologist, Dr. Roger Keresztes, also at Weill--whether COX-2 inhibitors have a role in making treatment more effective and in keeping the disease at bay. Celebrex would be taken during the chemotherapy phase of treatment--in my case, Taxol and Carboplatin. After chemo, I was to take 800 mg of Celebrex (that's two to four times the normal dose) for two years. Oh, yes, there would be nine hours of surgery to remove the offending esophagus. With this cancer, you get the full sushi.

Scientists initially became interested in the COX-2 enzyme because it's found in so many cancer cells. When active, COX-2 produces a chemical called a prostaglandin that helps keep the stomach lining healthy. It also helps the kidney and blood platelets function properly. In tumors, however, prostaglandin becomes a bad actor, an evil conspirator that helps build the new blood supplies that tumors need to grow. COX-2 also makes cancer cells more resistant to the body's immune response and more resistant to drugs. What would happen, scientists wondered, if you suppressed the COX-2 enzyme with an inhibitor such as Celebrex? "It makes sense that if you shut off the prostaglandin by turning off the COX-2, then the other things wouldn't happen," says Altorki. "The science is so strong, so persuasive."

And still unproven beyond the lab. Altorki and Keresztes had to halt my study when the Vioxx news broke. When they decided to resume, patients like me had to decide whether to continue and risk heart attack or stroke down the road. The doctors no longer require new subjects to enroll for a full two years, to track long-term survival--the heart danger seemed to kick in after about 18 months--but they are offering it as an option. Anyone who re-upped had to sign a revised waiver specifically advising them of the possible increased risk. On paper that risk wasn't much. In one study, and one study only, 2 out of 100 Vioxx users had cardiovascular incidents. The placebo group had 1 in 100. So the risk doubled. That's the headline (it's certainly the one I'd write). But if you read beyond the headline, the underlying risk is pretty low. It's important to note that there's no actual proof that Vioxx alone increases heart risk.

Here's what led me back to the trial: first, I didn't want to lose the potential benefit. Second, I'm middle aged and in pretty good shape, and thus younger and fitter than most people with my flavor of cancer. I figured the slightly elevated heart risk was, for me, a more manageable proposition. That's pure rationalization, of course. The bonus round: for an aging gym rat, Celebrex is a wonder at relieving the aches and pains that come from too much exercise.

There's another, more important part of the equation. The worst side effect of cancer that I can think of is being dead. The cure rate for all lung cancer patients is 14%; it's even lower for esophageal cancer. Hell, the treatment alone can kill you, given the toxicity of cancer drugs. "You tell me, what risk are these people willing to take?" asks Altorki. Only so much, it seems; about half of the surviving subjects in my study opted out.

COX-2's prospects as a cancer fighter continue to intrigue scientists. "Clinically, we are still at the beginning," says Dr. Steven Dubinett, director of the thoracic oncology program at UCLA Medical School. "It would really be a travesty if we were unable to continue." Dubinett says about 10% of his studies' participants dropped out. He is investigating whether Celebrex can prevent cancer, but he faces a real dilemma: How can he give to otherwise healthy people a drug that might not work and might increase their risk of heart attack? "It's going to make it very difficult to do long-term-treatment projects," says Keresztes. Dubinett's approach is to recruit ex-smokers, people who have already substantially increased their risk of both lung cancer and heart attack. Pick your poison.

Altorki's bigger fear is that the Vioxx scare will deter researchers from doing enough work on COX-2 to understand its true role in cancer. "If we do these studies and they show no evidence of efficacy, then I'm wrong. I'll get off that train and get on another," he says. "But it's important that we find out."

I'm hoping we find out that he's right. --With reporting by Alice Park/New York

With reporting by Alice Park/New York