Here's another one. COX-2 inhibitor drugs, particularly rofecoxib (Vioxx), have gone through a public flogging because of reported elevated incidences of cardiovascular events (heart attacks and strokes) in patients taking them for arthritis.



Most of these events have occurred as a result of thrombotic (clotting) episodes that lead to heart attack and stroke. The proposed mechanism is that blocking the COX-2 pathway appears to make the blood more viscous (thicker) because platelets (the cells that initiate clots) appear to become stickier and clump together.

A recent article details results from a trial of rofecoxib in patients with colon cancer showing that the COX-2 inhibitor--which was withdrawn from the market worldwide in September 2004--was associated with a twofold increased risk of adverse cardiovascular events, the same risk that has been seen in patients without cancer (Kerr DJ, Dunn JA, Langman ML, et al. Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer. New Engl J Med 2007; 357: 360-369).

However, it is too soon to know whether this increased risk of cardiovascular events is worth taking in patients with cancer, who are at a much higher risk of a recurrence of their cancer than they are of cardiovascular events. It is not yet known whether rofecoxib reduced the risk of cancer recurrence in this trial.

Although rofecoxib is no longer available, this issue is of great importance because there are a number of trials still ongoing in different cancers with COX-2 inhibitors that have remained on the market, such as celecoxib (Celebrex). Two such trials showed that celecoxib did have promise in reducing colorectal adenomas- also known as colon polyps, but the cardiovascular risks are still somewhat high, and the benefit was not thought to outweigh the risks.

COX-2 inhibitors were originally developed for patients with arthritis, but studies of them in various forms of cancer began after it was observed that patients taking non-steroidal anti-inflammatory drugs (NSAIDs) had a reduced incidence of cancer. Laboratory data suggested that the anticancer effects of these drugs were due to inhibition of an enzyme called cyclooxygenase-2 (COX-2), and a number of trials were begun with different COX-2 inhibitors in a variety of cancers.

The study reported in the New England Journal of Medicine was called Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime (VICTOR). It was conducted in patients who had undergone potentially curative surgery for colorectal cancer. Patients were randomized to receive either rofecoxib 25 mg daily or placebo, and the aim was to see whether rofecoxib would reduce the rates of recurrence of colorectal cancer. However, the trial had to be stopped prematurely, after a median duration of only 7.4 months of treatment, due to the withdrawal of rofecoxib from the market by the FDA. This short treatment duration limited complete interpretation of the study.

Nevertheless, they compared the rates of cardiovascular events and death during the period of study treatment in VICTOR and for two years after the trial closed. Of the 23 confirmed cardiovascular events, 16 occurred in the rofecoxib group during or within 14 days after the treatment period, with an estimated relative risk of 2.66 for rofecoxib vs placebo.

The scientists also evaluated cardiovascular events in the two years following the trial closure, during which a further 14 cardiovascular events were noted--six in the rofecoxib group and eight in the placebo group.

Four patients in the rofecoxib group and two in the placebo group died from cardiovascular causes during or within 14 days after the treatment period, and during the follow-up period, one patient in the rofecoxib group and five patients in the placebo group died from cardiovascular causes.

"This study confirms that the twofold increase in risk of adverse cardiovascular events reported in Vioxx clinical trials in patients without cancer applies in those with colorectal cancer," says Dr David Kerr, the lead author.

Kerr goes on to say, "Our results have implications when selecting patients for treatment with COX-2 inhibitors, but it has to be remembered that improved treatment for colorectal cancer is badly needed. By far the commonest cause of death to be expected in these patients in the decade following cancer treatment is from recurrence of their cancers, not from cardiovascular disease."

All researchers in this field still feel that it is too early to comment on the benefit of COX-2 inhibitors in preventing recurrences from colorectal cancer. Nonetheless, the preliminary evidence is encouraging.

So here's the dilemma. If you have the choice, which will you pick?