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Deaths Prompt Changes in Cancer Drug Trial

Unexpected toxicity seen in colorectal patients

THURSDAY, May 17, 2001 (HealthDayNews) -- Some unexpected patient deaths have cast a shadow over a promising new three-drug treatment for colorectal cancer.

A report in The New England Journal of Medicine finds "an excessive rate of early deaths" in two major trials of the treatment. The report, scheduled for official publication on June 21, was released early "because of its potential importance in the treatment of colorectal cancer," the journal says.

Both trials will continue, say the oncologists who head them, but adjustments will be made in the dosage and timing of the drug therapy. For the time being, new patients aren't being accepted.

"We don't see any cause for panic," says Dr. Leonard B. Saltz, associate attending physician at Memorial Sloan-Kettering Cancer Center in New York and director of one trial.

The treatment combines fluorouracil (5FU) and leucovorin, standard drugs for colorectal cancer, with a newer drug, irinotecan, also known as CPT-11. The Food and Drug Administration approved the three-drug combination for advanced colorectal cancer after a report of improved survival in an international trial last September, and it has been widely adopted as a standard of care.

The two newer trials are designed to see whether use of the three-drug combination can be widened. In one of them, the North Central Cancer Treatment Group (coded N9741), the combination is being tested against a different three-drug regimen and a two-drug regimen. In the other, the Cancer and Leukemia B trial (coded C89803), it is being given after surgery to see if it can prevent recurrence of the cancer.

The New England Journal of Medicine research letter says the patient monitoring system of the N9741 trial sounded an alert when 14 patients getting the three-drug combination died in the first 60 days after treatment began. There were also 14 early deaths of patients getting the three-drug combination in the C89803 trial.

The N9741 trial has enrolled its full complement of 1,250 patients. It will go on, says Dr. Michael J. O'Connell, deputy director for clinical affairs at the Mayo Clinic Cancer Center in Rochester, Minn., and director of the trial.

"What we propose to do is to continue the trial and reduce the doses to see what the safety level will be and what the effect will be at reduced doses," O'Connell says.

'Fix it, don't abandon it'

Patients in the trial are being told "it is important to speak to physicians about any side effects and to be monitored carefully," he says.

Enrollment of patients in the C89803 trial has been suspended temporarily, but "reactivation is underway," says Saltz, its director.

Physicians taking part in the trial have been informed about the potential problem, and it was discussed at length last weekend at the annual meeting of the American Society of Clinical Oncology in San Francisco, Saltz says. "The problem is to educate the public without scaring them," he says.

"The message that I hope to take forward is not to abandon this therapy but to improve on it," Saltz says. "This is a treatment that has been found to improve survival. I say fix it, don't abandon it."

One approach toward a fix is careful analysis of the patient deaths, O'Connell says. "Now that we have identified a problem, we will review the data for each and every patient who died in the first 60 days, looking for common factors so we might discover what the predisposing conditions could be."

One important point is that "the system we have for monitoring trials worked extremely well in this case," O'Connell says. "If there was no reporting system, we would not have been aware of the deaths rate in these patients. These toxicities were very promptly discovered through the rapid reporting system."

What To Do

Because they experiment with new drugs and treatments, clinical trials are risky by definition. They can produce lifesaving breakthroughs, but on occasion they can be dangerous, too. Talk to your doctor if you've been diagnosed with colorectal cancer or another disease about the potential rewards and risks of a new therapy.

If you're interested in clinical trials for the disease, visit Veritas Medicine.

The American Cancer Society and the Centers for Disease Control and Prevention have more information about the disease and screening for it..

Read more HealthDay articles about colorectal cancer.

SOURCES: Interviews with Leonard B. Saltz, M.D., associate attending physician, Memorial Sloan-Kettering Cancer Center, New York City; and Michael J. O'Connell, M.D., deputy director for clinical affairs, Mayo Clinic Cancer Center, Rochester, Minn.; June 21, 2001 New England Journal of Medicine
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