A widely publicized trial of a novel immune system treatment for advanced cancer patients has been disrupted and set back by many months because of an unusual epidemic of hepatitis A among some of the early participants in the nationwide experiment.
The source of the nonfatal outbreak appears to be infected blood that contaminated the nutrients used to stimulate the patients' own white blood cells to fight their tumors, according to Dr. Robert Wittes of the National Cancer Institute (NCI).
After the freak epidemic was discovered, officials interrupted the study and launched an investigation before allowing treatment to resume for the patients. The probe is still going on and no new patients are being enrolled in the experimental trials.
But neither the delay nor the outbreak is expected to affect the scientific validity of the "interleukin-2/killer cell" trials. All of the infected patients recovered.
The disruption comes amid reports that the highly touted immunotherapy is not living up to initial expectations and is sometimes causing serious side effects, including heart attacks, severe fluid accumulation in the lungs and temporary coma. Two patients have died from the treatments, according to Wittes.
The hepatitis outbreak was discovered in August, and NCI officials in September, without making a public announcement, stopped enrolling patients at the six participating medical centers, which include the City of Hope in Duarte and the University of California, San Francisco.
Those trials are expected to resume by mid-December or early January, but no date has been set, Wittes said. Several hundred patients were to have been treated this year, but fewer than 100 had been enrolled at the time of the outbreak.
Potential patients, who have been informed of the suspension, are being offered alternate treatments.
Institute's Trials Continue
Interleukin-2/killer cell trials at the cancer institute itself, involving more than 100 patients, are continuing because the blood that NCI used apparently was not contaminated.
In all, 32 out of about 90 patients in the six-center study received contaminated killer cells and 12 developed hepatitis A infections. But only five of them experienced mild symptoms of liver inflammation, such as nausea, fatigue and jaundice, Wittes said. Two transmitted the infection to their spouses.
The epidemic surprised researchers because the hepatitis A virus is almost exclusively transmitted by fecal contamination of food or water, according to Dr. Isaac B. Weisfuse of the federal Centers for Disease Control, who is investigating the outbreak.
The virus, unlike the equally common hepatitis B virus, is almost never transmitted through contaminated blood, and therefore donated blood is not tested for hepatitis A, he said.
About 25,000 cases of each of these forms of hepatitis are reported in the United States each year.
"This is major nuisance, but not a major stumbling block to the development of the treatment," Wittes said in a telephone interview from Bethesda, Md. "None of us had any ethical qualms about stopping the study until the problem was resolved."
But at least one of the investigators believes that the NCI has overreacted, noting that the transient symptoms of hepatitis A are minor compared to the toxic side effects of the experimental cancer therapy and to the incurable tumors themselves.
"Some of the patients would have been willing to take the chance of getting hepatitis A in order to get the therapy," said Dr. James Mier of the New England Medical Center in Boston. "I would have been willing to take the chance myself."
Another investigator said it was a "reasonable judgment" to stop the trials, given concern about transmitting hepatitis to family members and the possibility that the contaminated blood contained other viruses as well.
"This was not a major disaster; the study could have continued," said the investigator, Dr. Charles A. Coltman Jr. of the Audie Murphy Veterans Administration Hospital in San Antonio. "A physician from Alabama who is a prime candidate for the treatment calls me every two weeks wondering when this is going to start up again."
The treatment, developed by Dr. Steven A. Rosenberg, chief of surgery at the NCI, uses the protein interleukin-2, a natural immune system booster, to transform in the laboratory a patient's own white blood cells into activated tumor-killing cells, called "LAK" cells. Such cells are then reinfused into the patient's bloodstream through a vein, along with massive doses of interleukin-2.
At the NCI, Rosenberg initially treated 25 patients; one patient's tumor disappeared and tumors in 10 other patients shrunk by more than 50%, commonly defined as a partial response. After Rosenberg published these results in the New England Journal of Medicine last December, the cancer institute received thousands of calls from patients who also wanted to be treated.