The End of the Beginning?

By Dick Thompson/Washington

To avoid raising false hopes among cancer victims, researchers tend to use caution in reporting even the most promising advances in treatment for the dread disease. Yet two articles published in last week's New England Journal of Medicine, while containing caveats, seemed reason for guarded optimism. Both dealt with a controversial treatment known as adoptive immunotherapy, which involves the use of a naturally produced substance, interleukin-2 (IL- 2), to bolster a patient's immune system. Both reported striking improvements in some patients with advanced cases of cancer.

Dr. Steven Rosenberg of the National Cancer Institute, a principal author of one of the papers, stressed that the technique "is an experimental treatment in the infancy of its development." Still, he said, "it is a first step in a new direction of cancer therapy. It can work. The challenge is to improve it." In an accompanying editorial, Dr. John Durant of Philadelphia's Fox Chase Cancer Center wrote, "Perhaps we are at the end of the beginning of the search for successful immunotherapy for cancer."

Rosenberg is most widely known as the spokesman for the team of doctors that performed colon surgery on Ronald Reagan in 1985. At a nationally televised press conference he began his remarks with the chilling statement "The President has cancer." But Rosenberg also created news 16 months ago, when he and his NCI team published their initial reports about IL-2 therapy on humans, which the press generally heralded as a cancer "breakthrough."

Although Rosenberg says he never used the word, he was criticized for prematurely implying it. Dr. Charles Moertel of the Mayo Clinic argued that the technique was prohibitively expensive and that the side effects (including fever, fluid buildup and irregularities in kidney and cardiovascular function) were "unacceptably severe," and suggested that the press had overplayed the potential benefits.

But the new results, on a larger test group, confirmed the earlier findings. Rosenberg and his colleagues used the technique on 157 cancer patients with melanoma, non-Hodgkin's lymphoma, and colorectal, kidney and other cancers that were initially considered untreatable. What is more, the affected tumors were metastatic -- that is, they had spread to other sites in the body. Of the 157 patients, 20 had at least a 50% reduction in tumor size, while complete remissions were produced in nine. (Four patients died from side effects of therapy.) The second paper, by Dr. William West and a team of physicians and scientists affiliated with Biotherapeutics Inc. of Franklin, Tenn., showed similar results (though no complete remissions) with IL-2.

Rosenberg's treatment consisted of three parts, spread over approximately 16 days. First, the cancer patients were injected with large doses of IL-2 manufactured by genetic engineering techniques. These doses supplement the immune-system stimulation provided by the minute amounts of IL-2 produced naturally in the body. Next, blood was withdrawn, and specialized white cells -- principal agents of the immune system -- were separated from other blood components. These cells were bathed in IL-2, which causes them to reproduce faster. The cells were then reinjected into the patient's bloodstream. These IL-2-stimulated cells, known as LAK (for lymphokine-activate d killer) cells, are attracted to cancer cells, which they promptly destroy. (Among the third of Rosenberg's patients who received IL-2 but no LAK cells, there were positive results but only one complete remission.)

Because of IL-2's toxic side effects, some of Rosenberg's patients were required to stay in intensive-care units. But other researchers have shown that by carefully controlling the dosage of IL-2, they can reduce the side effects, eliminating the need for intensive care, which is one reason the treatment is now so expensive (estimates range from $30,000 to more than $100,000 a patient). "Intensive care will go by the wayside very quickly," predicts Harvard Medical School's Richard Kradin, who is also working on IL-2 therapy.

The FDA is weighing an NCI request to allow everyone with metastatic kidney cancer and melanoma to be given the option of IL-2 therapy. Still, there are lingering questions about the durability of the results and whether the treatment can be effective in other cancers. But the new studies, admits even the skeptical Moertel, put "the scientific question into much better perspective. It's interesting early finding has demonstrated the does have some against cancer."