Diminished Hope For A Cancer Drug

Posted: December 14, 1986

It was hailed throughout the land as a "cancer breakthrough," a promise scientists are generally loath to make.

A treatment combining the hormone interleukin-2 (IL-2), plus a patient's own "killer" cells, had caused malignant tumors to shrink - and in a few cases to disappear - in 44 percent of patients with certain advanced cancers that had proved unresponsive to other treatment.

Now, one year later, the early promise of that dazzling performance has dimmed.

In trials around the country, the response rates have dropped to an uninspiring 10 to 20 percent. Four people have died from the treatment. Others have suffered severe side effects, including fever, nausea, anemia and fluid retention. And an outbreak of hepatitis has halted the trials at the six centers approved by the National Cancer Institute (NCI) to conduct them.

Earlier this month, Dr. Steven A. Rosenberg, head of the interleukin research team at the NCI, told a group of immunologists that IL-2 "still has major problems with it" and that it had proved "very toxic . . . very cumbersome and very expensive."

Rosenberg is not the only one with reservations. An editorial in Friday's Journal of the American Medical Association, written by a researcher at the Mayo Clinic, declared: "This specific treatment approach would not seem to merit further application in the compassionate management of patients with cancer."

Meanwhile, some medical ethicists are denouncing the early media reports that hyped the promise of IL-2.

Despite these setbacks, some scientists are still optimistic.

"The bottom line, I think, is that there's something there," said Dr. John Glick, director of the University of Pennsylvania Cancer Center. "It is not a miracle, nor did the NCI investigators ever say it was a miracle."

The news about IL-2 first appeared on Dec. 5, 1985, in the New England Journal of Medicine, where Rosenberg first reported his findings: that he had used the genetically engineered hormone interleukin-2 alone and in combination with lymphokine activated killer cells (LAK), white blood cells taken from a patient's body. The treatments had caused tumors to regress in 11 of 25 patients with the most intractable, advanced cancers of the lung, colon, and kidney, and with melanoma, a skin malignancy.

Because these cancers are usually unresponsive to drugs, the 44 percent response rate was especially eye-catching. Some tumors shrank, some disappeared altogether, but the patients were not cured.

Rosenberg, appearing on NBC-TV's Today show, hailed the drug as "the first new kind of approach to cancer in perhaps 20 or 30 years."

The treatment involves removing a patient's white blood cells and treating them with IL-2 to convert them into killer cells. The cells are then injected back into the patient's blood along with more IL-2 to attack the tumor.

Although Rosenberg has declined to be interviewed about his research until further data are published, in a speech to the NCI's Division of Cancer Treatment, Board of Scientific Counselors, he disclosed some updated information about interleukin-2 used with and without LAK.

The results were published Oct. 24 in a private newsletter, the Cancer Letter:

* Of 30 patients with advanced kidney cancer, one patient had a complete response - that is, the cancer disappeared, but will probably recur. Three patients showed a partial response - the tumors shrank but did not disappear. That amounts to a 13 percent response rate, which was considerably lower than the results announced in December 1985, when 9 of 10 patients - 90 percent - responded.

* Of 29 patients with advanced melanoma, a type of skin cancer, five patients - or 17 percent - had some tumor shrinkage.

* In 17 patients with colon cancer, there were two partial responses, or 12 percent.

Overall, among 78 patients treated in the six treatment centers approved by the NCI to administer Rosenberg's regimen, there was a response rate of 15.6 percent.

The NCI itself had treated 104 patients as of October at its headquarters in Bethesda, Md. - achieving a 22 percent overall response rate.

Earlier this month, Rosenberg reported that one death had occurred among 106 patients who received LAK cells plus interleukin-2 and that three deaths occurred among 45 patients who received high-dose interleukin-2 alone.

"That represents about a 3 percent treatment-related mortality among our patients," he said.

For patients with most advanced cancers, these response rates do not translate into a cure, Glick said. (Some cancers, such as Hodgkin's disease - cancer of the lymph system - testicular cancer, and childhood leukemias, are curable even in their most advanced stages.)

But, he said, treatment can mean an improvement in the quality of life. It may reduce pain and shortness of breath and enable patients to function better. It may even increase their survival by months or even years, he said.

However, in the Journal of the American Medical Association published Friday, Dr. Charles G. Moertel of the Mayo Clinic in Rochester, Minn., wrote that the "treatment with IL-2 is an awesome experience. It requires weeks of hospitalization, much of which must be spent in intensive-care units if the patient is to survive the devastating toxic reactions. . . . The price in

dollars for treatment and management of toxicity may reach six figures."

And, Moertel wrote, the "unacceptably severe toxicity and astronomical costs . . . are not balanced by any persuasive evidence of true net therapeutic gain."

To be sure, said Dr. Robert E. Wittes, the NCI's associate director for cancer-therapy evaluation, the effects of IL-2 "are lower than we'd like to see. And the fact that the program has substantial toxicities means we have to do two things: make it more effective and make it more tolerable."

Rosenberg - who became widely known as the medical spokesman for the team that treated President Reagan for colon cancer, a treatment that did not involve interleukin-2 - now is experimenting with lower doses of the drug in an effort to reduce side effects.

Since Labor Day, IL-2 trials have been put on hold and no new patients have been accepted at the six treatment centers because of the hepatitis outbreak. Trials continue at the NCI headquarters, and patients who had been enrolled in the other centers who were responding to the treatment have been offered the option to continue, Wittes said.

Researchers said the hepatitis outbreak could not be traced, but probably came from the serum - a component of blood - from donors that was used to grow the patients' killer cells. It is unclear when the centers will be able to resume testing, Wittes said.

In some cancers, interleukin performs better than other available therapies. In advanced kidney cancer, for example, available treatments yield about 10 percent partial responses, but 13 percent respond with IL-2, Glick said, although patients don't always feel better.

But in other cancers, conventional treatments yield better results. In advanced melanoma, for example, drugs can be given without requiring patients to be hospitalized and "give us a 20 to 25 percent partial response," Glick said.

Some scientists and ethicists believe the hoopla over interleukin-2 illustrates once more that publishing preliminary results of small studies can be misleading to the public.

Arthur Caplan, an ethicist at the Hastings Center, a bioethical think tank at Hastings-on-Hudson, N.Y., said:

"Scientists were saying, 'We have an agent that's had some initial positive results on a very few people, and we need to do research. Period.' The public felt, 'Here's a cure. Why can't I get it?' "

The early reports caused excitement in many cancer victims, but some, like Leonard Borden, were guarded.

Borden, 39, a lawyer in Chicago, was diagnosed last June with advanced kidney cancer. His friends urged him to try interleukin-2, which had been in the news for several months.

"Treatment and cure are linked in our minds," Borden said recently. ''People have a hard time appreciating what experimental treatments involve. I don't want to be anybody's toxicity meter.

"I had to educate my friends, because they were getting very frustrated with me," he said. "My friends were (saying), 'Why doesn't he go in now, and how fast can we get it for him?' . . . It's not a magic bullet."

Caplan places responsibility for the public's premature faith in experimental drugs both on researchers and the news media.

"I think the coverage of interleukin was not always careful and responsible in some media reporting, but others were very careful . . . saying, 'It's a small sample, we have to see what's down the road. The

drug is years away from general availability,' " Caplan said.

"I think the NIH faces political pressures: It is being asked every day what they are doing to combat a plague. Sometimes it will hurry forward with announcements to meet that pressure. I'm not saying they're lying, but sometimes they go fast to show people that they're trying," he said.

"The NIH normally wouldn't release an announcement based on 25 patients if we were talking about acne medicine," he said. "But they probably have a faster track for announcements about AIDS and cancer."

Caplan said he thought the NIH had learned from the experience, and cited as an example last September's announcement concerning AZT - the AIDS drug that showed promise by reducing the symptoms of AIDS in some patients.

In the case of AZT, an independent committee analyzed the results, "not the same people who did the research," Caplan said. In contrast, "Rosenberg announced his own results," Caplan noted. "Researchers like to be first and can be biased. To separate those roles is more persuasive."

Said Glick: "Where it's going to end up, I don't know. I'm one of those optimists that believes we are making progress on the war against cancer. And I believe that basic tumor immunology will lead in time - the key phrase - to advances in the clinic.

"These will come slowly, not overnight and from well-designed, methodically conducted trials involving large numbers of patients," he said.

At the NCI, Wittes chose his comments about interleukin-2 carefully: ''We've concluded tentatively at this point that the technique and concept is very worth pursuing. . . . This is the first time this therapeutic approach has been taken in people. To see responses is encouraging."

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