Immune Response Key to Spontaneous Renal Cancer Regressions?

WASHINGTON—“The possibility of spontaneous regression suggests that immunotherapy is a valid route to pursue in kidney cancer research,” said Ronald M. Bukowski, MD, director of the experimental therapeutics program at the Cleveland Clinic Cancer Center.

Spontaneous regression is not common, but research suggests it may be related to immune response, he said at the 1999 Kidney Cancer Association Convention. Thus, immunotherapeutic measures to improve immune response may prove to have value against the disease.

Such regressions tend to occur in lung metastases of kidney tumors in patients who have had the primary tumor removed as well as in patients who are not being treated. In 5% of these individuals, the tumors shrink by themselves.

In a randomized, double-blind Canadian study in which kidney cancer patients received gamma interferon or placebo, 6% of the placebo group had regression of metastases, Dr. Bukowski said. “I interpret this as an observation of spontaneous regression,” he said.

In melanoma, he said, it has been shown that spontaneous regression is associated with an immune response, “and in renal cancer, we believe it to be the case, although we have not been able to prove it to date,” he commented.

Although T lymphocytes recognize and kill renal cancer cells, they are present and active in only 20% to 25% of renal cancer patients. “Why aren’t they there in the other 75%?” he asked. “It may be our inability to demonstrate their presence in the lab, or they may not have developed, or there may be a negative influence on their development.”

Administration of cytokines to kidney cancer patients has, in some cases, resulted in significant regression, which provides fuel for the argument that they are involved in provoking the appropriate immune response.

The cytokines tested in kidney cancer are interleukins 1 through 4, plus 6 and 12; the interferons; and the colony-stimulating factors GM-CSF, M-CSF, and erythropoietin. Of these, IL-2 and interferon have stood out, he said.

“When they work, these agents may work by modulating immune response, but they also may exert a direct antitumor effect, correct an immune defect that may occur in cancer patients, affect blood vessels, or all of these. They may also play different roles in different cases,” he said.

Many investigators continue to study various forms of interferon. “One in Great Britain compared interferon to the hormone methoxyprogesterone acetate (MPA), which is used for supportive care, and thus allowed a comparison of the cytokine to what amounted to no treatment,” Dr. Bukowski said.

Improved Survival

In the treated group, median survival was 8.5 months vs 6 months in the MPA group. One-year survival was 43% vs 31%. Although the research suggests that interferon may be useful, its potential benefits have to be weighed against its side effects, which varied from individual to individual. “These are the only data I’m aware of in which treatment for advanced metastatic kidney cancer showed any improvement in survival,” he said.

Dr. Bukowski suggested that the mixed performance of cytokines in cancer treatment probably means that the immune system interactions and other factors in the disease are stronger than the agents’ activity. Nevertheless, he said, “patients who do respond do so dramatically.”

He added that there is little evidence the responses are related to a mind-body or placebo effect. “The placebo effect may be active in pain control and measures of functionality, but not in measures of tumor regression,” Dr. Bukowski said.