Histamine boosts interlukin-2 in melanoma

Combining histamine dihy-drochloride and interlukin-2 significantly improved surgical rates for stage IV malignant melanoma patients with liver metastases in a randomized, multicenter study. The combination strategy is promising because it allows patients to gain the benefit of interlukin-2 (IL-2) at a lower dose without the toxic side effects that are often associated with higher doses of IL-2 alone, such as hypotension, vomiting, diarrhea, and confusion, according to a lead investigator for the study and associate director of the melanoma center at the University of Pittsburgh Cancer Institute. He stated that current treatment for advanced melanoma is very toxic. And they’re looking forward for a way to make IL-2 effective at a lower dose so that people can self-administer this at home instead of having to be in the hospital. If this treatment pans out, it would have widespread application.

For the study, 305 patients with stage IV melanoma were randomized to receive either IL-2 or IL-2 plus histamine dihydrochloride at 56 US medical centers. Among the 129 patients with liver metastases, the combination treatment resulted in a median survival of 283 days, compared with 153 days for patients who received IL-2 alone.

Among all patients in the study, the combination treatment resulted in a median survival of 272 days, compared with 245 for those treated with IL-2 alone. At 24 months of follow-up, 25 percent of patients in the IL-2 plus histamine dihydrochloride treatment groups were alive, compared with 17 percent of patients in the IL-2 alone treatment group.

Adverse events related to the administration of histamine dihydrochloride were described as mild to moderate, and included flushing, palpitations, mild hypotension, headache, injection site reaction, and dyspepsia. Maxim Pharmaceuticals, a San Diego-based company that holds the patent rights associated wih the therapeutic use of histamine dihydrochloride, funded the study. In 2000, Maxim used preliminary results from this trial in an effort to secure Food and Drug Administration approval for subcutaneous histamine dihydrochloride for adjunctive use with IL-2. But the FDA turned down the application, noting that the significant effect cited for patients with liver metastases appeared to be due in part to imbalances in known prognostic factors that favored the combination treatment arm. One doctor agreed that there were imbalances in the patients who had liver metastases at baseline.

Our impression was that a randomization would balance things out. But obviously it did not. In an effort to confirm the findings, these was recently launched a second randomized, multicenter trial that will follow only metanoma patients with liver metastases. The two-year trial will enroll 240 patients. Results are expected about a year after study completion. As for the mechanism of action, one hypothesis suggests that histamine dihydrochloride works best in the liver because it is known to scavenge toxic metabolites of oxygen, which are manufactured by monocytes and macrophages. The oxidative stress is highest in the liver, so one would think that histamine might have the best effect on the liver. But that is not proved. A more likely theory, is that patients with liver metastases have such a poor prognosis for survival that the benefit of any treatment is easier to see in that subgroup.