PITTSBURGHAn immunomod-ulating agent, histamine dihydrochloride
(Maxamine), used in combination with interleukin-2 (IL-2) may improve
survival in certain patients with stage IV malignant melanoma.
In a phase III multicenter study, 305 patients with advanced
melanoma, were randomized to receive the histamine/
IL-2 combination or IL-2 alone. Those receiving the combination
showed a trend toward improved overall survival; increased survival
rates at 12, 18, and 24 months; and improved time-to-disease
progression, compared with IL-2 alone.
Improvement in survival was statistically significant in patients
with metastatic liver disease, a patient population that historically
has had a very poor prognosis.
The study is the first well-controlled, multicenter phase III
trial to show a significant increase in survival among patients with
advanced metastatic melanoma, Sanjiv S. Agarwala, MD, said at a
press briefing. Dr. Agarwala, lead investigator for the study and
associate medical director, Melanoma Center, University of Pittsburgh
Cancer Institute, presented the results at the Perspectives in
Melanoma IV Meeting.
Less Toxicity with Lower Doses
All patients in the study received IL-2 in doses lower than in
regimens previously approved for IL-2. These lower doses resulted in
substantially less toxicity and allowed the patients to take the
treatment at home. The combination of IL-2 and histamine was
well-tolerated, and most patients maintained a good quality of
life, Dr. Agarwala said. Less than 10% had grade 3-4
High-dose IL-2 administered in a hospital, usually in intensive care,
is extremely toxic and very expensive, Dr. Agarwala
noted. We have, therefore, been looking for a way to use this
agent more effectively and to lower its toxicity.
In the study, the first dose of IL-2 was administered in the
outpatient clinical setting to make sure the first dose went
well, Dr. Agarwala said, and then patients were given
instructions, syringes, and drugs to take home. Family members
were taught how to help with the administration, and home care
nursing went to the patients homes to supervise the first three
or four injections.
Once on their own, patients were asked to keep a detailed diary of
events, including the schedule of drug administration and toxicity.
Follow-up included weekly phone calls and outpatient clinic visits at
least once every 2 to 4 weeks.
Patients in both arms followed the same dosing schedule for IL-2,
receiving 4 weeks of therapy, followed by a 2-week break, for a total
cycle duration of 6 weeks. During weeks 1 and 3, patients received 9
million U/m² twice daily on Monday and Tuesday. During weeks 2
and 4, they received 2 million U/m² twice daily on Monday
through Friday. Patients randomized to receive histamine did so on
Monday through Friday on weeks 1 to 4. Patients completed a minimum
of two cycles and a maximum of eight.
The rationale for the dose schedule was based on preclinical work
showing that alternating high and lower doses can maximize the immune
effect and make toxicities much more manageable.
Histamine enhances the activity of IL-2, Dr. Agarwala said, by acting
on T cells and natural killer (NK) cells within a tumor. These
are the common pathways for the action of IL-2, he said.
The problem is that in the tumor, these cells are inhibited by
toxic oxygen metabolites that are normally produced by macro-phages
and neutrophils. Histamine removes those toxic oxygen metabolites and
therefore allows the IL-2 to work more effectively upon the T cells
and NK cells.
Improvement in Survival
patients treated with IL-2 and histamine showed a trend toward
improved overall survival (P = .1255), Dr. Agarwala said (see
However, when looking at the patients with liver
metastases129 patients in this trialthere was a major
improvement in survival for patients treated with IL-2 and histamine
vs IL-2 alone (P = .004), Dr. Agarwala said. For these
patients, median survival was 283 days for those on the combination
regimen, compared with 154 days for IL-2 alone.
Among those patients who completed at least two cycles of therapy,
there was a significant improvement in survival for the patients
treated with Il-2 plus histamine (P = .03), Dr. Agarwala said.
For patients treated at centers that had experience with the regimen,
ie, centers that treated seven or more patients on the study,
once again there is a significant improvement in survival for
those patients treated with IL-2 and histamine vs IL-2 alone,
In the future, investigators should think about how to extend the
results of the trial to patients who have a higher risk of liver
disease than those with cutaneous melanomas, said John M. Kirkwood,
MD, director, Melanoma Center, University of Pittsburgh Cancer
Institute. As an example, he mentioned patients with ocular melanoma.
He pointed out that there are cytokines other than IL-2 that could be
rationally used in combination with histamine. I think that
many of these new disease settings, as well as many of these new
combinations with other cytokines, are very worthy topics for further
extended evaluation of this agent.