NEW YORKFor some stage IV melanoma patients who
achieve only a partial response or stable disease on a regimen of
biochemotherapy, a maintenance strategy using interleukin-2 (IL-2) may prolong
survival and in some instances produce durable complete responses, California
researchers have discovered. Steven J. O’Day, MD, associate director, medical
oncology, John Wayne Cancer Institute at St. John’s Health Center, Santa
Monica, reported the encouraging results of a pilot study of the biotherapy
maintenance strategy at the Chemotherapy Foundation Symposium XVIII.
Among the first 23 patients, 5 achieved an objective response
during the treatment, which followed an initial intensive biochemotherapy
regimen. "Four of these were complete remissions," Dr. O’Day said.
"Of these 5 patients, 4 remain alive more than 2 years out." The one
death in this subset was due to progression of central nervous system
Patients in the maintenance trial were drawn from a prior study
of poor-prognosis patients treated with a regimen that included IL-2 given in a
rapid decrescendo dosing pattern. Given over the first 4 days of each 21-day
cycle, the IL-2 doses were 18, 9, 4.5, and 4.5 mIU/m2. "The concept,"
Dr. O’Day explained, "was high dose early, then rapid tapering of IL-2
to affect the immune response maximally and decrease toxicity."
Also included in the inpatient bioche-motherapy regimen were
dacarbazine, vinblastine, cisplatin (Platinol), and interferon-alfa-2b (Intron
A). G-CSF (Neu-pogen) was begun on day 6 after discharge from the hospital.
Of the 45 patients in this study, 62% had metastases to three
or more organs, Dr. O’Day reported. More than 60% had non-lung visceral
metastases, including sites in bone, brain, and liver.
The overall response rate was 57%, with 23% achieving a
complete remission. "But what’s interesting is that, in addition to the
complete responding patients, about 55% of patients [34% partial response, 20%
stable disease] seem to have arrested tumor growth with this regimen," Dr.
The researchers wanted to focus on those 55% because they have
a uniformly poor survival rate, with about 100% progressing within 12 months
and a median time to progression of only 3 months. "It’s an
all-or-nothing phenomenon with biochemotherapy," he said. "Patients
who achieve a complete remission have a chance of long-term survival, but
anything less isn’t important in terms of survival." Thus, the
researchers decided to immediately follow biochemotherapy with an immune
strategy that was less toxic but might salvage some of these patients.
In the maintenance regimen, IL-2 was given subcutaneously at a
low dose of 1 mIU/m2 for 5 days. GM-CSF was given on a schedule of 14 days on,
14 days off. Periodically, patients were hospitalized for 48 hours for
high-dose decrescendo pulses of IL-2. These pulse doses were more frequent in
the first 6 months than in the next 6, when only 3 were given.
None of the patients had to discontinue the program because of
toxicity, Dr. O’Day said. About 10% to 20% of patients, he estimated, have
presented with "an interesting immune phenomenon"vitiligo, immune
thyroiditis, and immune-mediated thrombocytopenia. "All of this has been
relatively easily treated and managed," he said, "but this is clearly
a sign of immune activation."
Although encouraged by the four complete remissions achieved
with the maintenance strategy, Dr. O’Day and his colleagues were more
interested in its effect on disease progression and survival.
Progression-free survival at 12 months, he reported, was about
30%, compared with the 6% in historical controls from his institution who were
treated with biochemotherapy with no maintenance biotherapy.
The biotherapy maintenance strategy also appears to have
lengthened survival, Dr. O’Day reported. While the overall median survival
was 9.1 months among comparable historical patients, it increased to 14.1
months in the maintenance group.
Among the historical controls, 31% survived for 1 year, he
noted, while 69% of the maintenance group were alive 12 months after beginning
the initial bio-chemotherapy regimen.
Initially conceived as a 12-month protocol, the program has now
been extended to include a second year, with IL-2 pulses given every other
month to patients who wish to continue. "If it works early," Dr. O’Day
said, "there’s no reason that we have to stop at a year. It’s a lot of
treatment, but given the prognosis and the motivation of these patients, they’re
more than willing to do it."
Additional patients have also been put on the protocol, and the
total who have received it is now more than 40. Analyses of data from 42
patients, Dr. O’Day said, shows that that the survival advantage seen in the
initial group is holding up.
A multicenter single-arm trial is being launched, Dr. O’Day
announced, in which 130 stage IV melanoma patients will receive induction
biochemotherapy, and those with stable disease or an objective response will go
on to maintenance biotherapy. "If we can reproduce these data in the
larger multicenter trial," he said, "then the strategy would be
eligible for a phase III study."