SAN FRANCISCOAbout 8,000 people will die of malignant melanoma in the
United States this year, victims of a mortality rate approaching 100% in
recurrent disease. Sewa S. Legha, MD, painted this grim picture at the
Proleukin First International Congress, sponsored by Chiron. Traditional
chemotherapy produces response rates up to 40%, but complete remissions
are rare, even with the most aggressive combination therapies.
Biological agents produce a different profile. Response rates to interferon-alfa
(IFN-alfa) and interleukin-2 (IL-2, Proleukin) are around 20%, with duration
of response and median survival similar to, and in some studies higher
than, those of chemotherapy.
In the late 1980s at The University of Texas M.D. Anderson Cancer Center,
where Dr. Legha is professor of medicine in the Department of Melanoma/Sarcoma
Medical Oncology, researchers began combining the two types of therapy.
Based on the lack of cross-resistance and complementary mechanisms,
Dr. Legha and his colleagues have developed a combined biotherapy-chemotherapy
program that is more effective than either regimen alone.
Overall Response Rates of 60%
Among metastatic melanoma patients, overall response rates to the current
regimen have hit 60%, an unheard-of level with more traditional approaches.
Complete response rates are 20%, again far higher than those achieved with
other treatments. The median duration of response is eight months, but
60% of complete responders remain in remission more than five years after
“There is a very good chance that these remissions will be long-lasting,”
Dr. Legha said. And unlike many biochemo-therapy combinations, The M.D.
Anderson program can be used effectively by community oncologists with
minimal inpatient support.
The program has moved through several iterations, beginning with a six-week
alternating schedule of biotherapy (IFN-alfa plus IL-2) and combination
chemotherapy consisting of cisplatin (Platinol), vinblastine, and dacarbazine
(DTIC). The next step was sequential biochemotherapy, ie, chemotherapy
immediately followed by biotherapy.
Concurrent biochemotherapy (see Table
), the simultaneous administration of both components, provides a response
similar to that of the sequential regimen, Dr. Legha said. The five-day
treatment courses can be repeated at three-week intervals as needed, he
said, but clinicians can expect to see prompt results. Patients who do
not show tumor regression during the first two treatment cycles are unlikely
to respond at all, he added.
Toxicities are relatively moderate. Patients spend the first six to
seven days of each cycle in the hospital, but intensive care support is
rare. Most patients experience fever, nausea, vomiting, moderate hypotension,
and mild hepatic and renal dysfunction. Physicians can expect to write
liberal orders for antipyretics, antiemetics, antidiarrheals, and controlled
David Khayat, MD, head of the Department of Medical Oncology, Pitié-Salpêtrière
Hospital, Paris, France, has taken a slightly different approach to the
same problem. “We have been taught that metastatic melanoma is an incurable
disease,” he said at the meeting. “That is no longer an absolute.”
Dr. Khayat conducted three phase II clinical studies comparing the efficacy
and survival of several doses and schedules of IL-2, IFN-alfa, and cisplatin,
plus the trio with and without tamoxifen (Nolvadex). The response rates
were similar in all the groups, producing an overall response rate of 49%,
including 10% complete responses.
The biggest difference was in survival. Patients who did not respond
to biochemotherapy survived 7 months versus 17 months for responders. More
than three years after treatment, 7% of patients remain in complete remission
. The next step, Dr. Khayat said, is to boost the rate of complete responders
and move the treatment into ambulatory care.
Decrescendo IL-2 Dosing
Alexander Eggermont, MD, PhD, head of the Section of Experimental Surgical
Oncology, University Hospital Rotter-dam-Daniel den Hoed Cancer Center,
offered final results from a phase III EORTC trial of biochemotherapy.
Dr. Eggermont is chairman of the EORTC Melanoma Cooperative Group (EORTC-MCG)
and secretary general of the EORTC.
Patients with stage IV metastatic melanoma were randomized to receive
IL-2 plus IFN-alfa or IL-2/IFN-alfa plus cisplatin. Both arms of the trial
used a decrescendo, or decreasing dose, regimen for IL-2, which was developed
by Dr. Ulrich Keilholz, of the University of Heidelberg, who is currently
chairman of the immunotherapy subgroup of the EORTC-MCG.
“You actually deliver a larger IL-2 dose with decrescendo dosing, compared
to steady-dose regimens, but there is much better tolerance,” Dr. Eggermont
said. In standard regimens, he continued, patients typically receive 70%
to 75% of the prescribed drug because of dose-limiting toxicities. The
decrescendo regimen reduces the incidence and severity of side effects
to permit delivery of 95% of the prescribed dose.
In spite of a significant increase in response rates and time to progression
in the combination arm with cisplatin, median survival and overall survival
rates were identical in both arms of the study. (For a fuller report of
the findings, see J Clin Oncol 15:2579-2588, 1997.)
Value of Cisplatin ‘Debatable’
Cisplatin seemed to add only a number of relatively unimportant partial
remissions of short duration, he said. Thus, the value of the impact of
chemotherapy on top of the effect of IL-2/IFN-alfa is debatable. (This
point was also put forward by Dr. Steven Rosenberg of the National Cancer
At present, the EORTC-MCG is assessing the impact of IL-2 on survival
in a trial comparing dacarbazine, cisplatin, and IFN-alfa with and without
IL-2. “It is time to assess whether adding toxicity correlates with adding
meaningful time to the life of melanoma patients,” Dr. Eggermont said.