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 treatment.
“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(Drug information on cisplatin) (Platinol), vinblastine(Drug information on vinblastine), and dacarbazine(Drug information on 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 intravenous hydration.
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(Drug information on 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 Institute.)
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.