NEW YORK CITY—The presentation was titled “Does duration of interferon treatment make a difference?” in metastatic melanoma. The simple answer was, not much.
“We have no evidence from clinical trials that duration really matters, neither from a meta-analysis nor from individual clinical trials,” said Axel Hauschild, MD, Professor of Dermatology and Head of Dermatooncology and Dermatologic Surgery at University Hospital in Kiel, Germany.
Dr. Hauschild advised oncologists to stick with the duration of treatment used in trials that led to the drug's approval—typically 18 months for low-dose interferon-alpha and 12 months for a high-dose regimen.
In his presentation here at the International Symposium on Melanoma, Dr. Hauschild said there have been very few clinical trials that compared one-to-one the duration of treatment.
“And up to now, there is no clear evidence—but much speculation—that the treatment duration of interferon-alpha really matters,” he said.
Quality of Life
Quality of life is, of course, an issue that oncologists must consider when planning adjuvant interferon treatment.
“The duration can be affected by the patients' willingness to accept toxicity-related impaired quality of life and adverse reactions for a certain time frame. There may also be psychological problems in patients undergoing long-term treatment.”
The most favored low-dose regimen in Europe is 3 million international units (miu) three times a week, he said, which has been approved for 18 months but is often prescribed for 12 months up to 36 months.
The intermediate-dose schedule used by the European Organization for Research and Treatment of Cancer (EORTC) includes an initial dose of 10 miu five times a week for four weeks, and a maintenance schedule of either 10 miu three times weekly for 12 months, or 5 miu three times weekly for 24 months.
And the high-dose interferon regimen, known as the Kirkwood regimen, begins with 20 miu/m2 five times a week for four weeks, with maintenance at 10 miu/m2 three times a week for 12 months.
Meta-Analysis Shows Low Survival Advantage
Dr. Hauschild cited a meta-analysis by Dr. Keith Wheately and colleagues, presented at last year's American Society of Clinical Oncology Annual Meeting, of 10 placebo-controlled melanoma trials in which patients received high-, intermediate-, low-, and very low-dose interferon-alpha-2a and -alpha2b. There were data on 6,067 patients, with more than 3,000 deaths for overall survival analysis and more than 3,700 relapses for relapse-free survival.
The meta-analysis showed an advantage in relapse-free survival at five years of 7% compared with untreated controls; and the overall survival advantage was a 3% improvement.
“You may be impressed by the p value,” he said—0.00006 for relapse-free survivals and 0.008 for overall survival—“but these are small differences.”
Dr. Hauschild said this might explain why most of these clinical trials were negative: Because they were not hitting the endpoint if they overestimated the expected relapse-free and overall survival rates with the study regimen compared with untreated controls
“We need larger sample sizes.”
Dr. Hauschild said that he expected that the Eastern Cooperative Oncology Group 1697 trial, led by Sanjiv Agarwala, MD, Chief of Medical Oncology at St. Luke's Hospital in Bethlehem, PA (and the Program Director for the Symposium) will further the understanding of interferon treatment duration, since only four weeks of interferon-alpha are given to study patients whose outcomes will be compared with those of untreated controls.
“And it will tell us more about induction phase alone compared with induction plus maintenance in lower-risk Stage 2 patients,” Dr. Hauschild said.
“We need to discuss pegylated interferon-alpha data,” Dr. Hauschild said at the end of his presentation discussing the unknowns of standard interferon treatment,
Another speaker did just that: Alexander M. M. Eggermont, MD, PhD, Professor of Surgical Oncology and Head of the Department of Surgical Oncology at Erasmus University Medical Center and the Daniel den Hoed Cancer Center in Rotterdam, The Netherlands, reviewed the randomized Phase III EORTC 18991 study he led that compared long-term adjuvant treatment with pegylated interferon-alpha2b with observation in resected Stage III melanoma.
Dr. Eggermont said pegylated interferon is first and foremost a much more convenient delivery form, and on a unit-equality basis is much less toxic with a side-effect profile approximately the same as with low- to intermediate-dose standard interferon.
“We know that already from the hepatitis field, but it's also very clear from the large adjuvant trial, compared with high-dose interferon on a unit basis,” he said.
On the other hand, the overall impact of pegylated interferon on the natural course of metastatic melanoma is very similar to interferon in general—that is, the drug has a significant impact on disease-free survival, borderline on metastasis-free survival, and no significant impact on overall survival.
“So, in that sense, pegylated interferon is not a totally new drug, it's an improved version of interferon, so to speak, with a more advantageous risk-benefit balance.”
He said the prospective EORTC 18991 trial showed that the significant impact of pegylated interferon is actually confined to the sentinel node positive population, which now would include most patients diagnosed with early Stage 3 disease.
The study regimen included induction at a high-dose pegylated interferon for two months, and then maintenance at the lower dose for up to five years.
EORTC 18991 patients receiving pegylated interferon had significant benefit both in terms of disease-free survival and distant metastases-free survival, Dr. Eggermont said. “And it's the first trial showing that throughout five years, the relapse rate was lower in the treatment arm as compared with observation—meaning that there is proof that you can prolong that relapse-rate reduction as long as you give it, that there is something to maintenance therapy.”
But of course this is in a patient population where 50% of the patients have relapses or have died at two and a half years, so the maintenance benefit becomes a smaller and smaller fraction of the total patient population, he said. “So when you look at the larger picture [of pegylated interferon treatment], it's mostly a much more convenient form.”
‘Ambitious Time in Melanoma Research’
Dr. Eggermont added that this is an ambitious time in melanoma research, with several large, pivotal randomized Phase III trials of new drugs under way.
“There has never been a period with this kind of activity ever before,” he said. “If you have a patient with melanoma we would encourage everybody to refer for trials in these patients.
“These trials are all in competition with one another, and let's hope that finally we will identify a drug that is active enough to be called standard of care, because right now the standard of care is to put the patient on a clinical trial.”