The Oncologist, Vol. 2, No. 3, 194–195,
June 1997
© 1997 AlphaMed Press
SPECIAL FEATURE
BRIEF REPORT |
Current Therapy with Interferons
Scott Wadler, M.D.
Montefiore Medical Center, Department of Oncology, Hofhemer 1, 111 East 210th Street, Bronx, NY 10467-2401
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INTERFERONS
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Interferons (IFN) have been in clinical use in the United States since the early 1980s when large-scale trials by the National Cancer Institute and the American Cancer Society identified activity for these compounds in solid tumors that were otherwise refractory to cytotoxic drugs. Interest in these compounds was also generated by the observations that the IFNs could stimulate natural killer cell activity, suggesting that these compounds could combine the specificity of biologic agents with the absence of unacceptable toxicities associated with cytotoxic drugs. The initial enthusiasm for IFN has been tempered by recent evidence which suggests that the toxicities of IFN are comparable, although different, from that of cytotoxic agents. Furthermore, the mechanism of action of IFN remains to be identified precisely, and immunologic effects may be secondary, rather than primary mechanisms.
The clinical spectrum of activity for IFN has continued to expand over the past 20 years. Nevertheless, the optimal utility of these agents remains to be identified. Current clinical uses for IFNs are described below.
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MELANOMA
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Adjuvant Therapy
Patients with early-stage melanoma (<1.5 mm in depth) will have an 85% survival at 10 years. The prognosis for patients with lesions >4 mm is substantially worse, with survival <50%. Based on the results of a randomized trial conducted by the Eastern Cooperative Oncology Group (EST 1684), IFN
-2b has recently been approved for the adjuvant treatment of melanoma by the FDA. In this trial, patients with locally advanced melanoma at high risk for recurrence were randomized to either observation or to high-dose adjuvant therapy with IFN-2b for one year. Patients at high risk included those with Breslow thickness >4 mm or patients with primary or recurrent lymph node involvement. Treatment consisted of high-dose daily intravenous therapy for one month, followed by maintenance therapy. With a median follow-up of over seven years, there was an increase in the median survival duration for patients receiving IFN of 12.4 months (33.4 months versus 45.8 months, p = 0.02) and an increase in the median relapse-free survival of 8.8 months (11.8 months versus 8.8 months, p = 0.002).
Quality-of-life assessments were performed using the Q-TWIST instrument during the ECOG trial. The IFN arm had a significant gain in quality-of-life adjusted time, and that this was greatest in the node-positive strata, suggested that clinical benefits of the treatment could significantly offset the side effects of treatment.
Renal Cell Carcinoma
Single-agent IFN has modest activity in the treatment of renal cell carcinoma, with objective response rates in the 15%-20% range. Low- or intermediate-dose combinations of IL-2 and IFN have been employed in the out-patient setting. Recent trials from Europe using intermediate-dose IL-2 + IFN have suggested a survival or progression-free survival advantage for combination therapy versus either agent alone. This observation remains to be confirmed. While the severe toxicities observed in some studies do suggest caution in administering these regimens in the out-patient setting, this approach is clearly of interest in ameliorating the toxicities observed with high-dose IL-2 and with improving quality of life in this patient population.
Non-Hodgkin’s Lymphoma
IFN as a single agent has demonstrated clinical activity against follicular lymphomas in patients who have failed prior chemotherapy, with response rates of 30%-50%. Several clinical trials conducted by the ECOG, the EORTC and GELA have demonstrated a benefit in time to failure to combinations of IFN and cytotoxic agents. These results should be interpreted cautiously, however. The patient populations were often heterogeneous, with some patients having non-follicular lymphomas and some including both low-grade and intermediate-grade patients. In addition, only one trial demonstrated a clear survival advantage for the IFN group; there was no clear plateau in the survival curves. Additional studies are warranted to confirm these findings and attempt to improve the constitutional symptoms associated with IFN.
Chronic Myelogenous Leukemia
IFN has substantial clinical activity against CML. Response is highly dependent on stage of disease, however. In patients in blast crisis, a major cytogenetic response is almost never achieved, whereas in early chronic phase IFN treatment results in a major cytogenetic response in 20%-30%, with late chronic phase and accelerated phase being intermediate. In comparison with conventional chemotherapy, IFN treatment has demonstrated a survival advantage, and low-dose therapy may be as effective as high-dose therapy.
Multiple Myeloma
Several randomized trials have tested the role of chemotherapy with or without the addition of IFN. In addition, IFN has been studied in the maintenance setting following induction chemotherapy in patients with multiple myeloma. While not definitive, these trials suggest there may be benefits for selected patients with myeloma.
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Interferons
Melanoma
