Treatment
Immunotherapy: High & Low-Dose Interferon

-Introduction
-Interferons
  -High & Low-Dose Interferon
  -Side Effects of Interferon
-Interleukin-2
  -Side Effects of Interleukin-2
-Biochemotherapy
-Vaccine Therapy
  -Tumor Cell Vaccines
  -Tumor-Associated Antigen Vaccines
-Monoclonal Antibodies

Interferon must be delivered directly into the bloodstream or into tissue by injection. It cannot be taken orally because the strong acids and enzymes of the digestive system would destroy it.

Interferon alpha has been tested in high-dose and low-dose regimens.

High-dose interferon is delivered in a two-phase process. In the first phase, the induction phase, a maximum tolerable dose of interferon is administered intravenously in a hospital or in an office setting five days a week for a four-week period. Each infusion takes about 20 to 30 minutes, with an hour of IV fluids given prior to the interferon (for a total time of roughly 1½ hours). The second phase, the maintenance phase, begins in the fifth week. Subcutaneous interferon injections are given three times a week for the remainder of the year. During this phase, many patients and their loved ones learn to administer the injections themselves.

The effectiveness of high-dose interferon alfa-2b has been studied as an adjuvant treatment for patients with high-risk melanoma. A multicenter study conducted by the Eastern Cooperative Oncology Group (ECOG) included patients with tumors greater than 4 mm in depth whose melanoma had spread to regional lymph nodes. Patients were randomized to one of two treatment groups: high-dose, intravenous interferon alfa-2b for one year, or no additional treatment. The study showed interferon alfa 2-b to significantly prolong disease-free and overall survival.1 These results led to the U.S. Food and Drug Administration approval of interferon alfa-2b as adjuvant therapy for melanoma in 1996.

Another large ECOG study compared high-dose interferon to both low-dose interferon and no additional treatment in a similar group of patients. High-dose interferon alfa-2b showed a significant effect on disease-free survival, compared to the other treatments, although no difference in overall survival was demonstrated.2

The largest ECOG study of high-dose interferon compared the therapy to a promising melanoma vaccine in patients with high-risk melanoma. The study was closed early, when an interim data analysis showed compelling evidence that interferon alfa-2b was significantly superior to the vaccine in prolonging both overall and relapse-free survival.3

Clinical trials are currently underway to determine whether the highly significant benefit of high-dose interferon alfa-2b given for a full year can be duplicated when the treatment is given for only one month.

Low-dose interferon. The use of lower, less toxic doses of interferon alfa-2a as adjuvant therapy for high-risk melanoma has been studied in the United States and Europe. Clinical trials include an induction phase of daily subcutaneous injections for one to three weeks, followed by subcutaneous injections three times a week over a period of one to three years.

Low-dose interferon therapy has shown improvement in relapse-free survival, but not overall survival. Benefits diminished once therapy was discontinued, leading some researchers to conclude that low-dose interferon may need to be given indefinitely to be of continuing benefit.4

Clinical trials are currently underway to evaluate the effectiveness of intermediate doses of interferon, including a new form of long-acting, less toxic, pegylated (PEG) interferon given weekly for a number of years.

See Clinical Trials for information on these studies.

Note
An article by researchers from the Center for Evidence Based Medicine, University of Oxford, England, was recently published in the Journal of Clinical Oncology. (Lens MB, Dawes M. Interferon alfa therapy for malignant melanoma: a systemic review of randomized controlled trials. J Clin Oncol. 2002;20:1818-25.) It calls into question the effectiveness of interferon alfa-2b as an adjuvant treatment for melanoma.

A rebuttal to this article notes that the authors omitted from their analysis the largest and most positive of the US Melanoma Intergroup studies, in which interferon alfa-2b showed highly significant benefit over a melanoma ganglioside vaccine in prolonging relapse-free and overall survival. In addition, the authors used a statistical approach that is inappropriate for re-analysis of two other major interferon studies, raising questions about the validity of their study. (Kirkwood JM, Ibrahim J, Sondak VK, et al. Use and abuse of statistics in evidence-based medicine. J Clin Oncol. 2002;20:4122-4124.)

References
1Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14:7-17.
2Kirkwood JM, Sosman J, Ernstoff M, et al. E2690: A study of the mechanism of IFN alfa-2b in high risk melanoma in the ECOG/intergroup trial E1690. Proc Am Assoc Cancer Res 1995;36:641.
3Kirkwood JM, Ibrahim J, Sosman JA, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS 21 vaccine in patients with resected stage IIB-III melanoma: Results of intergroup trial E1694/S9512/C509801. J Clin Oncol. 2001;19:2370-2380.
4Lotze MT, Dallal RM, Kirkwood JM, Flickinger JC. Cutaneous melanoma. In DeVita VT, Rosenberg SA, Hellmon S (eds.), Principles and Practice of Oncology. 6 ed. Philadelphia: Lippincott, 2001.