Combined interferon-α and interleukin-2 as adjuvant treatment for melanoma
Authors: Reinhard Dummer, Axel Hauschild, Tilo Henseler, Günter Burg
Journal: The Lancet (1998)

J Kirkwood comments (June 27, p 1901)1Kirkwood JM Adjuvant IFNa2 therapy of melanoma.Lancet. 1998; 351: 1901-1903Summary Full Text Full Text PDF PubMed Scopus (30) Google Scholar on the data of the French randomised trial of interferon-α2a (IFN-α2a) as adjuvant therapy in resected primary melanoma thicker than 1·5 mm.2Grob JJ Dreno B delaSalmoniere P et al.Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1·5 mm without clinically detectable node metastases.Lancet. 1998; 351: 1905-1910Summary Full Text Full Text PDF PubMed Scopus (400) Google Scholar He states that "the data on the interferons afford the only rigorous basis for adjuvant therapy of melanoma", and claims that "interleukin-2… has not been formally studied as an adjuvant therapy". Since several in-vitro investigations3Schultz ES Dummer R Becker JC Zillikens D Burg G Influence of various cytokines on the interleukin-2-dependent lysis of melanoma cells in vitro.Arch Dermatol Res. 1994; 286: 73-76Crossref PubMed Scopus (3) Google Scholar and clinical trials suggest additive efficacy of IFN-α and interleukin-2 (IL-2) against melanoma, we have developed an adjuvant combination therapy with these cytokines.4Dummer R Hauschild A Kreusch J et al.A prospective randomized multicenter trial for the adjuvant treatment of primary highrisk melanoma using s.c. interleukin-2 and interferon-α.Melanoma Res. 1995; 5: 445Crossref Google Scholar In 1990, a prospective randomised trial of low-dose IFN-α2b and lowdose IL-2 was initiated in ten centres in Germany and Switzerland. Up to 1995, 225 melanoma patients with primary cutaneous melanoma thicker than 1·5 mm without clinical node metastasis (pT3/4, No, Mo) were included. The control group received only close observation. The therapy group was treated for 48 weeks (eight cycles of 6 weeks). In each cycle, patients received 3 millions IU IFN-α2b (IntronA) subcutaneously (sc) daily for the first week, followed by 9 million IU IL-2 (Proleukin) sc on days 8–11 (week 2), and injections three times weekly of 3 million IU IFN-α2b sc for the following 4 weeks. In most centres patients were treated as outpatients. The treatment and observationgroups were well balanced for prognostic factors such as sex, melanoma subtype, localisation of primary tumour, and Breslow's tumour thickness (mean [SD] Breslow thickness in treatment group 2·61 [0·18] mm; observation group 2·57 [0·16 mm]). IL-2 caused most of the side-effects, necessitating dose reductions or delay of treatment cessation in 15%. Side-effects included influenza-like symptoms, thyroid dysfunction, depression, or haematological toxicity (leucopenia, thrombocytopenia). In a subgroup of patients, intensive serological immunomonitoring was done. We showed consistent immunostimulation during the whole treatment phase by raised soluble IL-2 receptor, β2-microglobulin, and neopterin serum concentrations that was affected by the presence of IFN-α neutralising antibodies. However, IFN-α neutralising antibodies were seen in only three of 31 patients.5Davis-Daneshfar A Boni R von Wussow P Joller H Burg G Dummer R Adjuvant immunotherapy in malignant melanoma: impact of antibody formation against interferon-alpha on immunoparameters in vivo.J Immunother. 1997; 20: 208-213Crossref PubMed Scopus (13) Google Scholar In February, 1998, 108 treated patients and 107 controls were evaluable for follow-up. The median observation time was 60 months. The most frequent sites of first recurrence were the regional lymph nodes. Time to progression and overall survival did not differ between the two groups, but Kaplan-Meier curves indicate a trend (p=0·07) towards extended overall survival in treated patients. Follow-up has continued since only 29 relapses in the treated and 27 in the untreated group have been recorded. Our data clearly indicate that the combination of low-dose IFN-α with sc low-dose interleukin-2 is feasible and well tolerated. This combination induces persistent immunoactivation. However, statistical proof of its impact on overall and disease-free survival in our population of patients is missing. RD and AH contributed equally to this project.