Cancer Treatment Today

Adjuvant treatment of melanoma with interferon is toxic but recommended by NCCN. This is because phase III trials have provided conflicting evidence of effectiveness and the treatment is prolonged and toxic. Past trials gave conflicting results. Patients and practitioners should be aware that there have been four randomized trials of high-dose interferon alpha in patients at high risk for recurrent melanoma. The evidence from the randomized trials is conflicting. The Eastern Cooperative Oncology Group (ECOG) 1684 trial detected a significant improvement in overall survival, but a subsequent large randomized trial (ECOG 1690) failed to find any survival benefit for interferon compared with observation. Results from a third trial (ECOG 1694) that compared high dose interferon with a melanoma vaccine demonstrated a significant survival benefit for interferon. A fourth trial of high-dose interferon over a shorter treatment time failed to detect any benefit. Siilarly, systemic high dose and pegylated interferon alpha-2b are approved for the adjuvant treatment of patients who have undergone a complete surgical resection but are considered to be at high risk for relapse. Prospective randomized controlled trials with both agents have shown an increase in relapse-free survival (RFS) but not OS when compared to observation. Adjuvant therapy with lower doses of interferon have also not been consistently shown to have an impact on either RFS or OS

NCCN ME-6, 2012 has taken the position that this treatment can be offered as high dose or per-intereron for 5 years. It recommends it as level 2B and says that impact on survival is unclear.

ESMO say that in  in a subgroup of patients with low tumour burden interferon can be recommended, if the individual patient tolerates it well [C]. Adjuvant treatment in patients with resected macroscopic node involvement is preferentially applied in the context of randomized clinical trials in specialized centres. However, high-dose interferon a2b is an  FDA approved indication in the USA for this therapeutic situation.

The issue of how long after surgery can interferon still be beneficial is not resolved. The initial study by Kirkwood et al set the cutoff point for entry at no longer than 56 days. Since then, radiation, albeit optional for stage III per NCCN, when it is given, tends to make it difficult to meet this requirement and patients generally start on interferon later than 56 days after surgery. SYLATRON™ is an alpha interferon  pegylated intereron indicated for the adjuvant treatment ofmelanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resectionincluding complete lymphadenectomy. When prospectively studied, the 56 day limit is generally maintained(Levesque et al). Scienitfically, there exists evidence that in adjuvant settings, timing of therapy makes a difference. It remains to be proven that later therapy will have the same results as earlier therapy.

 
N. Levesque et al,Health management program: factors influencing completion of therapy with high-dose interferon alfa-2b for high-risk melanoma Curr Oncol. 2008 January; 15(1): 36–41.

A. Hauschild, Adjuvant interferon alfa for melanoma: new evidence-based treatment recommendations? Curr Oncol. 2009 May; 16(3): 3–6.

R. Dummer et al, Melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Oncol (2010) 21(suppl 5): v194-v197
Verma S, Quirt I, McCready D, Bak K, Charette M, Iscoe N, Melanoma Disease Site Group. Systemic adjuvant therapy for patients at high risk for recurrent melanoma: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2005 Aug 30. 39 p. (Evidence-based series; no. 8-1). [61 references]
nccn.org melanoma, 2012 ME-9

Kirkwood JM, Ibrahim JG, 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;19:2370–80.

Pros and Cons of Adjuvant Interferon in the Treatment of Melanoma
Oncologist 2003 8: 451-458