Long term follow up of the EORTC 18952 trial of adjuvant therapy in resected stage IIB-III cutaneous melanoma patients comparing intermediate doses of interferon-alpha-2b (IFN) with observation: Ulceration of primary is key determinant for IFN-sensitivity

Eur J Cancer. 2016 Mar:55:111-21. doi: 10.1016/j.ejca.2015.11.014. Epub 2016 Jan 17.

Abstract

Background: We report on the long term outcome of the EORTC 18952 adjuvant interferon (IFN) trial in 1388 resected stage IIB/III melanoma patients and identify key predictive factors for outcome.

Methods: We analysed outcome of the EORTC 18952 trial (4 weeks of IFN, 10 MU, 5 times/week for 4 weeks followed by 12 months IFN at 10 MU, 3 times/week versus followed by 24 months IFN at 5 MU 3 times/week versus observation) regarding relapse-free survival (RFS), distant metastasis-free interval/survival (DMFI/DMFS), and overall survival (OS), and analysed potential predictive factors of outcome.

Findings: At a median follow-up of 11 years, the comparison of IFN 13 months versus IFN 25 months versus observation yielded estimated hazard ratios (HR) for RFS of 0.94 versus 0.84 (p = 0.06); for DMFI 0.95 versus 0.82 (p = 0.027); for DMFS 0.95 versus 0.84 (p = 0.07); and for OS 0·95 versus 0.84 (p = 0.08), respectively. The impact of treatment was greatest in the ulceration group, whereas in patients with non-ulcerated primaries the impact was null (HR ≥ 1.0). In patients with ulcerated melanoma the HR for IFN 13 months versus 25 months versus observation were for: RFS 0.82 (p = 0.16) versus 0.61 (p = 0.0008); DMFS 0.76 (p = 0.06) versus 0.57 (p = 0.0003); OS 0.80 (p = 0.13) versus 0.59 (p = 0.0007). In stage IIB/III-N1 (microscopic nodal involvement only) patients with ulcerated melanoma the HR estimates were for: RFS 0.85 versus 0.62; DMFS 0.80 versus 0.56; OS 0.77 versus 0.54.

Conclusions: This long term report of the EORTC 18952 trial demonstrates the superiority of the 25-month IFN schedule and defines ulceration of the primary as the overriding predictive factor for IFN-sensitivity.

Keywords: Adjuvant; Interferon; Melanoma; Predictive factors; Randomised trial; Ulceration.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Chemotherapy, Adjuvant
  • Disease Progression
  • Disease-Free Survival
  • Drug Administration Schedule
  • Female
  • Humans
  • Interferon alpha-2
  • Interferon-alpha / administration & dosage*
  • Interferon-alpha / adverse effects
  • Kaplan-Meier Estimate
  • Lymph Node Excision
  • Lymphatic Metastasis
  • Male
  • Melanoma / mortality
  • Melanoma / secondary
  • Melanoma / therapy*
  • Middle Aged
  • Neoplasm Recurrence, Local
  • Neoplasm Staging
  • Proportional Hazards Models
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / adverse effects
  • Skin Neoplasms / mortality
  • Skin Neoplasms / pathology
  • Skin Neoplasms / therapy*
  • Skin Ulcer / pathology*
  • Time Factors
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Interferon alpha-2
  • Interferon-alpha
  • Recombinant Proteins