Highlights
- •The 25-month interferon (IFN) schedule yielded to better outcome than the observation group.
- •Ulceration of the primary is a strong predictive factor for IFN-alpha sensitivity.
- •Stage IIB–IIIN1 patients with an ulcerated primary had the highest treatment benefit.
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
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References
- Cutaneous melanoma.Lancet. 2014; 383: 816-827
- Final version of 2009 AJCC melanoma staging and classification.J Clin Oncol. 2009; 27: 6199-6206
- Multivariate analysis of prognostic factors among 2,313 patients with stage III melanoma: comparison of nodal micrometastases versus macrometastases.J Clin Oncol. 2010; 28: 2452-2459
- Site and timing of first relapse in stage III melanoma patients: implications for follow-up guidelines.J Clin Oncol. 2010; 28: 3042-3047
- Sentinel node tumor burden according to the Rotterdam criteria is the most important prognostic factor for survival in melanoma patients: a multicenter study in 388 patients with positive sentinel nodes.Ann Surg. 2008; 248: 949-955
- Prognosis in patients with sentinel node-positive melanoma is accurately defined by the combined Rotterdam tumor load and Dewar topography criteria.J Clin Oncol. 2011; 29: 2206-2214
- The prognostic significance of sentinel node tumour burden in melanoma patients: an international, multicenter study of 1539 sentinel node-positive melanoma patients.Eur J Cancer. 2014; 50: 111-120
- Does adjuvant interferon-alpha for high-risk melanoma provide a worthwhile benefit? A meta-analysis of the randomised trials.Cancer Treat Rev. 2003; 29: 241-252
- Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis.J Natl Cancer Inst. 2010; 102: 493-501
- Predictive importance of ulceration on the efficacy of adjuvant interferon-a (IFN): an individual patient data (IPD) meta-analysis of 15 randomized trials in more than 7,500 melanoma patients (pts).J Clin Oncol. 2014; 32 ([abstract 9067])
- Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial.Lancet. 2005; 366: 1189-1196
- Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial.Lancet. 2008; 372: 117-126
- Long term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma.J Clin Oncol. 2012; 30: 3810-3818
- Ulceration and stage are predictive of interferon efficacy in melanoma: results of the phase III adjuvant trials EORTC 18952 and EORTC 18991.Eur J Cancer. 2012; 48: 218-225
- On the use of Pocock and Simon's method for balancing treatment numbers over prognostic factors in the controlled clinical trial.Biometrics. 1976; 32: 691-694
EAST-3. Cytel Software Corporation. Cambridge, MA, USA.
- The survival analysis of failure time data.2nd ed. Wiley Series in Probabilities and Statistics. Wiley Inter-Science, New-Jersey, USA2002
- Is ulceration in cutaneous melanoma just a prognostic and predictive factor or is ulcerated melanoma a distinct biologic entity?.Curr Opin Oncol. 2012; 24: 137-140
- Interobserver reproducibility of ulceration assessment in primary cutaneous melanomas.Eur J Cancer. 2003; 39: 1861-1865
- Gene expression profiling of primary cutaneous melanoma and clinical outcome.J Natl Cancer Inst. 2006; 98: 472-482
- Integrative genomics identifies gene signature associated with melanoma ulceration.PLoS One. 2013; 8: e54958
- Long-term protective effect of mature DC-LAMP+ dendritic cell accumulation in sentinel lymph nodes containing micrometastatic melanoma.Clin Cancer Res. 2007; 13: 3825-3830
- Immune checkpoint inhibitors in melanoma provide the cornerstones for curative therapies.Semin Oncol. 2015; 42: 429-435
- Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial.Lancet Oncol. 2015; 16: 522-530
Article info
Publication history
Published online: January 17, 2016
Accepted:
November 9,
2015
Received:
November 9,
2015
Identification
Copyright
© 2015 Elsevier Ltd. Published by Elsevier Inc. All rights reserved.
