Elsevier

European Journal of Cancer

Volume 82, September 2017, Pages 171-183
European Journal of Cancer

Review
Adjuvant interferon-α for the treatment of high-risk melanoma: An individual patient data meta-analysis

https://doi.org/10.1016/j.ejca.2017.06.006Get rights and content

Highlights

  • Adjuvant IFN-α significantly reduces the risk of relapse and improves overall survival.

  • There was no evidence of a difference between higher and lower doses of adjuvant IFN-α.

  • There was no evidence that the benefit of IFN-α differed in different patient types, except for ulceration.

  • The finding that ulceration may be predictive of response to IFN-α needs confirmation in appropriately designed prospective studies.

Abstract

Background

Many randomised trials assessing interferon-α (IFN-α) as adjuvant therapy for high-risk malignant melanoma have been undertaken. To better assess the role of IFN-α, an individual patient data (IPD) meta-analysis of these trials was undertaken.

Methods

IPD was sought from all randomised trials of adjuvant IFN-α versus no IFN-α for high-risk melanoma. Primary outcomes were event-free survival (EFS) and overall survival (OS). Standard methods for quantitative IPD meta-analysis were used. Subgroup analyses by dose, duration of treatment and various patient and disease-specific parameters were performed.

Findings

Fifteen trials were included in the analysis (eleven with IPD). EFS was significantly improved with IFN-α (hazard ratio [HR] = 0.86, CI 0.81–0.91; P < 0.00001), as was OS (HR = 0.90, CI 0.85–0.97; P = 0.003). The absolute differences in EFS at 5 and 10 years were 3.5% and 2.7%, and for OS were 3.0% and 2.8% respectively in favour of IFN-α. There was no evidence that the benefit of IFN-α differed depending on dose or duration of treatment, or by age, gender, site of primary tumour, disease stage, Breslow thickness, or presence of clinical nodes. Only for ulceration was there evidence of an interaction (test for heterogeneity: P = 0.04 for EFS; P = 0.002 for OS); only patients with ulcerated tumours appeared to obtain benefit from IFN-α.

Conclusion

This meta-analysis provides clear evidence that adjuvant IFN-α significantly reduces the risk of relapse and improves survival and shows no benefit for higher doses compared to lower doses. The increased benefit in patients with ulcerated tumours, and lack of benefit in patients without ulceration, needs further investigation.

Introduction

Effective adjuvant therapy for melanoma remains an unmet need. Despite the approval of 2 new agents (ipilimumab, PEGylated interferon [PEG-IFN]), the last 5 years have not seen improvements in overall survival (OS) in any adjuvant therapy study. Interferon remains a standard of care in many countries without a consensus view on its clinical utility. Results from randomised trials of adjuvant interferon-α (IFN-α) in high-risk melanoma have been considered inconsistent, with some suggesting benefit with IFN-α and others showing no difference [1]. In 1996, high-dose IFN-α was approved in both the US and Europe based on the results of the ECOG 1684 trial in stage IIB/III patients, which showed a benefit for high-dose IFN-α on both relapse-free survival (RFS) and OS [2]. Updated results with a median follow-up of 12.6 years, showed that the RFS benefit was maintained (hazard ratio [HR] = 0.72, P = 0.02), but the HR for OS had decreased from 0.67 to 0.82 (P = 0.18), possibly due to competing causes of death [3]. The ECOG E1690 trial which compared high- and low-dose IFN-α versus observation also in stage IIB/III patients, had a very similar outcome for RFS for high and low dose, but did not confirm the benefit for high or low dose on OS [4].

In Europe, low-dose IFN-α was also approved based on a French trial in stage II patients, which showed a RFS benefit (HR = 0.75, P = 0.035), and a trend towards improved OS (HR = 0.72, P = 0.059) [5]. In 2011, the US Food and Drug Administration (FDA) approved PEG-IFN for stage III melanoma based on the EORTC 18991 trial, which showed an event-free survival (EFS) benefit (HR = 0.82, P = 0.01), but again no OS benefit [6].

Previous meta-analyses of the interferon trials have shown that IFN-α has a consistent effect on RFS, but no clear effect on OS [7], [8], [9]. No relationship with dose or duration of treatment with outcome has been demonstrated [7], [8]. IFN-α can have substantial side-effects, especially at high doses. Obtaining a reliable estimate of the true benefit of IFN-α, and determining whether the magnitude of the benefit differs in different treatment regimens or disease characteristics is important. To this end, we have performed an individual patient data (IPD) meta-analysis of randomised trials of IFN-α versus no IFN-α in patients with high-risk melanoma.

Section snippets

Trial identification

Randomised trials comparing IFN-α with no IFN-α in the adjuvant setting for the treatment of high-risk melanoma were identified by searches of registers and electronic databases including the Cochrane Controlled Trials Register, MEDLINE, EMBASE, PubMed, and Web of Science. This was supplemented by searching abstract books of conference proceedings from the main meetings (e.g. American Society of Clinical Oncology, World Melanoma Congress, ESMO/ECCO), scanning reference lists of retrieved

Results

Fifteen randomised trials of IFN-α versus no IFN-α (control) were identified (Table 1, Supplemental Material Fig. 1 and Supplemental Material Table 1) [2], [4], [5], [6], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24]. There were three 3-arm studies comparing different doses or schedules of IFN-α with control, meaning there was 18 comparisons included in the analysis; ECOG 1690 trial [4] contributes to both the high- and low-dose IFN-α versus control subgroups, and the EORTC 18952

Discussion

This IPD meta-analysis brings together all the currently available data from randomised trials of adjuvant IFN-α versus no IFN-α for the treatment of high-risk malignant melanoma, providing the most reliable assessment to date on the role of IFN-α.

We have showed that IFN-α produces a clear benefit in terms of reducing the risk of recurrence, with a smaller benefit on OS. There was a highly significant 14% proportional reduction in the risk of an event (recurrence or death without recurrence)

Sources of support

No funders were directly involved in the project. This work was supported by the University of Birmingham Clinical Trials Unit who received core support from the UK Department of Health, through the National Co-ordinating Centre for Research Capacity Development, up to March 2012, which funded Natalie Ives. A core grant from the Fonds Cancer, FOCA (BE), provides support for the EORTC Headquarters staff (co-author, Stefan Suciu).

Funding

No funders were directly involved in the project. This work was supported by the University of Birmingham Clinical Trials Unit who received core support from the UK Department of Health, through the National Co-ordinating Centre for Research Capacity Development, up to March 2012, which funded Natalie Ives. A core grant from the Fonds Cancer, FOCA (BE), provides support for the EORTC Headquarters staff (co-author, Stefan Suciu).

The following groups (listed alphabetically, with the names of

Author contributions

NI developed and designed the project, wrote the protocol and data requirement documents, undertook all the statistical analyses, interpreted the analyses and wrote the manuscript.

SS designed the project and was involved in the protocol development. SS also provided individual patient data from the EORTC trials, interpreted the analyses and reviewed and commented on the manuscript.

AE designed the project and was involved in the protocol development. AE also provided individual patient data from

Conflict of interest statement

AE has received personal fees from BMS and MSD for sitting on Scientific Advisory Boards. JK has received personal fees from Amgen, BMS, Genentech, Green Peptide and Roche and grants from Prometheus. PL has received personal fees from Amgen, BMS, Chugai, GSK, Merck, Novartis and Roche for sitting on Scientific Advisory Boards and to support travel to meetings. CG has received grants and personal fees from BMS, Novartis and Roche, and personal fees from Amgen, LEO and MSD for sitting on

Acknowledgements

The authors would like to thank all the patients who participated in the trials of adjuvant interferon for melanoma included in this meta-analysis. They also thank Professor Robert K. Hills for his help in creating the database that performed all the analyses.

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