Natalie J Ives1, Stefan Suciu2, Alexander M M Eggermont3, John Kirkwood4, Paul Lorigan5, Svetomir N Markovic6, Claus Garbe7, Keith Wheatley8. 1. Birmingham Clinical Trials Unit, College of Medical and Dental Sciences, Public Health Building, University of Birmingham, Birmingham, B15 2TT, UK. 2. EORTC Headquarters, Avenue Emmanuel Mounier 83/11, 1200 Brussels, Belgium. 3. Gustave Roussy Cancer Campus Grand Paris, 114 Rue Edouard Vaillant, 94800, Villejuif, France. 4. University of Pittsburgh Cancer Institute and School of Medicine, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA. 5. The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester, M20 4BX, UK. 6. Mayo Clinic Rochester, 200 First St. SW, Rochester, MN, 55905, USA. 7. University of Tubingen, Liebermeisterstraße 25, 72076, Tübingen, Germany. 8. Cancer Research UK Clinical Trials Unit, College of Medical and Dental Sciences, Robert Aitken Institute, University of Birmingham, Birmingham, B15 2TT, UK. Electronic address: k.wheatley@bham.ac.uk.
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.
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.
Authors: Shenying Fang; Jiachun Lu; Xinke Zhou; Yuling Wang; Merrick I Ross; Jeffrey E Gershenwald; Janice N Cormier; Jennifer Wargo; Dawen Sui; Christopher I Amos; Jeffrey E Lee Journal: Carcinogenesis Date: 2020-06-17 Impact factor: 4.944