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Melanoma: HELP
Articles by Stefan Suciu
Based on 36 articles published since 2008
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Between 2008 and 2019, S. Suciu wrote the following 36 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Relapse-Free Survival as a Surrogate for Overall Survival in the Evaluation of Stage II-III Melanoma Adjuvant Therapy. 2018

Suciu, Stefan / Eggermont, Alexander M M / Lorigan, Paul / Kirkwood, John M / Markovic, Svetomir N / Garbe, Claus / Cameron, David / Kotapati, Srividya / Chen, Tai-Tsang / Wheatley, Keith / Ives, Natalie / de Schaetzen, Gaetan / Efendi, Achmad / Buyse, Marc. ·European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium; Gustave Roussy Cancer Campus Grand Paris, Villejuif, France; The Christie NHS Foundation Trust, Manchester, UK; University of Pittsburgh Cancer Institute and School of Medicine, Pittsburgh, PA; Mayo Clinic Rochester, Rochester, MN; University of Tubingen, Tubingen, Germany; University of Edinburgh, Western General Hospital, Edinburgh, UK; Bristol-Myers Squibb, Wallingford, CT; Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK; Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK; Universitas Brawijaya, Malang, Indonesia; IDDI, Louvain-la-Neuve, Belgium. ·J Natl Cancer Inst · Pubmed #28922786.

ABSTRACT: Background: We assessed whether relapse-free survival (RFS; time until recurrence/death) is a valid surrogate for overall survival (OS) among resected stage II-III melanoma patients through a meta-analysis of randomized controlled trials. Methods: Individual patient data (IPD) on RFS and OS were collected from 5826 patients enrolled in 11 randomized adjuvant trials comparing interferon (IFN) to observation. In addition, IPD from two studies comparing IFN and vaccination in 989 patients were included. A two-level modeling approach was used for assessing Spearman's patient-level correlation (rho) of RFS and OS and the trial-level coefficient of determination (R²) of the treatment effects on RFS and on OS. The results were validated externally in 13 adjuvant studies without available IPD. We then tested the results on the European Organisation for Research and Treatment of Cancer (EORTC) 18071 double-blind trial comparing ipilimumab 10 mg/kg with placebo, which showed a statistically significant impact of the checkpoint inhibitor on RFS and OS. All statistical tests were two-sided. Results: With a median follow-up of seven years, 12 of 13 trials showed a consistency between the IFN vs No IFN differences regarding RFS (hazard ratio [HR]RFS = 0.88) and OS (HROS = 0.91), but the small trial, Eastern Cooperative Oncology Group 2696, was an outlier (HRRFS = 0.72 vs HROS = 1.11). Therefore, even if rho was high, R² was low and could not reliably be estimated. Based on the 12 trials, rho remained high (0.89), and the hazard ratios for RFS and OS were strongly correlated (R² = 0.91). The surrogate threshold effect for RFS was estimated to be 0.77. For the EORTC 18071 trial, the hazard ratio for RFS was 0.75, predicting an effect of ipilimumab on OS. This was subsequently confirmed (HROS = 0.72, 95.1% confidence interval = 0.58 to 0.88, P = .001). Conclusions: In high-risk stage II-III melanoma, RFS appeared to be a valid surrogate end point for OS for adjuvant randomized studies assessing interferon or a checkpoint inhibitor. In future similar adjuvant studies, a hazard ratio for RFS of 0.77 or less would predict a treatment impact on OS.

2 Review Adjuvant interferon-α for the treatment of high-risk melanoma: An individual patient data meta-analysis. 2017

Ives, Natalie J / Suciu, Stefan / Eggermont, Alexander M M / Kirkwood, John / Lorigan, Paul / Markovic, Svetomir N / Garbe, Claus / Wheatley, Keith / Anonymous3260912. ·Birmingham Clinical Trials Unit, College of Medical and Dental Sciences, Public Health Building, University of Birmingham, Birmingham, B15 2TT, UK. · EORTC Headquarters, Avenue Emmanuel Mounier 83/11, 1200 Brussels, Belgium. · Gustave Roussy Cancer Campus Grand Paris, 114 Rue Edouard Vaillant, 94800, Villejuif, France. · University of Pittsburgh Cancer Institute and School of Medicine, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA. · The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester, M20 4BX, UK. · Mayo Clinic Rochester, 200 First St. SW, Rochester, MN, 55905, USA. · University of Tubingen, Liebermeisterstraße 25, 72076, Tübingen, Germany. · 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. ·Eur J Cancer · Pubmed #28692949.

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.

3 Review Autoimmunity and treatment outcome in melanoma. 2011

Bouwhuis, Marna G / Ten Hagen, Timo L M / Suciu, Stefan / Eggermont, Alexander Mm. ·Department of Surgery, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. ·Curr Opin Oncol · Pubmed #21150603.

ABSTRACT: PURPOSE OF REVIEW: Only a subset of melanoma patients with advanced disease seems to benefit from immunotherapy. Predictive markers identifying these patients are unfortunately not available. Whether immune-related side effects could serve as predictors for treatment response or just resemble unwanted side effects from immunotherapy will be outlined in this review. RECENT FINDINGS: Early studies suggested an association of immune-related side effects such as vitiligo and autoimmune thyroiditis with response in patients receiving IL-2 or IFNα. However, conflicting data have been reported as well, mentioning the effect of a higher rate of immune-related toxicities during prolonged administration of the drug in responders/survivors. This type of bias is also known as guarantee-time bias. Recently, a clearly significant and clinically relevant prolongation of survival was demonstrated in patients with metastatic melanoma treated with ipilimumab. Immune-related adverse events were associated with response to ipilimumab, however, at the cost of considerable toxicity. SUMMARY: Evidence for an association of immune-related toxicities and response in patients receiving IL-2 or IFNα is weak, considering guarantee-time bias. On the contrary, this association for patients receiving anti-cytotoxic T-lymphocyte antigen-4 therapy (ipilimumab) appears much stronger. Importantly, can we uncouple tumor immunity from autoimmunity in order to optimize immunotherapy in melanoma?

4 Clinical Trial Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. 2018

Eggermont, Alexander M M / Blank, Christian U / Mandala, Mario / Long, Georgina V / Atkinson, Victoria / Dalle, Stéphane / Haydon, Andrew / Lichinitser, Mikhail / Khattak, Adnan / Carlino, Matteo S / Sandhu, Shahneen / Larkin, James / Puig, Susana / Ascierto, Paolo A / Rutkowski, Piotr / Schadendorf, Dirk / Koornstra, Rutger / Hernandez-Aya, Leonel / Maio, Michele / van den Eertwegh, Alfonsus J M / Grob, Jean-Jacques / Gutzmer, Ralf / Jamal, Rahima / Lorigan, Paul / Ibrahim, Nageatte / Marreaud, Sandrine / van Akkooi, Alexander C J / Suciu, Stefan / Robert, Caroline. ·From the Gustave Roussy Cancer Campus Grand Paris and University Paris-Saclay, Villejuif (A.M.M.E., C.R.), Hospices Civils de Lyon Cancer Institute, Cancer Research Center of Lyon, Lyon University, Lyon (S.D.), and Aix-Marseille University, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, Marseille (J.-J.G.) - all in France · Netherlands Cancer Institute-Antoni van Leeuwenhoek (C.U.B., A.C.J.A.) and VU University Medical Center (A.J.M.E.), Amsterdam, and Radboud University Medical Center Nijmegen, Nijmegen (R.K.) - all in the Netherlands · Azienda Ospedaliera Papa Giovanni XXIII, Bergamo (M. Mandala), Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Fondazione G. Pascale, Naples (P.A.A.), and Universita Degli Studi Di Siena-Policlinico le Scotte, Siena (M. Maio) - all in Italy · Melanoma Institute Australia, the University of Sydney, and Mater and Royal North Shore Hospitals (G.V.L.) and Westmead and Blacktown Hospitals, Melanoma Institute Australia and the University of Sydney (M.S.C.), Sydney, Princess Alexandra Hospital, University of Queensland, Brisbane (V.A.), Alfred Hospital (A.H.) and Peter MacCallum Cancer Centre (S. Sandhu), Melbourne, VIC, and Fiona Stanley Hospital-University of Western Australia-Edith Cowan University Perth, Perth (A.K.) - all in Australia · Cancer Research Center, Moscow (M.L.) · Royal Marsden Hospital, London (J.L.) · Hospital Clinic Universitari de Barcelona, Barcelona (S.P.) · Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland (P.R.) · University Hospital Essen, Essen and German Cancer Consortium, Heidelberg (D.S.), and the Skin Cancer Center, Department of Dermatology, Hannover Medical School, Hannover (R.G.) - all in Germany · Washington University School of Medicine, St. Louis (L.H.-A.) · Centre Hospitalier de l'Université de Montréal (CHUM), Centre de Recherche du CHUM, Montreal (R.J.) · Christie NHS Foundation Trust, Manchester, United Kingdom (P.L.) · Merck, Kenilworth, NJ (N.I.) · and the European Organization for the Research and Treatment of Cancer Headquarters, Brussels (S.M., S. Suciu). ·N Engl J Med · Pubmed #29658430.

ABSTRACT: BACKGROUND: The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma. METHODS: Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated. RESULTS: At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group. CONCLUSIONS: As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified. (Funded by Merck; ClinicalTrials.gov number, NCT02362594 ; EudraCT number, 2014-004944-37 .).

5 Clinical Trial Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. 2017

Coens, Corneel / Suciu, Stefan / Chiarion-Sileni, Vanna / Grob, Jean-Jacques / Dummer, Reinhard / Wolchok, Jedd D / Schmidt, Henrik / Hamid, Omid / Robert, Caroline / Ascierto, Paolo A / Richards, Jon M / Lebbé, Celeste / Ferraresi, Virginia / Smylie, Michael / Weber, Jeffrey S / Maio, Michele / Bottomley, Andrew / Kotapati, Srividya / de Pril, Veerle / Testori, Alessandro / Eggermont, Alexander M M. ·EORTC Headquarters, Brussels, Belgium. Electronic address: corneel.coens@eortc.be. · EORTC Headquarters, Brussels, Belgium. · IOV-IRCCS, Melanoma Oncology Unit, Padova, Italy. · Hôpital de la Timone, Marseille, France. · University of Zürich Hospital, Zürich, Switzerland. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Aarhus University Hospital, Aarhus, Denmark. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. · Istituto Nazionale Tumori Fondazione "G. Pascale", Naples, Italy. · Oncology Specialists S C, Park Ridge, IL, USA. · Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Paris. · Istituti Fisioterapici Ospitalieri, Rome, Italy. · Cross Cancer Institute, Edmonton, AB, Canada. · H Lee Moffitt Cancer Center, Tampa, FL, USA. · University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. · Bristol-Myers Squibb, Wallingford, CT, USA. · Bristol-Myers Squibb, Braine-l'Alleud, Belgium. · European Institute of Oncology, Milan, Italy. ·Lancet Oncol · Pubmed #28162999.

ABSTRACT: BACKGROUND: The EORTC 18071 phase 3 trial compared adjuvant ipilimumab with placebo in patients with stage III melanoma. The primary endpoint, recurrence-free survival, was significantly longer in the ipilimumab group than in the placebo group. Investigator-reported toxic effects of ipilimumab consisted mainly of skin, gastrointestinal, endocrine, and hepatic immune-related adverse events. Adjuvant treatment with ipilimumab in this setting was approved in October, 2014, by the US Food and Drug Administration based on the results of the primary outcome of this trial. Here, we report the results of the secondary endpoint, health-related quality of life (HRQoL), of this trial. METHODS: EORTC 18071 was a multinational, double-blind, randomised, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) in 19 countries worldwide. Participants were randomly assigned (1:1) centrally by an interactive voice response system, to receive either ipilimumab 10 mg/kg or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. HRQoL was assessed with the EORTC QLQ-C30 quality-of-life instrument at baseline, weeks 4, 7, 10, and 24, and every 12 weeks thereafter up to 2 years, irrespective of disease progression. Results were summarised by timepoint and in a longitudinal manner in the intention-to-treat population. Two summary scores were calculated for each HRQoL scale: the average score reported during induction (ipilimumab or placebo at a dose of 10 mg/kg, administered as one single dose at the start of days 1, 22, 43, and 64-ie, four doses in 3 weeks), and the average score reported after induction. A predefined threshold of a 10 point difference between arms was considered clinically relevant. The primary HRQoL endpoint was the global health scale, with the predefined hypothesis of no clinically relevant differences after induction between groups. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. FINDINGS: Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to treatment: 475 in the ipilimumab group and 476 in the placebo group. Compliance with completing the HRQoL questionnaire was 893 (94%) of 951 patients at baseline, 693 (75%) of 924 at week 24, and 354 (51%) of 697 at week 108. Patient mean global health scores during (77·32 [SD 17·36] vs 72·96 [17·82]; p=0·00011) and after induction (76·48 [17·52] vs 72·32 [18·60]; p=0·00067) were statistically significantly different between groups but were not clinically relevant. Mean global health scores differed most between the groups at week 7 (77 [SD 19] in the placebo group vs 72 [22] in the ipilimumab group) and week 10 (77 [20] vs 70 [23]). Mean HRQoL scores differed by more than 10 points at week 10 between treatment groups for diarrhoea (7·67 [SD 17·05] for placebo vs 18·17 [28·35] for ipilimumab) and insomnia (15·17 [22·53] vs 25·60 [29·19]). INTERPRETATION: Despite increased toxicity, which led to treatment discontinuation for most patients during the induction phase of ipilimumab administration, overall HRQoL, as measured by the EORTC QLQ-C30, was similar between groups, as no clinically relevant differences (10 points or more) in global health status scores were observed during or after induction. Clinically relevant deterioration for some symptoms was observed at week 10, but after induction, no clinically relevant differences remained. Together with the primary analysis, results from this trial show that treatment with ipilimumab results in longer recurrence-free survival compared with that for treatment with placebo, with little impairment in HRQoL despite grade 3-4 investigator-reported adverse events. FUNDING: Bristol-Myers Squibb.

6 Clinical Trial Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. 2016

Eggermont, Alexander M M / Chiarion-Sileni, Vanna / Grob, Jean-Jacques / Dummer, Reinhard / Wolchok, Jedd D / Schmidt, Henrik / Hamid, Omid / Robert, Caroline / Ascierto, Paolo A / Richards, Jon M / Lebbé, Céleste / Ferraresi, Virginia / Smylie, Michael / Weber, Jeffrey S / Maio, Michele / Bastholt, Lars / Mortier, Laurent / Thomas, Luc / Tahir, Saad / Hauschild, Axel / Hassel, Jessica C / Hodi, F Stephen / Taitt, Corina / de Pril, Veerle / de Schaetzen, Gaetan / Suciu, Stefan / Testori, Alessandro. ·From Gustave Roussy Cancer Campus Grand Paris, Villejuif (A.M.M.E., C.R.), Aix-Marseille University, Hôpital de La Timone, Marseille (J.-J.G.), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Paris (C.L.), University Lille, INSERM Unité-1189, Centre Hospitalier Universitaire (CHU) Lille, Service de Dermatologie, Lille (L.M.), and CHU Lyon, Lyon (L.T.) - all in France · the Oncology Institute of Veneto-Istituto di Ricovero e Cura a Carattere Scientifico, Padua (V.C.-S.), Istituto Nazionale Tumori Fondazione G. Pascale, Naples (P.A.A.), Istituti Fisioterapici Ospitalieri, Rome (V.F.), University Hospital of Siena, Istituto Toscano Tumori, Siena (M.M.), and the European Institute of Oncology, Milan (A.T.) - all in Italy · University of Zurich Hospital, Zurich, Switzerland (R.D.) · Memorial Sloan Kettering Cancer Center, New York (J.D.W.) · Aarhus University Hospital, Aarhus (H.S.), and Odense University Hospital, Odense (L.B.) - both in Denmark · the Angeles Clinic and Research Institute, Los Angeles (O.H.) · Oncology Specialists, Park Ridge, IL (J.M.R.) · Cross Cancer Institute, Edmonton, AB, Canada (M.S.) · H. Lee Moffitt Cancer Center, Tampa, FL (J.S.W.) · Broomfield Hospital, Chelmsford, United Kingdom (S.T.) · Universitätsklinikum Schleswig-Holstein, Kiel (A.H.), and University Hospital Heidelberg, Heidelberg (J.C.H.) - both in Germany · Dana-Farber Cancer Institute, Boston (F.S.H.) · Bristol-Myers Squibb, Princeton, NJ (C.T., V.P.) · and the European Organization for Research and Treatment of Cancer, Brussels (G.S., S.S.). ·N Engl J Med · Pubmed #27717298.

ABSTRACT: BACKGROUND: On the basis of data from a phase 2 trial that compared the checkpoint inhibitor ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram of body weight in patients with advanced melanoma, this phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had undergone complete resection of stage III melanoma. METHODS: After patients had undergone complete resection of stage III cutaneous melanoma, we randomly assigned them to receive ipilimumab at a dose of 10 mg per kilogram (475 patients) or placebo (476) every 3 weeks for four doses, then every 3 months for up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred. Recurrence-free survival was the primary end point. Secondary end points included overall survival, distant metastasis-free survival, and safety. RESULTS: At a median follow-up of 5.3 years, the 5-year rate of recurrence-free survival was 40.8% in the ipilimumab group, as compared with 30.3% in the placebo group (hazard ratio for recurrence or death, 0.76; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). The rate of overall survival at 5 years was 65.4% in the ipilimumab group, as compared with 54.4% in the placebo group (hazard ratio for death, 0.72; 95.1% CI, 0.58 to 0.88; P=0.001). The rate of distant metastasis-free survival at 5 years was 48.3% in the ipilimumab group, as compared with 38.9% in the placebo group (hazard ratio for death or distant metastasis, 0.76; 95.8% CI, 0.64 to 0.92; P=0.002). Adverse events of grade 3 or 4 occurred in 54.1% of the patients in the ipilimumab group and in 26.2% of those in the placebo group. Immune-related adverse events of grade 3 or 4 occurred in 41.6% of the patients in the ipilimumab group and in 2.7% of those in the placebo group. In the ipilimumab group, 5 patients (1.1%) died owing to immune-related adverse events. CONCLUSIONS: As adjuvant therapy for high-risk stage III melanoma, ipilimumab at a dose of 10 mg per kilogram resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis-free survival than placebo. There were more immune-related adverse events with ipilimumab than with placebo. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00636168 , and EudraCT number, 2007-001974-10 .).

7 Clinical Trial Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. 2015

Eggermont, Alexander M M / Chiarion-Sileni, Vanna / Grob, Jean-Jacques / Dummer, Reinhard / Wolchok, Jedd D / Schmidt, Henrik / Hamid, Omid / Robert, Caroline / Ascierto, Paolo A / Richards, Jon M / Lebbé, Céleste / Ferraresi, Virginia / Smylie, Michael / Weber, Jeffrey S / Maio, Michele / Konto, Cyril / Hoos, Axel / de Pril, Veerle / Gurunath, Ravichandra Karra / de Schaetzen, Gaetan / Suciu, Stefan / Testori, Alessandro. ·Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. Electronic address: alexander.eggermont@gustaveroussy.fr. · IOV-IRCCS, Melanoma Oncology Unit, Padova, Italy. · Aix-Marseille University, Hôpital de La Timone APHM, Marseille, France. · University of Zürich Hospital, Zürich, Switzerland. · Memorial Sloan-Kettering Cancer Center, New York, NY, USA. · Aarhus University Hospital, Aarhus, Denmark. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. · Istituto Nazionale Tumori Fondazione G Pascale, Naples, Italy. · Oncology Specialists SC, Park Ridge, IL, USA. · Assistance Publique Hôpitaux de Paris, Dermatology and CIC Departments, Hôpital Saint Louis, University Paris 7, INSERM U976, France. · Istituti Fisioterapici Ospitalieri, Rome, Italy. · Cross Cancer Institute, Edmonton, Alberta, Canada. · H Lee Moffitt Cancer Center, Tampa, FL, USA. · University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. · Bristol-Myers Squibb, Wallingford, CT, USA. · Bristol-Myers Squibb, Braine-l'Alleud, Belgium. · EORTC Headquarters, Brussels, Belgium. · European Institute of Oncology, Milan, Italy. ·Lancet Oncol · Pubmed #25840693.

ABSTRACT: BACKGROUND: Ipilimumab is an approved treatment for patients with advanced melanoma. We aimed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence. METHODS: We did a double-blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. FINDINGS: Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2·74 years (IQR 2·28-3·22), there were 528 recurrence-free survival events (234 in the ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26·1 months (95% CI 19·3-39·3) in the ipilimumab group versus 17·1 months (95% CI 13·4-21·6) in the placebo group (hazard ratio 0·75; 95% CI 0·64-0·90; p=0·0013); 3-year recurrence-free survival was 46·5% (95% CI 41·5-51·3) in the ipilimumab group versus 34·8% (30·1-39·5) in the placebo group. The most common grade 3-4 immune-related adverse events in the ipilimumab group were gastrointestinal (75 [16%] vs four [<1%] in the placebo group), hepatic (50 [11%] vs one [<1%]), and endocrine (40 [8%] vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started ipilimumab (182 [39%] during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barré syndrome. INTERPRETATION: Adjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk-benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value. FUNDING: Bristol-Myers Squibb.

8 Clinical Trial Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial. 2014

Leyvraz, S / Piperno-Neumann, S / Suciu, S / Baurain, J F / Zdzienicki, M / Testori, A / Marshall, E / Scheulen, M / Jouary, T / Negrier, S / Vermorken, J B / Kaempgen, E / Durando, X / Schadendorf, D / Gurunath, R Karra / Keilholz, U. ·Oncology Department, University Hospital, Lausanne, Switzerland. ·Ann Oncol · Pubmed #24510314.

ABSTRACT: BACKGROUND: In uveal melanoma (UM) with metastatic disease limited to the liver, the effect of an intrahepatic treatment on survival is unknown. We investigated prospectively the efficacy and toxicity of hepatic intra-arterial (HIA) versus systemic (IV) fotemustine in patients with liver metastases from UM. PATIENTS AND METHODS: Patients were randomly assigned to receive either IV or HIA fotemustine at 100 mg/m(2) on days 1, 8, 15 (and 22 in HIA arm only) as induction, and after a 5-week rest period every 3 weeks as maintenance. Primary end point was overall survival (OS). Response rate (RR), progression-free survival (PFS) and safety were secondary end points. RESULTS: Accrual was stopped after randomization of 171 patients based on the results of a futility OS analysis. A total of 155 patients died and 16 were still alive [median follow-up 1.6 years (range 0.25-6 years)]. HIA did not improve OS (median 14.6 months) when compared with the IV arm (median 13.8 months), hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.79-1.50, log-rank P = 0.59. However, there was a significant benefit on PFS for HIA compared with IV with a median of 4.5 versus 3.5 months, respectively (HR 0.62; 95% CI 0.45-0.84, log-rank P = 0.002). The 1-year PFS rate was 24% in the HIA arm versus 8% in the IV arm. An improved RR was seen in the HIA (10.5%) compared with IV treatment (2.4%). In the IV arm, the most frequent grade ≥3 toxicity was thrombocytopenia (42.1%) and neutropenia (62.6%), compared with 21.2% and 28.7% in the HIA arm. The main grade ≥3 toxicity related to HIA was catheter complications (12%) and liver toxicity (4.5%) apart from two toxic deaths. CONCLUSION: HIA treatment with fotemustine did not translate into an improved OS compared with IV treatment, despite better RR and PFS. Intrahepatic treatment should still be considered as experimental. EUDRACT NUMBER AND CLINICALTRIALSGOV IDENTIFIER: 2004-002245-12 and NCT00110123.

9 Clinical Trial Adjuvant ganglioside GM2-KLH/QS-21 vaccination versus observation after resection of primary tumor > 1.5 mm in patients with stage II melanoma: results of the EORTC 18961 randomized phase III trial. 2013

Eggermont, Alexander M M / Suciu, Stefan / Rutkowski, Piotr / Marsden, Jeremy / Santinami, Mario / Corrie, Philippa / Aamdal, Steinar / Ascierto, Paolo A / Patel, Poulam M / Kruit, Wim H / Bastholt, Lars / Borgognoni, Lorenzo / Bernengo, Maria Grazia / Davidson, Neville / Polders, Larissa / Praet, Michel / Spatz, Alan. ·Alexander M.M. Eggermont, Institut de Cancérologie Gustave Roussy, Villejuif, Paris-Sud, and Université Paris-Sud, Kremlin Bicêtre, Paris, France · Stefan Suciu, Larissa Polders, and Michel Praet, European Organisation for Research and Treatment of Cancer, Brussels, Belgium · Piotr Rutkowski, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland · Jeremy Marsden, University Hospital Birmingham, Birmingham · Philippa Corrie, Addenbrookes Hospital, Cambridge · Poulam M. Patel, University of Nottingham, Nottingham · Neville Davidson, Broomfield Hospital, Broomfield, United Kingdom · Mario Santinami, Istituto Nazionale dei Tumori, Milan · Paolo A. Ascierto, Istituto Nazionale Tumori Fondazione Pascale, Napoli · Lorenzo Borgognoni, Istituto Tumori Toscano, S. Maria Annunziata Hospital, Florence · Maria Grazia Bernengo, University Hospital Turin, Turin, Italy · Steinar Aamdal, Oslo University Hospital and Radium Hospital, Oslo, Norway · Wim H. Kruit, Erasmus University Medical Center-Daniel den Hoed Cancer Center, Rotterdam, the Netherlands · Lars Bastholt, Odense University Hospital, Odense, Denmark · and Alan Spatz, McGill University and Lady Davis Institute for Medical Research, Montreal, Quebec, Canada. ·J Clin Oncol · Pubmed #24019551.

ABSTRACT: PURPOSE: The GM2 ganglioside is an antigen expressed in the majority of melanomas. The GM2-KLH/QS-21 vaccine induces high immunoglobulin M (IgM) and IgG antibody responses. The EORTC 18961 trial compared the efficacy of GM2-KLH/QS-21 vaccination versus observation. PATIENTS AND METHODS: A total of 1,314 patients with a primary tumor > 1.50 mm in thickness (T3-4N0M0; American Joint Committee on Cancer stage II) were randomly assigned to GM2-KLH/QS-21 vaccination (n = 657) or observation (n = 657). Treatment consisted of subcutaneous injections once per week from week 1 to 4, then every 3 months for the first 2 years and every 6 months during the third year. Primary end point was relapse-free survival (RFS). Secondary end points were distant metastasis-free survival (DMFS) and overall survival (OS). Analyses were by intent to treat. RESULTS: After a median follow-up of 1.8 years, the trial was stopped at the second interim analysis for futility regarding RFS (hazard ratio [HR], 1.00; P = .99) and detrimental outcome regarding OS (HR, 1.66; P = .02). After a median follow-up of 4.2 years, we had recorded 400 relapses, nine deaths without relapse, a total of 236 deaths. At 4 years, the vaccination arm showed a decreased RFS rate of 1.2% (HR, 1.03; 95% CI, 0.84 to 1.25) and OS rate of 2.1% (HR, 1.16; 95% CI, 0.90 to 1.51). Toxicity was acceptable, with 4.6% of patients ending study participation because of toxicity. CONCLUSION: GM2-KLH/QS-21 vaccination does not improve outcome for patients with stage II melanoma.

10 Clinical Trial Selection of immunostimulant AS15 for active immunization with MAGE-A3 protein: results of a randomized phase II study of the European Organisation for Research and Treatment of Cancer Melanoma Group in Metastatic Melanoma. 2013

Kruit, Wim H J / Suciu, Stefan / Dreno, Brigitte / Mortier, Laurent / Robert, Caroline / Chiarion-Sileni, Vanna / Maio, Michele / Testori, Alessandro / Dorval, Thierry / Grob, Jean-Jacques / Becker, Juergen C / Spatz, Alan / Eggermont, Alexander M M / Louahed, Jamila / Lehmann, Frédéric F / Brichard, Vincent G / Keilholz, Ulrich. ·Department of Internal Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, the Netherlands. w.kruit@erasmusmc.nl ·J Clin Oncol · Pubmed #23715572.

ABSTRACT: PURPOSE: Active immunization against the tumor-specific MAGE-A3 antigen is followed by a few but impressive and durable clinical responses. This randomized phase II trial evaluated two different immunostimulants combined with the MAGE-A3 protein to investigate whether a more robust and persistent immune response could be associated with increased clinical benefit. PATIENTS AND METHODS: Patients with MAGE-A3-positive stage III or IV M1a melanoma were randomly assigned to receive the MAGE-A3 protein combined either with AS02B or with AS15 immunostimulant. Clinical end points were toxicity and rates of objective clinical responses, progression-free survival (PFS), and overall survival (OS). RESULTS: Seventy-five patients were treated, with 36 eligible patients per arm. Both treatments were well tolerated. In the AS15 arm, four objective responses were observed (three complete responses and one partial response) versus one partial response in the AS02B arm. In the AS15 and AS02B arms, the PFS rates after 6 months were 25% and 14%, respectively; and the median OS times were 33 months and 19.9 months, respectively, with a median observation period of 48 months. Antibodies against MAGE-A3, found in all patients, showed three-fold higher titers in the AS15 arm. The anti-MAGE-A3 cellular response was also more pronounced in the AS15 arm. CONCLUSION: In the MAGE-A3+AS15 arm, clinical activity was higher and the immune response more robust. Therefore, the AS15 immunostimulant was selected for combination with the MAGE-A3 protein in phase III trials.

11 Clinical Trial Predictive gene signature in MAGE-A3 antigen-specific cancer immunotherapy. 2013

Ulloa-Montoya, Fernando / Louahed, Jamila / Dizier, Benjamin / Gruselle, Olivier / Spiessens, Bart / Lehmann, Frédéric F / Suciu, Stefan / Kruit, Wim H J / Eggermont, Alexander M M / Vansteenkiste, Johan / Brichard, Vincent G. ·GlaxoSmithKline Vaccines, Rixensart, Belgium. ·J Clin Oncol · Pubmed #23715562.

ABSTRACT: PURPOSE: To detect a pretreatment gene expression signature (GS) predictive of response to MAGE-A3 immunotherapeutic in patients with metastatic melanoma and to investigate its applicability in a different cancer setting (adjuvant therapy of resected early-stage non-small-cell lung cancer [NSCLC]). PATIENTS AND METHODS: Patients were participants in two phase II studies of the recombinant MAGE-A3 antigen combined with an immunostimulant (AS15 or AS02B). mRNA from melanoma biopsies was analyzed by microarray analysis and quantitative polymerase chain reaction. These results were used to identify and cross-validate the GS, which was then applied to the NSCLC data. RESULTS: In the patients with melanoma, 84 genes were identified whose expression was potentially associated with clinical benefit. This effect was strongest when the immunostimulant AS15 was included in the immunotherapy (hazard ratio [HR] for overall survival, 0.37; 95% CI, 0.13 to 1.05; P = .06) and was less strong with the other immunostimulant AS02B (HR, 0.84; 95% CI, 0.36 to 1.97; P = .70). The same GS was then used to predict the outcome for patients with resected NSCLC treated with MAGE-A3 plus AS02B; actively treated GS-positive patients showed a favorable disease-free interval compared with placebo-treated GS-positive patients (HR, 0.42; 95% CI, 0.17 to 1.03; P = .06), whereas among GS-negative patients, no such difference was found (HR, 1.17; 95% CI, 0.59 to 2.31; P = .65). The genes identified were mainly immune related, involving interferon gamma pathways and specific chemokines, suggesting that their pretreatment expression influences the tumor's immune microenvironment and the patient's clinical response. CONCLUSION: An 84-gene GS associated with clinical response for MAGE-A3 immunotherapeutic was identified in metastatic melanoma and confirmed in resected NSCLC.

12 Clinical Trial Analysis of surrogate gene expression markers in peripheral blood of melanoma patients to predict treatment outcome of adjuvant pegylated interferon alpha 2b (EORTC 18991 side study). 2013

Busse, Antonia / Rapion, Jérôme / Fusi, Alberto / Suciu, Stefan / Nonnenmacher, Anika / Santinami, Mario / Kruit, Wim H J / Testori, Alessandro / Punt, Cornelis J A / Dalgleish, Angus G / Spatz, Alan / Eggermont, Alexander M M / Keilholz, Ulrich. ·Department of Medicine III, Charité-CBF, Hindenburgdamm 30, 12200, Berlin, Germany. antonia.busse@charite.de ·Cancer Immunol Immunother · Pubmed #23624802.

ABSTRACT: We analysed mRNA levels of interferon response genes (ISG15, STAT1, CXCL10) of inhibitors of the JAK/STAT pathway (STAT3, SOCS1, SOCS3) and of cytokines (TNFα, IL10, TGFß1) in peripheral blood of 91 stage III melanoma patients enrolled in EORTC 18991 trial to find biomarkers indicative for disease stage and predictive for efficacy of pegylated interferon alpha-2b (PEG-IFNα-2b) therapy. mRNA levels were analysed at baseline and after 6 months. Univariate and multivariate analyses were performed to estimate the prognostic and predictive role of mRNA levels for distant metastasis-free survival (DMFS) and relapse-free survival (RFS). Compared to healthy controls, melanoma patients showed significantly higher TGFβ1 mRNA levels. In a multivariate model, increasing SOCS1 and SOCS3 mRNA levels were associated with worse RFS (P = 0.02 and P = 0.04, respectively) and DMFS (P = 0.05 and P = 0.05, respectively) due to negative correlation between, respectively, SOCS1/SOCS3 mRNA levels and ulceration or Breslow thickness. No impact of PEG-IFNα-2b on mRNA levels was observed except for ISG15 mRNA levels, which decreased in the treatment arm (P = 0.001). It seems that patients with a decrease >60 % of ISG15 mRNA levels during 6 months PEG-IFNα-2b had inferior outcome.

13 Clinical Trial 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. 2012

Eggermont, Alexander M M / Suciu, Stefan / Testori, Alessandro / Santinami, Mario / Kruit, Wim H J / Marsden, Jeremy / Punt, Cornelis J A / Salès, François / Dummer, Reinhard / Robert, Caroline / Schadendorf, Dirk / Patel, Poulam M / de Schaetzen, Gaetan / Spatz, Alan / Keilholz, Ulrich. ·Institute de Cancérologie Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, Paris-Sud, France. alexander.eggermont@igr.fr ·J Clin Oncol · Pubmed #23008300.

ABSTRACT: PURPOSE: Adjuvant pegylated interferon alfa-2b (PEG-IFN-α-2b) was approved for treatment of resected stage III melanoma in 2011. Here, we present long-term follow-up results of this pivotal trial. PATIENTS AND METHODS: In all, 1,256 patients with resected stage III melanoma were randomly assigned to observation (n = 629) or PEG-IFN-α-2b (n = 627) for an intended duration of 5 years. Stratification factors were microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumor thickness, sex, and center. Recurrence-free survival (RFS; primary end point), distant metastasis-free survival (DMFS), and overall survival (OS) were analyzed for the intent-to-treat population. RESULTS: At 7.6 years median follow-up, 384 recurrences or deaths had occurred with PEG-IFN-α-2b versus 406 in the observation group (hazard ratio [HR], 0.87; 95% CI, 0.76 to 1.00; P = .055); 7-year RFS rate was 39.1% versus 34.6%. There was no difference in OS (P = .57). In stage III-N1 ulcerated melanoma, RFS (HR, 0.72; 99% CI, 0.46 to 1.13; P = .06), DMFS (HR, 0.65; 99% CI, 0.41 to 1.04; P = .02), and OS (HR, 0.59; 99% CI, 0.35 to 0.97; P = .006) were prolonged with PEG-IFN-α-2b. PEG-IFN-α-2b was discontinued for toxicity in 37% of patients. CONCLUSION: Adjuvant PEG-IFN-α-2b for stage III melanoma had a positive impact on RFS, which was marginally significant and slightly diminished versus the benefit seen at prior follow-up (median, 3.8 years). No significant increase in DMFS or OS was noted in the overall population. Patients with ulcerated melanoma and lower disease burden had the greatest benefit.

14 Clinical Trial Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032). 2011

Patel, Poulam M / Suciu, Stefan / Mortier, Laurent / Kruit, Wim H / Robert, Caroline / Schadendorf, Dirk / Trefzer, Uwe / Punt, Cornelis J A / Dummer, Reinhard / Davidson, Neville / Becker, Juergen / Conry, Robert / Thompson, John A / Hwu, Wen-Jen / Engelen, Kristel / Agarwala, Sanjiv S / Keilholz, Ulrich / Eggermont, Alexander M M / Spatz, Alain / Anonymous2540695. ·Academic Unit of Clinical Oncology, University of Nottingham, Nottingham, United Kingdom. poulam.patel@nottingham.ac.uk ·Eur J Cancer · Pubmed #21600759.

ABSTRACT: PURPOSE: To compare the efficacy of an extended schedule escalated dose of temozolomide versus standard dose dacarbazine in a large population of patients with stage IV melanoma. PATIENTS AND METHODS: A total of 859 patients were randomised to receive oral temozolomide at 150 mg/m(2)/day for seven consecutive days every 2 weeks or dacarbazine, administered as an intravenous infusion at 1000 mg/m(2)/day on day 1 every 3 weeks. The primary endpoint was overall survival (OS), using an intent-to-treat principle. EudraCT number 2004-000654-23 NCI registration number NCT00005052. RESULTS: Median OS was 9.1 months in the temozolomide arm and 9.4 months in the dacarbazine arm, with a hazard ratio (HR) of 1.00 (95%confidence interval [CI]: 0.86, 1.17; P=0.99). Median progression-free survival (PFS) was 2.3 months in the temozolomide arm and 2.2 months in the dacarbazine arm, with a HR of 0.92 (95%CI: 0.80, 1.06; P=0.27). In patients with measurable disease, overall response rate was higher in the temozolomide arm than in the dacarbazine arm (14.5% versus 9.8%, respectively), but the median duration of response was longer for dacarbazine. The extended schedule, escalated dose temozolomide arm showed more toxicity than the standard dose, single agent dacarbazine arm. The most common non-haematological treatment emergent adverse events reported in both treatment arms were nausea, fatigue and vomiting and constipation. CONCLUSION: Extended schedule escalated dose Temozolomide (7 days on 7 days off) is feasible and has an acceptable safety profile, but does not improve OS and PFS in metastatic melanoma when compared to standard dose dacarbazine.

15 Clinical Trial Prognostic value of serial blood S100B determinations in stage IIB-III melanoma patients: a corollary study to EORTC trial 18952. 2011

Bouwhuis, M G / Suciu, S / Kruit, W / Salès, F / Stoitchkov, K / Patel, P / Cocquyt, V / Thomas, J / Liénard, D / Eggermont, A M M / Ghanem, G / Anonymous2720679. ·Department of Surgical Oncology, Erasmus University MC - Daniel den Hoed Cancer Center, 301 Groene Hilledijk, 3075 EA Rotterdam, The Netherlands. ·Eur J Cancer · Pubmed #21087856.

ABSTRACT: S100B is a prognostic factor for melanoma as elevated levels correlate with disease progression and poor outcome. We determined its prognostic value based on updated information using serial determinations in stage IIb/III melanoma patients. 211 Patients who participated in the EORTC 18952 trial, evaluating efficacy of adjuvant intermediate doses of interferon α2b (IFN) versus observation, entered a corollary study. Over a period of 36 months, 918 serum samples were collected. The Cox time-dependent model was used to assess prognostic value of the latest (most recent) S100B determination. At first measurement, 178 patients had S100B values <0.2 μg/l and 33 ≥ 0.2 μg/l. Within the first group, 61 patients had, later on, an increased value of S100B (≥ 0.2 μg/l). An initial increased value of S100B, or during follow-up, was associated with worse distant metastasis-free survival (DMFS); hazard ratio (HR) of S100B ≥ 0.2 versus S100B < 0.2 was 5.57 (95% confidence interval (CI) 3.81-8.16), P < 0.0001, after adjustment for stage, number of lymph nodes and sex. In stage IIb patients, the HR adjusted for sex was 2.14 (95% CI 0.71, 6.42), whereas in stage III, the HR adjusted for stage, number of lymph nodes and sex was 6.76 (95% CI 4.50-10.16). Similar results were observed regarding overall survival (OS). Serial determination of S100B in stage IIb-III melanoma is a strong independent prognostic marker, even stronger compared to stage and number of positive lymph nodes. The prognostic impact of S100B ≥ 0.2 μg/l is more pronounced in stage III disease compared with stage IIb.

16 Clinical Trial Phase III trial comparing adjuvant treatment with pegylated interferon Alfa-2b versus observation: prognostic significance of autoantibodies--EORTC 18991. 2010

Bouwhuis, Marna G / Suciu, Stefan / Testori, Alessandro / Kruit, Wim H / Salès, François / Patel, Poulam / Punt, Cornelis J / Santinami, Mario / Spatz, Alain / Ten Hagen, Timo L M / Eggermont, Alexander M M. ·Department of Surgery, Division Surgical Oncology, Erasmus University Medical Center-Daniel den Hoed Cancer Center, Rotterdam, the Netherlands. ·J Clin Oncol · Pubmed #20385998.

ABSTRACT: PURPOSE: Conflicting data have been reported concerning the prognostic value of autoimmune antibodies in patients with melanoma treated with adjuvant interferon alfa-2b (IFN). We evaluated the prognostic significance of autoantibodies in the European Organisation for Research and Treatment of Cancer 18991 trial, comparing long-term administration of pegylated IFN (PEG-IFN) with observation. PATIENTS AND METHODS: Anticardiolipin, antithyroglobulin, and antinuclear antibodies were determined by enzyme-linked immunosorbent assays in 296 patients before random assignment and every 6 months after random assignment for up to 5 years. Prognostic impact of autoantibodies on recurrence-free survival (RFS) was assessed using the following three Cox models: a model that considered autoantibody appearance as a time-independent variable (model 1); a model that considered a patient to be autoantibody positive from the first positive test (model 2); and a model in which the most recent autoantibody test was used to define the status of the patient (model 3). RESULTS: Patients who were autoantibody negative at baseline were analyzed (n = 220). Occurrence of autoantibodies during follow-up was higher in the PEG-IFN-treated patients (18% in the observation arm v 52% in the PEG-IFN arm). Autoantibody appearance was of prognostic importance by using model 1 (hazard ratio [HR] = 0.56; 95% CI, 0.36 to 0.87; P = .01). However, when guarantee-time bias was taken into account using model 2 (HR = 1.19; 95% CI, 0.75 to 1.88; P = .46) or method 3 (HR = 1.14; 95% CI, 0.71 to 1.83; P = .59), significance was lost. Results were similar when treatment groups were analyzed separately. CONCLUSION: Appearance of autoimmune antibodies is neither a prognostic nor a predictive factor for improved outcome in patients with melanoma treated with PEG-IFN.

17 Clinical Trial Circulating melanoma cells and distant metastasis-free survival in stage III melanoma patients with or without adjuvant interferon treatment (EORTC 18991 side study). 2009

Fusi, Alberto / Collette, Sandra / Busse, Antonia / Suciu, Stefan / Rietz, Anika / Santinami, Mario / Kruit, Wim H J / Testori, Alessandro / Punt, Cornelis J A / Dalgleish, Angus G / Spatz, Alan / Eggermont, Alexander M M / Keilholz, Ulrich. ·Charité - Campus Benjamin Franklin, Berlin, Germany. ·Eur J Cancer · Pubmed #19793643.

ABSTRACT: AIM: To evaluate the prognostic and predictive importance of detection of melanoma cells in peripheral blood using reverse transcriptase polymerase chain reaction (RT-PCR) in stage III cutaneous melanoma patients after sentinel or regional lymph node dissection. PATIENTS AND METHODS: Serial testing for tyrosinase and Mart-1/Melan-A transcripts in peripheral blood was performed every 6 months over a maximum period of 60 months in a subset of patients enrolled in EORTC 18991 phase 3 trial, comparing pegylated interferon-alpha-2b with observation. Univariate and multivariate analyses were performed to estimate the role of RT-PCR as prognostic and predictive factor for distant metastasis-free survival (DMFS). RESULTS: Among 299 patients who underwent RT-PCR analyses, 109 (36.5%) had at least one positive sample, either at time of randomisation (N=17) or subsequently (N=92). The cumulative rate of positive results was similar in the two treatment groups, as the DMFS from first RT-PCR positivity. RT-PCR result, positive versus negative, at a given time point, had no prognostic impact on subsequent DMFS. Cox time-dependent analysis indicated a significantly higher risk of developing distant metastasis in patients with a positive sample as compared to those with a negative one: hazard ratio (HR) of 2.23 (95% confidence interval (CI), 1.40-3.55; p<.001). These results were comparable in the 2 treatment groups, indicating that RT-PCR assessment was not predictive for treatment outcome. CONCLUSION: Detection of circulating tumour cells by RT-PCR for tyrosinase and Mart-1/Melan-A was a time-dependent moderate prognostic factor for subsequent development of distant metastasis in stage III melanoma patients.

18 Clinical Trial Adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma: a phase III randomized controlled trial of health-related quality of life and symptoms by the European Organisation for Research and Treatment of Cancer Melanoma Group. 2009

Bottomley, Andrew / Coens, Corneel / Suciu, Stefan / Santinami, Mario / Kruit, Willem / Testori, Alessandro / Marsden, Jeremy / Punt, Cornelis / Salès, François / Gore, Martin / Mackie, Rona / Kusic, Zvonko / Dummer, Reinhard / Patel, Poulam / Schadendorf, Dirk / Spatz, Alain / Keilholz, Ulrich / Eggermont, Alexander. ·Quality of Life Department, EORTC Headquarters, Brussels, Belgium. andrew.bottomley@eortc.be ·J Clin Oncol · Pubmed #19433686.

ABSTRACT: PURPOSE: Interferon (IFN) -based adjuvant therapy in melanoma is associated with significant side effects, which necessitates evaluation of health-related quality of life (HRQOL). Our trial examined the HRQOL effects of adjuvant pegylated IFN-alpha-2b (PEG-IFN-alpha-2b) versus observation in patients with stage III melanoma. METHODS: A total of 1,256 patients with stage III melanoma were randomly assigned after full lymphadenectomy to receive either observation (n = 629) or PEG-IFN-alpha-2b (n = 627): induction 6 micrograms/kg/wk [DOSAGE ERROR CORRECTED] for 8 weeks then maintenance 3 micrograms/kg/wk [DOSAGE ERROR CORRECTED] for an intended total duration of 5 years. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 was used to assess HRQOL. RESULTS: At 3.8 years of median follow-up, for the primary end point, recurrence-free survival (RFS), risk was reduced by 18% (hazard rate = 0.82; P = .01) in the PEG-IFN-alpha-2b arm compared with observation. Significant and clinically meaningful differences occurred with the PEG-IFN-alpha-2b treatment arm compared with the observation group, showing decreased global HRQOL at month 3 (-11.6 points; 99% CI, -8.2 to -15.0) and year 2 (-10.5 points; 99% CI, -6.6 to -14.4). Many of the other scales showed statistically significant differences between scores when comparing the two arms. From a clinical point of view, important differences were found for five scales: two functioning scales (social and role functioning) and three symptom scales (appetite loss, fatigue, and dyspnea), with the PEG-IFN-alpha-2b arm being most impaired. CONCLUSION: PEG-IFN-alpha-2b leads to a significant and sustained improvement in RFS. There is an expected negative effect on global HRQOL and selected symptoms when patients undergo PEG-IFN-alpha-2b treatment.

19 Clinical Trial 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. 2008

Eggermont, Alexander M M / Suciu, Stefan / Santinami, Mario / Testori, Alessandro / Kruit, Wim H J / Marsden, Jeremy / Punt, Cornelis J A / Salès, François / Gore, Martin / Mackie, Rona / Kusic, Zvonko / Dummer, Reinhard / Hauschild, Axel / Musat, Elena / Spatz, Alain / Keilholz, Ulrich / Anonymous3870603. ·Erasmus University Medical Center, Rotterdam, Netherlands. a.m.m.eggermont@erasmusmc.nl ·Lancet · Pubmed #18620949.

ABSTRACT: BACKGROUND: Any benefit of adjuvant interferon alfa-2b for melanoma could depend on dose and duration of treatment. Our aim was to determine whether pegylated interferon alfa-2b can facilitate prolonged exposure while maintaining tolerability. METHODS: 1256 patients with resected stage III melanoma were randomly assigned to observation (n=629) or pegylated interferon alfa-2b (n=627) 6 mug/kg per week for 8 weeks (induction) then 3 mug/kg per week (maintenance) for an intended duration of 5 years. Randomisation was stratified for microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumour thickness, sex, and centre. Randomisation was done with a minimisation technique. The primary endpoint was recurrence-free survival. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00006249. FINDINGS: All randomised patients were included in the primary efficacy analysis. 608 patients in the interferon group and 613 patients in the observation group were included in safety analyses. The median length of treatment with pegylated interferon alfa-2b was 12 (IQR 3.8-33.4) months. At 3.8 (3.2-4.2) years median follow-up, 328 recurrence events had occurred in the interferon group compared with 368 in the observation group (hazard ratio 0.82, 95% CI 0.71-0.96; p=0.01); the 4-year rate of recurrence-free survival was 45.6% (SE 2.2) in the interferon group and 38.9% (2.2) in the observation group. There was no difference in overall survival between the groups. Grade 3 adverse events occurred in 246 (40%) patients in the interferon group and 60 (10%) in the observation group; grade 4 adverse events occurred in 32 (5%) patients in the interferon group and 14 (2%) in the observation group. In the interferon group, the most common grade 3 or 4 adverse events were fatigue (97 patients, 16%), hepatotoxicity (66, 11%), and depression (39, 6%). Treatment with pegylated interferon alfa-2b was discontinued because of toxicity in 191 (31%) patients. INTERPRETATION: Adjuvant pegylated interferon alfa-2b for stage III melanoma has a significant, sustained effect on recurrence-free survival.

20 Article Lymph node ratio as a prognostic factor in melanoma: results from European Organization for Research and Treatment of Cancer 18871, 18952, and 18991 studies. 2018

Testori, Alessandro A / Suciu, Stefan / van Akkooi, Alexander C J / Suppa, Mariano / Eggermont, Alexander M M / de Vries, Esther / Joosse, Arjen / Anonymous5131039. ·European Organization for Research and Treatment of Cancer Melanoma Group. · European Organization for Research and Treatment of Cancer (EORTC). · Department of Surgical Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam. · Department of Dermatology, Erasmus Hospital, Free University, Brussels, Belgium. · Gustave Roussy Oncology Institute, Villejuif/Paris-Sud, France. · Department of Public Health, Erasmus University Medical Center, Rotterdam. · Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine, Pontifical Javeriana University, Bogota, Colombia. · Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. ·Melanoma Res · Pubmed #29432281.

ABSTRACT: The aim of this study was to assess the prognostic importance of lymph node ratio (LNR) in stage III melanoma after complete lymph nodal dissections. From European Organization for Research and Treatment of Cancer randomized trials 18871, 18952, and 18991, 2358 patients had full information on positive and examined lymph nodes (LNs) and were included. Cox proportional hazards models stratified by trial were used to assess the prognostic impact of LNR adjusted for confounders on melanoma-specific survival. Optimal cutoff values for LNR were calculated for each LN dissection site (axillary, inguinal, and neck). LNR (≥ vs. <35%: hazard ratio=1.44, 95% confidence interval: 1.23-1.69) and number of positive LNs appeared to be of independent strong prognostic importance. Dissection sites impacted the optimal LNR cutoff: 35% for axillary, 40% for inguinal, and 50% for neck dissections. Combining these into one 'high versus low LNR' resulted in a highly significant multivariately adjusted hazard ratio of 1.48 (95% confidence interval: 1.26-1.74). In subgroup analyses, LNR was only significant in advanced disease (American Joint Committee on Cancer stage N2b, N3; IIIC). LNR was most significant for inguinal dissections, followed by axillary dissections, but seemed less useful in neck dissections. LNR is an independent significant prognostic factor in stage III melanoma patients. Our study showed higher than previously reported cutoffs that differed per dissection site. However, because of conflicting results compared with other studies and apparent limited prognostic impact confined to subgroups, the practical use of LNR seems limited.

21 Article Cost-effectiveness analysis in melanoma detection: A transition model applied to dermoscopy. 2016

Tromme, Isabelle / Legrand, Catherine / Devleesschauwer, Brecht / Leiter, Ulrike / Suciu, Stefan / Eggermont, Alexander / Sacré, Laurine / Baurain, Jean-François / Thomas, Luc / Beutels, Philippe / Speybroeck, Niko. ·Department of Dermatology, Institut Roi Albert II, Cliniques Universitaires St Luc, Université catholique de Louvain, Brussels, Belgium. Electronic address: Isabelle.tromme@uclouvain.be. · Institute of Statistics, Biostatistics and Actuarial Sciences, Université catholique de Louvain, Louvain-la-Neuve, Belgium. · Department of Public Health and Surveillance, Scientific Institute of Public Health (WIV-ISP), Brussels, Belgium. · Department of Dermatology, Eberhard Karls University, Tübingen, Germany. · European Organization for Research and Treatment of Cancer, Brussels, Belgium. · Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. · Department of Dermatology, Institut Roi Albert II, Cliniques Universitaires St Luc, Université catholique de Louvain, Brussels, Belgium. · Department of Medical Oncology, Institut Roi Albert II, Cliniques Universitaires St Luc, Université catholique de Louvain, Brussels, Belgium. · Department of Dermatology, Centre Hospitalier Lyon Sud, Lyon 1 University, Lyons Cancer Research Center, France. · Centre for Health Economics Research & Modelling Infectious Diseases, Vaccine & Infectious Disease Institute, Faculty of Medicine & Health Sciences, University of Antwerp, Belgium. · Institute of Health and Society (IRSS), Université catholique de Louvain, Brussels, Belgium. ·Eur J Cancer · Pubmed #27592070.

ABSTRACT: AIM: The main aim of this study is to demonstrate how our melanoma disease model (MDM) can be used for cost-effectiveness analyses (CEAs) in the melanoma detection field. In particular, we used the data of two cohorts of Belgian melanoma patients to investigate the cost-effectiveness of dermoscopy. METHODS: A MDM, previously constructed to calculate the melanoma burden, was slightly modified to be suitable for CEAs. Two cohorts of patients entered into the model to calculate morbidity, mortality and costs. These cohorts were constituted by melanoma patients diagnosed by dermatologists adequately, or not adequately, trained in dermoscopy. Effectiveness and costs were calculated for each cohort and compared. Effectiveness was expressed in quality-adjusted life years (QALYs), a composite measure depending on melanoma-related morbidity and mortality. Costs included costs of treatment and follow-up as well as costs of detection in non-melanoma patients and costs of excision and pathology of benign lesions excised to rule out melanoma. RESULTS: The result of our analysis concluded that melanoma diagnosis by dermatologists adequately trained in dermoscopy resulted in both a gain of QALYs (less morbidity and/or mortality) and a reduction in costs. CONCLUSION: This study demonstrates how our MDM can be used in CEAs in the melanoma detection field. The model and the methodology suggested in this paper were applied to two cohorts of Belgian melanoma patients. Their analysis concluded that adequate dermoscopy training is cost-effective. The results should be confirmed by a large-scale randomised study.

22 Article Prognostic and predictive value of YKL-40 in stage IIB-III melanoma. 2016

Krogh, Merete / Christensen, Ib / Bouwhuis, Marna / Johansen, Julia S / Nørgaard, Peter / Schmidt, Henrik / Hansson, Johan / Suciu, Stefan / Eggermont, Alexander M M / Bastholt, Lars / Anonymous5560864. ·aDepartment of Oncology, Odense University Hospital, Odense C bThe Finsen Laboratory, Rigshospitalet, and Biotech Research and Innovation Centre, University of Copenhagen, København Departments of cOncology dMedicine ePathology, Herlev University Hospital, Herlev fAarhus University Hospital, Aarhus, Denmark gDepartment of Surgical Oncology, Erasmus University Medical Center-Daniel Den Hoed Cancer Center, Rotterdam, The Netherlands hKarolinska Institute, Stockholm, Sweden iEORTC Headquarters, Brussels, Belgium jGustave Roussy Cancer Institute, Villejuif, France. ·Melanoma Res · Pubmed #27076041.

ABSTRACT: This study investigates the prognostic and predictive value of YKL-40 in stage IIB-III melanoma patients who were randomized to adjuvant interferon α-2b (IFN) or observation. Serum YKL-40 was determined postoperatively in patients from the Nordic IFN Trial (n=602), EORTC 18952 (n=246), and EORTC 18991 (n=386) (EORTC, European Organisation for Research and Treatment of Cancer). YKL-40 protein expression was determined in 300 tissue sections of primary melanoma or lymph node metastases from 204 Danish patients from the Nordic IFN Trial. Multivariate Cox analysis (including sex, age, stage, ulceration, YKL-40) showed that elevated baseline YKL-40 level was associated with shorter overall survival (OS) in observation groups from the Nordic IFN Trial and EORTC 18952 [hazard ratio (HR)=1.33; 95% confidence interval (CI) 1.01-1.74; P=0.04], but not in the interferon groups (1-year IFN: HR=0.97; 95% CI 0.76-1.25; P=0.83; 2-years IFN: HR=1.06; 95% CI 0.83-1.34; P=0.64). During follow-up, increases in YKL-40 were significantly associated with shorter OS, but not with recurrence-free survival in univariate analysis. YKL-40 expression was stronger in tumor-associated macrophages than melanoma cells in primary melanoma. High YKL-40 expression in macrophages in lymph node metastases was associated with shorter OS in the observation group (HR=2.76; 95% CI: 1.13-6.76, P=0.02), but not in the interferon-treated groups. YKL-40 was an independent prognostic biomarker of OS in melanoma patients stage IIB-III. High serum YKL-40 in poor-prognosis patients may originate from macrophages in the tumor microenvironment and the melanoma cells. Furthermore, we hypothesize that elevated serum YKL-40 after surgery may predict the efficacy of adjuvant IFN treatment.

23 Article 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. 2016

Eggermont, Alexander M M / Suciu, Stefan / Rutkowski, Piotr / Kruit, Willem H / Punt, Cornelis J / Dummer, Reinhard / Salès, François / Keilholz, Ulrich / de Schaetzen, Gaetan / Testori, Alessandro / Anonymous5230855. ·Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. Electronic address: alexander.eggermont@gustaveroussy.fr. · EORTC Headquarters, Brussels, Belgium. · Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland. · Erasmus MC Cancer Institute - Location Daniel den Hoed, Rotterdam, The Netherlands. · Academisch Medisch Centrum - Universiteit van Amsterdam, Amsterdam, The Netherlands. · Universitaetsspital Zurich, Zürich, Switzerland. · Institut Jules Bordet, Brussels, Belgium. · Charité, Berlin, Germany. · Istituto Europeo di Oncologia, Milan, Italy. ·Eur J Cancer · Pubmed #26790144.

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.

24 Article Melanoma burden by melanoma stage: Assessment through a disease transition model. 2016

Tromme, Isabelle / Legrand, Catherine / Devleesschauwer, Brecht / Leiter, Ulrike / Suciu, Stefan / Eggermont, Alexander / Francart, Julie / Calay, Frederic / Haagsma, Juanita A / Baurain, Jean-François / Thomas, Luc / Beutels, Philippe / Speybroeck, Niko. ·Department of Dermatology, Institut Roi Albert II, Cliniques Universitaires St Luc, Université catholique de Louvain, Brussels, Belgium. Electronic address: Isabelle.tromme@uclouvain.be. · Institute of Statistics, Biostatistics and Actuarial Sciences, Université catholique de Louvain, Louvain-la-Neuve, Belgium. · Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium; Institute of Health and Society (IRSS), Université catholique de Louvain, Brussels, Belgium. · Department of Dermatology, Eberhard Karls University, Tübingen, Germany. · European Organization for Research and Treatment of Cancer, Brussels, Belgium. · Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. · Belgian Cancer Registry, Brussels, Belgium. · Department of Public Health, Erasmus Medical Center, Erasmus University Rotterdam, The Netherlands. · Department of Medical Oncology, Institut Roi Albert II, Cliniques Universitaires St Luc, Université catholique de Louvain, Brussels, Belgium. · Department of Dermatology, Lyon 1 University, Centre Hospitalier Lyon Sud, France. · Centre for Health Economics Research & Modelling Infectious Diseases, Vaccine & Infectious Disease Institute, Faculty of Medicine & Health Sciences, University of Antwerp, Belgium. · Institute of Health and Society (IRSS), Université catholique de Louvain, Brussels, Belgium. ·Eur J Cancer · Pubmed #26693897.

ABSTRACT: BACKGROUND: The total burden of melanoma has already been studied but little is known about the distribution of this burden amongst localised, node metastatic and distant metastatic stages. METHODS: Disability-adjusted life years (DALY) assesses disease burden, being the sum of years of life with disability (YLD) and years of life lost (YLL). A melanoma disease model was developed in order to predict the evolution of patients from diagnosis until death. The model was applied to a large cohort of 8016 melanoma patients recorded by the Belgian Cancer Registry for incidence years 2009-2011. DALYs were calculated for each American Joint Committee on Cancer stage, considering stage at diagnosis on the one hand and time spent in localised, node metastatic and visceral metastatic stages on the other. Probabilistic sensitivity analyses and scenario analyses were performed to explore uncertainty. FINDINGS: Our analyses resulted in 3.67 DALYs per melanoma, 90.81 per 100,000 inhabitants, or 32.67 per death due to melanoma. The total YLL accounted for 80.4% of the total DALY. Stages I, II, III and IV patients at diagnosis generated, respectively, 27.8%, 32.7%, 26.2% and 13.3% of the total YLL. For the time spent in each stage, localised melanomas, node metastatic melanomas, and distant metastatic accounted, respectively, for 34.8%, 52.6% and 12.6% of the total YLD. Parametric uncertainty was very limited, but the influence of using pre-2010 Global Burden of Disease approaches was substantial. INTERPRETATION: The total DALY for melanoma was consistent with the previous studies. Our results in terms of proportions of DALY/YLL/YLD per stage could be extrapolated to other high-income countries. YLDs generated by localised melanoma which will never metastasize were inferior to YLLs resulting from stage IA melanomas. This result supports the hypothesis that efforts for an earlier diagnosis of melanoma are important. FUNDING: None.

25 Article Sex is an independent prognostic indicator for survival and relapse/progression-free survival in metastasized stage III to IV melanoma: a pooled analysis of five European organisation for research and treatment of cancer randomized controlled trials. 2013

Joosse, Arjen / Collette, Sandra / Suciu, Stefan / Nijsten, Tamar / Patel, Poulam M / Keilholz, Ulrich / Eggermont, Alexander M M / Coebergh, Jan Willem W / de Vries, Esther. ·Erasmus University Medical Center, Rotterdam, The Netherlands. ·J Clin Oncol · Pubmed #23690423.

ABSTRACT: PURPOSE: To study sex differences in survival and progression in patients with stage III or IV metastatic melanoma and to compare our results with published literature. PATIENTS AND METHODS: Data were retrieved from three large, randomized, controlled trials of the European Organisation for Research and Treatment of Cancer in patients with stage III and two trials in patients with stage IV melanoma. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% CIs for females compared with males, adjusted for different sets of confounders for stage III and stage IV, respectively. RESULTS: In 2,734 stage III patients, females had a superior 5-year disease-specific survival (DSS) rate compared with males (51.5% v 43.3%), an adjusted HR for DSS of 0.85 (95% CI, 0.76 to 0.95), and an adjusted HR for relapse-free survival of 0.86 (95% CI, 0.77 to 0.95). In 1,306 stage IV patients, females also exhibited an advantage in DSS (2-year survival rate, 14.1% v 19.0%; adjusted HR, 0.81; 95% CI, 0.72 to 0.92) as well as for progression-free survival (adjusted HR, 0.79; 95% CI, 0.70 to 0.88). This female advantage was consistent across pre- and postmenopausal age categories and across different prognostic subgroups. However, the female advantage seems to become smaller in patients with higher metastatic tumor load. CONCLUSION: The persistent independent female advantage, even after metastasis to lymph nodes and distant sites, contradicts theories about sex behavioral differences as an explanation for this phenomenon. A biologic sex trait seems to profoundly influence melanoma progression and survival, even in advanced disease.

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