The use of PET/CT to detect early recurrence after resection of high-risk stage III melanoma, prior to the start of adjuvant therapy and during follow-up.

e22039 Background: To date, international consensus concerning the use of PET/CT as a surveillance tool in the follow-up of high-risk melanoma patients after complete resection of disease is lacking. Moreover, with the rise of adjuvant therapy it seems appropriate to investigate the role of this imaging modality to exclude newly developed metastases after resection and prior to starting treatment. The aim of this study was to investigate the use of PET/CT as surveillance tool in the follow-up and prior to adjuvant therapy in asymptomatic patients with complete resection of stage IIIB and IIIC melanoma. Methods: Prospectively two cohorts were set up with stage III melanoma patients with complete resection of disease. In the first cohort (stage IIIB/C AJCC 7th) surveillance PET/CT was performed 6-monthly for two years if patients stayed asymptomatic with normal serum S100B, with a final scan at three years. In the second cohort (stage IIIB/C/D AJCC 8th) patients underwent one screening PET/CT after resection and prior to starting adjuvant treatment. Results: Eighty patients entered follow-up in cohort 1. Of these, the majority did not undergo surveillance scans, because they required treatment for newly detected clinical metastases. Thirty-five patients remained asymptomatic and were included in surveillance cohort one (105 scans) with a median follow-up of 33 months. Twelve patients (34%) developed a recurrence, seven (20%) of which were detected on the first scan at six months. Seven recurrences involved stage IIIC patients, five stage IIIB patients. Sensitivity and specificity were 92% and 100% respectively. Forty-two patients were included in cohort 2. Recurrence was suspected on nine scans, four (10%) of which were true positive. One patient proceeded to undergo a node dissection and then started adjuvant therapy. The other three patients had progressed to stage IV and therefore started radiotherapy and/or systemic immunotherapy. Five (12%) scans were false positive, the suspected lesions were not related to the preceded surgery. The number of scans needed to find one asymptomatic recurrence were 8.8 and 10.5 in cohort one and two, respectively. Conclusions: This study shows that PET/CT is a useful surveillance tool for detecting recurrence in asymptomatic high-risk resected stage III melanoma patients, especially within the first six months after surgery and therefore should be considered when monitoring these patients during follow-up as well as prior to starting adjuvant therapy.

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Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: New recurrence-free survival results from the EORTC 1325-MG/Keynote 054 double-blinded phase III trial at three-year median follow-up.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.10000 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 10000-10000 ◽

Cited By ~ 6

Author(s):

Alexander M. Eggermont ◽

Christian U. Blank ◽

Mario Mandalà ◽

Georgina V. Long ◽

Victoria Atkinson ◽

...

Keyword(s):

Lymph Node ◽

High Risk ◽

Complete Resection ◽

Phase Iii ◽

Stage Iii ◽

Recurrence Free Survival ◽

Stage Iiia ◽

Free Survival ◽

Stage Iii Melanoma

10000 Background: We conducted the phase 3 double-blind EORTC 1325/KEYNOTE-054 trial to evaluate pembrolizumab vs placebo in patients (pts) with resected high-risk stage III melanoma. Based on 351 recurrence-free survival (RFS) events and at a median follow-up of 1.25 years (yrs), pembrolizumab improved RFS (hazard ratio (HR) 0.57, P<0.0001) as compared to placebo (Eggermont, NEJM 2018). This led to the approval of pembrolizumab adjuvant treatment by EMA and FDA. Methods: Eligible pts included those ≥18 yrs of age with complete resection of cutaneous melanoma metastatic to lymph node(s), classified as AJCC-7 stage IIIA (at least one lymph node metastasis >1 mm), IIIB or IIIC (without in-transit metastasis). A total of 1019 pts were randomized (stratification by stage and region) to pembrolizumab at a flat dose of 200 mg (N=514) or placebo (N=505) every 3 weeks for a total of 18 doses (~1 year) or until disease recurrence or unacceptable toxicity. The 2 co-primary endpoints were RFS in the intention-to-treat overall population and in pts with PD-L1-positive tumors. Here, we report an updated RFS analysis based on a longer follow-up. Results: Overall, 15%/46%/39% of pts had stage IIIA/IIIB/IIIC. At 3.05-yr median follow-up, pembrolizumab (190 RFS events) compared with placebo (283 RFS events) prolonged RFS, in the overall population and in the PD-L1 positive tumor subgroup (see Table). RFS was consistently prolonged across subgroups, in particular according to AJCC-7 staging, BRAF-V600 E/K mutation status. Conclusions: Pembrolizumab, administered at 200 mg every 3 weeks for up to 1 year as adjuvant therapy, provided, at a 3-yr median follow-up, a sustained improvement in RFS, which was clinically meaningful, in resected high-risk stage III melanoma. This improvement was consistent across subgroups. In the overall population, the 3-yr cumulative incidence of distant metastasis being the first recurrence was 22.3% (pembrolizumab group) vs 37.3% (placebo group) (HR 0.55, 95% CI 0.44-0.69). Clinical trial information: NCT02362594. [Table: see text]

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Ipilimumab versus placebo after complete resection of stage III melanoma: Initial efficacy and safety results from the EORTC 18071 phase III trial.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.18_suppl.lba9008 ◽

2014 ◽

Vol 32 (18_suppl) ◽

pp. LBA9008-LBA9008 ◽

Cited By ~ 20

Author(s):

Alexander M. Eggermont ◽

Vanna Chiarion-Sileni ◽

Jean Jacques Grob ◽

Reinhard Dummer ◽

Jedd D. Wolchok ◽

...

Keyword(s):

Lymph Node ◽

High Risk ◽

Adjuvant Therapy ◽

Complete Resection ◽

Advanced Melanoma ◽

Phase Iii ◽

Stage Iii ◽

Phase Iii Trial ◽

Risk Of Recurrence ◽

Stage Iii Melanoma

LBA9008 Background: Ipilimumab (Ipi), a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to augment antitumor immune responses, is an approved treatment for advanced melanoma. Here, we report the results of a phase III trial designed to evaluate Ipi as an adjuvant therapy for resected stage III melanoma at high risk of recurrence. Methods: In this randomized, double-blind trial, eligible patients (pts) included those ≥18 yrs of age who underwent complete resection of stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis). 951 pts were randomized (stratified by stage and region) 1:1 to receive Ipi 10 mg/kg (n=475) or placebo (Pbo, n=476) every 3 wks for 4 doses, then every 3 mos for up to 3 yrs until completion, disease recurrence, or unacceptable toxicity. The primary endpoint was recurrence-free survival (RFS), analyzed on the intent-to-treat population. 512 RFS events (recurrence or death) were needed to provide 90% power to detect an Ipi vs Pbo hazard ratio (HR) of 0.75 (2-sided α=5%). Results: Overall, 20%/44%/36% of pts had stage IIIA/IIIB/IIIC, 42% ulcerated primary, and 58% macroscopic lymph node involvement. At a median follow-up of 2.7 yrs, Ipi significantly improved RFS vs Pbo. RFS benefit was consistent across subgroups (e.g., stage IIIB or IIIC, ulcerated primary). Most common grade 3/4 immune-related adverse events (irAEs) in the Ipi and Pbo arms were gastrointestinal (15.9% vs 0.8%), hepatic (10.6% vs 0.2%), and endocrine (8.5% vs 0%). Most irAEs were managed and resolved using established algorithms. Of 471 pts who started Ipi, 245 (52%) discontinued treatment due to AEs [182 (38.6%) within 12 weeks]; 5 (1.1%) died due to drug-related AEs. Conclusions: In this phase III trial, Ipi as adjuvant therapy provided a clinically and statistically significant improvement in RFS vs Pbo for pts with stage III melanoma at high risk of recurrence. AE profile was generally consistent with that observed in advanced melanoma, although with a higher incidence of endocrinopathies. Clinical trial information: NCT00636168. EudraCT Number: 2007-001974-10. [Table: see text]

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S‐100B as an extra selection tool for FDG PET/CT scanning in follow‐up of AJCC stage III melanoma patients

Journal of Surgical Oncology ◽

10.1002/jso.25682 ◽

2019 ◽

Vol 120 (6) ◽

pp. 1031-1037 ◽

Cited By ~ 1

Author(s):

Eric A. Deckers ◽

Kevin P. Wevers ◽

Anneke C. Muller Kobold ◽

Samantha Damude ◽

Otis M. Vrielink ◽

...

Keyword(s):

Fdg Pet ◽

Ct Scanning ◽

Stage Iii ◽

Selection Tool ◽

Ajcc Stage ◽

Pet Ct ◽

Melanoma Patients ◽

Stage Iii Melanoma ◽

Fdg Pet Ct

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Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial

Journal of Clinical Oncology ◽

10.1200/jco.20.02110 ◽

2020 ◽

Vol 38 (33) ◽

pp. 3925-3936 ◽

Cited By ~ 2

Author(s):

Alexander M. M. Eggermont ◽

Christian U. Blank ◽

Mario Mandala ◽

Georgina V. Long ◽

Victoria G. Atkinson ◽

...

Keyword(s):

Lymph Node ◽

High Risk ◽

Phase Iii ◽

Stage Iii ◽

Recurrence Free Survival ◽

Meaningful Improvement ◽

Free Survival ◽

Stage Iii Melanoma ◽

The Impact

PURPOSE We conducted the phase III double-blind European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial to evaluate pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. On the basis of 351 recurrence-free survival (RFS) events at a 1.25-year median follow-up, pembrolizumab prolonged RFS (hazard ratio [HR], 0.57; P < .0001) compared with placebo. This led to the approval of pembrolizumab adjuvant treatment by the European Medicines Agency and US Food and Drug Administration. Here, we report an updated RFS analysis at the 3.05-year median follow-up. PATIENTS AND METHODS A total of 1,019 patients with complete lymph node dissection of American Joint Committee on Cancer Staging Manual (seventh edition; AJCC-7), stage IIIA (at least one lymph node metastasis > 1 mm), IIIB, or IIIC (without in-transit metastasis) cutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity. The two coprimary end points were RFS in the overall population and in those with programmed death-ligand 1 (PD-L1)–positive tumors. RESULTS Pembrolizumab (190 RFS events) compared with placebo (283 RFS events) resulted in prolonged RFS in the overall population (3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively; HR, 0.56; 95% CI, 0.47 to 0.68) and in the PD-L1–positive tumor subgroup (HR, 0.57; 99% CI, 0.43 to 0.74). The impact of pembrolizumab on RFS was similar in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and BRAF mutation status (HR, 0.51 [99% CI, 0.36 to 0.73] v 0.66 [99% CI, 0.46 to 0.95] for V600E/K v wild type). CONCLUSION In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in RFS at 3-year median follow-up. This improvement was consistent across subgroups.

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Predicting clinical outcome through gene expression profiling in stage III melanoma

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.8502 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 8502-8502

Author(s):

T. John ◽

M. A. Black ◽

T. Toro ◽

C. A. Gedye ◽

I. D. Davis ◽

...

Keyword(s):

Gene Expression ◽

Clinical Outcome ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Stage Iiib ◽

Stage Iii ◽

Test Set ◽

Prognostic Groups ◽

Melanoma Patients ◽

Stage Iii Melanoma

8502 Background: Melanoma patients with clinically involved regional lymph nodes (Stage IIIB&C) represent a prognostically heterogeneous population. Current prognostic factors cannot distinguish the 30% of patients who will achieve long term survival from those who will relapse early. We hypothesized that gene expression profiling could identify these different prognostic groups and provide a greater understanding of the genetic mechanisms involved. Methods: Lymph node sections from 29 patients with Stage IIIB & IIIC melanoma and divergent clinical outcome as defined by time to tumor progression (TTP), including 16 poor (TTP<6 months) and 13 good (TTP>28 months) prognosis patients, were subjected to molecular profiling using spotted oligonucleotide arrays containing 30,888 probes as an initial test set. The differentially expressed genes were determined using a Wilcoxon-Mann-Whitney t-test with the false discovery rate controlling method of Benjamini-Hochberg and validated using quantitative real-time RT-PCR. Using logistic regression, a predictive score algorithm was developed based on the 15 genes for which the correlation between the two platforms was the strongest. The score was then applied to two independent validation sets of 10 and 14 patient samples. Results: Supervised analysis using differentially expressed genes was able to distinguish the two prognostic groups in the test set. The score correlated directly with clinical outcome, with higher scores associated with improved TTP. When the score was then applied to two independent sets of Stage III melanoma patient samples, it predicted clinical outcome accurately in 90% of samples. Conclusions: Stage IIIB and IIIC melanoma can be prognostically sub-classified according to the expression of 15 genes. To our knowledge this is the first study focused on Stage III disease using ex vivo patient samples. These results are encouraging and this genetic signature is currently being validated on a larger cohort. This method will allow appropriate stratification of stage III melanoma patients in adjuvant clinical trials, ameliorating the inherent biological heterogeneity that can confound these studies. [Table: see text]

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Adjuvant therapy utilization among stage III melanoma patients.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.e21574 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. e21574-e21574

Author(s):

C. Lance Cowey ◽

Sameer R. Ghate ◽

Whitney C. Rhodes ◽

Thomas Wilson ◽

Briana Ndife ◽

...

Keyword(s):

Adjuvant Therapy ◽

Stage Iii ◽

Melanoma Patients ◽

Stage Iii Melanoma

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Long-term follow-up of patients treated by adoptive transfer of melanoma tumor-infiltrating lymphocytes as adjuvant therapy for stage III melanoma

Cancer Immunology Immunotherapy ◽

10.1007/s00262-007-0340-1 ◽

2007 ◽

Vol 56 (11) ◽

pp. 1853-1860 ◽

Cited By ~ 39

Author(s):

Amir Khammari ◽

Jean-Michel Nguyen ◽

Marie Christine Pandolfino ◽

Gaëlle Quereux ◽

Anabelle Brocard ◽

...

Keyword(s):

Adjuvant Therapy ◽

Adoptive Transfer ◽

Tumor Infiltrating Lymphocytes ◽

Stage Iii ◽

Melanoma Tumor ◽

Long Term Follow Up ◽

Stage Iii Melanoma ◽

Infiltrating Lymphocytes

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Double venipuncture is not required for adequate S-100B determination in melanoma patients

BioTechniques ◽

10.2144/btn-2019-0147 ◽

2020 ◽

Vol 69 (5) ◽

pp. 371-378

Author(s):

Samantha Damude ◽

Anneke C Muller Kobold ◽

Esther Bastiaannet ◽

Schelto Kruijff ◽

Harald J Hoekstra ◽

...

Keyword(s):

Cancer Staging ◽

Stage Iii ◽

Tube System ◽

Serum Samples ◽

Blood Samples ◽

Significant Difference ◽

Melanoma Patients ◽

The Mean ◽

Stage Iii Melanoma

S-100B is used in melanoma follow-up. This serum biomarker is also present in adipocytes; therefore, subcutaneous adipocytes trapped in the needle before performing a venipuncture could contaminate the serum. The aim was to study the influence of adipocyte contamination on blood samples used for S-100B analysis, possibly resulting in falsely elevated S-100B values. A total of 294 serum samples were collected from 147 American Joint Committee on Cancer staging stage III melanoma patients. The mean difference between the first (dummy) and second tubes was 0.003 μg/l (p = 0.077), with a decrease in the second tube. Compared with the second tube, the S-100B level was higher in the first tube in 33.3% of the samples, equal in 36.8% of the samples and lower in 29.9% of the samples. No significant difference between the two consecutively drawn tubes was found. There seems to be no necessity of implementing a dummy tube system for accurate S-100B determination in melanoma patients.

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Early Recurrence in Sentinel Lymph Node Positive Stage III Melanoma Patients

The American Surgeon ◽

10.1177/000313481207800723 ◽

2012 ◽

Vol 78 (7) ◽

pp. 808-813

Author(s):

Justin J. Baker ◽

David W. Ollila ◽

Allison M. Deal ◽

Jill Frank ◽

Keith D. Amos ◽

...

Keyword(s):

Risk Factors ◽

Lymph Node ◽

Sentinel Lymph Node ◽

Risk Score ◽

Recurrence Risk ◽

Early Recurrence ◽

Stage Iii ◽

Melanoma Patients ◽

Stage Iii Melanoma

Patients with sentinel lymph node (SLN) positive melanoma have a significant recurrence risk. We sought to examine variables associated with development of early recurrence. A prospective institutional review board-approved database of cutaneous melanoma patients treated from 2003 to 2010 was used to identify SLN positive stage III patients with 1 year of follow-up. The Kaplan-Meier method, and logistic regression were used to evaluate variables associated with early recurrence. Seventy-four patients were identified. Twenty-four (32%) had an early recurrence. Five variables were highly significantly associated with early recurrence: location of head/neck, Breslow depth greater than two, ulceration, number of lymph nodes positive ≥ 2, and largest lymph node metastasis >1 mm. Using these five variables, a numerical risk score was created from 0 to 5 to determine if an early recurrence occurred as the number of risk factors increased. The proportion of patients with early recurrence increased in linear fashion with increasing risk score ( P < 0.0001). These data suggest that SLN positive stage III melanoma patients have a significant risk of early recurrence, which is associated with several defined variables and increases with the number of risk factors present. These data may be useful in stratifying patients to level of recurrence risk and adjusting follow-up schedules.

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