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Is there nowadays any benefit of continuing the practice of routine wide local excision (WLE) for primary stage I/II cutaneous melanoma?WLE aims to eradicate potential microsatellites around melanomas and thereby reduce local recurrence rates and improve overall survival. Six large prospective randomised trials investigated WLE versus wider WLE, they all failed to show any effect on overall survival (OS).A literature search was performed to identify data on outcome after omitting WLE. Additionally circumstantial evidence was gathered from pathology studies and outcomes of modified surgical techniques, as well as publications on morbidity.No prospective and one retrospective study was found. The retrospective study showed no difference in OS after correction for confounding factors. Pathology studies showed a low incidence of residual melanoma in WLE specimen (0-4.2%). Mohs surgery does not show a difference in recurrence rates or OS. WLE is associated with considerable postoperative morbidity, which increases with wider excision margins.There is no solid prospective evidence to support the classic dogma of a 2-step approach with the use of WLE for primary cutaneous melanoma that has been completely excised on diagnostic excision biopsy. We recommend to setup and conduct a prospective randomised trial to compare the classical 2-step approach with WLE to a complete diagnostic excision only to abolish the routine practice of WLE in the future.

Item does not contain fulltext BACKGROUND: Immune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in patients with advanced melanoma, but approximately half these patients will not have a durable benefit. Phase 1-2 trials of adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) have shown promising responses, but data from phase 3 trials are lacking to determine the role of TILs in treating advanced melanoma. METHODS: In this phase 3, multicenter, open-label trial, we randomly assigned patients with unresectable stage IIIC or IV melanoma in a 1:1 ratio to receive TIL or anti-cytotoxic T-lymphocyte antigen 4 therapy (ipilimumab at 3 mg per kilogram of body weight). Infusion of at least 5×10(9) TILs was preceded by nonmyeloablative, lymphodepleting chemotherapy (cyclophosphamide plus fludarabine) and followed by high-dose interleukin-2. The primary end point was progression-free survival. RESULTS: A total of 168 patients (86% with disease refractory to anti-programmed death 1 treatment) were assigned to receive TILs (84 patients) or ipilimumab (84 patients). In the intention-to-treat population, median progression-free survival was 7.2 months (95% confidence interval [CI], 4.2 to 13.1) in the TIL group and 3.1 months (95% CI, 3.0 to 4.3) in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; P

Background: Neoadjuvant systemic therapy has shown promising results in the treatment of high-risk stage III melanoma; however, the effects on surgery are currently unknown. This study aims to compare the surgical outcomes, in terms of postoperative complications, postoperative morbidity, duration of surgery and textbook outcomes, of patients with high-risk stage III melanoma who received neoadjuvant systemic therapy followed by lymph node dissection with patients who received an upfront lymph node dissection. Methods: In this retrospective cohort study, patients with high-risk stage III melanoma treated with neoadjuvant anti-PD1 and anti-CTLA4 in the OpACIN (NCT02437279) and OpACIN-neo (NCT02977052) trial between October 2014 and August 2018 were included and compared to patients who received upfront surgery in the same time period. Results: A total of 120 patients were included in this study, of whom 44 received neoadjuvant systemic therapy and 76 underwent upfront surgery. There was no significant difference in the overall rate of postoperative complications between the neoadjuvant group and the upfront surgery group (31.8% versus 36.8%, p = 0.578) and neither in rate of postoperative morbidity (seroma 56.8% versus 57.9%, p = 0.908) (lymphedema 22.7% versus 13.2%, p = 0.175). There was a non-significant difference towards a slightly longer duration of surgery after neoadjuvant immunotherapy (105 versus 90 min, p = 0.077). There were no differences in textbook outcomes (50% versus 49%, p = 0.889). Conclusion: This study shows that the surgical outcomes for patients who underwent a lymph node dissection after neoadjuvant systemic immunotherapy or underwent upfront lymph node dissection for high-risk stage III melanoma are comparable.

Figure S5 shows that complement factor B (CFB), component 7 (C7) and alpha-1B-glycoportein (A1BG) expression are increased upon melanoma progression and recurrence.

Table S3 shows the patient characteristics PRADO

Neoadjuvant ipilimumab + nivolumab has demonstrated high pathologic response rates in stage III melanoma. Patients with low intra-tumoral interferon-γ (IFN-γ) signatures are less likely to benefit. We show that domatinostat (a class I histone deacetylase inhibitor) addition to anti-PD-1 + anti-CTLA-4 increased the IFN-γ response and reduced tumor growth in our murine melanoma model, rationalizing evaluation in patients. To stratify patients into IFN-γ high and low cohorts, we developed a baseline IFN-γ signature expression algorithm, which was prospectively tested in the DONIMI trial. Patients with stage III melanoma and high intra-tumoral IFN-γ scores were randomized to neoadjuvant nivolumab or nivolumab + domatinostat, while patients with low IFN-γ scores received nivolumab + domatinostat or ipilimumab + nivolumab + domatinostat. Domatinostat addition to neoadjuvant nivolumab ± ipilimumab did not delay surgery but induced unexpected severe skin toxicity, hampering domatinostat dose escalation. At studied dose levels, domatinostat addition did not increase treatment efficacy. The baseline IFN-γ score adequately differentiated patients who were likely to benefit from nivolumab alone versus patients who require other therapies.

BACKGROUND: Postoperative radiotherapy (PORT) is currently recommended for the treatment of Merkel cell carcinoma. Nevertheless, deviations occur frequently due to the generally elderly and frail patient population. We aimed to evaluate the influence of PORT on survival in stage I-III MCC patients treated in the Netherlands.METHODS: Patients were included retrospectively between 2013 and 2018. Fine-Gray method was used for cumulative incidence of recurrence and MCC-related death, cox regression was performed for overall mortality. Analyses were performed in patients with clinical (sentinel node biopsy [SN] not performed) stage I/II (c-I/II-MCC), pathologic (SN negative) stage I/II (p-I/II-MCC) and stage III MCC (III-MCC), separately. Propensity score matching (PSM) was performed to assess confounding by indication.RESULTS: In total 182 patients were included, 35 had p-I/II-MCC, 69 had c-I/II-MCC and 78 had III-MCC. Median follow up time was 53.5 (IQR 33.4-67.4), 30.5 (13.0-43.6) and 29.3 (19.3-51.0) months, respectively. Multivariable analysis showed PORT to be associated with less recurrences and reduced overall mortality, but not with MCC-related mortality. In stage III-MCC, extracapsular extension (sub-distribution hazard [SDH] 4.09, p = 0.012) and PORT (SDH 0.45, p = 0.044) were associated with recurrence, and ≥ 4 positive lymph nodes (SDH 3.24, p = 0.024) were associated with MCC-related mortality.CONCLUSIONS: PORT was associated with less recurrences and reduced overall mortality in patients with stage I-III MCC, but not with MCC-related mortality. Trends in overall survival benefit are likely to be caused by selection bias suggesting further refinement of criteria for PORT is warranted, for instance by taking life expectancy into account.

Talimogene laherparepvec (T-VEC) is an oncolytic virus approved for the treatment of unresectable, recurrent melanoma. The role of T-VEC after progression on systemic immunotherapy (IO) remains undefined. The goal of this study was to characterize the efficacy of T-VEC after failure of IO in patients with unresectable metastatic melanoma. An international, multi-institutional review of AJCC version 8 stage IIIB-IV melanoma patients treated with T-VEC after failure of IO was performed at six centers from October 2015-December 2020. Primary outcome was in-field response; secondary outcomes included analyses of in-field and overall progression-free survival (PFS) and in-field and overall disease-free survival (DFS) after a complete response. Subset analysis of T-VEC initiation sequentially after or concurrently with IO was performed. Of 112 patients, median age at T-VEC initiation was 69 years (range 21–93); 65 (58%) were male. Before T-VEC, 57% patients received one IO regimen, 42% received two or more, with most patients (n = 74, 66%) receiving T-VEC sequential to IO. Most were stage 3C (n = 51, 46%) at T-VEC initiation, 29 (26%) received injections to nodal disease. Over median follow-up of 14 months, in-field response at final T-VEC injection was 37% complete (CR), 14% partial (PR). T-VEC initiation sequentially or concurrently did not significantly affect in-field response (p = 0.26). Median in-field PFS was 15 months (95% confidence interval 4.6-NE). Median overall DFS after CR was 32 months (95% confidence interval 17-NE). T-VEC after failure of IO is effective in unresectable, metastatic stage IIIB-IV melanoma. T-VEC initiation sequentially or concurrently did not significantly affect in-field response.

BACKGROUND: The extent of surgical management of regional lymph nodes in the treatment of cutaneous head and neck melanoma on and anterior to O'Brien's watershed line is controversial. By comparing patients' cohorts of two separate melanoma expert centers we investigate the effectiveness of comprehensive versus (super-) selective neck dissection approach.METHODS: Sixty patients with macroscopic (palpable) neck node metastases (N2b) from anterior scalp and face melanoma were retrospectively studied. Forty therapeutic modified radical neck dissections (MRND; levels I-V) combined with elective parotidectomy from The Netherlands Cancer Institute (NCI) were compared with 16 (super-) selective neck dissections [(S)SND; 3-4 levels] and 4 solely MRNDs from Erasmus Medical Center (EMC). Cohorts were analyzed for site of recurrence, overall survival (OS), melanoma-specific survival (MSS), and disease-free survival (DFS).RESULTS: Clinical characteristics of patients were equal in both groups. In the NCI cohort 62.5% (n = 25) of patients recurred versus 65% (n = 13) in the EMC cohort. None of the NCI recurrences affected the parotid gland in contrast to 3 patients in the EMC group. Survival characteristics were not different between the two groups: OS (p = 0.56), MSS (p = 0.98), DFS (p = 0.92).CONCLUSION: This study does not support to continue the practice of routine elective parotidectomy and MRND in melanoma patients undergoing a lymph node dissection for macroscopic (palpable) nodal disease and justifies (S)SND.

Single-agent Talimogene Laherparepvec (T-VEC) was developed for treatment of unresectable and injectable stage III-IV melanoma. Since its approval and reimbursement, studies have reported varying response rates. The purpose of this systematic review and meta-analysis was to investigate the efficacy and safety of T-VEC. Of 341 publications that were identified, eight studies with a total of 642 patients were included. In patients with stage IIIB-IVM1a, the pooled complete- and overall response rate (CRR and ORR) were 41% and 64%, respectively. In patients with stage IIIB-IVM1c, the pooled CRR and ORR were 30% and 44%, respectively. In patients with stage IVM1b and IVM1c, the pooled CRR and ORR were 4% and 9%, respectively. Adverse events (AEs) were seen in 41–100% of all patients and 0–11% of AEs were severe. In conclusion, single agent T-VEC achieves the highest response rates in patients with early metastatic melanoma and is well-tolerated with generally only mild toxicities.

Background Patients with synchronous clinical stage III melanoma can present with primary melanoma lesions, locally recurrent melanoma or in-transit metastases. Neoadjuvant ipilimumab plus nivolumab induces high pathologic response rates and an impressive relapse-free survival in patients with nodal macroscopic stage III melanoma. Whether primary site melanoma and in-transit metastases respond similarly to lymph node metastases with neoadjuvant immunotherapy is largely unknown. Such data would clarify whether surgical excision of these melanoma lesions should be performed before neoadjuvant therapy or whether it could be deferred and performed in conjunction with lymphadenectomy following neoadjuvant immunotherapy. Patients Patients with synchronous clinical stage III melanoma were identified from the OpACIN, OpACIN-neo and PRADO neoadjuvant trials, where all patients were treated with ipilimumab plus nivolumab. An additional case treated outside those clinical trials was included. Results Seven patients were identified; six patients had a concordant response in primary site melanoma lesions or in-transit metastasis and the lymph node metastases. One patient had concordant progression in both the primary and nodal tumour lesions and developed stage IV disease during neoadjuvant treatment, and thus, no resection was performed. Conclusion Pathologic response following neoadjuvant ipilimumab plus nivolumab in primary site melanoma lesions or in-transit metastasis is concordant with a response in the lymph node metastases, indicating that there may be no need to perform upfront surgery to these melanoma lesions prior to neoadjuvant treatment.

The management of melanoma patients with nodal metastases has undergone dramatic changes over the last decade. In the past, the standard of care for patients with a positive sentinel lymph node biopsy (SLNB) was a completion lymph node dissection (CLND), while patients with palpable macroscopic nodal disease underwent a therapeutic lymphadenectomy in cases with no evidence of systemic spread. However, studies have shown that SLN metastases present as a spectrum of disease, with certain SLN-based factors being prognostic of and correlated with outcomes. Furthermore, the results of key clinical trials demonstrate that CLND provides no survival benefit over nodal observation in positive SLN patients, while other clinical trials have shown that adjuvant immune checkpoint inhibitor therapy or targeted therapy after CLND is associated with a recurrence-free survival benefit. Given the efficacy of these systemic therapies in the adjuvant setting, these agents are now being evaluated and utilized as neoadjuvant treatments in patients with regionally-localized or resectable metastatic melanoma. Multiple options now exist to treat melanoma patients with nodal disease, and determining the best treatment course for a particular case requires an in-depth knowledge of current data and an informed discussion with the patient. This review will provide an overview of the various options for treating melanoma patients with nodal metastases and will discuss the data that supported the development of these treatment options.

Melanoma of unknown primary (MUP) is considered different from melanoma of known primary (MKP), and it is unclear whether these patients benefit equally from novel therapies. In the current study, characteristics and overall survival (OS) of patients with advanced and metastatic MUP and MKP were compared in the era of novel therapy. Patients were selected from the prospective nation-wide Dutch Melanoma Treatment Registry (DMTR). The following criteria were applied: diagnosis of stage IIIc unresectable or IV cutaneous MKP (cMKP) or MUP between July 2012 and July 2017 and treatment with immune checkpoint inhibition and/or targeted therapy. OS was estimated using the Kaplan–Meier method. The stratified multivariable Cox regression model was used for adjusted analysis. A total of 2706 patients were eligible including 2321 (85.8%) patients with cMKP and 385 (14.2%) with MUP. In comparative analysis, MUP patients more often presented with advanced and metastatic disease at primary diagnosis with poorer performance status, higher LDH, and central nervous system metastases. In crude analysis, median OS of cMKP or MUP patients was 12 months (interquartile range [IQR] 5 – 44) and 14 months (IQR 5 – not reached), respectively (P = 0.278). In adjusted analysis, OS in MUP patients was superior (hazard rate 0.70, 95% confidence interval 0.58–0.85; P

Nearly 10% of patients with high-risk early-stage melanoma will develop satellite or in-transit metastases (ITM), classified as stage III disease similar to lymph node metastases. The pivotal registration trials of the CTLA-4 antibody ipilimumab, and the PD-1 antibodies nivolumab and pembrolizumab, also included patients with unresectable stage III disease. However, there has been no analysis of patients with ITM, and anecdotal retrospective small series have indicated a potential lesser effect. This study aimed to identify patients with unresectable ITM within the randomized trials, and to determine response, progression-free survival and overall survival. The pivotal phase III randomized intervention trials that included melanoma patients with ITM, with or without nodal metastasis, and were treated with ipilimumab, nivolumab or pembrolizumab was identified. The datasets from each trial were then searched to identify the specific details of the investigated patient population for a pooled analysis. The primary endpoint was complete response rate. Seven trials that included stage III patients, and with accessible datasets, were identified. There was a total of 4711 patients, however, no patients with ITM could be identified, as this data was not captured by the case report forms. Evidence from prospective clinical trials on the use of immunotherapy in patients with ITM is lacking. We recommend pooling data from multiple institutions to examine efficacy of available drug therapies in this patient population, but more importantly, prospective clinical trials of locoregional treatments with or without systemic drug therapies are required.

The association among pathological response, recurrence-free survival (RFS) and overall survival (OS) with neoadjuvant therapy in melanoma remains unclear. In this study, we pooled data from six clinical trials of anti-PD-1-based immunotherapy or BRAF/MEK targeted therapy. In total, 192 patients were included; 141 received immunotherapy (104, combination of ipilimumab and nivolumab; 37, anti-PD-1 monotherapy), and 51 received targeted therapy. A pathological complete response (pCR) occurred in 40% of patients: 47% with targeted therapy and 33% with immunotherapy (43% combination and 20% monotherapy). pCR correlated with improved RFS (pCR 2-year 89% versus no pCR 50%, P

Background The role of surveillance imaging in high-risk stage III melanoma patients after complete surgical resection remains controversial, and with the advent of adjuvant therapy, it may also be expanded. Therefore, we evaluated two fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) protocols in two cohorts. Methods Cohort 1 (n = 35) focused on surveillance in asymptomatic patients (before approval and reimbursement of adjuvant therapy) and was assigned to 5x FDG-PET/CT's after surgery: one every 6 months for 2 years, with one final scan after 3 years. Cohort 2 (n = 42) was assigned to one screening FDG-PET/CT, which took place in between surgery and the start of adjuvant treatment. Results In cohort 1 (median follow-up: 33 months), 12 patients (34.3%) developed recurrence detected by FDG-PET/CT, of which 7 (20.0%) were detected with the first scan. Sensitivity and specificity were 92.3% and 100%, respectively. In cohort 2, recurrence was suspected on nine scans (21.4%) and four (9.5%) were true positive. The number of scans needed to find one asymptomatic recurrence were 8.8 and 10.5 in cohort 1 and 2, respectively. Conclusions FDG-PET/CT is a valuable imaging tool to detect recurrence in stage III melanoma, even shortly after surgery. A surveillance FDG-PET/CT protocol after surgery or a screening PET/CT before adjuvant therapy should be considered.

Talimogene laherparepvec (T-VEC) is an oncolytic virus, approved for the treatment of stage IIIb-IVM1a melanoma with injectable disease (cutaneous, subcutaneous or lymphatic). It is a modified herpes simplex virus type 1 that induces tumor-specific T-cell responses via reduction of virally mediated suppression of antigen presentation, stimulation of viral pathogenicity and enhancement of tumor-selective replication. Response rates up to 82.6% have been reported for stage III disease. Acral lentiginous melanoma (ALM) is a rare subtype of melanoma with a poor prognosis. Here, we present a case of an elderly and frail patient with primary ALM who refused surgical treatment and consented to receive T-VEC as first-line drug therapy. After 10 courses of treatment, a histopathologically confirmed complete response was achieved. To our knowledge, this is the first case ever reported in which a primary ALM is (successfully) treated with T-VEC.

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.

Background: Sentinel lymph node (SLN) biopsy remains crucial for melanoma staging. The European Organisation for Research and Treatment of Cancer Melanoma Group recommends performing immunohistochemical stainings for reproducible identification of melanoma metastases. S100 protein (pS100) is a commonly used melanocytic antigen because of its high sensitivity in spite of relatively low specificity. SRY-related HMG-box 10 protein (SOX10) is a transcription factor characterising neural crest-derived cells. It is uniformly expressed mostly in the nuclei of melanocytes, neural, and myoepithelial cells. Pathologists sometimes prefer SOX10 as a melanoma marker, but it has not yet been investigated on a large-scale to confirm that it is reliable and recommendable for routine SLN evaluation. Methods: Four hundred one treatment-naïve lymph node (LN) metastatic melanomas were included in high-density tissue microarrays and were assessed for the presence of SOX10 and pS100 by immunohistochemistry. The slides were digitalised, shared and evaluated by a panel of experienced melanoma pathologists. Results: The vast majority of melanomas were double-positive for pS100 and SOX10 (93.2%); a small percentage of the cases (3.9%) were double-negative melanomas. Discordance between the two markers was observed: 1.9% pS100(−)/SOX10(+) and 0.75% pS100(+)/SOX10(−). SOX10 was not expressed by immune cell types in the LN, resulting in a less controversial interpretation of the staining. Conclusions: SOX10 is as equally specific as pS100 for the detection of melanoma metastases in LNs. The interpretation of SOX10 staining is highly reproducible among different centres and different pathologists because of the absence of staining of immune cells.

Importance: Whether immune-related adverse events (irAEs) indicate drug activity in patients treated with immune checkpoint inhibitors remains unknown.Objective: To investigate the association between irAEs and recurrence-free survival (RFS) in the double-blind EORTC 1325/KEYNOTE-054 clinical trial comparing pembrolizumab therapy and placebo for the treatment of patients with high-risk stage III melanoma.Design, Setting, and Participants: A total of 1019 adults with stage III melanoma were randomly assigned on a 1:1 ratio to receive treatment with pembrolizumab therapy or placebo. Eligible patients were adults 18 years and older with complete resection of cutaneous melanoma metastatic to lymph nodes, classified with stage IIIA (at least 1 micrometastasis measuring >1 mm in greatest diameter), IIIB, or IIIC (without in-transit metastasis) cancer. Patients were randomized from August 26, 2015, to November 14, 2016. The clinical cutoff for the data set was October 2, 2017. Analyses were then performed on the database, which was locked on November 28, 2017.Interventions: Participants were scheduled to receive 200 mg of pembrolizumab or placebo every 3 weeks for a total of 18 doses for approximately 1 year or until disease recurrence, unacceptable toxic effects, major protocol violation, or withdrawal of consent.Main Outcomes and Measures: The association between irAEs and RFS was estimated using a Cox model adjusted for sex, age, and AJCC-7 stage, with a time-varying covariate that had a value of 0 before irAE onset and 1 after irAE onset.Results: Of 1011 patients who began treatment with pembrolizumab therapy or placebo, 622 (61.5%) were men and 389 (38.5%) were women; 386 patients (38.2%) were aged 50 to 64 years, 377 (37.3%) were younger than 50 years, and 248 (24.5%) were 65 years and older. Consistent with the reported main analysis in the intent-to-treat population, RFS was longer in the pembrolizumab arm compared with the placebo arm (hazard ratio [HR], 0.56; 98.4% CI, 0.43-0.74) among patients who started treatment. The incidence of irAEs was 190 (37.4%) in the pembrolizumab arm (n = 509) and 45 (9.0%) in the placebo arm (n = 502); in each treatment group, the incidence was similar for men and women. The occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm (HR, 0.61; 95% CI, 0.39-0.95; P = .03) in both men and women. However, in the placebo arm, this association was not significant. Compared with the placebo arm, the reduction in the hazard of recurrence or death in the pembrolizumab arm was greater after the onset of an irAE than without or before an irAE (HR, 0.37; 95% CI, 0.24-0.57 vs HR, 0.61; 95% CI, 0.49-0.77, respectively; P = .03).Conclusions and Relevance: In this study, the occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm.Trial Registrations: ClinicalTrials.gov identifier: NCT02362594; EudraCT identifier: 2014-004944-37.

Now effective adjuvant therapy has arrived in melanoma, accurate staging and patient selection to optimize its risk/benefit ratio is crucial. The American Joint Committee on Cancer staging system is the most widely used and validated melanoma staging system, which recently released its 8th edition. We aimed to externally validate the prognostic and discriminatory ability for survival of the 8th edition compared to the 7th edition and evaluate prognostic factors. Prospective database of stage III melanoma (2000-2016). Prognostic factors for melanoma-specific survival and distant metastasis-free survival were analyzed. Survival differentiation of the 7th and 8th edition was assessed with log-rank tests and Cox proportional hazards models. Discriminatory ability was compared using the receiver operating characteristic and Akaike's Information Criterion. Six hundred forty patients were included (median follow-up 59 months). Median melanoma-specific survival was 138 months, distant metastasis-free survival 96 months. Age, Breslow thickness, ulceration of the primary tumor and number of positive lymph nodes (N) were independent prognostic parameters for distant metastasis-free survival and melanoma-specific survival. The 8th edition performed slightly better than the 7th edition in terms of survival discrimination but showed slightly worse distant metastasis-free survival and melanoma-specific survival differentiation between stage IIIA and IIIB. Sentinel node (SN) metastasis size cutoff of 1 mm differentiated survival in both 7th and 8th edition stage IIIA, showing excellent distant metastasis-free survival and melanoma-specific survival for patients with a SN metastasis size

Background: β-adrenergic receptors are upregulated in melanoma cells and contribute to an immunosuppressive, pro-tumorigenic microenvironment. This study investigated the prognostic and predictive value of β-adrenoreceptor blockade by β-blockers in the EORTC1325/KEYNOTE-054 randomised controlled trial. Methods: Patients with resected stage IIIA, IIIB or IIIC melanoma and regional lymphadenectomy received 200 mg of adjuvant pembrolizumab (n = 514) or placebo (n = 505) every three weeks for one year or until recurrence or unacceptable toxicity. At a median follow-up of 3 years, pembrolizumab prolonged recurrence-free survival (RFS) compared to placebo (hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.47–0.68). β-blocker use was defined as oral administration of any β-blocker within 30 days of randomisation. A multivariable Cox proportional hazard model was used to estimate the HR for the association between the use of β-blockers and RFS. Results: Ninety-nine (10%) of 1019 randomised patients used β-blockers at baseline. β-blockers had no independent prognostic effect on RFS: HR 0.96 (95% CI 0.70–1.31). The HRs of RFS associated with β-blocker use were 0.67 (95% CI 0.38–1.19) in the pembrolizumab arm and 1.15 (95% CI 0.80–1.66) in the placebo arm. The HR of RFS associated with pembrolizumab compared to placebo was 0.34 (95% CI 0.18–0.65) among β-blocker users and 0.59 (95% CI 0.48–0.71) among those not using β-blockers. Conclusions: This study suggests no prognostic effect of β-blockers in resected high-risk stage III melanoma. However, β-blockers may predict improved efficacy of adjuvant pembrolizumab treatment. The combination of immunotherapy with β-blockers merits further investigation. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37.

Background: This study assessed whether electromagnetic navigation can be of added value during resection of recurrent or post-therapy intra-abdominal/pelvic soft tissue sarcomas (STS) in challenging locations. Materials and Methods: Patients were included in a prospective navigation study. A pre-operatively 3D roadmap was made and tracked using electromagnetic reference markers. During the operation, an electromagnetic pointer was used for the localization of the tumor/critical anatomical structures. The primary endpoint was feasibility, secondary outcomes were safety and usability. Results: Nine patients with a total of 12 tumors were included, 7 patients with locally recurrent sarcoma. Three patients received neoadjuvant radiotherapy and three other patients received neoadjuvant systemic treatment. The median tumor size was 4.6 cm (2.4–10.4). The majority of distances from tumor to critical anatomical structures was

Objective: To examine stage-specific trends in the incidence and survival of cutaneous melanoma in the Netherlands between 2003 and 2018, as well as the uptake of the sentinel lymph node biopsy (SLNB) and novel drugs during that period. Methods: Data were obtained from the nationwide population-based Netherlands Cancer Registry for all patients diagnosed with invasive primary cutaneous melanoma (n = 60,267). We presented age-standardized incidence rates, the proportion of patients with an SLNB, the proportion of patients who received a novel drug (for their primary diagnosis) and one- and five-year relative survival rates. Results: Between 2003 and 2018, the incidence rate increased from 10.9 to 23.9 for men and from 15.6 to 27.3 for women. This increase reflected the increasing incidence rate of patients with stage I and III. The proportion of patients with an SLNB increased from 23% to 64%. A reasonable increase was observed in the proportion of patients with a positive outcome (from 2% to 11%). For patients with stage IV, there was a shift from chemotherapy towards novel drugs as from 2013. The five-year relative survival rate increased from 81% to 92% for men and from 88% to 96% for women. This increase reflected the increasing five-year relative survival rate of patients with stage II, III, and IV. Conclusion: We observed an increase in incidence for patients with stage I and III and an improvement in survival for patients with stage II, III and IV. These trends can be partly explained by the introduction of the SLNB and the novel drugs.

Background: The incidence of metastatic melanoma is increasing in all ages. Multiple trials with targeted drugs and immune checkpoint inhibitors showed improved survival in metastatic melanoma. However, patients aged >_75 years are often under-represented in clinical trials, therefore raising questions on safety and efficacy of treatment. Patients and methods: We analyzed a real-world cohort of 3054 patients with metastatic melanoma stratified for age (_ 75 years), and BRAF status, providing data on treatment strategies, toxicity, and survival. Kaplan Meier curves and Cox Proportional Hazard Models were used to present overall survival (OS) and Melanoma Specific Survival (MSS). Results: Overall, 52.2% of patients were _75 years. BRAF mutated tumors were found less often in patients >_75 years: 34.5% versus 65% in patients _75 years received systemic therapy less frequently compared to their younger counterparts independent of the BRAF status. When receiving treatment, no statistical significant difference in grade 3 or 4 toxicity was observed. Three year Overall Survival rate was 13.7% (9.1-19.3) in patients >_75 years versus 26.7% (23.1-30.4) in patients _75 years are less frequently treated, but when treated there is no statistical significant increase in toxicity and only a borderline statistical significant difference in Melanoma Specific Survival was seen, compared to younger patients. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Background Merkel cell carcinoma (MCC) is a rare and potentially lethal skin cancer. MCC is known for its potential rapid growth and its propensity to metastasize. Objective To describe the incidence, treatment, and survival of MCC in a population-based setting. Methods All MCCs diagnosed in The Netherlands between 1993 and 2016 were selected from the Netherlands Cancer Registry. Patient and tumor characteristics, therapy, and vital status were obtained. Cox proportional hazards were computed, and relative survival analyses were performed. Results Our cohort included 1977 patients with MCC. Incidence increased from 0.17 per 100,000 person-years in 1993 to 0.59 per 100,000 in 2016. The mean age at diagnosis was 75.5. Most MCCs (59.8%) were treated with surgery alone. Relative 5-year survival was low (63.0%) and did not improve. Mortality was higher among males (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.11-1.39), higher age (HR, 1.07; 95% CI, 1.06-1.07), and nodal (HR, 1.26; 95% CI, 1.08-1.48) and distant spread of disease (HR, 2.44; 95% CI, 1.99-2.99). Limitations We lacked data on cause of death, comorbidity, and pathologic margins, which may have led to misinterpretation of the data. Conclusion This study shows continuously increasing incidence rates of MCC in The Netherlands. Survival after a diagnosis of MCC remained low. Our results emphasize the need for implementation of new therapies.

Advances in the treatment of metastatic melanoma have improved responses and survival. However, many patients continue to experience resistance or toxicity to treatment, highlighting a crucial need to identify biomarkers and understand mechanisms of response and toxicity. Neoadjuvant therapy for regional metastases might improve operability and clinical outcomes over upfront surgery and adjuvant therapy, and has become an established role for drug development and biomarker discovery in other cancers (including locally advanced breast cancer, head and neck squamous cell carcinomas, gastroesophageal cancer, and anal cancer). Patients with clinically detectable stage III melanoma are ideal candidates for neoadjuvant therapy, because they represent a high-risk patient population with poor outcomes when treated with upfront surgery alone. Neoadjuvant therapy is now an active area of research for melanoma with numerous completed and ongoing trials (since 2014) with disparate designs, endpoints, and analyses under investigation. We have, therefore, established the International Neoadjuvant Melanoma Consortium with experts in medical oncology, surgical oncology, pathology, radiation oncology, radiology, and translational research to develop recommendations for investigating neoadjuvant therapy in melanoma to align future trial designs and correlative analyses. Alignment and consistency of neoadjuvant trials will facilitate optimal data organisation for future regulatory review and strengthen translational research across the melanoma disease continuum.

Talimogene laherparepvec (T-VEC) is a modified herpes simplex virus, type 1 (HSV-1), which can be administered intralesionally in patients with stage IIIB/C-IVM1a unresectable melanoma (EMA label). The phase 3 OPTiM registration study showed an overall response rate (ORR) of 26%. Since December 2016, 48 eligible patients started treatment at the Netherlands Cancer Institute. We included 26 patients in this study with a follow up time ≥6 months, reporting Overall Response Rate (ORR), Disease Control Rate (DCR), Adverse Events (AE), prior treatment for melanoma and baseline characteristics, documented in a prospectively maintained database. In house developed treatment protocol consists of clinical evaluation, periodic PET-CT and histological biopsies for response evaluation. Median follow-up was 12.5 months. Of 26 patients, 16 (61.5%) had a Complete Response (CR) as their best response. Seven (26.9%) patients had a Partial Response (PR) as their best response, 1 (3.8%) patient Stable Disease (SD) and 2 (7.7%) patients Progressive Disease (PD). Best ORR was 88.5%. DCR was 92.3%. Grade 1-2 AEs occurred in all patients. Mostly, these consisted of fatigue, influenza-like symptoms and injection site erythema. All patients underwent prior treatment. Prior treatment did not influence response or toxicity of T-VEC. Best ORR for T-VEC monotherapy at our institute was 88.5% with 61.5% achieving a CR. This prospective study for T-VEC in early metastatic (stage IIIB/C-IVM1a) melanoma demonstrated superior results to the phase 3 OPTiM study and confirms the role of oncolytic immunotherapy for melanoma.

Background Parotidectomy in melanoma of the coronal scalp and face with clinically involved cervical lymph node metastasis is based on predicted cervical lymphatic drainage described by O'Brien. Methods In total, 40 parotidectomies with en bloc therapeutic neck dissection were retrospectively analyzed. Results Lymphatic spread of melanoma to the parotid lymph nodes was observed in 10 of 40 specimens (25%). Eight of the 10 parotid-positive patients developed a recurrence vs 17 of the 30 parotid-negative patients (P = 0.28). There were no differences in overall survival, melanoma-specific survival, and disease-free survival between the parotid-positive and parotid-negative patients. Conclusion Although in this series no survival differences were found, parotidectomy still merits a sustained role in therapeutic neck dissection procedures to improve regional control and to prevent facial nerve damage after surgery for a second relapse from occult metastases in the parotid.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a rare soft tissue sarcoma for which clinical examination up to 10 years is recommended. The objective of this study was to identify prognostic factors for recurrences and metastases that can be used to evaluate the validity of follow-up schedules after treatment for DFSP.METHODS: Patients with DFSP who received treatment between 1991 and 2016 at 3 tertiary centers were included. Cox regression analyses were conducted to identify variables associated with the primary endpoints.RESULTS: In total 357 patients were included, with a median age of 38 years (age range, 2-87 years) and a median follow-up of 60 months (interquartile range, 24-115 months). Eighty-one patients developed recurrent disease (22.7%), and the median time to recurrence was 55.5 months (interquartile range, 20-90 months). Of these, 50 tumors (61.7%) were identified by patient self-examination, whereas 3 recurrences (3.7%) were identified at clinical surveillance. For the remaining 28 tumors, no information was available on how the recurrences were identified (34.6%). Fibrosarcomatous change (hazard ratio, 21.865; P < .001), and positive resection margins (hazard ratio, 14.645; P < .001), were independent prognostic factors for recurrence. Metastases occurred in 4 patients (1.1%). All tumors were identified by imaging after patients presented with symptomatic metastases. Fibrosarcomatous change (P < .001) and tumor size >5 cm (P = .014) were associated with the development of metastases.CONCLUSIONS: Disease recurrence after resection of DFSP remains a significant issue, whereas metastases are uncommon. The majority of recurrences are identified by patient self-examination. Consideration should be given to individualized follow-up schedules based on risk factors for recurrences and metastases.

Background: The American Joint Committee on Cancer-8 (AJCC) classification of melanoma was implemented in January 2018. It was based on data gathered when checkpoint inhibitors were not used as adjuvant therapy in stage III melanoma. The European Organization for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 double-blind phase III trial evaluated pembrolizumab vs placebo in AJCC-7 stage IIIA (excluding lymph node metastasis ≤1 mm), IIIB or IIIC (without in-transit metastasis) patients after complete lymphadenectomy. Patients, methods and results: Patients (n = 1019) were randomised 1:1 to pembrolizumab 200 mg or placebo every 3 weeks (total of 18 doses, ∼1 year). At 1.25-year median follow-up, pembrolizumab prolonged relapse-free survival (RFS) in the total population (1-year RFS rate: 75.4% vs 61.0%; hazard ratio [HR] 0.57; logrank P < 0.0001) and consistently in the AJCC-7 subgroups. Prognostic and predictive values of AJCC-8 for RFS were evaluated in this study. Patient distribution according to the AJCC-8 stage subgroups was 8% (IIIA), 34.7% (IIIB), 49.7% (IIIC), 3.7% (IIID) and 3.8% (unknown). AJCC-8 classification was strongly associated with RFS (HRs for stage IIIB, IIIC and IIID vs IIIA were 4.0, 5.7 and 12.2, respectively) but showed no predictive importance for the treatment comparison regarding RFS (test for interaction: P = 0.68). The 1-year RFS rate for pembrolizumab vs placebo and the HRs (99% confidence interval) within each AJCC-8 subgroup were as follows: stage IIIA (92.7% vs 92.5%; 0.76 [0.11–5.43]), IIIB (79.0% vs 65.5%; 0.59 [0.35–0.99]), IIIC (73.6% vs 53.9%; 0.48 [0.33–0.70]) and IIID (50.0% vs 33.3%; 0.69 [0.24–2.00]). Conclusions: AJCC-8 staging had a strong prognostic importance for RFS but no predictive importance: the RFS benefit of pembrolizumab was observed across AJCC-8 subgroups in resected high-risk stage III melanoma patients.

e21523 Background: Little is known about the outcome of adjuvant therapy in melanoma patients beyond the clinical trial setting. The Dutch Melanoma treatment Registry (DMTR) is a population-based registry, set up in July 2013 to monitor the safety and quality of melanoma care. Since 2019, adjuvant treated melanoma patients have also been registered in the DMTR, following approval and reimbursement of adjuvant treatment in the Netherlands in December 2018. Methods: Analyses were performed on melanoma patients treated with adjuvant anti-PD1 therapy included in the DMTR between 01-07-2018 and 31-12-2019. Descriptive statistics were used to analyze patient-, and treatment characteristics, and death as well as relapse rates. Results: Six hundred and fifty-seven patients treated with adjuvant systemic therapy were included in the DMTR. The majority (94%) of these patients was treated with anti-PD1. Twenty percent of the anti-PD1-treated patients developed grade ≥3 toxicity. Of the 279 patients with a minimum follow-up of one year after start of anti-PD1, 170 (61%) prematurely discontinued therapy. Relapse and death occurred in respectively, 38% and 12% of patients within one year of follow-up. Relapse was significantly more frequent in older patients, with high Breslow thickness and ulcerated melanomas. Conclusions: These data show more frequent premature discontinuation of adjuvant anti-PD1 in daily clinical practice than reported in the registration trials. Moreover, incidence of severe toxicity, relapse and death during adjuvant treatment appears higher in the real-world setting.

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43–0·74], p1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37. Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5–45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9–69·5] in the pembrolizumab group vs 49·4% [44·8–53·8] in the placebo group; HR 0·60 [95% CI 0·49–0·73]; p

Objective: To evaluate the potency of short-term neoadjuvant cytoreductive therapy with dabrafenib plus trametinib (BRAF and MEK inhibitor) to allow for radical surgical resection in patients with unresectable locally advanced melanoma. Summary Background Data: Approximately 5% of stage III melanoma patients presents with unresectable locally advanced disease, making standard of care with resection followed by adjuvant systemic therapy impossible. Although neoadjuvant targeted therapy has shown promising results in resectable stage III melanoma, its potency to enable surgical resection in patients with primarily unresectable locally advanced stage III melanoma is still unclear. Methods: In this prospective, single-arm, phase II trial, patients with unresectable BRAF-mutated locally advanced stage IIIC or oligometastatic stage IV melanoma were included. After 8 weeks of treatment with dabrafenib and trametinib, evaluation by positron emission tomography/computed tomography and physical examination were used to assess sufficient downsizing of the tumor to enable resection. The primary objective was the percentage of patients who achieved a radical (R0) resection. Results: Between August 2014 and March 2019, 21 patients (20/21 stage IIIC American Joint Committee on Cancer staging manual 7th edition) were included. Planned inclusion of 25 patients was not reached due to slow accrual and changing treatment landscape. Despite this, the predefined endpoint was successfully met. In 18/21 (86%) patients a resection was performed, of which 17 were R0 resections. At a median follow-up of 50 months (interquartile range 37.7-57.1 months), median recurrence-free survival was 9.9 months (95% confidence interval 7.52-not reached) in patients undergoing surgery. Conclusions: This prospective, single-arm, open-label phase II trial, shows neoadjuvant dabrafenib plus trametinib as a potent cytoreductive treatment, allowing radical resection of metastases in 17/21 (81%) patients with prior unresectable locally advanced melanoma.

Background: In sentinel lymph node (SLN)-positive melanoma, two randomized trials demonstrated equivalent melanoma-specific survival with nodal surveillance vs completion lymph node dissection (CLND). Patients with microsatellites, extranodal extension (ENE) in the SLN, or >3 positive SLNs constitute a high-risk group largely excluded from the randomized trials, for whom appropriate management remains unknown.Study design: SLN-positive patients with any of the three high-risk features were identified from an international cohort. CLND patients were matched 1:1 with surveillance patients using propensity scores. Risk of any-site recurrence, SLN-basin–only recurrence, and melanoma-specific mortality were compared.Results: Among 1,154 SLN-positive patients, 166 had ENE, microsatellites, and/or >3 positive SLN. At 18.5 months median follow-up, 49% had recurrence (vs 26% in patients without high-risk features, p < 0.01). Among high-risk patients, 52 (31%) underwent CLND and 114 (69%) received surveillance. Fifty-one CLND patients were matched to 51 surveillance patients. The matched cohort was balanced on tumor, nodal, and adjuvant treatment factors. There were no significant differences in any-site recurrence (CLND 49%, surveillance 45%, p = 0.99), SLN-basin–only recurrence (CLND 6%, surveillance 14%, p = 0.20), or melanoma-specific mortality (CLND 14%, surveillance 12%, p = 0.86).Conclusions: SLN-positive patients with microsatellites, ENE, or >3 positive SLN constitute a high-risk group with a 2-fold greater recurrence risk. For those managed with nodal surveillance, SLN-basin recurrences were more frequent, but all-site recurrence and melanoma-specific mortality were comparable to patients treated with CLND. Most recurrences were outside the SLN-basin, supporting use of nodal surveillance for SLN-positive patients with microsatellites, ENE, and/or >3 positive SLN.

Background Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex type 1 virus and known as an effective oncolytic immunotherapy for injectable cutaneous, subcutaneous and nodal melanoma lesions in stage IIIB-IVM1a patients. This study set out to identify prognostic factors for achieving a complete response that can be used to optimize patient selection for T-VEC monotherapy. Methods Patients with stage IIIB-IVM1a melanoma, treated with T-VEC at the Netherlands Cancer Institute between 2016-12 and 2020-01 with a follow-up time > 6 months, were included. Data were collected on baseline characteristics, responses and adverse events (AEs). Uni- and multivariable analyses were conducted, and a prediction model was developed to identify prognostic factors associated with CR. Results A total of 93 patients were included with a median age of 69 years, median follow-up time was 16.6 months. As best response, 58 patients (62%) had a CR, and the overall response rate was 79%. The durable response rate (objective response lasting > 6 months) was 51%. Grade 1-2 AEs occurred in almost every patient. Tumor size, type of metastases, prior treatment with systemic therapy and stage (8Th AJCC) were independent prognostic factors for achieving CR. The prediction model includes the predictors tumor size, type of metastases and number of lesions. Conclusions This study shows that intralesional T-VEC monotherapy is able to achieve high complete and durable responses. The prediction model shows that use of T-VEC in patients with less tumor burden is associated with better outcomes, suggesting use earlier in the course of the disease.

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Melanomas can switch to a dedifferentiated cell state upon exposure to cytotoxic T cells. However, it is unclear whether such tumor cells pre-exist in patients and whether they can be resensitized to immunotherapy. Here, we chronically expose (patient-derived) melanoma cell lines to differentiation antigen-specific cytotoxic T cells and observe strong enrichment of a pre-existing NGFRhi population. These fractions are refractory also to T cells recognizing non-differentiation antigens, as well as to BRAF + MEK inhibitors. NGFRhi cells induce the neurotrophic factor BDNF, which contributes to T cell resistance, as does NGFR. In melanoma patients, a tumor-intrinsic NGFR signature predicts anti-PD-1 therapy resistance, and NGFRhi tumor fractions are associated with immune exclusion. Lastly, pharmacologic NGFR inhibition restores tumor sensitivity to T cell attack in vitro and in melanoma xenografts. These findings demonstrate the existence of a stable and pre-existing NGFRhi multitherapy-refractory melanoma subpopulation, which ought to be eliminated to revert intrinsic resistance to immunotherapeutic intervention., Dedifferentiation state has been associated with therapy resistance in melanoma. Here, the authors uncover a pre-existing NGFR-expressing, targetable subpopulation that is resistant to immunotherapy and other treatments in melanoma cells and preclinical models.

Introduction Talimogene laherparepvec (T-VEC; IMLYGIC®, Amgen Inc.) is an oncolytic immunotherapy approved in Europe for the treatment of unresectable metastatic melanoma (stage IIIB–IVM1a). This study characterised real-world use of T-VEC in four European countries. Methods Data on demographics, treatment pattern, safety, and clinical effectiveness were examined in a retrospective chart review of patients with stage IIIB–IVM1a unresectable melanoma treated with T-VEC in surgical (the Netherlands) and medical (Austria, Germany, UK) oncology settings. Results Overall, 66 patients were included (the Netherlands: n = 31; Austria, Germany, UK: n = 35). The median age was 69 years and 59.1% were female. At the time of T-VEC initiation, 47 patients (71.2%) had stage IIIB/C disease; of these, 30 were from the Netherlands. Although 72.7% patients overall received T-VEC as first-line therapy, this was higher in the Netherlands than the other countries (93.5% vs 54.3%). Of the 47 patients who discontinued T-VEC, 26 (55.3%) had no remaining injectable lesions (potentially indicating complete response); 20/26 of these patients were from the Netherlands. One patient discontinued T-VEC due to toxicity. Conclusion This study is the first comprehensive multinational evaluation of the use of T-VEC to treat unresectable stage IIIB/C–IVM1a melanoma in real-world clinical practice in Europe. The differences between European countries were apparent, with physicians in the Netherlands using T-VEC in patients with earlier advanced disease stage and in the first-line setting compared with other countries. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-020-01590-w.

Background For patients with sentinel lymph node (SLN)-positive cutaneous melanoma, the Second Multicenter Selective Lymphadenectomy trial demonstrated equivalent disease-specific survival (DSS) with active surveillance using nodal ultrasound versus completion lymph node dissection (CLND). Adoption and outcomes of active surveillance in clinical practice and in adjuvant therapy recipients are unknown.Methods In a retrospective cohort of SLN-positive adults treated at 21 institutions in Australia, Europe, and the United States from June 2017 to November 2019, the authors evaluated the impact of active surveillance and adjuvant therapy on all-site recurrence-free survival (RFS), isolated nodal RFS, distant metastasis-free survival (DMFS), and DSS using Kaplan-Meier curves and Cox proportional hazard models.Results Among 6347 SLN biopsies, 1154 (18%) were positive and had initial negative distant staging. In total, 965 patients (84%) received active surveillance, 189 (16%) underwent CLND. Four hundred thirty-nine patients received adjuvant therapy (surveillance, 38%; CLND, 39%), with the majority (83%) receiving anti-PD-1 immunotherapy. After a median follow-up of 11 months, 220 patients developed recurrent disease (surveillance, 19%; CLND, 22%), and 24 died of melanoma (surveillance, 2%; CLND, 4%). Sixty-eight patients had an isolated nodal recurrence (surveillance, 6%; CLND, 4%). In patients who received adjuvant treatment without undergoing prior CLND, all isolated nodal recurrences were resectable. On risk-adjusted multivariable analyses, CLND was associated with improved isolated nodal RFS (hazard ratio [HR], 0.36; 95% CI, 0.15-0.88), but not all-site RFS (HR, 0.68; 95% CI, 0.45-1.02). Adjuvant therapy improved all-site RFS (HR, 0.52; 95% CI, 0.47-0.57). DSS and DMFS did not differ by nodal management or adjuvant treatment.Conclusions Active surveillance has been adopted for most SLN-positive patients. At initial assessment, real-world outcomes align with randomized trial findings, including in adjuvant therapy recipients.Lay SummaryFor patients with melanoma of the skin and microscopic spread to lymph nodes, monitoring with ultrasound is an alternative to surgically removing the remaining lymph nodes.The authors studied adoption and real-world outcomes of ultrasound monitoring in over 1000 patients treated at 21 centers worldwide, finding that most patients now have ultrasounds instead of surgery.Although slightly more patients have cancer return in the lymph nodes with this strategy, typically, it can be removed with delayed surgery.Compared with up-front surgery, ultrasound monitoring results in the same overall risk of melanoma coming back at any location or of dying from melanoma.

PURPOSE: Based on recent advances in the management of patients with sentinel node (SN)-positive melanoma, we aimed to develop prediction models for recurrence, distant metastasis (DM) and overall mortality (OM).METHODS: The derivation cohort consisted of 1080 patients with SN-positive melanoma from nine European Organization for Research and Treatment of Cancer (EORTC) centres. Prognostic factors for recurrence, DM and OM were studied with Cox regression analysis. Significant factors were incorporated in the models. Performance was assessed by discrimination (c-index) and calibration in cross-validation across centres. The models were externally validated using a prospective cohort consisting of 705 German patients with SN-positive: 473 trial participants of the German Dermatologic Cooperative Oncology Group study (DeCOG-SLT) and 232 screened patients. A nomogram was developed for graphical presentation.RESULTS: The final model for recurrence and the calibrated models for DM and OM included ulceration, age, SN tumour burden and Breslow thickness. The models showed reasonable calibration. The c-index for the recurrence, DM and OM model was 0.68, 0.70 and 0.70, respectively, and 0.70, 0.72 and 0.74, respectively, in external validation. The EORTC-DeCOG model identified a robust low-risk group, with all identified low-risk patients (approximately 4% of the entire population) having a 5-year recurrence probability of CONCLUSIONS: The EORTC-DeCOG nomogram provides an adequate prognostic tool for patients with SN-positive melanoma, without the need for CLND. It showed consistent results across validation. The nomogram could be used for patient counselling and might aid in adjuvant therapy decision-making.