Five-year analysis of neoadjuvant dabrafenib and trametinib for stage III melanoma.

BACKGROUND: Neoadjuvant dabrafenib plus trametinib has a high pathological response rate and impressive short-term survival in patients with resectable stage III melanoma. We report 5-year outcomes from the phase II NeoCombi trial. PATIENTS AND METHODS: NeoCombi (NCT01972347) was a single-arm, open-label, single-centre, phase II trial. Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, American Joint Committee on Cancer seventh edition clinical stage IIIB-C BRAF V600E/K-mutant melanoma and Eastern Cooperative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with dabrafenib 150 mg (orally twice per day) plus trametinib 2 mg (orally once per day), with complete resection of the pre-therapy tumour bed at week 12. RESULTS: Between 20 August 2014 and 19 April 2017, 35 patients were enrolled. At data cut-off (17 August 2021), the median follow-up was 60 months [95% confidence interval (CI) 56-72 months]. Overall, 21 of 35 (60%) patients recurred, including 12 (57%) with first recurrence in locoregional sites (followed by later distant recurrence in 6) and 9 (43%) with first recurrence in distant sites, including 3 in the brain. Most recurrences occurred within 2 years, with no recurrences beyond 3 years. At 5 years, recurrence-free survival (RFS) was 40% (95% CI 27% to 60%), distant metastasis-free survival (DMFS) was 57% (95% CI 42% to 76%), and overall survival was 80% (95% CI 67% to 94%). Five-year survival outcomes were stratified by pathological response: RFS was 53% with pathological complete response (pCR) versus 28% with non-pCR (P = 0.087), DMFS was 59% versus 55% (P = 0.647), and overall survival was 88% versus 71% (P = 0.205), respectively. CONCLUSIONS: Neoadjuvant dabrafenib plus trametinib has high pathological response rates in clinical stage III melanoma, but low rates of RFS, similar to those achieved with adjuvant targeted therapy alone. Patients with a pCR to dabrafenib plus trametinib still had a high risk of recurrence, unlike that seen with immunotherapy where recurrences are rare.

Mohs micrographic surgery for the treatment of invasive melanoma: A systematic review with meta-analyses.

BACKGROUND: The use of Mohs micrographic surgery (MMS) in melanoma treatment has divided opinion and evidence-based guidelines are lacking. OBJECTIVES: This systematic review aimed to analyse clinical outcomes for patients with invasive melanomas treated with Mohs rather than wide local excision (WLE). METHODS: Embase, MEDLINE and Cochrane databases (to 30 August 2023) were searched for studies using Mohs to treat invasive melanoma. Outcomes of interest were local recurrence and death from melanoma. RESULTS: Thirty-five articles involving 41,499 patients with invasive melanoma treated with Mohs were identified. Sixteen studies compared Mohs with WLE and 19 were Mohs-only, non-comparative studies. Patients treated with Mohs differed significantly from those undergoing WLE, in particular Mohs patients were older and had thinner melanomas. Two comparative studies using the same data source reported adjusted hazard ratios for melanoma-specific death and both showed no significant difference between Mohs and WLE-treated patients; 0.87 (95% CI 0.55-1.35) and 1.20 (95% CI 0.71-20.36). There was also no statistically significant difference in local recurrence risk; the unadjusted risk ratio for patients treated with Mohs was 0.46 (95% CI 0.14-1.51 p = 0.20) with moderate heterogeneity (I2 = 62%). No studies reported multivariable analyses for risk of local recurrence. Many studies generated from relatively few and often overlapping data sets have reported the use of Mohs to treat patients with invasive melanoma. Fewer studies were comparative between Mohs and WLE and these reported substantially different baseline risks of recurrence and death from melanoma between the groups. Mohs has generally been used for thinner melanomas in older patients; therefore, comparisons based on univariable analyses are likely to have been misleading. CONCLUSIONS: On the basis of currently available data, it is not possible to reliably assess whether outcomes differ if invasive melanomas with comparable features are treated with Mohs or WLE, and randomized trial evidence will be required for reliable conclusions to be reached.

Sentinel node biopsy in patients with melanoma improves the accuracy of staging when added to clinicopathological features of the primary tumor.

BACKGROUND: It has been claimed, without supporting evidence, that knowledge of sentinel node (SN) status does not provide more accurate prognostic information than basic clinicopathological features of a primary cutaneous melanoma. We sought to investigate this claim and to quantify any additional value of SN status in predicting survival outcome. PATIENTS AND METHODS: Data for a Dutch population-based cohort of melanoma patients (n = 9272) and for a validation cohort from a large Australian melanoma treatment center (n = 5644) were analyzed. Patients were adults diagnosed between 2004 and 2014 with histologically-proven, primary invasive cutaneous melanoma who underwent SN biopsy. Multivariable Cox proportional hazards analyses were carried out in the Dutch cohort to assess recurrence-free survival (RFS), melanoma-specific survival (MSS) and overall survival (OS). The findings were validated using the Australian cohort. Discrimination (Harrell's C-statistic), net benefit using decision curve analysis and net reclassification index (NRI) were calculated. RESULTS: The Dutch cohort showed an improved C-statistic from 0.74 to 0.78 for OS and from 0.74 to 0.76 for RFS when SN status was included in the model with Breslow thickness, sex, age, site, mitoses, ulceration, regression and melanoma subtype. In the Australian cohort, the C-statistic increased from 0.70 to 0.73 for OS, 0.70 to 0.74 for RFS and 0.72 to 0.76 for MSS. Decision curve analyses showed that the 3-year and 5-year risk of death or recurrence were more accurately classified with a model that included SN status. At 3 years, sensitivity increased by 12% for both OS and RFS in the development cohort, and by 10% and 6% for OS and RFS, respectively, in the validation cohort. CONCLUSIONS: Knowledge of SN status significantly improved the predictive accuracy for RFS, MSS and OS when added to a comprehensive suite of established clinicopathological prognostic factors. However, clinicians and patients must consider the magnitude of the improvement when weighing up the advantages and disadvantages of SN biopsy for melanoma.

Predicting recurrence in patients with sentinel node-negative melanoma: validation of the EORTC nomogram using population-based data.

BACKGROUND: Identifying patients with sentinel node (SN)-negative melanoma who are at greatest risk of recurrence is important. The European Organization for Research and Treatment of Cancer (EORTC) Melanoma Group proposed a prognostic model that has not been validated in population-based data. The EORTC nomogram includes Breslow thickness, ulceration status and anatomical location as parameters. The aim of this study was to validate the EORTC model externally using a large national data set. METHODS: Adults with histologically proven, invasive cutaneous melanoma with a negative SN biopsy in the Netherlands between 2000 and 2014 were identified from the Dutch Pathology Registry, and relevant data were extracted. The EORTC nomogram was used to predict recurrence-free survival. The predictive performance of the nomogram was assessed by discrimination (C-statistic) and calibration. RESULTS: A total of 8795 patients met the eligibility criteria, of whom 14·7 per cent subsequently developed metastatic disease. Of these recurrences, 20·9 per cent occurred after the first 5 years of follow-up. Validation of the EORTC nomogram showed a C-statistic of 0·70 (95 per cent c.i. 0·68 to 0·71) for recurrence-free survival, with excellent calibration (R2 = 0·99; P = 0·999, Hosmer-Lemeshow test). CONCLUSION: This population-based validation confirmed the value of the EORTC nomogram in predicting recurrence-free survival in patients with SN-negative melanoma. The EORTC nomogram could be used in clinical practice for personalizing follow-up and selecting high-risk patients for trials of adjuvant systemic therapy.

Predicting sentinel node positivity in patients with melanoma: external validation of a risk-prediction calculator (the Melanoma Institute Australia nomogram) using a large European population-based patient cohort.

BACKGROUND: A nomogram to predict sentinel node (SN) positivity [the Melanoma Institute Australia (MIA) nomogram] was recently developed and externally validated using two large single-institution databases. However, there remains a need to further validate the nomogram's performance using population-based data. OBJECTIVES: To perform further validation of the nomogram using a European national patient cohort. METHODS: Patients with cutaneous melanoma who underwent SN biopsy in the Netherlands between 2000 and 2014 were included. Their data were obtained from the Dutch Pathology Registry. The predictive performance of the nomogram was assessed by discrimination (C-statistic) and calibration. Negative predictive values (NPVs) were calculated at various predicted probability cutoffs. RESULTS: Of the 3049 patients who met the eligibility criteria, 23% (691) were SN positive. Validation of the MIA nomogram (including the parameters Breslow thickness, ulceration, age, melanoma subtype and lymphovascular invasion) showed a good C-statistic of 0·69 (95% confidence interval 0·66-0·71) with excellent calibration (R2 = 0·985, P = 0·40). The NPV of 90·1%, found at a 10% predicted probability cutoff for having a positive SN biopsy, implied that by using the nomogram, a 16·3% reduction in the rate of performing an SN biopsy could be achieved with an error rate of 1·6%. Validation of the MIA nomogram considering mitotic rate as present or absent showed a C-statistic of 0·70 (95% confidence interval 0·68-0·74). CONCLUSIONS: This population-based validation study in European patients with melanoma confirmed the value of the MIA nomogram in predicting SN positivity. Its use will spare low-risk patients the inconvenience, cost and potential risks of SN biopsy while ensuring that high-risk patients are still identified.

A multicentre study of naevus-associated melanoma vs. de novo melanoma, tumour thickness and body site differences.

BACKGROUND: Whether melanoma in histological contiguity with a naevus [naevus-associated melanoma (NAM)] is distinctly different from melanoma arising de novo remains unclear. OBJECTIVES: To determine whether the characteristics of de novo melanoma differ from NAM and are not due to naevus obliteration in thicker tumours. METHODS: We conducted a multicentre retrospective study of de novo melanoma and NAM in seven referral centres in Europe, Australia and the USA between 2006 and 2015. RESULTS: In a total of 9474 localized melanomas, de novo melanoma was associated with thicker tumours and body site differences compared with NAM. In the subset of T1 melanomas (n = 5307), similar body site differences were found in multivariate analysis by body site. When compared with NAM, de novo melanoma was more likely to affect older individuals (≥ 70 years) when located on the head/neck [odds ratio (OR) 4·65, 95% confidence interval (CI) 2·55-8·46], the trunk (OR 1·82, 95% CI 1·40-2·36) or the upper extremity (OR 1·69, 95% CI 1·14-2·50), was more likely to affect female patients when located on the lower extremities (OR 1·36, 95% CI 1·03-1·80), and was more likely to be of the nodular melanoma subtype (OR 2·23, 95% CI 1·14-4·35) when located on the trunk. De novo melanoma was less likely to have regression present compared with NAM. CONCLUSIONS: Clinicopathological and body site differences between de novo melanoma and NAM support the divergent pathway model of development. These differences were also found in thin melanomas, suggesting that de novo melanomas are different from NAM and their differences are not due to the obliteration of naevus remnants in thicker tumours.

Desmoplastic melanoma: a review of its pathology and clinical behaviour, and of management recommendations in published guidelines.

Desmoplastic melanomas are uncommon. Their behaviour differs from that of other melanoma subtypes; therefore, management guidelines for non-desmoplastic melanomas may not be applicable. This review sought to examine all available evidence relating to the behaviour and management of desmoplastic melanomas, based on review of all relevant English-language publications, and to critically assess the recommendations for their management in current published melanoma management guidelines. Compared with other melanoma subtypes, patients with 'pure' desmoplastic melanomas (where ≥90% of the invasive melanoma is of desmoplastic melanoma subtype) have much lower rates of sentinel node positivity and distant metastasis. Local recurrence rates are higher for desmoplastic melanomas, but resection margins wider than those recommended for non-desmoplastic melanomas have not been shown to be of benefit. Adjuvant radiotherapy reduces the risk of local recurrence when a satisfactory histological clearance (≥8 mm) cannot be achieved. Of 29 published melanoma management guidelines identified, only 11 specified management for desmoplastic melanomas, while seven simply stated that the feature should be reported. Desmoplastic melanoma is a unique melanoma subtype with biology that differs from that of other melanoma subtypes. It requires specific management strategies but few current guidelines address these.

Same-day or next-day sentinel node biopsy after lymphoscintigraphy for melanoma using 99m Tc-labelled antimony sulphide colloid.

BACKGROUND: Two recent publications have reported that a shorter interval between preoperative lymphoscintigraphy and sentinel node biopsy (SNB) is associated with improved survival of patients with primary cutaneous melanoma. The aims of this study were to analyse prospectively collected survival data for patients who had SNB on the same day as lymphoscintigraphy or the day after; and to assess tracer migration from sentinel nodes to second-tier nodes after lymphoscintigraphy on the previous day. METHODS: Outcome data were obtained for patients who had lymphoscintigraphy and SNB on the same day (time interval less than 8 h) or the next day (interval more than 16 h). In a separate prospective cohort, same-day and next-day lymphoscintigraphic images of sentinel nodes and second-tier nodes were compared. RESULTS: Following lymphoscintigraphy, 2848 patients had same-day and 3328 had next-day SNB. Survival outcomes did not differ between these groups. In a prospectively studied cohort of 30 patients, none had significant tracer migration from sentinel nodes to second-tier nodes on imaging the following day. CONCLUSION: No difference in survival after same- or next-day sentinel node biopsy is seen when 99m Tc-labelled antimony sulphide colloid is used. This may be because of less tracer migration to second-tier nodes.

ANTECEDENTES: Dos publicaciones recientes han señalado que reducir el intervalo entre la linfografía isotópica preoperatoria y la biopsia del ganglio centinela (sentinel node biopsy, SNB) se asocia con una mejor supervivencia en pacientes con melanoma maligno primario. Los objetivos de este estudio fueron los siguientes: (1) analizar los datos de supervivencia recogidos prospectivamente en pacientes en los que se realiza la SNB el mismo día o al día siguiente de la linfografía isotópica, y (2) evaluar la migración del marcador desde los ganglios centinela a los ganglios de segundo nivel a partir de la linfografía del día anterior. MÉTODOS: Se analizaron los resultados de los pacientes a los que se realizó una linfografía isotópica y la SNB el mismo día (intervalo de tiempo < 8 h) o al día siguiente (intervalo > 16 h). En una cohorte prospectiva diferente, se compararon las imágenes de los ganglios centinela y de los ganglios de segundo nivel en linfografías isotópicas realizadas el mismo día o al día siguiente. RESULTADOS: Tras la linfografía isotópica, se realizó la SNB el mismo día en 2.848 pacientes y al día siguiente en 3.328 pacientes. No hubo diferencias en la supervivencia entre ambos grupos. En una cohorte de 30 pacientes estudiada de forma prospectiva, no hubo migración significativa del trazador de los ganglios centinela a los ganglios de segundo nivel en las imágenes obtenidas al día siguiente. CONCLUSIÓN: La mejor supervivencia que se obtiene cuando se realiza la SNB poco después de la linfografía isotópica podría explicarse por una diferencia en la migración del trazador a los ganglios de segundo nivel entre los dos marcadores utilizados: nanocoloide de albúmina humana o coloide de sulfuro de antimonio, ambos marcados con 99mTc. En este estudio y con este último marcador, no se observó migración a ganglios de segundo nivel durante la noche.

A risk prediction model for the development of subsequent primary melanoma in a population-based cohort.

BACKGROUND: Guidelines for follow-up of patients with melanoma are based on limited evidence. OBJECTIVES: To guide skin surveillance, we developed a risk prediction model for subsequent primary melanomas, using demographic, phenotypical, histopathological, sun exposure and genomic risk factors. METHODS: Using Cox regression frailty models, we analysed data for 2613 primary melanomas from 1266 patients recruited to the population-based Genes, Environment and Melanoma study in New South Wales, Australia, with a median of 14 years' follow-up via the cancer registry. Discrimination and calibration were assessed. RESULTS: The median time to diagnosis of a subsequent primary melanoma decreased with each new primary melanoma. The final model included 12 risk factors. Harrell's C-statistic was 0·73 [95% confidence interval (CI) 0·68-0·77], 0·65 (95% CI 0·62-0·68) and 0·65 (95% CI 0·61-0·69) for predicting second, third and fourth primary melanomas, respectively. The risk of a subsequent primary melanoma was 4·75 times higher (95% CI 3·87-5·82) for the highest vs. the lowest quintile of the risk score. The mean absolute risk of a subsequent primary melanoma within 5 years was 8·0 ± SD 4.1% after the first primary melanoma, and 46·8 ± 15·0% after the second, but varied substantially by risk score. CONCLUSIONS: The risk of developing a subsequent primary melanoma varies considerably between individuals and is particularly high for those with two or more primary melanomas. The risk prediction model and its associated nomograms enable estimation of the absolute risk of subsequent primary melanoma, on the basis of on an individual's risk factors, and can be used to tailor surveillance intensity, communicate risk and provide patient education. What's already known about this topic? Current guidelines for the frequency and length of follow-up to detect new primary melanomas in patients with one or more previous primary melanomas are based on limited evidence. People with one or more primary melanomas have, on average, a higher risk of developing another primary invasive melanoma, compared with the general population, but an accurate way of estimating individual risk is needed. What does this study add? We provide a comprehensive risk prediction model for subsequent primary melanomas, using data from 1266 participants with melanoma (2613 primary melanomas), over a median 14 years' follow-up. The model includes 12 risk factors comprising demographic, phenotypical, histopathological and genomic factors, and sun exposure. It enables estimation of the absolute risk of subsequent primary melanomas, and can be used to tailor surveillance intensity, communicate individual risk and provide patient education.

Pre-operative ctDNA predicts survival in high-risk stage III cutaneous melanoma patients.

BACKGROUND: The outcomes of patients with stage III cutaneous melanoma who undergo complete surgical resection can be highly variable, and estimation of individual risk of disease recurrence and mortality remains imprecise. With recent demonstrations of effective adjuvant targeted and immune checkpoint inhibitor therapy, more precise stratification of patients for costly and potentially toxic adjuvant therapy is needed. We report the utility of pre-operative circulating tumour DNA (ctDNA) in patients with high-risk stage III melanoma. PATIENTS AND METHODS: ctDNA was analysed in blood specimens that were collected pre-operatively from 174 patients with stage III melanoma undergoing complete lymph node (LN) dissection. Cox regression analyses were used to evaluate the prognostic significance of ctDNA for distant metastasis recurrence-free survival and melanoma-specific survival (MSS). RESULTS: The detection of ctDNA in the discovery and validation cohort was 34% and 33%, respectively, and was associated with larger nodal melanoma deposit, higher number of melanoma involved LNs, more advanced stage and high lactate dehydrogenase (LDH) levels. Detectable ctDNA was significantly associated with worse MSS in the discovery [hazard ratio (HR) 2.11 P < 0.01] and validation cohort (HR 2.29, P = 0.04) and remained significant in a multivariable analysis (HR 1.85, P = 0.04). ctDNA further sub-stratified patients with AJCC stage III substage, with increasing significance observed in more advanced stage melanoma. CONCLUSION: Pre-operative ctDNA predicts MSS in high-risk stage III melanoma patients undergoing complete LN dissection, independent of stage III substage. This biomarker may have an important role in determining prognosis and stratifying patients for adjuvant treatment.

Inguinal and Ilio-inguinal Lymphadenectomy in Management of Palpable Melanoma Lymph Node Metastasis: A Long-Term Prospective Evaluation of Morbidity and Quality of Life.

PURPOSE: Prospective data are lacking on long-term morbidity of inguinal lymphadenectomy including the influence of extent of surgery, use of radiotherapy, and patient factors. The aim of this study is to evaluate the effects of these factors on patient outcome, quality of life (QOL), regional symptoms, and limb volumes after inguinal or ilio-inguinal lymphadenectomy for melanoma. METHODS: Analysis of the subgroup of patients with inguinal lymph node field relapse of melanoma, treated by inguinal or ilio-inguinal lymphadenectomy in the ANZMTG/TROG randomized trial of adjuvant radiotherapy versus observation. RESULTS: Sixty-nine patients, 46 having undergone inguinal and 23 ilio-inguinal lymphadenectomy, with median follow-up of 73 months were analyzed. Mean limb volume increased rapidly after surgery (7% by 3 months) and continued to increase for at least another 18 months. Patients with body mass index (BMI) ≥ 25 kg/m2 had greater limb volume increase than normal-weight patients (13.3% versus 6.9%, P = 0.030). QOL improved over the first 18 months, but despite initial improvement, regional symptoms persisted long term. Type of surgery (inguinal or ilio-inguinal lymphadenectomy) had no demonstrably significant effect on limb volume (9.9% versus 13.4%, P = 0.35), QOL (P = 0.68), or regional symptoms (P = 0.65). There was no difference in overall survival between inguinal and ilio-inguinal lymphadenectomy [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.40-1.40, P = 0.43]. CONCLUSIONS: Inguinal lymphadenectomy for melanoma is a potentially morbid procedure with significant increases in limb volume. Patients report reasonable QOL but may have ongoing regional symptoms. Overweight/obesity is associated with poorer QOL, increased limb volume, and regional symptoms.

External validation of a prognostic model to predict survival of patients with sentinel node-negative melanoma.

BACKGROUND: Identifying patients with sentinel node-negative melanoma at high risk of recurrence or death is important. The European Organisation for Research and Treatment of Cancer (EORTC) recently developed a prognostic model including Breslow thickness, ulceration and site of the primary tumour. The aims of the present study were to validate this prognostic model externally and to assess whether it could be improved by adding other prognostic factors. METHODS: Patients with sentinel node-negative cutaneous melanoma were included in this retrospective single-institution study. The ß values of the EORTC prognostic model were used to predict recurrence-free survival and melanoma-specific survival. The predictive performance was assessed by discrimination (c-index) and calibration. Seeking to improve the performance of the model, additional variables were added to a Cox proportional hazards model. RESULTS: Some 4235 patients with sentinel node-negative cutaneous melanoma were included. The median follow-up time was 50 (i.q.r. 18·5-81·5) months. Recurrences and deaths from melanoma numbered 793 (18·7 per cent) and 456 (10·8 per cent) respectively. Validation of the EORTC model showed good calibration for both outcomes, and a c-index of 0·69. The c-index was only marginally improved to 0·71 when other significant prognostic factors (sex, age, tumour type, mitotic rate) were added. CONCLUSION: This study validated the EORTC prognostic model for recurrence-free and melanoma-specific survival of patients with negative sentinel nodes. The addition of other prognostic factors only improved the model marginally. The validated EORTC model could be used for personalizing follow-up and selecting high-risk patients for trials of adjuvant systemic therapy.

ANTECEDENTES: Es importante identificar a los pacientes con melanoma y ganglio centinela negativo con alto riesgo de recidiva o muerte. Con este fin, la European Organisation for Research and Treatment of Cancer (EORTC) ha desarrollado recientemente un modelo pronóstico que incluye el índice de Breslow, la presencia de úlcera y la localización del tumor primario. Los objetivos del presente estudio fueron efectuar la validación externa de este modelo pronóstico y evaluar si pudiera mejorarse agregando otros factores pronósticos. MÉTODOS: Estudio retrospectivo de una sola institución, en el que se incluyeron 4.235 pacientes con melanoma cutáneo y ganglio centinela negativo. La mediana de seguimiento fue de 50 meses (rango intercuartílico 18,5-81,5). Para predecir la supervivencia sin recidiva y la supervivencia específica para el melanoma se utilizaron los valores beta del modelo de pronóstico de la EORTC. La capacidad predictiva se evaluó mediante los índices de discriminación (índice c) y de calibración. Para mejorar el rendimiento de este modelo, se agregaron más variables utilizando un modelo de riesgos proporcionales de Cox. RESULTADOS: Las recidivas y muertes por melanoma fueron 793 (19%) y 456 (11%), respectivamente. La validación del modelo EORTC mostró una buena calibración para ambos resultados y un índice c de 0,69. El índice c sólo mejoró marginalmente a 0,71 cuando se agregaron otros factores pronósticos significativos (género, edad, tipo de tumor, índice mitótico). CONCLUSIÓN: La validación externa del modelo de pronóstico EORTC para la supervivencia sin recidiva y específica en pacientes con melanoma y ganglio centinela negativo fue satisfactoria. La adición de otros factores pronósticos solo mejoró marginalmente el modelo. El modelo validado de la EORTC podría utilizarse para personalizar las estrategias de seguimiento y seleccionar a pacientes de alto riesgo para ensayos con terapia sistémica adyuvante.

Impact of genomics on the surgical management of melanoma.

BACKGROUND: Although surgery for early-stage melanoma offers the best chance of cure, recent advances in molecular medicine have revolutionized the management of late-stage melanoma, leading to significant improvements in clinical outcomes. Research into the genomic drivers of disease and cancer immunology has not only ushered in a new era of targeted and immune-based therapies for patients with metastatic melanoma, but has also provided new tools for monitoring disease recurrence and selecting therapeutic strategies. These advances present new opportunities and challenges to the surgeon treating patients with melanoma. METHODS: The literature was reviewed to evaluate diagnostic and therapeutic advances in the management of cutaneous melanoma, and to highlight the impact of these advances on surgical decision-making. RESULTS: Genomic testing is not required in the surgical management of primary melanoma, although it can provide useful information in some situations. Circulating nucleic acids from melanoma cells can be detected in peripheral blood to predict disease recurrence before it manifests clinically, but validation is required before routine clinical application. BRAF mutation testing is the standard of care for all patients with advanced disease to guide therapy, including the planning of surgery in adjuvant and neoadjuvant settings. CONCLUSION: Surgery remains central for managing primary melanoma, and is an important element of integrated multidisciplinary care in advanced disease, particularly for patients with resectable metastases. The field will undergo further change as clinical trials address the relationships between surgery, radiotherapy and systemic therapy for patients with high-risk, early-stage and advanced melanoma.

EVERSUN: a phase 2 trial of alternating sunitinib and everolimus as first-line therapy for advanced renal cell carcinoma.

BACKGROUND: We hypothesised that alternating inhibitors of the vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin pathways would delay the development of resistance in advanced renal cell carcinoma (aRCC). PATIENTS AND METHODS: A single-arm, two-stage, multicentre, phase 2 trial to determine the activity, feasibility, and safety of 12-week cycles of sunitinib 50 mg daily 4 weeks on / 2 weeks off, alternating with everolimus 10 mg daily for 5 weeks on / 1 week off, until disease progression or prohibitive toxicity in favourable or intermediate-risk aRCC. The primary end point was proportion alive and progression-free at 6 months (PFS6m). The secondary end points were feasibility, tumour response, overall survival (OS), and adverse events (AEs). The correlative objective was to assess biomarkers and correlate with clinical outcome. RESULTS: We recruited 55 eligible participants from September 2010 to August 2012. DEMOGRAPHICS: mean age 61, 71% male, favourable risk 16%, intermediate risk 84%. Cycle 2 commenced within 14 weeks for 80% of participants; 64% received ≥22 weeks of alternating therapy; 78% received ≥22 weeks of any treatment. PFS6m was 29/55 (53%; 95% confidence interval [CI] 40% to 66%). Tumour response rate was 7/55 (13%; 95% CI 4% to 22%, all partial responses). After median follow-up of 20 months, 47 of 55 (86%) had progressed with a median progression-free survival of 8 months (95% CI 5-10), and 30 of 55 (55%) had died with a median OS of 17 months (95% CI 12-undefined). AEs were consistent with those expected for each single agent. No convincing prognostic biomarkers were identified. CONCLUSIONS: The EVERSUN regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. This supports the current approach of continuing anti-VEGF therapy until progression or prohibitive toxicity before changing treatment. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12609000643279.

A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma.

We report four previously undescribed families with germline BRCA1-associated protein-1 gene (BAP1) mutations and expand the clinical phenotype of this tumor syndrome. The tumor spectrum in these families is predominantly uveal malignant melanoma (UMM), cutaneous malignant melanoma (CMM) and mesothelioma, as previously reported for germline BAP1 mutations. However, mutation carriers from three new families, and one previously reported family, developed basal cell carcinoma (BCC), thus suggesting inclusion of BCC in the phenotypic spectrum of the BAP1 tumor syndrome. This notion is supported by the finding of loss of BAP1 protein expression by immunochemistry in two BCCs from individuals with germline BAP1 mutations and no loss of BAP1 staining in 53 of sporadic BCCs consistent with somatic mutations and loss of heterozygosity of the gene in the BCCs occurring in mutation carriers. Lastly, we identify the first reported recurrent mutation in BAP1 (p.R60X), which occurred in three families from two different continents. In two of the families, the mutation was inherited from a common founder but it arose independently in the third family.

Multicenter Selective Lymphadenectomy Trial-I confirms the central role of sentinel node biopsy in contemporary melanoma management: response to 'No survival benefit for patients with melanoma undergoing sentinel lymph node biopsy: critical appraisal of the Multicenter Selective Lymphadenectomy Trial-I final report'.

Sentinel lymph node (SLN) biopsy has become a standard procedure for many patients with melanoma and is recommended in numerous national and professional melanoma guidelines. The Multicenter Selective Lymphadenectomy Trial (MSLT-1) confirms earlier large database studies and prospective clinical trials in demonstrating the independent and unequalled prognostic value of the SLN. It also demonstrates the ability of biopsy-directed management to provide effective regional disease control with the least possible morbidity. These benefits are not in question and provide ample justification for the procedure, even without evidence of a survival benefit. However, MSLT-1 also provides strong evidence of a substantial reduction in the risk of melanoma death for patients with intermediate thickness melanomas who harbour occult nodal metastases at the time of presentation. Denying appropriately selected patients with melanoma the opportunity to undergo SLN biopsy is no longer reasonable or acceptable.