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.

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.

Thick melanomas without lymph node metastases: A forgotten group with poor prognosis.

INTRODUCTION: Although adjuvant therapy is available for melanoma patients with sentinel lymph node (SLN) metastases (pN+), this is not the case for thick melanomas without SLN involvement (pN-). OBJECTIVES: We assessed overall and relative survival (OS, RS) in patients with >4.0 mm Breslow thickness (BT) pN- and pN + melanomas and ≤4.0  mm pN+ patients. MATERIALS AND METHODS: Clinicopathological data were retrieved from a cohort of >4.0 mm thick and/or pN + melanoma patients in The Netherlands from 2000 to 2014. OS and RS was compared using Kaplan-Meier-curves. A Cox-regression-model was developed to assess determinants of OS in >4.0 mm pN- patients. RESULTS: In 54 645 patients, 3940 (7.2%) had >4.0 mm thick melanomas. SLN biopsy was performed in 1150 (29.2%) patients. Five-year OS was 70.5% for >4.0 mm pN- and 48.1% for >4.0  mm pN+ patients (p < 0.001), with a decreasing trend in OS for every mm BT. Five-year OS in 1877 ≤ 4.0  mm pN+ patients was 71.5%, which was not different from >4.0 mm pN- (p = 0.24). Higher age, higher BT category, ulceration and male gender were significantly associated with poor survival in >4.0 mm pN- patients. CONCLUSIONS: Thick pN- melanomas have a poor prognosis, comparable to that of less thick pN + melanomas, which is not accounted for in current guidelines. We encourage including these high-risk patients in adjuvant trials.

Sex matters: men with melanoma have a worse prognosis than women.

BACKGROUND: In Europe, one of the highest melanoma incidences is found in the Netherlands. Like in several other European countries, females are more prone to develop melanoma as compared to males, although survival is worse for men. OBJECTIVE: To identify clinicopathological gender-related differences that may lead to gender-specific preventive measures. METHODS: Data from the Dutch Nationwide Network and Registry of Histopathology and Cytopathology (PALGA) were retrieved from patients with primary, cutaneous melanoma in the Netherlands between 2000 and 2014. Patients initially presenting as stage I, II and III without clinically detectable nodal disease were included. Follow-up data were retrieved from the Netherlands Cancer Registry. Gender-related differences were assessed, and to compare relative survival between males and females, multivariable relative excess risks (RER) were calculated. RESULTS: A total of 54.645 patients were included (43.7% men). In 2000, 41.7% of the cohort was male, as compared to 47.3% in 2014 (P < 0.001). Likewise, in 2000, 51.5% of the deceased cohort was male compared to 60.1% in 2014 (P < 0.001). Men had significantly thicker melanomas at the time of diagnosis [median Breslow thickness 1.00 mm (interquartile range (IQR): 0.60-2.00) vs. 0.82 mm (IQR: 0.50-1.50) for females] and were significantly older at the time of diagnosis, more often had ulcerated melanomas and melanomas localized on the trunk or head and neck. Over time, survival for females improved while that of men decreased (P < 0.001). RER for dying was 1.37 (95% CI: 1.31-1.45) for men in multivariable analysis. CONCLUSION: There are evident clinicopathological differences between male and female melanoma patients. After multivariable correction for all these differences, relative survival remains worse for men. Clinicians as well as persons at risk for melanoma should be aware of these differences, as awareness and prevention might lead to a lower incidence and mortality of melanoma. This indicates the need of prevention campaigns integrating and targeting specific risk profiles.