Development and validation of a novel model to predict recurrence-free survival and melanoma-specific survival after sentinel lymph node biopsy in patients with melanoma: an international, retrospective, multicentre analysis.

BACKGROUND: The introduction of adjuvant systemic treatment for patients with high-risk melanomas necessitates accurate staging of disease. However, inconsistencies in outcomes exist between disease stages as defined by the American Joint Committee on Cancer (8th edition). We aimed to develop a tool to predict patient-specific outcomes in people with melanoma rather than grouping patients according to disease stage. METHODS: Patients older than 13 years with confirmed primary melanoma who underwent sentinel lymph node biopsy (SLNB) between Oct 29, 1997, and Nov 11, 2013, at four European melanoma centres (based in Berlin, Germany; Amsterdam and Rotterdam, the Netherlands; and Warsaw, Poland) were included in the development cohort. Potential predictors of recurrence-free and melanoma-specific survival assessed were sex, age, presence of ulceration, primary tumour location, histological subtype, Breslow thickness, sentinel node status, number of sentinel nodes removed, maximum diameter of the largest sentinel node metastasis, and Dewar classification. A prognostic model and nomogram were developed to predict 5-year recurrence-free survival on a continuous scale in patients with stage pT1b or higher melanomas. This model was also calibrated to predict melanoma-specific survival. Model performance was assessed by discrimination (area under the time-dependent receiver operating characteristics curve [AUC]) and calibration. External validation was done in a cohort of patients with primary melanomas who underwent SLNB between Jan 30, 1997, and Dec 12, 2013, at the Melanoma Institute Australia (Sydney, NSW, Australia). FINDINGS: The development cohort consisted of 4071 patients, of whom 2075 (51%) were female and 1996 (49%) were male. 889 (22%) had sentinel node-positive disease and 3182 (78%) had sentinel node-negative disease. The validation cohort comprised 4822 patients, of whom 1965 (41%) were female and 2857 (59%) were male. 891 (18%) had sentinel node-positive disease and 3931 (82%) had sentinel node-negative disease. Median follow-up was 4·8 years (IQR 2·3-7·8) in the development cohort and 5·0 years (2·2-8·9) in the validation cohort. In the development cohort, 5-year recurrence-free survival was 73·5% (95% CI 72·0-75·1) and 5-year melanoma-specific survival was 86·5% (85·3-87·8). In the validation cohort, the corresponding estimates were 66·1% (64·6-67·7) and 83·3% (82·0-84·6), respectively. The final model contained six prognostic factors: sentinel node status, Breslow thickness, presence of ulceration, age at SLNB, primary tumour location, and maximum diameter of the largest sentinel node metastasis. In the development cohort, for the model's prediction of recurrence-free survival, the AUC was 0·80 (95% CI 0·78-0·81); for prediction of melanoma-specific survival, the AUC was 0·81 (0·79-0·84). External validation showed good calibration for both outcomes, with AUCs of 0·73 (0·71-0·75) and 0·76 (0·74-0·78), respectively. INTERPRETATION: Our prediction model and nomogram accurately predicted patient-specific risk probabilities for 5-year recurrence-free and melanoma-specific survival. These tools could have important implications for clinical decision making when considering adjuvant treatments in patients with high-risk melanomas. FUNDING: Erasmus Medical Centre Cancer Institute.

Predicting Recurrence-Free and Overall Survival for Patients With Stage II Melanoma: The MIA Calculator.

PURPOSE: Improvements in recurrence-free survival (RFS) were demonstrated in two recent randomized trials for patients with sentinel node (SN)-negative stage IIB or IIC melanoma receiving adjuvant systemic therapy (pembrolizumab/nivolumab). However, adverse events also occurred. Accurate individualized prognostic estimates of RFS and overall survival (OS) would allow patients to more accurately weigh the risks and benefits of adjuvant therapy. Since the current American Joint Committee on Cancer eighth edition (AJCC-8) melanoma staging system focuses on melanoma-specific survival, we developed a multivariable risk prediction calculator that provides estimates of 5- and 10-year RFS and OS for these patients. METHODS: Data were extracted from the Melanoma Institute Australia (MIA) database for patients diagnosed with stage II (clinical or pathological) melanoma (n = 3,220). Survival prediction models were developed using multivariable Cox regression analyses (MIA models) and externally validated twice using data sets from the United States and the Netherlands. Each model's performance was assessed using C-statistics and calibration plots and compared with Cox models on the basis of AJCC-8 staging (stage models). RESULTS: The 5-year and 10-year RFS C-statistics were 0.70 and 0.73 (MIA-model) versus 0.61 and 0.60 (stage-model), respectively. For OS, the 5-year and 10-year C-statistics were 0.71 and 0.75 (MIA-model) compared with 0.62 and 0.61 (stage-model), respectively. The MIA models were well calibrated and externally validated. CONCLUSION: The MIA models offer accurate and personalized estimates of both RFS and OS in patients with stage II melanoma even in the absence of pathological staging with SN biopsy. These models were robust on external validations and may be used in everyday practice both with (ideally) and without performing SN biopsy to identify high-risk patients for further management strategies. An online tool will be available at the MIA website (Risk Prediction Tools).

Population-Based Validation of the MIA and MSKCC Tools for Predicting Sentinel Lymph Node Status.

Importance: Patients with melanoma are selected for sentinel lymph node biopsy (SLNB) based on their risk of a positive SLN. To improve selection, the Memorial Sloan Kettering Cancer Center (MSKCC) and Melanoma Institute Australia (MIA) developed predictive models, but the utility of these models remains to be tested. Objective: To determine the clinical utility of the MIA and MSKCC models. Design, Setting, and Participants: This was a population-based comparative effectiveness research study including 10 089 consecutive patients with cutaneous melanoma undergoing SLNB from the Swedish Melanoma Registry from January 2007 to December 2021. Data were analyzed from May to August 2023. Main Outcomes and Measures,: The predicted probability of SLN positivity was calculated using the MSKCC model and a limited MIA model (using mitotic rate as absent/present instead of count/mm2 and excluding the optional variable lymphovascular invasion) for each patient. The operating characteristics of the models were assessed and compared. The clinical utility of each model was assessed using decision curve analysis and compared with a strategy of performing SLNB on all patients. Results: Among 10 089 included patients, the median (IQR) age was 64.0 (52.0-73.0) years, and 5340 (52.9%) were male. The median Breslow thickness was 1.8 mm, and 1802 patients (17.9%) had a positive SLN. Both models were well calibrated across the full range of predicted probabilities and had similar external area under the receiver operating characteristic curves (AUC; MSKCC: 70.8%; 95% CI, 69.5-72.1 and limited MIA: 69.7%; 95% CI, 68.4-71.1). At a risk threshold of 5%, decision curve analysis indicated no added net benefit for either model compared to performing SLNB for all patients. At risk thresholds of 10% or higher, both models added net benefit compared to SLNB for all patients. The greatest benefit was observed in patients with T2 melanomas using a threshold of 10%; in that setting, the use of the nomograms led to a net reduction of 8 avoidable SLNBs per 100 patients for the MSKCC nomogram and 7 per 100 patients for the limited MIA nomogram compared to a strategy of SLNB for all. Conclusions and Relevance: This study confirmed the statistical performance of both the MSKCC and limited MIA models in a large, nationally representative data set. However, decision curve analysis demonstrated that using the models only improved selection for SLNB compared to biopsy in all patients when a risk threshold of at least 7% was used, with the greatest benefit seen for T2 melanomas at a threshold of 10%. Care should be taken when using these nomograms to guide selection for SLNB at the lowest thresholds.

Role of Concurrent Ultrasound Surveillance of Sentinel Node-Positive Node Fields in Melanoma Patients Having Routine Cross-Sectional Imaging.

PURPOSE: In sentinel node-positive (SN+ve) melanoma patients, active surveillance with regular ultrasound examination of the node field has become standard, rather than completion lymph node dissection (CLND). A proportion of these patients now receive adjuvant systemic therapy and have routine cross-sectional imaging (computed tomography [CT] or positron emission tomography [PET]/CT). The role of concurrent ultrasound (US) surveillance in these patients is unclear. The purpose of our study was to describe the modality of detection of nodal recurrence in SN+ve node fields. METHODS: SN+ve melanoma patients who did not undergo CLND treated at a single institution from January 1, 2016 to December 31, 2020 were included. RESULTS: A total of 225 SN+ve patients with a median follow-up of 23 months were included. Of these, 119 (53%) received adjuvant systemic therapy. Eighty (36%) developed a recurrence at any site; 24 (11%) recurred first in the SN+ve field, of which 12 (5%) were confirmed node field recurrence only at 2 months follow-up. The nodal recurrences were first detected by ultrasound in seven (3%), CT in seven (3%), and PET/CT in seven (3%) patients. All nodal recurrences evident on US were also evident on PET/CT and vice versa. CONCLUSIONS: The high rate of recurrences outside the node field and the identification of all US-detected nodal recurrences on concurrent cross-sectional imaging modalities suggest that routine concurrent ultrasound surveillance of the node-positive field may be unnecessary for SN+ve melanoma patients having routine cross-sectional imaging.

External validation in an Australian population of the EORTC-DeCOG nomogram predicting recurrence, distant metastasis and overall mortality in melanoma patients with positive sentinel lymph nodes.

BACKGROUND: Calculating an accurate prognosis for melanoma patients who have a positive sentinel node (SN) biopsy is important both for them and for their treating doctors to guide decision-making, particularly when adjuvant systemic therapy is being considered. The recently published EORTC-DeCOG nomograms aim to provide this via an online portal that predicts 5-year rates for recurrence, distant metastasis and overall mortality. The present study provides external validation of these nomograms. METHODS/MATERIALS: De-identified data from patients with a positive SN biopsy between 2003 and 2015 were extracted from the prospectively maintained Melanoma Institute Australia (MIA) research database. ROC-curves with C-statistics, regression co-efficients and Decision Curve Net Benefit analyses were performed using the integrated private validation portal on the nomograms' hosting platform (Evidencio). RESULTS: Complete data were available for 352 patients. The respective C-statistics for recurrence, distant metastasis and overall mortality nomogram validations were 0.68, 0.69 and 0.66. CONCLUSION: The performance of the nomograms in predicting recurrence and distant metastasis was similar in the MIA and the development populations, suggesting that they are robust. However, the overall mortality nomogram performance was significantly poorer in the MIA population (C-statistic 0.66) than in the original EORTC-DeCOG derivation cohort (C-statistic 0.70) and may therefore be less reliable for clinical use.

Does preoperative imaging for scalp non-melanocytic skin cancer accurately predict invasion of the cranial vault? A systematic review and meta-analysis.

PURPOSE: This study aimed to determine the diagnostic accuracy of CT and MRI in the preoperative detection of bone involvement for non-melanoma skin cancers (NMSCs) located on the scalp. This study further aimed to evaluate the predictive value of these imaging modalities in determining the need for craniectomy and to identify gaps in the existing literature. METHODS: Electronic searches of the MEDLINE, Embase, Cochrane and Google Scholar databases were performed for English language studies of any type. Studies reporting detection or exclusion of histopathologically confirmed bone involvement through preoperative imaging were identified according to PRISMA guidelines. Studies reporting dural involvement, non-scalp tumours, and lacking tumour type(s) or outcome data were excluded. Outcomes were preoperative imaging result and histopathologically confirmed bone invasion. Meta-analysis was performed and sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated (excluding case report and MRI data due to insufficient quality and quantity respectively). RESULTS: Four studies with a total of 69 patients were included in the final review, of which two studies totalling 66 patients were included in the meta-analysis. Preoperative CT had a sensitivity of 38%, specificity of 98%, PPV of 90% and NPV of 73%. CONCLUSIONS: The available data suggests that a preoperative CT finding of calvarial involvement by a scalp NMSC is likely to be real, but the absence of such a finding is unreliable. Current evidence suggests that preoperative imaging cannot exclude the necessity for craniectomy and future research is needed, particularly on the role of MRI.

Has the advent of modern adjuvant systemic therapy for melanoma rendered sentinel node biopsy unnecessary?

The prognostic value of sentinel node biopsy (SNB) is well established and SNB was therefore adopted as a requirement for pathological staging of melanomas>1 mm thick in the American Joint Committee on Cancer (AJCC) 8th edition. Consequently, a negative SNB status became an eligibility criterion for clinical trials of adjuvant systemic therapy in resected stage IIB/C melanoma. However, since the Keynote 716 trial demonstrated an improvement in relapse-free survival (RFS) in patients with Stage IIB/C melanoma, all of whom had SNB staging, some have argued that SNB is no longer required for patients with T3 and T4 primary melanomas. The rationale for omitting SNB is that these patients will be able to access adjuvant immunotherapy regardless of SNB status, avoiding the costs and potential complications of SNB. However, this argument overlooks the prognostic value of knowing a patient's nodal status and the therapeutic benefit of SNB in regional disease control. Based on extrapolation of data from multiple sources, we demonstrate that the risk of regional node-field relapse with SNB and immunotherapy for T3b and T4 melanomas is around 7-9% but is 20-27% without SNB. Similarly, the node-field recurrence rate with SNB alone is around 14% compared to around 40% with no SNB or immunotherapy. Consequently, in the absence of prospective data, we propose that the optimal management of the regional node-field for high-risk T3b and T4 primary melanomas is likely to be achieved by combining SNB and adjuvant immunotherapy for those patients who are suitable, rather than either treatment alone.

Clinical management of melanocytic tumours of uncertain malignant potential (MelTUMPs), including melanocytomas: A systematic review and meta-analysis.

Little guidance is currently available for managing patients with melanocytic tumours of uncertain or low malignant potential (MelTUMPs, including melanocytomas), in particular the optimal excision margins and whether to offer sentinel node biopsy (SNB). The objective of this review was to evaluate excision margins and the prognostic utility of SNB by systematic review of the literature and meta-analysis. PRISMA guidelines were followed. Medline, EMBASE and Cochrane databases were searched to October 2021 for studies of patients with MelTUMPs reporting excision margins and/or SNB-positivity. Meta-analysis was performed on the SNB-positivity rate using a random effects model, followed by sensitivity analyses on subgroups. 111 primary studies reported excision margins and/or SNB data for 1962 patients. Follow-up was available for 1649 patients: 1561 (94.7%) were alive without disease at last review, 53 (3.2%) had developed further disease, 29 (1.8%) had died of metastatic disease (melanoma) and six (0.4%) died of unrelated causes. SNB was performed in 837 patients. The pooled positivity rate on meta-analysis was 32% (95% CI: 23-44%). Clinical outcome could be correlated with excision margin in only 171 patients (60% of those with known follow up) and was therefore not analysed further. Evidence indicating the ideal excision margins for MelTUMPs was lacking. SNB had a high positivity rate despite very low rates of recurrence or melanoma-related death. Consequently, SNB should not be offered routinely for MelTUMPs (including melanocytomas), due to its lack of prognostic utility for this tumour type (high certainty of evidence).

Lack of association between anatomical sites of scalp melanomas and brain metastases does not support direct vascular spread.

Primary scalp melanomas are associated with a higher rate of brain metastasis than primary cutaneous melanomas occurring at other head and neck and body sites, but the reason is unclear. Spread to brain parenchyma via emissary veins draining from the scalp to dural sinuses has been suggested. We sought to examine the locations of metastases from primary scalp and nonscalp head and neck melanomas to determine whether there was anatomical evidence supporting direct venous spread to the brain. Data from patients who developed distant metastases from cutaneous head and neck melanomas (CHNMs) between 2000 and 2018 were analyzed. Anatomical sites of primary scalp melanomas and their respective intracranial metastases were compared. Times to first brain and nonbrain metastases were investigated for scalp and nonscalp primary CHNMs. Of 693 patients with CHNMs, 244 developed brain metastases: 109 (44.7%) had scalp primaries and 135 (55.3%) had nonscalp primaries. There was no significant association between anatomical sites of scalp primary melanomas and brain metastases (Cramer's V = 0.21; Chi-square P = 0.63). Compared with nonscalp CHNMs, scalp melanomas had no greater propensity for the brain as the first distant metastatic site ( P = 0.52) but had a shorter time to both brain metastasis (76.3 vs. 168.5 months; P < 0.001) and nonbrain metastasis (22.6 vs. 35.8 months; P < 0.001). No evidence was found to support a direct vascular pathway for metastatic spread of scalp melanomas to the brain. The increased incidence of brain metastases from scalp melanomas is probably driven by aggressive biological mechanisms.

Benchmarking Survival Outcomes Following Surgical Management of pT3 and pT4 Cutaneous Squamous Cell Carcinoma of the Head and Neck.

BACKGROUND: pT3/4 head and neck cutaneous squamous cell carcinomas (HNcSCCs) are associated with poor outcomes, including local recurrence, metastasis and death. Whilst surgery remains the standard treatment for advanced HNcSCC, novel systemic therapies, such as immunotherapy, are being used earlier in the treatment paradigm. It is imperative that the clinical outcomes of surgery are clearly described so that conventional and emerging treatment modalities can be better integrated and sequenced in the management of pT3/4 HNcSCC. METHODS: Patients with confirmed pT3/4 HNcSCC undergoing curative surgical resection between 2014-2020 were identified retrospectively from a prospectively maintained research database. The primary outcomes of interest were locoregional control (LRC), disease-specific survival (DSS), and overall survival (OS). The secondary outcome was surgical complication rate. RESULTS: A total of 104 patients (median age 74, range 41-94 years) were included, 90% of which had pT3 tumors; 36.5% received adjuvant radiotherapy. Median follow-up was 24.3 (range 1.0-84.3) months. LRC at 5 years was 62.0%, DSS at 5 years was 83.7%, and OS at 5 years was 71.9%. Median time to recurrence was 8.4 months. LRC was reduced in the presence of margin involvement and previous treatment (radiotherapy/surgery). The major surgical complication rate was 9.6%. CONCLUSIONS: More than 60% of patients treated surgically for pT3/4 head and neck cSCC were alive and free of disease at 5 years posttreatment. High-risk features such as margin involvement and having had previous treatment (radiotherapy/surgery) should be used to guide adjuvant therapy.

Merkel cell carcinoma in situ: A systematic review of prognosis and management.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine tumour. While dermally invasive MCC is known to have a five-year survival of only 30-40%, the prognosis and management of MCC in situ (MCCis) is not widely reported. OBJECTIVE: We present a systematic review to elucidate the prognosis and management of MCCis. METHODS: We performed a systematic review, searching three databases to 01 June 2021. Case reports, cohort studies, clinical trials and literature reviews were considered for inclusion. RESULTS: We identified 26 cases of MCCis published in the literature with a median age of 74 years and involving 19 males and 7 females. Most cases were on the face and neck (n = 17), followed by upper limb (n = 8) and lower limb (n = 1). Sentinel lymph node biopsy was performed in three patients, and all were negative. One subject underwent adjuvant radiotherapy. No MCCis-associated deaths were reported. CONCLUSION: This review suggests that MCCis has an excellent prognosis with minimal, if any, risk of mortality and a very low risk of dermal invasion and recurrence when treated with wide local excision alone. Sentinel lymph node biopsy is unlikely to be useful for MCCis.

BRAF mutation testing for patients diagnosed with stage III or stage IV melanoma: practical guidance for the Australian setting.

Targeted therapy (BRAF inhibitor plus MEK inhibitor) is now among the possible treatment options for patients with BRAF mutation-positive stage III or stage IV melanoma. This makes prompt BRAF mutation testing an important step in the management of patients diagnosed with stage III or IV melanoma; one that can help better ensure that the optimal choice of systemic treatment is initiated with minimal delay. This article offers guidance about when and how BRAF mutation testing should be conducted when patients are diagnosed with melanoma in Australia. Notably, it recommends that pathologists reflexively order BRAF mutation testing whenever a patient is found to have American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage III or IV melanoma (i.e., any metastatic spread beyond the primary tumour) and that patient's BRAF mutation status is hitherto unknown, even if BRAF mutation testing has not been specifically requested by the treating clinician (in Australia, Medicare-subsidised BRAFV600 mutation testing does not need to be requested by the treating clinician). When performed in centres with appropriate expertise and experience, immunohistochemistry (IHC) using the anti-BRAF V600E monoclonal antibody (VE1) can be a highly sensitive and specific means of detecting BRAFV600E mutations, and may be used as a rapid and relatively inexpensive initial screening test. However, VE1 immunostaining can be technically challenging and difficult to interpret, particularly in heavily pigmented tumours; melanomas with weak, moderate or focal BRAFV600E immunostaining should be regarded as equivocal. It must also be remembered that other activating BRAFV600 mutations (including BRAFV600K), which account for ∼10-20% of BRAFV600 mutations, are not detected with currently available IHC antibodies. For these reasons, if available and practicable, we recommend that DNA-based BRAF mutation testing always be performed, regardless of whether IHC-based testing is also conducted. Advice about tissue/specimen selection for BRAF mutation testing of patients diagnosed with stage III or IV melanoma is also offered in this article; and potential pitfalls when interpreting BRAF mutation tests are highlighted.

Survival Outcomes of Salvage Metastasectomy After Failure of Modern-Era Systemic Therapy for Melanoma.

BACKGROUND: Metastasectomy for selected patients with melanoma was associated with improved survival in the era before effective systemic therapy. Emerging evidence shows that these benefits persist even in this era of BRAF-targeted therapy and immune checkpoint inhibitor immunotherapy. This study aimed to evaluate the outcomes of salvage metastasectomy after failure of systemic therapy. METHODS: Stage 3 or 4 melanoma patients with extracranial disease progression after at least 4 weeks of systemic treatment between 2009 and 2020 were identified and categorized as resected to no evidence of disease (NED), non-progressive residual disease (NPRD), or progressive residual disease (PRD). Systemic therapy was stratified into BRAF-targeted therapy, immune checkpoint inhibitor immunotherapy, or both. The end points of overall survival (OS), progression-free survival (PFS), and locoregional disease control (LRC) were assessed using Kaplan-Meier curves. Uni- and multivariable Cox regression procedures were used to examine factors associated with OS, PFS and LRC. RESULTS: The study enrolled 190 patients. Among all the patients, the 5-year OS from metastatectomy was 52%, the 3-year PFS was 21%, and the 5-year LRC was 61%. After resection to NED, NPRD, and PRD, the 5-year OS values were 69%, 62% and 8%, respectively. Fewer lines of preoperative therapy, use of preoperative immunotherapy, and resection to NED were predictors of improved OS. After resection to NED, NPRD, and PRD, the 3-year PFS values were 23%, 24% and 10%, and the 5-year LRC values were 61%, 72% and 34%, respectively. CONCLUSIONS: Salvage metastasectomy was associated with durable survival and disease control, particularly after resection to NED, preoperative immunotherapy, and fewer lines of preoperative systemic therapy.

Re-defining the role of surgery in the management of patients with oligometastatic stage IV melanoma in the era of effective systemic therapies.

Although previously the mainstay of treatment, the role of surgery in the management of patients with oligometastatic stage IV melanoma has changed with the advent of effective systemic therapies (most notably immunotherapy). Contemporary treatment options for patients with asymptomatic solitary or oligo-metastases include upfront surgery followed by adjuvant immunotherapy or upfront immunotherapy with salvage surgery as required. For suspected solitary or oligo-metastases, surgery serves both diagnostic and therapeutic purposes. Advances in radiological technology allow metastases to be detected earlier and surgery to be less morbid. Surgical morbidities are generally more tolerable than serious immune-related adverse effects, but surgery may be less effective. Upfront immunotherapy ensures that futile surgery is not offered for rapidly progressive disease. It also provides an opportunity to assess response to treatment, which predicts outcome, and may obviate the need for surgery. However, it is important not to miss a window of opportunity for surgical intervention, whereby if disease progresses on immunotherapy it becomes unresectable. In situations where local therapy is recommended but surgery is not desired, stereotactic radiosurgery may be an effective alternative. The decision-making process regarding upfront surgery versus immunotherapy needs to take place within a specialist melanoma multidisciplinary setting and be customised to individual patient and tumour factors. Ultimately, high-level clinical trial evidence is required to resolve uncertainties in the management of patients with oligometastatic stage IV melanoma but the complexity of the varying presentations may make trial design challenging.

Development and Validation of Nomograms to Predict Local, Regional, and Distant Recurrence in Patients With Thin (T1) Melanomas.

PURPOSE: Although the prognosis of patients with thin primary cutaneous melanomas (T1, ≤ 1.0 mm) is generally excellent, some develop recurrence. We sought to develop and validate a model predicting recurrences in patients with thin melanomas. METHODS: A Dutch population-based cohort (n = 25,930, development set) and a cohort from an Australian melanoma treatment center (n = 2,968, validation set) were analyzed (median follow-up 6.7 and 12.0 years, respectively). Multivariable Cox models were generated for local, regional, and distant recurrence-free survival (RFS). Discrimination was assessed using Harrell's C-statistic for each outcome. Each nomogram performance was evaluated using calibration plots defining low-risk and high-risk groups as the lowest and top 5% of the nomogram risk score, respectively. The nomograms' C-statistics were compared with those of a model including the current American Joint Committee on Cancer staging parameters (T-stage and sentinel node status). RESULTS: Local, regional, and distant recurrences were found in 209 (0.8%), 503 (1.9%), and 203 (0.8%) Dutch patients, respectively, and 23 (0.8%), 61 (2.1%), and 75 (2.5%) Australian patients, respectively. C-statistics of 0.79 (95% CI, 0.75 to 0.82) for local RFS, 0.77 (95% CI, 0.75 to 0.78) for regional RFS, and 0.80 (95% CI, 0.77 to 0.83) for distant RFS were obtained for the development model. External validation showed C-statistics of 0.80 (95% CI, 0.69 to 0.90), 0.76 (95% CI, 0.70 to 0.82), and 0.74 (95% CI, 0.69 to 0.80), respectively. Calibration plots showed a good match between predicted and observed rates. Using the nomogram, the C-statistic was increased by 9%-12% for the development cohort and by 11%-15% for the validation cohort, compared with a model including only T-stage and sentinel node status. CONCLUSION: Most patients with thin melanomas have an excellent prognosis, but some develop recurrence. The presented nomograms can accurately identify a subgroup at high risk. An online calculator is available at www.melanomarisk.org.au.

Improved Risk Prediction Calculator for Sentinel Node Positivity in Patients With Melanoma: The Melanoma Institute Australia Nomogram.

PURPOSE: For patients with primary cutaneous melanoma, the risk of sentinel node (SN) metastasis varies according to several clinicopathologic parameters. Patient selection for SN biopsy can be assisted by National Comprehensive Cancer Network (NCCN) and ASCO/Society of Surgical Oncology (SSO) guidelines and the Memorial Sloan Kettering Cancer Center (MSKCC) online nomogram. We sought to develop an improved online risk calculator using alternative clinicopathologic parameters to more accurately predict SN positivity. PATIENTS AND METHODS: Data from 3,477 patients with melanoma who underwent SN biopsy at Melanoma Institute Australia (MIA) were analyzed. A new nomogram was developed by replacing body site and Clark level from the MSKCC model with mitotic rate, melanoma subtype, and lymphovascular invasion. The predictive performance of the new nomogram was externally validated using data from The University of Texas MD Anderson Cancer Center (n = 3,496). RESULTS: The MSKCC model receiver operating characteristic curve had a predictive accuracy of 67.7% (95% CI, 65.3% to 70.0%). The MIA model had a predictive accuracy of 73.9% (95% CI, 71.9% to 75.9%), a 9.2% increase in accuracy over the MSKCC model (P < .001). Among the 2,748 SN-negative patients, SN biopsy would not have been offered to 22.1%, 13.4%, and 12.4% based on the MIA model, the MSKCC model, and NCCN or ASCO/SSO criteria, respectively. External validation generated a C-statistic of 75.0% (95% CI, 73.2% to 76.7%). CONCLUSION: A robust nomogram was developed that more accurately estimates the risk of SN positivity in patients with melanoma than currently available methods. The model only requires the input of 6 widely available clinicopathologic parameters. Importantly, the number of patients undergoing unnecessary SN biopsy would be significantly reduced compared with use of the MSKCC nomogram or the NCCN or ASCO/SSO guidelines, without losing sensitivity. An online calculator is available at www.melanomarisk.org.au.