Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma.

BACKGROUND: Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown. METHODS: In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated. RESULTS: At a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group. CONCLUSIONS: Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).

Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study.

BACKGROUND: Checkpoint inhibitors are standard adjuvant treatment for stage IIB-IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma. METHODS: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB-IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881. FINDINGS: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309-1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0-85·6) versus 62% (46·9-74·3). Most treatment-related adverse events were grade 1-2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4-5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups. INTERPRETATION: Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting. FUNDING: Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Neoadjuvant Cemiplimab for Stage II to IV Cutaneous Squamous-Cell Carcinoma.

BACKGROUND: In a pilot study involving patients with cutaneous squamous-cell carcinoma, a high percentage of patients had a pathological complete response with the use of two doses of neoadjuvant cemiplimab before surgery. Data from a phase 2 study are needed to confirm these findings. METHODS: We conducted a phase 2, confirmatory, multicenter, nonrandomized study to evaluate cemiplimab as neoadjuvant therapy in patients with resectable stage II, III, or IV (M0) cutaneous squamous-cell carcinoma. Patients received cemiplimab, administered at a dose of 350 mg every 3 weeks for up to four doses, before undergoing surgery with curative intent. The primary end point was a pathological complete response (the absence of viable tumor cells in the surgical specimen) on independent review at a central laboratory, with a null hypothesis that a pathological complete response would be observed in 25% of patients. Key secondary end points included a pathological major response (the presence of viable tumor cells that constitute ≤10% of the surgical specimen) on independent review, a pathological complete response and a pathological major response on investigator assessment at a local laboratory, an objective response on imaging, and adverse events. RESULTS: A total of 79 patients were enrolled and received neoadjuvant cemiplimab. On independent review, a pathological complete response was observed in 40 patients (51%; 95% confidence interval [CI], 39 to 62) and a pathological major response in 10 patients (13%; 95% CI, 6 to 22). These results were consistent with the pathological responses determined on investigator assessment. An objective response on imaging was observed in 54 patients (68%; 95% CI, 57 to 78). Adverse events of any grade that occurred during the study period, regardless of whether they were attributed to the study treatment, were observed in 69 patients (87%). Grade 3 or higher adverse events that occurred during the study period were observed in 14 patients (18%). CONCLUSIONS: Neoadjuvant therapy with cemiplimab was associated with a pathological complete response in a high percentage of patients with resectable cutaneous squamous-cell carcinoma. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov number, NCT04154943.).

Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): long-term, health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial.

BACKGROUND: In the European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 study, adjuvant pembrolizumab improved recurrence-free survival and distant-metastasis-free survival in patients with resected stage III melanoma. Earlier results showed no effect of pembrolizumab on health-related quality of life (HRQOL). Little is known about HRQOL after completion of treatment with pembrolizumab, an important research area concerning patients who are likely to become long-term survivors. This study reports long-term HRQOL results. METHODS: This double-blind, randomised, controlled, phase 3 trial compared adjuvant pembrolizumab with placebo in patients aged 18 years or older with previously untreated stage IIIA, IIIB, or IIIC resected cutaneous melanoma and an Eastern Cooperative Oncology Group performance status score of 1 or 0, recruited from 123 academic centres and community hospitals in 23 countries. Patients were randomly assigned (1:1) with a minimisation technique stratified for stage and geographical region to receive 200 mg of intravenous pembrolizumab or placebo every 3 weeks for up to 18 doses. Investigators, patients, and those collecting or analysing data were masked to group assignment. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, measured with the EORTC Quality of Life Questionnaire-Core 30. All patients with a baseline HRQOL evaluation available who were alive 108 weeks from randomisation were included in this analysis of long-term HRQOL. Long-term HRQOL included assessments measured every 6 months between 108 weeks and 48 months after randomisation. The threshold of clinical relevance for all HRQOL scales used was an average change of 5 points. The trial is ongoing, recruitment is completed, and HRQOL data collection is finalised. 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 randomly assigned to pembrolizumab (n=514) or placebo (n=505). Completion of the HRQOL evaluation at baseline exceeded 90% (481 [94%] patients in the pembrolizumab group and 467 [92%] in the placebo group), and ranged between 60% and 90% for post-baseline timepoints. Among patients with a baseline HRQOL evaluation, 365 (39%) were female and 583 (61%) were male. The mean change from baseline to long-term HRQOL was -0·56 (95% CI -2·33 to 1·22) in the pembrolizumab group and 1·63 (-0·12 to 3·38) in the placebo group. The difference between the two groups was -2·19 (-4·65 to 0·27, p=0·081). Differences for all other scales were smaller than 5 and not statistically significant. INTERPRETATION: Adjuvant pembrolizumab did not have a significant impact on long-term HRQOL compared with placebo in patients with resected stage III melanoma. These findings, together with earlier results on efficacy and HRQOL, support the use of pembrolizumab in this setting. FUNDING: Merck Sharp & Dohme.

Long-term efficacy of neoadjuvant-adjuvant targeted therapy in borderline resectable stage IIIB-D and IV melanoma.

BACKGROUND: Neoadjuvant-adjuvant therapy for locally advanced or potentially resectable metastatic melanoma was expected to improve operability and clinical outcomes over upfront surgery and adjuvant treatment only. METHODS: Forty-seven consecutive patients were treated with neoadjuvant-adjuvant BRAF inhibitors (BRAFi)/MEK inhibitors (MEKi) and surgery. RESULTS: Twelve (26%) patients achieved a pathological complete response and 10 (21%) patients achieved a near-complete response. In the whole group, median recurrence-free survival was 19.4 months and median distant metastasis-free survival (mDMFS) was 21.9 months. In patients with a pathological complete response (pCR)/near-pCR median recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) were significantly longer than in patients with minor pathological response with hazard ratio (HR) = 0.37 (p = .005) for RFS and HR = 0.33 (p = .002) for DMFS. After median follow-up of 52.5 months, median progression-free survival since BRAFi/MEKi therapy initiation was 25.1 months. The median time-to-treatment-failure since initiation of neoadjuvant therapy was 22.2 months and was significantly longer in patients with pCR/near-pCR (HR = 0.45; p = .022). Neoadjuvant therapy did not result in any new specific complications of surgery. After 48 months, RFS and overall survival were 36.3% and 64.8% or 20% and 37.4% in patients with pCR/near-pCR and pathological partial response/pathological nonresponse, respectively. CONCLUSIONS: The authors confirmed that BRAFi/MEKi combination is an effective and safe regimen in the perioperative treatment of stage III/IV melanoma. Major pathological response to neoadjuvant treatment is a surrogate marker of recurrence including DMFS in these patients. PLAIN LANGUAGE SUMMARY: Our study presents a large comprehensive analysis of neoadjuvant-adjuvant systemic therapy in patients diagnosed with marginally resectable stage III or IV melanoma. Neoadjuvant therapy effectively reduced the volume of the disease, which facilitated subsequent surgical resection. After median follow-up of 52.5 months, median progression-free survival since therapy initiation was 25.1 months. Twelve patients had complete pathological response and 10 patients had a near-complete pathological response-and together they had median recurrence-free survival and distant metastasis-free survival significantly longer than in patients with pathological partial response or nonresponse. Complete/near-complete pathological response to neoadjuvant treatment is a surrogate marker of recurrence-free, including distant metastasis-free, survival in these patients.

Comparison of Outcomes Between Surveillance Ultrasound and Completion Lymph Node Dissection in Children and Adolescents With Sentinel Lymph Node-Positive Cutaneous Melanoma.

OBJECTIVE: To determine the impact of nodal basin ultrasound (US) surveillance versus completion lymph node dissection (CLND) in children and adolescents with sentinel lymph node (SLN) positive melanoma. BACKGROUND: Treatment for children and adolescents with melanoma are extrapolated from adult trials. However, there is increasing evidence that important clinical and biological differences exist between pediatric and adult melanoma. METHODS: Patients ≤18 years diagnosed with cutaneous melanoma between 2010 and 2020 from 14 pediatric hospitals were included. Data extracted included demographics, histopathology, nodal basin strategies, surveillance intervals, and survival information. RESULTS: Of 252 patients, 90.1% (n=227) underwent SLN biopsy (SLNB), 50.9% (n=115) had at least 1 positive node. A total of 67 patients underwent CLND with 97.0% (n=65/67) performed after a positive SLNB. In contrast, 46 total patients underwent US observation of nodal basins with 78.3% (n=36/46) of these occurring after positive SLNB. Younger patients were more likely to undergo US surveillance (median age 8.5 y) than CLND (median age 11.3 y; P =0.0103). Overall, 8.9% (n=21/235) experienced disease recurrence: 6 primary, 6 nodal, and 9 distant. There was no difference in recurrence (11.1% vs 18.8%; P =0.28) or death from disease (2.2% vs 9.7%; P =0.36) for those who underwent US versus CLND, respectively. CONCLUSIONS: Children and adolescents with cutaneous melanoma frequently have nodal metastases identified by SLN. Recurrence was more common among patients with thicker primary lesions and positive SLN. No significant differences in oncologic outcomes were observed with US surveillance and CLND following the identification of a positive SLN.

Clinical outcomes of adjuvant nivolumab in resected stage III melanoma: comparison of CheckMate 238 trial and real-world data.

OBJECTIVES: Nivolumab is approved as adjuvant therapy for resected stage III/IV melanoma based on the phase 3 CheckMate 238 trial. This analysis compared outcomes from CheckMate 238 with those from the real-world Flatiron Health electronic health record-derived de-identified database in patients with resected stage III melanoma (per AJCC-8) treated with adjuvant nivolumab. MATERIALS: Outcomes included baseline characteristics, overall survival (OS) in the CheckMate 238 cohort (randomization until death or last known alive), and real-world overall survival (rwOS) in the Flatiron Health cohort (nivolumab initiation until death or data cutoff). rwOS was compared with OS using unadjusted and adjusted Cox proportional hazards models. Inverse probability of treatment weighting (IPTW) was combined with the adjusted model to reduce baseline discrepancies. RESULTS: The CheckMate 238 and real-world cohorts included 369 and 452 patients, respectively (median age, 56.0 and 63.0 years; median follow-up, 61.4 vs. 25.5 months). rwOS was not different from OS in the unadjusted (hazard ratio [HR] 1.27; 95% CI 0.92-1.74), adjusted (HR 1.01; 95% CI 0.67-1.54), and adjusted IPTW (HR 1.07; 95% CI 0.70-1.63) analyses. In the adjusted analysis, 2-year OS and rwOS rates were 84%. Median OS and rwOS were not reached. After IPTW, OS and rwOS were not different (HR 1.07; 95% CI 0.70-1.64). CONCLUSIONS: In this comparative analysis, OS in the CheckMate 238 trial was similar to rwOS in the Flatiron Health database after adjustments in patients with resected stage III melanoma (per AJCC-8) treated with adjuvant nivolumab, validating the trial results.

Validation of the Melanoma Institute of Australia's Sentinel Lymph Node Biopsy Risk Prediction Tool for Cutaneous Melanoma.

BACKGROUND: For patients with cutaneous melanoma, sentinel lymph node biopsy (SLNB) is used to stage regional lymph nodes pathologically and inform prognosis, treatment, and surveillance. To reduce unnecessary surgeries, predictive tools aim to identify those at lowest risk for node-positive disease. The Melanoma Institute of Australia (MIA)'s Prediction Tool for Sentinel Node Metastasis Risk estimates risk of a positive SLNB using patient age and primary melanoma Breslow depth, histologic subtype, ulceration, mitotic rate, and lymphovascular invasion. METHODS: A single-institution validation was performed of the MIA Calculator with 982 cutaneous melanoma patients that included all relevant clinicopathologic factors and SLNB pathology outcomes. The study evaluated discrimination via receiver operating characteristic (ROC) curves, calibration via calibration plots, and clinical utility via decision curve analysis of the MIA model in various subgroups. The data were fit to MIA model parameters via a generalized linear model to assess the odds ratio of parameters in our dataset. RESULTS: The Calculator demonstrated limited discrimination based on ROC curves (C-statistic, 0.709) and consistently underestimated risk of SLN positivity. It did not provide a net benefit over SLNB performed on all patients or reduce unnecessary procedures in the risk domain of 0% to 16%. Compared with the original development and validation cohorts, the current study cohort had thinner tumors and a larger proportion of acral melanomas. CONCLUSIONS: The Calculator generally underestimated SLN positivity risk, including assessment in patients who would be counseled to forego SLNB based on a predicted risk lower than 5%. Recognition of the tool's current limitations emphasizes the need to refine it further for use in medical decision-making.

Intraparotid Sentinel Lymph Node Dissection for Melanoma: A Systematic Review and Meta-Analysis.

BACKGROUND: Surgical management of head and neck cutaneous melanoma (HNCM) has evolved tremendously since sentinel lymph node biopsy (SLNB) has become the prominent tool of prognosis and staging. This meta-analysis aimed to evaluate the safety and efficiency of intraparotid SLNB compared with a more extensive surgery of superficial parotidectomy (SP). METHODS: The electronic database of PubMed and Scopus were searched for publications until 10 March 2022. In addition, the study included data of patients from our institution who underwent cherry-picking procedures. Pooled estimates were calculated using the random-effects model. Heterogeneity was calculated using the I2 test. RESULTS: The pooled result regarding the rate of SLNB excision success was 97 % (95 % confidence interval [CI], 0.95-0.99; p < 0.0001), and the pooled probability of a positive SLNB result was 16 % (95 % CI 0.12-0.20; p < 0.0001). Failure of SLNB had pooled results of 4 % (95 % CI 0.02-0.06; p < 0.0009). For SP, no study examining N0 HNCM patients has met the authors' inclusion criteria. Cherry-picking SLNB had temporary and permanent facial nerve paralysis relative risks (RRs) of 0.12 (95 % CI 0.06-0.27; p < 0.0001) and 0.46 (95 % CI 0.17-1.22; p < 0.0001), respectively, compared with historical data from four weighted meta-analyses of SP. CONCLUSIONS: The data from this study suggest that intraparotid SLNB performed for N0 HNCM patients is a safe and reliable procedure, with very low complication rates. Failure of the procedure did not exceed 4 %. Therefore, intraparotid SLNB may be superior to an extensive surgery such as SP and should be examined in future prospective trials.

Using Nomograms Wisely: Predicting Sentinel Node Positivity in Melanoma.

BACKGROUND: Four externally validated sentinel node biopsy (SNB) prediction nomograms exist for malignant melanoma that each incorporate different clinical and histopathologic variables, which can result in substantially different risk estimations for the same patient. We demonstrate this variability by using hypothetical melanoma cases. METHODS: We compared the MSKCC and MIA calculators. Using a random number generator, 300 hypothetical thin melanoma "patients" were created with varying age, tumor thickness, Clark level, location on the body, ulceration, melanoma subtype, mitosis, and lymphovascular invasion (LVI). The chi-square test was used to detect statistically significant differences in risk estimations between nomograms. Multivariate linear regression was used to determine the most relevant contributing pathologic features in cases where the predictions diverged by > 10%. RESULTS: Of 300 randomly generated cases, 164 were deleted as their clinical scenarios were unlikely. The MSKCC nomogram generally calculated a lower risk than the MIA (p < 0.001). The highest risk score attained for any "patient" using MSKCC calculator was 15% achieved in one of 136 patients (0.7%), whereas using the MIA nomogram, 58 of 136 patients (43%, p < 0.001) had predicted risk >15%. Regression analysis on patients with >10% difference between nomograms revealed LVI (26, p < 0.001), mitosis (14, p < 0.001), and melanoma subtype (8, p < 0.001) were the factors with high coefficients within MIA that were not present in MSKCC. CONCLUSIONS: Nomograms are useful tools when predicting SNB risk but provide risk outputs that are quite sensitive to included predictors.

Impact of an Online Risk Calculator for Sentinel Node Positivity on Management of Patients with T1 and T2 Melanomas.

BACKGROUND: Predicting which patients with American Joint Committee on Cancer (AJCC) T1-T2 melanomas will have a positive sentinel lymph node (SLN) is challenging. Melanoma Institute Australia (MIA) developed an internationally validated SLN metastatic risk calculator. This study evaluated the nomogram's impact on T1-T2 melanoma patient management at MIA. METHODS: SLN biopsy (SLNB) rates were compared for the pre- and post-nomogram periods of 1 July 2018-30 June 2019 and 1 August 2020-31 July 2021, respectively. RESULTS: Overall, 850 patients were identified (pre-nomogram, 383; post-nomogram, 467). SLNB was performed in 29.0% of patients in the pre-nomogram group and 34.5% in the post-nomogram group (p = 0.091). The overall positivity rate was 16.2% in the pre-nomogram group and 14.9% in the post-nomogram group (p = 0.223). SLNB was performed less frequently in T1a melanoma patients in the pre-nomogram group (1.1%, n = 2/177) than in the post-nomogram group (8.6%, n = 17/198) [p ≤ 0.001]. This increase was particularly for melanomas with a risk score ≥ 5%, with an SLN positivity rate of 11.8% in the post-nomogram group (p = 0.004) compared with zero. For T1b melanomas with a risk score of > 10%, the SLNB rate was 40.0% (8/20) pre-nomogram and 75.0% (12/16) post-nomogram (p = 0.049). CONCLUSIONS: In this specialized center, the SLN risk calculator appears to influence practice for melanomas previously considered low risk for metastasis, with increased use of SLNB for T1a and higher-risk T1b melanomas. Further evaluation is required across broader practice settings. Melanoma management guidelines could be updated to incorporate the availability of nomograms to better select patients for SLNB than previous criteria.

Factors Affecting Recurrence and Survival for Patients with High-Risk Stage II Melanoma.

BACKGROUND: In the current era of effective adjuvant therapies and de-escalation of surgery, distinguishing which patients with high-risk stage II melanoma are at increased risk of recurrence after excision of the primary lesion is essential to determining appropriate treatment and surveillance plans. METHODS: A single-center retrospective study analyzed patients with stage IIB or IIC melanoma. Demographic and tumor data were collected, and genomic analysis of formalin-fixed, paraffin-embedded tissue samples was performed via an internal next-generation sequencing (NGS) platform (SNaPshot). The end points examined were relapse-free survival (RFS), distant metastasis-free survival (DMFS), overall survival (OS), and melanoma-specific survival (MSS). Uni- and multivariable Cox regressions were performed to calculate the hazard ratios. RESULTS: The study included 92 patients with a median age of 69 years and a male/female ratio of 2:1. A Breslow depth greater than 4 mm, a higher mitotic rate, an advanced T stage, and a KIT mutation had a negative impact on RFS. A primary lesion in the head and neck, a mitotic rate exceeding 10 mitoses per mm2, a CDH1 mutation, or a KIT mutation was significantly associated with a shorter DMFS. Overall survival was significantly lower with older age at diagnosis and a higher mitotic rate. An older age at diagnosis also had a negative impact on MSS. CONCLUSION: Traditional histopathologic factors and specific tumor mutations displayed a significant correlation with disease recurrence and survival for patients with high-risk stage II melanoma. This study supported the use of genomic testing of high-risk stage II melanomas for prognostic prediction and risk stratification.

The Utility of Sentinel Lymph Node Biopsy in Elderly Patients with Melanoma.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is performed less often for older patients with melanoma. We investigated the association of SLNB and melanoma-specific survival (MSS) in the elderly. METHODS: We retrospectively reviewed the Surveillance, Epidemiology, and End Results (SEER: 2010-2019) for patients ≥ 70 years with cT2-4N0M0 melanoma. We used multivariable Cox proportional hazard models to evaluate the impact of SLNB performance and SLN status on MSS at increasing age cutoffs. In addition, we evaluated the association of different factors with SLNB performance using multivariable logistic regression. RESULTS: We identified 11,548 patients. Sentinel lymph node biopsy occurred in 6754 (58.5%) patients, 1050 (15.5%) of whom had a positive SLN. On adjusted SEER analysis, a negative SLN was independently associated with improved MSS (overall hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.63-0.67) for patients up to 87 years old. Positive SLNB was independently associated with inferior MSS (HR 1.71, 95% CI 1.93-1.98). Increasing age groups were significantly associated with decreased SLNB performance. CONCLUSIONS: Sentinel lymph node biopsy is associated with cancer-specific survival and adds prognostic information for elderly patients with melanoma. Sentinel lymph node biopsy performance should not be eliminated in elderly patients based on age alone, unless justified by poor performance status, patient preference, or other surgical contraindications. Decreased SLNB performance with increasing age in our cohort may indicate a missed therapeutic opportunity in the care of elderly patients with melanoma.

Clinical Variables Influencing Outcomes in Patients with Atypical Intradermal Smooth Muscle Neoplasms (Formerly Cutaneous Leiomyosarcomas): Single-Institution Study of 95 Surgical Patients.

BACKGROUND: Atypical intradermal smooth muscle neoplasm, also commonly termed cutaneous leiomyosarcoma, is a soft tissue tumor with a low risk of aggressive behavior. These lesions arise in the dermis with possible superficial subcutaneous extension, demonstrate cytologic atypia, and often show mitotic activity. METHODS: A retrospective review of patient demographics, tumor characteristics, and treatment methods was conducted in a consecutive series of patients presenting to MD Anderson Cancer Center (MDACC) from 2002 to 2021 (n = 95). All pathology was reviewed by MDACC pathologists and determined to be atypical intradermal smooth muscle neoplasm. RESULTS: Median age at diagnosis was 58 years (range 22-86), and 74% were male. Ninety-five percent (n = 90) of patients identified as White, non-Hispanic. Most tumors were slow-growing, solitary, and painless nodules. Tumors were in the lower extremities (44.2%), followed by the upper extremity (28.4%), trunk (22.1%), and head and neck (5.2%). All patients (n = 44, 46.3%) who had a punch/incisional biopsy for diagnostic purposes had a subsequent tumor excision. Unplanned excision or excisional biopsy was performed on the remaining 46 (48%) patients. Of this subset, 41 of the 46 aforementioned patients (89%) had positive margins and underwent re-excision. Final pathology in 25/38 (66%) re-excision specimens was negative for residual tumor despite an initial positive margin. Two patients in the cohort had local recurrence 2 and 3 years after initial surgery. Both patients had positive margins, underwent excision of the recurrent tumor, and remain free of disease. After median follow-up of 6.9 years (range 1 day-18 years), 5-year recurrence-free survival was 96% and overall survival (OS) of the entire cohort was 78%. CONCLUSION: In this study of consecutive patients presenting with atypical intradermal smooth muscle neoplasm, we found good OS and local control after definitive surgical excision with negative margins, including excisional biopsy with close margins. Atypical intradermal smooth muscle neoplasm is unlikely to metastasize and has an excellent prognosis. Guidelines to determine optimal surveillance strategies for these patients should be revisited.

Leg Lymphoedema After Inguinal and Ilio-Inguinal Lymphadenectomy for Melanoma: Results from a Prospective, Randomised Trial.

BACKGROUND: The Evaluation of Groin Lymphadenectomy Extent for Melanoma (EAGLE FM) study sought to address the question of whether to perform inguinal (IL) or ilio-inguinal lymphadenectomy (I-IL) for patients with inguinal nodal metastatic melanoma who have no clinical or imaging evidence of pelvic disease. Primary outcome measure was disease-free survival at 5 years, and secondary endpoints included lymphoedema. METHODS: EAGLE FM was designed to recruit 634 patients but closed with 88 patients randomised because of slow recruitment and changes in melanoma management. Lymphoedema assessments occurred preoperatively and at 6, 12, 18, and 24 months postoperatively. Lymphoedema was defined as Inter-Limb Volume Difference (ILVD) > 10%, Lymphoedema Index (L-Dex®) > 10 or change of L-Dex® > 10 from baseline. RESULTS: Prevalence of leg lymphoedema between the two groups was similar but numerically higher for I-IL at all time points in the first 24 months of follow-up; highest at 6 months (45.9% IL [CI 29.9-62.0%], 54.1% I-IL [CI 38.0-70.1%]) and lowest at 18 months (18.8% IL [CI 5.2-32.3%], 41.4% I-IL [CI 23.5-59.3%]). Median ILVD at 24 months for those affected by lymphoedema was 14.5% (IQR 10.6-18.7%) and L-Dex® was 12.6 (IQR 9.0-17.2). There was not enough statistical evidence to support associations between lymphoedema and extent of surgery, radiotherapy, or wound infection. CONCLUSIONS: Despite a trend for patients who had I-IL to have greater lymphoedema prevalence than IL in the first 24 months after surgery, our study's small sample did not have the statistical evidence to support an overall difference between the surgical groups.

The Effect of Neoadjuvant Systemic Therapy on Surgical Outcomes After Lymph Node Dissections for Stage III Melanoma; An Australian Cohort.

BACKGROUND: Neoadjuvant systemic therapy (NAST) for patients with stage III melanoma achieves high major pathologic response rates and high recurrence-free survival rates. This study aimed to determine how NAST with targeted therapies (TTs) and immune checkpoint inhibitors (ICIs) influences surgical outcomes after lymph node dissection in terms of complications, morbidity, and textbook outcomes. METHODS: Patients who underwent a lymph node dissection after either NAST in a clinical trial or upfront surgery for stage III melanoma between 2014 and 2022 were identified from an institutional research database. RESULTS: The study included 89 NAST-treated patients and 79 upfront surgery-treated patients. The rate of postoperative complications did not differ between the NAST- and upfront surgery-treated patients (55% vs. 51%; p = 0.643), and steroid treatment for drug toxicity did not influence the complication rate (odds ratio [OR], 1.1; 95% confidence interval [CI], 0.4-3; p = 0.826). No significant differences in postoperative morbidity were observed in terms of seroma (23% vs. 11%; p = 0.570) or lymphedema (36% vs. 51%; p = 0.550). The rate of achieving a textbook outcome was comparable for the two groups (61% vs. 57%; p = 0.641). CONCLUSIONS: The surgical outcomes after lymph node dissections were comparable between the patients who received NAST and those who had upfront surgery, indicating that surgery can be safely performed after NAST with TT or ICI for stage III melanoma.

Interdisciplinary Implementation of a Synoptic Reporting Template for Melanoma Nodal Surveillance Ultrasound.

BACKGROUND: With nodal surveillance increasingly used for sentinel lymph node-positive (SLN+) melanoma following the Second Multicenter Selective Lymphadenectomy Trial (MSLT-II), high-quality nodal ultrasonography (U/S) has become a critical need. Previous work has demonstrated low utilization of MSLT-II U/S criteria to define abnormal lymph nodes requiring intervention or biopsy. To address this gap, an evidence-based synoptic template was designed and implemented in this single-center study. METHODS: Sentinel lymph node-positive patients undergoing nodal surveillance at a tertiary cancer center from July 2017 to June 2023 were identified retrospectively. Ultrasound reporting language was analyzed for MSLT-II criteria reported and clinically actionable recommendations (e.g., normal, abnormal with recommendation for biopsy). Following a multidisciplinary design process, the synoptic template was implemented in January 2023. Postimplementation outcomes were evaluated by using U/S reports and provider surveys. RESULTS: A total of 337 U/S studies were performed on 94 SLN+ patients, with a median of 3 U/S per patient (range 1-12). Among 42 synoptic-eligible U/S performed postimplementation, 32 U/S (76.0%) were reported synoptically. Significant increases were seen in the number of MSLT-II criteria reported (Pre 0.5 ± 0.8 vs. Post 2.5 ± 1.0, p < 0.001), and clinically actionable recommendations for abnormal findings (Pre 64.0% vs. Post 93.0%, p = 0.04). Nearly all surgeon and radiologist survey respondents were "very" or "completely" satisfied with the clinical utility of the synoptic template (90.0%). CONCLUSIONS: Following implementation of a synoptic template, U/S reports were significantly more likely to document MSLT-II criteria and provide an actionable recommendation, increasing usefulness to providers. Efforts to disseminate this synoptic template to other centers are ongoing.

Randomized Trial of Postoperative Radiation Therapy After Wide Excision of Neurotropic Melanoma of the Head and Neck (RTN2 Trial 01.09).

BACKGROUND: Cutaneous neurotropic melanoma (NM) of the head and neck (H&N) is prone to local relapse, possibly due to difficulties widely excising the tumor. This trial assessed radiation therapy (RT) to the primary site after local excision. METHODS: Participants from 15 international centers were randomized to observation or RT. The participants were required to have microscopically negative excision margins 5 mm wide or wider and no evidence of disease elsewhere. The primary outcome was time to local relapse. The secondary outcomes included time to any recurrence, overall survival (OS), and toxicity. RESULTS: The trial ceased prematurely due to slow recruitment and the COVID-19 pandemic. During 2009-2020, 50 participants were randomized: 23 to observation and 27 to RT. The most common NM subsites were scalp (32%), midface (22%), and lip (20%). The median depth of invasion was 5 mm, and desmoplasia observed in 69%. The median duration from randomization to last contact was 4.8 years. Four participants (8%) experienced local relapse as a first recurrence during the study period: 3 in the observation arm and 1 in the RT arm (hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.03-2.76; p = 0.279). No statistically significant difference in time to any relapse or OS was observed. More than 6 months after randomization, grade 3 or greater toxicity was experienced by 10% of the participants in the observation arm and 12.5% of the participants in the RT arm of the study. CONCLUSION: Due to low accrual, the role of adjuvant RT for cutaneous NM of the H&N excised with microscopically negative margins 5 mm wide or wider remains undefined. Its routine use cannot be recommended. Local relapse might be less common than previously anticipated based on retrospective reports.

Natural language processing to automate a web-based model of care and modernize skin cancer multidisciplinary team meetings.

BACKGROUND: Cancer multidisciplinary team (MDT) meetings are under intense pressure to reform given the rapidly rising incidence of cancer and national mandates for protocolized streaming of cases. The aim of this study was to validate a natural language processing (NLP)-based web platform to automate evidence-based MDT decisions for skin cancer with basal cell carcinoma as a use case. METHODS: A novel and validated NLP information extraction model was used to extract perioperative tumour and surgical factors from histopathology reports. A web application with a bespoke application programming interface used data from this model to provide an automated clinical decision support system, mapped to national guidelines and generating a patient letter to communicate ongoing management. Performance was assessed against retrospectively derived recommendations by two independent and blinded expert clinicians. RESULTS: There were 893 patients (1045 lesions) used to internally validate the model. High accuracy was observed when compared against human predictions, with an overall value of 0.92. Across all classifiers the virtual skin MDT was highly specific (0.96), while sensitivity was lower (0.72). CONCLUSION: This study demonstrates the feasibility of a fully automated, virtual, web-based service model to host the skin MDT with good system performance. This platform could be used to support clinical decision-making during MDTs as 'human in the loop' approach to aid protocolized streaming. Future prospective studies are needed to validate the model in tumour types where guidelines are more complex.

Service implications of the revised 2022 National Institute for Health and Care Excellence (NICE) follow-up guidelines for stage IA-IIC melanoma.

BACKGROUND: The 2022 National Institute for Health and Care Excellence melanoma guideline update made significant changes to follow-up. The aim of this study was to assess the impact these changes will have on a national melanoma cohort over a 5-year follow-up interval. METHODS: Anonymized, individual-level, population-scale, linkable primary and secondary care National Health Service data for an 18-year interval (2000-2018) in Wales, UK were analysed. These data were used to predict the number of patients over a 10-year interval (2020-2030) that would be diagnosed with melanoma. Follow-up schedules for the 2015 and 2022 National Institute for Health and Care Excellence melanoma guidelines were then used to calculate the number of clinician-led appointments, the number of radiological investigations, and the total healthcare cost between 2025 and 2030, corresponding to a 5-year patient follow-up interval, for those with stage IA-IIC melanoma. RESULTS: Between 2025 and 2030 it is predicted that implementation of the 2022 guidelines would lead to 21 122 (range 19 194-23 083) fewer clinician-led appointments for patients with stage IA-IIC melanoma. However, there would be a significant increase in the number of radiological investigations (7812; range 7444-8189). These changes would lead to a €2.74 million (€1.87 million-€3.61 million) reduction in the total cost of follow-up over the interval 2025-2030. CONCLUSION: Melanoma follow-up guideline changes will result in a substantial reduction in the number of clinical follow-up appointments, but a significant additional burden to radiological services. The overall cost of follow-up at a national level will be reduced.