Neoadjuvant relatlimab and nivolumab in resectable melanoma.

Relatlimab and nivolumab combination immunotherapy improves progression-free survival over nivolumab monotherapy in patients with unresectable advanced melanoma1. We investigated this regimen in patients with resectable clinical stage III or oligometastatic stage IV melanoma (NCT02519322). Patients received two neoadjuvant doses (nivolumab 480 mg and relatlimab 160 mg intravenously every 4 weeks) followed by surgery, and then ten doses of adjuvant combination therapy. The primary end point was pathologic complete response (pCR) rate2. The combination resulted in 57% pCR rate and 70% overall pathologic response rate among 30 patients treated. The radiographic response rate using Response Evaluation Criteria in Solid Tumors 1.1 was 57%. No grade 3-4 immune-related adverse events were observed in the neoadjuvant setting. The 1- and 2-year recurrence-free survival rate was 100% and 92% for patients with any pathologic response, compared to 88% and 55% for patients who did not have a pathologic response (P = 0.005). Increased immune cell infiltration at baseline, and decrease in M2 macrophages during treatment, were associated with pathologic response. Our results indicate that neoadjuvant relatlimab and nivolumab induces a high pCR rate. Safety during neoadjuvant therapy is favourable compared to other combination immunotherapy regimens. These data, in combination with the results of the RELATIVITY-047 trial1, provide further confirmation of the efficacy and safety of this new immunotherapy regimen.

Society of Surgical Oncology Consensus Statement: Assessing the Evidence for and Utility of Gene Expression Profiling of Primary Cutaneous Melanoma.

INTRODUCTION: Gene expression profiling (GEP) of primary cutaneous melanoma aims to offer prognostic and predictive information to guide clinical care. Despite limited evidence of clinical utility, these tests are increasingly incorporated into clinical care. METHODS: A panel of melanoma experts from the Society of Surgical Oncology convened to develop recommendations regarding the use of GEP to guide management of patients with melanoma. The use of currently available GEP tests were evaluated in three clinical scenarios: (1) the utility in patient selection for sentinel lymph node biopsy; (2) the utility to guide surveillance; and (3) the utility to inform adjuvant therapy. As a basis for these recommendations, the panel performed a systematic review of the literature, including articles published from January 2012 until August 2023. RESULTS: After review of 137 articles, 50 met the inclusion criteria. These articles included evidence related to three available GEP tests: 31-GEP, CP-GEP, and 11-GEP. The consensus recommendations were finalized using a modified Delphi process. The panel found that current evidence often fails to account for known clinicopathologic risk factors and lacks high-level data. The panel recognizes that the study of GEP tests is still evolving. The integration of GEP into routine clinical practice for predicting sentinel lymph node status and patient prognosis in melanoma is therefore not currently recommended. CONCLUSION: At present, GEP should be considered primarily an investigational tool, ideally used in the context of clinical trials or specialized research settings.

International Center-Level Variation in Utilization of Completion Lymph Node Dissection and Adjuvant Systemic Therapy for Sentinel Lymph Node-Positive Melanoma at Major Referral Centers.

OBJECTIVE: The aim of this study was to determine overall trends and center-level variation in utilization of completion lymph node dissection (CLND) and adjuvant systemic therapy for sentinel lymph node (SLN)-positive melanoma. SUMMARY BACKGROUND DATA: Based on recent clinical trials, management options for SLN-positive melanoma now include effective adjuvant systemic therapy and nodal observation instead of CLND. It is unknown how these findings have shaped practice or how these contemporaneous developments have influenced their respective utilization. METHODS: We performed an international cohort study at 21 melanoma referral centers in Australia, Europe, and the United States that treated adults with SLN-positive melanoma and negative distant staging from July 2017 to June 2019. We used generalized linear and multinomial logistic regression models with random intercepts for each center to assess center-level variation in CLND and adjuvant systemic treatment, adjusting for patient and disease-specific characteristics. RESULTS: Among 1109 patients, performance of CLND decreased from 28% to 8% and adjuvant systemic therapy use increased from 29 to 60%. For both CLND and adjuvant systemic treatment, the most influential factors were nodal tumor size, stage, and location of treating center. There was notable variation among treating centers in management of stage IIIA patients and use of CLND with adjuvant systemic therapy versus nodal observation alone for similar risk patients. CONCLUSIONS: There has been an overall decline in CLND and simultaneous adoption of adjuvant systemic therapy for patients with SLN-positive melanoma though wide variation in practice remains. Accounting for differences in patient mix, location of care contributed significantly to the observed variation.

Undifferentiated and Dedifferentiated Metastatic Melanomas Masquerading as Soft Tissue Sarcomas: Mutational Signature Analysis and Immunotherapy Response.

The distinction between undifferentiated melanoma (UM) or dedifferentiated melanoma (DM) from undifferentiated or unclassifiable sarcoma can be difficult and requires the careful correlation of clinical, pathologic, and genomic findings. In this study, we examined the utility of mutational signatures to identify patients with UM/DM with particular attention as to whether this distinction matters for treatment because the survival of patients with metastatic melanoma has dramatically improved with immunologic therapy, whereas durable responses are less frequent in sarcomas. We identified 19 cases of UM/DM that were initially reported as unclassified or undifferentiated malignant neoplasm or sarcoma and submitted for targeted next-generation sequencing analysis. These cases were confirmed as UM/DM by harboring melanoma driver mutations, UV signature, and high tumor mutation burden. One case of DM showed melanoma in situ. Meanwhile, 18 cases represented metastatic UM/DM. Eleven patients had a prior history of melanoma. Thirteen of 19 (68%) of the tumors were immunohistochemically completely negative for 4 melanocytic markers (S100, SOX10, HMB45, and MELAN-A). All cases harbored a dominant UV signature. Frequent driver mutations involved BRAF (26%), NRAS (32%), and NF1 (42%). In contrast, the control cohort of undifferentiated pleomorphic sarcomas (UPS) of deep soft tissue exhibited a dominant aging signature in 46.6% (7/15) without evidence of UV signature. The median tumor mutation burden for DM/UM vs UPS was 31.5 vs 7.0 mutations/Mb (P < .001). A favorable response to immune checkpoint inhibitor therapy was observed in 66.6% (12/18) of patients with UM/DM. Eight patients exhibited a complete response and were alive with no evidence of disease at the last follow-up (median 45.5 months). Our findings support the usefulness of the UV signature in discriminating DM/UM vs UPS. Furthermore, we present evidence suggesting that patients with DM/UM and UV signatures can benefit from immune checkpoint inhibitor therapy.

Does Stage Migration Occur as a Consequence of Omitting Completion Lymph Node Dissection for Melanoma?

INTRODUCTION: Completion lymph node dissection (CLND) is no longer recommended routinely in the treatment of melanoma. CLND omission may understage patients for whom the distinction between stage IIIA and IIIB-C could alter adjuvant therapy recommendations. The aim of this study is to determine if stage migration has occurred with the declining use of CLND. METHODS: Patients with clinically node-negative ≥ T1b cutaneous melanoma were identified from the National Cancer Database (NCDB) from 2012 to 2018. CLND utilization and changes in AJCC staging were analyzed. Patients undergoing sentinel lymph node biopsy (SLNB) alone were compared with those undergoing SLNB + CLND. RESULTS: Overall, 68,933 patients met inclusion criteria and 60,536 underwent SLNB, of which 9031 (14.9%) were tumor positive. CLND was performed in 3776 (41.8%). Patients undergoing CLND were younger (58 versus 62 years, p < 0.0001) and more likely male (61.5% versus 57.9%, p = 0.0005). Patients were more likely to have an N classification >N1a if they received SLNB + CLND (36.8%) versus SLNB alone (19.3%), p < 0.0001. This translated to a small difference in stage IIIA patients between groups (SLNB alone 34.0%, SLNB + CLND 31.8%, p < 0.0001). Of the patients with T1b/T2a tumors who would be upstaged from IIIA to IIIC with identification of additional positive nodes, IIIC incidence was only slightly higher after SLNB + CLND compared with SLNB alone (4.4% versus 1.1%, p < 0.0001). CLND utilization dramatically decreased from 59% in 2012 to 12.6% in 2018, p < 0.0001. However, the incidence of stage IIIA disease for all patients remained stable over the 7-year study period. CONCLUSIONS: While the utilization of CLND after positive SLNB has declined dramatically in the last 7 years, stage migration that may affect adjuvant therapy decisions has not occurred to a clinically meaningful degree.

Timing of Adjuvant Immunotherapy in Stage III Melanoma, Does it Matter?

BACKGROUND: The optimal time to initiate adjuvant immune checkpoint inhibitors (ICI) following resection remains undefined. Herein, we investigated the impact of time to adjuvant ICI on survival in patients with stage III melanoma. METHODS: Patients with resected stage III melanoma receiving adjuvant immune therapy were identified within a multi-institutional retrospective cohort. Patients were stratified by time to adjuvant ICI: within 6 weeks, 6-12 weeks, and greater than 12 weeks from surgery. Recurrence-free survival (RFS) was compared among time strata with Kaplan-Meier and Cox proportional hazards methods in the multi-institutional cohort. RESULTS: Altogether, 626 patients were identified within the multi-institutional cohort: 39% of patients initiated adjuvant ICI within 6 weeks, 42.2% within 6-12 weeks, and 18.8% greater than 12 weeks from surgery. In a multivariate Cox model, adjusting for histology, nodal tumor burden, and pathologic stage, we found that increased time to adjuvant ICI was associated with improved RFS. Patients who initiated adjuvant ICI within 6 weeks of surgery had worse RFS. These findings were preserved in a conditional landmark analysis and separate subgroups of patients with (1) new melanoma diagnoses, (2) occult stage III disease, and (3) those receiving anti-PD-1 monotherapy. CONCLUSIONS: Outcomes for patients with stage III melanoma are not compromised when adjuvant ICI is initiated beyond 6 weeks from resection. Additional work is needed to better understand the underlying mechanisms and implications of timing of adjuvant ICI on long-term outcomes.

Are the MIA and MSKCC nomograms useful in selecting patients with melanoma for sentinel lymph node biopsy?

BACKGROUND AND METHODS: The Melanoma Institute of Australia (MIA) and Memorial Sloan Kettering Cancer Center (MSKCC) nomograms were developed to help guide sentinel lymph node biopsy (SLNB) decisions. Although statistically validated, whether these prediction models provide clinical benefit at National Comprehensive Cancer Network guideline-endorsed thresholds is unknown. We conducted a net benefit analysis to quantify the clinical utility of these nomograms at risk thresholds of 5%-10% compared to the alternative strategy of biopsying all patients. External validation data for MIA and MSKCC nomograms were extracted from respective published studies. RESULTS: The MIA nomogram provided added net benefit at a risk threshold of 9% but net harm at 5%-8% and 10%. The MSKCC nomogram provided added net benefit at risk thresholds of 5% and 9%-10% but net harm at 6%-8%. When present, the magnitude of net benefit was small (1-3 net avoidable biopsies per 100 patients). CONCLUSION: Neither model consistently provided added net benefit compared to performing SLNB for all patients. DISCUSSION: Based on published data, use of the MIA or MSKCC nomograms as decision-making tools for SLNB at risk thresholds of 5%-10% does not clearly provide clinical benefit to patients.

Regional control after precision lymph node dissection for clinically evident melanoma metastasis.

INTRODUCTION: Completion lymph node dissection (CLND) for microscopic lymph node metastases has been replaced by observation; however, CLND is standard for clinically detectable nodal metastases (cLN). CLND has high morbidity, which may be reduced by excision of only the cLN (precision lymph node dissection [PLND]). We hypothesized that same-basin recurrence risk would be low after PLND. METHODS: Retrospective review at four tertiary care hospitals identified patients who underwent PLND. The primary outcome was 3-year cumulative incidence of isolated same-basin recurrence. RESULTS: Twenty-one patients underwent PLND for cLN without synchronous distant metastases. Reasons for forgoing CLND included patient preference (n = 11), comorbidities (n = 5), imaging indeterminate for distant metastases (n = 2), partial response to checkpoint blockade (n = 1), or not reported (n = 2). A median of 2 nodes (range: 1-6) were resected at PLND, and 68% contained melanoma. Recurrence was observed in 33% overall. Only 1 patient (5%) developed an isolated same-basin recurrence. Cumulative incidences at 3 years were 5.0%, 17.3%, and 49.7% for isolated same-basin recurrence, any same-basin recurrence, and any recurrence, respectively. Complications from PLND were reported in 1 patient (5%). CONCLUSIONS: These pilot data suggest that PLND may provide adequate regional disease control with less morbidity than CLND. These data justify prospective evaluation of PLND in select patients.

Sentinel lymph node biopsy status improves adjuvant therapy decision-making in patients with clinical stage IIB/C melanoma: A population-based analysis.

BACKGROUND: Given the results of the recent KEYNOTE-716 trial, the performance of sentinel lymph node (SLN) biopsy for patients with clinical stage IIB/C melanoma has been questioned. OBJECTIVE: Determine the utility of SLN status in guiding the recommendations for adjuvant therapy. METHODS: Patients with clinical stage IIB/C cutaneous melanoma who underwent wide local excision and SLN biopsy between 2004 and 2011 were identified from the Surveillance, Epidemiology, and End Results database. Two prognostic models, with and without SLN status, were developed predicting risk of melanoma-specific death (MSD). The primary outcome was net benefit at treatment thresholds of 20% to 40% risk of 5-year MSD. RESULTS: For the 4391 patients included, the 5-year MSD rate was 46%. The model estimating 5-year MSD risk that included SLN status provided greater net benefit at treatment thresholds from 30% to 78% compared to the model without SLN status. The added net benefit for the SLN biopsy-containing model persisted in subgroup analysis of patients in different age groups and with various T stages. LIMITATIONS: Retrospective study. CONCLUSIONS: A prognostic model with SLN status estimating patient risk for 5-year MSD provides superior net benefit compared to a model with primary tumor staging factors alone for threshold mortality rates ≥30%.

Sentinel lymph node biopsy in patients with T1a cutaneous malignant melanoma: A multicenter cohort study.

BACKGROUND: Sentinel lymph node biopsy is not routinely recommended for T1a cutaneous melanoma due to the overall low risk of positivity. Prognostic factors for positive sentinel lymph node (SLN+) in this population are poorly characterized. OBJECTIVE: To determine factors associated with SLN+ in patients with T1a melanoma. METHODS: Patients with pathologic T1a (<0.80 mm, nonulcerated) cutaneous melanoma from 5 high-volume melanoma centers from 2001 to 2020 who underwent wide local excision with sentinel lymph node biopsy were included in the study. Patient and tumor characteristics associated with SLN+ were analyzed by univariate and multivariable logistic regression analyses. Age was dichotomized into ≤42 (25% quartile cutoff) and >42 years. RESULTS: Of the 965 patients identified, the overall SLN+ was 4.4% (N = 43). Factors associated with SLN+ were age ≤42 years (7.5% vs 3.7%; odds ratio [OR], 2.14; P = .03), head/neck primary tumor location (9.2% vs 4%; OR, 2.75; P = .04), lymphovascular invasion (21.4% vs 4.2%; OR, 5.64; P = .01), and ≥2 mitoses/mm2 (8.2% vs 3.4%; OR, 2.31; P = .03). Patients <42 years with ≥2 mitoses/mm2 (N = 38) had a SLN+ rate of 18.4%. LIMITATIONS: Retrospective study. CONCLUSION: SLN+ is low in patients with T1a melanomas, but younger age, lymphovascular invasion, mitogenicity, and head/neck primary site appear to confer a higher risk of SLN+.

Clinically Significant Risk Thresholds in the Management of Primary Cutaneous Melanoma: A Survey of Melanoma Experts.

BACKGROUND: Risk-based thresholds to guide management are undefined in the treatment of primary cutaneous melanoma but are essential to advance the field from traditional stage-based treatment to more individualized care. METHODS: To estimate treatment risk thresholds, hypothetical clinical melanoma scenarios were developed and a stratified random sample was distributed to expert melanoma clinicians via an anonymous web-based survey. Scenarios provided a defined 5-year risk of recurrence and asked for recommendations regarding clinical follow-up, imaging, and adjuvant therapy. Marginal probability of response across the spectrum of 5-year recurrence risk was estimated. The risk at which 50% of respondents recommended a treatment was defined as the risk threshold. RESULTS: The overall response rate was 56% (89/159). Three separate multivariable models were constructed to estimate the recommendations for clinical follow-up more than twice/year, for surveillance cross-sectional imaging at least once/year, and for adjuvant therapy. A 36% 5-year risk of recurrence was identified as the threshold for recommending clinical follow-up more than twice/year. The thresholds for recommending cross-sectional imaging and adjuvant therapy were 30 and 59%, respectively. Thresholds varied with the age of the hypothetical patient: at younger ages they were constant but increased rapidly at ages 60 years and above. CONCLUSIONS: To our knowledge, these data provide the first estimates of clinically significant treatment thresholds for patients with cutaneous melanoma based on risk of recurrence. Future refinement and adoption of thresholds would permit assessment of the clinical utility of novel prognostic tools and represents an early step toward individualizing treatment recommendations.

sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance.

Cancer is a disease of ageing. Clinically, aged cancer patients tend to have a poorer prognosis than young. This may be due to accumulated cellular damage, decreases in adaptive immunity, and chronic inflammation. However, the effects of the aged microenvironment on tumour progression have been largely unexplored. Since dermal fibroblasts can have profound impacts on melanoma progression, we examined whether age-related changes in dermal fibroblasts could drive melanoma metastasis and response to targeted therapy. Here we find that aged fibroblasts secrete a Wnt antagonist, sFRP2, which activates a multi-step signalling cascade in melanoma cells that results in a decrease in ß-catenin and microphthalmia-associated transcription factor (MITF), and ultimately the loss of a key redox effector, APE1. Loss of APE1 attenuates the response of melanoma cells to DNA damage induced by reactive oxygen species, rendering the cells more resistant to targeted therapy (vemurafenib). Age-related increases in sFRP2 also augment both angiogenesis and metastasis of melanoma cells. These data provide an integrated view of how fibroblasts in the aged microenvironment contribute to tumour progression, offering new possibilities for the design of therapy for the elderly.

Active surveillance of patients who have sentinel node positive melanoma: An international, multi-institution evaluation of adoption and early outcomes after the Multicenter Selective Lymphadenectomy Trial II (MSLT-2).

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

Histologic Subtype Defines the Risk and Kinetics of Recurrence and Death for Primary Extremity/Truncal Liposarcoma.

OBJECTIVE: We sought to define the prognostic significance of histologic subtype for extremity/truncal liposarcoma (LPS). BACKGROUND: LPS, the most common sarcoma, is comprised of 5 histologic subtypes. Despite their distinct behaviors, LPS outcomes are frequently reported as a single entity. METHODS: We analyzed data on all patients from a single-institution prospective database treated from July 1982 to September 2017 for primary, nonmetastatic, extremity or truncal LPS of known subtype. Clinicopathologic variables were tested using competing risk analyses for association with disease-specific death (DSD), distant recurrence (DR), and local recurrence (LR). RESULTS: Among 1001 patients, median follow-up in survivors was 5.4 years. Tumor size and subtype were independently associated with DSD and DR. Size, subtype, and R1 resection were independently associated with LR. DR was most frequent among pleomorphic and round cell LPS; the former recurred early (43% by 3 years), and the latter over a longer period (23%, 3 years; 37%, 10 years). LR was most common in dedifferentiated LPS, in which it occurred early (24%, 3 years; 33%, 5 years), followed by pleomorphic LPS (18%, 3 years; 25%, 10 years). CONCLUSIONS: Histologic subtype is the factor most strongly associated with DSD, DR, and LR in extremity/truncal LPS. Both risk and timing of adverse outcomes vary by subtype. These data may guide selective use of systemic therapy for patients with round cell and pleomorphic LPS, which carry a high risk of DR, and radiotherapy for LPS subtypes at high risk of LR when treated with surgery alone.

Assessment of Frailty Can Guide Decision Making for Utilization of Sentinel Lymph Node Biopsy in Patients with Thick Melanoma.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is often omitted in selected patients with advanced primary melanoma, although the justification/criteria for omission have been debated. OBJECTIVE: We sought to determine whether assessment of frailty could serve as an objective marker to guide selection for SLNB in patients with advanced primary melanoma. METHODS: Patients presenting with clinical stage IIC (ulcerated, > 4 mm Breslow thickness) cutaneous melanoma from January 1999 through June 2019 were included. Frailty was assessed using the Memorial Sloan Kettering Frailty Index (MSK FI), a composite score of functional status and medical comorbidities. Five-year melanoma-specific survival (MSS) and overall survival (OS) were estimated using Cox regression, and predictors of OS were identified using competing risk models. RESULTS: MSS did not differ between patients who did (n = 451) or did not undergo SLNB (n = 179) [63.2% vs. 65.0%, p = 0.14]; however, omission of SLNB was associated with decreased 5-year OS (29% vs. 44%, p < 0.001). In a multivariable competing risk model, selection for SLNB omission was an independent predictor of death from non-melanoma causes (hazard ratio [HR] 1.7, 95% confidence interval [CI] 1.2-2.3, p < 0.001). After incorporation of the MSK FI score into the multivariable model in this subset, MSK FI (HR 2.4, 95% CI 1.5-4.1, p < 0.001), but not SLNB omission, was an independent predictor of poorer OS. CONCLUSION: We observed worse OS in patients with thick melanoma selected not to undergo SLNB, which was attributed to death due to non-melanoma causes. Formal assessment of frailty may provide an objective prognostic measure to guide selective use of SLNB in these patients.

The emerging role of immunotherapy for the treatment of sarcoma.

Clinicians caring for patients with sarcoma founded the field of cancer immunotherapy. Despite this, contemporary success with immunotherapy for sarcoma has been limited. Here, we review immunotherapy for sarcoma including Coley's toxins, interleukin-2, adoptive cell transfer, and checkpoint blockade. We detail recent and ongoing efforts to combine checkpoint blockade with other immune modulators, surgery, or radiation. These results, along with ongoing investigations, have identified immunotherapeutic approaches as a promising avenue for progress in advanced sarcomas.

High neutrophil-to-lymphocyte ratio (NLR) is associated with treatment failure and death in patients who have melanoma treated with PD-1 inhibitor monotherapy.

BACKGROUND: An elevated neutrophil-to-lymphocyte ratio (NLR) is associated with poor survival in patients with cancer, including those who receive immunotherapies. The authors sought to investigate NLR as a biomarker of treatment outcomes in patients with melanoma who were treated with PD-1 inhibition. METHODS: Patients undergoing initial treatment with PD-1 inhibitor monotherapy for stage IV melanoma at a single center from 2012 to 2015 were included. Clinical characteristics and the NLR at baseline and before subsequent treatment cycles were collected. The time to treatment failure (TTF) and overall survival (OS) were evaluated using Kaplan-Meier and landmark analyses. RESULTS: Among 224 study patients, 63 (28%) had a baseline NLR ≥5. The baseline NLR was significantly associated with Eastern Cooperative Oncology Group performance status and the number of involved metastatic sites. With a median follow-up of 39 months in survivors, a baseline NLR ≥5 was independently associated with shorter OS (hazard ratio, 2.0; 95% CI, 1.3-2.9) and TTF (hazard ratio, 1.7; 95% CI, 1.2-2.4). An NLR increase ≥30% during the first 2 cycles of treatment was associated with worse OS (median, 47 vs 13.5 months; P < .001) and a trend toward shorter TTF (12.8 vs 5.9 months; P = .05). A combined baseline NLR ≥5 and an NLR increase ≥30% identified a small cohort with markedly shortened OS (median, 5.8 months) and TTF (median, 1.8 months). CONCLUSIONS: Elevated baseline NLR and an increased NLR early during treatment are prognostic for TTF and OS in patients who have melanoma treated with PD-1 inhibitor monotherapy. Combined, these biomarkers can widely risk-stratify patients for treatment failure and survival.

Sentinel Lymph Node Biopsy for T1b Melanoma: Balancing Prognostic Value and Cost.

BACKGROUND: The purpose of this study is to report the additional prognostic information and cost associated with sentinel lymph node biopsy (SLNB) for patients with T1b melanoma. PATIENTS AND METHODS: An institutional database was queried for patients with T1b melanoma (0.8-1.0 mm or < 0.8 mm with ulceration) with at least 5 years of follow-up. Results of SLNB, completion lymphadenectomy (CLND), recurrence, and melanoma-specific survival (MSS) were assessed. Institutional costs of melanoma care were converted to Medicare proportional dollars. A Markov model was created to estimate long-term costs. RESULTS: Among the total 392 patients, 238 underwent SLNB. Median follow-up was 10.5 years. SLNB was positive in 19 patients (8.0%). Patients who underwent SLNB had higher 10-year nodal recurrence-free survival (98.6% vs. 91.2%, p < 0.001) but not MSS (94.4% vs. 93.2%, p = 0.55). Ulceration (HR 4.7, p = 0.022) and positive sentinel node (HR 11.5, p < 0.001) were associated with worse MSS. Estimates for 5-year costs reflect a fourfold increase in total costs of care associated with SLNB. However, a treatment plan that forgoes adjuvant therapy for resected stage IIIA melanoma but offers systemic therapy for a node-basin recurrence would nullify the additional cost of SLNB. CONCLUSIONS: SLNB is prognostic for T1b melanoma. Its impact on the overall cost of melanoma care is intimately tied to systemic therapy in the adjuvant and recurrent settings.

Microsatellitosis in Patients with Melanoma.

BACKGROUND: Microsatellitosis (mS) in melanoma has been considered a marker of unfavorable tumor biology, leading to the current American Joint Committee on Cancer staging of IIIB/C/D disease, despite few investigative studies of this entity limited by the small sample sizes and incomplete nodal microstaging. We sought to better characterize outcomes and prognostic factors in a multi-institutional cohort of patients with mS and nodal microstaging. METHODS: The Sentinel Lymph Node Working Group cohort included 414 mS patients who underwent sentinel lymph node (SLN) biopsy. Cox regression analysis was used to evaluate the prognostic significance of established clinicopathologic characteristics. Melanoma-specific survival (MSS) of patients with mS was compared with 3002 similarly staged patients from the Surveillance, Epidemiology, and End Results (SEER) Program registry. RESULTS: The median age of the mS cohort was 64.9 years; 39.6% were female. Median thickness was 3 mm, 40.6% of cases were ulcerated, and the SLN positivity rate was 46.7%. Increasing thickness, male sex, and SLN positivity were significantly associated with poorer MSS. Stage IIIB/C/D 5-year MSS rates were 86.3% (95% confidence interval [CI] 79.4-93.3%), 54.1% (95% CI 45.4-59.7%), and 44.2% (95% CI 25.4-63.0%), respectively. MSS survival for the stage IIIB mS cohort was significantly better than a similarly staged SEER cohort (5-year MSS of 70.1%, 95% CI 66.0-74.2%), while no significant difference was observed for the stage IIIC or D cohorts. CONCLUSIONS: SLN metastases are common and are a significant prognostic factor in patients with mS. Survival in stage IIIB patients with mS was considerably more favorable than their stage would otherwise suggest, which has important implications for decisions regarding adjuvant therapy for patients with mS.