The efficacy of immune checkpoint blockade for melanoma in-transit with or without nodal metastases - A multicenter cohort study.

PURPOSE: Guidelines addressing melanoma in-transit metastasis (ITM) recommend immune checkpoint inhibitors (ICI) as a first-line treatment option, despite the fact that there are no efficacy data available from prospective trials for exclusively ITM disease. The study aims to analyze the outcome of patients with ITM treated with ICI based on data from a large cohort of patients treated at international referral clinics. METHODS: A multicenter retrospective cohort study of patients treated between January 2015 and December 2020 from Australia, Europe, and the USA, evaluating treatment with ICI for ITM with or without nodal involvement (AJCC8 N1c, N2c, and N3c) and without distant disease (M0). Treatment was with PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab). The response was evaluated according to the RECIST criteria modified for cutaneous lesions. RESULTS: A total of 287 patients from 21 institutions in eight countries were included. Immunotherapy was first-line treatment in 64 (22%) patients. PD-1 or CTLA-4 inhibitor monotherapy was given in 233 (81%) and 23 (8%) patients, respectively, while 31 (11%) received both in combination. The overall response rate was 56%, complete response (CR) rate was 36%, and progressive disease (PD) rate was 32%. Median PFS was ten months (95% CI 7.4-12.6 months) with a one-, two-, and five-year PFS rate of 48%, 33%, and 18%, respectively. Median MSS was not reached, and the one-, two-, and five-year MSS rates were 95%, 83%, and 71%, respectively. CONCLUSION: Systemic immunotherapy is an effective treatment for melanoma ITM. Future studies should evaluate the role of systemic immunotherapy in the context of multimodality therapy, including locoregional treatments such as surgery, intralesional therapy, and regional therapies.

Protocol for the implementation of a stepped-care model to address fear of cancer recurrence in patients previously diagnosed with early-stage (0-II) melanoma.

INTRODUCTION: Fear of cancer recurrence (FCR) is commonly reported by patients diagnosed with early-stage (0-II) melanoma and can have a significant impact on daily functioning. This study will pilot the implementation of the Melanoma Care Program, an evidence-based, psychological intervention to reduce FCR, into routine practice, using a stepped-care model. METHODS AND ANALYSIS: Intervention effectiveness and level of implementation will be investigated using a hybrid type I design. Between 4 weeks before and 1 week after their next dermatological appointment, patients with melanoma will be invited to complete the Fear of Cancer Recurrence Inventory Short-Form, measuring self-reported FCR severity. Using a stepped-care model, clinical cut-off points will guide the level of support offered to patients. This includes: (1) usual care, (2) Melanoma: Questions and Answers psychoeducational booklet, and (3) three or five psychotherapeutic telehealth sessions. This longitudinal, mixed-methods pilot implementation study aims to recruit 108 patients previously diagnosed with stage 0-II melanoma. The primary effectiveness outcome is change in FCR severity over time. Secondary effectiveness outcomes include change in anxiety, depression, stress, health-related quality of life and melanoma-related knowledge over time. All outcomes are measured at baseline, within 1 week of the final telehealth session, and 6 and 12 months post-intervention. Implementation stakeholders at each study site and interested patients will provide feedback on intervention acceptability and appropriateness. Implementation stakeholders will also provide feedback on intervention cost, feasibility, fidelity and sustainability. These outcomes will be measured throughout implementation, using questionnaires and semistructured interviews/expert group discussions. Descriptive statistics, linear mixed-effects regression and thematic analysis will be used to analyse study data. ETHICS AND DISSEMINATION: Ethics approval was granted by the Sydney Local Health District-Royal Prince Alfred Zone (2020/ETH02518), protocol number: X20-0495. Results will be disseminated through peer-reviewed journals, conference presentations, social media and result summaries distributed to interested participants. TRIAL REGISTRATION DETAILS: (ACTRN12621000145808).

Clinicopathological characteristics of new primary melanomas in patients receiving immune checkpoint inhibitor therapy for metastatic melanoma.

BACKGROUND: Immune checkpoint inhibitors have improved survival in advanced stage melanoma patients. Rates of new primary melanomas (NPM) in patients with prior melanoma have been reported to be as high as 12%. Little is currently known regarding the frequency or characteristics of NPMs occurring in melanoma patients treated with immune checkpoint inhibitors. AIM: To determine the frequency and describe clinicopathologic characteristics of NPMs diagnosed in patients during or after treatment with immune checkpoint inhibitors for metastatic melanoma. METHODS: A retrospective analysis of prospectively collected data from the Melanoma Institute Australia and Westmead Hospital Dermatology databases. Clinicopathological data for the initial primary melanoma (IPM) and NPM were compared. RESULTS: Between 2013-2017, 14 NPMs in 13 patients (out of a total of 1047) treated with checkpoint inhibitors were identified. NPMs were significantly thinner than the IPM (median Breslow thickness 0.35 mm vs 2.0 mm, P = 0.0003), less likely to be ulcerated (0/14 vs 6/13, P = 0.004) and less likely to have nodal metastases (0/14 vs 6/13, P = 0.004). NPMs were significantly more likely to be detected in the in-situ stage (6/14 vs 0/13, P = 0.0016). CONCLUSION: NPMs are infrequent in patients treated with checkpoint inhibitors. When they occur, they are usually detected at an early stage and have features associated with a favourable prognosis, most likely reflecting close surveillance. Further study is required to determine long-term risk in patients achieving a durable response to immune checkpoint inhibitors, and to determine whether the immunotherapy itself influences both their development and biology.

Effect of the time interval between melanoma diagnosis and sentinel node biopsy on the size of metastatic tumour deposits in node-positive patients.

INTRODUCTION: This study sought to assess whether the interval between diagnostic excision-biopsy of a primary melanoma and definitive wide excision with sentinel node biopsy (SNB) influenced the size of SN metastatic deposits, which might have implications for management and prognosis. METHODS: Data were collected for (i) a Dutch population-based cohort of patients treated between 2004 and 2014 who underwent SNB within 100 days of complete excision of their primary melanoma and who were SN-positive with known SN metastasis diameter (n = 1027) and (ii) a cohort from a large Australian melanoma treatment centre (n = 541) who presented in the same time period. The effects of SNB timing on the size of SN metastatic deposits were analysed. RESULTS: Dutch patients whose SNB was performed in the second or third months after diagnosis had significantly larger SN metastasis diameters than patients who had their SNB in the first month (median increases of 17% (95%CI -14, 60%, p = 0.211) and 71% (95%CI 15, 119%, p = 0.004), respectively). No significant difference in tumour diameter for early and late SNB was found in the Australian cohort. CONCLUSIONS: SN metastasis diameter became progressively greater with SN biopsy in the second and third months after primary melanoma diagnosis in the larger, population-based patient cohort. An increase in metastasis diameter was not observed in the smaller, institutional cohort, possibly due to detection of larger SN metastases by routine pre-operative ultrasound, with fine-needle biopsy confirmation. These patients did not proceed to SNB and were therefore not included in the study.

Perspectives and Experiences of Patient-Led Melanoma Surveillance Using Digital Technologies From Clinicians Involved in the MEL-SELF Pilot Randomized Controlled Trial: Qualitative Interview Study.

BACKGROUND: The growing number of melanoma patients who need long-term surveillance increasingly exceeds the capacity of the dermatology workforce, particularly outside of metropolitan areas. Digital technologies that enable patients to perform skin self-examination and send dermoscopic images of lesions of concern to a dermatologist (mobile teledermoscopy) are a potential solution. If these technologies and the remote delivery of melanoma surveillance are to be incorporated into routine clinical practice, they need to be accepted by clinicians providing melanoma care, such as dermatologists and general practitioners (GPs). OBJECTIVE: This study aimed to explore perceptions of potential benefits and harms of mobile teledermoscopy, as well as experiences with this technology, among clinicians participating in a pilot randomized controlled trial (RCT) of patient-led melanoma surveillance. METHODS: This qualitative study was nested within a pilot RCT conducted at dermatologist and skin specialist GP-led melanoma clinics in New South Wales, Australia. We conducted semistructured interviews with 8 of the total 11 clinicians who were involved in the trial, including 4 dermatologists (3 provided teledermatology, 2 were treating clinicians), 1 surgical oncologist, and 3 GPs with qualifications in skin cancer screening (the remaining 3 GPs declined an interview). Thematic analysis was used to analyze the data with reference to the concepts of "medical overuse" and "high-value care." RESULTS: Clinicians identified several potential benefits, including increased access to dermatology services, earlier detection of melanomas, reassurance for patients between scheduled visits, and a reduction in unnecessary clinic visits. However, they also identified some potential concerns regarding the use of the technology and remote monitoring that could result in diagnostic uncertainty. These included poor image quality, difficulty making assessments from a 2D digital image (even if good quality), insufficient clinical history provided, and concern that suspicious lesions may have been missed by the patient. Clinicians thought that uncertainty arising from these concerns, together with perceived potential medicolegal consequences from missing a diagnosis, might lead to increases in unnecessary clinic visits and procedures. Strategies suggested for achieving high-value care included managing clinical uncertainty to decrease the potential for medical overuse and ensuring optimal placement of patient-led teledermoscopy within existing clinical care pathways to increase the potential for benefits. CONCLUSIONS: Clinicians were enthusiastic about the potential and experienced benefits of mobile teledermoscopy; however, managing clinical uncertainty will be necessary to achieve these benefits in clinical care outside of trial contexts and minimize potential harms from medical overuse. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12616001716459; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371865.

Surgical excision margins in primary cutaneous melanoma: A systematic review and meta-analysis.

BACKGROUND: The main treatment of primary cutaneous melanoma is surgery. This review aims to assess the width of excision margin that minimises the risk of adverse outcome from surgery, locoregional recurrence, distant recurrence, and death. METHODS: PRISMA guidelines were followed. MEDLINE, EMBASE, and four other databases were searched by using the term "melanoma", "margin", and limiting the search to randomised clinical trials (RCTs). RESULTS: Seven RCTs involving 4579 patients data were analysed. No statistically significant difference was found in locoregional recurrence RR 1.09 (95%CI 0.98-1.22, p = 0.12), local recurrence RR 1.20 (95%CI 0.66-2.21, p = 0.55), in-transit metastasis RR1.30 (95%CI 0.86-1.97, p = 0.21), regional nodal metastasis RR 1.04 (95%CI 0.91-1.18, p = 0.56), distant metastasis RR 0.95 (95%CI 0.72-1.24, p = 0.68), death RR 1.00 (95%CI 0.93-1.07, p = 0.97), death from melanoma RR 1.11 (95%CI 0.96-1.28, p = 0.16), wound infection RR 1.22 (95%CI 0.68-2.17, p = 0.50), and wound dehiscence RR 0.96 (95%CI 0.54-1.71, p = 0.88) when narrow (1-2 cm) versus wide (3-5 cm) excision margins were compared. In contrast, patients with narrow excision margins had a significant reduction in complex surgical reconstruction RR 0.30 (95%CI 0.19-0.49, p < 00001). When studies were excluded because of high risk of bias the only significant difference was death due to melanoma RR 1.25 (95%CI1.01-1.55, P = 0.04). CONCLUSIONS: No significant difference between narrow and wide excision margins in locoregional or distant recurrence, metastasis, death, or death due to melanoma. Wide margins (2-5 cm) increased the need for surgical reconstruction. Further studies are needed to assess optimal excision margins with regards to Breslow thickness and other prognostic factors and are in progress.

Tumor MHC Expression Guides First-Line Immunotherapy Selection in Melanoma.

Immunotherapy targeting T-cell inhibitory receptors, namely programmed cell death-1 (PD-1) and/or cytotoxic T-lymphocyte associated protein-4 (CTLA-4), leads to durable responses in a proportion of patients with advanced metastatic melanoma. Combination immunotherapy results in higher rates of response compared to anti-PD-1 monotherapy, at the expense of higher toxicity. Currently, there are no robust molecular biomarkers for the selection of first-line immunotherapy. We used flow cytometry to profile pretreatment tumor biopsies from 36 melanoma patients treated with anti-PD-1 or combination (anti-PD-1 plus anti-CTLA-4) immunotherapy. A novel quantitative score was developed to determine the tumor cell expression of antigen-presenting MHC class I (MHC-I) molecules, and to correlate expression data with treatment response. Melanoma MHC-I expression was intact in all tumors derived from patients who demonstrated durable response to anti-PD-1 monotherapy. In contrast, melanoma MHC-I expression was low in 67% of tumors derived from patients with durable response to combination immunotherapy. Compared to MHC-I high tumors, MHC-I low tumors displayed reduced T-cell infiltration and a myeloid cell-enriched microenvironment. Our data emphasize the importance of robust MHC-I expression for anti-PD-1 monotherapy response and provide a rationale for the selection of combination immunotherapy as the first-line treatment in MHC-I low melanoma.

Australian general practitioners' attitudes and knowledge of sentinel lymph node biopsy in melanoma management.

BACKGROUND AND OBJECTIVES: In Australia, the uptake of the sentinel lymph node biopsy (SLNB) appears low despite clinical practice guideline recommendations. The aim of this study was to describe the knowledge and attitudes of general practitioners (GPs) to SLNB. METHOD: GPs were recruited at an annual conference and a skin cancer skills workshop, and using GP professional communications. A mixed methods approach comprised a cross-sectional questionnaire and, for a subset of participants, semi-structured interviews. RESULTS: Overall, 231 GPs completed the questionnaire, of whom 23 were interviewed. One-third (32%) described themselves as quite or very familiar with the guidelines, and two-thirds (68%) thought that SLNB had an important role in the management of patients with melanoma. Of GPs who would discuss SLNB with eligible patients, <40% correctly identified that SLNB is recommended for patients with an invasive melanoma >1 mm thick. DISCUSSION: GPs were generally supportive of SLNB. Familiarity with the guidelines was low, particularly regarding which patients should be considered for SLNB.

Primary dermal melanoma: clinical behaviour, prognosis and treatment.

PURPOSE: Primary dermal melanoma (PDM) is a subtype of cutaneous melanoma, confined to the dermis, which poses a challenging clinical dilemma. It may represent a true primary melanoma or a dermal cutaneous metastasis. This study aimed to delineate the histopathological characteristics and prognosis of PDM in a large patient cohort to guide appropriate treatment strategies. METHODS: A search of the Melanoma Research Database at Melanoma Institute Australia was conducted to identify all possible PDM patients at our institution diagnosed from 1978 to 2013. Overall, melanoma-specific and disease-free survival outcomes of the PDM group were compared to those of similar cohorts of Stage I-II and Stage IV M1a melanoma patients based on propensity score matching. RESULTS: Sixty-two PDM patients were identified from the MRD with a median follow-up of 6.3 years. Five-year survival was 87.1% and overall survival was 74.2%. PDMs had a significantly improved overall survival (p = 0.0002) and melanoma-specific survival (p = 0.001) compared to Stage I-II controls, however there was no difference in disease-free survival (p = 0.08). PDMs also demonstrated improved overall survival (p < 0.0001), melanoma-specific survival (p < 0.0001) and disease-free survival (p < 0.0001) compared to Stage IV M1a controls. CONCLUSION: These findings demonstrate that PDMs have a more favorable prognosis compared to stage I-II cutaneous melanomas and suggest that these are in fact true primary lesions. This study thus provides evidence to justify a treatment approach, by way of a wide local excision and possibly sentinel lymph node biopsy, as for early stage primary cutaneous melanomas.

Identifying challenges to implementation of clinical practice guidelines for sentinel lymph node biopsy in patients with melanoma in Australia: protocol paper for a mixed methods study.

INTRODUCTION: Sentinel lymph node biopsy (SLNB) is a diagnostic procedure developed in the 1990s. It is currently used to stage patients with primary cutaneous melanoma, provide prognostic information and guide management. The Australian Clinical Practice Guidelines state that SLNB should be considered for patients with cutaneous melanoma >1 mm in thickness (or >0.8 mm with high-risk pathology features). Until recently, sentinel lymph node (SLN) status was used to identify patients who might benefit from a completion lymph node dissection, a procedure that is no longer routinely recommended. SLN status is now also being used to identify patients who might benefit from systemic adjuvant therapies such as anti-programmed cell death 1 (PD1) checkpoint inhibitor immunotherapy or BRAF-directed molecular targeted therapy, treatments that have significantly improved relapse-free survival for patients with resected stage III melanoma and improved overall survival of patients with unresectable stage III and stage IV melanoma. Australian and international data indicate that approximately half of eligible patients receive an SLNB. METHODS AND ANALYSIS: This mixed-methods study seeks to understand the structural, contextual and cultural factors affecting implementation of the SLNB guidelines. Data collection will include: (1) cross-sectional questionnaires and semistructured interviews with general practitioners and dermatologists; (2) semistructured interviews with other healthcare professionals involved in the diagnosis and early definitive care of melanoma patients and key stakeholders including researchers, representatives of professional colleges, training organisations and consumer melanoma groups; and (3) documentary analysis of documents from government, health services and non-government organisations. Descriptive analyses and multivariable regression models will be used to examine factors related to SLNB practices and attitudes. Qualitative data will be analysed using thematic analysis. ETHICS AND DISSEMINATION: Ethics approval has been granted by the University of Sydney. Results will be disseminated through publications and presentations to clinicians, patients, policymakers and researchers and will inform the development of strategies for implementing SLNB guidelines in Australia.

Quality of Life Following Sentinel Node Biopsy for Primary Cutaneous Melanoma: Health Economic Implications.

BACKGROUND: Sentinel node biopsy (SNB) is commonly performed in contemporary melanoma management, however there is a paucity of long-term quality of life (QoL) estimates required for economic evaluation of this treatment. METHODS: A single-center, prospective, cross-sectional study of adults with American Joint Committee on Cancer stage I/II/IIIA melanoma of the limbs, trunk, or neck who had undergone wide excision and SNB, but not complete regional node dissection, was undertaken. Limb volume was measured using perometry, with lymphedema defined as a ≥10% volume increase in the ipsilateral limb compared with the contralateral limb. The Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire measured QoL. Associations between patient and treatment characteristics were assessed using linear regression. RESULTS: Among 694 patients (median time from SNB of 37 months), 14 (2%) had objectively measured lymphedema (i.e. an increase in limb volume of ≥10%). Of 687 stage I/II patients with complete QoL data, the mean weighted QoL was 0.745 (standard deviation 0.04) on a 0-1 scale (i.e. death to full health). In multivariable analysis, weighted QoL was 0.0004 higher for each year of increasing age (p = 0.001); 0.011 lower for females (p = 0.001), 0.018 lower following post-SNB limb trauma (p = 0.002); 0.252 lower for patients who perceived a large increase in limb size (p = 0.015); and 0.027 lower with self-reported difficulty in walking, running, or climbing stairs (p = 0.043). CONCLUSIONS: Our data suggest that very few patients treated at our institution had lymphedema in the long-term following SNB, with weighted QoL strongly associated with perceived rather than actual changes in limb size.

Pigmented lesions of the nail bed - Clinical assessment and biopsy.

BACKGROUND: Subungual melanoma is an uncommon type of melanoma that can be difficult to diagnose. Patients often present with advanced primary lesions and have an associated increased risk of nodal disease. Delays in diagnosis are believed to contribute to poor patient outcomes. OBJECTIVE: The objective of this article is to offer an approach to assessing and managing patients who present with subungual pigmented lesions. We describe the anatomy of the nail bed to offer a rationale for our technique of nail bed biopsy, and warn of the potential to cause permanent nail dystrophy through other approaches. DISCUSSION: Many clinicians have limited experience in assessing lesions of the nail apparatus.Subungual pigmentation has extremely broad differential diagnoses, which include a variety of benign pathologies. A systematic approach to assessment, and early referral of patients with suspicious lesions to a specialist unit, has the potential to improve patient outcomes.

Outcome following sentinel node biopsy plus wide local excision versus wide local excision only for primary cutaneous melanoma: analysis of 5840 patients treated at a single institution.

OBJECTIVE: Worldwide, sentinel node biopsy (SNB) is now a standard staging procedure for most patients with melanomas 1 mm or more in thickness, but its therapeutic benefit is not clear, pending randomized trial results. This study sought to assess the therapeutic benefit of SNB in a large, nonrandomized patient cohort. METHODS: Patients with primary melanomas 1.00 mm or more thick or with adverse prognostic features treated with wide local excision (WLE) at a single institution between 1992 and 2008 were identified. The outcomes for those who underwent WLE plus SNB (n = 2909) were compared with the outcomes for patients in an observation (OBS) group who had WLE only (n = 2931). Median follow-up was 42 months. RESULTS: Melanoma-specific survival (MSS) was not significantly different for patients in the SNB and OBS groups. However, a stratified univariate analysis of MSS for different thickness subgroups indicated a significantly better MSS for SNB patients with T2 and T3 melanomas (>1.0 to 4.0 mm thick) (P = 0.011), but this was not independently significant in multivariate analysis. Compared with OBS patients, SNB patients demonstrated improved disease-free survival (DFS) (P < 0.001) and regional recurrence-free survival (P < 0.001). There was also an improvement in distant metastasis-free survival (DMFS) for SNB patients with T2 and T3 melanomas (P = 0.041). CONCLUSIONS: In this study, the outcome for the overall cohort after WLE alone did not differ significantly from the outcome after additional SNB. However, the outcome for the subgroup of patients with melanomas more than 1.0 to 4.0 mm in thickness was improved if they had a SNB, with significantly improved disease-free and DMFS.