The prognostic significance of primary cutaneous melanoma tumor mitotic rate (TMR) has been of worldwide clinical interest for decades. Is there a path forward to build on the contributions from the ...report by Patuzzo et al. and other studies to refine the classification and staging of melanoma and to develop clinical tools to improve risk and prognostic assessment that include TMR to inform decision‐making?
Advances in our understanding of melanoma biology and the role of immune checkpoint blockade and targeted therapy have ushered in a new and rapidly evolving era of multidisciplinary care for patients ...with melanoma. Based on efficacy for patients with metastatic melanoma, these systemic treatment approaches have been introduced into the adjuvant and, more recently, the neoadjuvant landscape. This report highlights the results of key clinical studies published or initially presented in 2021 that have informed our evidence-based approach to melanoma multidisciplinary care, primarily related to adjuvant and neoadjuvant approaches for patients with resectable or resected stage III or high-risk stage II melanoma and their impact on clinical care. Knowledge concerning these areas of active clinical investigation is critical for surgical oncologists who care for melanoma patients as the treatment landscape continues to evolve.
The incidence of primary cutaneous melanoma continues to increase each year. Melanoma accounts for the majority of skin cancer–related deaths, but treatment is usually curative following early ...detection of disease. In this American Academy of Dermatology clinical practice guideline, updated treatment recommendations are provided for patients with primary cutaneous melanoma (American Joint Committee on Cancer stages 0-IIC and pathologic stage III by virtue of a positive sentinel lymph node biopsy). Biopsy techniques for a lesion that is clinically suggestive of melanoma are reviewed, as are recommendations for the histopathologic interpretation of cutaneous melanoma. The use of laboratory, molecular, and imaging tests is examined in the initial work-up of patients with newly diagnosed melanoma and for follow-up of asymptomatic patients. With regard to treatment of primary cutaneous melanoma, recommendations for surgical margins and the concepts of staged excision (including Mohs micrographic surgery) and nonsurgical treatments for melanoma in situ, lentigo maligna type (including topical imiquimod and radiation therapy), are updated. The role of sentinel lymph node biopsy as a staging technique for cutaneous melanoma is described, with recommendations for its use in clinical practice. Finally, current data regarding pregnancy and melanoma, genetic testing for familial melanoma, and management of dermatologic toxicities related to novel targeted agents and immunotherapies for patients with advanced disease are summarized.
The analysis by Broman and colleagues in this issue contributes to a still rapidly developing evidence base of patients with melanoma and a positive sentinel node who are followed with active ...surveillance. It reveals substantial adoption of randomized clinical trial findings that support active surveillance for these patients and, with limited follow‐up, suggests that loss of regional basin control is a very uncommon event in this era of effective adjuvant therapy.
Meta-analyses were performed to examine the utility of ultrasonography, computed tomography (CT), positron emission tomography (PET), and a combination of both (PET-CT) for the staging and ...surveillance of melanoma patients.
Patient-level data from 74 studies containing 10,528 patients (between January 1, 1990, and June, 30, 2009) were used to derive characteristics of the diagnostic tests used. Meta-analyses were conducted by use of Bayesian bivariate binomial models to estimate sensitivity and specificity. Diagnostic odds ratios ie, true-positive results/false-negative results)/(false-positive results/true-negative results) and their 95% credible intervals (CrIs) and positive predictive values were used as indicators of test performance.
Among the four imaging methods examined for the staging of regional lymph nodes, ultrasonography had the highest sensitivity (60%, 95% CrI = 33% to 83%), specificity (97%, 95% CrI = 88% to 99%), and diagnostic odds ratio (42, 95% CrI = 8.08 to 249.8). For staging of distant metastases, PET-CT had the highest sensitivity (80%, 95% CrI = 53% to 93%), specificity (87%, 95% CrI = 54% to 97%), and diagnostic odds ratio (25, 95% CrI = 3.58 to 198.7). Similar trends were observed for melanoma surveillance of lymph node involvement, with ultrasonography having the highest sensitivity (96%, 95% CrI = 85% to 99%), specificity (99%, 95% CrI = 95% to 100%), and diagnostic odds ratio (1675, 95% CrI = 226.6 to 15,920). For distant metastases, PET-CT had the highest sensitivity (86%, 95% CrI = 76% to 93%), specificity (91%, 95% CrI = 79% to 97%), and diagnostic odds ratio (67, 95% CrI = 20.42 to 229.7). Positive predictive values were likewise highest for ultrasonography in lymph node staging and for PET-CT in detecting distant metastases.
Among the compared modalities, ultrasonography was superior for detecting lymph node metastases, and PET-CT was superior for the detection of distant metastases in both the staging and surveillance of melanoma patients.
Obesity has been linked to increased mortality in several cancer types; however, the relation between obesity and survival outcomes in metastatic melanoma is unknown. The aim of this study was to ...examine the association between body-mass index (BMI) and progression-free survival or overall survival in patients with metastatic melanoma who received targeted therapy, immunotherapy, or chemotherapy.
This retrospective study analysed independent cohorts of patients with metastatic melanoma assigned to treatment with targeted therapy, immunotherapy, or chemotherapy in randomised clinical trials and one retrospective study of patients treated with immunotherapy. Patients were classified according to BMI, following the WHO definitions, as underweight, normal, overweight, or obese. Patients without BMI and underweight patients were excluded. The primary outcomes were the associations between BMI and progression-free survival or overall survival, stratified by treatment type and sex. We did multivariable analyses in the independent cohorts, and combined adjusted hazard ratios in a mixed-effects meta-analysis to provide a precise estimate of the association between BMI and survival outcomes; heterogeneity was assessed with meta-regression analyses. Analyses were done on the predefined intention-to-treat population in the randomised controlled trials and on all patients included in the retrospective study.
The six cohorts consisted of a total of 2046 patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy between Aug 8, 2006, and Jan 15, 2016. 1918 patients were included in the analysis. Two cohorts containing patients from randomised controlled trials treated with targeted therapy (dabrafenib plus trametinib n=599 and vemurafenib plus cobimetinib n=240), two cohorts containing patients treated with immunotherapy (one randomised controlled trial of ipilimumab plus dacarbazine n=207 and a retrospective cohort treated with pembrolizumab, nivolumab, or atezolizumab n=331), and two cohorts containing patients treated with chemotherapy (two randomised controlled trials of dacarbazine n=320 and n=221) were classified according to BMI as normal (694 36% patients), overweight (711 37%), or obese (513 27%). In the pooled analysis, obesity, compared with normal BMI, was associated with improved survival in patients with metastatic melanoma (average adjusted hazard ratio HR 0·77 95% CI 0·66–0·90 for progression-free survival and 0·74 0·58–0·95 for overall survival). The survival benefit associated with obesity was restricted to patients treated with targeted therapy (HR 0·72 0·57–0·91 for progression-free survival and 0·60 0·45–0·79 for overall survival) and immunotherapy (HR 0·75 0·56–1·00 and 0·64 0·47–0·86). No associations were observed with chemotherapy (HR 0·87 0·65–1·17, pinteraction=0·61 for progression-free survival and 1·03 0·80–1·34, pinteraction=0·01 for overall survival). The association of BMI with overall survival for patients treated with targeted and immune therapies differed by sex, with inverse associations in men (HR 0·53 0·40–0·70), but no associations observed in women (HR 0·85 0·61–1·18, pinteraction=0·03).
Our results suggest that in patients with metastatic melanoma, obesity is associated with improved progression-free survival and overall survival compared with those outcomes in patients with normal BMI, and that this association is mainly seen in male patients treated with targeted or immune therapy. These results have implications for the design of future clinical trials for patients with metastatic melanoma and the magnitude of the benefit found supports further investigation of the underlying mechanism of these associations.
ASCO/CCF Young Investigator Award, ASCO/CCF Career Development Award, MD Anderson Cancer Center (MDACC) Melanoma Moonshot Program, MDACC Melanoma SPORE, and the Dr Miriam and Sheldon G Adelson Medical Research Foundation.
Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the ...results of an ongoing phase II clinical trial testing the efficacy of ACT using TIL in patients with metastatic melanoma and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response.
Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL, followed by two cycles of high-dose interleukin (IL)-2 therapy. The effects of patient clinical features and the phenotypes of the T cells infused on the clinical response were determined.
Overall, 15 of 31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC) with 2 patients (6.5%) having a complete response. Progression-free survival of more than 12 months was observed for 9 of 15 (60%) of the responding patients. Factors significantly associated with the objective tumor regression included a higher number of TIL infused, a higher proportion of CD8(+) T cells in the infusion product, a more differentiated effector phenotype of the CD8(+) population, and a higher frequency of CD8(+) T cells coexpressing the negative costimulation molecule "B- and T-lymphocyte attenuator" (BTLA). No significant difference in the telomere lengths of TIL between responders and nonresponders was identified.
These results indicate that the immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in patients with metastatic melanoma and that CD8(+) T cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression.
PDF
