Role of Sarcopenia in Advanced Malignant Cutaneous Melanoma Treated with Immunotherapy: A Meta-Analysis

Introduction: The role of sarcopenia in malignant cutaneous melanoma is unclear. The aim of the present meta-analysis was to analyze the prevalence and clinical role of sarcopenia in patients with advanced cutaneous melanoma based on a large cohort. Methods: MEDLINE, Cochrane, and SCOPUS databases were checked for relationships between sarcopenia and clinical outcomes in melanoma up to September 2021. Overall, 6 studies including 719 patients met the inclusion criteria. The meta-analysis was performed using RevMan 5.3 software. Results: The prevalence of sarcopenia was 40.23%. Sarcopenia did not influence dose-limiting toxicity of treatment, hazard ratio (HR) 1.01, 95% CI (0.70–1.47). Sarcopenia was associated with lower progression-free survival (PFS): HR 1.49, 95% CI (0.98–2.26), and lower overall survival (OS): HR 1.67, 95% CI (1.11–2.52). Conclusions: The cumulative prevalence of sarcopenia in malignant cutaneous melanoma is 40.77%. Sarcopenia is slightly associated with PFS and OS and it is not associated with treatment toxicity.

The current data about sarcopenia in malignant cutaneous melanoma are based on small studies and, therefore, cannot apply as evident. The purpose of the present meta-analysis was to provide evident data about associations between sarcopenia and clinical outcomes in patients with advanced cutaneous melanoma treated with immunotherapy.

Data Acquisition
For the present analysis, a search in MEDLINE library, Cochrane, and SCOPUS databases was performed for studies analyzed associations between sarcopenia and relevant clinical outcomes in melanoma up to September 2021. All papers within the last 10 years were evaluated. Figure 1 demonstrates a flowchart of the data acquisition. For the data collection, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA) was used [7]. The following search criteria were used: "sarcopenia OR low skeletal muscle mass OR body composition OR skeletal muscle index AND melanoma." The primary search identified 124 items. Inclusion criteria for the present meta-analysis were as follows: − Original investigation involved human patients with cutaneous melanoma; − Estimation of pretreatment sarcopenia defined by CT images; − Treatment with immunotherapy in a palliative setting; − Reported data regarding influence of sarcopenia on relevant outcomes (hazard and/or odds ratios and 95% CI) including OS, progression-free survival (PFS), treatment toxicity; − Exclusion criteria were as follows: − Review articles and/or letters; − Case reports; − Non-English language; − Experimental studies; − Absence of statistical data about influence of sarcopenia on outcomes (hazard and/or odds ratios and 95% CI). Duplicate articles (n = 109) were removed. Furthermore, the full texts of the remaining 15 articles were checked for possible data inclusion. Overall, 6 articles met the inclusion criteria [8][9][10][11][12][13][14]. The following data were acquired for the analysis: authors, year of publication, number of patients, prevalence of sarcopenia, and statistical data about influence of sarcopenia on relevant outcomes (hazard/odds ratios and 95% CI).

Meta-Analysis
The methodological quality of the included 6 studies was checked by two observers (H.-J.M. and A.S.) using the Newcastle-Ottawa Scale (Table 2) [15]. The meta-analysis was performed by using the RevMan 5.3 software (Computer program, version 5.3. Copenhagen: The Nordic Cochrane Center, the Cochrane Collaboration, 2014) [16,17]. Heterogeneity was calculated by means of the inconsistency index I 2 . Furthermore, DerSimonian and Laird [18] random-effects models with inverse-variance weights were performed without corrections.

Discussion
This is the first analysis regarding associations between sarcopenia identified on CT and relevant outcomes in malignant cutaneous melanoma treated with immunotherapy. As shown, sarcopenia is a frequent event in melanoma patient with an approximately prevalence of 40%. This value is comparable with the frequencies reported for other malignant tumors. For example, in malignant hematological diseases, it is 39.1% [19]. In esophageal cancer, it accounts 48% [20].
Furthermore, the present analysis shows that LSMM is only slightly associated with relevant outcomes in melanoma patients treated with immunotherapy. Notably, in contrast to other malignancies, the identified heterogeneity among the studies is low or moderate according to the guidelines from the Cochrane handbook [21]. This suggests that the present results can be applied as true. Interestingly, the identified associations between LSMM and clinical outcomes in melanoma are lower than those in other frequent malignant tumors. So far, in lung cancer, sarcopenia is associated with a shorter OS, HR, 2.23; 95% CI: 1.68-2.94 [22]. Similar results were reported for gastric cancer, colorectal cancer, and pancreatic cancer [4][5][6]. This finding indicates that LSMM represents no great limitation in advanced malignant melanoma.
According to the literature, LSMM influences significantly DLT on chemotherapy [1]. For example, in breast cancer patients, sarcopenic patients had more grade 3-5 toxicity compared to nonsarcopenic patients with a risk ratio of 2.17, 95% CI (1.4-3.34) [1].   141.17) [23]. Interestingly, the influence of sarcopenia on treatment related toxicity in melanoma is very low. It may be related to the fact that in the present analysis, relationships between treatment toxicity and LSMM were analyzed in patients received immunotherapy. This finding is in agreement with a recent large meta-analysis that showed that LSMM predicted DLT in patients treated with conventional (5-fluoruracil and/or platin-based) chemotherapy and several kinase inhibitors but not in patients treated with immunotherapy [24].
The results of the present analysis indicate radiological reports should also provide information regarding body composition. The estimation of skeletal muscle mass is not complex and is a by-product of staging computer tomography.
Importantly, LSMM/sarcopenia is a potential modifiable factor [25,26]. Some previous studies showed that exercise and nutritional support program can reduce sarcopenia and improve clinical outcomes in oncologic patients [25,26].
There are some limitations of the present analysis to address. All included studies are retrospective. Furthermore, the analysis includes only studies in English language. Additionally, some studies have patient selection bias. Finally, different measurements and cut-offs for LSMM/sarcopenia were used in the studies. However, this meta-analysis is based on the largest cohort to date and provides evident data about the role of LSMM in melanoma. Clearly, large prospective studies are needed to confirm our results.
In conclusion, the cumulative prevalence of LSMM in malignant cutaneous melanoma is 40.23%. LSMM is slightly associated with PFS and OS and is not associated with treatment toxicity.

Statement of Ethics
An ethics statement is not applicable because this study is based exclusively on published literature.

Conflict of Interest Statement
The authors have no conflict of interest to declare.

Funding Sources
No funding was received.

Author Contributions
Alexey Surov: study concept and design, acquisition of data, statistical analysis, and drafting of the manuscript. Hans-Jonas Meyer: acquisition of data and critical revision. Andreas Wienke: acquisition of data and statistical analysis.

Data Availability Statement
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.