Mengyuan ZHANG ,Qiong HE ,Yuifang YU ,Baolin ZHANG,*

ABSTRACT Background It is necessary to determine the optimal treatment for melanoma as the incidence of melanoma is increasing every year.In this study,we conducted a metaanalysis to compare the effectiveness of available treatments for melanoma.Methods The index keywords“melanoma”and“treatment”were used to search the PubMed,Cochrane Library,Web of Science,and Embase databases,and the articles were limited to randomized controlled trials.The search was filtered for articles published until February 2020,and articles were independently extracted by two reviewers.Network metaanalysis (Stata? 14.0 software network package,StataCorp LLC,TX,USA) was used to compare the effectiveness of the mentioned treatments of melanoma.Results A total of 616 articles were screened of which 6 were selected for meta-analysis,involving 5 treatment measures and 2 047 patients (those who were not followed up on were excluded).The treatment strategies reported for melanoma included tumor necrosis factor (L19-TNFα) and interleukin-2 (L19IL2) in combination with dacarbazine (L19IL2 +DTIC),DTIC,programmed cell death-1 plus cytotoxic T cell antigen-4 (PD-1+CTLA-4),PD-1,and CTLA-4.Conclusion Among L19IL2+DTIC,DTIC,PD-1+CTLA-4,PD-1,and CTLA-4,CTLA-4 is found to be the best treatment method for melanoma.Our study findings provide a reference for the clinical treatment of melanoma and can clarify the direction for setting up controlled clinical trials.

KEY WORDS Melanoma treatment;Network;Meta-analysis

INTRODUCTION

Melanoma is a lethal malignant tumor,and its incidence continues to increase as the incidences of many types of tumors decline[1].However,a statistical analysis of cancer published in 2020 shows that after the US Food and Drug Administration approved new therapies for metastatic diseases,the mortality rate of cutaneous melanoma has decreased significantly.In those who are 50-64 years of age,the incidence of melanoma increased from 1% annually from 2006 to 2010,to 7% annually from 2013 to 2017.The incidence in males in the 20-49 year age group and those who are 65 years of age increased from 2% to 3%,and the increase from 5% to 6% annually in people over 65 years of age is particularly alarming.Before 2013,the incidence of melanoma in those over 65 years of age was also on the rise[2].Therefore,it is imperative to determine the best treatment for melanoma.Here,we summarized the currently available methods for the treatment of melanoma to ascertain which of them is the optimal choice.

MATERIALS AND METHODS

Literature Search

The PubMed,Cochrane Library,Web of Science,and Embase databases were searched using the keywords“melanoma”and“treatment”,and articles published after February 2020 were filtered out.

Literature Exclusion Criteria

The following exclusion criteria were applied:Ⅰ) duplicate publications;Ⅱ) secondary research articles,such as reviews or meta-analyses;Ⅲ) articles with unclear results or descriptions;Ⅳ) articles with small sample size and those with treatment plans that featured in few articles were excluded.

Literature Inclusion Criteria

Articles that met the following criteria were included:Ⅰ)research subjects:adults older than 18 years with a history of melanoma;Ⅱ) intervention measures:L19IL2 +DTIC,DTIC,PD-1+CTLA-4,PD-1,and CTLA-4;Ⅲ)outcome indicators:effectiveness of treatment,evaluation of solid tumors,and indicators achieved complete regression (CR) (all target lesions disappeared) or partial regression (PR) (the sum of the baseline lesion diameter and the diameter decreased by 30%);Ⅳ) study types:randomized controlled trials (RCTs).

Criteria for Solid Tumor Efficacy Evaluation

Solid tumor efficacy was evaluated based on the following criteria:Ⅰ) CR:all target lesions disappeared;Ⅱ) PR:≥ 30% reduction in the sum of the length and diameter of the baseline lesion;Ⅲ) stable disease:baseline lesions have a total diameter that decreased but did not reach PR or increased but did not reach progressive disease (PD);Ⅳ) PD:baseline lesions have a total increase of ≥ 20%or new lesions appear).

Quality Evaluation Standard

The included randomized controlled trials were evaluated using theCochrane Handbook for Systematic Reviews of Interventions,which included six aspects:sequence generation,allocation sequence concealment,blinding,incomplete outcome data,selective outcome reporting,and other potential risks.

Statistical Analysis

Statistical software STATA14.0 was used to analyze relative risks (RRs) and 95% confidence intervals (CIs).RRs and 95% CIs were used to estimate the effects of each treatment and to draw forest plots.The inconsistency factors (IFs) and CI were calculated to evaluate the consistency of each closed loop,and a local inconsistency test was performed.The therapeutic effects were ranked according to the surface under the cumulative ranking curve (SUCRA) value.

RESULTS

Article Information

A total of 616 articles were selected,of which 6 articles were included for the network meta-analysis.Table 1 shows the details of these articles,including the following:the first author and the year of publication,the number of patients,interventions,injection doses,effects,and adverse reactions of treatment.

Table 1 Study information

Bias Evaluation

The funnel chart shown in Fig.1 is basically symmetrical,which indicates that the small sample size and publication of the study were unlikely to affect bias.

Fig.1 Funnel chart. A:L19IL2+DTIC;B:DTIC;C:PD-1 +CTLA-4;D:PD-1;E:CTLA-4.

The red line represents the combined RR value,the two dashed lines represent the 95% CI,and the different-colored points represent a direct comparison of two different studies.

Comparison Between Groups

There were 10 different pairwise comparisons among the 5 treatments;4 of the 6 articles included were directly compared,and the remaining 2 indirect comparisons were generated by network meta-analysis.RRs and 95% CIs of each comparison are listed in Table 2.

Comparison of Effects

The effects of the treatments were ranked based on SUCRA values (Fig.2).The therapeutic effects according to the SUCRA value were ranked from high to low:CTLA-4,L19IL2+DTIC,PD-1,PD-1+CTLA-4,and DTIC.

DISCUSSION

Dacarbazine is a cell cycle phase non-specific antitumor calculating agent that is widely used as a consensus drug for the treatment of metastatic malignant melanoma[9].High-dose interleukin-2 (IL-2) in a small fraction of patients has shown the ability to induce remission of metastatic melanoma.Studies have shown that one strat-egy to increase the therapeutic index of IL-2 is to fuse with antibodies so that IL-2 can be selectively localized to the disease site.L19IL2 is a polysaccharide form of the L19 antibody fused to human IL-2;L19 specifically recognizes the alternative splicing extra domain B domain of fibronectin,which has been shown to selectively localize in mouse tumor models.In solid tumors,it can significantly increase the density and activity of white blood cells in the diseased area and,combined with IL-2,can achieve targeted localization and treatment of disease[3].programmed death-1/programmed death receptor ligand-1 (PD-1/PD-L1) immunotherapy is a recently developed treatment currently attracting much attention.Anti-cancer immunotherapy that incorporates blocking the PD-1/ PD-L1 signaling pathway can cause cancer cells to lose their protective outer membrane,thereby enhancing the clearance effect of lymphocytes on cancer cells.PD-1/ PD-L1 is an immune epidemic therapy that offers the opportunity to treat many types of tumors and is expected to substantially improve the overall survival of patients.Representative PD-1 antibodies are involved,and CTLA-4 can affect the immune system and weaken its ability to shoot cancer cells.Ipilimumab is a monoclonal antibody that effectively blocks the effects of CTLA-4[8].

Table 2 RRs and 95% CI of each comparison

Fig.2 SUCRA values,expressed as percentages,ranking the therapeutic effects and safety of treatments for melanoma

The statistical analysis of cancer published in 2020 shows that after the US Food and Drug Administration approved a new therapy for metastatic disease-protease inhibitors,the mortality rate of cutaneous melanoma has declined significantly.This article summarizes the clinical trialtype articles published by the Cochrane Library,Embase,Web of Science,and PubMed databases on clinical trials of protease inhibitor therapy.The article information is presented in Table 3.

Table 3 Article information of Protease inhibitor

Studies have demonstrated that in melanoma,the probability of mutations in the mitogen-activated protein kinase (MAPK) pathway is greater than 80%,and the mitogen-activated protein kinase/extracellular regulated protein kinase (MAPK/ERK) pathway is mainly composed of protein kinases,such as rat sarcoma (RAS),rapidly accelerated fibrosarcoma (RAF),MEK,and ERK.By catalyzing the occurrence of lower-level protein kinases,the entire signaling pathway is generated.ERK can affect factors such as microphthalmia-associated transcription factors in the cell cycle and cause cells to overgrow,resulting in the transformation of normal cells into tumor cells[10].At the same time,some studies have shown that in melanoma tissues,even without RAS and BRAF gene mutations,ERK protein continues to be activated;inhibiting ERK protein activity can inhibit the malignant growth and proliferation of melanoma cells[11-12].Therefore,the MAPK pathway is a hotspot in the development of targeted melanoma drugs,especially BRAF and MEK inhibitors.Emulsified dabrafenib and encorafenib are types of typical BRAF transplants;the new generation of MEK inhibitors,trametinib,cobimetinib,and binimetinib,have shown significant clinical activity against BRAF-mutated melanoma.

As shown in Table 2,only a few studies have compared traditional melanoma treatment drugs (dacarbazine) and protease inhibitors.Studies have shown that the combined effect of protease inhibitors and dacarbazine is better than that of dacarbazine alone,the combined use of BRAF inhibitors and MEK inhibitors is superior to the use of BRAF inhibitors alone,and treatment with BRAF inhibitors combined with CP is also superior to the use of CP alone to treat melanoma.Due to the limited number of published experimental articles and our study not meeting the standards for statistical data analysis,we summarized the articles as a reference for more articles that can be analyzed in future studies in order to better treat melanoma.

Ethics Approval and Consent to Participate

Not applicable.

Consent for Publication

All the authors have consented to the publication of this article.

Competing Interests

The authors declare that they have no competing interests.The authors state that the views expressed in the article are their own and not the official position of the institution or funder.