Melanoma is a type of skin cancer that arises from melanocytes. Advanced melanoma, including metastatic and unresectable cases, has consistently been one of the most lethal cancers in the world. Patients with metastatic melanoma have a 5-year survival rate of less than 16% (1). Patients with stage IV melanoma have a 6.2-month median overall survival (OS) and a 25.5% 1-year survival rate (2). Over the last several decades, the worldwide incidence of malignant melanoma has risen steadily (3). According to the American Cancer Society’s most recent epidemiological data, the number of new invasive melanoma cases detected each year has grown by 31% over the last decade (2012–2022). Besides, it is predicted that the number of melanoma mortality would rise by 6.5% in 2022 (4). The etiology of melanoma is related to the human body and environment. Ultraviolet radiation, skin phototype, pigmented nevi, pesticide usage, prolonged sun exposure and sunburn, geographical location, heredity, genetic factors, immunosuppressive conditions, and non-melanoma skin cancer are all risk factors for the occurrence of melanoma (3). Given all of that, combined with the recently developed research, the main pathogenesis of melanoma can be considered as excessive ultraviolet exposure, gene mutations (BRAF, NRAS and NF1 gene mutations) and molecular signaling pathways (MAPK pathway and PI3K pathway), etc. (3, 5–7)

Melanoma is cancer that is basically incurable. To date, several treatment options for melanoma have been developed, including surgery, chemotherapy, radiotherapy, hormone therapy, targeted therapy, etc. Cancer cells do not migrate to distant cells and tissues in the early stages of cancer, hence surgery is commonly utilized at this stage. In contrast, surgery is not recommended for advanced cancer due to its invasiveness (8–10). Adjuvant treatments such as chemotherapy, radiotherapy, hormone therapy and targeted therapy are commonly used in the treatment of advanced melanoma. In addition to these conventional therapies, mesoporous bioactive glasses (MBGs, a special class of bioactive glasses) play a role in innovative cancer treatment methodologies. Due to their outstanding stability and high drug loading capacity, MBGs are an excellent candidate for the development of advanced drug delivery systems with sustained and/or controlled drug release profiles in cancer treatment (11). Moreover, nanotechnology is a unique material with transformation potential in cancer diagnosis, screening and treatment. The application of nanotechnology enables drugs and active biomolecules to identify and target tumor cells more accurately and effectively (12). Another review discusses more research and development of tannic acid-incorporated medical applications, with cancer therapy being a particular focus of this article (13). These new advanced materials have bright prospects in the treatment of melanoma.

Nevertheless, immune checkpoint inhibitors and targeted therapies remain the most common adjuvant treatments for unresectable advanced or metastatic melanoma.The Food and Drug Administration (FDA) of the United States has authorized several novel adjuvant treatments for unresectable advanced or metastatic melanoma since 2011. For instance, kinase inhibitors (targeting mutant BRAF or MEK) inhibit driving pathways in around half of the melanoma patients (14) and immune checkpoint inhibitors (targeting CTLA-4, PD-1, or PD-L1) can kill melanoma cells. These adjuvant treatments have significantly altered the therapeutic landscape. The most often used checkpoint inhibitors are monoclonal antibodies that block the CTLA-4 (ipilimumab) and PD-1 (pembrolizumab and nivolumab) pathways (15, 16). The FDA has approved ipilimumab which can increase the overall survival (OS) rate of advanced melanoma patients, in which approximately 11% of patients have objective responses (17, 18). Similarly, pembrolizumab and nivolumab were authorized by the FDA as the first anti-PD-1 (CD279) directed monoclonal antibodies in the treatment of advanced cancers (namely advanced or metastatic melanoma). Nivolumab has been proven to increase progression-free survival (PFS) and OS in unresectable melanoma patients (19). Intriguingly, research has shown that ipilimumab combined with nivolumab had better efficiency with higher response rates and long-term OS rates than monotherapies. Unfortunately, the combination therapy possessed a high toxicity rate, making it ineffective for treating advanced melanoma (20, 21). Pembrolizumab had a 4-year OS rate of 37%, while the 3-year OS rate of ipilimumab combined with nivolumab was 58% (22, 23). It was observed that the median OS was 72.1 months for the combination of ipilimumab and nivolumab, 19.9 months for ipilimumab, and 36.9 months for nivolumab after 6.5 years of follow-up (24). Overall, ipilimumab combined with nivolumab has become a gold standard for treating metastatic melanoma. In addition, targeted therapies, including BRAF and MEK inhibitors (BRAFi/MEKi), are authorized for patients with BRAF V600-mutant melanoma. BRAFi/MEKi is beneficial for significantly prolonging OS, with dabrafenib and trametinib having 44% 3-year OS rates (25).

Despite the breakthrough advances in treating unresectable advanced or metastatic melanoma, the best course of therapy remains unclear. Interestingly, no previous similar article on patients with unresectable advanced or metastatic melanoma was found. The efficacy and side effects of these medications alone, as well as their combination usage, have not been well assessed, and further research is necessary to confirm the efficacy and safety of adjuvant treatments for advanced melanoma. Additionally, it is difficult to obtain a comprehensive and satisfactory synthesis of current scientific evidence on adjuvant treatments by traditional meta-analysis methods, owing to a paucity of head-to-head trials. Network meta-analysis (NMA) is a statistical approach that assesses numerous treatments in a single study by incorporating direct and indirect evidence from randomized controlled trials in a network of randomized controlled trials (RCT) (26, 27). Therefore, we employed an NMA technique for the major adjuvant treatments in terms of OS, PFS, and adverse events (AEs) of grade 3 or 4 and obtained the optimum adjuvant treatment for advanced melanoma.

The PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) are the basis for implementing the network meta-analysis. Details of the methodology and reporting follow the PRISMA guidelines. The PROSPERO registration number is CRD42021291959.

This meta-analysis explores the most effective and safest adjuvant treatments for unresectable advanced or metastatic melanoma, based on the drugs currently available on the market. We conducted a thorough search for qualifying RCTs, critically evaluated trial quality, meticulously synthesized trial data, and finally, classified treatments based on the efficacy and safety demonstrated in randomized clinical trials. The network method attempts to prevent the lack of direct comparison across several available options, particularly the comparison of checkpoint inhibitors to targeted therapies as well as checkpoint inhibitors Therefore, we conducted NMA to evaluate their efficacy and safety indirectly. This method yielded intriguing findings.

Our findings revealed that NIVO+IPI was superior to other therapies in terms of increasing OS and PFS in advanced melanoma patients. The combination of NIVO and IPI was considered to have complimentary benefits in the treatment of metastatic melanoma, and our findings were consistent with previous research (37). Although single-agent NIVO was ranked lower than NIVO+IPI, it might still offer more advantages in terms of OS and PFS than any other treatments. Additionally, TRAM (an investigational hot spot in targeted therapy) is a specific allosteric inhibitor of MEK1/2, and many trials with supportive preclinical evidence confirmed its efficacy in non-V600 mutant melanomas (38–40). In addition to NIVO+IPI and NIVO, TRAM appeared to be more efficacious than other treatments in improving OS, and PFS. Thus, it is reasonable to believe that NIVO+IPI, NIVO, and TRAM targeted therapies remarkably have improved OS and PFS in patients with unresectable advanced or metastatic melanoma.

Among the authorized therapy options at the time of this study, NIVO+IPI and NIVO had the longest follow-up duration. Long-term survival studies have shown a considerable improvement in OS with NIVO alone or NIVO+IPI compared to IPI alone. The median OS of NIVO+IPI was around twice as long as that of NIVO alone, showing that the combination’s survival rate was much higher than that of NIVO alone (36). Similarly, for melanoma patients with BRAF mutations, NIVO-containing regimens still outperformed IPI alone in terms of survival (21, 31, 36). Overall, the NIVO+IPI response characteristics detected in this investigation were similar to previously reported results (41, 42). Despite checkpoint inhibitors’ dominance, TRAM still improved PFS and OS among metastatic melanoma patients with BRAF V600E or V600K mutation. Therefore, TRAM may be an alternate option for BRAF wild-type or BRAF-mutated patients.

Although adjuvant treatments have offered significant benefits for advanced melanoma, they still have some limitations. Since chemotherapy cannot differentiate between cancer and healthy cell types, it will damage both (43). Similarly, high radiation doses can also damage surrounding healthy tissues. As hormone treatment alters hormone levels and function, it may cause unwanted side effects including organ dysfunction (44). In addition, the combination of BRAFi and MEKi has shown clinical effectiveness and long-term disease control in metastatic melanoma. However, there may be a drug resistance mechanism during therapy, and around 15% of patients are intolerant to treatment (45). Ipilimumab stimulates T-cell proliferation, which can result in immune-related side effects such as dermatitis, endocrinopathy, and hepatitis, as well as other side effects like pruritus, fatigue, and colitis (46–48). Our current study highlighted grade 3 and 4 AEs associated with different immune checkpoint inhibitors and targeted therapies. The NIVO group showed the lowest chance of developing grade 3/4 AEs, followed by DTIC. Most notably, NIVO+IPI had the greatest risk of grade 3 or 4 AEs. It indicates that NIVO+IPI was highly efficacious while also having a significant level of toxicity. TRAM also showed a relatively higher probability of grade 3 or 4 AEs. Another study discovered that the high toxicity of checkpoint inhibitors made the development of combination therapy problematic (49). In this study, the combination of IPI and DTIC had high toxicity, but the combination of IPI and gp100 showed a relatively lower rate of grade 3 or 4 AEs. IPI+DTIC and IPI+gp100 were more effective in improving OS/PFS over monotherapy (IPI, DTIC, IPI, gp100). Therefore, we hypothesized that IPI+gp100, rather than IPI+DTIC, appeared to be more suitable for long-term therapy in patients with advanced melanoma.

This meta-analysis investigated the optimum adjuvant treatment for advanced melanoma and provided clinical suggestions on different administration regimens. As in our research, NIVO+IPI was the most effective in extending the survival of advanced melanoma patients, although it was associated with an excessive number of AEs. As the result, NIVO+IPI treatment should be carefully considered for advanced melanoma patients with poor physical conditions. Similarly, the side effects of TRAM also limit its use. NIVO dramatically increased the survival of patients with advanced melanoma, ranked second only to NIVO+IPI. Simultaneously, across all treatment modalities, NIVO showed the lowest rate of grade 3 or 4 AEs, and its safety profile was manageable. Undoubtedly, NIVO is the best appropriate treatment in this study for patients with unresectable advanced or metastatic melanoma. This conclusion is consistent with previous research results (50). Compared with monotherapy, combination therapy was more beneficial to improve OS and PFS for advanced melanoma patients. IPI+gp100 ranked below IPI+DTIC and NIVO+IPI with concerning OS/PFS, but IPI+gp100 had a lower rate of grade 3 or 4 AEs compared to other treatments (except NIVO). More importantly, additional innovations need to be explored in the future to alleviate the toxicity associated with combination therapy.

However, this analysis has several limitations. Firstly, we were unable to obtain detailed individual patient data, which limited our ability to evaluate outcomes and patient characteristics.Secondly, we conducted our data analysis on a relatively small number of included RCTs. Thirdly, we did not analyze patients with BRAF mutation-positive tumors, because subgroup analysis could not be performed in the metadata. Fourthly, two of the trials included in this study were open-ended, which might introduce unintentional bias. Furthermore, due to the limitation of just including level 3 or 4 AES in this analysis, some outcomes might be inconsistent with reality. According to our results, NIVO had a high therapeutic effect and the lowest toxicity; nevertheless, large-scale prospective studies were necessary to provide credible evidence.

Despite all of the shortcomings described above, we can properly compare several adjuvant treatments and propose the best therapy for advanced melanoma. At the moment, single-agent NIVO is a suitable option for patients with unresectable advanced or metastatic melanoma. Longer follow-up in those adjuvant treatments, combined with further investigation of combination treatments, may improve outcomes in advanced melanoma.

In conclusion, NIVO is the best adjuvant therapy with a promising profile for patients with unresectable advanced or metastatic melanoma. This study offered evidence for the comparison among these adjuvant treatments. NIVO+IPI ranked first in efficacy but had the highest toxicity. TRAM ranked third in efficacy but had high toxicity. Combination therapy is more successful in treating unresectable advanced or metastatic melanoma, although it is associated with a higher risk of adverse events. Conversely, IPI+gp100 had a lower rate of grade 3 or 4 AEs than other treatments (except NIVO). These results might have a significant impact on the individualized therapy of patients with advanced melanoma.

However, there are several limitations to this overview. First, we may be missing some information because only SRs published in English are included. Furthermore, the sample size of this study was relatively small. Second, we could not obtain detailed data from each patient, which limited the evaluation of outcomes. Third, we were unable to conduct a subgroup analysis of BRAF mutation-positive tumors patients. Finally, the subjective assessment of the authors may affect the outcome of the quality evaluation process. In the future, for the treatment of patients with advanced melanoma, clinicians must consider the efficacy and safety of monotherapy and combination therapy, and the patients’ physical status. MBGs, nanotechnology, and tannic acid-incorporated medical applications have bright prospects in the treatment of advanced melanoma. More new schemes about adjuvant treatments are necessary to provide stronger evidence for definitive conclusions.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

MJ, Yc, JS, and XZ contributed equally to the work. MJ, Yc contributed to the initial design and drafting of the research. MJ, JS and XZ participated in the drafting process process and analyzed the data. FY evaluated the data. BZ and JZ participated in article revision. MX and MC supervised the study. All authors contributed to the article and approved the submitted version.

The study was funded by the Sichuan Provincial Administration of Traditional Chinese Medicine (Grant No. H2021076).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.