Novel treatment vs. standard of care in melanoma-associated leptomeningeal metastases: a systematic review and network meta-analysis

Introduction

Background

Leptomeningeal disease (LMD), otherwise referred to as “carcinomatosis meningitis”, “neoplastic meningitis”, “leptomeninges carcinomatosis” and “leptomeningeal metastases” (1,2), stems from the rampant dissemination of cancer to the leptomeninges- consisting of the arachnoid and pia mater; and the subarachnoid space (2). It often occurs in conjunction with brain metastases (3), and it is considered a grave pathology with a devastatingly poor prognosis, ranging between two to four months despite aggressive interventions (1,2). Among the predominant aetiologies of LMD are lung cancer, breast cancer, malignant melanoma, non-Hodgkin lymphoma and acute lymphocytic leukaemia, with melanoma being the third most common cause (1-5).

Melanoma is categorised as the 17th most common cancer in the world by the World Health Organization (WHO) (6), and a recent global cancer epidemiological assessment stated that in 2020, there were 325,000 new cases with 57,000 deaths (7). The melanoma burden is estimated to rise to 510,000 new cases with 96,000 deaths by 2040 due to advancements in medical interventions in the management of systemic disease leading to improved prognosis (1,4,7). A recently conducted study indicated that the incidence of up to about 30% of melanoma LMD often goes undiagnosed until gross and microscopic inspection upon autopsy (4). LMD can be diagnosed with either MRI imaging or cerebrospinal fluid (CSF) analysis (8). This disease has been delineated into two radiological categories: classical LMD (cLMD) and nodular LMD (nLMD) (8,9). In the classical subtype, LMD appears more diffused in the leptomeninges with a “sugar-coating” characteristic (10), while nodular LMD presents with more focal-enhanced lesions (9).

Rationale and knowledge gap

While the therapeutic measures for melanoma LMD have been evolving with multiple ongoing trials involving novel treatments and different delivery approaches, the prognosis continues to be grim.

Objective

We performed a network meta-analysis of immunotherapy + targeted therapy, immunotherapy, intrathecal (IT) therapy, targeted therapy, radiotherapy, systemic therapy and systemic therapy + radiotherapy. This study aims to analyse and compare the different types of treatment arms and their efficacy on patients’ overall survival (OS). We present this article in accordance with the PRISMA-NMA reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-24-104/rc).

Methods

Search strategy

Five electronic databases including PubMed/Medline (National Library of Medicine), EMBASE (Elsevier), ScienceDirect (Elsevier), SCOPUS (Elsevier) and Web of Science were searched for studies published between January 2014 and September 2024. The stated search strategy was used in our study “Carcinomatosis Meningitis” OR “Neoplastic Meningitis” OR “Leptomeningeal Carcinomatoses” OR “Leptomeningeal Metastasis” OR “Leptomeningeal Spread” AND “Melanoma”. The protocol for this study was registered on PROSPERO (CRD42024529626).

Study selection

After sourcing for existing studies in the respective databases, the studies were then imported to Zotero and duplicates were removed. Two reviewers independently assessed the articles via screening of titles and abstracts, then proceeded with reviewing the full-text articles. A third reviewer conducted a cross-check to resolve any disagreements. The inclusion criteria of this study consist of articles published in English, observational clinical studies (cohort, case-control), randomised control trials, quasi-experimental design studies, clinical trials, and experimental studies that focus on LMD caused by metastatic melanoma. We excluded non-human studies, studies with irrelevant outcomes, studies where full-text were unretrievable, non-peer-reviewed sources, such as editorials, commentaries, letters, pre-proofed articles, articles published ahead of print, case reports, opinion pieces, conference papers, book chapters, systematic reviews and meta-analyses.

Outcomes

Our study assessed primary and secondary outcomes: primary outcomes include OS, progression-free survival (PFS) and adverse effects directly caused by therapeutic interventions, and secondary outcomes include performance status (PS) [assessed by Eastern Cooperative Oncology Group (ECOG)/Karnofsky Performance Score/WHO Performance Status], patient comfort (PC) and quality of life (QoL).

Data extraction & quality assessment

All required data were extracted by two independent reviewers, and a third reviewer was present to review and resolve any disagreements. For quality assessment, the grading of evidence was individually and independently assessed using the GRADE method by two reviewers, followed by a cross-check by a third reviewer. The studies were initially graded based on the study type and were assessed according to their limitations, inconsistencies, indirectness, imprecision, and risks of bias (11-13).

Statistical analysis

We constructed a network of evidence using a frequentist framework. Pairwise meta-analyses were performed using a random-effects model to estimate direct treatment effects. Subsequently, we extended the pairwise meta-analyses to network meta-analyses to estimate the relative effectiveness of all interventions. We used a frequentist random-effects model to synthesise the available evidence, which estimates the between-study heterogeneity using the moment-based method described by Jackson and White. The network estimates were presented as differences in log hazard ratio (HR). We adopted P-score (14) and SUCRA (15) methods for ranking of treatment. We decomposed Cochrane’s Q statistic to assess heterogeneity, and the inconsistency between direct and indirect evidence within each network estimate was evaluated using the SIDE method and visual inspection of the net heat plot.

Sensitivity analysis was conducted with fixed-effect models to assess the robustness of the results to the model assumptions. Publication bias was evaluated through visual inspection of comparison-adjusted funnel plots and with Egger’s test for small-study effects.

All statistical analyses were performed using R software v4.2.2 with Netmeta package v2.9.0 using default parameters.

Results

Search results, study selection & characteristics

In the initial search of literature, a sum of 973 articles was identified and exported to Zotero. Upon removal of duplicates, 843 titles and abstracts were screened, 67 full-text articles were assessed for eligibility and finally, 7 studies were included. The studies consisted of 4 retrospective cohort studies (16-19), 2 observational cohort studies (20,21) and 1 clinical trial (22). Figure 1 shows the procedure of the study selection. All seven studies (100%) assessed OS, two studies (29%) evaluated PFS, and three (43%) documented adverse events. Six out of seven studies (86%) included the PS of patients, with 4 studies (67%) assessed using ECOG, 1 (17%) Karnofsky and 1 (17%) WHO. Although we included PC and QoL as secondary outcomes, none of the selected studies evaluated these parameters.

Figure 1 PRISMA 2020 flow diagram.

Method assessment of included studies

Six out of seven studies (86%) analysed the efficacy of treatment interventions using the HR of OS (95% confidence interval). The quality of included studies ranges from low to very low, and the risks of bias range from moderate to serious. A more detailed description of the selected studies can be found in Table 1.

Overall comparison of the effect of interventions

The network of eligible comparisons for the primary outcome consisted of 7 interventions (including standard-of-care systemic therapy + radiotherapy) and formed an almost fully connected network. The network plot is presented in Figure 2, illustrating the direct comparisons between interventions along with the number of trials contributing to each comparison.

Figure 2 Network graph of network meta-analysis. The labels/nodes correspond to the interventions. The thickness of the edge shows the number of trials, and the shaded triangle represents a multi-arm study.

The results of the network meta-analysis using systemic therapy/chemotherapy, radiotherapy, or systemic therapy + radiotherapy as a reference for the primary outcome-HR of OS are summarised in Figure 3 and Table 1. Immunotherapy + targeted therapy was found to be most effective (logHR =−2.52, 95% CI: −4.21 to −0.83) when compared against the standard of care-systemic therapy + radiotherapy, reaching a high statistical significance (P=0.003). Immunotherapy alone showed a trend towards improved outcomes (logHR =−2.03, 95% CI: −3.54 to −0.51) and achieved statistical significance (P=0.009).

Figure 3 Forest plot of results from network meta-analyses using random effects model. The effect shown is the log hazard ratio of overall survival with its 95% confidence interval (CI) for different interventions, using systemic therapy (top), radiotherapy (middle), or systemic therapy + radiotherapy (bottom) as reference.

We conducted treatment ranking analysis using SUCRA (15) and rankogram (Figure 4). The results similarly showed that immunotherapy with or without targeted therapy is the most effective treatment. The league table presenting all possible pairwise comparisons is provided as Figure S1.

Figure 4 Ranking of treatment. (A) Surface under the cumulative ranking curve (SUCRA) plot. (B) Rankogram.

Heterogeneity was minimal across the network (I²=13.4%; Figure 3). The global test for inconsistency was not statistically significant (P=0.33; Figure 3), suggesting no major inconsistency between direct and indirect evidence within the network. Results from the net splitting approach, which provides pairwise estimates of inconsistency for each direct comparison, are reported in Figure 5A and Table S1. The net heat plot (Figure 5B) also corroborates the same conclusion as the net splitting approach, which shows that there is no significant inconsistency in our network model.

Figure 5 Assessment of heterogeneity and inconsistency. (A) Direct and indirect evidence of treatment comparisons. The bar plot shows the proportion of direct evidence (orange) with respect to indirect evidence (blue) for each pairwise estimate. Minimal parallelism and mean path length metrics are given on the right of the bar plot. Mean path length >2 indicates results derived only from indirect evidence and should be interpreted with caution. (B) Net heat plot of network meta-analysis designs. The size of the grey box indicates the importance of a treatment design (direct estimate) in deriving another treatment comparison (network estimate). Background colour indicates the amount of inconsistency of a design (cool color indicates increase; warm color indicates decrease).

The fixed-effect model sensitivity analysis was consistent with the main random-effects analysis results (Table S2).

Comparison-adjusted funnel plots did not indicate the presence of publication bias for the primary outcome (Figure 6). Egger’s test supported this finding, with no evidence of small-study effects (P=0.57).

Figure 6 Comparison-adjusted funnel plot. There is no asymmetrical distribution of studies. P value was assessed by Egger’s test.

Discussion

This systematic review and meta-analysis provide a comprehensive comparison of various therapies for melanoma-associated LMD, a condition characterised by poor prognosis. The results from our study provide valuable insight into the relative efficacy of these treatments and have considerable implications for the clinical management of melanoma-associated LMD and its future research. Furthermore, this study highlights the adverse effects of treatments and indicates the lack of research into the quality of life of individuals suffering from melanoma-associated LMD. Primarily, grasping the sophistication of how melanoma invades the brain is a crucial factor in determining therapeutic strategies. According to Braeuer et al., melanoma when compared to other types of metastatic cancers, not only has a remarkable capability to bypass the host’s defensive mechanisms but also uses the body’s own microenvironment to encourage the proliferation of tumour cells due to its enhanced mutagenic tendency (23,24).

Metastatic melanoma contains specific cell adhesion molecules (MCAM/MUC18) due to accumulated mutations, allowing the tumour cells to resist the turbulent vascular flow, leak out of vessels and eventually adhere to other organs, including the brain. Utilising the same process, the tumour cells invade the leptomeninges by seeping into the vascular system of the arachnoid and pia mater, ultimately extravasating out of the vessels and into the subarachnoid space where they metastasise through the CSF (24). Vascular supply is needed for melanoma to continue proliferating and this is achieved by angiogenesis expressed by inflammatory molecules such as metalloproteinase (MMP-2), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF) and many more (24,25).

Another crucial marker in determining the impact of the therapeutic landscape of melanoma LMD is the BRAF gene. Including BRAF kinase inhibitors such as vemurafenib and dabrafenib to the treatment regimen of the majority of BRAF-mutant patients greatly transforms the approach of treating melanoma LMD. Although there are many studies showing that BRAF kinase inhibitors achieve a high rate of tumour response in melanoma brain metastases (MBM), more extensive research is needed for assessment in patients with BRAF-mutated melanoma LMD as there is limited evidence of their efficacy and it still remains uncertain if these inhibitors achieve therapeutic concentrations in the CSF (24). Apart from BRAF kinase inhibitors, a new MEK1 inhibitor, E6201, has demonstrated effectiveness in treating brain metastases in patients with BRAF V600E and CTNNB1 mutations (26). While the combination of BRAF and MEK inhibitors shows promise in BRAFV600-mutated MBM, their efficacy in LMD is less established and warrants further investigation (26).

OS

The OS for melanoma patients with LMD remains poor across the studies, but certain treatments such as targeted therapy, immunotherapy, and radiotherapy have shown the potential to extend life expectancy. Geukes Foppen et al. demonstrated the median OS for treated patients was 16.9 weeks compared to 2.9 weeks for untreated patients (17). Similarly, the study by Glitza Oliva et al. demonstrated a median OS of 4.9 months for treated individuals (22), whereas Ferguson et al. also showed an OS of 0.7 months for untreated patients compared to an OS of 4.4 months for individuals treated with any therapy (16).

Our NMA indicated that immunotherapy combined with targeted therapy showed the most substantial improvement in OS, with a logarithmic HR (logHR =−2.52, 95% CI: −4.21 to −0.83) compared to the standard of care (systemic therapy and radiotherapy), and had a statistical significance of P=0.003. Immunotherapy alone also exhibited a trend towards improved outcomes (logHR =−2.03, 95% CI: −3.54 to −0.51), with a statistical significance of P=0.009. Given this observed trend, clinicians should consider immunotherapy as the first port of call for melanoma-associated LMD with the potential to include targeted therapy in the regimen.

A possible explanation for the efficacy of immunotherapy, especially programmed death-1 (PD-1) inhibitors, could be due to the distinct tumour microenvironment in LMD. The immune-privileged leptomeninges with lower baseline immune activity might lead to more exhausted T cells and higher PD-1 expression in LMD, as described by Smalley et al. (21). Hence, therapies targeting PD-1/PDL-1 checkpoints may provide greater survival outcomes. Supporting these findings, a study by Chu et al. highlighted the efficacy of PD-1 monoclonal antibodies in extending survival for patients with leptomeningeal metastasis from various solid tumours (27). Similarly, the study by Larkin et al. showed that combined nivolumab and ipilimumab treatment resulted in significant long-term survival benefits in advanced melanoma (28). However, the evidence for PD-1/PDL-1 inhibitors remains scarce and larger studies are required to look at these checkpoint proteins, the disease microenvironment, and mechanisms for resistance to immunotherapy in the context of melanoma-associated LMD.

The emerging evidence supporting the efficacy of immunotherapy and targeted therapy combinations should be considered for inclusion in clinical guidelines for the treatment of melanoma-associated LMD. This would help standardise care and improve outcomes across different clinical settings, as well as make it easier to produce homogenous research findings. The development of novel therapeutic agents, including next-generation immune checkpoint inhibitors and targeted therapies, holds promise for further improving outcomes for patients with melanoma-associated LMD. These agents should be evaluated in the context of combination regimens.

PFS

PFS was reported in only two studies: Tétu et al. and Le Rhun et al. (19,20). Both studies indicated PFS of roughly two months, but the heterogeneity of treatment approaches within the two studies makes it difficult to extrapolate the true PFS rate associated with individual treatments. The PFS data indicated significant variability in patient responses to different treatments, highlighting the need for personalised medicine. Molecular profiling of tumours and patient-specific characteristics should guide the selection of therapeutic strategies to optimise outcomes.

Additional studies, such as those by Sherman et al. (29) and Steininger et al. (30), have also demonstrated that systemic therapies, particularly those involving immunotherapy, offer significant benefits in controlling disease progression in melanoma-associated LMD. Moreover, Chu et al. (27) demonstrated that first-line PD-1 monoclonal antibody treatment in patients with leptomeningeal metastasis from solid tumours significantly extended PFS. Senko et al. (31) also highlighted the importance of molecular drivers in determining the efficacy of systemic therapies for central nervous system metastases, including LMD. Their findings suggest that personalised treatment approaches targeting specific molecular pathways can enhance PFS in melanoma patients.

Some of the studies included “super-responders”. For example, Geukes Foppen et al. reported a patient alive at 235 weeks after diagnosis, treated with whole brain radiation therapy (WBRT) and ipilimumab (17). Whereas, Smalley et al. had a patient alive at 165 weeks after diagnosis, treated with dabrafenib/trametinib until 26 months (102 weeks) and then started on nivolumab monotherapy and binimetinib-encorafenib (21). This is the only super-responder whose CSF sample was analysed post-PD-1-therapy and it showed an immune profile similar to that of a non-cancerous patient (21). Contrastingly, an individual with poor survival after PD-1 therapy demonstrated minimal T cell response compared to a significant increase in T cell proliferation and activation in the super-responder (21). Tétu et al. also reported five individuals with OS >45 months, all alive, treated with various combinations of nivolumab, ipilimumab, stereotactic radiosurgery, and WBRT (20). These findings demonstrate the importance of further research into molecular pathways of the disease and the need for personalised therapy in the future.

Adverse effects

Adverse effects were reported in two out of the seven included studies. The study by Glitza Oliva et al. documented adverse effects associated with IT nivolumab and combined IT & intravenous (IV) nivolumab (22). These included gastrointestinal symptoms, dermatological manifestations, haematological abnormalities, and various other systemic and local reactions. Similarly, the study by Tétu et al. reported radiation necrosis and immune-related toxicities, including eosinophilic fasciitis-like toxicity and pulmonary toxicity (20). Much like this systematic review, the data for efficacy as well as side effects of radiation therapy remain limited and heterogeneous within the literature for LMD (32).

In the study by Glitza Oliva et al., common adverse effects of IT nivolumab were primarily mild (Grade 1), such as nausea, vomiting, dizziness, pruritus, and anorexia. There were fewer Grade 2 events, including transient aphasia and neck pain. For the combination of IT & IV Nivolumab, adverse effects were more varied and included mild to moderate (Grade 1/2) symptoms like nausea, diarrhoea, decreased lymphocyte count, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, headache, maculopapular rash, arthralgia, pruritus, and fatigue. More severe adverse effects (Grade 3) were also reported, including significant lymphocyte count decrease, vomiting, increased ALT levels, headache, and fatigue (22). This might suggest that while IT administration is generally safer, adding IV administration increases the systemic impact and the risk of more severe adverse effects (22). The study by Tétu et al. highlighted severe toxicities such as radiation necrosis and immune-related toxicities, including Grade 4 eosinophilic fasciitis-like toxicity and Grade 3 pulmonary toxicity (20). These were primarily in patients treated with Nivolumab and Ipilimumab (20).

A comparison of the most common adverse effects reported by Glitza Oliva et al., Larkin et al., and Weber et al. shows significant overlap. These common adverse effects include nausea, vomiting, diarrhoea, fatigue, pruritus, maculopapular rash, headache, arthralgia, and elevated transaminases (22,28,33). This consistency across studies suggests these are key adverse effects clinicians should monitor in patients receiving these treatments. It is also important to note that a phase I/II study has also shown good safety and efficacy with Nivolumab for Ipilimumab refractory patients (33).

Additional studies on adverse effects of similar therapies, although not tested specifically in the setting of LMD but instead in advanced melanoma, can provide further insights. For instance, CheckMate 067, a trial involving nivolumab and ipilimumab in melanoma, reported adverse effects such as fatigue, diarrhoea, rash, and endocrine disorders (34). These were twice as likely in dual therapy of nivolumab and ipilimumab, compared to monotherapy with either of the two drugs (34). Another study on pembrolizumab in melanoma patients noted common adverse effects including fatigue, pruritus, and diarrhoea, which were at a lower rate compared to ipilimumab (35).

PS

PS is a crucial factor in determining the prognosis and treatment outcomes for patients with melanoma-associated LMD. For instance, evaluation of the Karnofsky Performance Status (KPS) scale is crucial in excluding patients from undergoing intensive treatment modalities such as radiation therapy. A study by Nguyen et al. showed that a KPS scale of less than 60 indicates that patients are unlikely to respond to treatment and should be eliminated from these radical interventions (24). Out of our selected studies, four studies utilised the ECOG scale (16,18,20,22), one used the KPS scale (19), one used the WHO scale (17), and one study did not measure PS (21).

The studies using the ECOG scale as performance indicators homogenously reported that patients with lower scores (0–1) showed better survival rates and treatment tolerance compared to those with higher ECOG scores (16,18,20,22). Patients with lower ECOG scores (better PS) demonstrated a more favourable response to immunotherapy, targeted therapies, and radiotherapy (16,18,20). Similarly, Le Rhun et al. utilised the KPS scale which showed that higher scores (better PS) had significantly better survival and disease control compared to those with lower scores (below 80) (19). Moreover, Geukes Foppen et al. which utilised the WHO scale as a performance marker also showed that lower scores (0–1) (better PS) benefited the most from targeted therapies and immunotherapy, showing improved OS and PFS (17).

The reviewed studies consistently show that better baseline PS and functional capacity, whether assessed by the ECOG, Karnofsky, or WHO scale, is associated with improved survival rates, better disease control, and enhanced quality of life for patients with melanoma-associated LMD. Further supporting these findings, research by Fidler et al. found that patients with better PS had improved outcomes with various treatments for metastatic melanoma, including immunotherapy and targeted therapy (36). This underscores the necessity of assessing PS in clinical practice to tailor treatment strategies effectively and optimise patient outcomes.

Patient comfort and quality of life

None of the studies selected in our analysis discussed quality of life or patient comfort, highlighting the gap in the current literature. Although improving survival and quantity of life remains the primary focus of oncological research, it is essential to look at the quality of life as well. Studies focusing on other cancers have demonstrated that treatments can have substantial impacts on quality of life. For instance, research has shown that patients receiving immunotherapy for melanoma experience varying degrees of fatigue, gastrointestinal symptoms, and dermatological reactions, all of which can affect daily functioning and overall well-being (16,20,28,33-35). In the context of melanoma-associated LMD, considering the aggressive nature of the disease and the intensive treatments required, it is imperative that future research includes robust assessments of patient comfort and quality of life. These aspects should be evaluated using validated instruments such as the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) or the Functional Assessment of Cancer Therapy (FACT) scales, which have been widely used in oncology studies to measure various dimensions of quality of life, including physical, emotional, and social well-being (37,38). Addressing these outcomes could provide a more comprehensive understanding of the patient experience and guide the development of supportive care strategies to improve the overall management of melanoma-associated LMD.

Limitations

The study has several limitations that should be considered. Firstly, the included 7 studies varied in design, encompassing 2 observational cohort studies, 4 retrospective cohort studies, and 1 clinical trial. The nature of these studies may have initially resulted in low-quality evidence, and the absence of randomised controlled trials (RCTs) may limit the strength of the conclusions drawn from the study. Additionally, the small number of studies meeting the specific inclusion criteria and the relatively limited sample size of the included studies (397 patients) may limit the generalizability of the results. However, the results from Egger’s test did not indicate any bias from small study samples, suggesting that the data obtained was not influenced by publication bias, although, the study’s reliance on non-RCTs and the potential impact on data quality should be acknowledged. It is also important to note that the effectiveness of the interventions may be influenced by various factors such as patient characteristics, disease stage, and treatment regimens, and the drastically varying times at which LMD was diagnosed in each patient which were not consistently reported across all included studies. These factors should be carefully considered when interpreting the results and drawing conclusions from this systematic review and network meta-analysis. Despite assessing primary and secondary outcomes, the study encountered limitations related to the lack of evaluation of progression-free survival as one of the primary outcomes, as reported in two studies only (19,20). The absence of an evaluation of patient comfort and quality of life as secondary outcomes in all the selected studies highlights the need for more comprehensive and patient-centred research in melanoma-associated leptomeningeal metastases. In addition, out of the 7 studies, only 2 studies (21,22) have reported adverse effects as a result of the treatment interventions.

Moreover, four studies solely reported the ECOG values (16,18,20,22), one study (19) reported the Karnofsky values, and one study (17) reported the WHO values. Thus, due to the use of different scales to assess PS, it was difficult for us to coherently analyse the PS as one of the secondary outcomes across all studies and make proper comparisons. The study revealed minimal heterogeneity and no statistically significant inconsistency between direct and indirect evidence within the network. However, it is crucial to recognise potential limitations related to the quality and consistency of the included studies, emphasising the need for future research to prioritise high-quality, consistent, and comprehensive data to ensure robust and reliable findings.

Conclusions

This systematic review and network meta-analysis observed that immunotherapy + targeted therapy was the most effective treatment intervention in patients with melanoma-associated LMD, followed closely by the utilisation of immunotherapy alone when compared to the standard of care. The lack of higher-quality studies necessitates further large-scale studies to confirm its validity.

Acknowledgments

This topic of study has been presented in the form of a poster presentation at the 19th Asian Society for Neuro-Oncology Annual Meeting 2024 in Singapore.

Footnote

Reporting Checklist: The authors have completed the PRISMA-NMA reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-24-104/rc

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-104/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-104/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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