Treatment delays due to the COVID-19 pandemic in uveal melanoma (UM) patients have led to an increased rate of enucleations in Europe. The impact of multiple COVID-19 lockdowns on UM management has not been assessed in France. The goal of this study was to assess whether delayed diagnosis could have led to more advanced stages and thus a higher rate of enucleations.

Two datasets were analyzed: patients from two ocular oncology centers (dataset-1), with recording of sizes, prognostic stages (TNM) and treatments, and a national database (dataset-2), obtained by ICD-10 codes and medical procedures for clip placement. After year-by-year comparison, the pre-COVID-19 (2018–2019) and post-COVID-19 (2021–2022) periods were compared for each dataset. Five hundred and thirty-seven patients were diagnosed with UM (dataset-1), including 213 patients in the pre-COVID-19 period and 212 patients in the post-COVID-19 period. Similarly, 2187 patients were diagnosed with UM (dataset-2), of whom 914 patients and 864 patients were diagnosed in the pre-COVID-19 and post-COVID-19 periods, respectively.

A higher number of patients had locally advanced tumors during the post-COVID-19 period compared to the pre-COVID-19 period (cT1=66, cT2=64, cT3=66 and cT4=21 vs. cT1=59, cT2=82, cT3=65 and cT4=7, P
                     =0.03), but without difference in ciliary body involvement, extraocular extension or AJCC stage (dataset-1). Treatments were similar between the pre-COVID-19 and post-COVID-19 periods in dataset-1 (P
                     =0.36) and dataset-2 (P
                     =0.47), with a higher ratio of proton beam therapy to primary enucleation in 2020 than in the pre-COVID-19 and post-COVID-19 periods (21.4 vs. 8.6 and 6.3, P
                     =0.02).

The COVID-19 pandemic did not impact the ophthalmological management of UM patients in France, but more locally advanced stages were observed upon initial presentation during the post-COVID-19 period.

Les retards de traitement dus au COVID-19 chez les patients atteints de mélanome uvéal (MU) ont entraîné une augmentation du taux d’énucléations en Europe. L’impact des multiples confinements liés au COVID-19 sur la prise en charge du MU n’a pas été évalué en France. Le but de cette étude était d’évaluer si des diagnostics tardifs ont pu conduire à des stades plus avancés et donc à un taux d’énucléations plus élevé.

Deux ensembles de données ont été analysés : les patients de deux centres d’oncologie oculaire (données-1), avec la collecte des tailles, de stades pronostiques (TNM) et des traitements, et une base de données nationale (données-2), obtenue par codes CIM-10 et actes médicaux pour la pose de clips. Après comparaison année par année, les périodes pré-COVID-19 (2018–2019) et post-COVID-19 (2021–2022) ont été comparées pour chaque ensemble de données. Cinq cent trente-sept patients ont été diagnostiqués pour un MU (données-1) dont 213 patients pendant la période pré-COVID-19 et 212 patients pendant la période post-COVID-19. De même, 2187 patients ont été diagnostiqués pour un MU (données-2), dont 914 patients et 864 patients ont été diagnostiqués respectivement pendant les périodes pré-COVID-19 et post-COVID-19.

Il y avait plus de patients avec des tumeurs localement avancées en période post-COVID-19 qu’en période pré-COVID-19 (cT1=66, cT2=64, cT3=66 et cT4=21 vs. cT1=59, cT2=82, cT3=65 et cT4=7, p
                     =0,03), mais sans différence sur l’atteinte du corps ciliaire, l’extension extraoculaire ou le stade AJCC (données-1). Les traitements étaient similaires entre les périodes pré-COVID-19 et post-COVID-19 dans les données-1 (p
                     =0,36) et les données-2 (p
                     =0,47) avec un ratio de protonthérapie par énucléation primaire plus important en 2020 que durant les périodes pré-COVID-19 et post-COVID-19 (21,4 vs 8,6 et 6,3, p
                     =0,02).

La pandémie de COVID-19 n’a pas impacté la prise en charge ophtalmologique du MU en France, mais des stades localement plus avancés ont été observés au diagnostic en post-COVID-19.

# Introduction

The COVID-19 pandemic has had a major impact on national healthcare due to limited access to care. In France, the pandemic has required a rapid in-depth reorganization of the healthcare system, and its impact on chronic disease management is currently being assessed (NCT05013047). One of the main effects of the pandemic has been to delay medical care, particularly cancer treatment [1,2].

In ocular oncology, several studies have reported an impact on cancer management. The multiple COVID-19 lockdowns, especially in 2020, have led to significant delays and interruptions in the treatment of children with retinoblastoma in India [3]. In uveal melanoma, increased tumor thickness and diameter have been observed during the pandemic, leading to a reduction in the use of conservative treatments and an increase in the rate of enucleations [4–8]. However, the impact of the pandemic on the management of ocular malignant tumors in France is unknown. As in other countries, such as the United Kingdom, patients with suspected intraocular or ocular surface malignant tumors are referred by ophthalmologists to specialized centers (Paris, Nice, Lyon). About 460 new cases of uveal melanoma are diagnosed every year in France, with a stable incidence [9]. Most uveal melanomas are treated with proton beam therapy (PBT), while larger tumors (>10-mm thickness or >20-mm diameter) require primary enucleation. The aim of our study was to analyze the size, stage, and treatment modalities of uveal melanoma (excluding iris melanoma) in patients who consulted 2years before (2018–2019) and after 2020 (2021–2022), to investigate whether delaying care led to later diagnoses when all healthcare facilities were reopened.

# Methods

This retrospective study was conducted in accordance with the tenets of the Declaration of Helsinki and has been approved by the Ethics Committee of the French Society of Ophthalmology (IRB 00008855). Data were collected from two datasets: from two ocular oncology centers (Nice University Hospital Centre and Lyon Civil Hospices) and from a national database. Patient treated for iris melanoma were excluded from all analyses. Two calendar years before (2018/2019) and after pandemics (2021/2022) were studied to limit sampling fluctuation bias and increase the statistical power of the study.

## Retrospective analysis of the data of patients from two ocular oncology centers

In the two ocular oncology centers, data on patients’ age, gender, tumor thickness, tumor largest basal diameter, allowing clinical TNM staging (AJCC 8th edition) [10], pathological staging (when available) and treatment modalities used for uveal melanoma were collected from January 2018 to December 2022. A diagnosis of uveal melanoma was made based on French guidelines [11], clinical features and findings from a dilated slit-lamp fundus examination and multimodal imaging consisting of color fundus photography, optical coherence tomography, B-scan ultrasonography followed by expert consensus from ocular oncology specialists at a multidisciplinary team meeting before making treatment decisions (PBT or primary enucleation). Patients were then classified according to the year of surgery (clip placement or enucleation).

## Retrospective analysis from a French national database

Data from the French national PMSI (Programme de Médicalisation des Systèmes d’Information) database collected between January 2018 and December 2022 were analyzed. The PMSI allows synthetically and standardizedly describing the medical activity of French healthcare facilities since the law of July 31, 1991. Since then, both public and private healthcare facilities must provide data on their medical and surgical activities to the French Health Authorities. Thereby, all diagnoses are coded according to the 10th edition of the International Classification of Diseases (ICD-10) and all the medical acts performed are coded using the Common Classification of Medical Acts (CCAM for Classification Commune des Actes Médicaux). The PMSI database is fully anonymized according to the recommendations of the French Commission Nationale de l’Informatique et des Libertés (CNIL). The CCAM codes for tantalum marker placement with ICD-10 codes of uveal melanoma were used in this study (Supplementary Table 1).

## Analyses

The data of patients managed in the two ocular oncology centers and from the PMSI database were first compared according to the year (from 2018 to 2022) and then between two periods: the pre-COVID-19 period (2018/2019) and the post-COVID-19 period (2021/2022). Numerical variables are presented as a mean (±SD) and discrete outcomes as absolute and relative (%) frequencies. Normality and heteroskedasticity of continuous data were assessed using a Shapiro-Wilk test and a Levene's test, respectively. Continuous outcomes were compared using a Kruskal-Wallis's test according to data distribution. Discrete outcomes were compared using a Chi-squared or Fisher's exact test accordingly. Finally, a multivariate logistic regression was performed to assess the relationship between enucleation, the cTNM stage, a ciliary body involvement, an extraocular extension and the pre-COVID-19 and post-COVID-19 periods. Data were controlled for multicollinearity using the Belsley-Kuh-Welsch technique. The alpha risk was set at 5% and two-tailed tests were used. Statistical analyses were performed using EasyMedStat (version 3.30.2; www.easymedstat.com) and SPSS software (version 29; IBM, Armonk, New York, USA).

# Results

## Retrospective analysis of data of patients from two ocular oncology centers

A total of 537 patients were diagnosed with choroidal and ciliary melanoma in the ocular oncology departments of Nice and Lyon between January 2018 and December 2022. Among them, 213 (39.7%) were diagnosed during the pre-COVID-19 period and 212 (39.5%) during the post-COVID-19 period. The mean age at the time of diagnosis was 66.1years (±13.9). There were no statistical differences in gender (P
                        =0.56), age (P
                        =0.56), tumor thickness (P
                        =0.51), tumor largest basal diameter (P
                        =0.26), extraocular extension (P
                        =0.97) and ciliary body involvement (P
                        =0.07), clinical and pathological TNM stage (P
                        =0.31 and P
                        =0.35, respectively), and AJCC stage (P
                        =0.68) between the different years. There was a statistical difference in the proportion of patients treated with PBT or primary enucleation each year (P
                        =0.02, Table 1
                        ). The comparison of the pre- and post-COVID-19 periods did not show any significant difference between both groups except for the clinical TNM stage, with more locally advanced tumors in the post-COVID-19 period than in the pre-COVID-19 period (27.7%, 38.5%, 30.5% and 3.3% vs. 28.7%, 30.2%, 31.1% and 9.9% for cT1, cT2, cT3 and cT4 stage respectively, P
                        =0.03, Table 2
                        ). The enucleation rate was lower in 2020 than in the pre-COVID-19 or post-COVID-19 periods (4.5% vs. 10.3% and 13.7%, respectively, P
                        =0.04). Conversely, the number of patients treated with PBT was relatively higher in 2020 than in the pre- or post-COVID-19 periods (95.5% vs. 89.7% and 86.3%, respectively, P
                        =0.04), with a higher PBT/primary enucleation ratio (21.4% vs. 8.6% and 6.3%, respectively, P
                        =0.04). In the multivariate logistic regression, a ciliary body involvement (OR=2.3, 95%CI: [1.18–4.50], P
                        =0.0146), an extraocular extension (OR=3.82, 95%CI: [1.46–10.02], P
                        =0.0064), and the cT3 (OR=15.4, 95%CI: [3.58–66.27], P
                        =0.0002) and cT4 (OR=70.01, 95%CI: [14.48–338.46], P
                        <0.0001) stages were independently associated with an increased risk of primary enucleation (Table 3
                        ). As the enucleation rate did not significantly differ between the pre- and post-COVID-19 periods (10.3% and 13.7%, respectively, P
                        =0.36), the risk of primary enucleation during these 2 periods was not compared.

## Retrospective analysis of data from the French national database

According to the PMSI database, 2187 patients underwent tantalum marker placement for uveal melanoma between 2018 and 2022 (Supplementary Table 2). There was no statistical difference in the number of patients undergoing surgery and gender ratio (P
                        =0.47) between the different years. Similarly, the age distribution did not significantly differ between the years (P
                        =0.47 and P
                        =0.66, respectively). There was no statistical difference between the pre- and post-COVID-19 periods (P
                        =0.12 for the number of patients undergoing surgery and gender ratio and P
                        =0.41 for the age distribution, Table 4
                        ).

## Trends in the treatment of patients with uveal melanoma

Overall, the data from the PMSI and the Nice and Lyon ocular oncology departments did not show any change in treatment trends for patients with uveal melanoma (Supplementary Figure).

# Discussion

Our study aimed to analyze changes in practice in uveal melanoma (except iris melanoma) management before and after 2020. In particular, the main question was whether the pandemic had led to later diagnoses with more advanced tumor sizes and stages, and possibly an increased rate of enucleations. In our multicentric study, we found a significantly lower enucleation rate in 2020 than in the pre- or post-COVID-19 periods (P
                     =0.04) although the rate of more locally advanced tumors was higher in the post-COVID-19 period than in the pre-COVID-10 period, according to cTNM stages (P
                     =0.03). Although not significant, a trend towards more advanced pT stages was also observed in enucleated eyes after the pandemic compared to before the pandemic. Other clinical data such as the tumor thickness and largest basal diameter, a ciliary body involvement, an extraocular extension or the AJCC stage were not significantly modified during these periods. National PMSI data suggested that patients were not treated with different modalities in 2020 compared to other years (Supplementary Table 2), while the pre- and post-COVID-19 periods did not show any significant difference in tantalum clip placement rate (Table 4). According to the literature, the risk of enucleation diverges (Table 5
                     ). Wang et al. have not found any significant difference in enucleation rate between the first 4months of 2020 (27.7%) and the previous 2years (22.8%). They have also found that PBT was performed less frequently (17.5%) during the lockdown periods compared to the mean rate (29.2%, P
                     =0.011) for the same periods in 2018 and 2019. The stage of uveal melanomas was significantly higher (AJCC stage III and IV) in the post-lockdown period between July and October 2020 (13.4% vs. 28.2%, P
                     =0.006) than between March and June 2018, 2019 and 2020 [6]. Mc Glacken-Byrne et al. have reported similar results, with more advanced tumor stages associated with a higher rate of enucleations [4]. In the study by Bermudez-Castellanos, despite a similar time to diagnosis of uveal melanoma between the two periods analyzed (March 15, 2019 to March 15, 2020, and March 16, 2020 to March 16, 2021), a higher rate of enucleations was reported (47.5% vs. 11.9% during the pre-COVID period) as opposed to patients treated with brachytherapy or observation (P
                     <0.05). Thus, the risk of enucleation increased in patients over the 2020–2021 period (OR=10, 95%CI: [1.1–90.2], P
                     =0.04), especially in patients with intermediate and large tumors according to the Collaborative Ocular Melanoma Study (COMS) classification (OR=250, 95%CI: [27.7–2256.4], P
                     <0.01) [12]. In the USA, Hasegawa et al. have reported results similar to ours, with no change in treatment modalities and AJCC stage [8]. These results are surprising given that France had a lockdown policy close to that of the United Kingdom, while the Texas government never issued a stringent lockdown order.

The restrictions applied during the COVID-19 pandemic had a significant impact in the field of ophthalmology, affecting both outpatient and emergency care. According to reports from different countries, ophthalmological emergencies decreased by 41–73% in the first months of the pandemic [13–15]. The decline in the number of patients treated for non-COVID-19 conditions has exposed patients to a risk of not detecting rare diseases, such as uveal melanoma, which are sometimes diagnosed incidentally in asymptomatic patients during a routine examination or in symptomatic patients requesting treatment [6,7]. Similarly, the strict lockdown measures implemented in France and the difficulties in traveling during several periods (from March 17 to May 20, 2020, from October 30 to December 15, 2020, and from April 3 to May 3, 2021) could also have had an impact on the referral and transfer of these patients to reference units such as those in Paris, Lyon or Nice [16].

In France, conservative treatment of uveal melanoma is based on PBT, which does not require two surgical procedures like brachytherapy, and limits the risk of transmission with a short hospital stay for tantalum marker placement. PBT allows treating larger uveal melanomas than brachytherapy, which could explain the lack of changes in treatments offered in France [17]. This risk is also limited by the short period of treatment with significant hypofractionation during PBT. In addition, the various lockdowns had no major impact on the ocular oncology care chain, allowing a rapid diagnosis and effective treatment of patients [18]. Even with the closure of many medical practices during the first lockdown between March and May 2020, all ophthalmology emergency departments remained open in France, allowing patients to be rapidly referred to ocular oncology centers. In France, there is a well-established network of ocular oncologists who have been able to rapidly treat patients with uveal melanoma and, more generally, ocular cancers [19]. Despite the deprogramming of a large number of treatments considered non-urgent during the peak of the pandemic, cancer care has remained a public health priority. All ocular oncology surgical procedures and radiotherapies have been maintained through continued access to operating rooms in public hospitals. PMSI data confirmed this at a national level, with an unchanged number of patients having undergone tantalum marker placement between 2018 and 2021 (Supplementary Table 2). Finally, one of the strengths of the French healthcare system is the operational maintenance and reimbursement of medical transport for patients from ophthalmology consultation centers to specialized ocular oncology centers, which have allowed maintaining an overall stable number of new patients during the post-COVID-19 period.

Regarding the reduction in the rate of primary enucleations performed in 2020 in Nice and Lyon, some patients could have benefited from primary enucleation elsewhere (in another reference center or a non-reference center), due to successive lockdowns. Another explanation could be a bias due to sampling fluctuations, some patients having undergone surgery before or after 2020.

The limitations of our study include the PMSI data on enucleation which are not very detailed, as they include both primary and secondary enucleations. Clinical data such as the size or stage of uveal melanoma were not available from the PMSI. The CCAM system does not differentiate between primary and secondary enucleations, which is why these data could not be used in this study. Another possible bias is the miscoding of diagnoses according to the ICD-10 classification, a bias that should be limited in the future by the implementation of ICD-11, which is more precise regarding the diagnosis of cancers.

In conclusion, we found no impact of the COVID-19 pandemic on ophthalmic care in uveal melanoma patients in France. However, more locally advanced stages were observed upon initial presentation in the post-COVID-19 period. A long-term study is needed to analyze the long-term effects of the pandemic on uveal melanoma patients in terms of metastasis and mortality rates.

# Disclosure of interest

The authors declare that they have no competing interest.

Julien Brand of the Caisse Nationale de l’Assurance Maladie (CNAM) for providing data from the PMSI (Programme de Médicalisation des Systèmes d’Information) national database.