Both BNPB and ER are confirmed in our study as effective treatment options for large UM, enabling satisfactory eye and visual function preservation. Three years after therapy, eye preservation was achieved in 88.0% of cases and local tumor control was achieved in 92.9%. Individuals undergoing ER without aBT were at lower risk of LB at 12 months and SE at 36 months. Age and tumor thickness were identified as significant risk factors for LB and SE at 36 months.

Several studies have investigated the outcomes of eye-preserving therapy for large UMs [1, 2, 5, 15,16,17,18,19,20]. Research on brachytherapy with 125I for large UMs has reported SE rates of 16% and 24% at 5 years [1, 15]. Plaque radiotherapy for extra-large UMs (≥ 10 mm thickness) resulted in an eye preservation rate of 68% [20]. These results are comparable to reported rates of SE of up to 23% after ER [5, 6, 12, 21]. However, in two studies with a small patient sample, dealing with outcome after ER, eye retention was achieved even in 100% of cases over mean follow-up periods of 31 and 54.5 months, respectively [22, 23].

Despite initial concerns about potential tumor cell dissemination during ER, there was no difference in the number of circulating melanoma cells in peripheral blood following different therapeutic approaches, including ER [24, 25]. This could be attributed to the detection methods used or the sensitivity threshold of the assays. But studies comparing overall survival and disease-specific survival between ER and brachytherapy have found no significant differences, supporting the safety of this therapeutic option [12, 18].

In the same studies the authors also found no significant differences in eye retention rates between both groups. In contrast to these findings, our study showed the most favorable anatomical outcomes among the 3 therapeutic arms after ER without BT, with only 6.3% of patients requiring SE at 36 months. Multivariable regression analysis further confirmed this treatment modality as protective regarding SE at 36 months post-treatment.

A recent review evaluating proton beam therapy for UM of various sizes favored its use over brachytherapy, particularly for tumors larger than 8 mm, due to its unique physical properties that provide better sparing of critical ocular structures [26]. In this context, one study showed that patients with tumor height more than 7 mm who underwent 125I brachytherapy had significantly higher risk for enucleation than patients with lesions < 7 mm [27]. In contrast, a recent meta-analysis found no significant advantage of charged-particle therapy over brachytherapy in terms of SE rates [28]. Consistent with these findings, our cohort demonstrated a slightly higher eye retention rate of 88% following BNPB, compared to the 85.8% reported at 3 years post-treatment in a study evaluating long-term outcomes after proton therapy [29]. These results suggest that, with careful patient selection, plaque brachytherapy remains an effective treatment option for UM.Overall, 29 patients (12%) required SE within 36 months of treatment. In line with previous reports [30, 31], LR was the primary reason for SE in our study. At 36 months, 7.1% of patients developed LR. This outcome is comparable to LR rates reported following proton beam irradiation, where recurrence has been documented at approximately 5% [29]. Similarly, another study evaluating 125I brachytherapy in patients with large, American Joint Committee on Cancer T4-staged tumors reported a LR rate of 9% at the same follow-up interval [32]. Eye-preserving therapy of LR was possible in only a quarter of these cases in our cohort. Although the LR rate was lower in the ER-group, both with and without BT, compared to BNPB, the difference was not statistically significant. These findings are consistent with studies reporting no differences between brachytherapy and ER for LR rates [12, 18].

Comparing functional outcomes after therapy for UMs is challenging due to variations in patient cohorts, treatment modalities and, most importantly, differing endpoint cutoffs. As VA < 0.05 decimal has a significant impact on quality of life, making basic tasks such as reading or orientation nearly impossible, we chose this cutoff to identify individuals with the most severe visual impairment.

Notably, the literature specifically addressing functional outcomes following eye-preserving therapy for large UMs remains limited. However, it is well established that larger tumors are associated with greater visual loss compared to smaller and medium-sized tumors [33].

Findings from a small cohort suggest that ER may provide better visual outcomes than brachytherapy in selected cases [2]. However, another study comparing primary ER to primary 125I brachytherapy found no statistically significant difference in final VA between the two groups [18].

In the Collaborative Ocular Melanoma Study trial, which evaluated visual outcomes following brachytherapy with 125I, 76% of patients with large UM’s had a VA of ≤ 0.1 at 3 years [34]. Puusaari et al. reported a median VA of only light perception at 36 months following 125I brachytherapy for large UM, with only 4% of patients maintaining VA ≥ 0.1 decimal [1]. In contrast, our cohort demonstrated significantly better VA outcomes, with a median VA of 0.05 decimal at the same time point. 99 out of 241 patients (41%) in our study retained a VA of ≥ 0.1 decimal at 36 months post-treatment. In comparison, only 22.6% of patients treated with proton therapy achieved a VA of ≥ 0.1 decimal at the same follow-up interval [29]. Of course, we must acknowledge the potential selection bias due to missing follow-up data, as only 60.6% of patients were available at the 36 month evaluation. Incomplete follow-up data could potentially distort the interpretation of results. Nevertheless, the observed trends in visual outcome support the long-term efficacy of the evaluated treatment approaches.

The reported functional outcomes after ER are quite variable. In a study of Caminal et al., the Kaplan Meier probability of maintaining a VA equal or superior to 0.1 decimal at 5 years after ER was 59.9% [18]. Bechrakis et al. reported the median VA after ER with neoadjuvant proton radiotherapy of 0.1 decimal [21]. In contrast, another study evaluating outcome after ER with aBT revealed the median VA of only 0.01 decimal [6].

In our study, among the three treatment arms, the ER-group without aBT achieved the best results, with a median VA of 0.08 decimal at 36 months. At this interval 24 (50%) of 48 patients in this group remained VA of ≥ 0.1 decimal. But similarly to the results of Caminal et al. [18], the differences in VA in groups observed in our study at 36 months were not statistically significant. Consistently with other reports [14, 15, 32], patient’s age and tumor thickness were associated with VA deterioration with development of LB in multivariable analysis.

While the use of a unique bi-nuclide plaque specific to our institution may initially appear to limit the generalizability of our findings, conventional single nuclide 125I brachytherapy remains a widely accepted and suitable alternative. The dose exposure ratio between the bi-nuclide and the 125I plaques is approximately 0.7 and remains relatively stable with increasing distance from the plaque [4]. For tumors with a thickness of 10 mm or greater the 125I component becomes the predominant contributor [4]. Therefore, our findings are applicable to centers employing conventional 125I brachytherapy, especially in cases with tumor thickness exceeding 10 mm, where dosimetric differences between plaque types are minimal.

The eyes with large UM, which may have previously required enucleation, can now often be preserved through various therapeutic approaches, such as radiotherapy alone or in combination with surgical resection. Preserving functionality is another key goal of globe-conserving therapy, while VA is a complex outcome influenced by multiple factors.

Generally, an accurate therapy planning beginning with identification of proper treatment modality depending on tumor thickness and location, interdisciplinary cooperation of ocular oncologist and radiation therapist and physicist is crucial for therapy success.