Current management of uveal melanoma: A review

Uveal melanoma is the most frequent primary intraocular cancer in adulthood and is mostly localised to the choroid. It can be treated using radiation therapy, laser therapy, local resection and enucleation, with the best results achieved by combining these procedures. However, up to half of patients develop metastatic disease. There are no efficacious treatment methods for patients in advanced stage or with metastasis. In recent years, several novel treatment modalities aimed at improving tumour control and reducing adverse events have emerged. This review summarises current clinical treatment methods and new therapeutic perspectives for uveal melanoma.


| INTRODUCTION
Uveal melanoma (UM) is the most frequent primary intraocular malignancy in adults. Choroidal melanomas account for 85%-90% of UMs, and 9%-15% of cases involve the iris or ciliary body. 1,2 Iris melanomas are usually discovered in an early phase and have a favourable outcome, whereas ciliary body melanomas have a poor prognosis. [3][4][5] Around half of UM patients ultimately develop tumour metastasis, which often spreads to the liver and results in death within a year. It has been reported that patients with metastases had a 15% chance of surviving 1-year, and a median survival period of 4-15 months. 6 Ocular management for UM aims to retain the eyeball and visual function, and furthermore, reduce tumour metastasis. Enucleation used to be the preferred treatment, but has now been replaced with a combination of phototherapy, radiotherapy and local tumour resection. Once the diagnosis is confirmed, treating patients with UM depends on the tumour diameter and location, and other relevant features such as vitreous haemorrhage, retinal detachment or retinal involvement. 2,7 Other influencing factors include patient age, physical condition, economic condition and personal preference. Unfortunately, there is no definitive therapeutic strategy for UM with metastasis. Recently, several studies devoted to targeted therapy, immune therapy and other new therapeutic perspectives of UM have been conducted, amongst which several have achieved inspiring results. We attempt to highlight and review these promising studies ( Figure 1).

| RADIOTHERAPY
Radiotherapy is one of the most commonly used globesparing therapies for UM. Brachytherapy, charged particle radiotherapy and stereotactic radiotherapy are the main types of radiotherapy. Ionising radiation induces cell lysis, senescence or apoptosis in tumour cells and vascular endothelial cells, leading to tumour ischemia, necrosis, shrinkage and fibrosis. 8 In recent years, encouraging results have been achieved in UM patients treated with local radiotherapy.

| Brachytherapy
Plaque radiotherapy is a type of brachytherapy utilising radioisotopes such as iodine-125, ruthenium-106, cobalt-60, palladium-103 and iridium-192. [9][10][11][12] A dish-shaped applicator is attached with sutures to the sclera externally at the site of the tumour. It delivers radiation from the sclera to the tumour, and can be removed when a tumour apex dose of approximately 80-100 Gy is attained. At present, the radionuclides I-125 and Ru-106 are mainly used. Ruthenium applicators are effective for tumours with the largest basal diameter (LBD) of up to 20 mm and height of up to 7 mm, whereas iodine applicators are suitable for tumours with a height of less than 10 mm. Tumours begin to degenerate one or 2 months after therapy, and the effect lasts for several years. The final rate of local tumour control and eyeball preservation is influenced by many factors, such as tumour volume, position, the type of radioisotope, and operator experience. 13 In a randomised trial, called Collaborative Ocular Melanoma Study, for patients with moderate-sized UM (LBD ≤16.0 mm, height from 2.5 to 10 mm), the 5-year and 12-year survival rates of patients treated with iodine-125 brachytherapy were 82% and 57% respectively. The survival rates of the enucleation group were no different. 9,14 This study proved the effectiveness of brachytherapy for most middle-sized UMs rather than enucleation. During the first 5 years after brachytherapy, 12.5% of patients underwent enucleation, and the therapeutic failure rate was 10.3%. 15 Around one-third of patients reported relatively good sight 3 years after I-125 brachytherapy. 16 For patients with large-sized UM (LBD >16 mm and height >10 mm), a 10-year follow-up F I G U R E 1 The various therapeutic modalities for the management of uveal melanoma reported in previous studies. showed no survival advantage of radiotherapy before enucleation, 17 which was therefore not recommended.

| Charged particle radiotherapy
Charged particle radiotherapy has significant advantages over brachytherapy owing to the homogeneity of dose transmitted to the tumour and minimal amount of damage inflicted on the surrounding tissue (Bragg peak effect). 18 The globe-conserving rate of patients with UM treated by proton beam irradiation (PBI) is over 85%, and the 5-year survival rate is above 80%. 19,20 Ten years after PBI therapy, 70.4% of patients retain their eyes, and tumours were controlled in 87.5% of the eyes. 21 In patients with choroidal melanoma who received carbon ion radiation therapy, the 5-year local control rate and cause-specific survival rate were 92.8% and 82.2% respectively. 22 Owing to its favourable targeting and dose distribution, charged particle radiotherapy is more suitable for complex tumours near the macula or optic papilla. Salvage proton beam therapy has also been described for treating recurrent iris melanoma. 23

| Stereotactic radiotherapy
For this type of radiotherapy, beams of photons from different directions are focused on the tumour, simultaneously or sequentially, thus delivering high-dose radiation to the tumour and decreasing the damage to the surrounding healthy tissue. Stereotactic radiotherapy is easy to execute, and can therefore be used in small centres. Local control rates were found to be reasonable with linear accelerator-based stereotactic fractionated photon radiotherapy, with a 5-year local progression-free survival rate of 82% and a 2-year vision preservation rate of 75%. 24 For tumours ≤6 mm thick, CyberKnife robotic radiosurgery reports a similar safety profile to Ru-106 brachytherapy with regards to secondary glaucoma. 25 Patients treated with robotic stereotactic radiotherapy reported better therapeutic parameters, with higher uniformity and organ-at-risk sparing, than patients treated with linac-based techniques. Unfortunately, robotic stereotactic radiotherapy was about twice as likely to lead to subsequent malignant tumours as the linac-based system. 26

| Complications
To a large extent, radiotherapy controls the tumour locally, but damage to the surrounding area is inevitable and should be considered. Complications following radiotherapy are another evaluation indicator, especially considering the critical visual functions of the tumourbearing eye. Radiation retinopathy, serous retinal detachment, papillopathy, exudative maculopathy, vitreous haemorrhage, cataracts, neovascular glaucoma (NVG), and eye dryness have been reported. 27,28 The most serious complication is NVG, which is usually caused by highdose exposure and can lead to secondary enucleation. The residual tumour scar is speculated to secrete proinflammatory mediators and vascular endothelial growth factor (VEGF), resulting in persistent inflammation and even NVG. Complications can be managed by transpupillary thermotherapy, intravitreal injections of anti-VEGF or steroids, or endoresection of the nidus in patients with toxic tumour syndrome. 29

| LASER THERAPY
Laser photocoagulation for UM by xenon-arc, argon laser or krypton laser has mainly been abandoned because of the increased rates of local control failure, and the risks of haemorrhage, retinal traction, choroidal or retinal neovascularization, and trans-scleral tumour extension. Today, it is rarely used in cases of small-sized choroidal melanomas situated in the posterior pole and is mainly used for tumour-related retinal detachments, radiation retinopathy and NVG. 30,31 Other options, including photodynamic therapy (PDT) and transpupillary thermotherapy (TTT), can prevent local recurrence by activating photosensitive compounds and free radicals, then focusing the energy to destroy tumour cells directly.

| Photodynamic therapy
In PDT, a photosensitive dye such as verteporfin, which can selectively remain in the tumour blood vessels, is intravenously administered to induce vascular closure, tumour apoptosis and necrosis due to photochemical toxicity. 32 It is no longer a common therapy for UM since the curative effect is often interfered with by tumour pigmentation. As a neoadjuvant therapy prior to brachytherapy, PDT can reduce the height of the tumour in 73.4% of amelanotic choroidal melanomas and decrease the toxic effects on visual function. 33

| Transpupillary thermotherapy
Transpupillary thermotherapy can target the tumour through the pupil by using an infrared laser (810 nm wavelength), which induces hyperthermia in the tumour up to a depth 4 mm. 31 In the past, TTT was used alone in cases of limited juxtapapillary or juxtafoveal tumours. More than 90% of patients with (with a total of 256 smallsized choroidal melanomas) treated with TTT achieved local control in an early study. 34 Visual field defects and maculopathy are common complications associated with this method. Currently, TTT is operated mostly in combination with radiotherapy (to decrease the tumour size before irradiation or decrease the rate of secondary enucleation after proton beam radiotherapy). [35][36][37] A recent analysis of 391 patients showed a direct correlation between high-risk factors and a higher recurrence rate in small-sized choroidal melanomas after primary TTT, indicating that for patients with small-sized choroidal melanomas with multiple risk factors, TTT treatment is not suitable. 36

| SURGICAL THERAPY
Surgical therapy for UM involves various invasive procedures, including globe-conserving operations, such as local tumour resection (endoresection or exoresection), and radical approaches, such as enucleation of the eyeball or orbital exenteration.

| Local tumour resection
Choroidal melanomas can be excised by en bloc resection via a scleral flap (exoresection) or by subretinal piecemeal removal using a vitreous cutter (endoresection). This may be a suitable treatment allowing for tumour removal with globe preservation and potentially useful vision. In particular, for UMs unsuitable for radiotherapy due to their juxtapapillary location or large size, local resection can be considered. 38 Furthermore, it provides tumour specimens for histopathological and cytogenetic examinations. 39 Local resection surgery should be performed by a proficient retinal surgeon because of the technical difficulties. Potential perioperative and postoperative complications may include retinal detachment, haemorrhage and tumour recurrence.

| Iridectomy and iridocyclectomy
As well as plaque radiotherapy or proton beam radiotherapy, iridectomy is a potential treatment for iris melanoma. 40,41 An incision 2-3 mm beyond the limbus and parallel to it, with radial incisions around 2 mm outside the tumour boundary, creates a sclero-corneal flap with a three-quarter thickness. Subsequently, a deep keratectomy is performed for an accessible tumour. Peripheral or sector iridectomies can be carried out according to tumour location. 42 Iridotrabeculectomy is performed for tumours invading the chamber angle, whereas irido-cyclectomy is conducted for tumours that simultaneously invade the anterior segment of ciliary body. 41 Following rigorous diagnostic and surgical protocols, local resection can be a safe treatment for smallsized iris and ciliary body melanomas with normal preoperative ocular pressure. The postoperative vision acuity remains good. 42 The most common postoperative complications include cataracts, hypotony, hyphaema, cyclodialysis, bullous keratopathy and leakage of the wound. 43

| Exoresection
Iridociliary melanomas involving no more than 90 of the pars plicata or choroid tumours with a basal diameter <15 mm are appropriate for exoresection. 44 Postradiation exoresection can be performed for ciliary body tumours and large anterior choroid tumours. Furthermore, exoresection is suitable for occult iridociliary lesions with worrying signs, such as tumour enlargement or extensive vascularization.
Exoresection typically requires general anaesthesia and controlled systemic hypotension to reduce the risk of haemorrhage. By a technique termed "Partial lamellar sclerouvectomy", a scleral flap is created after 270 perilimbal incision and disinsertion of nearby extraocular muscles. The uveal tumour and the adjacent thin lamellar sclera are carefully removed by a "no-touch" technique, without disrupting the underlying retina or vitreous, simultaneously to prevent tumour cells from spreading into the surgical field. 38,45 Blunt dissection using scissors or the Bard-Parker scalpel is suggested if the retina and tumour are firmly adherent to each other. 46 One study compared the effects of exoresection and iodine-125 brachytherapy on UMs with a thickness of ≥6 mm. Side effects such as cataracts, intraocular haemorrhage and macular diseases were more common in the brachytherapy group, and the exoresection group reported a better final visual acuity. However, the probability of local recurrence after exoresection was 8 times greater than after iodine-125 brachytherapy. 47 A combination of exoresection and adjuvant plaque radiotherapy can be employed to reduce tumour recurrence. A decreased risk of recurrence on long-term follow-up was demonstrated with the use of Ru-106 plaque radiotherapy as adjuvant treatment after exoresection. The absence of adjuvant brachytherapy increased the recurrence rate more than four times. 44,48 In addition, exoresection may be appropriate for patients undergoing radiotherapy. Patients with toxic choroidal melanoma due to previous proton beam radiotherapy reported encouraging outcomes with exoresection, mostly with flat retina and reasonable vision. 49 A major perioperative complication is an inadequate solid scleral flap. Once the scleral flap is deepened, there is a risk of scleral perforation which could lead to extraocular dissemination of the tumour. The most common adverse events after surgery include haemophthalmos, scleral flap infiltration, choroidal ablation, retinal detachment, cystoid macular oedema, subretinal fibrosis, cataracts, bullous keratopathy, local tumour recurrence and secondary glaucoma. 43

| Endoresection
Tumours situated posteriorly around optic papilla or macula can be difficult to treat, as radiotherapy can lead to optic neuropathy or maculopathy, whereas exoresection is technically challenging in this region. Endoresection is appropriate for patients with posteriorly situated choroidal melanomas that extend at least 1 PD beyond the optic disc and fovea. 44 Endoresection is not limited by tumour size; however, there is the risk of perioperative and postoperative complications is increased for tumours with a base diameter >15 mm. In this method, the melanoma is resected following a conventional three-or four-channel vitrectomy, with excision of the posterior vitreous and removal of the vitreous base. Retinotomy is performed at the site of maximum tumour height. Then the actual transretinal endoresection of the tumour is performed with a vitrector using the piecemeal technique, leaving a bare sclera in the tumour area. To reduce bleeding, it is advised to maintain systemic hypotension and increase the intraocular pressure to 80 mmHg. Perfluorodecalin and silicone oil are usually used during surgery, and the latter can be removed after 3 months. Due to the possibility of cerebral air embolism, gas filling should only be cautiously considered, as it may result in deadly complications. 50,51 A lining of remnants from the original tumour may remain on the bare sclera; therefore, to kill any possible seeded tumour cells, cryocoagulation or laser photocoagulation should be applied to the scleral bed. Adjuvant plaque brachytherapy is recommended, particularly for tumours with indistinct margins or peripheral extension. 52,53 Haemorrhage is a major perioperative and postoperative complication that can be controlled by increasing intraocular pressure or targeted endodiathermy perioperatively. 44 The risk of tumour dissemination during endoresection is disputed. 54 Some researchers recommend a combined approach with irradiation before endoresection. 55 Preoperative gamma knife or proton beam irradiation renders endoresection more reliable because the disseminated tumour cells are not viable. 56

| Enucleation
Patients with UM were treated by enucleation as a firstline treatment before the advent of plaque radiation therapy. Currently, enucleation is often used to treat advanced tumours (diameter > 20 mm, thickness > 12 mm) that cannot be treated efficiently by radiation and/or are accompanied by painful secondary glaucoma, total vision loss or orbital invasion. Artificial eyeball implantation can be undertaken 4-6 weeks after enucleation.

| Exenteration
Orbital exenteration is appropriate for advanced tumours with extraocular involvement or recurrent tumours in orbit after prior enucleation and includes the excision of the eyeball, nerves, muscles and fatty tissue nearby. An eyelid-preserving technique can be used to facilitate rapid rehabilitation if possible. It is feasible to implant an orbital prosthesis 6-8 weeks after exenteration. 57

| SYSTEMIC THERAPY
Local therapeutic options provide a spectrum of options for several primary UM stages and manifestations. Local tumour control in the eye can be achieved in most cases. This is in sharp contrast to the therapeutic efficacy for metastatic disease and the options for controlling the progression of metastases to distant visceral organs. The overall survival of patients with metastatic UM is still remarkably low. In the second part of this paper, we provide a focused summary of the therapeutic options for UM metastases. We will focus on molecular targeted therapy and immunotherapy.

| Targeted therapy
Molecular targeted therapy is a treatment modality with high specificity that can block the signal transduction pathways and affect the biological behaviour of tumour or stromal cells by acting on specific tumour proliferation-related molecules. It has been used as monotherapy or in combination with other therapies. UM with metastatic disease responds poorly to conventional chemotherapy; targeted therapy may be a prospective treatment. 58 Recently, several clinical tests have studied diverse types of targeted drugs for UMs.

| Tyrosine kinases
Tyrosine kinases are prime targets for anti-tumour molecular targeted therapy in UM. The c-kit protein, an important membrane-bound tyrosine kinase receptor, has been reported to be overexpressed in multiple tumours including metastatic UM. Imatinib mesylate is an FDA-approved compound that can suppress c-kit. It has been confirmed that imatinib mesylate inhibits the proliferation and invasion of human UM cells in vitro. 59 In a phase II clinical study, patients with metastatic UM received imatinib mesylate 400 mg twice daily. The results showed that imatinib mesylate slightly prolonged the survival period; however, the trial was halted after adverse events were experienced. 60 Sunitinib is another tyrosine kinase inhibitor with better therapeutic effects than imatinib. It can be safely administered, and showed potential clinical benefits in UM patients with metastasis. In a pilot study, the overall clinical effective rate was 80%, with a median overall survival of 8.2 months and non-progression survival of 4.2 months. 61 In a retrospective cohort study, the overall survival of patients with primary high risk UM who were given adjuvant sunitinib and historic institutional controls was calculated. Interestingly, it was observed that the use of sunitinib was related to higher overall survival. 62 Crizotinib, a restrainer of ALK/ ROS1/MET, was used for high-risk UM patients who had undergone previous therapy in another single-arm, multi-centre study. The patients were given 12 four-week cycles of adjuvant crizotinib at an initial dosage of 250 mg twice a day. After a follow-up of 36 months, it was found that adjuvant crizotinib failed to improve the recurrence-free survival in high-risk patients with UM when compared with historical controls. 63

| Vascular endothelial growth factor
VEGF expression and angiogenesis are familiar mechanisms of tumour growth, and their potential role in UM has been reported many times. In one paper, 74 enucleated UM eyeballs without primary treatment were studied, and the researchers discovered that the VEGF concentration of aqueous humour in UM specimens was remarkably higher than that in non-neoplastic eyes undergoing cataract surgery. 64 Furthermore, the level of VEGF showed a positive correlation with basal diameter and tumour thickness, two important histopathological parameters. Subsequently, other researchers discovered that intraperitoneal injections of bevacizumab led to a dose-related inhibition of tumour growth and liver metastases in mice. 65 However, different results were observed in patients with UM treated with bevacizumab.
Lima et al. assessed three patients with UM who were given monthly intravitreal injections of bevacizumab for presumed choroidal neovascularization. 66 Despite its effect on decreasing subretinal fluid, tumour progression was not slowed. Moreover, two patients developed complications of retinal gliosis and fibrosis. In a prospective study, two patients with a large UM (with a diameter of >10 mm) received one intravitreal injection of bevacizumab. Unfortunately, both tumours grew 1 week after injection, necessitating enucleation and demonstrating that neoadjuvant intravitreal bevacizumab was unsuitable for UM with a large size. 67 Enucleation rates were not lowered by using intravitreal bevacizumab for UM eyes with NVG. 68 Similar results with intravitreal bevacizumab were confirmed in recent studies, suggesting a potential correlation between intravitreal bevacizumab and increased growth of previously untreated UM. 69,70 The mechanism of this adverse effect of intravitreal bevacizumab remains unclear and is subject to ongoing research.
Tura et al. evaluated the physiological effects of bevacizumab and ranibizumab, another anti-VEGF antibody, on UM cells in vitro. They found that ranibizumab can induce a more potent and prolonged suppressive effect, probably owing to its higher uptake rate and persistent intracellular retention. 71 However, no clinical relief was experienced in patients with primary ocular melanoma treated with intravitreal ranibizumab. 72 Despite these data, intraocular injections of anti-VEGF are still useful to treat radiotherapy complications, and thus they may be an appropriate adjuvant therapy for UMs rather than a primary treatment. 72 Sorafenib is an oral multikinase inhibitor that can prevent tumour progression via its anti-proliferative, anti-angiogenic and pro-apoptotic effects. A single-arm, multi-centre phase II trial including 32 patients with metastatic UM reported 6-month progression-free rate of 31.2% in the sorafenib-treatment group, at a dose of 800 mg daily. Due to issues with toxicity, the dosage for 41.4% of the patients had to be reduced, and therefore further studies are required. 73

| Mitogen-activated protein kinase
GNAQ or GNA11 gene mutation, which can activate the mitogen-activated protein kinase (MAPK) signal pathway, exists in almost 80% of large-sized UMs. 74 Selumetinib has been tested for treating UMs with metastasis by inhibiting mitogen-activated protein kinase (MEK), either as monotherapy or combined with chemotherapy.
Carvajal et al. performed a multi-centre phase II study contrasting selumetinib with chemotherapy in patients with metastatic UM. 75 Patients were divided into two equal groups and randomised to be treated with selumetinib or chemotherapy. The results showed a median nonprogression survival of 15.9 weeks in the selumetinib group, whilst that of the chemotherapy group was 7 weeks. The median overall survival was 11.8 and 9.1 months in selumetinib group and chemotherapy group, respectively. 49% of the patients in the selumetinib group reported tumour regression, whereas no significant responses were detected with chemotherapy. However, 97% of patients in the selumetinib group developed side effects, such as erythra, CPK elevation and fatigue, as well as AST or ALT elevation. Three patients presented with neck myopathy or myositis. In a subsequent international double-blind phase III clinical study, Carvajal et al. estimated the safety and efficacy of selumetinib combined with dacarbazine for metastatic UMs without primary systemic therapy. They discovered that selumetinib enhanced the effect of dacarbazine, prolonged the median non-progression survival of patients, and improved the objective remission rate of a subset of patients. 76

| Immunotherapy
A further promising treatment modality for metastatic UM is immunotherapy, specifically cytokine modulation and immune checkpoint blockade. 77 Compared to cutaneous melanoma (CM), the clinical benefit of immunotherapy for UM is limited by its low mutation load and "immune privilege", especially checkpoint blockade. Despite these disappointing results with checkpoint blockade, immunotherapeutic approaches hold promise, as exemplified by the recent results of tebentafusp. 78 We will now address these forms of immunotherapy.

| Interferon
In a clinical trial, 121 patients with high-risk UM given interferon (IFN)-α-2a treatment for 2 years reported no change in survival rate when compared with patients given radiation or enucleation. 79 Richtig et al. collected 39 patients with UM to record the safety and efficacy of adjuvant IFN-α-2b treatment. Eighteen cases required dose reduction due to leukopenia, cardiac diseases, thrombocytopenia, abnormal liver function or faintness. Therapy was stopped for eight patients after experiencing severe adverse effects, or progression of metastases. There was no evidence that IFN treatment improved the survival of patients with UM. 80

| Anti-CTLA-4 antibody
Ipilimumab is a specific inhibitor of human cytotoxic T lymphocyte antigen 4 (CTLA-4), which can increase the immune response mediated by T lymphocytes to suppress tumour growth. Danielli et al. examined its effectiveness and safety in patients with UM. 81 Thirty patients were given ipilimumab intravenously at a dose of 10 mg/kg and clinically assessed 12, 24 and 36 weeks after injection. The results showed disease control in certain patients and an increased overall survival rate, with serious adverse reactions such as thrombocytopenia and diarrhoea in three patients. In a multi-centre clinical trial by Zimmer et al., 52 patients in phase III or IV were given ipilimumab for 4 cycles at a dose of 3 mg/kg. 82 47% of patients had stable disease after treatment. The tumour control rates were 47% at 12 weeks, and 21% at 24 weeks. Complications occurred in 66% of patients, involving 19 high-grade (grade 3-4) events. A recent study revealed that ipilimumab, in combination with nivolumab, a checkpoint blocker targeting PD-1, had potential activity in metastatic UM, with significant and continuous responses. 83

| Tebentafusp
Tebentafusp is a bispecific fusion protein targeting gp100, a melanocytic antigen expressed in both CM and UM. It can redirect CD3 + T cells to melanoma cells expressing gp100 and induce cytolysis by these T cells. Middleton et al. carried out the first-in-human (FIH) phase I trial of tebentafusp in 84 patients with metastatic melanoma, including 16 with UM. The results demonstrated that two (14%, n = 14 evaluable) patients with UM achieved a partial response, whilst eight (57%) achieved clinical control for 16 weeks or more. The most common complications were erythra, pruritus, fever and periorbital swelling in the dose escalation cohort. In general, tebentafusp is well tolerated and active in patients with advanced UM, 84 with a 1-year overall survival rate of 65% in both the UM and CM cohorts. 85 Subsequently, Carvajal et al. conducted a single-arm, multi-centre, open-label phase II trial of tebentafusp and found that tebentafusp had a beneficial clinical effect with an acceptable safety profile in 127 patients with treatment-refractory metastatic UM. Despite the low response rate of 5%, the 1-year survival rate was 62%, with a median overall survival of 16.8 months as well as a favourable mild to moderate toxicity profile, indicating patient benefit beyond traditional radiography-based response criteria in a subset of patients with UM. 86,87 In a recent open-label phase III trial, 378 patients were randomly treated with tebentafusp or single-agent ipilimumab, pembrolizumab or dacarbazine. The 1-year overall survival rate and 6-month non-progression survival in the tebentafusp group (73% and 31%, respectively) were higher than in the control group (59%; 19%). Few serious adverse events leading to the termination of the treatment were observed. 88 These results with tebentafusp indicate that immunotherapy can be effective in UM and merit further studies with immune-oncologic compounds in UM patients with metastatic disease.

| NEW THERAPEUTIC PERSPECTIVES
High-Intensity Focused Ultrasound, a potential therapy which treats solid tumours in the deep subcutaneous layer via thermal destruction, and sonodynamic therapy, which could induce reactive oxygen species, were reported to show advantages in treating primary UM using ultrasonographic techniques. 89 Another mechanism potentially raises the penetration of anticancer agents into primary UM cells, such as trans-corneal iontophoresis and electrically enhanced chemotherapy. 89 A recent study discovered that light-activated molecules, like the drug AU-011, appear promising for treating small choroidal melanomas. Small AU-011 molecules injected into the eyes can selectively bind to tumour cells and can be activated by a diode laser to destroy the target cells. 90 However, these methods are primarily utilised during the preliminary phases of clinical development.

| CONCLUSION
As our understanding of the cellular and molecular pathogenesis of primary UM deepens, the traditional laser photocoagulation has faded, and enucleation has gradually been extended to radiotherapy and local tumour resection. Complex and personalised therapies are becoming the focus of UM treatment, specifically in metastatic settings. New therapeutic strategies, such as molecular-targeted therapy and immunotherapy, clearly offer perspectives for improving the survival of patients with metastatic UM. An exploration of adjuvant treatment strategies, also for high-risk primary UM, may offer new perspectives but cannot be implemented without long-term multidisciplinary cooperation between all relevant disciplines involved in UM research and clinics.

FUNDING INFORMATION
German Research Foundation FOR2240 to JJB and LMH.