MD Christophe Baudouin
email: cbaudouin@15-20.fr

Maurizio Rolando

Jose M Benitez

Del Castillo

Elisabeth M Messmer

Murat Irkec Francisco C Figueiredo

Gysbert Van Setten

Marc Labetoulle

Murat Irkec

Gysbert Van Setten

Brill, Dompe, Santen Bausch & Lomb

Théa Elisabeth

M Messmer

Thea Santen

Marc

Reconsidering the central role of mucins in dry eye and ocular surface diseases

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

ABSTRACT:

The most frequent site of ocular metastasis is the choroid. The occurrence of choroidal metastases has increased steadily due to the longer survival of metastatic patients and the improvement of diagnostic tools. Fundoscopy, ultrasonography, and fluorescein angiography are now complemented by indocyanine green angiography and optical coherence tomography.

Choroidal tumor biopsy may also confirm the metastatic nature of the tumor and help to determine the site of the primary malignancy.

There is currently no consensus on the treatment strategy. Most patients have a limited life expectancy and for these complex treatments are generally not recommended. However, recent advances in systemic therapy have significantly improved survival of certain patients who may benefit from an aggressive ocular approach that could preserve vision. Although external beam radiation therapy is the most widely used treatment, more advanced forms of radiotherapy that are associated with fewer side effects can be proposed in select cases.

In patients with a shorter life expectancy, systemic therapies such as those targeting oncogenic drivers, or immunotherapy can induce a regression of the choroidal metastases, and may be sufficient to temporarily decrease visual symptoms. However, they often acquire resistance to systemic treatment and ocular relapse usually requires radiotherapy for durable control. Less invasive office-based treatment, such as photodynamic therapy and intravitreal injection of anti-VEGF, may also help to preserve vision while reducing time spent in medical settings for patients in palliative care.

The aim of this review is to summarize the current knowledge on choroidal metastases, with emphasis on the most recent findings in epidemiology, pathogenesis, diagnosis and treatment.

Introduction

The first case of choroidal metastasis (CM) was documented by Perls in 1872 [START_REF] Perls | Beitrage zur geschwulstlehere[END_REF].

Although CM have long been considered a rare entity, they are now known to be the most common intraocular malignancy (Albert et al., 1967b;[START_REF] Ferry | Carcinoma metastatic to the eye and orbit. I. A clinicopathologic study of 227 cases[END_REF]Shields et al., 1997b). The increasing survival of patients with metastases and better diagnostic tools may explain these findings, yet the incidence of CM is probably even higher than reported due to underdiagnosis among patients with poor general condition. Nonetheless, CM is the first sign of a systemic malignancy in up to a third of patients with cancer [START_REF] Konstantinidis | Management of patients with uveal metastases at the Liverpool Ocular Oncology Centre[END_REF].

Given the visual consequences, the ophthalmologist should play a key role for prompt and accurate diagnosis to begin the general work-up. The methods for CM diagnosis have improved over recent decades. Fundoscopy, ultrasonography (US), and fluorescein angiography are now complemented by indocyanine green angiography (ICGA), optical coherence tomography (OCT), and, more recently, spectral domain-OCT (SD-OCT). Histopathological diagnosis is also made possible by choroidal tumor biopsy that can confirm the nature of the tumor and help determine the site of the primary cancer.

There is still debate as to the best way to treat patients with CM. As most patients have a limited life expectancy, complex treatments are generally not recommended. Ocular treatment in a patient with multiple metastases is considered a palliative measure, and, as such, aims to save vision and prevent the development of pain in order to improve quality of life. Fulfilling this objective provides a double challenge: on the one hand, the treatment should be easy to implement and should have a low risk of complication, and on the other hand it should be effective and improve or stabilize vision, which is essential for end-of-life well-being.

However, recent advances in systemic therapies have significantly improved the survival of metastatic patients. Such patients may benefit from an effective and durable ocular treatment that will preserve vision throughout their prolonged survival.

The present review will focus on recent findings that have enhanced the clinical understanding and the management of CM.

Epidemiology of choroidal metastases

Prevalence of choroidal metastases

Until the 1970s there was a belief that metastatic tumors in the uveal tissue were relatively rare but it has since been shown in several studies that these are the most common uveal malignancy; they are even more frequent than primary uveal melanoma (Albert et al., 1967a;[START_REF] Bloch | The incidence of ocular metastatic carcinoma[END_REF][START_REF] Ferry | Carcinoma metastatic to the eye and orbit. I. A clinicopathologic study of 227 cases[END_REF]Shields et al., 1997b).

The prevalence of intraocular metastases has been studied using two different methods: systematic post-mortem histopathological examination of ocular globes in cohorts of patients who died of cancer [START_REF] Bloch | The incidence of ocular metastatic carcinoma[END_REF][START_REF] Eliassi-Rad | Frequency of ocular metastases in patients dying of cancer in eye bank populations[END_REF][START_REF] Nelson | A histopathologic study of 716 unselected eyes in patients with cancer at the time of death[END_REF], and complete ophthalmologic examination in cohorts of patients diagnosed with cancer (Albert et al., 1967a;[START_REF] Barak | Decreased prevalence of asymptomatic choroidal metastasis in disseminated breast and lung cancer: argument against screening[END_REF][START_REF] Kreusel | Choroidal metastasis in disseminated lung cancer: frequency and risk factors[END_REF][START_REF] Mewis | Breast carcinoma metastatic to the choroid. Analysis of 67 patients[END_REF][START_REF] Su | Symptomatic ocular metastases in lung cancer[END_REF][START_REF] Wiegel | Frequency of asymptomatic choroidal metastasis in patients with disseminated breast cancer: results of a prospective screening programme[END_REF]. The prevalence of metastases estimated from post-mortem examination ranged from 4 to 10%. As expected, this was higher than the prevalence in patients living with cancer, which ranged from 2 to 7%, with the exception of Mewis et al. who reported a much higher prevalence that is likely to be related to the large proportion of symptomatic patients referred for examination (Table 1) [START_REF] Mewis | Breast carcinoma metastatic to the choroid. Analysis of 67 patients[END_REF].

Authors Primary cancer

Number of patients Number of patients with choroidal metastases Albert et al. (Albert et al., 1967a) All cancers 213 5 (2.3%) 10 patients with ocular metastases overall Mewis et al. [START_REF] Mewis | Breast carcinoma metastatic to the choroid. Analysis of 67 patients[END_REF] Breast 250 67 (26.8%)

Wiegel et al. [START_REF] Wiegel | Frequency of asymptomatic choroidal metastasis in patients with disseminated breast cancer: results of a prospective screening programme[END_REF] Breast 120 6 (5.0%) Kreusel et al. [START_REF] Kreusel | Choroidal metastasis in disseminated lung cancer: frequency and risk factors[END_REF] Lung 84 6 (7.1%) [START_REF] Barak | Decreased prevalence of asymptomatic choroidal metastasis in disseminated breast and lung cancer: argument against screening[END_REF] Breast and Lung 169 patients (77 breast, 92 Lung)

2 (1.2%) Only among patients with breast cancer Su et al. [START_REF] Su | Symptomatic ocular metastases in lung cancer[END_REF] Lung 8484 11 (<1%)

Table 1: Occurrence of choroidal metastases in patients with known cancer

Primary neoplasms associated with choroidal metastases

The most frequent primary tumor site of CM is breast, which is found in 40-53% of cases [START_REF] Demirci | Uveal metastasis from breast cancer in 264 patients[END_REF][START_REF] Ferry | Carcinoma metastatic to the eye and orbit. I. A clinicopathologic study of 227 cases[END_REF][START_REF] Freedman | Metastatic tumors to the eye and orbit. Patient survival and clinical characteristics[END_REF][START_REF] Merrill | Breast cancer metastatic to the eye is a common entity[END_REF]Shields et al., 1997b). The second most frequent is lung, which is found in 20-29% of cases [START_REF] Ferry | Carcinoma metastatic to the eye and orbit. I. A clinicopathologic study of 227 cases[END_REF][START_REF] Freedman | Metastatic tumors to the eye and orbit. Patient survival and clinical characteristics[END_REF][START_REF] Shah | Uveal metastasis from lung cancer: clinical features, treatment, and outcome in 194 patients[END_REF]Shields et al., 1997b).

Less frequent primary tumors include carcinomas of the gastrointestinal tract (4%), prostate (2%), kidney (2%), and skin (2%) [START_REF] De Potter | Uveal metastasis from prostate carcinoma[END_REF][START_REF] Dieckert | Prostatic carcinoma metastatic to choroid[END_REF][START_REF] Ferry | Carcinoma metastatic to the eye and orbit. I. A clinicopathologic study of 227 cases[END_REF][START_REF] Harbour | Uveal metastasis from carcinoid tumor. Clinical observations in nine cases[END_REF]Shields et al., 1997b). There are also reports of tumors originating from the salivary glands [START_REF] Gutmann | Choroidal metastasis of adenocystic carcinoma of the salivary gland[END_REF]Shields et al., 2000a), thyroid [START_REF] Avram | Choroidal and skin metastases from papillary thyroid cancer: case and a review of the literature[END_REF][START_REF] Besic | Choroidal and orbital metastases from thyroid cancer[END_REF], testes [START_REF] Ferry | Carcinoma metastatic to the eye and orbit. I. A clinicopathologic study of 227 cases[END_REF][START_REF] Freedman | Metastatic tumors to the eye and orbit. Patient survival and clinical characteristics[END_REF], female genital organs [START_REF] Krohn-Hansen | Carcinoma of the ovary with primary presentation in the choroid[END_REF], and urothelial tract [START_REF] Nabi | Eye metastasis form urothelial tumours[END_REF]. Ocular metastases from neuroendocrine tumors are rare, but given the scarcity of this cancer, ocular spread should be investigated [START_REF] Eagle | Choroidal metastasis as the initial manifestation of a pigmented neuroendocrine tumor[END_REF][START_REF] Isidori | Ocular metastases secondary to carcinoid tumors: the utility of imaging with [(123)I]meta-iodobenzylguanidine and [(111)DTPA pentetreotide[END_REF][START_REF] Schalenbourg | Metastatic choroidal paraganglioma[END_REF]. Sarcomas even more rarely metastasize to the choroid [START_REF] Anderson | Choroidal metastasis from primary pulmonary leiomyosarcoma[END_REF][START_REF] Feinstein | Choroidal metastasis from leiomyosarcoma in two cases[END_REF][START_REF] Jampol | Metastasis of Ewing's sarcoma to the choroid[END_REF] (Figure 1).

CM may also follow cutaneous, mucosal, or choroidal melanomas [START_REF] De Bustros | Intraocular metastases from cutaneous malignant melanoma[END_REF][START_REF] Font | Primary malignant melanoma of the skin metastatic to the eye and orbit. Report of ten cases and review of the literature[END_REF][START_REF] Ramaesh | Intraocular metastases of cutaneous malignant melanoma: a case report and review of the literature[END_REF]. These metastases account for approximately 2-3% of ocular metastatic disease but their prevalence is probably underestimated. Post-mortem studies found ocular involvement in a third of patients who died from metastatic cutaneous melanoma [START_REF] Fishman | Malignant melanoma of the skin metastatic to the eye. Frequency in autopsy series[END_REF]. In a series of 68 eyes of patients with cutaneous melanoma metastatic to the eye, Ramaesh et al. found 40% choroidal and 35% ciliary/iris involvement; moreover, 49% of patients had a vitreoretinal involvement, and 13% an anterior chamber involvement [START_REF] Ramaesh | Intraocular metastases of cutaneous malignant melanoma: a case report and review of the literature[END_REF].

Most patients have known systemic cancer at the time of CM diagnosis, but in 8-30% of cases the diagnosis of CM precedes that of systemic cancer. In these cases, a complete workup revealed lung cancer in 35-59% of cases and breast cancer in 7-15% of cases [START_REF] Amer | Treatment options in the management of choroidal metastases[END_REF][START_REF] Konstantinidis | Management of patients with uveal metastases at the Liverpool Ocular Oncology Centre[END_REF]Shields et al., 1997b). These findings suggest that the presence of uveal metastases in a patient without history of cancer should prompt a thorough investigation for lung and breast cancer. However, in the study reported by Shields et al., the primary site was not found after initial general work-up in 51% of such patients (Shields et al., 1997b).

Table 2 presents a comparison between CM from breast and lung cancer. It appears that clinical and epidemiological features could help identify the type of primary neoplasm. The bilateral and the multifocal involvement are more suggestive of breast cancer than of lung cancer. In cases of breast cancer, almost all are women, and diagnosis of CM precedes that of primary tumor in about 10% of patients. In cases of lung cancer, the majority of cases occur in men, and the primary tumor is known in about a half of cases [START_REF] Demirci | Uveal metastasis from breast cancer in 264 patients[END_REF][START_REF] Shah | Uveal metastasis from lung cancer: clinical features, treatment, and outcome in 194 patients[END_REF]. The mean interval between diagnosis of primary neoplasm and CM is shorter for lung carcinomas than for breast cancers [START_REF] Demirci | Uveal metastasis from breast cancer in 264 patients[END_REF][START_REF] Freedman | Metastatic tumors to the eye and orbit. Patient survival and clinical characteristics[END_REF][START_REF] Shah | Uveal metastasis from lung cancer: clinical features, treatment, and outcome in 194 patients[END_REF], as is the mean survival following CM diagnosis [START_REF] Demirci | Uveal metastasis from breast cancer in 264 patients[END_REF][START_REF] Freedman | Metastatic tumors to the eye and orbit. Patient survival and clinical characteristics[END_REF][START_REF] Shah | Uveal metastasis from lung cancer: clinical features, treatment, and outcome in 194 patients[END_REF]. Most studies reporting CM of lung cancer did not differentiate between non-small cell and small cell carcinoma, although it is well known that small cell lung carcinoma preferentially affects younger patient and leads to worse prognosis than non-small cell carcinoma. [START_REF] Demirci | Uveal metastasis from breast cancer in 264 patients[END_REF][START_REF] Freedman | Metastatic tumors to the eye and orbit. Patient survival and clinical characteristics[END_REF][START_REF] Konstantinidis | Management of patients with uveal metastases at the Liverpool Ocular Oncology Centre[END_REF][START_REF] Mewis | Breast carcinoma metastatic to the choroid. Analysis of 67 patients[END_REF][START_REF] Shah | Uveal metastasis from lung cancer: clinical features, treatment, and outcome in 194 patients[END_REF]Shields et al., 1997b) * When primary cancer is known at the time of ocular diagnosis. CM: choroidal metastasis

Other ocular localizations of metastases

Uveal metastases involves the choroid in 88-89% of cases, and less frequently the iris (9%) or ciliary body (2%); isolated involvement of the retina, optic disc, or vitreous are exceptional [START_REF] Konstantinidis | Management of patients with uveal metastases at the Liverpool Ocular Oncology Centre[END_REF]Shields et al., 1997b).

In iris metastases, breast cancer origin is less frequent than in choroidal involvement [START_REF] Demirci | Uveal metastasis from breast cancer in 264 patients[END_REF][START_REF] Konstantinidis | Management of patients with uveal metastases at the Liverpool Ocular Oncology Centre[END_REF][START_REF] Shah | Uveal metastasis from lung cancer: clinical features, treatment, and outcome in 194 patients[END_REF]. Iris involvement is usually unilateral, with a synchronous choroidal localization in a third of cases (J. A. Shields et al., 1995). Ciliary body involvement is rare, and may be secondary to a choroidal localization.

Optic disc metastases represent less than 5% of intraocular metastases and are in continuity with a juxtapapillary choroidal lesion in about 75% of cases. The other 25% are isolated optic nerve lesions in the pre-and retrolaminar portions (Shields et al., 2000b). Breast and pulmonary carcinomas are the most common causes of optic nerve metastases and their prognosis is poor; mean survival is approximately one year (Shields et al., 2000b). Retinal metastases are rare and only a few cases have been described in the literature [START_REF] Leys | Metastatic carcinoma to the retina. Clinicopathologic findings in two cases[END_REF]Shields et al., 1997b;[START_REF] Spraul | Metastatic adenocarcinoma to the retina in a patient with Muir-Torre syndrome[END_REF]. Vitreous metastases are even more rare, and may occur via seeding from the retina secondary to inflammation of the internal limiting membrane [START_REF] Young | Metastatic carcinoma to the retina: case report[END_REF]. Overall the incidence of extra-choroidal involvement is low, and this may be explained by a choroidal preference of metastatic cells.

Physiopathology of the metastasis mechanism

Advances in membrane cell staining have led to a better understanding of the mechanisms involved in cancer metastasis [START_REF] Kuhn | A mouse model of breast cancer metastasis to the choroid of the eye[END_REF][START_REF] Paris | Metastasis models: the green fluorescent revolution?[END_REF], which consist of multiple steps that begin when tumor cells leave the extracellular matrix and invade the surrounding tissue. These migrate towards the blood supply and pass through thin-walled vessels to reach the systemic circulation. Tumor cells then form small aggregates that can be retained in distal microvascular beds and some of them may access the underlying tissue and interact with stromal cells which promote their growth [START_REF] Langley | The seed and soil hypothesis revisited--the role of tumorstroma interactions in metastasis to different organs[END_REF]. With increasing metabolic needs associated with unrestrained cell division, tumor cells secrete proangiogenic factors that induce adjacent endothelial cells to form new vascular networks.

The whole metastatic process is nonetheless highly inefficient, with less than 0.01% of circulating tumor cells eventually leading to secondary tumor growths [START_REF] Fidler | Metastasis: quantitative analysis of distribution and fate of tumor emboli labeled with 125 I-5-iodo-2'-deoxyuridine[END_REF]. Many studies have investigated potential limiting steps in this process and it appears that the most difficult step is initiating cell growth in secondary organs [START_REF] Chambers | Steps in tumor metastasis: new concepts from intravital videomicroscopy[END_REF]. After exiting from the cell cycle, some tumor cells remain dormant in secondary organs [START_REF] Barkan | Extracellular matrix: a gatekeeper in the transition from dormancy to metastatic growth[END_REF], while others are incapable of triggering the angiogenic switch necessary for tumor expansion [START_REF] Hedley | Tumor dormancy and metastasis[END_REF]. This complex series of interactions between metastatic cells and their target organ will determine whether metastatic growth occurs in a given organ.

There are two major theories attempting to explain the preferential target organ, and these are detailed below.

Anatomical-mechanical mechanism

The first mechanism suggests an important role of vascular and lymphatic drainage from the site of the primary tumor [START_REF] Ewing | A multimodal approach to the treatment of bilateral choroidal metastases from thyroid carcinoma[END_REF]. According to this hypothesis, tumor cells follow the circulatory drainage from the primary tumor and are retained non-specifically in the capillary bed of the first organ encountered. This is supported by the higher frequency of metastases in the first organ "downstream" of the primary tumor. The typical example is liver metastases of colorectal tumors that drain through the portal vein directly into the liver [START_REF] Bierman | Studies on the blood supply of tumors in man. III. Vascular patterns of the liver by hepatic arteriography in vivo[END_REF].

More specifically for CM, Duke-Elder and Perkins were the first to hypothesize that the short posterior ciliary arteries are the preferable route for embolic cells [START_REF] Duke-Elder | Diseases of the Uveal Tract, System of Ophthalmology[END_REF]. This would explain why the choroid is the most frequently involved ocular site. Ferry and Font then speculated that the abundant supply of posterior ciliary arteries to the posterior choroid is one of the causes of the predominant post-equatorial location of metastases in the choroid [START_REF] Ferry | Carcinoma metastatic to the eye and orbit. I. A clinicopathologic study of 227 cases[END_REF]. This may explain the greater involvement of the choroid than the iris or ciliary body (Shields et al., 1997b). Moreover, the metastatic cells do not have to cross the blood-retinal barrier to reach the choroid, potentially explaining the low rate of retinal involvement.

The laterality of CM has been discussed by several authors. In some studies, the left eye was more frequently involved [START_REF] De Ocampo | Bronchogenic metastatic carcinoma of the choroid[END_REF][START_REF] Jensen | Metastatic tumours of the eye and orbit. A histopathological analysis of a Danish series[END_REF][START_REF] Singh | Choroidal metastasis as a presenting manifestation of lung cancer: a report of 3 cases and systematic review of the literature[END_REF],

and it has been proposed that this is related to the more direct path to the eye provided by the left common carotid that originates from the aorta. However, other studies found CM more frequently in the right eye [START_REF] Amer | Treatment options in the management of choroidal metastases[END_REF][START_REF] Goldberg | Tumors metastatic to the orbit: a changing picture[END_REF][START_REF] Kreusel | Incidence and clinical characteristics of symptomatic choroidal metastasis from lung cancer[END_REF] and large studies found no particular difference in laterality [START_REF] Freedman | Metastatic tumors to the eye and orbit. Patient survival and clinical characteristics[END_REF][START_REF] Konstantinidis | Management of patients with uveal metastases at the Liverpool Ocular Oncology Centre[END_REF]Shields et al., 1997b).

Seed and soil mechanism

It is well known that breast metastases have particular organ preference. In the "seed and soil" theory proposed by Paget, metastatic growth does not occur randomly but is due to appropriate tumor cells ("seed") needing suitable microenvironment ("soil") to grow [START_REF] Paget | The distribution of secondary growths in cancer of the breast[END_REF]. This theory, partially based on the work of Fuchs on emboli from uveal melanoma [START_REF] Fuchs | Das Sarcom des Uvealtractus[END_REF], suggests that metastases grow only if the seed is implanted in its suitable soil.

Paget proposes that the microenvironment plays the most important role in regulating the growth of metastases. This concept is supported by multiple experimental studies in which metastatic cells were grafted into different target organs, showing good correlation between in vitro and in vivo organ preference [START_REF] Auerbach | Specificity of adhesion between murine tumor cells and capillary endothelium: an in vitro correlate of preferential metastasis in vivo[END_REF][START_REF] Greene | THE RELATIONSHIP BETWEEN THE DISSEMINATION OF TUMOR CELLS AND THE DISTRIBUTION OF METASTASES[END_REF][START_REF] Kinsey | An experimental study of preferential metastasis[END_REF][START_REF] Schackert | Site-specific metastasis of mouse melanomas and a fibrosarcoma in the brain or meninges of syngeneic animals[END_REF].

Blood flow through a given organ is an important factor in the "seeding" process, allowing a greater number of cells to be delivered in a given time, or more efficient "seeding". Weiss proposed to quantify and compare the ability of different organs to promote metastatic growth depending on their blood flow. He developed the metastatic efficiency index (MEI), which is defined as the ratio between incidence of metastases in an organ and the organ's blood flow [START_REF] Weiss | Comments on hematogenous metastatic patterns in humans as revealed by autopsy[END_REF]:

. Thus, high MEI indicates "fertile" seed and soil interactions, whereas low MEI indicates "hostile" seed and soil interactions. If the frequency of metastases in an organ is high compared to its blood flow (high MEI), there may be strong seed and soil interaction, indicating a good match between tumor type and target organ. On the other hand, a highlyvascularized organ with a low frequency of metastases (low MEI) could be explained by weak seed and soil interaction. [START_REF] Weiss | Comments on hematogenous metastatic patterns in humans as revealed by autopsy[END_REF].

= % ( / )

The choroid is one of the most vascularized tissues in the body, and although only 0.013% of cardiac output is directed to the eye (approximately 0.6-0.8 ml per minute), 80-85% of this flow is dedicated to the choroid, [START_REF] Alm | The effects of pilocarpine and neostigmine on the blood flow through the anterior uvea in monkeys. A study with radioactively labelled microspheres[END_REF][START_REF] Langham | Decreased choroidal blood flow associated with retinitis pigmentosa[END_REF]. According to Weiss, the choroid has the highest MEI of any site in the body with a choroidal tissue involvement in 8-10% of metastatic cases [START_REF] Mccartney | Intraocular metastasis[END_REF][START_REF] Weiss | Analysis of the incidence of intraocular metastasis[END_REF]. Comparison of the MEI value of the choroid for primary breast cancer (MEI = 13.5) with that of the adrenal glands (MEI = 0.347) is particularly interesting because the adrenal glands were previously considered to be the preferential target site for metastatic breast cancer; the same was found for primary lung and colorectal carcinomas [START_REF] Weiss | Analysis of the incidence of intraocular metastasis[END_REF]. This high affinity for the choroid may be due to specific vessel wall architecture, or interactions between adhesion molecules on the surface of the cancer cells and endothelial ligand sites (Albert et al., 1967b;[START_REF] Mccartney | Intraocular metastasis[END_REF]. However, the "seed and soil" and the anatomical-mechanical hypothesis are not mutually exclusive, and it is possible that one or both models could be at play.

Wound-oncogene-wound-healing model

A recent hypothesis, termed wound-oncogene-wound-healing (WOWH), proposes another type of metastasis which does not require cell migration [START_REF] Meng | A new hypothesis for the cancer mechanism[END_REF]. According to this theory, cancer is the result of an attempt of the body to heal a wound. At the site of the "abnormal" wound, oncogenes are activated, and various "wound" molecules are produced;

these circulate through the body and are able to activate oncogenes in distant tissues. The cells with activated oncogenes will transform and overproliferate, leading to a metastatic foci on the remote site without primary cancer cell migration.

According to the WOWH mechanism, oncogenes are physiologically activated in some tissues, and the presence of circulatory wound molecules could stimulate this activity. This could explain why cancer cells are found in the brain despite the presence of the blood-brain barrier, or why there is often no trail of cells on the path from the primary site to the distant metastatic sites [START_REF] Nathoo | Pathobiology of brain metastases[END_REF]) (Figure 2).

Diagnosis of choroidal metastases

Clinical findings

Symptoms

Blurred vision occurs in 55-70% of eyes and is often related to macular or juxtapapillary retinal involvement or due to foveal exudative retinal detachment [START_REF] Konstantinidis | Management of patients with uveal metastases at the Liverpool Ocular Oncology Centre[END_REF]Shields et al., 1997b). Phosphenes and floaters are less frequent than in choroidal melanoma (12% of cases of CM), as are visual field defects (15.5.% of cases of CM) (Konstantinidis et al., 2014;Shields et al., 1997b). Pain, outside the context of uveitis or glaucoma, is more frequently reported by patients with CM from lung cancer (12%) than breast cancer (6%) [START_REF] Demirci | Uveal metastasis from breast cancer in 264 patients[END_REF][START_REF] Konstantinidis | Management of patients with uveal metastases at the Liverpool Ocular Oncology Centre[END_REF][START_REF] Shah | Uveal metastasis from lung cancer: clinical features, treatment, and outcome in 194 patients[END_REF]. There remains 15-20% of patients who are non-symptomatic in which metastases are discovered by a routine exam or during a systemic evaluation of a generalized cancer [START_REF] Demirci | Uveal metastasis from breast cancer in 264 patients[END_REF]Konstantinidis et al., 2014;[START_REF] Konstantinidis | Intraocular Metastases--A Review[END_REF].

Clinical examination

CM generally appear as creamy white or pale yellow masses associated with subretinal fluid (SRF). Their appearance can be either flat or plateau shaped, but there are rare descriptions of CM that are mushroom shaped as result of Bruch's membrane rupture [START_REF] Konstantinidis | Management of patients with uveal metastases at the Liverpool Ocular Oncology Centre[END_REF]). An orange color can be seen in metastases that originate from carcinoid tumors [START_REF] Harbour | Uveal metastasis from carcinoid tumor. Clinical observations in nine cases[END_REF], renal cell [START_REF] Freedman | Metastatic tumors to the eye and orbit. Patient survival and clinical characteristics[END_REF][START_REF] Haimovici | Choroidal metastases from renal cell carcinoma[END_REF][START_REF] Kindermann | Metastatic renal cell carcinoma to the eye and adnexae: a report of three cases and review of the literature[END_REF], or thyroid carcinomas [START_REF] Ferry | Carcinoma metastatic to the eye and orbit. I. A clinicopathologic study of 227 cases[END_REF][START_REF] Freedman | Metastatic tumors to the eye and orbit. Patient survival and clinical characteristics[END_REF][START_REF] Harbour | Uveal metastasis from carcinoid tumor. Clinical observations in nine cases[END_REF]) (Figure 3). A dark-brown color can be seen in case of CM from melanoma (cutaneous, mucosal, or uveal), which can appear clinically similar to primary choroidal melanoma [START_REF] De Bustros | Intraocular metastases from cutaneous malignant melanoma[END_REF][START_REF] Font | Primary malignant melanoma of the skin metastatic to the eye and orbit. Report of ten cases and review of the literature[END_REF][START_REF] Ramaesh | Intraocular metastases of cutaneous malignant melanoma: a case report and review of the literature[END_REF] although they are more frequently multifocal with a faster growth pattern. Some CM have orange lipofuscin pigment at the surface, mimicking choroidal melanoma, or dark pigment patches resembling "leopard skin" (Shields et al., 1997b) (Figure 4).

The most common associated feature of CM is SRF, which is observed in 28-73% of patients [START_REF] Konstantinidis | Management of patients with uveal metastases at the Liverpool Ocular Oncology Centre[END_REF]Shields et al., 1997b). This fluid, located between photoreceptor outer segments and retinal pigment epithelium (RPE), is preferentially perilesional or positional.

Bilateral (15-50% of cases), multifocal (mean number of foci ranges from 1.4 to 1.6), and diffuse forms are more commonly associated with breast cancer [START_REF] Demirci | Uveal metastasis from breast cancer in 264 patients[END_REF][START_REF] Jardel | Management of choroidal metastases[END_REF][START_REF] Konstantinidis | Management of patients with uveal metastases at the Liverpool Ocular Oncology Centre[END_REF][START_REF] Maor | Radiotherapy of choroidal metastases: breast cancer as primary site[END_REF][START_REF] Mewis | Breast carcinoma metastatic to the choroid. Analysis of 67 patients[END_REF][START_REF] Röttinger | Radiation therapy of choroidal metastases from breast cancer[END_REF]Rudoler et al., 1997b;Shields et al., 1997b) (Figure 5). Most CM are posterior to the equator (80%) (Shields et al., 1997b) and it has been reported that up to 40% are located in the macular region [START_REF] Konstantinidis | Management of patients with uveal metastases at the Liverpool Ocular Oncology Centre[END_REF]. The mean size of CM is 9 mm at the base and 3 mm in thickness, although thicker tumors can be found (Shields et al., 1997b) (Figure 6).

Echography

The clinical appearance of CM and amelanotic tumors (for instance amelanotic melanoma or hemangioma) is sometimes similar. In these cases, US is required to evaluate tumor reflectivity, internal structure, and degree of vascularization. US enables localization of the intraocular mass, estimation of its size, and characterization of its tissue reflectivity. It is a useful exam for measuring tumor dimensions, although the lateral margins of CM are frequently poorly defined [START_REF] Konstantinidis | Intraocular Metastases--A Review[END_REF]. Sequential measurement of thickness is also important in the follow-up of patients and to assess treatment response.

The US features of CM are characterized by a flat or a slightly dome-shaped mass with a medium-to-high non-homogeneous reflectivity, unlike choroidal melanomas that are more frequently dome-shaped with a low-to-medium homogeneous reflectivity [START_REF] Sobottka | Choroidal metastases and choroidal melanomas: comparison of ultrasonographic findings[END_REF][START_REF] Verbeek | Echographic classification of intraocular tumours. A 15-year retrospective analysis[END_REF]. The typical melanoma A-scan ultrasonography shows high amplitude initial echoes with a low amplitude internal reflection compared to the moderate amplitude of spike in case of CM (Figure 7).

Moreover, CM are often multilobular with an irregular surface [START_REF] Sobottka | Choroidal metastases and choroidal melanomas: comparison of ultrasonographic findings[END_REF].

Exudative peritumoral or gravitational retinal detachment can be seen [START_REF] Perri | Choroidal metastases. Echographic experience from 42 patients[END_REF][START_REF] Verbeek | Echographic classification of intraocular tumours. A 15-year retrospective analysis[END_REF], with rare choroidal detachment [START_REF] Sneed | Choroidal detachment associated with malignant choroidal tumors[END_REF]. The differences in US characteristics between CM and choroidal melanoma are explained by the histoarchitecture of the tumor. For example, CM from the breast has solid epithelial nests or glandular structures, which act as echo-producing interfaces, resulting in high reflectivity and an irregular internal structure in US [START_REF] Perri | Choroidal metastases. Echographic experience from 42 patients[END_REF][START_REF] Verbeek | Echographic classification of intraocular tumours. A 15-year retrospective analysis[END_REF]. Melanomas, however, are dense cellular masses of low-to-moderate vascularization with only a few necrotic areas, thus containing few echo producing interfaces. As a result, these tumors are of low-to-medium reflectivity with a regular internal structure [START_REF] Fuller | Ultrasonographic features of choroidal malignant melanomas[END_REF][START_REF] Goldberg | Ultrasonographic diagnosis of choroidal malignant melanoma[END_REF][START_REF] Sobottka | Choroidal metastases and choroidal melanomas: comparison of ultrasonographic findings[END_REF][START_REF] Verbeek | Echographic classification of intraocular tumours. A 15-year retrospective analysis[END_REF].

The growth pattern of CM differs to that of melanomas. While metastases appear to infiltrate diffusely the normal choroidal tissue, melanomas are tumors that grow slowly and usually expand through an intact Bruch membrane [START_REF] Coleman | Ultrasonic diagnosis of tumors of the choroid[END_REF][START_REF] Ferry | Carcinoma metastatic to the eye and orbit. I. A clinicopathologic study of 227 cases[END_REF][START_REF] Sobottka | Choroidal metastases and choroidal melanomas: comparison of ultrasonographic findings[END_REF]. They grow in a nodular configuration, thickening the choroid, and progression ultimately leads to the rupture of Bruch's membrane, giving the classical mushroom shape [START_REF] Coleman | Ultrasonic diagnosis of tumors of the choroid[END_REF][START_REF] Goldberg | Ultrasonographic diagnosis of choroidal malignant melanoma[END_REF][START_REF] Sobottka | Choroidal metastases and choroidal melanomas: comparison of ultrasonographic findings[END_REF].

This difference in growth pattern has been confirmed by US. Furthermore, CM are found as flat tumors with a large infiltration of the choroid that give an irregular shape in US [START_REF] Perri | Choroidal metastases. Echographic experience from 42 patients[END_REF]. Conversely, choroidal melanoma has a higher mean tumor thickness, giving it a higher height to base ratio (HBR: 0.6) than metastases (HBR: 0.18) [START_REF] Coleman | Ultrasonic diagnosis of tumors of the choroid[END_REF][START_REF] Sobottka | Choroidal metastases and choroidal melanomas: comparison of ultrasonographic findings[END_REF]. HBR determined by US potentially enables the discrimination of choroidal melanoma from CM (Figure 8).

Choroidal excavation is created by the difference in reflectivity between the abnormal tissue that replaces the choroid and the underlying normal choroid. About two-thirds of melanoma lesions are associated with choroidal excavation, while it is found in only up to a fifth of CM. [START_REF] Coleman | Ultrasonic diagnosis of tumors of the choroid[END_REF][START_REF] Fuller | Ultrasonographic features of choroidal malignant melanomas[END_REF][START_REF] Sobottka | Choroidal metastases and choroidal melanomas: comparison of ultrasonographic findings[END_REF][START_REF] Verbeek | Echographic classification of intraocular tumours. A 15-year retrospective analysis[END_REF].

Choroidal hemangiomas are also associated with choroidal excavation in about a fifth of cases [START_REF] Verbeek | Echographic classification of intraocular tumours. A 15-year retrospective analysis[END_REF].

As the resolution of US is about 50-200 ??m (Webb, 1988), it is more valuable as tumor thickness increases, and is thus mandatory for a precise measurement of large tumors.

However, the differentiation between small tumor entities can be challenging, as they could appear similar clinically; in such cases SD-OCT may help as its resolution is about 5 ??m [START_REF] Leung | Comparison of macular thickness measurements between time domain and spectral domain optical coherence tomography[END_REF] (see section 4.4).

Another application of US associated with Doppler technology is color flow mapping that can display blood flow on the background of the US image [START_REF] Belden | Color Doppler US of the orbit[END_REF]. Quantitative parameters do not seem useful to determine tumor type and their diagnostic value remains unclear at this time [START_REF] Neudorfer | Color flow mapping: a non-invasive tool for characterizing and differentiating between uveal melanomas and choroidal metastases[END_REF][START_REF] Wolff-Korman | Duplex and color Doppler ultrasound in the differential diagnosis of choroidal tumors[END_REF]. Qualitative parameters seem to be more useful to differentiate choroidal melanomas from CM. Vascular features, such as hypovascularity, with a dominant centrally located vessel with blood flow is typically associated with choroidal melanoma, whereas hypervascularity with lack of dominant vessel is typically associated with CM. Neudorfer et al. have described this 'central pattern' of blood flow in melanoma, contrasting with the 'peripheral pattern' in metastasis [START_REF] Neudorfer | Color flow mapping: a non-invasive tool for characterizing and differentiating between uveal melanomas and choroidal metastases[END_REF].

Angiography

Fluorescein angiography (FA) is generally not decisive for the diagnosis of CM [START_REF] Meyer | Independent diagnostic value of fluorescein angiography in the evaluation of intraocular tumors[END_REF] because almost all choroidal tumors have the same angiographic features: usually hypofluorescent in the early phase and heterogeneously hyperfluorescent in the late phase. In some cases, pinpoints and leakage areas are seen on the mass (Konstantinidis and Damato, 2017) (Figure 9).

Conversely to FA, ICGA helps in the differential diagnosis of choroidal tumors. CM are usually defined as hypofluorescent at all phases on an underlying isofluorescent background (C. L. Shields et al., 1995a), and the "double circulation" pattern, first described in choroidal melanoma by Augsburger, is generally not found in CM [START_REF] Augsburger | Fluorescein angiography of choroidal malignant melanomas with retinal invasion[END_REF][START_REF] Konstantinidis | Intraocular Metastases--A Review[END_REF]. Furthermore, due to better visualization of the choroid,

ICGA generally shows a larger area of choroidal involvement of the metastases than does clinical examination or FA (Figure 10).

Blue light fundus autofluorescence shows a heterogeneous pattern with areas of hypo and hyper-autofluorescence [START_REF] Ishida | Autofluorescence of metastatic choroidal tumor[END_REF][START_REF] Natesh | Choroidal metastases fundus autofluorescence imaging: correlation to clinical, OCT, and fluorescein angiographic findings[END_REF]. This exam detects lipofuscin in the RPE, which is disturbed in cases of RPE alterations. This pattern is also found in hemangioma or choroidal melanoma.

Optical coherence tomography

The small size and posterior location of most CM (Shields et al., 1997b) make these tumors ideal candidates for investigation using OCT. Anatomical features on SD-OCT, enhanced depth imaging (EDI)-OCT, and OCT-angiography (OCTA) can help identify the type of choroidal tumor, and are most useful for the follow-up of the tumor aspect, size, and retinal consequences.

Choroidal thickness estimated by optical coherence tomography

Time domain OCT was limited for the exploration of choroidal structures, including CM [START_REF] Arevalo | Optical coherence tomography characteristics of choroidal metastasis[END_REF]. SD-OCT with EDI, and more recently swept-source OCT, have improved our understanding of the choroid and provided detailed information about the morphological features of choroidal tumors [START_REF] Demirci | Enhanced depth imaging optical coherence tomography of choroidal metastasis[END_REF][START_REF] Ferrara | Investigating the choriocapillaris and choroidal vasculature with new optical coherence tomography technologies[END_REF][START_REF] Ishida | Swept-source optical coherence tomographic findings in eyes with metastatic choroidal tumor[END_REF]. In EDI-OCT, CM has a low internal optical reflectivity, with an enlarged suprachoroidal space [START_REF] Cennamo | Evaluation of choroidal tumors with optical coherence tomography: enhanced depth imaging and OCT-angiography features[END_REF]. The internal reflectivity can increase after treatment.

EDI-OCT is also more sensitive for the detection of very small CM before they are clinically visible [START_REF] Al-Dahmash | Enhanced depth imaging optical coherence tomography of choroidal metastasis in 14 eyes[END_REF][START_REF] Torres | Optical coherence tomography enhanced depth imaging of choroidal tumors[END_REF][START_REF] Witkin | Enhanced depth imaging spectral-domain optical coherence tomography of a subtle choroidal metastasis[END_REF] and it is estimated that 20% of CM are visible only on EDI-OCT [START_REF] Demirci | Enhanced depth imaging optical coherence tomography of choroidal metastasis[END_REF]. For instance, in a series of 31 eyes with CM, tumors as small as 550 µm were imaged using EDI-OCT but were not readily identified by US or ophthalmoscopy; they were located in the outer choroid, with a loss of large choroidal vessels [START_REF] Al-Dahmash | Enhanced depth imaging optical coherence tomography of choroidal metastasis in 14 eyes[END_REF].

Although some lesions are visible both in US and EDI-OCT, US overestimates thickness by 55-133% according to tumor size [START_REF] Al-Dahmash | Enhanced depth imaging optical coherence tomography of choroidal metastasis in 14 eyes[END_REF][START_REF] Demirci | Enhanced depth imaging optical coherence tomography of choroidal metastasis[END_REF]Shields et al., 2012) and the mean difference in tumor thickness between the two modalities was found to be 536 µm [START_REF] Demirci | Enhanced depth imaging optical coherence tomography of choroidal metastasis[END_REF]. This difference is explained by the greater axial resolution of EDI-OCT [START_REF] Webb | Diagnostic ultrasound[END_REF]) compared to US [START_REF] Leung | Comparison of macular thickness measurements between time domain and spectral domain optical coherence tomography[END_REF] that allows a more precise placement of calipers with respect to surrounding ocular structures, and which is most useful for very small choroidal lesions (Figure 11).

Specific signs in optical coherence tomography

In addition to tumor thickness, OCT allows to visualize specific patterns associated with CM.

The most noticeable feature is the irregular or "lumpy bumpy" anterior surface of the lesion, despite an apparently smooth surface on US [START_REF] Al-Dahmash | Enhanced depth imaging optical coherence tomography of choroidal metastasis in 14 eyes[END_REF]. This aspect is different from the smooth "mound" of nevus or the smooth "dome" of melanoma, and can help identify the type of choroidal tumor (Table 3 and Figure 12).

OCT features Choroidal nevus

Smooth mound shape Small melanoma Dome shape Choroidal metastasis Lumpy bumpy Choroidal osteoma Lamellar shape Choroidal hemangioma Abrupt smooth dome-shape Table 3: Optical coherence tomography (OCT) features of the anterior surface of various choroidal tumors (according to [START_REF] Al-Dahmash | Enhanced depth imaging optical coherence tomography of choroidal metastasis in 14 eyes[END_REF]).

Another sign frequently associated with CM is SRF. This is found in 67-95% of cases, mostly with hyper-reflective dots within the SRF that are known as speckles [START_REF] Al-Dahmash | Enhanced depth imaging optical coherence tomography of choroidal metastasis in 14 eyes[END_REF][START_REF] Demirci | Enhanced depth imaging optical coherence tomography of choroidal metastasis[END_REF][START_REF] Vishnevskia-Dai | Optical Coherence Tomography: An Adjunctive Tool for Differentiating between Choroidal Melanoma and Metastasis[END_REF]. These dots may be shed photoreceptor outer segments in longstanding SRF overlying CM [START_REF] Demirci | Enhanced depth imaging optical coherence tomography of choroidal metastasis[END_REF]. The optical density or substance reflectivity of the SRF can also be measured by OCT, and can be indicative of the cause of SRF [START_REF] Baek | Optical density ratio in the subretinal fluid: differentiating chronic central serous chorioretinopathy and polypodial choroidal vasculopathy[END_REF][START_REF] Neudorfer | Differential optical density of subretinal spaces[END_REF] as the optical density ratio of SRF was found to be significantly lower in CM than in melanoma [START_REF] Leshno | OPTICAL DENSITY RATIO OF THE SUBRETINAL FLUID IN CHOROIDAL MELANOMA AND METASTASIS[END_REF]. This suggests that the composition of the SRF, mainly its protein content, is different between tumor types. As the composition may change over time, one can assume that fluid detected earlier would have a lower protein concentration and a lower optical density than fluid that is detected later during disease progression. Because CM are usually in the posterior pole, they become symptomatic and are evaluated by OCT earlier than choroidal melanoma. This may explain why the SRF has a low optical density at time of evaluation.

Conversely, choroidal melanoma can be peripheral and asymptomatic for a long time, and therefore imaging may occur after a longer duration of SRF secretion, when it has a higher optical density. Another explanation could be the difference in the vascular properties of the tumors. For instance, CM have been shown to be more hypervascularized than choroidal melanoma [START_REF] Neudorfer | Color flow mapping: a non-invasive tool for characterizing and differentiating between uveal melanomas and choroidal metastases[END_REF] and a higher vascular permeability may affect the composition of the SRF and cause the lower optical density observed in metastasis. Other OCT features of metastatic tumors include shaggy photoreceptors, alteration of the ellipsoid zone, RPE changes (atrophy or hyperplasia), and choriocapillaris compression [START_REF] Demirci | Enhanced depth imaging optical coherence tomography of choroidal metastasis[END_REF] (Table 4 andFigure 13). Despite the variety of described OCT features in CM, we did not identify any difference in features according to the type of primary cancer.

OCT is also useful in the follow-up of choroidal lesions after therapy, especially to monitor changes in thickness, quantity of SRF, shaggy photoreceptor appearance and reflectivity, which can confirm the anatomical effectiveness of therapy. As mentioned earlier, the internal optical reflectivity of the tumor increases as the metastatic tumor becomes inactive, consistent with an increase in fibrotic tissue content [START_REF] Demirci | Enhanced depth imaging optical coherence tomography of choroidal metastasis[END_REF]. 4: Optical coherence tomography features of choroidal metastasis (according to [START_REF] Al-Dahmash | Enhanced depth imaging optical coherence tomography of choroidal metastasis in 14 eyes[END_REF][START_REF] Demirci | Enhanced depth imaging optical coherence tomography of choroidal metastasis[END_REF][START_REF] Vishnevskia-Dai | Optical Coherence Tomography: An Adjunctive Tool for Differentiating between Choroidal Melanoma and Metastasis[END_REF]). RPE: retinal pigment epithelium.

Frequency, range (%)

Optical coherence tomography-angiography

OCT angiography (OCTA) is a non-invasive, high speed based imaging technique enabling visualization of blood flow in the retina and choroid through comparison of successive Ascans [START_REF] Borrelli | OCT angiography and evaluation of the choroid and choroidal vascular disorders[END_REF][START_REF] Spaide | Optical coherence tomography angiography[END_REF]. OCTA may help differentiate tumors as in CM there is a lack of flow at the level of the lesion and absence of pathological blood flow in the outer retinal layer, whereas in choroidal melanoma, hemangioma, and osteoma there may be a dense, irregular vascular network inside the tumor and even increased flow in the outer nuclear layer [START_REF] Cennamo | Evaluation of choroidal tumors with optical coherence tomography: enhanced depth imaging and OCT-angiography features[END_REF]. This seems contradictory to US findings of hypervascularity in CM [START_REF] Neudorfer | Color flow mapping: a non-invasive tool for characterizing and differentiating between uveal melanomas and choroidal metastases[END_REF], but the lack of flow detection may be explained by the masking effect of the RPE on the underlying tumor neovascularization, or by a fringe washout due to higher flow speed inside the tumor [START_REF] Chen | Classification of image artefacts in optical coherence tomography angiography of the choroid in macular diseases[END_REF][START_REF] Spaide | IMAGE ARTIFACTS IN OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY[END_REF] (Figure 14).

Neuro-imaging: CT-scan and MRI

Computed tomography (CT) is rarely useful in cases of ocular tumors. Magnetic resonance imaging (MRI) shows a well-defined choroidal mass that appears isointense on T1-weighted images and hypointense on T2-weighted images [START_REF] Peyster | Intraocular tumors: evaluation with MR imaging[END_REF]. The resolution of conventional MRI is limited when it comes to the eye, primarily because of motion artefacts due to blinking and gaze changes, but also because of field inhomogeneity at the air-cornea interface. Additionally, the use of head coils for imaging the eye produces a low signal-tonoise ratio [START_REF] Atlas | Surface-coil MR of orbital pseudotumor[END_REF][START_REF] Bilaniuk | Ocular and orbital lesions: surface coil MR imaging[END_REF]. High resolution MRI (HRMRI) limits motion artefacts by using conjugate gaze and cued blinking. Interface artefacts are limited by applying a wetted gauze on the eyelids [START_REF] Bert | Highresolution MR imaging of the human eye 2005[END_REF]. Surface coils and high magnetic fields (3 and 7 Tesla) also result in a better signal-to-noise ratio [START_REF] Beenakker | High-resolution MRI of uveal melanoma using a microcoil phased array at 7 T[END_REF].

Several HRMRI studies have been conducted on choroidal melanoma and retinoblastoma. In melanoma, both 1.5 Tesla and 7 Tesla HRMRI better reveal internal structure and scleral invasion than conventional MRI [START_REF] Beenakker | High-resolution MRI of uveal melanoma using a microcoil phased array at 7 T[END_REF][START_REF] Lemke | Appearance of choroidal melanoma on high resolution MRI using 1.5T with a dedicated surface coil in 200 consecutive patients[END_REF][START_REF] Lindner | Anatomic and pathological characterization of choroidal melanoma using multimodal imaging: what is practical, what is needed?[END_REF]. In retinoblastoma, both 1.5 and 3 Tesla HRMRI are established as predictors of metastatic risk, based on scleral, choroidal, and optic nerve invasion [START_REF] De Jong | The potential of 3T high-resolution magnetic resonance imaging for diagnosis, staging, and follow-up of retinoblastoma[END_REF][START_REF] Sirin | High-resolution MRI using orbit surface coils for the evaluation of metastatic risk factors in 143 children with retinoblastoma: Part 1: MRI vs[END_REF]. To date there are no published in vivo HRMRI patient studies on CM, but it is reasonable to believe that it would be useful when the tumor is not visible because of intravitreal or subretinal hemorrhage, or complete retinal detachment. As resolution increases, HRMRI may give insight on the histological type of the metastasis and help differentiate CM from a primary ocular tumor. Recently, a novel MRI modality, MR microscopy (MRM), was assessed ex vivo for the diagnosis of intraocular lesions. MRM provides resolution in the submillimeter range with an excellent signal-to-noise ratio, and has allowed the visualization of tumor ultrastructure with good correlation to histology. This could help differentiate CM from other tumors, but also identify the type of primary cancer [START_REF] Falke | Experimental differentiation of intraocular masses using ultrahigh-field magnetic resonance imaging--a case series[END_REF].

Diagnosis work-up

Up to a third of patients presenting with intraocular metastases have no known history of cancer [START_REF] Konstantinidis | Management of patients with uveal metastases at the Liverpool Ocular Oncology Centre[END_REF]Shields et al., 1997b). It is therefore important to manage systemic work-up to identify the primary site of neoplasia. If no primary tumor has been found, biopsy for cytological or histopathological analysis should be considered. Unlike most organs where a biopsy is readily accessible, retrieving a biopsy from a small choroidal lesion requires a skilled and experienced surgeon and carries a risk of intraocular injury. Biopsy is further limited by the necessity of a qualified pathologist and often insufficient or inadequate retrieved material [START_REF] Cohen | Transvitreal fine needle aspiration biopsy: the influence of intraocular lesion size on diagnostic biopsy result[END_REF]. These limitations highlight the need for a non-invasive ancillary diagnostic test that will help characterize intraocular lesions.

General work-up

The diagnostic work-up depends on whether there is a history of cancer and whether it is already generalized when CM is diagnosed. If the CM is very large (and enucleation is performed), the work-up is usually guided by the histological findings. If there is no history of primary tumor, a thorough medical history (including gender, smoking habit, previous breast cancer screening) and physical examination is required and these will guide the ophthalmologist in the search for primary tumor. In cases with known metastatic dissemination, past medical history is usually sufficient to guide ocular and general treatment.

In cases where there is a history of cancer but no history of metastases, diagnostic work-up should be specific to the suspected cancer type; it may include mammograms, positron emission tomography (PET)-CT, etc.

Tumor biopsy

Rationale

Histological proof of cancer is generally required by oncologists to guide treatment [START_REF] Chin | Second cancers discovered by (18)FDG PET/CT imaging for choroidal melanoma[END_REF][START_REF] Overgaard | Uveal malignant melanoma. An ophthalmological or oncological disease?[END_REF]. The eye is, however, an exception to this rule, as intraocular tissues are not readily accessible for biopsy, and it is accepted to start treatment without cytological or histological confirmation in case of uveal melanoma [START_REF] Foulds | The uses and limitations of intraocular biopsy[END_REF][START_REF] Harbour | Molecular prognostic testing in uveal melanoma: has it finally come of age?[END_REF]. Tumor biopsy is nowadays widely used for the prognostication in choroidal melanoma and can help the oncologist determine the risk of metastasis [START_REF] Damato | Ocular treatment of choroidal melanoma in relation to the prevention of metastatic death -A personal view[END_REF][START_REF] Damato | Estimating prognosis for survival after treatment of choroidal melanoma[END_REF]. However, in CM, the aim is quite different because biopsy is mostly indicated to determine the type of primary tumor when it is still unknown after a thorough systemic workup [START_REF] Konstantinidis | Management of patients with uveal metastases at the Liverpool Ocular Oncology Centre[END_REF].

Although a tissue sample will support the diagnosis, obtaining it is not without risk for the vision or life of the patient, and the risk-benefit ratio must be considered. It is thought that intraocular biopsy may increase the risk of dissemination of malignant cells, and presents a risk of severe ocular complications, which may explain its limited use [START_REF] Eide | Fine-needle aspiration biopsy and other biopsies in suspected intraocular malignant disease: a review[END_REF]. However, intraocular tumors are generally accessible to sampling using fine needle aspiration biopsy (FNAB) transsclerally or transvitreally [START_REF] Augsburger | Frequency and implications of discordant gene expression profile class in posterior uveal melanomas sampled by fine needle aspiration biopsy[END_REF][START_REF] Mccannel | Multi-year follow-up of fine-needle aspiration biopsy in choroidal melanoma[END_REF][START_REF] Sellam | Fine Needle Aspiration Biopsy in Uveal Melanoma: Technique, Complications, and Outcomes[END_REF][START_REF] Singh | Fine-needle aspiration biopsy of uveal melanoma: outcomes and complications[END_REF]. This technique does not consist of an actual biopsy, but rather cytological tissue sampling. The aim is to confirm the metastatic nature of the tumor, and to help determine the likely site of primary malignancy in order to plan imaging and complete workup accordingly [START_REF] Eide | Fine-needle aspiration biopsy and other biopsies in suspected intraocular malignant disease: a review[END_REF][START_REF] Shields | Fine-needle aspiration biopsy of suspected intraocular tumors. The 1992 Urwick Lecture[END_REF].

One of the limitations of FNAB is the risk of inadequate sampling experience resulting in false negatives, which must be considered when dealing with small tumors. The of the cytopathologist is important to reduce this risk, as decisions need to be made on a small number of cells. Optimally, the cytologist should be present in the operating room to ensure that an adequate amount of biopsy material is obtained [START_REF] Konstantinidis | Management of patients with uveal metastases at the Liverpool Ocular Oncology Centre[END_REF].

Another technique, more recently described, consists of an intraocular biopsy using the vitreous cutter or special forceps penetrating directly into the tumor and is highly effective in obtaining a tissue sample [START_REF] Akgul | Intraocular biopsy using special forceps: a new instrument and refined surgical technique[END_REF][START_REF] Bagger | The ocular consequences and applicability of minimally invasive 25-gauge transvitreal retinochoroidal biopsy[END_REF][START_REF] Konstantinidis | Management of patients with uveal metastases at the Liverpool Ocular Oncology Centre[END_REF][START_REF] Sen | Transretinal choroidal tumor biopsy with a 25-gauge vitrector[END_REF][START_REF] Seregard | Diagnostic incisional biopsies in clinically indeterminate choroidal tumours[END_REF]. A transscleral incisional biopsy with forceps, recently described by Angi et al. in cases of choroidal melanomas, could yield more successful histological analysis [START_REF] Angi | Prognostic biopsy of choroidal melanoma: an optimised surgical and laboratory approach[END_REF].

Ocular tumor biopsy is most useful in patients with atypical clinical findings, when it is challenging to differentiate between CM and primary choroidal melanoma, or when systemic investigation has failed to identify primary malignancy. In our opinion, any discordance between non-invasive tests should warrant ocular tumor biopsy to confirm the histological nature of the tumor. For instance, in a group of patients with intraocular masses, major diagnostic uncertainty was reported in 2.4% of cases (159 of 6500 patients evaluated) [START_REF] Shields | Fine-needle aspiration biopsy of suspected intraocular tumors. The 1992 Urwick Lecture[END_REF]. In these patients, a biopsy was required in order to establish the diagnosis and to initiate the appropriate treatment. FNAB yielded adequate cytological material in 88% of cases. Furthermore, when no primary tumor is identified by systemic workup, tissue sampling has been shown to successfully confirm the metastatic nature of the lesion and identify its origin in most cases [START_REF] Akgul | Intraocular biopsy using special forceps: a new instrument and refined surgical technique[END_REF][START_REF] Konstantinidis | Management of patients with uveal metastases at the Liverpool Ocular Oncology Centre[END_REF][START_REF] Sen | Transretinal choroidal tumor biopsy with a 25-gauge vitrector[END_REF].

In addition to histological confirmation, tumor biopsy can also help to identify specific molecular alterations, some of which may be targeted by so-called targeted therapies. For example, in breast cancer, immunohistochemical evaluation can identify patients with HER2/neu-positive disease, which is associated with a higher risk of recurrence, and may benefit from adjuvant anti-HER2/neu-directed therapy [START_REF] Wolff | American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer[END_REF]. Furthermore, histopathological evaluation can identify estrogen and/or progesterone receptor-positive tumor cells, predicting benefit from endocrine therapy [START_REF] Hammond | American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer[END_REF]. In non-small cell lung cancer, deoxyribose nucleic acid (DNA) can be extracted from the residual biopsy material and assessed for the presence of epidermal growth factor receptor (EGFR) mutations.

When these are present, targeted therapy with EGFR-tyrosine kinase inhibitors, such as gefitinib and erlotinib, has been shown to increase survival in lung carcinoma patients (see section 6.2) [START_REF] Lin | Optimal management of patients with non-small cell lung cancer and epidermal growth factor receptor mutations[END_REF][START_REF] Rosell | Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial[END_REF]. KRAS mutation can also be tested, especially in cases where colorectal cancer is suspected (KRAS oncogene is mutated in 35-45% of colorectal cancer and is a biomarker of poor response to anti-EGFR therapy [START_REF] Karapetis | K-ras mutations and benefit from cetuximab in advanced colorectal cancer[END_REF][START_REF] Van Cutsem | Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer[END_REF].

Technique

FNAB of choroidal tumors takes practice, and sometimes several attempts before yielding useful material [START_REF] Mccannel | Fine-needle aspiration biopsy in the management of choroidal melanoma[END_REF]. Depending on the tumor site, it may be performed by transscleral or transvitreal approach. The transscleral approach, which is easier and more widespread, is indicated for pre-equatorial lesions, and for large lesions away from the posterior pole (lesions > 10 mm at the base, > 3mm in height, and with the anterior border halfway between the equator and the optic disc) [START_REF] Eide | Fine-needle aspiration biopsy and other biopsies in suspected intraocular malignant disease: a review[END_REF]. It involves placing the needle through the sclera and into the tumor after precise localization by transillumination and indirect ophthalmoscopy if necessary. This procedure can be performed at the same time as the placement of brachytherapy plaques or tantalum fiducials (for proton therapy). Small lesions with a posterior location, especially if they are thin, are more safely biopsied with a transvitreal approach (Shields et al., 2007a(Shields et al., , 2007b)). The transvitreal FNAB is performed by inserting a needle through a sclerotomy opposite the tumor, which is visualized directly with a wide-field lens. The needle is then inserted transretinally into the tumor and material aspirated [START_REF] Augsburger | Frequency and implications of discordant gene expression profile class in posterior uveal melanomas sampled by fine needle aspiration biopsy[END_REF][START_REF] Mccannel | Multi-year follow-up of fine-needle aspiration biopsy in choroidal melanoma[END_REF][START_REF] Sellam | Fine Needle Aspiration Biopsy in Uveal Melanoma: Technique, Complications, and Outcomes[END_REF][START_REF] Singh | Fine-needle aspiration biopsy of uveal melanoma: outcomes and complications[END_REF].

The biggest challenge with FNAB is to obtain sufficient material for analysis. In general, the yield is greater for large tumors, but they may contain areas of necrotic material which is not useful for the pathologist. Several passes may be necessary in order to obtain sufficient material [START_REF] Mccannel | Fine-needle aspiration biopsy in the management of choroidal melanoma[END_REF].

A variation of transvitreal needle biopsy consists of aspirating inside the tumor using a 25 gauge vitrector, with [START_REF] Bechrakis | Biopsy in indeterminate intraocular tumors[END_REF] or without prior vitrectomy [START_REF] Bagger | The ocular consequences and applicability of minimally invasive 25-gauge transvitreal retinochoroidal biopsy[END_REF][START_REF] Konstantinidis | Management of patients with uveal metastases at the Liverpool Ocular Oncology Centre[END_REF][START_REF] Sen | Transretinal choroidal tumor biopsy with a 25-gauge vitrector[END_REF]. This method was shown to yield larger tissue samples with a 92% chance of successful diagnosis [START_REF] Sen | Transretinal choroidal tumor biopsy with a 25-gauge vitrector[END_REF]. Another variation of this technique is to use biopsy forceps after small incision at the chosen biopsy site [START_REF] Akgul | Intraocular biopsy using special forceps: a new instrument and refined surgical technique[END_REF][START_REF] Seregard | Diagnostic incisional biopsies in clinically indeterminate choroidal tumours[END_REF].

Transvitreal choroidal biopsies for tissue sampling have become more common over recent years due to the improvement of surgical techniques such as sutureless 25-gauge vitrectomy that reduces surgical trauma.

Complications

It is accepted in oncology that a tumor biopsy carries a risk of tumor cell dissemination, increased rate of local recurrence, and increased risk of metastatic development. However, this has not been reported for biopsy of CM or choroidal melanoma. To the best of our knowledge there is no report of secondary tumor implantation at an eye wall entry site used for biopsy, nor any report of enucleation secondary to biopsy complication. Other local complications may include intravitreal hemorrhage or retinal detachment. For instance, in a series of FNAB reported by Augsburger et al., about 60% of patients undergoing FNAB had any-grade vitreous hemorrhage [START_REF] Augsburger | Frequency and implications of discordant gene expression profile class in posterior uveal melanomas sampled by fine needle aspiration biopsy[END_REF]. However, in a recent series reported by Grixti et al., only 20/739 eyes (2.7%) that underwent choroidal tumor biopsy required vitreoretinal surgery for biopsy-related complications including persistent vitreous hemorrhage in 14 eyes, rhegmatogenous retinal detachment in 5 eyes, and endophthalmitis in 1 eye [START_REF] Grixti | Vitreoretinal surgery for complications of choroidal tumor biopsy[END_REF].

Guidelines

Tumor biopsy should only be performed when it is likely to provide a diagnosis and this is largely determined by tumor thickness, especially for FNAB. There is a strong correlation between the rate of successful diagnosis from a FNAB and the thickness of the lesions on US (< 1.9 mm: 40%; 1.9-4 mm: 90%; > 4 mm: 98%) [START_REF] Cohen | Transvitreal fine needle aspiration biopsy: the influence of intraocular lesion size on diagnostic biopsy result[END_REF], and it is also of note that sufficient aspirate was obtained in almost two-thirds of tumors that had a thickness of 1.5-3 mm [START_REF] Augsburger | Diagnostic transvitreal fine-needle aspiration biopsy of small melanocytic choroidal tumors in nevus versus melanoma category[END_REF]. Overall, FNAB can be expected to give useful information in lesions > 3 mm in thickness, but is unreliable in lesions thinner than 2 mm [START_REF] Eide | Fine-needle aspiration biopsy and other biopsies in suspected intraocular malignant disease: a review[END_REF]. No thickness cut-off has been described for transvitreal biopsy using the vitreous cutter or forceps [START_REF] Damato | Ocular treatment of choroidal melanoma in relation to the prevention of metastatic death -A personal view[END_REF].

As a rule of thumb, it is unnecessary to perform an eye biopsy in a patient with multi-organ metastases if the primary tumor is known. If it is not known but other systemic metastases are present, the more readily accessible metastasis should be favored for biopsy. Nevertheless, the risk of ocular complications associated with biopsy should always be taken into consideration in the decision and discussed with the patient prior to the procedure.

Liquid biopsies

When cytology of the CM cannot be obtained, liquid biopsy could provide additional diagnostic clues. This emerging non-invasive diagnostic method usually consists of blood samples (saliva and urine are also possible) that are used to identify biomarkers of microscopic tumor dissemination, such as circulating cancer cells or circulating tumor DNA, and are mostly used to guide treatment and to monitor response during follow-up [START_REF] Heitzer | Circulating Tumor DNA as a Liquid Biopsy for Cancer[END_REF]. For example, a liquid biopsy was used in a patient with bilateral CM to detect both circulating thyroid transcription factor 1 (TTF1) positive cells and EGFR mutation that allowed the diagnosis of lung cancer and the treatment by anti-EGFR therapy [START_REF] Bouhlel | The liquid biopsy: a tool for a combined diagnostic and theranostic approach for care of a patient with late-stage lung carcinoma presenting with bilateral ocular metastases[END_REF]. Moreover, circulating tumor DNA and its mutational load has been identified as a marker of effectiveness of systemic treatments in breast cancer and may be used to switch treatment line before clinically evident disease progression [START_REF] Hench | Liquid Biopsy in Clinical Management of Breast, Lung, and Colorectal Cancer[END_REF].

Multimodal treatment: the strategy

Clinical context

Complex treatments are generally controversial for CM because metastatic patients are believed to have limited life expectancy and thus derive minimal benefit from the treatment of CM. One should, however, consider the broad spectrum of metastatic disease. As emphasized by Hellman and Weichselbaum, survival can vary from weeks to years according to whether patients have widely diffuse metastases or oligometastatic disease [START_REF] Hellman | Oligometastases[END_REF].

One of the aims of the treatment of metastatic disease is to improve progression-free survival.

This palliative approach implies a short delay of care, short and minimally invasive procedures, rapid functional results, and a low rate of treatment-induced complications.

Depending on the performance status of the patient and the type of primary cancer, the progression-free survival could, however, be drastically different. Multimodal treatment of metastatic disease is also increasingly being used to cure patients. Zacharakis et al. have recently reported a complete and durable (more than 22 months) regression of a chemoresistant metastatic breast cancer treated by specific tumor-infiltrating lymphocytes [START_REF] Zacharakis | Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer[END_REF], and overall survival in cases of breast or renal cancer after more than ten years of metastatic disease is not unusual.

Mortality in patients with CM is correlated with the presence of synchronous metastasis in the liver or lungs (d'Abbadie et al., 2003). For instance, patients with breast cancer had survival rates of 65% at 1 year, and 24% at 5 years after diagnosis of CM [START_REF] Demirci | Uveal metastasis from breast cancer in 264 patients[END_REF]. In another series reported by Shah et al., 1-year survival was 46% in CM patients with lung cancer [START_REF] Shah | Uveal metastasis from lung cancer: clinical features, treatment, and outcome in 194 patients[END_REF]. In light of these data, the term "metastatic patient" needs to be cautiously interpreted. Taking into account personalized prognosis allows the most appropriate treatment strategy to be chosen, which is especially true in end-stage disease as the primary goal of the physician must remain to do no harm; it implies weighing the potential benefits of a medical intervention against the annoyance it may cause, allowing the patient to retain the highest possible quality of life.

Although it is often overlooked in oncology, loss of visual function is a major issue in patients with ocular metastases as they may quickly loose autonomy. The treatment aims to prevent or reverse visual function loss in order to improve the patient's quality of life. It can also help prevent serious psychological consequences, by avoiding enucleation for example [START_REF] Demirci | Uveal metastasis from breast cancer in 264 patients[END_REF][START_REF] Shah | Uveal metastasis from lung cancer: clinical features, treatment, and outcome in 194 patients[END_REF]. While it may be challenging for ophthalmologists to make a therapeutic decision in the context of metastases, one should not wait too long as the risk of irreversible blindness is probably related to the duration and severity of tissue injuries before treatment.

The decision to pursue local therapy for CM is multidisciplinary, involving the patient, oncologist, ophthalmologist, and radiation oncologist. Important considerations include overall health, life expectancy, location and extent of intraocular lesion, visual symptoms, and patient preference. A detailed office evaluation is performed before treatment (indirect ophthalmoscopy, fundus drawing, photography, FA, ICGA, OCT, and US) to measure tumor size and evaluate whether it threatens the optic disk or fovea.

In case of isolated CM or oligometastatic disease: a local treatment is considered upfront. If general prognosis and performance status are relatively good, and the available therapeutic resources are not too invasive, local treatment is proposed with a good chance to retain or restore visual function. In such cases, depending on histology and ocular extent, focalized radiation techniques may be proposed, such as brachytherapy or proton therapy, or stereotactic body radiation therapy with appropriate eye tracking.

In case of multimetastatic disease threatening survival: life threatening metastases are treated with a combination of systemic and sometimes local treatments. The local treatment of CM is usually postponed, definitively or until overall metastatic disease is properly controlled. There are exceptions if the ocular symptoms are very intense and there is a long delay before chemotherapy (due to organizational reasons); in such cases, short palliative radiotherapy can be done in the first place.

Systemic therapies

Do systemic therapies effectively reach the choroid?

There are three ways to deliver drugs to the eyes: topical, intraocular, and systemic. Topical drugs are quickly drained away and the intravitreal bioavailability is estimated to be 0.0001-0.0004% [START_REF] Maurice | Drug delivery to the posterior segment from drops[END_REF], and in practice this route is not used for the delivery of oncological treatments for intraocular tumors. The intraocular administration allows the highest intravitreal or intraretinal drug concentration, as it bypasses the blood-ocular barrier [START_REF] Jordán | Advances in the understanding of retinal drug disposition and the role of blood-ocular barrier transporters[END_REF]) that works as a filter between the general circulation and the retina to maintain a protected micro-environment around the neuro-retina. It is composed of the blood-aqueous barrier (anterior) and the blood-retinal barrier (posterior). The latter is divided into inner blood-retinal barrier, formed by tight junctions between the retinal capillary endothelial cells, and the outer-blood retinal barrier, formed by the tight junctions between the RPE cells [START_REF] Hosoya | Advances in the cell biology of transport via the inner bloodretinal barrier: establishment of cell lines and transport functions[END_REF]. The retina is therefore described as a "sanctuary" protected by barriers on both sides. Similarly to the blood-brain barrier, it makes it difficult for systemic drugs to reach the retina [START_REF] Del Amo | Pharmacokinetic aspects of retinal drug delivery[END_REF]. As for the choroid itself, the notion of sanctuary is challenged by the presence of fenestrated endothelium in the highly vascularized choriocapillaris. This high permeability may allow rapid entry of drugs from the blood to the extravascular choroid [START_REF] Bill | Permeability of the intraocular blood vessels[END_REF].

Effective systemic treatments

In lung cancer

Molecular targeting has led to a paradigm shift in the treatment of several cancers, and there is an increasing number of publications reporting the effectiveness of systemic treatments on CM (Table 5). In non-small cell lung cancer for example, specific EGFR mutations make it sensitive to tyrosine kinase inhibitors such as gefitinib or erlotinib. Anaplastic lymphoma kinase (ALK) gene rearrangement can also be targeted with specific drugs such as crizotinib.

As discussed above, liquid biopsies could become sufficient to detect activated oncogenes and drug susceptibility in the near future, allowing a precise diagnosis and targeted therapy without need for an invasive biopsy [START_REF] Bouhlel | The liquid biopsy: a tool for a combined diagnostic and theranostic approach for care of a patient with late-stage lung carcinoma presenting with bilateral ocular metastases[END_REF].

Yang et al. reviewed the literature and found only 12 published cases (between 1995-2014) in which patients received systemic chemotherapy alone (several chemotherapy regimens) instead of local therapy. At least two cases had only CM and no other distant metastasis. Eight (66.7%) of them demonstrated CM regression after treatment with survival ranging from 3 to more than 18 months after CM diagnosis. They did not detail the delay nor the duration of the response [START_REF] Yang | The effect of chemotherapy with cisplatin and pemetrexed for choroidal metastasis of non-squamous cell carcinoma[END_REF]. Shah et al. described 22 patients with lung cancer treated by chemotherapy alone among which regression of CM was found in 68% of cases, whereas 15 eyes managed by observation only showed regression in only 20% of cases [START_REF] Shah | Uveal metastasis from lung cancer: clinical features, treatment, and outcome in 194 patients[END_REF]. 5: Cases of patients with CM and lung cancer treated by systemic therapy only published in the last 10 years (English language). Crizotinib and alectinib are tyrosine kinase inhibitors indicated in lung cancer with rearrangement of Echinoderm Microtubule Associated Protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) genes; erlotinib and gefitinib are anti-epidermal growth factor receptor (EGFR) drugs. Gene mutations were identified in lung tumor before administration of the specific anti-tyrosine kinases; PD-L1: programmed death ligand 1; CM: choroidal metastases; NR: not reported.

Study

In breast cancer

There are fewer reported cases of breast cancer CM responding to systemic treatment, and most of these concern patients with high tumor expression of estrogen and progesterone receptors. This represents about 80% of breast cancer cases, and is associated with better systemic prognosis, but also with a higher rate of choroidal involvement [START_REF] Parrozzani | Intraocular Metastases Secondary to Breast Carcinoma Correlates With Upregulation of Estrogen and Progesterone Receptor Expression in the Primary Tumor[END_REF]. Interestingly, the majority of such cases had a good ocular response to hormonal monotherapy (Table 6 and Figure 15). Human epidermal growth factor receptor 2 (HER2)positive breast cancer is prone to brain metastases; whether it is also prone to CM is less well understood. HER2 inhibitors such as trastuzumab have been a major advance in oncology, allowing to reverse the poor prognosis associated with HER2 overexpression. HER2 mutation can be associated with high hormonal receptor (HR) expression, and in such cases a combination of targeted drugs is used. In about 17% of cases, patients have triple negative breast cancer (i.e. HER2, estrogenic, and progesterone receptors are not expressed) [START_REF] Dent | Triple-negative breast cancer: clinical features and patterns of recurrence[END_REF][START_REF] Haffty | Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer[END_REF]. These are more likely to develop metastases within 5 years of diagnosis and there are fewer effective systemic drugs. Current evidence shows that triple negative and HER2-positive breast cancers have a higher rate of brain metastases, but the hormonal receptor positive cases (especially the luminal B subtype) are more likely to develop CM [START_REF] Parrozzani | Intraocular Metastases Secondary to Breast Carcinoma Correlates With Upregulation of Estrogen and Progesterone Receptor Expression in the Primary Tumor[END_REF].

As a decision support tool, the overall survival rates of stage IV breast cancer according to the different subtypes are as follows (data from the USA) [START_REF] Cronin | Annual Report to the Nation on the Status of Cancer, part I: National cancer statistics[END_REF][START_REF] Howlader | Differences in Breast Cancer Survival by Molecular Subtypes in the United States[END_REF]. All types: 26.5% at 5 years; HR-positive and HER2-negative (mostly luminal A subtype): 35.9% at 4 years; HR-positive and HER2-positive (luminal B subtype): 45.5% at 4 years (the difference between this subtype and the HR-positive/HER2-negative is likely to be due to the effectiveness of HER2-targeted therapies); HR-negative and HER2-positive (subtype HER2-enriched): approximately 34% at 4 years; HR-negative and HER2-negative (triple negative): 11.2% at 4 years. 6: Cases of patients with CM from breast cancer treated by systemic therapy only that have been published in the last 20 years (English language). Expression of human epidermal growth factor receptor 2 (HER2) or hormonal receptors was identified in the tumor before administration of trastuzumab or hormone therapy (tamoxifen and aromatase inhibitors, including letrozole) respectively. CM: choroidal metastases.

Authors

In other primary cancers

There are very few reports of CM from malignancies other than breast or lung cancer, and most of these where managed by external beam radiation therapy (EBRT), with or without systemic therapy. Essadi et al. reported a case of a CM from clear-cell renal carcinoma successfully treated by everolimus alone (an inhibitor of mammalian target of rapamycin, mTOR,) as second-line systemic treatment (the patient also had lung metastases). The patient had complete recovery of vision at 4 months and partial response as assessed by tumor size [START_REF] Essadi | Successful management of retinal metastasis from renal cancer with everolimus in a monophthalmic patient: a case report[END_REF]. In CM from prostate cancer, some case reports have shown the effectiveness of hormonal blockade monotherapy [START_REF] Primavera | Choroidal metastasis from clinically regressed prostate adenocarcinoma: imaging of a rare case[END_REF].

It should be kept in mind that the prognosis of stage IV disease status varies greatly among the various types of cancer. For instance, in a study of 1028 patients with metastatic renal cell carcinoma, those who had no identified risk factor survived several years (mean: 43.2 months) with a good quality of life [START_REF] Heng | External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study[END_REF], whereas in metastatic prostate cancer, one in four men survived more than five years [START_REF] Wu | No improvement noted in overall or cause-specific survival for men presenting with metastatic prostate cancer over a 20-year period[END_REF]. This illustrates the necessity of close cooperation between the ophthalmologist and the oncologist in order to properly consider the risks and benefits of CM treatment.

Targeted therapies: can they replace local treatment?

The multiple reports of improvement or stabilization of vision under targeted therapy is encouraging, both for the patient and the ophthalmologist (Tables 5 and6). In such cases, one may argue that local treatment, together with the risk of serious side effects it carries, is unnecessary. However, some limitations must be considered. For instance, evidence is only provided by case reports with limited follow-up (usually less than one year) and therefore the level of proof is not sufficient to assert the superiority of targeted treatments on CM. There may even be a reporting bias, as cases where systemic treatment was not effective on CM are probably under-reported. In the absence of randomized studies, and given the scarcity of oncological studies with a specific focus on CM, no definite conclusion can be drawn.

Furthermore, it appears that systemic treatment may have a lower rate of initial response and a higher rate of ocular relapse compared to local treatment (and results presented as positive after systemic treatment may not make the distinction between complete and partial clinical response). However, consolidative local treatment is helpful in achieving a higher response rate, and preventing ocular relapses. For instance, in a series of 194 patients with uveal metastases of lung cancer, partial response was reported in 68% of patients receiving systemic treatment alone, versus 82-86% of patients receiving additional local treatment by photonbased-EBRT or brachytherapy; regrowth at one year occurred in 32% of patients receiving systemic therapy, versus 14-18% for patients who had local treatment [START_REF] Shah | Uveal metastasis from lung cancer: clinical features, treatment, and outcome in 194 patients[END_REF].

Systemic molecular treatments are also subject to secondary resistance due to clonal selection, which is less the case for local physical treatments. Because of this, response to targeted therapies may not be durable, preventing the use of the same molecule in retreatment.

Illustrating this point is a case report of a patient with lung cancer who developed CM while receiving crizotinib, prompting the switch to another ALK inhibitor achieving only partial ocular response [START_REF] Okuma | Alectinib for choroidal metastasis in a patient with crizotinib-resistant ALK rearranged positive non-small cell lung cancer[END_REF]. Similarly, Cui et al. reported the case of a single CM, also from ALK-mutated lung cancer, which was treated successfully with crizotinib but later became resistant and developed a second CM in the same eye. A switch to another ALK inhibitor led only to a partial response. Visual acuity improved from 20/200 to 20/50 after treatment of the first CM, and from 20/200 to 20/60 after the treatment of the second CM [START_REF] Cui | Development of a new choroidal metastasis in resistance to crizotinib therapy in anaplastic lymphoma kinaserearranged non-small cell lung cancer[END_REF]. These examples suggest that regression of CM is a good reflection of tumor sensitivity to the systemic therapy. However, this regression can be falsely reassuring, and postponing local treatment may have consequences on visual function. Thus, initial CM response may not be clinically relevant when deciding to treat locally or not. Finally, the possibility of adverse ophthalmological events with systemic treatments should not be forgotten [START_REF] Liu | Retinal toxicities of cancer therapy drugs: biologics, small molecule inhibitors, and chemotherapies[END_REF]. For instance, mitogen-activated protein kinase kinase (MEK) inhibitors have been widely reported to be associated with uni-or pluri-focal serous detachments of the neurosensory retina, with spontaneous regression [START_REF] Francis | Clinical and Morphologic Characteristics of MEK Inhibitor-Associated Retinopathy: Differences from Central Serous Chorioretinopathy[END_REF][START_REF] Weber | Subretinal Fluid Associated With MEK Inhibitor Use in the Treatment of Systemic Cancer[END_REF]. EGFR inhibitors are also associated with ocular toxicities, most commonly dysfunctional tear syndrome, blepharitis, and eyelash changes [START_REF] Borkar | Spectrum of ocular toxicities from epidermal growth factor receptor inhibitors and their intermediate-term follow-up: a five-year review[END_REF].

Radiotherapy for choroidal metastases

Radiotherapy techniques

There are various forms of radiotherapy and various fractionation schemes depending on the local extent of the disease, its proximity to the macula, the number of lesions, the general prognosis, and the treatment goals. Another major factor is tumor radioresistance, in which case a higher total dose is required. There are also technical constraints governing the choice of the technique. They include dose conformality, dose spillage, treatment duration (beam delivery), the possibility to use numerous small doses or a single large dose, and of course access to the technique. All these integrate a patient-specific risk-benefit ratio, bearing in mind that healthy tissues are better spared with smaller doses per fraction while there is a spectrum of dose-response patterns for primary cancer. Radiotherapy techniques used to treat CM are presented below and include brachytherapy (contact brachytherapy with plaques) and external beam radiotherapy (EBRT) that itself includes tridimensional (conventional) EBRT, intensity modulated EBRT (IMRT), fractionated stereotactic EBRT (SBRT), stereotactic radiosurgery (single fraction SBRT), and proton beam therapy (PBT). Dose distributions, treatment planning and cost vary widely between these techniques. Conventional EBRT with photons is the most common treatment for CM as it is cost effective and readily accessible worldwide (it is commonly called EBRT).

Complications of radiotherapy may occur months or years after irradiation, which is relevant to long-term survivors. Depending on prognosis, the aims of radiotherapy are not only to control tumor growth, but also to preserve vision in the long term by sparing the macula and the optic disc. When possible, the anterior chamber is excluded from the irradiation field. CM that occur secondary to radioresistant tumors (for instance melanoma, renal cancer, or sarcoma) are more likely to respond to high-dose radiotherapy. On the other hand, the macula is also sensitive to radiation dose. Thus, the radiotherapy technique and treatment scheme should be adapted carefully after evaluation of the risk-benefit ratio (Figure 16).

Basic radiophysics and radiobiology

The cellular response to radiation is caused by interaction of ionizing radiation with DNA. Its clinical effect relies on differences in damage response pathways between tumor and normal tissues. At the molecular level, ionization of molecules through water radiolysis produces reactive free radicals which secondarily react with neighbouring materials, including DNA.

DNA damage schematically includes single or double strand breaks and base/sugar damages.

Higher linear energy transfer radiation, using charged particles (protons, carbon ions, etc.), also induces direct effects on molecules and higher concentration of ionizing events. It is more likely to produce complex DNA damage than low linear energy transfer radiation as achieved with EBRT, IMRT, SBRT, and brachytherapy. More complex DNA damage is associated with less efficient DNA repair and higher anti-tumor activity [START_REF] Lomax | Biological consequences of radiation-induced DNA damage: relevance to radiotherapy[END_REF].

Intriguingly, the dose necessary to achieve CM control seems to be lower than that used for primary tumors. It may be that choroid tumor burden is limited but the precise mechanisms for such observations are unclear. The radiobiology of stereotactic radiosurgery is not fully understood but it is thought that it delivers a greater biologically equivalent dose, and that different molecular mechanisms are involved. This would account for a better local control rate than with conventional EBRT, even in radioresistant tumors [START_REF] Shibamoto | Radiobiology of hypofractionated stereotactic radiotherapy: what are the optimal fractionation schedules?[END_REF].

Organs at risk in ocular radiation oncology

There is a dose-response relationship for the tissue effects of radiation therapy (Table 7) and therefore treatment decision is based on the tolerance of a given organ or tissue to a given dose based on previous knowledge. The dose threshold is either given as maximal or mean dose (and associated dose volume relationships) depending on whether the organ is considered to have "serial" or "parallel" architecture (by analogy with electricity). Serial organs are sensitive to hot spots while parallel organs are sensitive to relatively lower doses in larger portions of their volume. Fractionation plays a major role in the tolerance of healthy organs and tissues. Normofractionation of 2 Gray (Gy) fractions is the standard curative radiotherapy scheme. Alternative fractionation may be used in different situations, including metastases. Equieffective dose is then calculated from the dose per fraction and the duration of the treatment to estimate tumor response and normal tissue tolerance. For CM, the most common regimen of 30 Gy in 10 fractions is estimated to be equivalent to around 38-40 Gy in normofractionation [START_REF] Kuperman | Effect of radiation protraction in hypofractionated radiotherapy[END_REF]. A total dose of 40 Gy is under the critical "toxic" threshold for maculopathy. This may explain the good visual preservation rate obtained with conventional EBRT using this common radiotherapy scheme for CM. However, pathological changes to the eye due to the CM or other health conditions may also influence the organ's tolerance and visual preservation after radiotherapy.

OCULAR TISSUES DOSE OBJECTIVE (standard fractionation) COMMENTS

Lens [START_REF] Thariat | Cataract Avoidance With Proton Therapy in Ocular Melanomas[END_REF] Mean lens dose < 0.5 Gy avoids lens opacities. Mean lens dose < 5-8 Gy avoids symptomatic cataract.

Acute lens toxicity is not seen. Radiation-induced cataract occurs generally 1 to 3 years after irradiation. Cornea [START_REF] Jeganathan | Ocular risks from orbital and periorbital radiation therapy: a critical review[END_REF] Maximal dose to cornea < 40-60 Gy avoid risk of keratitis, ulcer or edema. Perforation is rare and seen only above 60 Gy Acute toxicity is due to loss of the tear film and generally resolves within a few weeks.

Retina [START_REF] Emami | Tolerance of normal tissue to therapeutic irradiation[END_REF][START_REF] Parsons | Radiation optic neuropathy after megavoltage external-beam irradiation: analysis of time-dose factors[END_REF] Volume of retina receiving 45 Gy < 50% Acute retinal toxicity is not seen. Significant retinopathy occurred typically 3 months to 3 years after radiotherapy, depending on the dose and other medical condition (diabetes). Optic nerve [START_REF] Bhandare | Does altered fractionation influence the risk of radiation-induced optic neuropathy?[END_REF][START_REF] Parsons | Radiation optic neuropathy after megavoltage external-beam irradiation: analysis of time-dose factors[END_REF] Maximal dose to optic nerve < 55Gy Acute toxicity is not reported. Radiation-induced optic neuropathy occurs between 3 months and 8 years after treatment with a peak at 18 months. Chiasma [START_REF] Bhandare | Does altered fractionation influence the risk of radiation-induced optic neuropathy?[END_REF][START_REF] Parsons | Radiation optic neuropathy after megavoltage external-beam irradiation: analysis of time-dose factors[END_REF] Maximal dose to the chiasma < 55Gy

Chiasma is posterior and generally preserved in the treatment of CM. Hypofractionation (i.e. fraction dose greater than 2.5 Gy and shorter treatment course) is associated with an increased risk of cataract [START_REF] Belkacémi | Radiation-induced cataract: physiopathologic, radiobiologic and clinical aspects[END_REF][START_REF] Thariat | Cataract Avoidance With Proton Therapy in Ocular Melanomas[END_REF]. It can be reduced by lens shielding and lens-sparing techniques. The success rate for routine cataract surgery following radiation therapy is similar to that for the general population. In practice, the risk of cataract is not a limiting factor for delivering radiation therapy, neither in patients with a short life expectancy for whom there is a low probability of cataract occurrence (Rudoler et al., 1997b), nor in patients with long life expectancy to whom surgery could be proposed if necessary. Radio-induced cataract remains rare as the sparing of the anterior chamber of the eye is often possible: physical restraints, physical field measurements and dosimetric studies are quite precise and allow control of the dose clinically delivered to the lens.

In the study reported by Rudoler et al., 12% of the eyes developed significant complications after EBRT (28/233 eyes) with 30 to 40 Gy in 2 to 3 Gy fractions to the posterior or entire globe. The median follow-up for the entire cohort was 5.8 months (range: 0.7-170.0 months).

Sixteen eyes developed cataracts, 6 eyes retinopathy, 5 eyes neuropathy, 5 eyes keratopathy, and 4 eyes iris neovascularization. Two eyes had narrow-angle glaucoma (one required enucleation). The authors concluded that the benefit of ocular EBRT for preservation of vision outweighed the risk of treatment complications (Rudoler et al., 1997a(Rudoler et al., , 1997b)).

Outcomes

EBRT for CM appears to yield good outcomes, although with a limited level of proof, as no randomized study against another treatment has been published and there are only two published prospective studies [START_REF] Jardel | Management of choroidal metastases[END_REF]. Despite short follow-up due to limited survival associated with metastatic cancer, radiation therapy seems to be an effective treatment for CM (Table 8). It is of note that clinical response to EBRT is often delayed (1 to 3 months or more) and the duration of improvement is of almost one year [START_REF] Doig | Symptomatic choroidal metastases in breast cancer[END_REF][START_REF] Rosset | Radiotherapy of choroidal metastases[END_REF][START_REF] Röttinger | Radiation therapy of choroidal metastases from breast cancer[END_REF]) (Figure 17). In most cases, EBRT is performed after the initiation of a systemic therapy protocol (Figure 18). However, in some cases, especially when the primary cancer is not known at the time of CM diagnosis, EBRT can be performed prior to initiation of systemic treatment, possibly allowing for faster recovery of visual function (Figure 19). Performing irradiation before any systemic treatment allows to define precisely the target and to manage patients with rapid loss of vision. Treatment may also be concomitant: for known associations, such as gefitinib and irradiation in lung cancer, both treatments may be given at the same time without concerns for safely [START_REF] Bhardwaj | Molecular targeted therapy to improve radiotherapeutic outcomes for non-small cell lung carcinoma[END_REF][START_REF] Jiang | Radiotherapy plus EGFR TKIs in non-small cell lung cancer patients with brain metastases: an update meta-analysis[END_REF][START_REF] Zheng | Combining Whole-Brain Radiotherapy with Gefitinib/Erlotinib for Brain Metastases from Non-Small-Cell Lung Cancer: A Meta-Analysis[END_REF]; if there is no data on the combination, the 5-half-life rule for drug washout is recommended. In cases of life threatening progressive extra-choroidal metastases without rapid loss of vision, systemic treatment with re-evaluation of the need for choroidal irradiation after 3 to 6 courses is recommended; if progressive disease occurs with rapid loss of vision, as the volume of irradiation is limited the risk of toxicity should be reasonably low and may be worth taking.

Authors

b) EBRT planning

Few authors have reported the details of radiotherapy treatment planning and EBRT technique. The patient's head is immobilized using a personalized thermoplastic mask. To ensure a reproducible lens position it is easiest for the eyes to be closed, which is normally associated with a downward gaze. However, for a better control of macular position the patient is asked to look straight ahead or to fixate a light in a defined position [START_REF] Bellmann | Stereotactic radiation therapy for malignant choroidal tumors: preliminary, short-term results[END_REF]. The metastasis, or gross tumor volume (GTV), is then identified on the dosimetric CT-scan as a mass attached to the posterior edge of the eyeball; planar fundus images are used when available and a high-resolution MRI may be helpful for better delineation of the volumes using image fusion. The clinical target volume (CTV) includes probabilistic areas of microscopic invasion next to the GTV; five millimeter expansions are applied around the GTV to create a CTV [START_REF] Bellmann | Stereotactic radiation therapy for malignant choroidal tumors: preliminary, short-term results[END_REF]. Once the CTV is determined, a supplementary circumferential margin of 3-5 mm is applied to offset positional and physical uncertainties (planning target volume, PTV). Organs at risk are then delineated. Field geometry varies greatly in the literature and tumor targeting may be achieved using one or two beams, laterally or with non-coplanar oblique beams. The ultimate goal is to deliver at least 95% and up to 100% of the total dose to the target while the organs at risk receive the minimal achievable dose. The simplest field arrangement for a unilateral treatment could be a lateral 6 MV photon field (inclined and edged to avoid the lens); possibly together with a smaller dose to the anterior field for better dose homogeneity (Figure 20). A recent advance in EBRT for the treatment of CM is IMRT. Five to nine fields are used (instead of 1-3 with 3D EBRT) and modulated with a multileaf collimator. Complex concave dose distributions can be achieved, which may be better shaped in the high-dose regions, despite some low-dose spillage to the anterior chamber. The treatment planning process of IMRT is more complex and its use is usually limited to extended posterior pole metastases in patients with relatively good general prognosis.

c) Target

Pre-treatment evaluation. For conventional 3D EBRT and SBRT, routine ophthalmological exams and visual evaluation are sufficient to diagnose the CM and to plan treatment. The aim is to not needlessly delay the treatment. Histological proof is not required, unless there is an atypical clinical presentation. A brain MRI is nonetheless required to eliminate synchronous brain metastases.

Bilaterality. The risk of bilateral CM is well documented (see section 4.1.2). Bilateral CM can be synchronous or metachronous, symptomatic or not. Including the contralateral posterior orbital cone in a target volume is controversial. Some recommend unilateral treatment, arguing that the exit dose using a lateral beam is sufficient to eradicate microscopic disease (i.e. the fraction of dose received by the other eye due to its proximity and dose distribution with EBRT using photons). For instance, in the German study ARO 95-08, none of the patients with unilateral CM irradiated with a unilateral field developed contralateral metastasis during a median follow-up of 5.8 months [START_REF] Wiegel | External beam radiotherapy of choroidal metastases--final results of a prospective study of the German Cancer Society (ARO 95-08)[END_REF]. However, this study was conducted in the 90's and less advanced irradiation techniques and conformation may have resulted in a higher dose delivery to the contralateral eye. Others recommend bilateral fields [START_REF] Rosset | Radiotherapy of choroidal metastases[END_REF][START_REF] Wiegel | Radiotherapy of unilateral choroidal metastasis: unilateral irradiation or bilateral irradiation for sterilization of suspected contralateral disease?[END_REF], but there is no strong evidence to support prophylactic irradiation of an eye showing no sign of CM at baseline. The complexity of treating the second eye at a later date is also dependent on the initial dose received.

Risk of synchronous or metachronous brain metastases. About two-thirds of patients with

CM have extra-ocular metastases [START_REF] Jardel | Management of choroidal metastases[END_REF]. A high incidence of central nervous system involvement was reported in breast and lung cancer patients with CM: 32% of synchronous brain metastases in the series reported by Kreusel et al. (patients with lung cancer) and by Amer et al. (62% of patients with breast cancer) [START_REF] Amer | Treatment options in the management of choroidal metastases[END_REF][START_REF] Kreusel | Incidence and clinical characteristics of symptomatic choroidal metastasis from lung cancer[END_REF]. MRI is thus recommended to look for concomitant brain metastases, the presence of which is technically challenging because there may be overlaps (and overdose, which may be associated with radiation-induced toxicity) between radiation fields for CM and brain metastases. For instance, when EBRT is performed for brain metastases or brain prophylaxis, the posterior orbits receive a significant dose of radiation which has to be taken into account to minimize the risk of radiation-induced complications, especially on the central nervous system and optic nerves. Conversely, in case of isolated CM, the fields have to be carefully chosen to avoid overlapping with the brain, as whole-brain irradiation may be needed at a later date. In case of synchronous and symptomatic brain metastases, whole brain irradiation is indicated, and it will encompass the posterior orbits and choroids. EBRT is rapidly delivered, during the time needed to organize chemotherapy (radiation therapy is given during 5 to 10 consecutive working days). This is the best way to obtain a strong and rapid response on neurological symptoms as systemic treatments might be too slow, hindered by the bloodbrain barrier. Moreover, radiotherapy decreases the risk of developing other brain metastases.

d) EBRT Dose and fractionation

In the largest published series to date, Rudoler et al. reported outcomes from 233 eyes irradiated for posterior uveal metastases. The majority (72%) of patients received total doses between 30-40 Gy in 2-3 Gy fractions corresponding to a biologically effective dose between 50-70 Gy (Rudoler et al., 1997b). Another study reported by Demirci et al. described a series of patients treated by 20-64 Gy in 8 to 32 fractions [START_REF] Demirci | Uveal metastasis from breast cancer in 264 patients[END_REF]. However, short hypofractionated palliative courses are often preferred for patients with short life expectancy; the most common regimens are 30 Gy in 10 fractions, or 20 Gy in 5 fractions. For those with a life expectancy greater than one year, a normofractionated scheme could be considered in order to minimize the long-term side effects. Moreover, when OCT confirms involvement of the subfoveolar region, a more conservative approach using a normofractionated scheme is justified and should be considered.

e) In case of choroidal metastasis relapse

improvement after treatment; five CM disappeared completely on MRI. No acute complication attributable to the treatment itself was reported [START_REF] Cho | Gamma Knife Radiosurgery for Cancer Metastasized to the Ocular Choroid[END_REF].

Several limitations are encountered with SBRT. It is minimally invasive but it implies complete immobilization of the eye to reduce the intra-and inter-fraction movements, thus reducing the volume to treat. This is made difficult by the length of the treatment session (always greater than 30 minutes) which requires perfect patient cooperation. For instance, in the study reported by Cho et al., anesthetic ocular blocks and bridle suture were performed [START_REF] Cho | Gamma Knife Radiosurgery for Cancer Metastasized to the Ocular Choroid[END_REF]. The technique may not be applicable in patients with severe loss of vision as eye fixation is not possible. Taken together, stereotactic irradiation is feasible for CM treatment but its value has to be evaluated in larger series and it may require invasive eye fixation tools.

Proton beam therapy

PBT is another radiotherapy technique that is effective in treating choroidal melanomas [START_REF] Caujolle | Proton Beam Radiotherapy for Uveal Melanomas at Nice Teaching Hospital: 16 Years' Experience[END_REF][START_REF] Damato | Proton beam radiotherapy of choroidal melanoma: the Liverpool-Clatterbridge experience[END_REF][START_REF] Gragoudas | Proton Beam Irradiation of Uveal Melanomas: Results of 5½-Year Study[END_REF]. In the treatment of CM, it is usually reserved for patients with long life expectancy and relatively radioresistant tumors (sarcomas, melanomas, kidney carcinomas) or unifocal tumors. Due to the physical properties of protons, the energy is delivered with a sharp final peak known as the Bragg peak. This allows a very focused and high-dose volume with preservation of surrounding tissues. Ocular PBT is performed in a limited number of centers, although numerous construction projects are underway worldwide. Tsina et al. published a series of 63 patients with CM treated by PBT [START_REF] Tsina | Treatment of metastatic tumors of the choroid with proton beam irradiation[END_REF]; they received 2 fractions of 14 Gy corrected for the relative biologic effectiveness of protons compared to photons (Gy_RBE). Eighty-four percent of treated tumors regressed completely within 5 months of treatment and there was no case of recurrence during follow-up (mean: 10 months). Complications occurred in 56% of cases and included minor 57 and major adverse effects: dermatitis (17%); madarosis (28%), dry eye syndrome (6%) keratitis (8%), cataract (11%), neovascular glaucoma (8%), maculopathy (19%), chorioretinal atrophy (3%), and papillopathy and optic atrophy (22%). Similarly, Kamran et al. described a retrospective cohort of 77 patients with CM mostly treated with 2 fractions of 10 Gy; median follow-up was 7.7 months and local control was achieved in 94% of patients. Treatmentrelated adverse effects were reported in 31% of patients and visual acuity improved or was stable in 38% of eyes treated [START_REF] Kamran | Outcomes of proton therapy for the treatment of uveal metastases[END_REF].

The main drawback of PBT as proposed in these series is the limited potential for macular sparing for tumors mainly located in the posterior pole. For patients with tumors next to the macula, PBT may be best performed in smaller doses per fraction that can be achieved by fractionated PBT, and helps spare normal tissues that are more easily damaged by high doses per fraction (Figure 21). However, the procedure may last 10 seconds to more than 2 minutes requiring therefore ocular gating or tracking. The use of fiducials ensures proper positioning of the eye before beam delivery; these are best placed around the metastasis to target the proton beam and better preserve sensitive tissues. Furthermore, an ocular gating system based on an infrared camera is also used for immediate interruption of the proton beam in case of gaze deviation.

Overall, PBT should be considered in cases of peripheral or radioresistant tumors, but additional studies are required. It is of note that the great majority of published data on ocular treatments concerns passive, single scattering, proton therapy with dedicated eyelines. There is very limited experience in ocular treatments with active, pencil beam scanning, or PBT using high energy equipment. Most centers are not properly equipped (from a technical and physical standpoint) to perform ocular treatments. However, beam quality, as reflected by dose gradient and sharpness in the Bragg peak area is expected to be lower with pencil beam scanning than with passive scattering. Similar to SBRT, such techniques are encouraging in selected patients who have oligometastatic radioresistant disease with relatively good prognosis for whom visual preservation is an important objective.

Plaque brachytherapy

The principle of plaque brachytherapy is to apply a radioactive isotope to the sclera that will deliver radiation over a short distance to the target tissue. It basically requires suturing a radioactive plaque onto the sclera, above the tumor. The plaque remains in place until the therapeutic dose is fully delivered (2-4 days). The patient can return home after surgical removal of the plaque to avoid radiation risk to others [START_REF] Bell | Choroidal melanoma: natural history and management options[END_REF][START_REF] Lim | Radioactive plaque therapy for metastatic choroidal carcinoma[END_REF]. The first reports were published in the 1930s for the treatment of malignant tumors of the eye [START_REF] Moore | CHOROIDAL SARCOMA TREATED BY THE INTRAOCULAR INSERTION OF RADON SEEDS[END_REF]. A thin piece of metal (usually gold) is used, with radioactive seeds placed on one side. The dose distribution varies depending on the chosen isotope Srontium-90, which have various profiles of radiation emission) and the way the metallic plaque is manufactured and shaped [START_REF] Chiu-Tsao | Dosimetry of (125)I and (103)Pd COMS eye plaques for intraocular tumors: report of Task Group 129 by the AAPM and ABS[END_REF]. The most widely used isotope is Iodine-125, which allows sparing of the adjacent tissues such as the lens and the retina due to its low energy photon-emitting profile [START_REF] Shields | Plaque radiotherapy for the management of uveal metastasis[END_REF]. It also enables a safe surgical procedure as its radioactivity can be contained on a gold sheet a mere 0.5 mm thick [START_REF] Earle | Selection of iodine 125 for the Collaborative Ocular Melanoma Study[END_REF][START_REF] Echegaray | Iodine-125 Brachytherapy for Uveal Melanoma: A Systematic Review of Radiation Dose[END_REF]Packer et al., 1980;Packer and Rotman, 1980;[START_REF] Rotman | Radiation therapy of choroidal melanoma[END_REF]. It may be used in select cases of CM such as solitary and well delineated anterior tumors. Indeed, while EBRT delivers a uniform dose to the whole eye structure, plaque brachytherapy delivers a much more heterogeneous dose from the sclera to the apex of the tumor. Shields et al. treated the largest series of patients (36 individuals) with CM by iodine-125 plaque brachytherapy. The mean treatment time was 86 hours, and the mean therapeutic dose was 68.80 Gy (45-70 Gy) to the tumor apex and 235.64 Gy to the tumor base. All tumors regressed, and a complete response was found in 94% of cases. The metastases flattened while the exudative signs resolved. Recurrence occurred in only 2 cases over a mean followup period of 11 months. The overall complication rate was low, and included radiation retinopathy, optic neuropathy and cataract (Shields et al., 1997a).

Fifteen other studies are presented in Table 9. An objective response was achieved in most cases, generally within the first 3 months after treatment (C. L. Shields et al., 1995b;Shields et al., 1997a). Iodine-125 brachytherapy was used in most cases, with anecdotal use of It must be noted that a third of these patients had undergone EBRT and/or systemic chemotherapy beforehand. Only four studies reported radiation complications such as optic atrophy, radiation retinopathy, or cataract and iris neovascularization. This low complication rate might be due to the rather short life expectancy of metastatic patients. Overall, plaque radiotherapy can be considered as a more rapid alternative to EBRT, even if this irradiation technique remains invasive (Shields et al., 1997a). However, it is only available in some specialized radiation oncology departments.

Authors

Nb of tumors

Primary lesion

Local treatment performed by ophthalmologists

The goal in emerging "office-based" local therapies is to restore visual function while minimizing ocular toxicity, here defined as collateral damage to other parts of the eye. When metastatic patients have a short life expectancy, quality of life is preferred over the chance of remission, and conservative treatments which are able to preserve vision are required.

Moreover, autonomy and improvement of quality of life are key goals in the management of ocular metastases.

Photodynamic therapy

Photodynamic therapy (PDT) is a minimally invasive treatment in which a nontoxic lightsensitive compound (photosensitizer) is administered and subsequently activated by light exposure. The photosensitive molecules accumulate in the target tissue and their activation produce photochemical effects in the tissue. Thus, PDT combines the benefits of a preferential concentration of the photosensitizer in a definite area and the specific activation by the light irradiation [START_REF] Moan | Photochemotherapy of cancer: experimental research[END_REF].

PDT is currently used to treat solid tumors and is approved by the Food and Drug Administration in the treatment of skin, esophageal, and non-small cell lung cancer. In ophthalmology, PDT is known to treat, with limited side-effects, choroidal lesions including choroidal neovascularization, choroidal hemangiomas, and chronic central serous chorioretinopathy [START_REF] Newman | Photodynamic therapy: current role in the treatment of chorioretinal conditions[END_REF].

While many photosensitizers are used in oncology, verteporfin (benzoporphyrin derivative monoacid ring A, BPD-MA) is the most used in ophthalmology. Verteporfin is a lipophilic photosensitizer and is more easily taken up by activated cells such as malignant cells [START_REF] Allison | Evidence for low-density lipoprotein receptor-mediated uptake of benzoporphyrin derivative[END_REF][START_REF] Jamieson | Preferential uptake of benzoporphyrin derivative by leukemic versus normal cells[END_REF]. Verteporfin is administered intravenously in a liposomal form. In the circulation, liposomal verteporfin (LV) binds to low density lipoprotein (LDL) with a strong affinity [START_REF] Allison | The plasma distribution of benzoporphyrin derivative and the effects of plasma lipoproteins on its biodistribution[END_REF] and it is known that tumor tissue and cells have a higher number of LDL receptors than normal cells [START_REF] Ho | Low-density lipoprotein (LDL) receptor activity in human acute myelogenous leukemia cells[END_REF][START_REF] Vitols | Elevated low density lipoprotein receptor activity in leukemic cells with monocytic differentiation[END_REF] and a higher vascular permeability [START_REF] Roberts | Role of neovasculature and vascular permeability on the tumor retention of photodynamic agents[END_REF]. Although there is limited published data regarding LV-LDL vectorization to human tumor tissue, in mice the administration of BPD premixed with LDL resulted in enhanced delivery to the tumor area and increased photosensitization compared with BPD administered in an aqueous solution [START_REF] Allison | The effects of plasma lipoproteins on in vitro tumor cell killing and in vivo tumor photosensitization with benzoporphyrin derivative[END_REF][START_REF] Schmidt-Erfurth | Photodynamic targeting of human retinoblastoma cells using covalent low-density lipoprotein conjugates[END_REF]. Moreover, LV is also selectively taken up by neovascular endothelium in mice [START_REF] Roberts | Role of neovasculature and vascular permeability on the tumor retention of photodynamic agents[END_REF]. In summary, the mechanism for specific accumulation of verteporfin in tumors may be explained as follows: building of a complex with LV and LDL in the circulation, vectorization of the LV-LDL to the targeted tumor cell and adjacent neovascularization, and selective delivery and accumulation of the photosensitizer to the tumor by LDL receptor -mediated endocytosis (Figure 22).

Exposure to light then leads to activation of the photosensitizer, which produces reactive oxygen species (ROS) in the tissue microenvironment. There are 3 mechanisms of action for these ROS: direct tumor cytotoxic effect leading to cell death predominantly by apoptosis and necrosis [START_REF] Dougherty | Photodynamic therapy[END_REF]; intraluminal thrombosis and destruction of peritumoral vasculature [START_REF] Fingar | Analysis of acute vascular damage after photodynamic therapy using benzoporphyrin derivative (BPD)[END_REF]; local inflammatory reaction resulting in increased autophagy. In the latter case, PDT induces an acute inflammation at the targeted site secondary to oxidative stress [START_REF] Dougherty | Photodynamic therapy[END_REF]. The production of ROS and tumor cell death is accompanied by activation of the complement pathway and secretion of inflammatory cytokines. This leads to the recruitment of macrophages and dendritic cells, and the phagocytosis of tumor cell debris. Dendritic cells migrate to the local lymph nodes and differentiate into professional antigen-presenting cells. Tumor antigen presentation within the lymph nodes is followed by clonal expansion of tumor-sensitized lymphocytes that home to the tumor and eliminate residual tumor cells [START_REF] Agostinis | Photodynamic therapy of cancer: an update[END_REF] Harbour et al. were the first to report the use of PDT for the treatment of CM in a patient with persistent ocular symptoms despite both chemotherapy and ocular EBRT in a context of pulmonary carcinoid tumor [START_REF] Harbour | Photodynamic therapy for choroidal metastasis from carcinoid tumor[END_REF]. Few authors have subsequently reported cases of different types of primary tumor [START_REF] Isola | Photodynamic therapy with verteporfin of choroidal malignancy from breast cancer[END_REF][START_REF] Kaliki | Photodynamic therapy for choroidal metastasis in 8 cases[END_REF][START_REF] Kawakami | A case of presumed choroidal metastasis from carcinoid tumor treated by photodynamic therapy with verteporfin[END_REF][START_REF] Mauget-Faÿsse | Photodynamic therapy for choroidal metastasis from lung adenocarcinoma[END_REF][START_REF] Soucek | Photodynamic therapy with Verteporfin in subfoveal choroidal metastasis of breast carcinoma (a controlled case)[END_REF]. Ghodasra et al. treated 21 tumors in 13 eyes of 10 patients that led to 81% of total tumor resorption despite 70% systemic cancer progression in these patients [START_REF] Ghodasra | Photodynamic Therapy for Choroidal Metastasis[END_REF]. These data suggest that PDT provides reasonable rates of tumor regression with good safety [START_REF] Ghodasra | Photodynamic Therapy for Choroidal Metastasis[END_REF][START_REF] Kaliki | Photodynamic therapy for choroidal metastasis in 8 cases[END_REF]. Multiple sessions of PDT may be necessary and well tolerated in cases of recurrence or inefficacy, suggesting that PDT is still effective while systemic treatment may not be [START_REF] Ghodasra | Photodynamic Therapy for Choroidal Metastasis[END_REF][START_REF] Kaliki | Photodynamic therapy for choroidal metastasis in 8 cases[END_REF][START_REF] Soucek | Photodynamic therapy with Verteporfin in subfoveal choroidal metastasis of breast carcinoma (a controlled case)[END_REF]) (Figure 23). Systematic analysis of the published literature on the treatment of CM by PDT as a first or second line of treatment suggests treating selected patients with one or two CM (Table 10). PDT seems to be more effective in treating retro-equatorial tumor with low to moderate exudative symptoms, and with a thickness less than 3 mm and diameter less than 10 mm. Lesions that are too thick might not be eligible for PDT, since the wavelength (689 nm) of the laser used will not penetrate the entire tumor. Moreover, visual acuity seems to improve after PDT probably due to the decrease of SRF. [START_REF] Ghodasra | Photodynamic Therapy for Choroidal Metastasis[END_REF]. However, these failures might be explained by the large tumor size, the short duration of follow-up, the lack of adjuvant chemotherapy or the aggressive multimetastatic status of the patient.

Authors

The overall clinical effectiveness is rather promising, especially for patients who often have short survival rates and might be looking for time-sparing treatments. While EBRT takes weeks to treat ocular tumor, PDT allows treatment in a single day, which is desirable for the quality of life of these patients with limited survival. Furthermore, contrary to PBT or plaque brachytherapy, this treatment avoids interventional surgery and potential side effects of irradiation.

PDT should be performed at full-fluence: intravenous verteporfin (6 mg/m2) is infused over 10 minutes. Five minutes later, a 689 nm diode laser is delivered to the area of the CM for 83 seconds at an intensity of 600 mW/cm2 (50 J/cm2). If multiple spots are required, they must be overlapping to cover the whole diameter of the tumor. Furthermore, a 1 mm free margin may be treated around the tumor area.

Intravitreal injection

Another local treatment that could be performed by ophthalmologists alone is intravitreal injection (IVI) of anti-vascular endothelial growth factor (VEGF). The pathogenesis of CM begins with the hematogenous spread of the primary tumor. Once implanted in the choroidal space, tumor cells secrete neovascular factors allowing the supply of nutrients and oxygen necessary for proliferation [START_REF] Langley | The seed and soil hypothesis revisited--the role of tumorstroma interactions in metastasis to different organs[END_REF]. These are initially supplied from the host vascular system, but the demand soon exceeds the supply from this source, and therefore tumors develop their own functional vascular supply [START_REF] Folkman | How is blood vessel growth regulated in normal and neoplastic tissue? G.H.A. Clowes memorial Award lecture[END_REF] from the normal host vascular network by the process of angiogenesis [START_REF] Bergers | Tumorigenesis and the angiogenic switch[END_REF]. Pathological angiogenesis is not auto-regulated and results from alterations in growth control. The induction of angiogenesis has been shown to correlate with the invasive properties of tumors and is associated with poor prognosis [START_REF] Nishida | Angiogenesis in Cancer[END_REF].

VEGF is an angiogenic agent that increases vessel permeability and enhances endothelial cell growth, proliferation, migration, and differentiation [START_REF] Johnstone | Expression of vascular endothelial growth factor (VEGF) in normal oral mucosa, oral dysplasia and oral squamous cell carcinoma[END_REF]. VEGF also promotes angiogenesis in different tumor types and may affect tumor growth, metastatic potential, and response to radiotherapy [START_REF] Nishida | Angiogenesis in Cancer[END_REF]. VEGF expression may prove to be an important prognostic factor in head and neck cancer as VEGF positivity is the most significant predictor of poor prognosis [START_REF] Smith | Prognostic significance of vascular endothelial growth factor protein levels in oral and oropharyngeal squamous cell carcinoma[END_REF]. Angiogenic factors and isoforms of VEGF were found to be over-expressed in choroidal melanoma [START_REF] Boyd | Vascular endothelial growth factor is elevated in ocular fluids of eyes harbouring uveal melanoma: identification of a potential therapeutic window[END_REF].

CM are not exempt of these rules and have been shown to have hypervascularity [START_REF] Neudorfer | Color flow mapping: a non-invasive tool for characterizing and differentiating between uveal melanomas and choroidal metastases[END_REF]. As primary tumor and CM growth seems to be strongly dependent on angiogenesis and VEGF, one can imagine that anti-VEGF therapy could lead to a reduction in tumor mass and exudation.

From a pharmacological standpoint, it is not clear how the anti-VEGF injected in the vitreous is able to reach the choroid that is protected by the outer blood-retinal barrier (see 6.2.1).

Some investigations on anti-VEGF clearance have shown that bevacizumab permeates through the blood-retinal barrier and are found in the choroid [START_REF] Heiduschka | Penetration of Bevacizumab through the Retina after Intravitreal Injection in the Monkey[END_REF][START_REF] Shahar | Electrophysiologic and retinal penetration studies following intravitreal injection of bevacizumab (Avastin)[END_REF][START_REF] Stewart | Pharmacokinetics, pharmacodynamics and pre-clinical characteristics of ophthalmic drugs that bind VEGF[END_REF]. Although mechanisms of barrier breakdown are still unknown, it is suspected that RPE alterations caused by the underlying choroidal tumor, which are clearly visible on FA, may lead to blood-retinal barrier disruption, facilitating drug access to the choroid.

The very first reports of intravitreal anti-VEGF use in CM found dramatic improvement; three out of 4 cases showed a nearly complete regression of the CM, and huge improvement in visual acuity a few months after the first injection [START_REF] Kim | Complete regression of choroidal metastasis secondary to non-small-cell lung cancer with intravitreal bevacizumab and oral erlotinib combination therapy[END_REF][START_REF] Kuo | Regression of a subfoveal choroidal metastasis of colorectal carcinoma after intravitreous bevacizumab treatment[END_REF][START_REF] Yao | Regression of choroidal metastasis secondary to breast carcinoma with adjuvant intravitreal injection of bevacizumab[END_REF]. Many authors have since reported cases of successful management of CM from various primary locations with systemic [START_REF] George | Complete and durable response of choroid metastasis from non-small cell lung cancer with systemic bevacizumab and chemotherapy[END_REF][START_REF] Kourie | Complete Disappearance of Choroidal Metastasis from Lung Adenocarcinoma Treated with Bevacizumab and Chemotherapy[END_REF] or intravitreal anti-VEGF (Table 11). Intravitreal anti-VEGF shows promising results, regarding both clinical outcome and quality of life of patients, as it is by far less invasive than conventional chemotherapy or radiation therapy. Combined with systemic chemotherapy, it allowed local control of the CM in most cases, often leading to complete regression of both tumor and exudative retinal detachment. Interestingly, FA after IVI shows a marked reduction of vascularity and leakage in the tumor bed, suggesting an antiangiogenic and antipermeability effect on the tumor neovessels [START_REF] Kim | Complete regression of choroidal metastasis secondary to non-small-cell lung cancer with intravitreal bevacizumab and oral erlotinib combination therapy[END_REF][START_REF] Kuo | Regression of a subfoveal choroidal metastasis of colorectal carcinoma after intravitreous bevacizumab treatment[END_REF][START_REF] Mansour | Intravitreal bevacizumab for consecutive multiple choroidal breast metastatic lesions[END_REF].

Several IVI are sometimes needed to treat the tumor and an as-needed-regimen is used in this case. It should be noted that most of the patients treated by IVI were receiving systemic chemotherapy before or during intraocular treatment and therefore the true effectiveness of IVI may have been overestimated. However, in most patients, the immediate effect observed after IVI should be attributed to the intravitreal anti-VEGF and it can be effective even in cases refractory to conventional treatment [START_REF] Lai | Intravitreal administration of bevacizumab in the treatment of choroidal metastasis in a patient with erlotinib-failed pulmonary adenocarcinoma[END_REF][START_REF] Yao | Regression of choroidal metastasis secondary to breast carcinoma with adjuvant intravitreal injection of bevacizumab[END_REF]. This therapy could also be proposed in association with other local treatments to hasten fluid resorption and thus improve functional results. However, some failures have also been reported [START_REF] Boss | Effect of treatment of rectal cancer metastasis with intravitreal bevacizumab (Avastin) in patient with subretinal fluid and macular oedema: shortterm follow-up[END_REF][START_REF] Lin | The effect of intravitreal bevacizumab treatment on choroidal metastasis of colon adenocarcinoma--case report[END_REF][START_REF] Maturu | Combination of intravitreal bevacizumab and systemic therapy for choroidal metastases from lung cancer: report of two cases and a systematic review of literature[END_REF][START_REF] Maudgil | Failure of intravitreal bevacizumab in the treatment of choroidal metastasis[END_REF]; for these cases, systemic therapies were generally not given at the same time of IVI or failed to control other metastases. Overall, IVI treatment might be a good therapeutic option for patients with a metastatic disease as it preserves the quality of life without reducing clinical effectiveness. Clear guidelines concerning the use of IVI are still to be determined. It may be suggested to begin with a single dose followed by a monthly as-needed regimen. Conversely to other local treatments, IVI has a very low rate of side effects, including the risk of endophthalmitis which, for this treatment, is about 1 in 2000 patients ( [START_REF] Benoist D'azy | Antibioprophylaxis in Prevention of Endophthalmitis in Intravitreal Injection: A Systematic Review and Meta-Analysis[END_REF][START_REF] Fileta | Meta-analysis of infectious endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents[END_REF]; it could be proposed to multi-metastatic patients under systemic chemotherapy with short life expectancy, as it improves or preserves the vision in most cases without timeconsuming treatment. Furthermore, unlike PDT, this treatment can be given in cases of exudative or large tumors.

Authors

Decisional trees in a multimodal approach of choroidal metastases

When dealing with a CM, several points should be raised: are the CM responsible for ocular symptoms; how is patient's life-expectancy; are there other metastases, are they lifethreatening, and how should multimodal treatment be managed?

Most of the patients with CM have systemic molecular treatment for their primary tumor or metastatic spread. Patients with specific oncogenic driver mutations or translations may exhibit dramatic tumor response under specific targeted therapies, including a decrease in tumor mass and exudative syndrome [START_REF] Demirci | Uveal metastasis from breast cancer in 264 patients[END_REF][START_REF] Manquez | Management of choroidal metastases from breast carcinomas using aromatase inhibitors[END_REF][START_REF] Shah | Uveal metastasis from lung cancer: clinical features, treatment, and outcome in 194 patients[END_REF][START_REF] Yang | The effect of chemotherapy with cisplatin and pemetrexed for choroidal metastasis of non-squamous cell carcinoma[END_REF]. However, secondary resistance to systemic molecular treatments is common and may ultimately be associated with treatment failure after initial (transient) tumor response [START_REF] Cui | Development of a new choroidal metastasis in resistance to crizotinib therapy in anaplastic lymphoma kinaserearranged non-small cell lung cancer[END_REF][START_REF] Okuma | Alectinib for choroidal metastasis in a patient with crizotinib-resistant ALK rearranged positive non-small cell lung cancer[END_REF]. Therefore, it makes sense to propose local treatment concomitantly or after systemic therapy to provide a more sustainable response.

There are no guidelines about the treatment of asymptomatic CM; management depends on the area involved by the tumor. In case of asymptomatic lesions located in critical areas, such as macula and optic disc, the risk for iatrogenic complications from irradiation may outweigh the risk for vision loss in the short term. In such tumors, strict follow-up may help to determine whether the lesion is rapidly progressive or stable. If it is progressive, irradiation using a conservative approach may be recommended, such as normofractionated EBRT or PDT. If the lesion is stable, continued observation may be recommended provided that the patient is compliant to medical visits. In case of asymptomatic lesions located outside critical areas, a strict follow-up is recommended. In case of progression, high-dose irradiation may be used safely.

In cases of short life expectancy (Figure 25)

Local treatment in such cases should be carefully discussed with the patient and the oncologist. The priority is to maintain the quality of life, and this may include, for some patients, retaining some vision for the end of their life. When a treatment is proposed for a palliative-care patient it should include minimal time spent in a medical setting and should avoid redundant consultations. If systemic therapy fails to sustain sufficient vision, local treatment could be proposed. It should be prompt and effective to allow rapid vision gain.

When patients have synchronous cerebral metastases requiring brain EBRT, the choroids can be treated at the same time. In cases of unilateral and unique CM, PDT and/or anti-VEGF IVI is proposed, knowing that PDT leads to poorer results if exudation is intense or in large and thick tumors as the laser beam does not penetrate as well. Follow-up of patients treated by anti-VEGF IVI should be regular because some failures are reported, especially in the absence of systemic therapy. A combined treatment with a few anti-VEGF IVI followed by PDT could be proposed to patients with an intense exudative lesion. In cases of multiple or bilateral CM, a short palliative hypofractionated EBRT is proposed; if there are a few unilateral CM, anti-VEGF IVI and/or PDT can be considered.

Conclusion and future direction

Enhanced imaging of the retina and choroid allows a better understanding and precise diagnosis of CM, even before they are visible on fundus. This diagnosis is most often made using clinical findings in the context of a known cancer, with or without known metastases.

However, up to a third of patients have no history of cancer at the time of CM diagnosis, and ocular manifestations are the first sign of systemic disease. Therefore, ophthalmologists must be familiar with the diagnostic features and general work up of CM, allowing prompt treatment of the primary cancer. When work-up fails to identify the primary cancer, choroidal tumor biopsy or liquid biopsy can help speed up the diagnosis. This is especially important since the emergence of targeted treatments in the past decade have greatly improved survival.

Several therapeutic options are available, but randomized studies comparing different approaches are still needed to guide optimized treatment schemes depending on cancer phenotypes and general status of the patient. In this review, we provide an overview of the treatment options available, their advantages and their limits. The common objectives of all treatments are to preserve or improve vision, avoid enucleation, and maintain quality of life.

To date, radiotherapy remains the treatment of choice for CM: there is longstanding experience and good results are reported in the literature. It may be performed alone for solitary tumors located in the eye only, or it can be associated with systemic treatment in case of disseminated metastatic disease. Fractionated conventional lens sparing techniques can be considered as a gold standard. In selected patients, local irradiation techniques used to treat primary eye tumors may be considered for the management of CM, such as plaque

Figure 1 :

 1 FIGURE CAPTIONS:

Figure 2 :

 2 Figure 2: Wound oncogene wound healing mechanism. Oncogenes that have

Figure 3 :

 3 Figure 3: Color features of choroidal metastases may indicate the primary source of

Figure 4 :

 4 Figure 4: Choroidal metastases with a "leopard skin" pattern. Color fundus photography

Figure 5 :

 5 Figure 5: Bilaterality and multifocality of choroidal metastases (CM). A. Widefield

Figure 6 :

 6 Figure 6: Voluminous choroidal metastases (CM). A. Retinophotography of CM from a

Figure 14 :

 14 Figure 14: Swept-source optical coherence tomography-angiography (OCTA) of

Figure 15 :Figure 16 :

 1516 Figure 15: Choroidal effectiveness of systemic therapy (Tamoxifen) in a patient treated

Figure 17 :

 17 Figure 17: External beam radiotherapy (EBRT) for bilateral choroidal metastases. A.

Figure 18 :

 18 Figure 18: External beam radiotherapy (EBRT) following initiation of systemic therapy

Figure 19 : 2 monthsFigure 20 :

 19220 Figure 19: External beam radiotherapy (EBRT) for choroidal metastases from lung

Table 2 :

 2 Comparison between choroidal metastases from breast (n=623 patients) and lung cancer (n=327 patients)

		Breast	Lung
	Mean age, range (year)	51-57	57-63
	Sex, range (% Female)	99-100	22-45
	Proportion of cases where	3-15	44-59
	diagnosis of CM preceded
	diagnosis of cancer, range
	(%)
	Bilateral involvement, range	24-48	17-25
	(%)
	Multifocal involvement,	20-48	23-24
	range (%)
	Concurrent systemic	54-92	26-37
	metastases, range (%)
	Mean interval between	36-65	9-31
	diagnosis of primary cancer
	and CM*, range (months)
	Mean survival after	9-22	6-12
	diagnosis of CM, range
	(months)

Number of patients Histopathological type Systemic treatment Outcomes Comments

	Shimomura		Adenocarcinoma, ROS-1	Gefitinib (first-and	Slight improvement of General and ocular
	et al.		mutation of EGFR rearrangement	line) maintenance	visual acuity but floaters response at 12 months
	(Shimomura			(pemetrexed +	and blurred vision greatly with crizotinib.
	George et et al., 2013)	1	Large cell	Gemcitabine + bevacizumab)	Lung and CM regression. improved at 3 weeks and At 3 months, tumor size
	al.		carcinoma	carboplatin + for a total of 1	Survived more than 5 remained stable for 5 decreased by 39%.
	(George et			bevacizumab year.	months after the diagnosis months. Subsequent Improvement of vision 3
	al., 2009)			Then crizotinib	of CM. visual loss and brain weeks after beginning
	Singh A et	1	Adenocarcinoma	Gemcitabine +	CM regression. relapse not improved by crizotinib.
	al. (Singh et al., 2010) Singh N et al. (Singh et al., 2012) Shah et al. (Shah et al., 2014) Okuma et Yang et al. (Yang et al., 2014) al. (Okuma et al., 2015) Funazo et al. Inoue et al. (Inoue et al., 2010) (Funazo et al., 2017) Maskell et Table	1 NR (22 eyes) 1 1 1	Adenocarcinoma NR Non-small cell Adenocarcinomas, mutation of EGFR for 1 patient (bilateral CM) and no mutation for 3 patients lung cancer, EML4/ALK rearrangement, PD-L1 expressed Adenocarcinoma wild-type Adenocarcinoma EGFR, EML4/ALK translocation Adenocarcinoma,	cisplatin Pemetrexed + cisplatin Chemotherapy (drugs not specified) Third-line anti Pemetrexed + cisplatin (3 patients) PD-L1 Fourth-line alectinib Alectinib (first-line) Gefitinib Gefitinib (1 patient) Gefitinib	Survived more than 13 months after the diagnosis of CM. Lung and CM regression. Survived more than 11 months after the diagnosis of CM. Tumor size: second-line cisplatin + General and ocular pemetrexed. disease progression. Regression of tumor size General and ocular after 1 to 2 months improvement in 1 week. Two patients died at 3 and Vision completely 6 months after the recovered within 2 weeks. diagnosis of CM, one Partial response for more survived more than 16 months with no than 5 months. Regression of tumor size: recurrence of his unique General disease 68%, CM at 6 months. regression, improvement Progression of tumor size: 32%. Improvement of vision at 3 months. Complete response of the right CM. of vision after 5 months. General and CM Survived more than 15 progression months after the diagnosis Died 3 months after the of CM. diagnosis of CM Improvement of visual
	al.		mutation of EGFR		No follow-up after 3 acuity and tumor size at 3
	(Maskell et				months. weeks. After 5 months,
	Daniels et al., 2017)	1	Adenocarcinoma	First line	Progression of the CM progressive general
	al.			carboplatin +	with carboplatin + disease but CM
	(Daniels et			paclitaxel	paclitaxel. Three days controlled.
	al., 2010) Cui et al.		Adenocarcinoma,	Then, addition Crizotinib	after addition of erlotinib, Improvement of visual
	(Cui et al.,		wild-type EGFR,	of erlotinib (second-line)	improved vision and acuity at 2 weeks (20/200
	2017)		EML4/ALK		marked tumor regression to 20/50) and regression
			rearrangement	Then Second	at fundus. Complete of CM.
				generation of	response at 3 months. No Recurrence at 16 months:
				anti-ALK agent	follow-up thereafter. new CM near the initial
	Chen et al.	1	Papillary	Erlotinib (7	Improvement of visual one revealing crizotinib
	(Chen et al.,		carcinoma,	months)	acuity from 20/60 to resistance. Improvement
	2011)		mutation of EGFR	Then docetaxel	20/25 after 2 months of of vision and decrease in
				10 cycles	erlotinib and decrease of tumor size with second-
					tumor thickness by a line anti-ALK.
	Rao et al.		Adenocarcinoma,	Crizotinib	third. Choroidal and brain
	(Rao and		wild-type EGFR,	(third-line)	CM progression at 7 metastases detected 6
	Gragoudas,		EML4/ALK		months. Whole-brain months after the
	2015)		rearrangement		radiotherapy for introduction of crizotinib.
					intracranial metastases. The patient died 6 months
					Stabilization of vision 2 after the diagnosis of CM.
	Lu et al.		Adenocarcinoma,	6 cycles of	years after diagnosis of Partial systemic response
	(Lu et al.,		wild-type EGFR,	carboplatin +	CM. but no improvement of
	2015)		No mutation of	pemetrexed +	vision with
			ALK,	bevacizumab	chemotherapy.

Table 7 :

 7 Organs at risk (OAR) in orbital radiation therapy. Standard fractionation = 1.8-2.0 Gy per fraction, 5 fractions per week.

Number of patients Primary Cancer Follow- up (median) Total Dose Outcomes

	Shah et al.	88	Lung	12	NR	Among the eyes with
	(Shah et al.,		100%	months		follow-up information:
	2014)					-74% improvement
						and 12% stability with
						EBRT alone (27 eyes)
						-82% of improvement
						with chemotherapy +
						EBRT (22 eyes).
	Rudoler et	188	Breast 53%	5.8	30-40 Gy in	57% improvement of
	al.		Lung 23%	months	2-3fractions	visual acuity or
	(Rudoler et					stability
	al., 1997b)
	Demirci et	129	Breast	10	20-64 Gy in	64% improvement
	al.		100%	months	8-32	18% stable
	(Demirci et				fractions
	al., 2003)
	D'Abbadie	97	Breast 71%	NR	Most	Visual improvement at
	et al.		Lung 9%		frequently	3 months in 55%
	(d'Abbadie		(of the		30 Gy in 10	(EBRT) and 80%
	et al., 2003)		entire		fractions	(chemotherapy +
			cohort, 123			EBRT) of cases.
			patients)

Table 8 :

 8 The largest series of choroidal metastases treated by radiation therapy. EBRT: external beam radiotherapy; NR: Not reported

6.3.1.4. Prescription a) Timing of irradiation: pre-or post-chemotherapy?

Table 9 :

 9 Studies using plaque brachytherapy for the treatment of choroidal metastases. CM: Choroidal metastases; VA: Visual acuity; EBRT: external beam radiotherapy; CT: chemotherapy; NR: not reported

	Previous	Concomitant	Type of	VA after	Mean	Tumor	Complication Follow-
	treatment	treatment	plaque	treatment	thickness/	response	up
	for CM		used		diameter		(months
					(mm)		)

Table 10 :

 10 Studies using PDT for treatment of choroidal metastases. NR: not reported; PDT: photodynamic therapy Despite these promising results, there are reports of PDT failures. Hua et al. describe the case of a patient with a 4.2 mm-thick CM of a lung cancer who received PDT treatment with no concomitant chemotherapy. Multimodal imaging at 3 weeks follow-up found an increase in tumor size and exudative signs. Systemic evaluation showed progression of the metastatic disease. Ghodasra et al. also described the failure of PDT treatment in one of ten patients with aggressive multi metastatic disease who did not receive any previous or concomitant chemotherapy

		Nb of	Primary tumor	Mean Thickness/	Mean	Mean	Complicati	Primary or
		patients		Mean diameter	percentage	follow-up	ons	secondary
				(range, mm)	reduction after	(months)		treatment
					PDT (%)
	Ghodasra et al.	10	Breast (7)	1.3 (0-2.6)/8.6 (3-16) 81	12	0	Secondary (4)
	(Ghodasra and		Thyroid (1)
	Demirci, 2016)		Lung (1)
			Pancreas (1)
	Kaliki et al.	8	Breast (4)	2.9 (1.6-4)/7(2-13)	39	17	intraretinal	Primary (8)
	(Kaliki et al., 2012)		Lung (4)				hemorrhage	Secondary (1)
			Leiomyosarcoma (1)				(1)
	Harbour et al.	1	Lung carcinoid	4.8/13	25	2	0	Secondary
	(Harbour, 2004)
	Isola et al.	1	Breast	NR	NR	4	0	Primary
	(Isola et al., 2006)
	Mauget-Faÿsse et al.	1	Lung	3.0/7.4	100	6	0	Primary
	(Mauget-Faÿsse et al.,
	2006)
	Kawakami et al.	1	Breast or lung	NR	100	14	0	Primary
	(Kawakami et al.,		carcinoid
	2013)
	Soucek et al.	1	Breast	2.2	100	6	0	Primary
	(Soucek and
	Cihelkova, 2006)
	Hua et al.	1	Lung	4.2/8.7	NR (+23% in	3	0	Primary
	(Hua et al., 2017)				diameter)

Table 11 :

 11 Studies using intravitreal injection (IVI) of Bevacizumab (except one with Ranibizumab) for treatment of choroidal metastases.

	CM:

brachytherapy, PBT, or optimized photon-based techniques. Other local treatments, such as PDT or intravitreal anti-VEGF, are available and can decrease the need for radiation and its side effects, and reduce time spent in medical settings for multimetastatic patients. The effectiveness of systemic therapies, especially targeted agents, should be assessed more specifically, and their place in the treatment strategy should be discussed in future recommendations. Further identification of biomarkers is needed to unravel disease mechanisms and to tailor management of CM to the individual.

KEYWORDS:

Choroidal metastases; Ocular oncology; Optical coherence tomography; Radiotherapy; Tumor biopsy.

When CM relapses after initial radiation therapy, re-irradiation may not be possible owing to dose limiting constraints for sensitive ocular tissues irradiated during the initial treatment.

There is a lack of data for ocular re-irradiation, but as is the case for other organs target volumes are usually limited to the recurrent GTV and careful evaluation of the risk-benefit ratio should be carried out [START_REF] Mbeutcha | Salvage prostate re-irradiation using high-dose-rate brachytherapy or focal stereotactic body radiotherapy for local recurrence after definitive radiation therapy[END_REF]; in CM, PBT, SBRT, or plaque brachytherapy may be used as they allow the delivery of a high dose in a smaller target volume with better sparing of surrounding tissues.

Stereotactic irradiation

The principle of stereotactic irradiation is to deliver a high dose of radiation in a small tumor volume in a single fraction (radiosurgery) or a few fractions (hypofractionated stereotactic irradiation). It can be used as an alternative to PBT in unifocal CM, and is becoming widely available although it requires long treatment times and eye tracking capabilities, unless ocular immobilization is performed. Bellman et al. published a series of 10 patients treated for CM by stereotactic radiosurgery (12-20 Gy in one fraction) and long-term tumor control was achieved using shorter treatment course than with conventional EBRT. During follow-up (median: 26 months, range: 4 to 144 weeks) tumor regression was noted on ultrasound or MRI in 5/10 patients but only 4/10 patients had stabilization or improvement of their vision; no chronic side-effect was observed [START_REF] Bellmann | Stereotactic radiation therapy for malignant choroidal tumors: preliminary, short-term results[END_REF]. A Korean study analyzed 7 cases of CM treated by Gamma Knife radiosurgery with a single dose (median: 20 Gy, range: 15-25Gy). Median follow-up was 8 months. Five patients had lung cancer; the other two had gastric and renal cell cancer. Interestingly, four patients had multiple brain metastases that were treated simultaneously with radiotherapy (SBRT or EBRT). Two patients even received repeated SBRT after the first treatment for new intracranial lesions. Six patients had visual Depending on the life-expectancy, the number of CM, and their localization different approaches can be proposed to the patient, and these are described below.

In cases of long life expectancy (Figure 24)

When life expectancy is considered long, a more effective and durable response to treatment of the CM is preferred. The patient may be willing to undergo a multimodal treatment with numerous appointments (EBRT) or requiring eye surgery (PBT, Brachytherapy).

In cases of multiple and disseminated CM foci, and/or when bilateral CM metastases are present, EBRT is considered upfront. When the metastasis is unilateral and unique, a more localized treatment, such as PBT, plaque brachytherapy or SBRT should be considered as an alternative to conventional EBRT. Although PBT and plaque brachytherapy provide similar results for the majority of ocular tumors, plaque brachytherapy is less frequently used for tumors posterior to the equator due to the intra-operative accessibility, or in cases of large tumor diameter. More studies are needed to evaluate the effectiveness of SBRT and to define the place of this technique as ocular immobilization remains the main obstacle for its use.

PBT is the treatment of choice for radioresistant tumors as the proton beam provides a highdose volume with sharp dose deposition allowing the preservation of surrounding tissues.

When the CM is very close to the macula, there is a risk for visual deterioration, but tumor control may be privileged in case of unilateral CM. It should be performed after fiducial implantation at the surface of the sclera to define tumor borders and for stereotactic modeling of eye orientation.

When the CM is near the macula or the optic disc area and primary cancer is relatively radiosensitive, EBRT may be preferred. PDT could be an alternative, but patients should be followed carefully due to the risk of relapse.