Though innumerable scientific articles start with “the most common intraocular malignancy is choroidal melanoma,” choroidal metastases are much more common.1 Uveal metastases are seen histologically at postmortem in up to 12.6% of patients dying from metastatic cancer.2 However, clinically observable metastatic disease has been noted in only 2%–7% of patients with dissem-inated disease.3-5 Similarly, orbital metastases have been found in up to 5% of patients with systemic malignancy.6,7 This disparity is likely due to the patients being asymptomatic, having little time to live, or a combination of both.5,8 Further, systemic treatment may render the ocular metastasis occult, leaving the patient and oncologist unaware of its existence. , However, the life expectancy for patients with metastatic disease from cancers that commonly spread to the eye has improved over time, particularly in the case of breast cancer.9,10 This longevity has resulted in increased numbers of patients needing ocular treatment to prevent vision loss and ensure their quality of life.11,12 Further, ocular metastases may be the first presentation of systemic disease. One study found that uveal metastases from lung carcinoma (47%), pancreatic cancer (37%), and lung carcinoid (33%) often preceded the systemic diagnosis; by contrast, 94% of patients with breast metastases had a history of the disease.13 Other studies have reported similar results.9,14,15 Similarly, 15% of patients with orbital metastases do not have a cancer diagnosis at presentation.7 Some ocular metastases may, albeit rarely, occur after a tumor has been in remission for years (reported up to 43 years later), which may be a diagnostic shock.16-18 The ocular presentation of metastatic disease is also changing. For instance, because the eye is a relatively immunologically privileged site, vitreous metastases of cutaneous melanoma (Fig. 35-1) are increasingly common in patients on checkpoint inhibitors and who are otherwise in remission.19,20 Prior to this therapy, vitreous involvement was seen only in 18% of eye, lid, or orbital cutaneous melanoma metastases.21 , Further, there has been an evolution of local therapies. The goal of local treatment is to retain vision. Thus, observation for response to systemic therapy may work but risks vision loss in cases where the reattachment of the macula is delayed. Treatments to decrease exudative retinal detachments include laser (e.g., PDT), intravitreal anti-VEGF injections, and steroid implants.22 Larger tumors may be treated with EBRT and smaller extramacular tumors with plaque brachytherapy. However, both forms of radiation carry dose-dependent risks of long-term side effects in longer-lived patients.23 Finger has used anti-VEGF drugs as a bridge therapy to more definitive EBRT irradiation.
Chapter Publication Title: Finger’s Essential Ophthalmic Oncology
Ocular Proton Beam Therapy: Experience Maximizing Outcomes
Primary malignant tumors of the eye and orbit are rare. Their treatment requires special knowledge of the anatomical, conditions, individualized, usually very complex, irradiation techniques, and cooperation between the, clinical disciplines involved. The risks are blindness-related, extreme loss of quality of life, cosmetic changes, to patient appearance, and economic effects. With few, able to pay for complex radiation techniques, only select, patients, willing insurance companies, and high-resource, national health systems allow complex radiation therapy, techniques that preserve eye, function, and life., The rarity of eye tumors and the complex technical, requirements needed to develop conservative treatments, led to the formation of highly specialized regional, referral centers. Unfortunately, each center typically has, only one radiation technology for ocular malignancies., These radiation alternatives include plaque brachytherapy, (e.g., iodine-125 [125I], palladium-103 [103Pd], and/, or ruthenium-106 [106Ru]) or proton beam irradiation.1, Since there is usually only one approach available at each, center, there is little possibility of choosing the optimal, radiation technique for each clinical situation., This chapter reflects our initiative to pair two clinical, centers—one in Essen, Germany and one in Nice,, France—such that each offered a different treatment, modality to maximize clinical outcomes based on select, physical tumor characteristics. We considered the following, hypothetical treatment recommendations. For, example, in Essen we used 106Ru beta-applicators for relatively, flat tumors, as to utilize its most favorable ratio, of tumor dose/dose to normal tissues, as well as 125I (or, mixed 106Ru with 125I), whose dose distribution allows, treatment of larger target tumor volumes.2 Other nonparticipating, centers have reportedly used low-dose rate, (LDR) 90Sr and 103Pd as well as high-dose rate (HDR) 90Y, (see Chapters 17–19, 21, and 22).3-5 However, it is important, to note that along with deeper plaque radiation, penetration, existing LDR plaque therapy is associated, with a wider side-scatter penumbra, leading to less, favorable irradiation of surrounding healthy tissues.6-8 In, our experience, plaque brachytherapy for tumors at the, posterior pole (in the immediate vicinity of the radiation-, sensitive structures of the macula, optic disc, and, optic nerve) rarely results in functional vision. In contrast,, proton treatment of tumors of the posterior pole, offers at least theoretical advantages, provided that the, beam energy, treatment planning, and technical implementation, offer the highest quality to obtain precision., In our experience, compared to LDR plaque brachytherapy,, proton therapy can produce better results in large, tumor volumes where there exists more dose homogeneity., Thus, we have seen less subsequent necrosis, local, accumulation of toxic degradation products, and secondary, glaucoma. However, in general practice, the potential, of proton therapies has not yet been realized in that the, currently used high single-dose fractions have had an, opposite effect., In 1991, a collaboration between the Cancer Center, Antoine Lacassagne in Nice (France) and the University, Hospital in Essen (Germany) provided availability, to a dedicated proton facility for German patients. Cases, were selected for proton therapy when brachytherapy, was not technically feasible (Mind map 20-1). Examples, include diffuse conjunctival melanoma and intraocular, tumor locations that would certainly lead to short-term, blindness (e.g., choroidal melanomas near or touching, the optic disc and/or fovea). This chapter reports on our, subjective experience over 3 decades of proton therapy, and teaches on pragmatic aspects we have used to optimize, our proton beam therapy.
High-Dose Rate Brachytherapy for Ocular Tumors and Benign Growths
Brachytherapy has long been used to treat benign and, malignant ocular tumors as well as neovascular and fibrovascular, growths.1-24 Widespread acceptance of eye- and, vision-sparing plaque brachytherapy started with lowdose, rate (LDR) cobalt-60 eye plaques.1 Later, LDR, iodine-125 (125I) and then LDR palladium-103 (103Pd), seeds were affixed within high-Z gold, shielded plaque, seed carriers, and thus blocked the radiation posterior, and to the sides of the plaque (Table 21-1).25-28 Iodine-125, and 103Pd plaque brachytherapy diminished radiation, exposure to clinicians, improved the intraocular radiation, distribution, and allowed for outpatient, continuous,, multiday treatments (Mind Map 21-1).24, LDR ruthenium-106/rhodium-106 (106Ru/106Rh) and, high-dose rate (HDR) strontium-90/yttrium-90, (90Sr/90Y) beta-emitting radiation devices were commercialized, in England, Germany, and Russia.21,29-35 Of, these, Amersham’s legacy SIAQ 7321 (Amersham Corporation,, Amersham, UK) and Resutech (Moscow, Russia), HDR 90Sr/90Y sources are most like the currently available, LV Y-90 Disc (Liberty Vision Corp., Portsmouth,, NH, USA). However, unlike those prior 90Sr/90Y applicators, (which contain 2 radionuclides), the LV Y-90 Disc, is a single-source, disc-shaped device capable of being, assembled into clinical applicators (Fig. 21-1).36, For the purposes of this chapter, we will examine the, ocular use of beta-radiation-based brachytherapy for, ocular tumors and benign growths (Table 21-1). Beta-radiation, has been used to treat cancers such as choroidal, melanoma, RB, choroidal metastasis, conjunctival melanoma,, and conjunctival SCC.1,3,4,6,9,13,15,16,18,20-22,24,29,31,33-36, Beta-radiation has also been used to treat benign growths, such as uveal and retinal hemangioma (e.g., circumscribed, choroidal and retinal capillary angiomas) as, well as neovascular macular degeneration, eccentric, disciform degeneration, polypoidal choroidal vasculopathy,, pterygium, and as adjuvant for trabeculectomy, surgery.2,7,8,11,12,14,17-19,37-44, These reports include both LDR and HDR treatments., Of these, the most popularly known HDR 90Sr/90Y treatments, have been performed to prevent the recurrence, of pterygium.2,43,44 However, there also exists statistically, significant medical evidence that 90Sr/90Y has been used, as a tool to treat and prevent both the neovascularization, and fibrovascularization associated with failure of filtering, glaucoma surgery (e.g., trabeculectomy) in high-risk, patients compared to the antifibrotic drug 5-FU.8,13,14,42, Clearly, the literature shows that beta-radiation has been, effective for the treatment of both malignant ocular tumors, and benign growths., This chapter includes Liberty Vision’s experience creating, a new HDR 90Y beta-radiation brachytherapy system., It has been implemented by medical physics, radiation, oncology, and ophthalmology for the treatment of ocular, cancers.36 It is important to note that the 90Y radionuclide, has been previously used for the treatment of cancer in, the form of 90Y-laden glass or plastic microspheres arterially, perfused for radioembolization. Such 90Y treatments, have been directed toward hepatocellular carcinomas,, colon metastases, cholangiocarcinoma, and metastatic, choroidal melanoma. Such HDR 90Y brachytherapy offers, medical evidence of 90Y anticancer efficacy.45-50, Prior to bringing a new beta-radiation source to patient, care, Liberty Vision conducted preclinical studies examining, the dose distribution attributes of a variety of beta, sources. After choosing 90Y, Liberty Vision developed,, produced, and then obtained US Food and Drug Administration, (FDA) clearance for discrete 90Y disc sources to, be used in ophthalmic applicators.51 The clinical practice, parameters were then developed to implement this, new brachytherapy system. These included source calibration,, radiobiological dose derivation, sterilization,, assembly, radiation safety, and surgical techniques.36
Management of Radiation Retinopathy
Radiation therapy for uveal melanoma offers high, local control rates. Radiation therapy has been proven, noninferior to enucleation for the prevention of metastatic, melanoma by the medium-sized melanoma trial, of COMS.1 In 2014, the consensus guidelines produced, by the AJCC-OOTF for the American Brachytherapy, Society (ABS) and American Association of Physicists, in Medicine (AAPM) showed that only a few tumors are, considered untreatable by ophthalmic brachytherapy, plaques.2 This shift to eye-conserving radiation therapy, is supported by patients who prefer to keep vision and, their eye., Recent research has focused on vision preservation., Although radiation-related cataracts are common, surgical, vision rehabilitation by lens replacement is both safe, and effective. In contrast, the macular retina and optic, disc are irreplaceable, leaving retinopathy and optic neuropathy, as the most common, irreversible, sight-limiting, side effects of irradiation. Depending on the dose, dose, rate, and thus treatment modality, up to 50% of patients, with posterior uveal melanoma are at risk.3 In the past,, prior to undergoing radiation therapy, patients with posterior, and select large choroidal melanomas were told to, expect severe radiation-related vision loss.4, However, since 2006, Dr. Finger found that anti-VEGF, therapy slowed or stabilized radiation maculopathy and, optic neuropathy.5-8 This discovery ushered in a new era, where treatment not only provides local cancer control, but also makes long-term vision preservation an attainable, goal.
Diagnosis of Iris Tumors
Primary iris tumors are relatively uncommon and are, readily discernible through multimodality examination, (see Chapter 4). Of these, most are benign, occult, iridociliary, cysts.1,2 Anterior segment malignancies are most, commonly iris melanomas, followed by ciliary body, neoplasia that invade the iris and/or anterior segment.3,4, Most commonly occurring in Caucasian patients, these, brown or tapioca-colored malignancies commonly contrast, with their underlying lightly pigmented iris stoma.5,6, However, when pigmented iris melanomas arise within, dark irides, additional findings may be needed to establish, a clinical diagnosis., Iris tumors can be broadly classified as cystic or solid,, discernible through slit-lamp examination, transillumination,, and gonioscopy (Mind map 23-1). However,, advanced imaging techniques such as high-frequency, UBM and/or anterior segment optical coherence, tomography (AS-OCT) are the most valuable tools in, confirming and differentiating these characteristics (see, Chapter 3). Herein, we offer our clinical approach, delve, into their classification, and highlight the specialized, imaging techniques utilized for their differentiation.
Treatment of Iris Tumors
Iris neoplasms include nevi, melanocytomas, melanomas,, hamartomas (e.g., Lisch nodules), as well as cysts of the, iris stroma and pigment epithelium. Amelanotic tumors, are more likely vascular, epithelial, or metastatic.1,2 Most, can be distinguished by clinical examination, including, slit lamp, gonioscopic, ultrasound, optical coherence, tomography (OCT), and angiographic techniques.3, However, diagnosing small indeterminate lesions can be, difficult. They may require photographic documentation, for growth over several weeks, months, or even years as, well as for biopsy (see Chapter 5)., It is important to determine the entire anatomic extent, of the tumor, as tissue invasion and displacement can, help determine if a tumor is benign or malignant. For, example, this is particularly important for iris melanoma, extending into the ciliary body or a primary ciliary body, tumor extending into or through the iris root. For this, reason, slit-lamp imaging, gonio-photography, UBM,, and anterior segment OCT imaging as well as fluorescein, angiography (FA) help this determination. The usefulness, of CT and MRI has been described but is less helpful, in discriminating between different types of iris tumors.4, Treatments for any individual tumor depend highly on the, clinical or biopsy-proven diagnosis, size, and extent. Benign, lesions (e.g., nevi and small cysts) are typically observed, and may not require treatment. Because of their anterior, and clearly visible location, iris tumors—especially iris, melanomas—are treated when relatively small compared, to more posteriorly located uveal melanoma, yielding, more favorable prognoses. Treatment modalities typically, include surgical excision (sector iridectomy), radiation (e.g.,, charged particle, plaque brachytherapy), and enucleation.5-7
Diagnosis of Choroidal and Ciliary Body Melanoma
Extending from the optic disc to the pupillary margin,, the vascular uvea contains melanocytes that can transform, into what is the most common primary intraocular, malignancy in adults, uveal melanoma (UM).1-3 Further,, the uveal layer can be anterior to posteriorly divided into, iris, ciliary body, and choroidal portions. COMS examined, choroidal melanomas and found their average, presenting age to be 60 years; however, uveal melanomas, can occur as early as infancy.1,4,5, Younger patients with choroidal melanoma tend to, have a better prognosis, and it’s thought due to a better, immunological profile.1-3,6 UM incidence is nearly equally, distributed between males and females.1,7 The most common, location of the tumor is the choroid (85%–90%),, followed by the ciliary body (5%–8%) and iris (3%–, 5%).1,2 The annual age-adjusted incidence per million, population is 6.02 for non-Hispanic whites, 1.67 for Hispanics,, 0.38 for Asians, and 0.31 for blacks.8, UMs may arise de novo or from pre-existing uveal nevi., They are also more common in patients with outdoor, occupations, beneath Australia’s ozone hole, on the, sun-exposed lower half of the iris, and in arc welders., This suggests ultraviolet light exposure is a predisposing, factor. However, the etiologic risks of ultraviolet, light exposure have been disputed.9 In addition, several, geographical clusters of UM (primarily affecting, young patients) have been discovered with no identifiable, genetic or environmental factors (e.g., Huntersville,, NC, USA and Auburn, AL, USA).10, UM is not hereditary; however, there have been reports, of familial cases affecting several family members.11, Melanoma is typically a unilateral, unifocal disease, but, cases of primary bilateral or multifocal tumors have been, published.12,13 BAP1 tumor predisposition syndrome has, been associated with an increased risk of developing UM, (2.8% incidence) compared to 0.0061% in the general, population.14,15 Like most cancers, the development of, UM is likely multifactorial.
Prognostication in Uveal Melanoma
Uveal melanoma (UM) has a propensity for metastasis which results in high mortality.1,2 As metastases are rarely detectable at the time of diagnosis, great efforts have been directed toward accurate prognostication and identifying high-risk factors for metastasis.3-5 One can differentiate between clinical, histopathologic, and genetic prognostic factors.6 However, this chapter reveals the breadth of parameters that must be taken into account when trying to predict a patient’s prognosis.7 These include, but are not limited to, the age of the patient, tumor-specific factors, patient comorbidities, the effectiveness of local treatment, and a plethora of tumor-associated mutations and aberrations, all of which influence the risk for metastatic disease.6,8,9
Screening for Uveal Melanoma Metastasis
Metastasis is the leading cause of death amongst patients, diagnosed with uveal melanoma (UM).1-3 Depending on, the AJCC cT category and method of detection, overall, 1.9% (cT1–cT4) and up to 20% of select cT4 patients, have demonstrable metastatic disease at the time of ocular, diagnosis.4,5 However, even after local treatment, a, tumor-size-based risk of metastasis (mean 50%, range, 10%–90%) exists within 10 years (Fig. 27-1).4,6-8 This is, attributed to the slow growth of previously seeded metastatic, tumor cells, which are undetectable to all existing, screening methods. It is widely accepted that subclinical, metastases remain occult for years until they grow, to a certain size to become radiologically detectable.9,10, Therefore, multiple research studies have focused on, extending life for patients with metastatic UM utilizing, early detection as to allow time for palliative and sometimes, curative treatment.2,9,11, The hunt for metastatic UM starts at initial diagnostic, staging. Large multicenter international studies have, revealed that clinical characteristics (e.g., ciliary body, origin, presence of extrascleral extension, greater tumor, thickness, and largest basal diameter) are associated with, a greater risk for metastases at initial presentation.2,4-6,9, The most common metastatic sites at presentation are, the liver (91%), lung (16%), bone (9%), brain (6%), skin, (4%), and others (5%).4,5,7,12 In that multiorgan disease has, been identified in over 80% of patients with metastatic, disease, this data supports multiorgan screening (Figs., 27-2 and 27-3).4,5,7,9,12 In addition, multiple centers have, reported that UM patients are at risk for second nonocular, primary cancers, suggesting a genetic predisposition, to cancer (Fig. 27-2)., Genetic studies support mutations in BAP1, GNAQ,, GNA11, LZTS1 (8p22), DDEF1 (8q24.21), PTP4A3, (8q24.3), TCEB1 (8q21.11), EIF1AX, and SF3B1 (see, Abbreviations section) as predisposing factors for UM, metastasis (see Chapter 26).2,13 Structurally, monosomy, 3, 1p loss, 1q gain, 6q loss, 6p gain, 8p loss, and 8q gain, are common chromosomal abnormalities in UM.14-19, The data suggests that both AJCC cT-category, genetic, information, and the patient’s health status may be selectively, employed to modify the intensity or periodicity, of post-treatment systemic surveillance (Mind map, 27-1).4,6,9,14,18-22, However, to date, no consensus guidelines have been, established for methods of diagnosis, surveillance, or, treatment for metastatic UM. In 1985, the COMS methods, for metastatic surveillance included a combination of, physical examination for hepatomegaly, enlarged lymph, nodes, and subcutaneous nodules, as well as ancillary, chest X-rays (CXR) and liver function tests (LFT). These, methods were specific but not sensitive, thus typically, diagnosing only late-stage disease.20,21, In the modern era, a shift toward radiographic systemic, screening has allowed metastatic screening to, be more sensitive and specific for early asymptomatic, metastasis.5,23 Today, we rely more heavily on PET/CT,, abdominal CT or MRI, CXR, or abdominal-hepatic, ultrasound (USG).4,5,23-26 Of these radiographic methods,, only whole-body, PET/CT offers radiographic screening, that can reveal both hepatic and extrahepatic UM, metastasis.4,5 PET/CT has also been found to reveal second, nonocular primary cancers and help differentiate, melanoma from uveal metastasis in this population.5,25,27, Clearly, hematologic surveys now play a less prominent, role. In general, current options for surveillance of metastatic, UM include physical examination, hematologic, screening, and radiographic imaging (Table 27-1).
Treatment of Choroidal Melanoma
Uveal melanoma (UM) management is based on tumor, characteristics, prognostic factors, local availability of, treatment modalities, and patient preference.1 A detailed, discussion between the physician and the patient helps, navigate the complex shared decision-making process, (see Chapter 7). Herein, we discuss UM treatment, options (Mind map 28-1).