Retinal pigment epithelial tumors are both congenital, and acquired. The most common are created by laser,, cryotherapy, infection, inflammation, trauma, neovascularization,, and long-standing SRF. However, there exist, other forms, such as congenital hypertrophy of the RPE, (CHRPE), acquired hamartomas, as well as adenomas, and adenocarcinoma (Mind map 31-1). It is important, for the eye cancer specialist to be familiar with retinal, pigment epithelial tumors, as they need to be differentiated, from choroidal melanoma.1, CHRPE, or “bear tracks”, are typically discovered in children, and young adults as multifocal, flat, inactive, and, grouped pigmented fundus lesions. They are associated, with familial adenomatous polyposis (FAP), suggesting, their treatment must be coordinated with a gastroenterologist, (see Chapter 10).2,3 Hamartomas of the RPE can, be subdivided into simple acquired hypertrophic or idiopathic, RPE hamartomas, to more complex combined, hamartomas of the retina and RPE, and unilateral RPE, dysgenesis.4,5, Retinal pigment epithelial dysplasias include idiopathic, RPE hyperplasia, adenoma, and adenocarcinoma, and, are described later in this chapter. These 3 entities are, clinically and histopathologically challenging to distinguish, and likely represent stages along a continuous, spectrum (Mind map 31-1).6
Chapter Publication Title: Finger’s Essential Ophthalmic Oncology
Scleral Toxicity and Repair
The sclera is the outermost coat of the eyeball and provides structural support and protection for intraocular structures. In contrast to the other coats, the sclera is hypovascular, hypocellular, and composed of dense con-nective tissue. Histologically, it consists of interwoven collagen fibrils and a dense extracellular matrix. Scleral rigidity is imparted by glycation-induced cross-linking of collagen fibrils.1 Despite a low metabolic activity, the sclera undergoes remodeling throughout life. For example, fibroblastic activity and increased scleral thickness have been reported in response to thermal stimuli.2 Scleral metabolism plays an integral role in emmetropization by precisely regulating the growth of the extracellular matrix, suggesting that the sclera is metabolically active.3 Although sparsely populated, scleral fibroblasts can be activated to proliferate after injury, pathology, or infection.4
Treatment of benign and malignant intraocular (e.g., uveal, retinal, neural) tumors as well as extraocular (e.g., ocular surface and orbital) often require episcleral or trans-scleral modalities. Therefore, scleral toxicity can be an adverse effect, manifesting as scleral thinning or scleral melt. In addition, these tumors can directly invade and thus weaken the sclera in select cases. Resultant scleral thinning can lead to perforation and expulsion of intraocular contents. Early diagnosis and appropriate management can prevent the consequences of scleral toxicity.
This chapter discusses the various mechanisms of scleral toxicity, scleral complications of cancer therapy, indications, and techniques of scleral repair.
Diagnosis of Retinoblastoma
RB is a retinal developmental tumor and the most frequent, intraocular malignancy in chidlren.1,2 Though, others may have done so before, Dr. James Wardrop is, often credited for the first RB enucleations with curative, intent. However, only later did enucleation of early-stage, RB become the standard of care.3 Along with progress in, pathology and the advent of ophthalmoscopy, Virchow, and subsequently Flexner and Wintersteiner described, the tumor’s retinal origin and histopathologic characteristics., 4 However, it wasn’t until 1926 that the consensus, term “retinoblastoma” was accepted based on its cytological, origin from retinoblasts.5, The scientific advances and increased RB awareness in, the last few decades have resulted in early detection,, diagnosis, and protocol-based treatment. This, in turn,, improved RB patient survival and globe salvage, often, with the preservation of useful vision.6-8 However, there, exists a disparity in RB outcomes globally.9 In lower-resource, nations, birth rates and RB incidence are higher,, and it is made worse by a lack of access to RB care.10, Therefore, it is imperative to focus on raising awareness,, subspecialty eye cancer training, and thereby employment, of effective treatment strategies for children in, low- and middle-resource countries (see Chapter 9).8,11, In this chapter, we will discuss the epidemiology, clinical, presentation, and socioeconomic aspects of RB.
Overview of Ophthalmic Radiation Therapy
Radiation therapy is widely used for the treatment of intraocular and orbital tumors as well as inflammatory ocular diseases.1-3 Both implant brachytherapy and EBRT techniques are widely employed. For example, linear accelerator (LINAC)-based EBRT is widely used to treat metastatic uveal, orbital, and sinus tumors as it involves directing an external radiation beam source to the eye, eyelids, sinuses, and orbit. Should one or both eyes need be irradiated, LINAC-based EBRT can be delivered using an anterior unilateral approach as seen in Figure 1, or as 2 apposing, bilateral confrontational fields.4 In contrast, most patients with uveal melanoma are commonly treated with ophthalmic plaque brachytherapy. Here, disc-shaped radioactive devices are affixed to the sclera beneath the tumor volume within the eye (Fig. 17-2).
Orbital disease is most commonly treated with LINAC-derived EBRT, and less frequently with proton beam, stereotactic radiosurgery (SRS) and Gamma Knife®, and intensity-modulated radiation therapy (IMRT).2 Radiation can be used alone, after surgery, and with chemotherapy. In contrast, orbital brachytherapy involves surgical placement of radiation sources next to a tumor or within a targeted orbital volume. Typically considered the most conformal form of radiotherapy, brachytherapy relatively increases the radiation dose within the targeted volume while decreasing exposure to most normal tissues.
At The New York Eye Cancer Center, orbital high-dose rate brachytherapy is used to treat the resected tumor bed followed by an overlay of lower-dose EBRT to the entire orbit (Fig. 17-3).5-7 Called “brachy-boost”, this technique increases the dose to a targeted portion of the orbit.
This chapter explores the unique challenges associated with irradiation of the eye, lids, and orbit. It includes basic radiobiology, doses, indications, and results of treatment. We discuss the tolerances of normal ocular and orbital tissues. Herein, we review the literature to offer a unique perspective of the world’s experience with ocular and orbital radiation therapy.
Ocular and orbital anatomy, as well as tissue radiosensitivity, provide unique challenges for radiation-based patient care. By definition, the eye globe is bounded by the sclera and cornea, within which there exist tissues that contain melanocytes, retinal, and epithelial cells, amongst others. Each gives rise to unique tumors with different radiosensitivities. Most orbital tumors occur between the eyeball and bony orbital walls, within which there exist even more varieties of progenitor cells and their related tumors. Orbital tumors may also extend either into or from the eye, orbit orbital bone, brain, and sinuses. As a result, radiation delivery systems (teletherapy or brachytherapy)—each with unique characteristics—are carefully selected to deliver tailored dose distributions within the eye and orbit. To better understand the differences between these radiation modalities, this chapter reviews their inherent differences and why each is typically selected.
While any radiation modality can sterilize a cancer, the location and intensity of side effects or normal tissue tolerances typically govern the physician’s choice of method. However, individual tissue tolerances and
thus the incidence of radiation side effects are variable. For example, the sclera, cornea, bones, ocular muscles, optic nerve, and orbital fat can tolerate relatively high doses, whereas the lens, eyelashes, retina, and lacrimal system are more radiosensitive.2 Therefore, side effects of ocular and orbital irradiation commonly include dry eye, eyelash loss, cataracts, neovascular glaucoma, radiation retinopathy (see Chapter 22), and optic neuropathy as opposed to osteonecrosis, strabismus, or enophthalmos.1,2 Depending on the tissue and its function, each ophthalmic side effect results in either cosmetic or functional morbidities. In practice, modality selection and treatment plans are typically created to avoid the retina, lacrimal system, and natural lens.2,8-10 In addition, there exists an oncogenic risk associated with ionizing radiation as most commonly seen in children.11-16
It is important to note that the incidence of side effects is proportional to the volume of irradiated tissue. Therefore, any technique that reduces the irradiated volume, conforms to the tumor, and reduces organ dose will be beneficial. Despite the risks of side effects, radiation therapy has become an essential tool used by eye cancer specialists to provide local control of benign and malignant ocular and orbital diseases. The clinical benefits of improving survival and preserving vision have clearly outweighed the radiation risks. Herein, we review how radiotherapy has played an integral role in the treatment of benign and malignant ocular tumors.
Treatment of Retinoblastoma
The aims of RB treatment in order of priority are to save, life, the eye, and vision. Early detection, prompt treatment,, and advanced treatment modalities have improved, survival leading to increased interest in globe salvage., All patients should be initially staged using the 8th edition, AJCC TNMH staging of RB as shown in Table 33-1.1, Many centers use the International Intraocular RB Classification, (IIRC) in addition to the AJCC.2 Staging can help, determine the type of treatment required and has been, shown to accurately predict both mortality from metastatic, disease and globe salvage rates.3,4 Table 33-1 includes, a column showing how the IIRC classification compares, to AJCC staging, as many studies discussed in this chapter, use the older, less robust classification. In contrast to IIRC, and other RB classification systems, the 8th edition AJCC, RB staging system is the only comprehensive classification, that addresses intraocular, orbital, and metastatic RB,, predicts metastatic death and local treatment outcomes,, accounts for sporadic and germline RB, and has been periodically, updated with new medical evidence.3,4, Treatment modalities have evolved from external radiation, in the 1960s, to systemic chemotherapy with sequentially, aggressive local treatments (SALT) in the 1990s.5 The, last decade has witnessed a growing interest in therapies, where treatment is delivered through regional arteries or, directly into the globe. In high resource countries, where, patients present early and more treatment options are readily, available, there exists a 3%–5% risk of metastasis-related, mortality.6-8 In contrast, children with RB from middle- and, lower-resource countries have a 10.3-fold and 9.3 to 10-fold, higher risk of metastasis-related mortality, respectively.9
Finger’s Methods for Ophthalmic Plaque Surgery
Plaque surgical techniques are rarely described in the literature. 1-6 When available, they are typically found in the methods sections of papers describing a new radiation source or plaque position verification technique.3,7-14 This understates their importance in that our surgical methods affect the incidence of secondary radiation complications, local control, and thus metastasis.1,15-17 Plaque modality, construction, and medical physics calculations are critical foundational elements of treatment success.4,18-20 Significant research indicates that failure of local control is associated with a 6.3x hazard for metastatic disease.15,21 My techniques have been refined over the last 35 years, leading to a current local control rate greater than 99% as measured by doctor-reported outcomes.22,23 Herein, I offer my thoughts, methods, and experience with surgical ophthalmic plaque radiation therapy. The lack of consensus guidance is related to the complexity of plaque therapy. For example, there exist a variety of radiation plaque modalities: palladium-103 (103Pd), iodine-125 (125I), ruthenium-106 (106Ru), strontium-90 (90Sr), and most recently yttrium-90 (90Y).24-28 In addition, ophthalmic plaques come in different shapes and sizes.18,20 Although the American Brachytherapy Society (ABS) together with the American Association of Physicists in Medicine (AAPM) have published guidelines for ophthalmic plaque brachytherapy for choroidal melanoma and RB, there exist nuances that were beyond the scope of that multicenter, international effort.18,29 Intraocular tumors also occur at different intraocular locations.30 Clearly, epicorneal plaque positioning differs from that on the posterior pole, particularly due to optic nerve sheath obstruction.6,17,31,32 However, there are commonalities and differences that need be described to improve ophthalmic plaque surgery.
Intraocular Lymphomas and Leukemias
Hematologic malignancies are generally categorized by, their cell of origin. Most commonly, leukemias arise from, early myeloid or lymphoid progenitors (blasts), whereas, lymphomas are derived from mature lymphocytes or, their progenitors. As a result, leukemias are characterized, by infiltration of the bone marrow and peripheral blood, with malignant cells, whereas lymphomas are diagnosed, from biopsies of solid lymphoid tissues., Ophthalmic manifestations of hematologic malignancies, can arise via direct and indirect mechanisms, with the, former due to infiltration of neoplastic cells and the latter, resulting from downstream hematologic alterations, (anemia, hyperviscosity, and/or thrombocytopenia)., This chapter reviews the ophthalmic manifestations of, vitreoretinal lymphoma (VRL), choroidal lymphoma, (CL), and leukemia, and discuss an approach to diagnosing, and managing each condition (Mind map 34-1).
A Review of Ophthalmic Plaque Brachytherapy Consensus Guidelines
Brachytherapy involves the application of a radioactive, source inside or close to a tumor or benign growth.1 During, application, this radiation is delivered continuously, but over a fixed amount of time. Therefore, in radiation, oncology there exist short-term (temporary) implants, and long-term (even permanent) implants. Temporary, brachytherapy implants can be either low-dose rate, (LDR) or high-dose rate (HDR), requiring days or minutes, of application respectively. In radiation oncology,, brachytherapy is used because it is conformal, allowing, irradiation of targeted tissue volume with limited radiation, to nearby healthy tissues.1-3, As early as 1911, Dr. Albert Terson used radium to prevent, pterygium recurrence.4 Since that time, a number of, beta and gamma applicators have been important tools, for delivering radiation within the eye and orbit.2,3 Given, the small size of the eye and proximity of visually significant, structures, precise calculation of the radiation, dose to these vital structures is essential.5,6 However,, there exists scant clinical research comparing the efficacy, of various methods and brachytherapy types. The, closest research includes a 2012 American Association, of Physicists in Medicine (AAPM) comparison of, iodine-125 (125I) versus palladium-103 (103Pd) sources, used in eye plaques which included a review of ophthalmic, brachytherapy.7 Then, in 2014 the American, Brachytherapy Society (ABS) OOTF together with the, AAPM published a 47-person consensus, multicenter,, international OOTF guideline for plaque brachytherapy, of choroidal melanoma and RB.8 We suggest that all, eye cancer specialists obtain these open-access publications, and integrate their recommendations into clinical, practice. Lessons learned from these 2 publications are, presented in this chapter.
Metastatic Cancer to the Eye, Lids, and Orbit
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.
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.