Radiotherapy External and chapteEpimacular• 49

the 15-year actuarial risk of optic neuropathy after doses of > 60 Gy ranged from 11% to 47%.50

LENS TOXICITY

The incidence of cataract development following radiation treatment for tumors has been reported to be as low as 3.4% and as high as 86%. This variance is believed to be the result of different lens exposures for the radiation and dosage regimens. Protocols using lens-sparing techniques or lower radiation dosage have lower incidence of cataract while eyes with greater exposure during radiation treatment have higher incidence of cataract development.

Several studies indicate that the radiation dosage threshold for cataract development is between 5.5 and 8 Gy.

SCLERA/CHOROID TOXICITY

The underlying sclera and choroid tolerate radiation well, as evidenced by several studies. A study by Gragoudas et al. in 15 owl monkeys (30 eyes) with a long-term follow-up (3 1 2 years or more) showed that the choroid is not affected at doses below 4275 rad (approximately 42.75 Gy).51 At 42 months after receiving 42.75 Gy, obliteration of the choriocapillaris and small choroidal vessels was observed, but some medium-sized and most large choroidal vessels were preserved. Gragoudas et al. also observed decreased thickness of the choroidal layer compared with the adjacent normal choroid. There were no scleral changes observed in any specimen evaluated. In addition, in a study by Brady and Hernandez using brachytherapy for choroidal melanomas, scleral complications occurred only at doses above 50 Gy.52 In a study by Amoaku et al. ultrastructural changes were described in rats 1 hour to 1 month following X-ray radiation with single doses between 2 and 20 Gy.53 No choroidal or scleral changes were observed at followup. In another study by Amoaku et al., late ultrastructural changes were described in rats 3–12 months after X-ray radiation with single dosages of 2–20 Gy.54 At 12 months, there was no evidence of radiation damage in the choroidal vessels in any subgroup. No scleral complications were reported at the maximum dose of 20 Gy in this study.

SUMMARY AND KEY POINTS

Radiotherapy has become a quite successful treatment modality in several types of ocular diseases. There are many forms of radiation administration and, currently, external beam radiotherapy and brachytherapy are the most commonly used. Advantages and disadvantages of each should be considered for each clinical scenario.

A number of questions remain unanswered regarding the appropriate form of administration, dosage for each type of tumor, and administration strategy regarding dose fractioning and intervals. Regardless of some toxic-related controversies, there is extensive information in the literature regarding thresholds for ocular toxicity. Radiation retinopathy and optic neuropathy remain the main concerns affecting the preservation of vision in eyes treated with radiation and are clearly dose-dependent. Radiation-related complications commonly become apparent about 2 years after therapy. Efforts to develop new techniques to eliminate or to minimize radiation-related complications are warranted.

A thorough review of the literature has shown that many antiangiogenic agents administered concurrently with radiotherapy result in synergistic effect. Early warnings of a theoretical disadvantage to this combined approach due to hypoxia have been disproved. However, much still needs to be learned in both preclinical and clinical trials. For example, timing of drug administration, duration of drug exposure, and combination antiangiogenic drug therapies must be investigated. It is of concern that there are no data concerning the late effects in normal tissues of antiangiogenic agents in combination with radiotherapy. This new treatment paradigm has led to the investigation of localized epimacular brachytherapy combined with anti-VEGF therapy

and a multicenter clinical trial is under way to determine its role in the treatment of exudative age-related macular degeneration.

Although radiotherapy is effective in maintaining vision and preserving eyes in many cases of ocular tumor, adjuvant forms of therapy including chemotherapy or immunotherapy may decrease complications and improve survival rates. In patients at high risk for metastasis, new systemic therapies are necessary.

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Surgery and Pharmacotherapy • 5 section

Human retinal transplantation has followed many years of experimental research showing that transplanted retinal pigment epithelial (RPE) cells have the potential to rescue photoreceptors. This article reviews the current status of human retinal transplantation, surgical techniques, and outcome of clinical studies. The mechanisms leading to RPE dysfunction, as well as future tissue engi­neering strategies for Bruch’s membrane prosthetics, stem cell applications, and deconstructive reaction induced by retinal detachment are also discussed. By overviewing the current literature on retinal transplantation this should also allow us to anticipate the part it will play relative to new treatments such as photodynamic therapy (PDT), angiostatic steroids, antivascular endothelial growth factor agents, gene therapy, and the artifical retina – some available, some only proposed.

INTRODUCTION

Anatomically relatively well isolated, the RPE is a self-contained monolayer that can be readily accessed with a retinotomy through the subretinal space. As the RPE orchestrates metabolism between photoreceptors and the choriocapillaries, it was considered to be a logical experimental starting point, in any attempt to repair or reconstruct the retina through transplantation.1

The RPE and Bruch’s membrane (BM) suffer cumulative damage over a lifetime; this is thought to induce age-related macular degeneration (AMD) in susceptible individuals. As AMD is the leading cause of blindness in the population over 50 years old and about 30 million people will suffer one form of AMD over the next 20 years, the social and economic burden of this disease will increase enormously, especially in countries with aging populations.

Two main routes of the disease occur: a slower-progressing atrophic form where most patients have limited therapeutic options and a rapidly blinding neovascular form. The intravitreal injection of antiangiogenic therapies now offers a highly effective, yet palliative, treatment for many forms of wet AMD. Still, long-term effects remain to be elucidated, and “nonresponders” do exist. Whether curative treatments can involve targeting a single component in the inflammatory cascade of neovascular AMD is not very likely.

The use of the RPE cell as a “therapeutic agent” is an attractive strategy, as healthy RPE cells would, in theory, restore all of the functions of their degenerated counterparts. The success of these cellular replacement strategies, however, clearly depends on delivery and maintenance of cells in a properly polarized state, capable to perform most, if not all, complex functions of the RPE.

This chapter describes the current state and some future prospects for RPE transplantation. Our hope is that achievements described within this chapter will foster more contributions to the growing field of RPE replacement and tissue engineering to benefit our patients.

RPE DISEASE AND INDICATIONS FOR TREATMENT BY TRANSPLANTATION

Dysfunction of RPE may alter the extracellular environment for photoreceptors and BM and thereby contribute to a variety of sight-

threatening diseases. These include AMD, a multifactorial and complex genetic disorder, yet also a number of monogenetic diseases involving the RPE, such as gyrate athrophy and chorioderemia. The high blood perfusion of the choroid puts the RPE at risk for toxic side-effects from systemic medications (e.g., chloroquine).

Monogenetic diseases, such as Leber’s congenital amaurosis (LCA), which is an early-onset form of retinitis pigmentosa, are in future more likely to be treated with gene therapy. Such clinical trials for a variant of LCA with a mutation in the RPE65 gene are currently underway in the UK and USA.

With long-standing disease and/or associated structural damage to the RPE and surrounding structures, a more invasive treatment with RPE transplantation, if necessary combined with gene therapy, is justified.2 Diseases such as AMD or Best’s disease would fall into this category. In these instances, a remodeling of the sub­ macular architecture or maculoplasty would represent a curative treatment.3,4

BRUCH’S MEMBRANE AS A SUBSTRATE FOR TRANSPLANTED RPE

Early animal studies involving RPE transplantation into areas where normal native RPE and undisturbed BM were present do not accurately reflect the clinical situation of most patients. In an experimental study, Tezel and associates have shown that the survival of cultured RPE seeded on BM is partially dependent on the layer on which the cells are seeded. The authors found lesser apoptosis and improved proliferation on the basal lamina when compared to deeper layers or BM.5 However, they also state that the microenvironment of RPE cells seeded on to BM in tissue culture may be different from the subretinal space in clinical situations, because the neurosensory retina, choriocapillaris, and choroid were not present in their in vitro experiments. Subsequent studies from this group were able to demonstrate reversal of the aforementioned observation by removal of age-related debris in different layers of BM.

In contrast to the previous work, Wang et al.6 demonstrated with RPE wound-healing experiments on aged human BM explants closure of localized monolayer defects, albeit with a dedifferentiated cell morphology. The deeper portion of the inner collagenous layer of aged submacular human BM were more limited and variable in their ability to support RPE resurfacing when compared to superficial portions of the RPE basement membrane.

Wang’s experiment may in part reflect age-related changes in the ability of the RPE to differentiate. Gullapalli et al.7 therefore grew fetal human RPE on isolated aged submacular BM. Within a week of seeding, the RPE phenotype deteriorated compared to controls seeded on a basal laminar equivalent.

Thus the pathologic observations by all the above investigators may be deriving from BM and are commonly referred to as dynamic reprocity reactions. While the in vivo situation may differ from laboratory conditions, alterations of BM (e.g., advanced glycation endproducts accumulation) presumably compromise attempts to restore a physiologic subretinal environment.