KEY FEATURES

Chemotherapeutic approaches, including chemoreduction (CRD), chemothermotherapy, periocular and intravitreal chemotherapy, and intra-arterial chemotherapy, are effective tools in managing different types of ocular tumors. Treatments are often individualized to patient and tumor types to yield best possible outcomes.

INTRODUCTION

Chemotherapy for intraocular malignancies has evolved since 1953, when nitrogen mustard (chlormethine) was first used to treat retinoblastoma.1 This chapter discusses chemotherapy for retinoblastoma, uveal metastases, uveal melanoma, and intraocular lymphoma.

RETINOBLASTOMA (Tables 44.1 and 44.2)

GENERAL CONSIDERATIONS

Retinoblastoma is the most common primary intraocular malignancy in children, with an incidence of 1 in 15 000 live births.2 Treatment of this tumor has evolved over the last several decades, increasing rates of survival, globe salvage, and visual preservation. Currently available options include laser photocoagulation, thermotherapy, cryotherapy, intravenous CRD, subconjunctival chemotherapy (carboplatin), plaque radiotherapy, external beam radiotherapy (EBRT), and enucleation.

Most experts consider enucleation to be the standard of care for advanced unilateral disease, defined as eyes with large tumors (20 mm in base, 10 mm in height), long-standing retinal detachment, neovascular glaucoma, iris neovascularization or seeding, suspicion of optic nerve or choroid invasion or extrascleral extension, or no expectation for useful vision.3 Enucleation affords greater than a 99% cure rate in cases of unilateral retinoblastoma without extraocular disease.4

Retinoblastoma is a radiosensitive tumor, responding to plaque radiotherapy or EBRT. Episcleral plaque radiotherapy can help treat small solitary lesions up to 18 mm in diameter.5 Low-energy plaques, those using iodine-125 or palladium-103, provide localized irradiation and minimize effect to the orbit and surrounding soft tissues.2,5,6 Historically, EBRT was a common and effective treatment alternative to enucleation. Recurrence after EBRT is low, usually occurring within 2 years of treatment.7,8

Several reasons contributed to the emergence of CRD as an alternative to EBRT, including risk of disfiguration and secondary tumors.9 These tumors are mostly osseous and soft-tissue sarcomas,10 and are more common in children carrying the Rb-1 germline mutation.9,11 Moreover, children younger than 12 months of age are more prone to the soft-tissue and bone tumors of the head associated with EBRT12; CRD can delay its use.

The selection of an appropriate treatment strategy for an individual patient is based on multiple factors, including risk of metastases or second cancers, laterality of disease, systemic status, size and location of tumor(s), and estimated visual prognosis.13 One group of experts offers a general guideline. For unilateral retinoblastoma, International Classification of Retinoblastoma (ICRB) group A is usually treated with cryotherapy or laser photocoagulation; groups B and C are treated with either CRD or plaque radiotherapy; group D lesions receive CRD plus subconjunctival carboplatin or enucleation, and group E eyes are enucleated. For bilateral retinoblastoma, which is managed according to the worse eye, group A tumors are usually treated with cryotherapy or laser photocoagulation; groups B and C receive CRD; group D eyes receive CRD plus subconjunctival carboplatin or enucleation; group E eyes are enucleated unless both eyes are advanced, in which case CRD with subconjunctival carboplatin and low-dose EBRT is attempted.13

CHEMOREDUCTION

CRD is a strategy that combines chemotherapeutic tumor debulking with localized ophthalmic treatment (laser photocoagulation, thermotherapy, cryotherapy, or plaque radiotherapy). The strategy involves administration of intravenous chemotherapy for several cycles, coupled with focal therapy after the second or third cycle once adequate reduction in tumor size and subretinal fluid has been achieved.14–18

The indications for CRD have not yet been clearly established. CRD has been used for all retinoblastomas except in unilateral cases undergoing primary enucleation or in certain ICRB group A cases that can be treated with cryotherapy or laser photocoagulation alone. Some experts use CRD for all nonenucleated eyes.19 One group11 classifies the indications for CRD into three general categories: eyes with visual potential containing tumors too large to treat with focal treatments, children less than 1 year of age to avoid or postpone the adverse risks of EBRT, and, by some experts, any advanced unilateral or bilateral retinoblastoma.

AGENTS

CRD protocols vary in regimen and duration per center, precluding a universally accepted standard recommendation. Regimens generally use three agents: alkylating agents (carboplatin, cisplatin), DNA topoisomerase II inhibitors (etoposide, teniposide), and vinca alkaloids (vincristine). Most recent studies use vincristine, etoposide, and carboplatin (VEC) for six cycles.20 Excluding etoposide for its potential oncogenic risk, CRD regimens using only carboplatin and vincristine do elicit tumor response. However, when compared to regimens employing etoposide as a third agent, two-agent regimens have inferior recurrence and ocular salvage rates (83% ocular salvage rate in total for Reese– Ellsworth I–III, 63% without EBRT).21 Other experts selectively choose between twoand three-agent regimens, treating ICRB group B tumors with two agents and more advanced tumors with three agents.13 Carboplatin has been used as a single agent, proving effectiveness against retinoblastoma but less so than multiagent regimens.22 Almost half (47%) of eyes initially treated with carboplatin developed new tumors.23