Table 44.1  Reese–Ellsworth classification of retinoblastoma

Group I: very favorable for maintenance of sight

(a)Solitary tumor, smaller than 4 disc diameters, at or behind the equator

(b)Multiple tumors, none larger than 4 disc diameters, all at or behind the equator

Group II: favorable for maintenance of sight

(a)Solitary tumor, 4–10 disc diameters at or behind the equator

(b)Multiple tumors, 4–10 disc diameters behind the equator

Group III: possible for maintenance of sight

(a)Any lesion anterior to the equator

(b)Solitary tumor, larger than 10 disc diameters behind the equator

Group IV: unfavorable for maintenance of sight

(a)Multiple tumors, some larger than 10 disc diameters

(b)Any lesion extending anteriorly to the ora serrata

Group V: very unfavorable for maintenance of sight

(a)Massive tumors involving more than one-half the retina

(b)Vitreous seeding

Cyclosporine is an adjuvant agent employed by some experts for CRD. In vitro, cyclosporine blocks the multidrug-resistant P-glyco­ protein (an adenosine triphosphate membrane transport protein) found in 30% of untreated, enucleated retinoblastoma eyes, thereby blocking a cell’s ability to clear antineoplastic drugs.16,24 A study treated 40 eyes that would have otherwise undergone enucleation or EBRT with variable chemotherapeutic regimens that included cyclosporine. The authors reported an 85% rate of tumor control, better than the 37% rate reported in their prior study that did not use cyclosporine.25 Further, 7 of 9 cases responded to the regimen with cyclosporine after failing prior CRD without cyclosporine.

Though experts agree that tumor control with CRD requires local consolidation with laser photocoagulation, thermotherapy, cryotherapy, or plaque radiotherapy, there is no consensus on its timing. Several authors have suggested that focal treatments can usually be administered after two to three cycles of CRD, given that tumors have nearly reached their maximal reduction after two cycles.16,26 The type and timing of focal treatments require clinical judgment to tailor management for individual patients.

RESULTS

Ocular salvage rates have improved with the advent of CRD.18 Six cycles of CRD with vincristine, etoposide, and carboplatin plus local treatment with thermotherapy or cryotherapy are highly successful in avoiding enucleation or EBRT, particularly for tumors with lower ICRB classifications. A series of 249 eyes reported success in 100% of group A, 93% of group B, 90% of group C, and 47% of group D eyes. Group E eyes were managed with primary enucleation.6 For Reese–Ellsworth group V eyes treated with CRD, a meta-analysis of nine studies found only 37% avoided both enucleation and EBRT; 41% required EBRT but avoided enucleation; and 40% required eventual enucleation11 (Figures 44.1 and 44.2).

Moreover, CRD may decrease the incidence of intracranial neuroblastic malignancy (trilateral retinoblastoma), a highly fatal malignancy associated with retinoblastoma.27 It remains possible, though, that the absence of EBRT, and not the addition of CRD, deserves credit for decreased incidence of intracranial neuroblastic malignancy.28

Table 44.2  International classification system for intraocular retinoblastoma13

CHEMOREDUCTION FAILURE

There are several possible explanations owing to CRD failure. The presence of subretinal seeds at time of CRD portends a higher risk of retinal tumor and vitreous seed recurrence.29 Subretinal and vitreal seeds initially respond to CRD, but can recur later, requiring additional treatment.18,20,29 Most cases can be managed with cryotherapy or plaque brachytherapy, but some require EBRT or enucleation. Some experts feel seed dispersion can be induced or exacerbated by CRD, as tumors can fragment while they regress, dispelling seeds into the vitreous.30 Further, persistent seeds may represent inadequate chemotherapeutic penetration into the vitreous cavity or avascular subretinal areas.4 Another explanation for failure is that CRD does not appear to have a prophylactic effect against new retinoblastoma tumors, possibly representing primary tumor resistance, selection of a resistant tumor cell line, or inadequate chemotherapeutic concentrations within small, minimally vascularized tumor foci.31 Tumors unresponsive to CRD may be welldifferentiated.32,33

SIDE-EFFECTS

The adverse effects of chemotherapeutic agents must be considered in counseling patients. Common side-effects include fatigue, nausea, vomiting, diarrhea, fever, leucopenia, thrombocytopenia, anemia, and vincristine neurotoxicity.34 Ototoxicity is a potential side-effect of carboplatin, though clinically this risk appears to be minimal. A study examining 164 children who received six cycles of carboplatin (18.6 mg/ kg every 4 weeks) failed to reveal any carboplatin-related hearing impairment.35 Secondary acute myelogenous leukemia may be associated with chemotherapy.36 Patients with hereditary, or germline, retinoblastoma are already at increased risk for secondary malignancy.10,37 The largest study evaluating secondary acute myelogenous leukemia, a retrospective multicentered study of 15 cases, suggested that this rare secondary malignancy might be associated with topoisomerase II inhibitor and epipodophyllotoxin therapy for retinoblastoma.36 Ophthalmic

Diseases Retinal in Mechanisms and Drugs • 4 section