In 1971, based on the mathematical analysis of the age at presentation of bilateral (hereditary) and unilateral (mostly nonhereditary) cases of retinoblastoma, Knudson ⁷ proposed the “two-hit hypothesis,” in which two mutational events in a developing retinal cell lead to the development of retinoblastoma. This hypothesis was subsequently extended to suggest that the two events could be mutations of both alleles of the RB1 gene, located on chromosome 13q14 and identified in 1986.^8,⁹ Its product, pRb, is required for the transition of the cell through the G1 phase of mitosis. pRb appears to function as a tumor suppressor at least in part by inhibiting cell cycle progression past the G1-S restriction point; on entry to the S phase, cells become irreversibly committed to division. pRb is the major gatekeeper to control this critical point in growth regulation; lack of pRb activity removes the pRb constraint on cell cycle control, resulting in deregulated cell proliferation.

The RB1 gene is a large gene, containing 27 exons over about 200 kilobases of DNA, and mutations have been described in almost every exon.¹⁰ New germline mutations have an overwhelming preference for the paternal allele. Penetrance of the trait is greater than 90%.¹¹

In both hereditary and nonhereditary retinoblastoma the second tumorigenic event is usually chromosomal, often as a result of mitotic recombination errors.¹² This second hit occurs at a much higher frequency than the first hit, and it is more sensitive to environmental factors such as ionizing radiation, perhaps explaining the increased risk of radiation-induced malignancies in survivors of retinoblastoma.

Prevention, Early Detection, and Genetic Counseling

The successful management of retinoblastoma depends on the ability to detect the disease while it is still intraocular. Disease stage correlates with delay in diagnosis.¹⁴ In developing countries, late diagnosis is associated with orbital and metastatic disease.¹⁵ Eye assessment is encouraged in all neonates and at subsequent health visits. Mass screening is being considered, especially where the tumor is common in areas of South America and Asia.

Retinoblastoma is a unique neoplasm in that the genetic form imparts a predisposition to developing tumor in an autosomal dominant fashion with almost complete penetrance (85% to 95%).¹⁶ The majority of such children acquire the first mutation as a new germline mutation, with only 15% to 25% having a positive family history. However, some families display an inheritance pattern characterized by reduced penetrance and expressivity. Also, the RB1 gene mutation can occur at a late stage of embryogenesis, resulting in a variable expression depending on the tissue, causing mosaicisms in 10% to 15% of the patients or their progenitors.¹⁷ Recognizing the inheritance pattern and the existence of mosaicisms, the following familial risk estimates can be made¹⁶:

1 Risk for offspring of survivors of retinoblastoma:

a The risk of retinoblastoma arising in the offspring of survivors of bilateral disease is 45%.

b In patients with unilateral disease, the risk of retinoblastoma in offspring is 2.5%. (The estimate includes offspring of the 10% of unilateral retinoblastoma with a positive family history in whom the risk is similar to that of bilateral cases—45%.)

2 Risk for siblings of patients with retinoblastoma: In siblings of bilaterally affected children whose parents are also affected the risk of retinoblastoma is 45%; if the sibling is unilaterally affected the risk is 30%. Without a family history the risk is 2% for siblings of bilateral cases and 1% for siblings of unilateral cases.

Genetic counseling is of the utmost importance to assist parents in understanding the genetic consequences of each form of retinoblastoma and to estimate the risk in relatives. With the refinement in methods of mutational analysis over the past decade, detection rates have increased to more than 90%.¹⁰

Pathology and Pathways of Spread

Macroscopically, retinoblastoma is soft and friable, tending to outgrow its blood supply with resultant necrosis and calcification. Dissemination within the vitreous and retina in the form of small, white nodules (seeds) is common, sometimes making it difficult to distinguish a multicentric primary tumor from a disseminated tumor.¹⁸ The microscopic appearance depends on the degree of differentiation. Undifferentiated retinoblastoma is composed of small, round, densely packed cells with hypochromatic nuclei and scant cytoplasm. Several degrees of photoreceptor differentiation have been described, characterized by distinctive cellular arrangements. Flexner-Wintersteiner rosettes (clusters of low columnar cells arranged around central lumens bounded by eosinophilic membranes analogous to the external membrane of the normal retina) are specific for retinoblastoma and are noted in 70% of tumors. Fleurettes (composed of larger cells with abundant eosinophilic cytoplasm arranged in a distinctive fleur-de-lis pattern) are less frequent; cells exhibit ultrastructural characteristics of photoreceptor differentiation. Especially well-differentiated tumors composed almost entirely of fleurettes have been called retinomas or retinocytomas. Ultrastructurally, retinoblastoma cells demonstrate photoreceptor differentiation with the presence of the 9-0 microtubule doublet pattern, abundant cytoplasmic microtubules, synaptic ribbons, and neurosecretory granules.

Clinical Manifestations, Patient Evaluation, and Staging

Retinoblastoma is a tumor of young children. Bilateral retinoblastoma presents at a younger age (usually before 1 year of age) than patients with unilateral disease (typically at age 1 to 3 years).16,18,19 Half the cases of retinoblastoma diagnosed during the first year are bilateral, compared with fewer than 10% when diagnosed after 1 year of age.

In over 50% of cases, the presenting sign is leukocoria, sometimes first noticed after a flash photograph. Strabismus is the second most common presenting sign and is usually correlated with macular involvement. The differential diagnosis includes other childhood diseases that can present as leukocoria, such as persistent hyperplastic primary vitreous, retrolental fibrodysplasia, Coats disease, congenital cataracts, toxocariasis, and toxoplasmosis.

Although most patients with bilateral retinoblastoma carry a germline mutation of the RB1 gene, only 5% carry a deletion involving the 13q14 locus large enough to be detected by karyotyping. In those cases, retinoblastoma is part of a more complex syndrome resulting from the loss of additional genetic material. Patients with the 13q− syndrome are characterized by typical facial dysmorphic features, subtle skeletal abnormalities, and varying degrees of mental retardation and motor impairment.²⁰ The severity of deficits correlate with the size of the deletion; normal psychomotor development may be seen in those patients in whom the deletion is restricted to the 13q14 band.

Trilateral retinoblastoma refers to the association of bilateral retinoblastoma with a typically asynchronous brain tumor.²¹ The majority of tumors are pineal region primitive neuroectodermal tumors (PNETs, pineoblastomas); 20% to 25% of the tumors are suprasellar or parasellar. The PNETs exhibit varying degrees of neuronal or photoreceptor differentiation, suggesting an origin from the germinal layer of primitive cells. Trilateral disease occurs in 3% to 9% of patients with the genetic form of retinoblastoma and appears to be more common in familial cases. The prognosis until recently has been almost uniformly fatal. The median age at diagnosis of trilateral retinoblastoma is 23 to 48 months; the interval between initial diagnosis of bilateral retinoblastoma and the diagnosis of the brain tumor is usually more than 20 months.²² In recent years, with the more widespread use of chemoreductive therapy and less use of radiation therapy (RT) for patients with bilateral retinoblastoma, the incidence of trilateral retinoblastoma has decreased dramatically.²³ Approximately 5% of patients with bilateral disease develop pineal cysts, which appear to be a forme fruste of trilateral retinoblastoma.²⁴

The diagnosis of intraocular retinoblastoma is usually made without pathologic confirmation. An examination under anesthesia with a maximally dilated pupil and scleral indentation is required to examine the entire retina (Fig. 69-1). Endophytic tumors are those that grow inward to the vitreous cavity and may seed the vitreous cavity. Exophytic retinoblastoma grows into the subretinal space, causing progressive retinal detachment and subretinal seeding. A very detailed documentation of the number, location, and size of tumors, of the presence of retinal detachment and subretinal fluid, and of the presence of vitreous and subretinal seeds must be performed. Wide-angle real-time retinal imaging systems such as RetCam (Clarity Medical Systems, Pleasanton, Calif.) provide a 130-degree field of view and digital recording, thus facilitating diagnosis and follow-up.

Figure 69-1 A, Advanced intraocular retinoblastoma in a patient with bilateral disease. B, Same eye after 4 cycles of chemotherapy.

Imaging studies that aid in the diagnosis include bidimensional ultrasonography, computed tomography, and magnetic resonance imaging (MRI). Imaging is particularly important to evaluate extraocular extension and to differentiate retinoblastoma from other causes of leukocoria. Evaluation for the presence of metastatic disease also needs to be considered in a subgroup of patients. Metastatic disease occurs in 10% to 15% of patients, usually in association with advanced intraocular features, such as deep choroidal and scleral invasion, or involvement of the iris or ciliary body or of the optic nerve beyond the lamina cribrosa.¹³ In such cases, additional staging should include bone scintigraphy, bone marrow aspiration and biopsy, and lumbar puncture.

The Reese-Ellsworth grouping system has been the standard for intraocular disease. This system was designed to predict the outcome after external beam radiation therapy (EBRT). It divides eyes into five groups on the basis of the size, location, and number of lesions and on the presence of vitreous seeding ²⁵ (Table 69-1). The changed paradigm for “conservative” chemoreduction strategies for intraocular retinoblastoma has made the Reese-Ellsworth system less predictive of ocular preservation. A new staging system (i.e., the International Classification of Retinoblastoma) has been developed to provide a simpler, more user-friendly classification applicable to current therapies. The new system is based on the extent of tumor seeding within the vitreous cavity and subretinal space and seems to be a better predictor of treatment success²⁶ (Table 69-2).

TABLE 69-1 Reese-Ellsworth Grouping for Suitability for Treatment of Retinoblastoma by Radiation Therapy

Group	Description
I (Very Favorable)
Ia	Solitary tumor smaller than 4 dd at or behind the equator
Ib	Multiple tumors, none larger than 4 dd, all at or behind equator
II (Favorable)
IIa	Solitary tumor 4-10 dd, at or behind equator
IIb	Multiple tumors 4-10 dd, at or behind equator
III (Doubtful)
IIIa	Any lesion anterior to equator
IIIb	Solitary tumor larger than 10 dd behind equator
IV (Unfavorable)
IVa	Multiple tumors, some larger than 10 dd
IVb	Any lesion extending anteriorly to the ora serrata
V (Very Unfavorable)
Va	Massive tumors involving more than half the retina
Vb	Vitreous seeding

dd, disc diameter (1.5 mm).

From Reese AB, Ellsworth RM: The evaluation and current concept of retinoblastoma therapy, Trans Am Acad Ophthalmol Otolaryngol 67:164-172, 1963.

TABLE 69-2 International Classification of Retinoblastoma

Group A

Small tumors away from foveola and disc

• Tumors ≤3 mm in greatest dimension confined to the retina, and

• Located at least 3 mm from the foveola and 1.5 mm from the optic disc

Group B

All remaining tumors confined to the retina

• All other tumors confined to the retina not in group A

• Subretinal fluid (without subretinal seeding) ≤3 mm from the base of the tumor

Group C

Local subretinal fluid or seeding

• Local subretinal fluid alone >3 to ≤6 mm from the tumor

• Vitreous seeding or subretinal seeding ≤3 mm from the tumor

Group D

Diffuse subretinal fluid or seeding

• Subretinal fluid alone >6 mm from the tumor

• Vitreous seeding or subretinal seeding >3 mm from tumor

Group E

Modified from Shields CL, Mashayekhi A, Au AK, et al: The International Classification of Retinoblastoma predicts chemoreduction success, Ophthalmology 113:2276-2280, 2006.

For patients undergoing enucleation, pathologic staging incorporates features known to influence outcome, guiding the therapeutic approach; such factors include choroidal and scleral involvement, optic nerve extension, and presence of metastatic disease. A third proposed staging system developed by an international consortium of ophthalmologists and pediatric oncologists incorporates the most important elements of the older systems ²⁷ (Table 69-3). Growth and invasion occur as a sequence of events, and extraretinal extension occurs only after the tumor has reached large intraocular dimensions. As part of this process, retinoblastoma extends into the ocular coats (choroids and sclera), the optic nerve, and the anterior segment. Extraocular disease is the next step in this progression; locoregional dissemination occurs by direct extension through the sclera into the orbital contents and preauricular lymph nodes. Extraorbital disease manifests as intracranial tumor, leptomeningeal dissemination, or hematogenous metastasis.

TABLE 69-3 International Retinoblastoma Staging System, Proposed

Stage	Treatment
0	Patients treated conservatively
I	Eye enucleated, completely resected histologically
II	Eye enucleated, microscopic residual tumor
III	Regional extension
IIIa	Overt orbital disease
IIIb	Preauricular or cervical lymph node extension
IV	Metastatic disease
IVa	Hematogenous metastasis (without CNS involvement) 1 Single lesion 2 Multiple lesions
IVb	CNS extension (with or without any other site of regional or metastatic disease) 1 Prechiasmatic lesion 2 CNS mass 3 Leptomeningeal and cerebrospinal fluid disease

From Chantada G, Doz F, Antonelli CB, et al: A proposal for an international retinoblastoma staging system, Pediatr Blood Cancer 47:801-805, 2006.

Primary Therapy

Principles of Treatment

Treatment of retinoblastoma aims to save life and preserve useful vision, with attention to late functional and carcinogenic effects. Contemporary care requires coordination among the patient’s ophthalmologist, pediatric oncologist, and radiation oncologist.²⁸

Surgery

Enucleation is indicated for large tumors filling the vitreous when there is little or no likelihood of restoring vision and when tumor is present in the anterior chamber or associated with neovascular glaucoma. The eye must be removed intact, without seeding tumor cells into the orbit.²⁹ For optimal staging, a long segment (10 to 15 mm) of the optic nerve is removed with the globe. An orbital implant is usually fitted during the same procedure, and the extraocular muscles are attached to it. A ceramic false eye is later fitted in the orbital socket. Orbital exenteration is very seldom indicated. For patients presenting with orbital (extraocular) disease, judicious use of chemotherapy, surgery, and RT provides tumor control and often orbital exenteration can be avoided.

Focal Surgical Therapies

Focal treatment is used for small tumors (<3-6 mm), classically in patients with bilateral disease and in combination with chemotherapy. Focal therapies are central to ongoing studies utilizing conservative therapy (chemotherapy and focal treatment) to avoid enucleation and EBRT in unilateral intraocular disease. Photocoagulation with the argon laser is used for the treatment of tumors situated at or posterior to the equator of the eye and for the treatment of retinal neovascularization occasionally seen after RT.³⁰ This technique is limited to tumors measuring no greater than 4.5 mm at its base and no greater than 2.5 mm in height. The treatment aims to obliterate blood supply to the tumor. Two or three monthly sessions are usually required, and local tumor control is achieved in approximately 70% of cases. Cryotherapy is used for the treatment of small equatorial and peripheral lesions that measure no more than 3.5 mm at the base and no more than 2 mm in height.³¹ One or two monthly sessions of triple freeze and thaw are performed; the resultant tumor control is usually excellent. A more recently introduced focal therapy is transpupillary thermotherapy, which applies focused heat at sub-photocoagulation levels, usually with a diode laser.³² In thermotherapy, the goal is to deliver a temperature of 42° C to 60° C for 5 to 20 minutes to the tumor, relatively sparing retinal vessels from photocoagulation. The use of focal treatments is especially important in conjunction with chemotherapy, when both treatment modalities appear to have synergistic effects. Sequential thermotherapy and carboplatin enhances the antitumor effect by increasing the platinum-DNA adducts; thus, thermochemotherapy is becoming an important component of therapy for intraocular retinoblastoma.³³ In general, local control rates of 70% to 80% can be achieved. Complications of focal treatments include transient serous retinal detachment, retinal traction and tears, and localized fibrosis.

Chemotherapy

Chemotherapy is indicated in patients with extraocular disease, in the subgroup of patients with intraocular disease with high-risk histologic features, and in patients with bilateral disease in conjunction with aggressive focal therapies. In patients with early-stage unilateral disease, chemotherapy is central to conservation therapy when combined with focal therapy. Agents effective in the treatment of retinoblastoma include platinum compounds, etoposide, cyclophosphamide, doxorubicin, vincristine, and ifosfamide.28,34

Radiation Therapy

RT had historically been the primary curative treatment for patients with bilateral disease. Through the early 1990s, debate focused on optimizing irradiation for localized and locally advanced intraocular disease, extraocular extension, and central nervous system disease (primarily trilateral, but also leptomeningeal extension). Although disease control in most locoregional presentations was excellent, the documentation of increasing second malignancies continuing three to five decades after irradiation prompted a paradigm shift. Neoadjuvant or primary chemotherapy combined with focal therapy for consolidation or focally “resistant” disease has become the standard for early-stage disease, either unilateral or bilateral. Focal therapies include physical agents summarized earlier as well as radioactive plaques, employed in advanced intraocular disease requiring postchemotherapy consolidation or postprogression salvage. For cases of more advanced intraocular disease, documented extraocular extension, or distant metastasis, consolidative EBRT is the standard for local tumor control. Consolidative EBRT at a point when advanced intraocular or central nervous system disease is minimal, yet “responsive” to rather than resistant to chemotherapy, is under investigation.

The spectrum of radiation techniques includes local brachytherapy plaques, focal external beam irradiation (intensity-modulated radiation therapy [IMRT] or stereotactic photon RT, or proton beam), full ocular EBRT (with the same technical options as just mentioned, recent reports documenting techniques to limit dose to the bony orbit and contralateral eye), and orbital irradiation.³⁵^–⁴⁷ Recognizing the balance of potential secondary carcinogenesis (particularly in bilateral or hereditary retinoblastoma) and orbital growth changes, while noting the long documented efficacy of RT in this disease, challenges the radiation oncologist as to indications and timing for management, optimal treatment planning and delivery, and requisite follow-up.⁴⁸^–⁵⁰

Intraocular Retinoblastoma

Unilateral Retinoblastoma

For unilateral intraocular presentations, enucleation is curative for 85% to 90% of children. Outcome after enucleation is excellent, with good functional results and minimal long-term effects.⁴⁸ In view of the apparent success in treating bilateral intraocular disease with chemotherapy and focal therapy, a similar “conservative” approach may be appropriate in unilateral intraocular disease, especially in very young children who may later evidence contralateral disease.⁴⁸ For patients with early intraocular disease (Reese-Ellsworth groups I to III, International Classification of Retinoblastoma group B), a nonintense two-drug regimen of vincristine and carboplatin had been suggested, based on overall results with three-drug chemotherapy (also including etoposide) documented at nearly 100% for ocular and visual preservation.²⁸ A Children’s Oncology Group trial in moderately advanced intraocular disease was discontinued when the event-free survival rate with the two-drug regimen fell below the monitoring guidelines.* Variations on the three-drug “standard regimen” are under investigation. In patients with advanced intraocular tumors (groups C and D), ocular preservation rates are typically at 50% to 70% and EBRT may be required.^36,50

Postoperative chemotherapy and RT are indicated with findings of scleral invasion, microscopic tumor at the transection line of the optic nerve, or overt invasion of the optic nerve (see later under treatment of extraocular retinoblastoma).^51,⁵² Postoperative chemotherapy may be beneficial for selected patients with higher risk for extraocular dissemination (i.e., with concurrent retrolaminar and choroidal involvement and possibly with massive choroidal involvement).^{28,53,54,55,56}

Chemotherapy regimens with apparent efficacy in these settings include VCE (vincristine, carboplatin, and etoposide), VDC (vincristine, doxorubicin, and cyclophosphamide), or a hybrid.

Bilateral Retinoblastoma

Bilateral disease typically presents as advanced disease in one eye and relatively more localized disease contralaterally. The classic treatment has been enucleation of the eye with more advanced disease (when little or no visual potential is apparent) and EBRT for the remaining eye. The radiation oncologist has argued to irradiate both eyes when one has tumor burden, clearly obviating any likelihood of useful vision. Two major sequelae led to changing the classic approach: irradiation of the orbit during a period of rapid growth in very young children results in significant reduction in orbital and zygomatic facial growth, whether symmetrical (after opposed lateral radiation techniques) or asymmetrical (with unilateral orbital irradiation), with dysmorphic changes apparent before puberty.43,46,48 Of greater importance, the risk for development of secondary cancers approaches 40% in hereditary forms of retinoblastoma after irradiation; the standard incidence ratio for largely infield sarcomas exceeds 100 times the expected rate, with late development of carcinomas (e.g., breast, thyroid, lung, head, and neck) at or above 10 times the expected rate. This risk may be age related and is less in older children.^49,57

The treatment of patients with bilateral retinoblastoma now incorporates upfront chemotherapy, intended to achieve maximum chemoreduction of the intraocular tumor burden, followed by aggressive focal therapies (see Fig. 69-1). Relatively effective carboplatin-based multiple-agent chemotherapy and planned consolidative local therapies have resulted in increased ocular and visual preservation and a decrease (and delay) in the necessity for enucleation or EBRT. The best results have followed combinations of vincristine, carboplatin, and etoposide* (Tables 69-4 and 69-5).

TABLE 69-4 Recommended Approach to the Treatment of Intraocular Retinoblastoma

TABLE 69-5 Treatment of Intraocular Retinoblastoma

With more advanced disease, a major proportion of failures represent tumor growth as vitreous seeding and/or subretinal implants. Carboplatin diffuses well into the vitreous, but recent interest has stimulated a large prospective Children’s Oncology Group trial including systemic and subtenon administration (injected posteriorly between a thin membrane that surrounds the globe posterior to the limbus or beneath the conjunctiva), based on preclinical data documenting intraocular carboplatin concentrations 7 to 10 times higher when administered subconjunctivally.64,65,66 Improvement in the outcome of advanced ocular disease after subtenon instillation has not yet been documented clinically; there is recent interest in intra-arterial carboplatin administration.^67,⁶⁸

New agents with better intraocular penetration are being investigated. Topotecan is of interest and has excellent intraocular penetration and preclinical efficacy.⁶⁹

The recent description of MDM4 amplification as the mechanism of inactivation of the TP53 pathway in retinoblastoma has opened the door to the use of specific targeted molecular therapies. Nutlin-3 is a small-molecule inhibitor of the MDM2-TP53 interaction.⁷⁰ MDM4 and MDM2 bind TP53 with similar affinities, and studies have shown that nutlin-3 prevents the MDM4-T53 interaction in retinoblastoma cells, inducing TP53-mediated apoptosis in vitro and in vivo. Subconjunctival injection of nutlin-3 to mice with intraocular retinoblastoma resulted in significant tumor responses. The combination of nutlin-3 with a DNA-damaging agent such as topotecan resulted in a synergistic effect.¹³

Intravitreal and Intra-arterial Chemotherapy for Intraocular Retinoblastoma

Japanese investigators have pioneered the administration of intravitreal and intra-arterial melphalan for patients with advanced or recurrent intraocular retinoblastoma.⁷¹ Clinical responses have been documented after intravitreal melphalan and hyperthermia.⁷¹ A small, localized retinoblastoma would seem an excellent candidate for chemotherapy directly into the tumor vasculature. However, cannulation of the retinal artery is required, limiting the applicability of this procedure.^67,⁷¹ Abramson and associates reported that direct cannulation of the ophthalmic artery using a microcatheter to instill melphalan resulted in high ocular salvage rates.^68,⁷²

Treatment of Extraocular Retinoblastoma

Extraocular dissemination of retinoblastoma usually reflects delayed diagnosis and treatment. In Europe and the United States, fewer than 5% of patients present with extraocular disease, in contrast to more than 20% to 40% in less developed countries.^53,⁵⁴ Four patterns of extraocular disease have been recognized: (1) locoregional, including orbital infiltration, tumor extending into the optic nerve or to the cut end of the nerve, and lymphatic spread to preauricular lymph nodes; (2) CNS dissemination; (3) trilateral retinoblastoma; and (4) metastatic retinoblastoma.

Orbital and Locoregional Retinoblastoma

Orbital retinoblastoma occurs as a result of progression of the tumor through the emissary vessels and sclera; scleral disease is considered to be extraocular and is treated as such. Orbital retinoblastoma is isolated in 60% to 70% of cases; lymphatic, hematogenous, and CNS metastases occur in 30% to 40% of patients with metastasis.⁵⁵ Treatment includes systemic chemotherapy and RT; with this approach, 60% to 85% of patients are cured. Failures occur predominantly in the CNS, highlighting the importance of drugs with well-documented CNS penetration. Different chemotherapy regimens have proved to be effective and have included vincristine, cyclophosphamide, and doxorubicin; platinum- and epipodophyllotoxin-based regimens; or combinations thereof.²⁸ For patients with macroscopic orbital disease, initial chemotherapy is followed by surgery, usually obviating the need for orbital exenteration. Postoperative chemotherapy and orbital irradiation (40 to 45 Gy) consolidate therapy.⁵⁶ Similar management should be followed for patients with scleral disease, including RT, although good outcomes without RT also have been reported.⁵³ Patients with isolated involvement of the optic nerve at the transection level should also receive similar systemic treatment with irradiation to the entire orbit (typically to 36 Gy) and a 9- to 10-Gy boost to the chiasm (total: 45 to 46 Gy).^51,⁵² The preauricular and cervical lymph nodes should be explored carefully because 20% of patients with orbital extension have lymphatic metastases.⁵⁵ Lymphatic dissemination may not carry a worse prognosis, provided that the involved lymph nodes are also irradiated.

Central Nervous System Disease

Intracranial dissemination occurs by direct extension through the optic nerve, and its prognosis is dismal.53,56 Treatment includes platinum-based intensive systemic chemotherapy and CNS-directed therapy. Although intrathecal chemotherapy has been traditionally used, there is no preclinical or clinical evidence to support its use. The use of irradiation in these patients is controversial, yet standard therapy includes craniospinal irradiation (23.4 to 36 Gy to the neuraxis and a boost to 45 Gy to sites of overt or nodular disease). Therapeutic intensification with high-dose, marrow ablative chemotherapy and autologous hematopoietic progenitor cell rescue has been explored, but its role is not yet clear.^73,⁷⁴ Reports of survivors are anecdotal.

Trilateral Retinoblastoma

The prognosis for patients with trilateral retinoblastoma is very poor; most patients die of disseminated neuraxis disease in less than 9 months.²² The rare survivors are usually asymptomatic (diagnosed by screening imaging) and treated with intensive chemotherapy with or without craniospinal irradiation.^22,⁷⁵ Given the short interval between the diagnosis of retinoblastoma and the occurrence of trilateral retinoblastoma, routine screening might detect the majority of cases within 2 years. Current strategies include avoiding irradiation and using intensive chemotherapy followed by consolidation with myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue, an approach similar to that being used in the treatment of brain tumors in infants.⁷⁶ Success has been noted anecdotally and in a series from Memorial Sloan-Kettering Cancer Center.^75,77

Extracranial Metastatic Retinoblastoma

Hematogenous metastases are most common in the bones, bone marrow, and, less frequently, liver. Although long-term survivors have been reported after treatment with conventional chemotherapy, cures are anecdotal. Recent reports show that metastatic retinoblastoma can be cured using high-dose, marrow-ablative chemotherapy and autologous hematopoietic progenitor cell rescue 73,74,78,79,80 (Table 69-6). The approach is similar to that for metastatic neuroblastoma; patients receive short and intensive induction regimens usually containing alkylating agents, anthracyclines, etoposide, and platinum compounds and are then consolidated with marrow-ablative chemotherapy and autologous hematopoietic cell rescue.⁷⁴ In the series from Memorial Sloan-Kettering Cancer Center,⁷⁴ patients with hematogenous bone metastases who responded to induction chemotherapy did not always require RT.

TABLE 69-6 Treatment of Extra-CNS Metastatic Retinoblastoma

Irradiation Techniques/tolerances

Contemporary therapy for retinoblastoma incorporates irradiation most often as consolidative therapy or as “salvage” for disease resistant to or recurrent after chemotherapy. As such, the target volume for RT varies widely from focal irradiation to encompassing the entire retina for intraocular disease and from orbital irradiation to inclusion of optic nerves and chiasm for regional disease. Radiation techniques include local brachytherapy (episcleral plaques) or EBRT (three-dimensional conformal, intensity-modified, or stereotactic RT, including proton beam irradiation).

Episcleral Plaque Brachytherapy

The indications for radioactive plaques have evolved along with progress in technology and physics from the introduction of radon seed implants in the 1920s, through broad experience with cobalt-60 plaques in the 1950s, and more recent use of iodine-125 (¹²⁵I), iridium-192 (¹⁹²Ir), and ruthenium-106 (¹⁰⁶Ru).³⁸^–⁴² Primary plaque therapy is an option for localized retinoblastoma that is typically limited to one or two foci not involving the optic disc or macula. As an option among focal therapies in conjunction with chemoreduction therapy, radioactive plaques can be curative with small or moderate-sized lesions, including those with focal vitreous seeding immediately overlying the tumor(s).⁴¹

Most plaques today use ¹²⁵I, a low-energy gamma ray emitter (27 to 35 keV; half-life, 60 days) that is readily available in encapsulated form, allowing custom fabrication of gold plaques of varying sizes and configured either as round or notched templates, the latter to allow placement adjacent to the optic nerve.^39,^41,⁴² One can differentially load ¹²⁵I seeds within the wells of the plaque to achieve the dose distribution appropriate for the tumor volume (based on diameter and height). One typically uses ¹²⁵I plaques for tumor height up to 10 mm and diameter less than or equal to 16 mm. Figure 69-2 shows some current and prototype plaques; Figure 69-3 demonstrates a case using a collimating plaque to treat retinoblastoma. ¹⁹²Ir is an alternative radioisotope (a higher-energy gamma ray emitter at 295 to 612 keV; half-life, 74 days), also available as sealed sources with somewhat less desirable dosimetric characteristics. Experience with ¹⁰⁶Ru has primarily been reported from Europe.^39,⁴² This pure beta emitter provides a spectrum of beta particles with energies up to 3.5 MeV; the half-life is 374 days, which is important because ¹⁰⁶Ru is an integral part of the plaque that can be used for up to a year. The dosimetric profile of ¹⁰⁶Ru limits utilization to tumors with height of 6 mm or less; the uniformly round plaques are typically not applied within 2 mm of the optic nerve.³⁹ Both ¹²⁵I and ¹⁰⁶Ru limit radiation exposure to patient and medical personnel while allowing diminished dosing to the underlying orbital bones and the optic lens.

Figure 69-2 A, A mixture of some of the current plaques that are available today from various vendors. B, Prototypes showing the shapes that are possible in modern plaques.

From Astrahan M: Plaque Simulator X computer program and electronic manual [screen capture of the program written by Dr. Melvin Astrahan called Plaque Simulator X]. Image used with permission, 2010.

Figure 69-3 This 8-month-old child’s eye had a diameter of 22 mm and required a plaque with an 11-mm radius of curvature; the dose prescribed was 30 Gy in 71 hours to the apex of the 6.7-mm high tumor. Only the seeds at the posterior end of this semi-elliptical, mildly notched plaque that lie under the tumor are loaded. This allows the sutures to be placed anteriorly. The perfect fit of the plaque to the eye ensures that the plaque will not lift up at the posterior end when sutured anteriorly. A, Retinoblastoma with a grooved plaque in which the grooves help collimate the radiation dose as shown by the isodose levels. B, Diagram of the retina in the same plan with suture marks in the model to help guide the team in the operating room. C, Three-dimensional conformal isodose map of the same plan. D, Measuring the actual plaque’s eyelets from the same plan using Castroviejo calipers.

Planning for plaque placement includes tumor size and location as identified by the ophthalmologist, often enhanced by direct visual record (e.g., with RetCam), ocular ultrasonography, and sometimes MRI. The target volume includes the specific tumor base area as projected through the sclera with a 1- to 2-mm margin; tumor height is a direct measurement from the imaging data. The plan provides proper positioning based on the plaque’s center and suture eyelets and the distance from the limbus. The surgeon provides access to the sclera underlying the typically posterior tumor, marking the center and edges of the tumor based on projection as a visual shadow and through sclera indentation. A dummy plaque of identical configuration is used to verify positioning, and the loaded episcleral plaque is sutured onto the sclera by the ophthalmologist. A lead eye shield limits concerns about radiation safety when using ¹²⁵I. Inpatient or outpatient status depends on radiation exposure and local requirements.

The dose is prescribed at the tumor apex or extended to include overlying localized vitreous seeds if present. The target dose is usually 40 Gy at the apex for ¹²⁵I at 40 to 80 cGy/hr.^38,^40,⁴¹ Most of the experience with ¹⁰⁶Ru reports apical doses of 50 Gy, sometimes 70 Gy.^39,⁴² The dose at the tumor base (scleral dose) approximates 120 Gy for ¹²⁵I and 150 to 200 Gy with ¹⁰⁶Ru.

A review from both the Wills Eye Hospital and Hahnemann University Hospital in Philadelphia showed use of episcleral plaques in 15% of 900 cases treated between 1976 and 1999.³⁸ Of the 208 tumors treated largely with ¹²⁵I plaques, 29% used plaques as primary intervention and 71% after progression (prior EBRT and/or chemoreduction therapy). Ocular control was documented in 83% of eyes treated; recurrence occurred in 12% of those without prior therapy and in 20% after initial or subsequent progression. Ocular complications included nonproliferative retinopathy (27% at 5 years), papillopathy (26%), and nonproliferative maculopathy (25%).³⁸ A subsequent report from the same institutions updates ¹²⁵I plaques used at the time of progression after chemoreduction therapy (1994-2005).⁴¹ Eighty-four tumors were treated in 71 eyes of 64 patients with dosimetric factors as outlined earlier; average area at the base was 9 mm, and average height was 4 mm. Plaques were round (83%) or notched to allow placement adjacent to the optic nerve (17%); the average dose received at the fovea was 45 Gy, and at the optic nerve it was 22 Gy. Tumor control was documented in 95% of patients after chemoreduction therapy with or without earlier EBRT; failures occurred at a median of 4 months post implant.

Experience with 175 ¹⁰⁶Ru plaques (134 patients, 119 with bilateral disease) at the Jules-Gonin Eye Hospital, Lausanne, Switzerland, between 1992 and 2006 indicated tumor control in 94% of lesions and ocular retention in 89% of patients at 5 years.³⁹ Enucleation was ultimately required in 13% of eyes for tumor, with intraocular hemorrhage obscuring visual follow-up, or because of radiation neuropathy or retinopathy (in equal proportions).³⁹

External Beam Irradiation

EBRT is most commonly used as consolidative therapy in conjunction with chemoreduction therapy for intraocular disease, for therapy for regionally extensive tumor, and for salvage after chemotherapy and/or radiation resistance. Although almost systematically targeting the entire globe or retinal surface posterior to the optic lens in the past, current techniques also include focal stereotactic conformal RT and proton beam therapy to sites of active residual, progression, or recurrence after initial chemotherapy and/or prior irradiation (EBRT or brachytherapy).

The classic presentation requiring full orbital irradiation has been the young child with bilateral disease, in which the more advanced eye was enucleated and irradiation indicated for contralateral ocular disease or, less commonly, irradiation was administered for both eyes when reasonable likelihood of disease control and visual preservation were both present bilaterally. The single ipsilateral or bilateral opposed “D” fields provided coverage to the posterior retina, with acknowledged underdosage to the eye anterior to the equator associated with attempts to spare the ipsilateral lens and the contralateral eye when uninvolved or the disease was under control (e.g., after brachytherapy). Whether through straight lateral or coronally oblique fields to miss the contralateral eye, the retina between the ora serrata anteriorly and the equator of the globe was relatively underdosed. Hence, the Reese-Ellsworth staging system that includes not only disease volume and centricity but also location—where anterior disease resulted in higher stage designation—reflects the difficulty in achieving radiation control through then standard approaches.^43,^44,⁴⁷

Initial indications for focal therapies (especially cryotherapy) were in the setting of disease recurrence after EBRT, ultimately achieving “success” in controlling tumor while avoiding enucleation and, where disease did not preclude such with massive retinal involvement or macular extension, useful vision.^26,⁴⁴ EBRT alone or in combination with subsequent focal therapy is successful (see earlier discussion) in 80% to 100% of children in Reese-Ellsworth groups I to III. With adequate attention to anterior beam placement, ocular preservation has been documented in 50% to 80% of cases even with group IV or V disease.^26,⁴³

In the setting of primary chemoreduction therapy, low-dose consolidative EBRT has been tested at a reduced “prophylactic” dose of 26 Gy when initially advanced disease (International Classification of Retinoblastoma group E) is yet responsive to induction chemotherapy. “Prophylactic” full ocular irradiation (26 Gy) resulted in ocular disease control without enucleation or requirement for full “therapeutic” doses of EBRT) in 80% of patients at 5 years compared with 33% with somewhat less advanced disease treated with the same chemoreduction technique alone.³⁶

Reports over the past 5 years document more sophisticated approaches to either full ocular or focal radiation techniques. Stereotactic conformal RT has been used to mimic the focal dose distribution of episcleral implants for locally progressive disease or as focal consolidative therapy.^35,^37,⁴³ Ocular suction systems provide precision localization and immobilization of the eye during anesthesia for stereotactic techniques^35,³⁷ (Fig. 69-4). Such techniques allow full therapeutic doses to focal posterior tumors (40 to 42 Gy) while limiting dose to the remainder of the globe, the optic nerve, and the ipsilateral lens.^43,⁴⁵ IMRT techniques document coverage of the entire retina/vitreous while limiting dose to the lacrimal gland and the bones of the orbit.^43,47,50 The potential superiority of proton beam therapy, utilizing relatively simple scatter or scanning proton plans (e.g., single lateral field [Fig. 69-5]) to encompass the entire retina or for focal therapy at recurrence, has been reported with impressive dosimetry, if clinical experience is yet evolving.^43,⁴⁵ Figure 69-6 shows a patient’s plan with bilateral disease with frontal lobe sparing using active proton scanning.

Figure 69-4 A, Lubrication placed onto the suction device used to keep the globe from moving during radiation therapy. B, The suction cup on the eye placed to keep the lens medial for lateral proton beam therapy. C, Detailed view of the device on the eye.

Figure 69-5 A, Single proton field anterior dosimetry using active scanning. B, Single proton field lateral dosimetry using active scanning.

From Simmons J: Active Scanning Proton Beam Plans from the Midwest Proton Radiotherapy Institute. Bloomington, IN, 2010.

Figure 69-6 A, Initial bilateral proton plan using active scanning. B, Boost bilateral proton plan using active scanning.

From Simmons J: Active Scanning Proton Beam Plans from the Midwest Proton Radiotherapy Institute. Bloomington, IN, 2010.

When there is overt disease involving the optic nerve (MRI at diagnosis or histology showing tumor at the cut end of the nerve after initial enucleation), the standard therapy is to combine aggressive chemotherapy with enucleation and postoperative orbital RT, the posterior aspect of the target volume encompassing the optic nerve to the chiasm. Recent data from Argentina and Children’s Hospital of Los Angeles show disease control in 70% or more of cases; seven of nine disease-free children from the Children’s Hospital of Los Angeles had not received RT.^51,⁵² The use of photon IMRT or proton beam irradiation shows significant advantages in dose distribution, with full orbital RT targeting soft tissues and optic nerve extension.^43,47,50

The prescription dose for retinoblastoma is classically 40 to 45 Gy at 1.8 to 2.0 Gy per fraction. Foote and colleagues ⁴⁴ reviewed the Mayo Clinic experience, documenting a lack of dose response above 45 Gy. A similar review by Merchant and associates⁴⁶ showed similar rates of ocular preservation and potentially fewer treatment-related toxicities with 36 Gy in 18 fractions, with apparent diminution in disease control for more advanced disease (Reese-Ellsworth groups III to V). There is some evidence suggesting a lower threshold for postirradiation retinopathy when full ocular RT follows chemotherapy.⁴³ The most recent dose relationship from Wills Eye Hospital in Philadelphia shows excellent disease control and ocular preservation in advanced intraocular disease (International Classification of Retinoblastoma group E) with 26-Gy consolidative full-eye irradiation when given on completion of chemotherapy, at a time when there is no evidence of recurrent or “active” tumor; toxicities appear to be less than when full dose (40 Gy) is required for overt residual/progressive tumor.³⁶

Long-Term Effects of Retinoblastoma and Its Treatment

Children with retinoblastoma have the highest rate of secondary cancers of any cancer cohort. The risk is largely in patients with germline mutations of the RB1 gene, identified in long-term survivor cohorts as those with hereditary retinoblastoma (a family history—10% of children presenting with retinoblastoma; and those with bilateral disease absent a family history—30%). Patients with nonhereditary retinoblastoma are not inherently at increased risk. Exposure to RT increases the risk of second malignant neoplasms by over threefold.57,81,82 The largest cohort study combines data from major pediatric centers in Boston and New York City to report standard incidence ratios of subsequent cancers in 1601 cases surviving over 1 year post diagnosis treated between 1914 and 1984.⁵⁷ The cumulative incidence of second malignant neoplasms at 50 years after diagnosis is 36% with the hereditary form and 5.7% in the sporadic/nonhereditary cohort. Within the hereditary cohort, the incidence of second malignant neoplasms is over 38% after RT and 21% without RT; the standard incidence ratios for second malignant neoplasms range from 22 times the expected incidence after RT in the hereditary population to 7 times without RT.⁵⁷ Within the sporadic cohort, the incidence of second malignant neoplasms exceeds the normal population only for breast cancer (2.8 times), especially among those with radiation exposure (10 times).⁵⁷ Second cancers correlate as well with timing of RT; children receiving RT during their first year may have a higher risk of developing a second cancer within the field of irradiation.⁸¹

The most common second malignant neoplasm is osteogenic sarcoma, which arises both inside and outside the radiation fields and accounts for nearly one third of all second cancers.57,81,82,83 Among the hereditary retinoblastoma cohort, 75% of second malignant neoplasms occurring within 25 years of initial therapy are sarcomas; osteosarcomas usually develop during the growth spurt years and occur with increased frequency even among the nonirradiated population, noting the proximity of genetic aberrations associated with osteosarcoma and the RB1 gene.⁸³ Soft tissue sarcomas and melanomas are second in frequency, accounting for 20% to 25% of cases. Patients with hereditary retinoblastoma are also at risk of developing epithelial cancers late in adulthood; the most common such tumors are lung, breast, and colon carcinomas.^57,⁸² Finally, an interesting observation is the increased incidence of lipomas in survivors of hereditary retinoblastoma. The incidence of a second neoplasm appears to be higher in patients with lipomas, suggesting that the presence of lipomas could be a clinical marker of susceptibility to second neoplasms.⁸⁴

Children treated for retinoblastoma are at risk of functionally and cosmetically significant bony orbital abnormalities. The sequelae become evident by early adolescence, when orbital growth is largely complete. Both enucleation, which causes orbital contraction, and RT, which induces arrest of bone growth, adversely affect orbital growth. In children treated for bilateral retinoblastoma, the impact of enucleation in orbital development is not different from that of RT.

Studies show that the therapeutic strategy of chemoreduction and aggressive focal treatments can successfully delay the use of RT for at least 6 or 7 months (to median age 21 months). Because abnormal bone development and susceptibility to carcinogenesis appear to be particularly prominent after radiation exposure during the first year of life, the “conservative” chemoreduction therapeutic approach may reduce the frequency and severity of the most prevalent, and most serious postirradiation sequelae.