Retinoblastoma: Treatment and outcome

INTRODUCTION — Retinoblastoma is the most common primary intraocular malignancy of childhood and accounts for 10 to 15 percent of cancers within the first year of life [1]. Retinoblastoma typically presents as leukocoria (picture 1) in a child under the age of two years. Untreated retinoblastoma is a deadly disease; however, with advances in treatment, survival in the contemporary era is >95 percent. Prompt referral to an ocular oncologist and appropriate management by a multidisciplinary team are necessary to optimize visual outcome and ocular and overall survival.

The clinical treatment and outcome of retinoblastoma are reviewed here. The clinical presentation, evaluation, and diagnosis of retinoblastoma and the approach to children with leukocoria are discussed separately. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis" and "Approach to the child with leukocoria".)

MULTIDISCIPLINARY APPROACH — Management of children with retinoblastoma is best accomplished by a multidisciplinary team, which can consolidate clinic visits and provide the caregivers with opportunities to discuss the full spectrum of treatment and outcomes. The multidisciplinary team may include the following health care professionals:

●Pediatric ophthalmologist

●Primary care practitioner

●Pediatric oncologist

●Radiation oncologist

●Clinical geneticist

●Retina specialist

●Ocular oncologist

●Neuroradiologist

●Craniofacial plastic specialist

●Nurse specialist

●Pharmacist

●Child life specialist

●Clinical social worker

●Low-vision specialist

●Ocularist

●Nutritionist

TREATMENT

Goals — Treatment of retinoblastoma is aimed at achieving the following goals [2]:

●Eradication of the disease to prevent mortality

●Salvage of the eye, if done without risk to the child's life

●Preservation of vision to the greatest extent possible

●Prevention of late sequelae, particularly subsequent neoplasms (see 'Second malignancies' below)

Treatment approach — A variety of treatment options are available for children with retinoblastoma, including several globe- and vision-sparing therapies [3-5]. First-line therapeutic options include ophthalmic artery chemosurgery (OAC), systemic chemotherapy, radioactive plaques (I-125 brachytherapy), and enucleation. Adjunctive salvage therapies include cryotherapy, laser photoablation, and intravitreal injection of chemotherapy. In the contemporary era, external beam radiation therapy (EBRT) is rarely used, except in certain salvage situations.

The choice of initial treatment is based on the tumor size, location, and laterality; presence or absence of vitreous or subretinal seeds; patient age; and visual prognosis. Group classification systems that evaluate the extent of disease in the eye, including the International Intraocular Retinoblastoma Classification and the American Joint Committee on Cancer 8^th edition TNM, are commonly used to characterize the extent of disease and assess the likelihood of globe salvage (table 1 and table 2) [3,6,7]. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Classification'.)

Initial therapy — Treatment options for initial therapy in children with newly diagnosed retinoblastoma are as follows (algorithm 1) [3]:

Low-risk tumors — Most patients with unilateral or bilateral small extrafoveal tumors without subretinal or vitreous seeding (ie, group A and B tumors, particularly peripheral group B tumors) (table 1) can be managed with focal techniques, including cryotherapy or laser photocoagulation or (less commonly) plaque radiation therapy. (See 'Cryotherapy and laser photocoagulation' below.)

In patients with tumors that involve the macula, laser photocoagulation and cryotherapy compromise central vision and, therefore, OAC or systemic intravenous chemotherapy is typically used to shrink the tumor before performing focal therapy. (See 'Chemotherapy' below.)

Moderate- and high-risk tumors — Treatment of advanced intraocular retinoblastoma is tailored according to the tumor burden with the aim of globe salvage if possible:

●Unilateral group C and D tumors – Unilateral group C and many group D tumors (table 1) are treated with OAC or intravenous chemotherapy depending on the practice patterns of the center. Enucleation may be required for some group D tumors, particularly when the patient is young and presents with unilateral disease. For young infants (ie, <3 months), single-agent systemic chemotherapy may be used as "bridge therapy" to provide time for the infant to grow to a size (typically >6 or 7 kg) that permits successful arterial cannulation, at which time, OAC can be performed. (See 'Chemotherapy' below and 'Enucleation' below.)

●Unilateral group E tumors – Children with unilateral group E tumors (table 1) are treated with enucleation. Adjuvant chemotherapy and radiotherapy are provided following enucleation if there are microscopic residua at the cut section of the optic nerve or sclera or if there are other high-risk pathologic features. (See 'Enucleation' below.)

●Bilateral disease – For patients with bilateral disease in which advanced stage tumor (ie, group C, D, or E) (table 1) is present in one or both eyes, treatment options may include:

•Focal treatment (eg, laser photocoagulation, cryotherapy) for the least affected eye if the tumor is small and extrafoveal with enucleation of the more advanced eye. The child may require adjuvant chemotherapy if there are pathologic risk factors for the more advanced eye. (See 'Cryotherapy and laser photocoagulation' below and 'Enucleation' below.)

•Systemic intravenous chemotherapy augmented by other consolidative therapies (laser, cryotherapy, brachytherapy, intravitreous chemotherapy). (See 'Systemic chemotherapy' below.)

•Bilateral OAC with or without intravitreous chemotherapy or other consolidative therapies. (See 'Local chemotherapy' below.)

For patients with bilateral advanced disease, if one eye is primarily enucleated, systemic or local chemotherapy can be used in attempt to salvage the second eye. When salvage of both eyes is attempted, systemic intravenous chemotherapy or simultaneous (tandem) OAC to both eyes may be used as primary therapy [8].

Intracranial tumor ("trilateral" retinoblastoma) — Trilateral retinoblastoma consists of unilateral or bilateral retinoblastoma associated with an intracranial tumor that is histologically similar but anatomically distinct (image 1). It is not metastatic nor from local spread but rather a separate primary tumor. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Intracranial tumors ("trilateral" retinoblastoma)'.)

Historically, treatment for patients with trilateral retinoblastoma has been neurosurgical resection followed by chemotherapy and cranial or craniospinal radiation therapy. Despite aggressive therapy, trilateral retinoblastoma was usually fatal [5,9,10]. The use of intensive chemotherapy regimens combined with autologous hematopoietic stem cell rescue has been associated with prolonged disease-free survival in case series [11-13].

Metastatic disease — Metastatic disease, though rarely present at the time of diagnosis, is associated with a poor prognosis. Intensive multimodal therapy (including high-dose multiagent chemotherapy and radiotherapy to bulky sites) with autologous hematopoietic stem cell rescue is used in some centers for treatment of metastatic disease [3]. Based on several case series and one prospective study, the reported three- to five-year event-free survival is 60 to 80 percent with this approach [14-18]. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Metastatic evaluation'.)

Treatment failure and recurrence — Recurrent intraocular disease is common in retinoblastoma. Many treatment failures or recurrences can be treated with repeat laser photocoagulation, cryotherapy, plaque brachytherapy, or intravitreal chemotherapy, depending on the size, location, and previous treatment history. However, larger recurrences may require OAC or further cycles of systemic chemotherapy for eye salvage [19]. For large recurrences wherein the visual prognosis is poor, secondary enucleation is usually required to prevent spread of disease to sites outside the eye. Many centers use OAC with intravitreous chemotherapy if there is seeding for treatment of group D tumors that fail initial systemic chemotherapy. Reported globe salvage rates with this strategy are >70 percent [3,20].

There are no reliable molecular biomarkers to predict which eyes will respond well to chemotherapy versus those that are more likely to fail therapy and relapse. However, work in this area, which often uses a "liquid biopsy" approach (ie, molecular testing performed on a blood sample and/or aqueous humor rather than a histopathologic specimen), is ongoing [21-23]. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Disease extent'.)

Treatment modalities for intraocular disease

Chemotherapy — The high risk of secondary radiation-induced cancers in patients with retinoblastoma has led to efforts to replace radiation therapy with either intravenous chemotherapy (popularized in the late 1980s) or OAC (popularized in the mid-2000s) combined with local consolidative measures, such as cryotherapy, laser photocoagulation, or local intravitreal injection of chemotherapeutic agents.

Retinoblastoma is a chemotherapy-sensitive malignancy. The agents used most commonly for OAC include melphalan, carboplatin, and topotecan; various regimens are used for systemic therapy, most typically carboplatin, vincristine, etoposide, and topotecan [4,24-26].

Local chemotherapy — The management of larger tumors is evolving with the development of ophthalmic artery (also known as intraarterial) chemotherapy:

●Intraarterial chemotherapy – In an effort to decrease systemic side effects and deliver high-dose, localized chemotherapy to the tumor, OAC was pioneered [4,27,28]. This procedure is performed by a neuro- or endovascular surgeon. A cannula is introduced through the femoral artery and advanced to the ostium of the ophthalmic artery. Chemotherapy (typically melphalan, carboplatin, and/or topotecan) is then delivered into the ophthalmic artery over approximately 30 minutes in a pulsatile fashion. The procedure is performed under general anesthesia, and nasal decongestant (vasoconstrictor) is typically sprayed in the nostril on the treatment side to shunt the blood away from the nasal mucosa in attempt to reduce local side effects [4]. Successful OAC requires a high degree of specialized surgical skill, and it should be performed at centers experienced in this procedure.

Indications and treatment protocols for OAC vary considerably between centers. There are no prospective trials comparing OAC with other treatment modalities in patients with retinoblastoma. It is generally believed that compared with systemic chemotherapy, which rarely cures intraocular retinoblastoma by itself, OAC may achieve higher drug levels in the eye and therefore theoretically has the potential to increase cure rates for advanced disease. It is important to note, however, that systemic chemotherapy is typically combined with local consolidative techniques (cryotherapy, photocoagulation, intravitreal injection of chemotherapy), which improves cure rates.

The evidence for the efficacy and safety of OAC comes largely from case series [29-36]. In a systematic review and meta-analysis that included 12 case series reporting outcomes in 655 patients (747 eyes) treated with OAC, globe salvage was achieved in 66 percent overall [37]. The globe salvage rate was 86 percent in eyes with less advanced disease (ie, groups A, B, and C) compared with 57 percent in advanced disease (ie, groups D and E). Primary treatment with OAC was associated with a globe salvage rate of 74 percent, whereas the salvage rate was 67 percent in eyes where OAC was used as secondary treatment after failure of other modalities. Metastatic disease developed in 2.1 percent of patients treated with OAC in the published series; however, through author correspondence and a social media survey, the authors of the systematic review identified nine additional patients with metastases. Secondary malignant neoplasm occurred in 2.4 percent of patients, all of whom also received EBRT.

Overall, there is a procedural learning curve to OAC, with higher rates of complications in the initial reports of OAC; however, with experience, complication rates are low (<5 percent) in later reports [3,36]. Local adverse effects of intraarterial chemotherapy may include eyelid edema; ptosis; loss of eyelashes; extraocular muscle dysfunction; delayed vitreous hemorrhage; potential blindness from stenosis or occlusion of the ophthalmic artery, central retinal artery, or branch retinal artery; chorioretinal atrophy; vasculopathy in ophthalmic, choroidal, and retinal vessels; and radiation exposure (from fluoroscopy). Systemic side effects include iodine allergy, risk for ischemia and hemorrhagic stroke, and bone marrow suppression [27,28,37-42]. In addition, adverse autonomic cardiorespiratory reactions (bronchospasm) may occur [28,37,43,44]. A pilot study from the Children's Oncology Group designed to study the feasibility of OAC with melphalan for the treatment of unilateral group D disease was closed early due to multiple adverse events, most of which were post-procedural cardiorespiratory complications (bronchospasm) caused by cannulation of the internal carotid artery [45]. As these events had not been well detailed in previous published reports, they were not anticipated in the study planning and, ultimately, this led to early closure of the study. Thus, the impact of OAC on globe salvage could not be evaluated. To date, there still remains no head-to-head prospective trial on the efficacy of OAC versus systemic chemotherapy and other consolidative therapies like intravitreal chemotherapy.

In the systematic review described above, the most commonly reported ocular complications were periorbital edema or inflammation (66 of 196 eyes; 33 percent), retinal detachment (11 of 57 eyes; 19 percent), vitreous hemorrhage (30 of 166 eyes; 18 percent), ptosis (24 of 177 eyes; 14 percent), loss of eyelashes (14 of 134 eyes; 10 percent), dysmotility in (10 of 154 eyes; 6 percent), and vascular, ischemic, or atrophic effects (45 of 725 eyes; 6 percent) [37]. Systemic complications were rare, and there were no reported episodes of stroke or neurologic complications. However, stroke has been reported in a single case report [46].

Systemic and local side effects may be under-reported due to lack of protocol-driven monitoring and/or follow-up for patients who were included in the available case series.

●Intravitreous chemotherapy – Intravitreal chemotherapy is commonly used in conjunction with OAC or systemic chemotherapy for treatment of recurrent or refractory vitreous seeds, and in this setting, it has a success rate that approaches 100 percent [3]. Historically, its use was limited due to concerns for potential tumor dissemination following intravitreal penetration; however, safety enhancing techniques (eg, use of small volume doses, lowering intraocular pressure prior to the injection with a paracentesis, treating the injection site with cryotherapy, irrigating the surface of the eye) have essentially eliminated any risk of tumor spread. In a 2013 systematic review of 14 studies (including >1300 intravitreal injections), only a single reported case of extraocular tumor spread was identified [47]. The optimal dose and potential toxicity of this treatment modality have yet to be fully elucidated; however, it has been exceedingly successful in the treatment of vitreous seeding and moreover, the avoidance of EBRT in these at-risk children. An ongoing clinical trial is evaluating the impact of intravitreal chemotherapy added to systemic chemotherapy on globe salvage in patients with persistent vitreous seeds [48].

●Periocular injections – Sub-Tenon carboplatin was previously utilized as an adjunctive treatment with chemoreduction for groups C, D, and E tumors [49-51]. However, this approach is limited by the risks of local side effects, which include orbital fat atrophy, motility limitation due to orbital scarring, orbital fat necrosis, and rarely, optic nerve atrophy [52-54].

Systemic chemotherapy — Systemic chemotherapy may be used in the following circumstances [3,55-57]:

●In patients with smaller tumors that impinge on the fovea to shrink the tumor before performing focal therapy

●In patients with large tumors and bilateral disease, for globe salvage and to shrink tumors that are too large for isolated local therapy (so-called "chemoreduction")

●In young infants (ie, <3 months), as a "bridge therapy" to provide time for the infant to grow to a size that permits successful arterial cannulation for OAC (see 'Local chemotherapy' above)

●For adjuvant treatment after enucleation in patients at high risk for metastatic disease (ie, microscopic residua at the cut section of the optic nerve or sclera, or if there are other pathologic risk factors) (see 'Enucleation' below)

●For treatment of trilateral retinoblastoma and metastatic disease (see 'Intracranial tumor ("trilateral" retinoblastoma)' above and 'Metastatic disease' above)

Since most retinoblastomas are large at the time of presentation, chemoreduction may be used to reduce tumor volume, which enhances the success of local therapies. Chemoreduction has become a critical component of the initial treatment of retinoblastoma and has improved the ocular salvage rate [24,58-63]. The most common chemoreduction regimen contains carboplatin, vincristine, and etoposide given approximately every 28 days for three to six cycles (depending on group classification). Alternatively, a topotecan-containing regimen has also proven to be effective in treatment of naïve patients [26]. Other agents used include cyclophosphamide, doxorubicin, and ifosfamide [64].

In a retrospective report of 249 consecutive eyes treated with chemoreduction, treatment success (defined as avoidance of EBRT or enucleation) was achieved in 100 percent of group A, 93 percent of group B, 90 percent of group C, and 47 percent of group D eyes [65].

Chemoreduction is generally not an effective therapy for group E retinoblastoma, and the general recommendation for these tumors is enucleation, particularly if unilateral. For patients with bilateral high-grade tumors, systemic chemoreduction may be used (with or without other modalities such as low-dose EBRT) for ocular salvage [62,63,66]. (See 'Enucleation' below.)

Chemoreduction may also protect against the development of trilateral retinoblastoma [67]. However, this is controversial, and the reduction in the rate of trilateral retinoblastoma observed in the chemoreduction era may also be related to the avoidance of radiation and its oncogenic effects in patients with heritable retinoblastoma. Other reports suggest chemotherapy (specifically etoposide) may predispose to the development of secondary acute myeloid leukemia later in life in patients with heritable retinoblastoma [67-69].

Cryotherapy and laser photocoagulation — Cryotherapy and/or laser photocoagulation can be used to treat smaller tumors (<6 mm in diameter and <3 mm thick) [70,71] and may be used in conjunction with chemotherapy [70-74]. If these local modalities are successful, the treated tumor usually regresses within six weeks, although it may take longer [70,71]. Complications of these methods include transient serous retinal detachment, rhegmatogenous retinal detachment (particularly with cryotherapy), visually significant retinal vascular occlusion, vitreous hemorrhage, retinal traction, and preretinal fibrosis [19,70,75].

Radioactive plaques — Radioactive plaque therapy (I-125 brachytherapy) involves securing a radioactive plaque to the sclera at the base of the tumor. The radiation dose is approximately 40 to 45 gray (Gy) delivered to the tumor apex.

Based on retrospective data, plaque therapy achieves tumor control in approximately 80 percent of tumors and is most effective in small tumors without vitreous or subretinal seeding [76].

Limitations of plaque therapy include the following [76-78]:

●Plaque therapy is generally not effective as primary therapy for large tumors (ie, ≥15 mm in diameter or ≥8 mm thick), multifocal tumors, or tumors in the posterior one-half of the globe or if there is active seeding far from the main tumor.

●Radiation complications (eg, cataract, radiation retinopathy, optic neuropathy) may occur in up to one-third of patients.

●The amount of radiation delivered to the optic nerve and fovea must be carefully considered, particularly if there is potential for preserved vision as this will be limited with radiation.

●Placement of plaques can be technically difficult, and a second surgical procedure is required for removal.

●Depending on local radiation safety laws, children may have to be hospitalized for the duration of treatment. In the United States, many states have laws requiring individuals with implanted radioactive devices to stay in the hospital during their treatment due to the potential risk of public and environmental exposure.

●There is a theoretical risk of developing radiation-induced secondary malignancies in patients with heritable retinoblastoma; however, this risk is very low if custom-designed plaques are used along with radiation shielding.

Because of these limitations, other modalities (eg, cryotherapy and laser phototherapy for small tumors, local chemotherapy or systemic chemotherapy for larger tumors) are often preferred over plaque therapy for primary therapy. Radioactive plaque therapy is most commonly used as a secondary therapy, after local treatment failure.

Enucleation — Enucleation usually is indicated for (table 1) [19,70,71]:

●Unilateral disease in which there is a large tumor and limited to no visual potential

●Blind, painful eyes

●Tumors that extend into the optic nerve

●For large recurrences after "globe-conserving" treatment wherein the visual prognosis is poor (secondary enucleation)

Most unilateral group E and some unilateral group D eyes require enucleation. In addition, enucleation is often performed if the eye has secondary glaucoma, poor view to the fundus with presumed active tumor (eg, from vitreous hemorrhage), or anterior chamber invasion.

Potential complications of enucleation include inadvertent scleral perforation with seeding of tumor cells into the orbit.

Following enucleation, adjuvant systemic chemotherapy is provided (often combined with focal radiotherapy to the orbit) if there is a positive optic nerve margin or trans-scleral/extrascleral extension (which is, thankfully, a rare event) [3,55]. Patients with these findings are at high risk for metastatic spread. Additional, more common factors associated with increased risk of metastatic disease include tumor extension beyond the lamina cribrosa, intrascleral invasion, and massive choroidal invasion [55,56,79]. Practice varies regarding the use of adjuvant chemotherapy (without radiotherapy) in patients with these risk factors [3].

An orbital implant (typically hydroxyapatite or porous polyethylene, although some surgeons prefer nonporous silicone implants) is placed at the time of enucleation. After the overlying conjunctiva has healed (approximately six weeks), a prosthesis can be fitted by an ocularist. Implant migration or exposure are known complications and increase during chemotherapy [80].

Children who undergo enucleation for retinoblastoma must be monitored closely for orbital relapse in the two years after surgery. In a cohort of 1674 consecutive patients undergoing enucleation between 1914 and 2006, the incidence of orbital recurrence was 4.2 percent [81]. All recurrences were diagnosed within 24 months of enucleation and 97 percent within 12 months. Most patients (85 percent) with orbital recurrence also developed metastatic disease. Seventy-five percent of patients with orbital recurrence died from metastatic retinoblastoma. However, the mortality rate appears to be lower in patients diagnosed with orbital recurrence after 1984 (1 of 11 patients, 9 percent after 1984, compared with 75 percent for the entire cohort).

External beam radiation therapy — EBRT was the original globe-sparing treatment for retinoblastoma; however, in the contemporary era it is rarely utilized, except in certain salvage situations. Due to the delayed tumorigenic potential of radiotherapy in patients with retinoblastoma, intravenous chemotherapy, OAC, and focal therapies have replaced EBRT as the primary globe-conserving treatments for retinoblastoma [57,72,73]. (See 'Chemotherapy' above and 'Cryotherapy and laser photocoagulation' above.)

EBRT is a highly effective treatment modality for eyes with active retinoblastoma, but the risk of secondary cancers and local side effects limit its use to globe salvage after failure of other treatment modalities in children older than 12 to 18 months of age. The risk of tumor recurrence following EBRT in one series of 180 tumors was 7 percent, with all recurring within 40 months [82].

The major complication of EBRT is induction of secondary malignancies [77,83-87]. The importance of radiation-induced secondary malignancies is illustrated by the fact that in the United States, more patients with retinoblastoma die of second tumors than of the retinoblastoma itself [83]. The increased risk of secondary tumors is seen primarily in patients with heritable retinoblastoma. In one report, the 30-year cumulative incidence of second cancers was markedly increased in the 137 patients treated with radiotherapy (35 percent, compared with 6 percent in the 78 who did not receive radiation) [85]. Secondary malignancies occur most commonly in the field of radiation and the risk appears to be dose related [88,89].

Other radiation-related complications include radiation damage to the retina, optic nerve, lacrimal gland, and lens; loss of eyelashes [90]; and midface hypoplasia with retardation of orbital bone growth when radiation is given before 12 months of age [91-95].

OUTCOME

Prognostic factors — Various clinical and histopathologic features influence prognosis in patients with retinoblastoma. Features associated with a poor prognosis include [96]:

●Delay in diagnosis of more than six months [97-100]

●Extraocular disease

●Presenting with orbital pseudocellulitis due to massive tumor necrosis

●Increased intraocular pressure (IOP) at time of diagnosis, which correlates with high-risk histopathologic features [101]

●Massive choroidal, optic nerve, scleral, or orbital invasion, which increases the risk of metastatic disease [97,102-105]

●High-grade tumor anaplasia [105]

●Use of external beam radiotherapy (EBRT), due to the risk of subsequent secondary cancers, as previously discussed (see 'External beam radiation therapy' above)

Survival — Retinoblastoma survival varies geographically, ranging from <30 percent in resource-limited settings to >90 percent in resource-abundant settings [106]. The overall five-year survival rate for children with retinoblastoma in the United States is >95 percent [107,108]. Patients who develop metastatic disease usually do so within one year of diagnosis; a child who remains recurrence free for five years after diagnosis is generally considered cured [109].

●Metastatic disease – The prognosis for children with metastatic disease has historically been poor, particularly for relapses in the central nervous system [110]. In most reports, 1-year to 18-month survival rates for patients with hematogenous metastases are approximately 50 percent [110-114]. As previously discussed, several case series have reported improved survival with intensive multimodal therapy with autologous hematopoietic stem cell rescue [14-18]. In a prospective multicenter trial from the Children's Oncology Group involving 57 children with metastatic retinoblastoma who were treated with intensive multimodal therapy, event-free survival at 36 months was 88 percent among patients with regional extraocular disease and 79 percent for patients with disseminated metastatic disease (excluding central nervous system disease) [18]. (See 'Metastatic disease' above.)

●Trilateral retinoblastoma – Survival for children with trilateral retinoblastoma (ie, intraocular retinoblastoma and concomitant intracranial tumor, usually in the pineal gland) has improved since the mid-1990s, when it was almost universally fatal [115]. In a 2014 systematic review and meta-analysis of cases reported after 1994, five-year survival for patients with pineal trilateral retinoblastoma was 44 percent (95% CI 26-61 percent) and five-year survival for nonpineal trilateral retinoblastoma was 57 percent (95% CI 30-77) [13]. As previously discussed, intensive chemotherapy regimens with autologous hematopoietic stem cell rescue has been associated with prolonged disease-free survival in small case series. (See 'Intracranial tumor ("trilateral" retinoblastoma)' above.)

Vision — The prognosis for vision in bilaterally affected children depends upon the extent of tumor involvement; the prognosis is better for tumors that are small, do not involve the fovea, and have limited retinal detachment and seeding [116].

Among children with group A to D tumors successfully treated with chemoreduction, factors that predict preservation of visual acuity of 20/40 or better at five years after treatment include tumor location ≥3 mm from the foveola and optic disc and the absence of subretinal fluid [117]. Predicting visual outcome is difficult with advanced disease; however, factors predictive of poor vision in group D eyes include involvement of >50 percent of the macula, complete retinal detachment, and three or more quadrants of vitreous seeding at presentation [116].

For children with unilateral disease, the prognosis for vision in the unaffected eye is excellent [19]. The risk of developing tumors in the contralateral eye depends primarily on germline RB1 status. However, if the contralateral eye remains disease-free after three years, the risk is very low.

Second malignancies — In patients with heritable retinoblastoma (ie, a germline RB1 gene mutation), the risk of developing a second nonocular malignancy is approximately 0.5 to 1 percent per year. Thus, the cumulative risk over 40 years is approximately 18 to 35 percent [118,119]. In contrast, second malignancies are far less common in patients with nonheritable retinoblastoma, occurring in only 2 percent of cases in one large cohort [119].

Patients with heritable retinoblastoma are at risk for developing PNET tumors, usually in the pineal gland (ie, trilateral retinoblastoma). In some patients, these tumors may be present at the time of diagnosis, whereas in others, the tumor may develop subsequent to initial diagnosis, typically before the age of five years. For this reason, many centers perform routine magnetic resonance imaging screening during the first three to five years of life in patients with heritable retinoblastoma [69]. (See 'Imaging' below.)

The risk of secondary malignancy appears to be greatest among patients treated with radiation therapy before the age of one year [83]. In a meta-analysis of 676 second primary tumors reported in the literature between 1961 and 2006, the type of second primary tumors was related to age [89]. The median age for PNET was 2.7 years; for sarcomas, 13 years; for melanomas, 27 years, and for carcinomas, 29 years.

The most common second malignancies in survivors of retinoblastoma include osteogenic and soft tissue sarcomas [88,119-124]. These tumors are presumed to be radiation-related, and the risk appears to correlate with the dose of radiation. Epithelial cancers (eg, melanoma, bladder, lung, breast) have also been reported [84,88,118,119,122,123]. In the modern era, the use of radiation therapy in globe salvaging treatment for retinoblastoma is quite rare. (See "Radiation-associated sarcomas", section on 'Genetic predisposition' and "Radiation-associated sarcomas", section on 'Childhood RT'.)

Quality of life — Studies reporting on quality of life (QoL) in survivors of retinoblastoma have reached variable conclusions [125-129]. Most studies report that survivors have similar QoL compared with their peers [126,127,129]. However, in some studies QoL scores were lower in retinoblastoma survivors compared with reference population, though the differences were generally small [125,126]. Visually impaired survivors reported lower QoL compared with those with normal vision. Parents tended to rate the survivors' QoL lower than the survivors did themselves [126,127,129].

LONG-TERM FOLLOW-UP — Long-term follow-up for patients with retinoblastoma is best accomplished by multidisciplinary subspecialty teams. It includes monitoring for tumor recurrence and following for long-term treatment-related complications, as discussed in the following sections. Additional aspects of long-term follow-up are addressed in guidelines published by the Children's Oncology Group.

Ophthalmologic follow-up — The risk period for extraocular spread after successful treatment or enucleation is generally recognized to be 24 months with most occurring in the first 12 months [81]. Ophthalmologic follow-up after treatment for retinoblastoma varies based upon the level and activity of disease; however, it is generally monthly during active treatment with a progressive increase in treatment interval. Once the child has remained disease free without treatment for an extended time (typically two years), the frequency of examinations can be decreased and the examinations can often be done in the office instead of under anesthesia, provided the child is cooperative with the examination.

Children who have undergone enucleation may participate in sports as long as they use proper polycarbonate protective eyewear. The need for protective eyewear for all patients cannot be overemphasized. Participation in boxing is discouraged because protective eyewear is not permitted.

Lifelong ophthalmologic follow-up is necessary for all survivors of childhood retinoblastoma because late complications may occur (eg, cataract, optic neuropathy, retinopathy, socket issues), particularly in patients treated with radiotherapy. (See "Delayed complications of cranial irradiation", section on 'Effects on the eyes and optic pathways'.)

Imaging

●Surveillance for intracranial tumors – Many centers perform routine screening with brain magnetic resonance imaging (including images through the pineal region) every six months until age three to five in children with heritable retinoblastoma to screen for development of intracranial tumors (commonly called "trilateral" retinoblastoma) [130]. The value of magnetic resonance imaging screening was evaluated in a meta-analysis that included individual data from 106 children with trilateral retinoblastoma [69]. Intracranial tumors were detected through routine screening in 15 cases, whereas in 31 patients, screening was not performed and the intracranial tumor was detected based on symptoms (in the remaining 60 cases, trilateral retinoblastoma was either present at the time of initial diagnosis or it was unclear whether screening was performed). Compared with patients whose tumors were detected at a symptomatic stage, those who underwent screening had earlier detection of the intracranial tumor (1 versus 22 months) and smaller tumor size (20 versus 30 mm). Children who underwent screening survived longer (16 versus 8 months); however, the age at death was similar (36 versus 37 months). Cumulative five-year survival was 27 percent among children who underwent screening, whereas no child whose tumor was detected at a symptomatic stage survived beyond five years. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Intracranial tumors ("trilateral" retinoblastoma)'.)

●Other imaging – Routine computed tomography scans and bone scans are generally not necessary. Imaging confers risks and burdens and has not been shown to improve outcomes.

Second malignancies — In addition to the risks associated with metastatic spread from the original tumor, survivors of retinoblastoma require lifetime follow-up because of their propensity to develop second nonocular primary malignancies. Patients should receive counseling on the importance of routine measures to reduce the likelihood of second malignancies, including refraining from smoking, using sunscreen, and avoiding exposure to other DNA-damaging agents [84]. Long-term survivors should be followed for the development of late second malignancies with periodic physical examination, laboratory screening, and radiology testing, depending upon specific risk factors. (See 'Second malignancies' above.)

Hearing — Children who receive systemic intravenous carboplatin are at risk for hearing loss and require long-term audiologic follow-up. The risk may be higher when chemotherapy is given to infants <6 months old [131,132]. In a long-term follow-up study, 3 percent of adult survivors of childhood retinoblastoma developed severe hearing loss [124]. An ongoing clinical trial is evaluating the risk of hearing loss in patients treated with intra-arterial carboplatin (ie, ophthalmic artery chemosurgery [OAC]) [133]. (See "Overview of neurologic complications of platinum-based chemotherapy", section on 'Carboplatin'.)

Endocrinopathies — Endocrine dysfunction (eg, hypothalamic and pituitary endocrinopathies, hypothyroidism) may occur in patients treated with radiotherapy. Systemic chemotherapy can reduce ovarian function and spermatogenesis; however, these effects are usually temporary [134]. In a small study, ovarian function was not affected after OAC [135]. (See "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood".)

SUMMARY AND RECOMMENDATIONS

●Multidisciplinary approach – Retinoblastoma typically presents as leukocoria (picture 1) or strabismus (crossing of the eyes) in a child under the age of two years. Untreated retinoblastoma is a deadly disease. Prompt referral to an ophthalmologist and appropriate management by a multidisciplinary team are necessary to optimize visual outcome and survival. (See 'Introduction' above and 'Multidisciplinary approach' above.)

●Treatment goals – Treatment of retinoblastoma is aimed at achieving the following goals (see 'Goals' above):

•Eradication of the disease to prevent mortality

•Salvage of the globe, if done without risk to the child's life

•Preservation of vision to the greatest extent possible

•Prevention of late sequelae, particularly subsequent neoplasms

●Treatment approach – A variety of treatment options are available for children with retinoblastoma, including several globe- and vision-sparing therapies. First-line therapeutic options include ophthalmic artery chemosurgery (OAC), systemic chemotherapy, radioactive plaques (I-125 brachytherapy), and enucleation. Adjunctive salvage therapies include cryotherapy, laser photoablation, and intravitreal injection of chemotherapy. In the contemporary era, external beam radiation therapy (EBRT) is rarely used, except in certain salvage situations. (See 'Treatment modalities for intraocular disease' above.)

The choice of initial treatment is based upon (algorithm 1) (see 'Treatment approach' above):

•Tumor size, location, and laterality

•Presence or absence of vitreous or subretinal seeds

•Patient age

•Visual prognosis

●Prognosis

•Survival – The overall five-year survival rate for children with retinoblastoma in the United States is >95 percent. Patients who develop metastatic disease usually do so within one year of diagnosis; a child who remains recurrence free for five years after diagnosis is considered cured. (See 'Survival' above.)

•Vision – The prognosis for vision in bilaterally affected children depends upon the extent of tumor involvement; the prognosis is better for tumors that are small, do not involve the fovea, and have limited retinal detachment and seeding. (See 'Vision' above.)

•Risk of secondary malignancies – Survivors of heritable retinoblastoma have a lifelong increased risk of second nonocular malignancy, most commonly osteogenic and soft tissue sarcomas. The risk of secondary malignancy is greatest among patients treated with radiation therapy before the age of one year. (See 'Second malignancies' above.)

●Long-term follow-up – Long-term follow-up for patients with retinoblastoma includes monitoring for tumor recurrence and following for long-term treatment-related complications. The risk period for extraocular spread after successful treatment or enucleation is 12 to 24 months. In addition to routine ophthalmologic follow-up, many centers perform screening with brain magnetic resonance imaging (including images through the pineal region) every six months until age three to five in children with heritable retinoblastoma to screen for development of a midline primitive neuroectodermal tumors. (See 'Long-term follow-up' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Ronald Teed, MD, Paul L Kaufman, MD, and Jonathan Kim, MD, who contributed to earlier versions of this topic review.