Retinoblastoma treatment

Retinoblastoma (Rb) is the most common pediatric ocular malignancy, accounting for 2% of all childhood cancers. (1)(2)(3) Rb is defined as an abnormal and uncontrolled growth of retinoblasts, progenitor cells of the retina, initiated by a mutation of the RB1 tumor suppressor gene located on chromosome 13. (4) The loss of a RB1 allele predisposes an individual to tumor formation after loss of the second allele.(5)

Rb occurs in 2 forms: 

1) Unilateral and unifocal, characterized by a single tumor in 1 eye, and 
2) multifocal, bilateral or unilateral Rb, with multiple tumor foci in 1 or both eyes. 

Rb is a disease of young children, with two-thirds of cases diagnosed before the age of 2 years and 95% before the age of 5 years. (1)(2)(3) If left untreated, rapid tumor expansion can result in visual morbidity as well as systemic mortality due to metastasis and local invasion through the optic nerve.

Fortunately, due to the increased availability of genetic testing and early diagnoses, new targeted therapies, and multimodal treatment approaches, disease-free survival rates in developed countries have approached 100%, with dramatic improvements in visual prognosis. (6) However, the overall prognosis in low- and middle-income countries remains poor.

Current efforts to expand accessibility to newer treatments aim to improve Rb outcomes globally. In this review, the clinical presentation, diagnosis and management of Rb is summarized, with a focus on new treatment approaches. For the purposes of this review, the term hereditary will refer to bilateral or unilateral multifocal Rb and nonhereditary will refer to unilateral, unifocal Rb.

The incidence of Rb worldwide is 11.8 cases per million children aged 0 to 4 years, with approximately 7,000 to 8,000 new cases per year and 250 to 300 new cases per year in the United States alone.(7) (8) Most Rb cases arise in Asia, followed by Africa and Latin America.(7)(8)

The rate of more advanced Rb is higher in low- and middle-income countries due to late diagnosis, limited access to care, and fewer treatment options.(9)

The majority of Rb cases (60%) are non-inherited and require 2 independent somatic RB1 mutations for tumor initiation, while the remaining 40% of cases involve an inherited RB1 mutation . All bilateral Rb is heritable, although a small portion (15%) of unilateral cases may also harbor an RB1 germline mutation .(2)(10)(11) Rb is a disease of young children, with an average of Age at diagnosis estimated worldwide at 0.46 years in hereditary cases and 1.77 years in non-hereditary cases.(11)

The RB1 gene was the first tumor suppressor to be cloned and was central to Knudson’s "double hit hypothesis" that both recessive alleles require inactivation for a phenotypic change.(12) The product of the RB1 gene , pRB, is a key protein in the regulation of the cell cycle. Although this protein is present in all cycling cells, its role is more critical in certain lines, such as retinal progenitor cells, which are highly dependent on pRB for their proper differentiation into mature and functional retinal cells.(13)

Specific gene “hotspots” have not yet been identified; Instead, RB1 mutations tend to be family-specific and are identified through next-generation sequencing technology. RB1 mutations demonstrate high penetrance and expressivity (13). In addition, there is a small subset of non-hereditary cases with normal RB1 , but with a mutated MYCN oncogene, which tend to be very aggressive and present in very young children, on average 4.5 months old.(14)

Hereditary Rb is differentiated from non-hereditary Rb by younger age at diagnosis, risk of trilateral disease from an associated non-metastatic pineal gland tumor, higher risk of secondary non-ocular tumors, and greater likelihood of passing a RB1 mutation to future generations.(2)(10)

The 10-year survival rate for those with hereditary Rb is lower, at 90.3% compared to 96.1% for those with non-hereditary Rb.(15)(16) Therefore, genetic counseling is central for the patient’s future family planning. There is an approximate 45% risk of Rb for the offspring of patients with hereditary Rb, while the risk of inheriting the mutant allele is only 7.5% in the offspring of patients with non-hereditary Rb.(15)(16)

The presentation of Rb varies depending on the extent of tumor growth. The most common initial clinical sign is leukocoria, defined as a white pupil, which is usually detected by parents, a neonatologist or pediatrician. Less commonly, Rb presents with strabismus or reduced vision due to macular involvement.(10)(16)

Cases mimicking orbital cellulitis caused by extensive tumor necrosis, significant proptosis, glaucoma, or spontaneous hyphema occur only in the most advanced cases and typically in developing countries that lack widespread routine visual screening for infants and children.(10)(10) 16)(17)

The initial tumor usually appears as a raised white mass, which becomes vascularized and opaque as it increases in size. It may exhibit endophytic growth in the vitreous cavity, exophytic growth in the subretinal space, or a mixed growth pattern. Less commonly, Rb can be diffusely infiltrative, which is more difficult to diagnose given the absence of a discrete lesion.(17)(18)(19)

The spontaneously regressing tumor, known as retinoma or retinocytoma , is rare and appears as a grayish lesion with calcification and atrophy. Retinomas can progress to active Rb and require monitoring.(20) An untreated active Rb lesion will continue to grow, leading to complete retinal detachment, intraocular hemorrhage, and/or neovascular glaucoma. (17)(18)(19) Metastatic Rb or local extension beyond the eyeball may result in survival rates of less than 1 year in the affected child.(10)(16)

Sometimes the initial ophthalmologic examination confirms the diagnosis of Rb. However, most of the time, a complete evaluation requires an examination under anesthesia (EBA) to carefully view the entire posterior segment with scleral depression to identify all tumor foci and definitively rule out Rb inside or outside.(10)

Additional imaging techniques during an EBA help with the diagnosis, such as B-scan (two-dimensional) ultrasound, which is used to measure tumor size and depth of invasion and identify calcifications that support the diagnosis of Rb.(21) Photographic documentation with wide-angle images is also often carried out.

Fluorescein angiography can be used to evaluate tumor vascular supply both at initial evaluation and throughout the course of treatment.(21) Optical coherence tomography (OCT) provides structural information about retinal and nerve involvement. optical. OCT can also detect small tumors missed in indirect ophthalmoscopy.(21)(22)

Diagnostic confirmation and tumor staging during an EBA are critical for treatment planning and prognosis.

Once the diagnosis of Rb is confirmed, magnetic resonance imaging (MRI) of the brain and orbits is a critical part of the initial evaluation to evaluate for optic nerve involvement, extraocular spread, or trilateral Rb secondary to a brain tumor. the pineal gland.(21)(22)

Rb screening guidelines have been optimized for high sensitivity to correctly identify Rb cases as early as possible. The population’s baseline risk of developing Rb is 0.007%.(23) Children of parents with non-hereditary Rb have a 7.5% risk of having Rb, and children of parents with hereditary Rb have a 45% risk. %.(15)(16)

All children who are relatives of Rb patients should undergo genetic testing and receive a complete baseline ophthalmologic examination. Risk stratification is then completed based on family history of Rb (i.e., which relatives are affected and how many) and the results of genetic testing.(23) Such factors help determine the timing and longevity of testing. serial ophthalmology.

Current guidelines suggest screening at-risk patients from birth to 7 years of age. After 7 years, if there is no clinical evidence of Rb and if the patient does not harbor an RB1 mutation , no further ophthalmological follow-up is required.(23) However, if an RB1 mutation exists , ophthalmological screening should be performed every year and for an indefinite period.(23)

Additionally, children with a family history of Rb and a known RB1 mutation in one or both parents are at significantly increased risk of developing Rb, for which prenatal testing can currently be performed through chorionic villus sampling or amniocentesis. to confirm an RB1 mutation in the fetus.(22)(24)

Prenatal confirmation of an RB1 mutation with close follow-up and early serial testing allows for earlier treatment when necessary, decreases morbidity, and improves outcomes in these patients who are in the highest risk category.(22)(24)

Specialized centers with multidisciplinary teams (ophthalmologists, pediatric oncologists, interventional radiologists, and geneticists) and established treatment protocols are the operational basis for extended Rb care. Treatment protocols have been established with the primary goal of minimizing morbidity and mortality. Recent advances in the treatment of Rb have significantly reduced visual morbidity without having a negative impact on overall survival.(22)

Newer therapies that focus on local drug delivery have resulted in increased intraocular concentration of therapeutic agents, decreased systemic exposure, and improved overall tolerability.(6) Unfortunately, in developing countries where access to Treatment and/or therapeutic options are more limited, blindness and even death still occur.

Several new classification systems have evolved to replace the original Reese-Ellsworth classification, which was developed to predict globe salvage after external beam radiation therapy (EBRT).(25)

Newer treatment modalities have largely replaced RHE, leading to the Reese-Ellsworth classification system becoming obsolete. The International Classification of Retinoblastoma (CIRB) was introduced in the early 2000s to better predict outcomes after systemic chemotherapy (Table 1). (26)(27)

Classification of Rb severity using CIRB staging is essential to guide treatment in the current era of systemic chemotherapy combined with local therapies. Tumors are classified from groups A to E, based on the decreasing probability of balloon salvage after treatment. Group A and B tumors are restricted to the retina, while local spread is seen in group C and diffuse spread in group D.

Finally, group E eyes are those that have been destroyed by the tumor and have the lowest probability of rescue.(10)(26)(27) It should be noted that tumor categorization, especially for the most severe cases, may vary slightly between treatment centers. With the increasing use of local chemotherapy, CIRB staging may soon be replaced by a more relevant classification scheme.

The American Joint Committee on Cancer staging system is an alternative rubric that uses the TGM (tumor, node, metastasis) criteria to estimate survival and globe preservation, considering clinical and histological risk factors, presence or absence of a gene mutation. the germ line and the presence of lymph node involvement or distant metastasis.(28)(29)

Ultimately, tumor classification, laterality, number of foci, location and size, presence or absence of vitreous seeding, age and health of the child, and family preferences are all factors that together have an impact. significant in the course of treatment.(6)(30) The universal principles of Rb treatment include reducing mortality above all and eliminating the tumor in its entirety while minimizing damage to other tissues.

Prevention of metastasis or extraocular spread is paramount, and reducing the long-term risk of secondary tumors, saving the eye, and preserving as much vision as possible are additional critical considerations.

In general, group A eyes may require only focal treatments, such as cryotherapy or transpupillary thermotherapy, while group B to D eyes typically respond poorly to focal treatments alone and require systemic treatment and/or also local chemotherapy (Fig. 4).(10)(31)

>  Enucleation

Enucleation, the removal of the affected eye, remains a mainstay of treatment since the inception of Rb care, even with the advent of more modern treatments.

It is still the treatment of choice for advanced Rb in low-income and some middle-income countries. However, since the late 1990s, major Rb centers have been able to reduce their enucleation rates significantly in favor of new eyeball-saving techniques. (32)

Enucleation remains a primary treatment for group E and some group D eyes. It is also an option for less severe cases, such as unilateral Rb which affects families who may not be able to handle the potential psychological and economic impact of recurrent treatments that require many more hospital visits, EBA and days lost from work due to other treatments. (32)(33)

Enucleation may also be the best option for eyes with recurrent tumor after primary treatment. Finally, enucleation is a unique procedure that offers a potentially definitive cure, reduces treatment burden, and avoids recurrent anesthesia, which can have neurological implications in the very young pediatric population.

During enucleation, transection of the optic nerve is attempted as far back as feasible to increase the chances of a negative surgical margin. The entire eye is removed with minimal trauma to prevent seeding of the tumor in the orbit.(34)

Histopathological evaluation of the eye can identify high-risk features such as invasion of the choroid, optic nerve, sclera, or anterior chamber. These findings would prompt the administration of adjuvant systemic chemotherapy to prevent metastasis, which would be very likely in light of such findings.(27)(34)

After enucleation, a synthetic implant can be inserted into the orbit and attached to the extraocular muscles for better restoration of ocular motility. Once a scleral shell, designed by an ocularist to match the remaining eye, has been placed, the aesthetics give a very natural appearance.

>  Systemic chemotherapy

Systemic intravenous chemotherapy (SIC) was introduced and popularized in the mid-1990s as a treatment for Rb. Shortly thereafter, the results of Rb began to be significantly marked by better overall survival and globe salvage rates due to the reduction of intraocular tumor burden and early effective treatment of systemic micrometastases.(6)

QIS is also used to treat extraocular and trilateral Rb and has become a standard primary treatment for most group B, C, and D tumors.(35) QIS not only helps protect against and/or treat secondary non-ocular tumors, but also allows chemoreduction of the sentinel tumor and, therefore, greater effectiveness of subsequent local treatments.(36)

QIS is used in most hereditary cases, given the increased risk of secondary non-ocular tumors, and also as an adjuvant treatment after enucleation if there is evidence of extraocular invasion (optic nerve, scleral, anterior chamber, etc.), as mentioned above.(6) Additionally, QIS can be used in children who are too small for intra-arterial chemotherapy due to the limitation of their small distal vessel caliber (radial or femoral).(37)

The most commonly used chemotherapeutic agents include carboplatin, etoposide, and vincristine.(6)(36)(38) On average, patients receive 6 to 9 cycles of monthly intravenous treatments.(6) QIS has the additional advantage of making EBRT obsolete . EBRT is associated with an extensive local side effect profile, resulting in significantly higher rates of secondary non-ocular tumors.

Possible radiation-related adverse events such as orbital deformity, cataracts and radiation-induced retinopathies, and secondary non-ocular local tumors are not seen with QIS. Systemic adverse events tend to be mild and include fever, hair loss, cytopenia, nausea, and constipation. More serious side effects, such as hyponatremia, nephrotoxicity, ototoxicity, secondary leukemia, infertility, and treatment failure are rare.(6)(36)(39)

>  Intra-arterial chemotherapy

Local chemotherapy for Rb was developed with the goals of reducing systemic side effects associated with QIS and increasing globe salvage for eyes with more advanced disease at diagnosis.

Intra-arterial chemotherapy (IAC) for Rb was first introduced in Japan in the late 1980s to safely deliver melphalan to the affected eye via the carotid artery under general anesthesia.(40)(41) Since then, The QIA has become a key modality in the current management of the Rb.(42)

QIA was initially used in the United States by Abramson et al.(37)(40)(41)(42) The most commonly used chemotherapeutic agents include melphalan, topotecan, and carboplatin, which are infused by transfemoral microcatheterization with advancement into the ophthalmic artery. under fluoroscopic guidance, resulting in a much higher local concentration compared to QIS.

At least 3 monthly treatments are generally required, and the number of chemotherapeutic agents required will vary depending on the tumor scenario.(40)(41)(42) The femoral artery may be difficult to access in very young children under 3 months, limiting thus the use of the QIA.(37)

QIA is widely accepted as a primary treatment for eyes with unilateral RB of groups B to D.(10)(31)(43) QIA is also used as secondary therapy for tumor recurrence and subretinal or vitreous seeding. (6)(31) QIA can be used in conjunction with QIS for advanced bilateral cases to reduce the QIS burden required and can also be repeated after an initial round of QIA.

QIA is not ideal for primary treatment in patients with extraocular dissemination, including invasion of the optic nerve or sclera, systemic metastases, or signs of advanced disease such as aseptic cellulitis, vitreous hemorrhage, hyphema, or neovascular glaucoma.(31)(43) The use of QIA in more advanced unilateral Rb remains controversial; However, there are data that demonstrate higher balloon rescue rates with QIA than with QIS for unilateral Rb.(32)(44)

Studies have reported 5-year solid tumor regression rates as high as 94% with primary QIA, as well as globe salvage rates greater than 85% even for eyes with advanced Rb group D receiving primary QIA.(43 ) If a patient has advanced bilateral disease, QIA may be combined with other therapies instead of bilateral enucleation.

In many patients, QIA is followed by other focal treatments to achieve complete union. In these cases, chemoreduction with QIA significantly helps the success of secondary therapies.(6)

Results from a recent survey demonstrated that for a large majority (>75%) of eyes with group D RB, the first line of treatment is AIC.(45) Unfortunately, it is not feasible to conduct robust randomized clinical trials on the management of Rb to scientifically prove whether one primary treatment is superior to another.

QIA offers the clear advantages of avoiding most of the systemic adverse effects associated with QIS while delivering a much higher concentration of drug to the tumor site.(31) Despite its advantages, there are local ocular toxicities associated with QIS. QIA that cannot be ignored.

Ocular vascular ischemic events, vitreous hemorrhage, myositis, orbital congestion leading to compartment syndrome, optic atrophy, ophthalmic artery stenosis and vision loss have been reported.(43)(46)(47)(48) In addition, it has been reported observed transient neutropenia and complications of catheterization, such as occlusion of the femoral artery with distal ischemia.(37)(49)

Life-threatening complications of catheterization, such as stroke and death, are theoretical. Additional limitations for many affected patients and their families include the need for trained subspecialists (neurosurgeon or interventional radiologist), high cost, and access to a treatment center that performs QIA.(31)

>  Intravitreal chemotherapy

Intravitreal chemotherapy (IVC), which involves injecting medication directly into the vitreous cavity, was first formalized as a treatment in the early 2000s.(50) The risk of potential tumor reseeding resulting in local metastasis had been long the key obstacle to IVC becoming a therapeutic option.

With refinement of process technique and encouraging results regarding the very low actual risk of associated extraocular extension, IVC is gaining favor in many Rb treatment centers for group D and E eyes that may otherwise have required enucleation. IVC is not considered primary treatment and is reserved to treat refractory subretinal and/or vitreous seedings.(51)(52)(53)

The current refined technique for administering QIV involves first lowering eye pressure with an anterior chamber paracentesis before injection to help prevent reflux. Under general anesthesia, chemotherapeutic agents are injected directly into the posterior segment through a pars plana approach. After injection of the medication (melphalan, topotecan, or a combination) with a small gauge needle (30 or 32), cryotherapy is applied to the injection site to destroy any residual tumor seeding.(52)(53)(54) )

A systematic review on IVC demonstrated that with this technique, the increased risk of tumor spread is essentially zero, compared to a risk of approximately 0.4% before refinement of the procedure.(53)(55)(56)

On average, patients require at least 6 injections once every 2 to 4 weeks.(51)(52)(53) Like QIA, IVC avoids the risk of systemic side effects, although side effects such as bleeding have been described. vitreous, chorioretinal atrophy, ocular hypotonia, anterior uveitis, inflammation of the optic nerve, secondary cataract, transient conjunctivitis and extraocular tumor seeding.(52)(56)(57)(58)

Retinal toxicity reflected by reduced electroretinographic amplitudes has been demonstrated in Rb rabbit and human eyes that received IVK.(56) Patients with vitreous seeding throughout the vitreous cavity, secondary glaucoma, or significant anterior invasion are poor candidates for IVK. (54)

> Intracameral chemotherapy and precision intravitreal chemotherapy

Intracameral chemotherapy and precision intravitreal chemotherapy are the 2 most recent evolutions in the administration of local chemotherapy for the treatment of Rb, introduced in 2017 and 2018, respectively.(59)(60)

The first was designed to help save eyes with anterior chamber seeding that would have previously required enucleation. Intracameral chemotherapy requires transcorneal aspiration of the aqueous humor and replacement of that volume with melphalan or topotecan.

Cryotherapy is applied at the injection site.(59) The latter has been used to treat localized vitreous seeding by injecting chemotherapy very close to the vitreous seeding under direct visualization using indirect ophthalmoscopy(60). Data on both modalities are limited. and none have yet progressed to widespread use, but they may contribute to the next wave of advances in Rb treatment.

> Periocular chemotherapy

Carboplatin or topotecan can be injected into the subconjunctival or subtenon space to achieve higher levels in the vitreous than can be achieved with QIS. Periocular chemotherapy has been used as an adjuvant treatment in group D or E eyes requiring a higher local dose of chemotherapy. However, due to its high side effect profile and the advent of alternative treatment options, periocular chemotherapy is rarely used.

As a single therapy, periocular treatment results in high failure rates and therefore should be combined with other therapies.(61) Complications associated with this modality include eyelid edema, periorbital ecchymosis, orbital fat atrophy, fibrosis of the extraocular muscles with posterior strabismus and atrophy of the optic nerve. (61)(62)(63)

> Focal Therapies

Cryotherapy, transpupillary thermotherapy (TTT), laser coagulation, and plate brachytherapy are used as primary treatments for small, isolated tumors in group A and B eyes, as secondary treatments after primary consolidation with QIS for more advanced eyes, or for tumor recurrence.

Sometimes a combination of focal therapies is used to achieve sufficient tumor consolidation. Caution should be used in cases of macular involvement, as chorioretinal scarring is a known side effect with all focal therapies.

Cryotherapy delivers liquid nitrogen to the sclera overlying the tumor under indirect ophthalmoscopy. It is typically used in conjunction with QIS or QIA and can be used to access tumors located posteriorly or anteriorly in the retina.(38) TTT uses an 810 nm diode laser to heat and destroy tumor cells.

It is a useful approach for small, posteriorly located tumors and, like cryotherapy, is used in conjunction with chemotherapy. Up to 6 cycles of monthly TTT may be necessary to achieve calcification or complete healing of the tumor. Side effects may include focal cataracts, retinal fibrosis or vascular occlusion, and sectoral iris atrophy.(32)(64)(65)

Laser photocoagulation and plate brachytherapy are currently only rarely used as focal treatments in favor of cryotherapy and TTT. Laser photocoagulation uses a 520-nm argon laser to interrupt the blood supply to the tumor. Like TTT, this is a useful treatment for small posterior tumors.

Photocoagulation can also be used to treat Rb-associated retinal neovascularization. Plating brachytherapy is used as a secondary treatment for middle tumors and for tumor recurrence after QIS or QIA. It involves securing a radioactive plate to the sclera overlying the tumor.

Ionizing radiation (most commonly iodine-125 or ruthenium-106) results in the gradual death of tumor cells. Rb cells are sensitive to this therapy due to the high rate of tumor cell replication.(66) Radiation retinopathy and optic neuropathy that can compromise vision, as well as the 2 additional surgeries to implant and explant the plaque , have contributed to the decrease in its use.(64)(66)

Once treatment has been initiated, patients are followed on average once every 3 to 4 weeks. MRI of the brain and orbits is repeated every 6 months until 5 years of age to monitor local extension and trilateral Rb.

The pediatric oncologist may request additional systemic evaluation involving laboratory studies, cerebrospinal fluid analysis, or body imaging.

Once the patient is completely treated and "cancer free," follow-up should continue indefinitely. Studies have shown that recurrences are very rare beyond 3 years after treatment; however, late remissions have been reported.(67)

Regular ophthalmic surveillance not only focuses on optimizing visual recovery, treating amblyopia, protecting the unaffected eye, and detecting tumor recurrence, but also focuses on managing any potential side effects of Rb treatment such as cataracts and glaucoma. .

Given the still low overall survival and eyeball salvage rates worldwide caused by health care disparities in developing countries, current efforts in Rb treatment focus on increasing affordability and accessibility. to available treatments, minimizing associated side effects and complications, and increasing the longevity of treatment effectiveness.

In addition, there are new areas of research into alternative chemotherapeutic agents, such as anthracyclines, which may be effective in Rb, as well as molecularly targeted therapy.(68) The latter has not yet had great success and is based on the theory of that mutations or specific secondary genes can be identified in addition to RB1 that may be involved in tumorigenesis.

One example involves a small molecule targeting nutilin-3, which is involved in p53 activation. In mouse models, subconjunctival injection of this small molecule, which inhibits p53 and leads to apoptosis, resulted in a decrease in tumor burden when used together with topotecan; This modality is now in phase 1 trials.(69)

Inhibition of the SYK protein, which is required for Rb cell survival, caused Rb cell death in mouse models.(70) It has been shown that histone deacetylase (HDAC) inhibitors, which are also found in phase 1 studies, slow tumor growth in mouse models with limited systemic side effects, suggesting that HDAC inhibitors may be specific for Rb cells.(71)

Gene therapy is another area of ​​research, which involves the introduction of viral or bacterial genetic material into tumor cells that is preprogrammed to kill malignant cells. A Phase 1 study of an adenovirus vector for the treatment of vitreous seedings is currently underway.(72) Local drug delivery using nanotechnology presents another potential area for further investigation.

Various drug delivery materials such as liposomes and gold nanoparticles can target specific cells and be designed to release the drug, increasing the half-life of intraocular chemotherapy. Ongoing studies are examining nanotechnology for the treatment of Rb in rabbit and mouse models.(73)(74)

Finally, the suprachoroidal space is being investigated as a site for drug delivery for Rb, which avoids entering the vitreous cavity completely, making it theoretically safer than IVC, while still achieving sufficiently high concentrations of local chemotherapy. . Phase 1 trials using a microneedle to inject triamcinolone into the suprachoroidal space for the treatment of uveitis and to inject chemotherapy in an Rb rabbit model are ongoing.(75)

Due to recent advances in the management of Rb over the past 30 years, a life-threatening disease that causes blindness can now be managed with tools that markedly reduce previous high levels of morbidity and mortality.

With a multitude of options and possible variations in treatment combinations, certain core principles should not be overshadowed by this exciting shift in the Rb treatment paradigm. Average survival remains the top priority, and should not be subverted by the prospect of eyeball salvage.

A multidisciplinary team approach is the cornerstone to achieving immediate and long-term success. Finally, the best treatment approach for each patient should be one that considers the individual characteristics of the disease, as well as the family’s financial and psychological needs.

Looking back at the rapid rate of discovery in Rb treatment, it is exciting to consider what the next decade of research on this tumor will reveal.

Table 1 . International Classification of Retinoblastoma(10)(26)(27)

aThe foveola is the center of the macula and is responsible for the clearest vision