NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); 2002-.
![Cover of PDQ Cancer Information Summaries](/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-pdqcis-lrg.png)
PDQ Cancer Information Summaries [Internet].
Show detailsThis PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of retinoblastoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
General Information About Retinoblastoma
Retinoblastoma is a pediatric cancer that requires a careful integration of multidisciplinary care. Treatment of retinoblastoma aims to save the patient's life and preserve useful vision and, therefore, needs to be individualized. The management of intraocular retinoblastoma has evolved to a more risk-adapted approach that aims to minimize systemic exposure to drugs, optimize ocular drug delivery, and preserve useful vision. For patients presenting with extraocular retinoblastoma, treatment with intensive chemotherapy is required, including consolidation with high-dose chemotherapy and autologous hematopoietic stem cell rescue. While most patients with orbital disease and a large proportion of patients with systemic extra–central nervous system (CNS) metastases can be cured, the prognosis for patients with intracranial disease is dismal.
Incidence
Retinoblastoma is a relatively uncommon tumor of childhood that arises in the retina and accounts for about 3% of the cancers occurring in children younger than 15 years.
Retinoblastoma is a cancer of the very young child; two-thirds of all cases of retinoblastoma are diagnosed before age 2 years.[1] Thus, while the estimated annual incidence in the United States is approximately 4 cases per 1 million children younger than 15 years, the age-adjusted annual incidence in children aged 0 to 4 years is 10 to 14 cases per 1 million (approximately 1 in 14,000–18,000 live births).
Anatomy
Retinoblastoma arises from the retina, and its growth is usually under the retina and toward the vitreous. Involvement of the ocular coats and optic nerve occurs as a sequence of events as the tumor progresses. Invasion of the choroid is common, although occurrence of massive invasion is usually limited to advanced disease. After invading the choroid, the tumor gains access to systemic circulation and creates the potential for metastases. Further progression through the ocular coats leads to invasion of the sclera and the orbit. Anteriorly, tumor invading the anterior chamber may gain access to systemic circulation through the canal of Schlemm. Progression through the optic nerve and past the lamina cribrosa increases the risk of systemic and CNS dissemination (refer to Figure 1).
Screening
The following screening and monitoring strategies reflect common practices in the management of retinoblastoma.
In children with a positive family history of retinoblastoma, early-in-life screening by fundus exam is performed under general anesthesia at regular intervals according to a schedule based on the absolute estimated risk, as determined by the identification of the RB1 mutation in the family and the presence of the RB1 mutation in the child. Infants born to affected parents have a dilated eye examination under anesthesia as soon as possible in the first month of life, and a genetic evaluation is performed. Infants with a positive genetic test are examined under anesthesia on a monthly basis. In infants who do not develop disease, monthly exams continue throughout the first year; the frequency of those studies may be decreased progressively during the second and subsequent years. Screening exams can improve prognosis in terms of globe sparing and use of less intensive, ocular-salvage treatments in children with a positive family history of retinoblastoma.[2]
Common practice for the parents and siblings of patients with retinoblastoma is to have screening ophthalmic examinations to exclude an unknown familial disease. Siblings continue to be screened until age 3 to 5 years or until it is confirmed that they do not have an RB1 gene mutation.
Clinical Presentation
Age at presentation correlates with laterality; patients with bilateral disease present at a younger age, usually in the first 12 months of life.
Most cases present with leukocoria, which is occasionally first noticed after a flash photograph is taken. Strabismus is the second most common presenting sign and usually correlates with macular involvement. Very advanced intraocular tumors present with pain, orbital cellulitis, glaucoma, or buphthalmos. As the tumor progresses, patients may present with orbital or metastatic disease. Metastases occur in the preauricular and laterocervical lymph nodes, in the CNS, or systemically (commonly in the bones, bone marrow, and liver).
In the United States, children of Hispanic origin and children living in lower socioeconomic conditions have been noted to present with more advanced disease.[3]
Diagnostic Evaluation
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. A very detailed documentation of the number, location, and size of tumors; the presence of retinal detachment and subretinal fluid; and the presence of subretinal and vitreous seeds must be performed.
Bidimensional ocular ultrasound and magnetic resonance imaging (MRI) can be useful to differentiate retinoblastoma from other causes of leukocoria and in the evaluation of extrascleral and extraocular extension in children with advanced intraocular retinoblastoma. Optic nerve enhancement by MRI does not necessarily indicate involvement; cautious interpretation of those findings is needed.[4] The detection of the synthetase of ganglioside GD2 mRNA by reverse transcriptase–polymerase chain reaction in the cerebrospinal fluid at the time of diagnosis may be a marker for CNS disease.[5]
Evaluation for the presence of metastatic disease also needs to be considered in the subgroup of patients with suspected extraocular extension by imaging or high-risk pathology in the enucleated eye (i.e., massive choroidal invasion or involvement of the sclera or the optic nerve beyond the lamina cribrosa). Patients presenting with these pathological features in the enucleated eye are at high risk of developing metastases. In these cases, bone scintigraphy, bone marrow aspirates and biopsies, and lumbar puncture may be performed.[6]
Genetic counseling is recommended for all patients with retinoblastoma. (Refer to the Genetic Counseling section of this summary for more information.)
Heritable and Nonheritable Forms of Retinoblastoma
Retinoblastoma is a tumor that occurs in heritable (25%–30%) and nonheritable (70%–75%) forms. Heritable disease is defined by the presence of a germline mutation of the RB1 gene. This germline mutation may have been inherited from an affected progenitor (25% of cases) or may have occurred in a germ cell before conception or in utero during early embryogenesis in patients with sporadic disease (75% of cases). The presence of positive family history or bilateral or multifocal disease is suggestive of heritable disease.Heritable retinoblastoma may manifest as unilateral or bilateral disease. The penetrance of the RB1 mutation (laterality, age at diagnosis, and number of tumors) is probably dependent on concurrent genetic modifiers such as MDM2 and MDM4 polymorphisms.[7,8] All children with bilateral disease and approximately 15% of patients with unilateral disease are presumed to have the heritable form, even though only 25% have an affected parent.
In heritable retinoblastoma, tumors tend to be diagnosed at a younger age than in the nonheritable form of the disease. Unilateral retinoblastoma in children younger than 1 year raises concern for heritable disease, whereas older children with a unilateral tumor are more likely to have the nonheritable form of the disease.[9]
The genomic landscape of retinoblastoma is driven by alterations in RB1 that lead to biallelic inactivation.[10,11] A rare cause of RB1 inactivation is chromothripsis, which may be difficult to detect by conventional methods.[12] Other recurring genomic changes that occur in a small minority of tumors include BCOR mutation/deletion, MYCN amplification, and OTX2 amplification.[10-12] A study of 1,068 unilateral nonfamilial retinoblastoma tumors reported that a small percentage of cases (approximately 3%) lacked evidence of RB1 loss. Approximately one-half of these cases with no evidence of RB1 loss (representing approximately 1.5% of all unilateral nonfamilial retinoblastoma) showed MYCN amplification.[11] The functional status of the retinoblastoma protein (pRb) is inferred to be inactive in retinoblastoma with MYCN amplification. This suggests that inactivation of RB1 by mutation or inactive pRb is a requirement for the development of retinoblastoma, independent of MYCN amplification.
[13]Postdiagnosis Surveillance
Children with a germline RB1 mutation may continue to develop new tumors for a few years after diagnosis and treatment; for this reason, they need to be examined frequently. It is common practice for examinations to occur every 2 to 4 months for at least 28 months.[14] The interval between exams is based on the stability of the disease and age of the child (i.e., less frequent visits as the child ages).
A proportion of children who present with unilateral retinoblastoma will eventually develop disease in the opposite eye. Periodic examinations of the unaffected eye are performed until the germline status of the RB1 gene is determined.
Because of the poor prognosis for patients with trilateral retinoblastoma, screening with neuroimaging until age 5 years is a common practice in the monitoring of children with the heritable form of the disease. (Refer to the Trilateral retinoblastoma section in the Causes of Retinoblastoma-Related Mortality section of this summary for more information.)
Genetic Testing
Blood and tumor samples can be tested to determine whether a patient with retinoblastoma has a mutation in the RB1 gene. Once the patient's genetic mutation has been identified, other family members can be screened directly for the mutation with targeted sequencing.
A multistep assay that includes the following may be performed for a complete genetic evaluation of the RB1 gene:[15]
- DNA sequencing to identify mutations within coding exons and immediate flanking intronic regions.
- Southern blot analysis to characterize genomic rearrangements.
- Transcript analysis to characterize potential splicing mutations buried within introns.
In cases of somatic mosaicism or cytogenetic abnormalities, the mutations may not be easily detected; more exhaustive techniques such as karyotyping, multiplex ligation-dependent probe amplification, fluorescence in situ hybridization, and methylation analysis of the RB1 promoter may be needed. Allele-specific deep (2500x) sequencing of an RB1 genomic amplicon from lymphocyte DNA can reveal low-level mosaicism.[16] Because mosaicism is caused by a postzygotic mutation, such a finding obviates the need for serial examination of siblings under anesthesia. Some RB1 mutations thought to be heterozygous with Sanger sequencing were also found to be mosaic. Deep sequencing will not discover some mosaic mutations with very low levels of amplification, mutations outside of the RB1 amplicon, mutations not found in lymphocytes but in other tissues, or mosaic large rearrangements of RB1.[16] Combining the above techniques, a germline mutation may be detected in more than 90% of patients with heritable retinoblastoma.[17,18]
The absence of detectable somatic RB1 mutations in approximately 3% of unilateral, nonheritable retinoblastoma cases suggests that alternative genetic mechanisms may underlie the development of retinoblastoma.[19] In one-half of these cases, high levels of MYCN amplification have been reported; these patients had distinct, aggressive histologic features and a median age at diagnosis of 4 months.[11] In another small subset of tumors without detectable somatic RB1 mutations, chromothripsis is responsible for inactivating the RB1 gene.[12]
Genetic Counseling
Genetic counseling is an integral part of the management of patients with retinoblastoma and their families, regardless of clinical presentation; counseling assists parents in understanding the genetic consequences of each form of retinoblastoma and in estimating the risk of disease in family members.[17] Genetic counseling, however, is not always straightforward. Approximately 10% of children with retinoblastoma have somatic genetic mosaicism, which contributes to the difficulty of genetic counseling.[20] In addition, for one specific mutation, the risk of retinoblastoma in a sibling may depend, in part, on whether the mutation is inherited from the mother or father.[21] (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)
Causes of Retinoblastoma-Related Mortality
While retinoblastoma is a highly curable disease, the challenge for those who treat retinoblastoma is to preserve life and to prevent the loss of an eye, blindness, and other serious effects of treatment that reduce the patient's life span or quality of life. With improvements in the diagnosis and management of retinoblastoma over the past several decades, metastatic retinoblastoma is observed less frequently in the United States and other developed nations. As a result, other causes, such as trilateral retinoblastoma and subsequent neoplasms (SNs), have become significant contributors to retinoblastoma-related mortality in the first and subsequent decades of life.
Death from a second neoplasm is the most common cause of death and contributes to about 50% of deaths in patients with bilateral disease and genetically defined heritable retinoblastoma.[22,23] In the United States, before the advent of chemoreduction as a means of treating heritable or bilateral disease and the implementation of neuroimaging screening, trilateral retinoblastoma contributed to more than 50% of retinoblastoma-related mortality in the first decade after diagnosis.[24]
Trilateral retinoblastoma
Trilateral retinoblastoma is a well-recognized syndrome that occurs in 5% to 15% of patients with heritable retinoblastoma. It is defined by the development of an intracranial midline neuroblastic tumor, which typically develops between the ages of 20 and 36 months.[25]
Trilateral retinoblastoma has been the principal cause of death from retinoblastoma in the United States during the first decade of life.[26] Because of the poor prognosis for patients with trilateral retinoblastoma and the apparent improved survival with early detection and aggressive treatment, screening with routine neuroimaging could potentially detect most cases within 2 years of first diagnosis.[25] Routine baseline brain MRI is recommended at diagnosis because it may detect trilateral retinoblastoma at a subclinical stage. In a small series of patients, the 5-year overall survival rate was 67% for those detected at baseline, compared with 11% for the group with a delayed diagnosis.[27] Although it is not clear whether early diagnosis can impact survival, screening with MRI has been recommended as often as every 6 months for 5 years for patients suspected of having heritable disease or those with unilateral disease and a positive family history.[28] Computed tomography scans are generally avoided for routine screening in these children because of the risk related to ionizing radiation exposure.
A cystic pineal gland, which is commonly detected by surveillance MRI, needs to be distinguished from a cystic variant of pineoblastoma. In children without retinoblastoma, the incidence of pineal cysts has been reported to be 55.8%.[29] In a case-control study that included 77 children with retinoblastoma and 77 controls, the incidence of pineal cysts was similar (61% and 69%, respectively), and the size and volume of the pineal gland was not significantly different between the groups.[30] However, a cystic component has been described in up to 57% of patients with histologically confirmed trilateral retinoblastoma.[27] An excessive increase in the size of the pineal gland seems to be the strongest parameter indicating a malignant process.[30]
Subsequent neoplasms (SNs)
Survivors of retinoblastoma have a high risk of developing SNs. Factors that influence this risk include the following:
- Heritable retinoblastoma. Patients with heritable retinoblastoma have a markedly increased incidence of SNs, independent of treatment with radiation therapy.[22,23,31] In a German series of 643 patients with heritable retinoblastoma, chemotherapy with or without radiation therapy was the only significant risk factor for the onset of second cancers outside the periorbital region.[23] A possible association between the type of RB1 mutation and incidence of SNs may exist, with complete loss of RB1 activity associated with a higher incidence of SNs.[32] With the increase in survival of patients with heritable retinoblastoma, it has become apparent that they are also at risk of developing epithelial cancers late in adulthood. A marked increase in mortality from lung, bladder, and other epithelial cancers has been described.[33,34]Among retinoblastoma survivors with heritable retinoblastoma, those with an inherited germline mutation are at a slightly higher risk of developing an SN than are those with a de novo mutation; this increase appears to be most significant for melanoma.[35]
- Past treatment for retinoblastoma with radiation therapy. The cumulative incidence of SNs was reported to be 26% (± 10%) in nonirradiated patients and 58% (± 10%) in irradiated patients by 50 years after diagnosis of retinoblastoma—a rate of about 1% per year.[36] A German series of 633 patients with heritable retinoblastoma demonstrated a 5-year survival of 93%; however, 40 years later, only 80% of patients survived, with most succumbing to radiation-induced SNs (hazard ratio, approximately 3).[37] Other studies analyzing cohorts of patients treated with more advanced radiation planning and delivery technology have reported the SN rates to be about 9.4% in nonirradiated patients and about 30.4% in irradiated patients.[38] In a nonrandomized study that compared two contemporary cohorts of patients with hereditary retinoblastoma who were treated with either photon (n = 31) or proton (n = 55) therapy, the 10-year cumulative incidence of radiation-induced SNs was significantly different between the two groups (0% for proton radiation vs. 14% for photon radiation, P = .015).[39] A longer follow-up will be required to further define the risk of SNs associated with proton radiation.The most common SN is sarcoma, specifically osteosarcoma, followed by soft tissue sarcoma and melanoma; these malignancies may occur inside or outside of the radiation field, although most are radiation induced. The carcinogenic effect of radiation therapy is associated with the dose delivered, particularly for subsequent sarcomas; a step-wise increase is apparent at all dose categories. In irradiated patients, two-thirds of SNs occur within irradiated tissue, and one-third of SNs occur outside the radiation field.[31,36,38,40]
The issue of balancing long-term tumor control with the consequences of chemotherapy is unresolved. Most patients who receive chemotherapy are exposed to etoposide, which has been associated with secondary leukemia in patients without a predisposition to cancer, but at modest rates when compared with the risks associated with EBRT in heritable retinoblastoma. Despite the known increased risk of acute myeloid leukemia (AML) associated with the use of etoposide, patients with heritable retinoblastoma are not at an increased risk of developing this SN.[45-47] An initial report conducted by informal survey methods described 15 patients who developed AML after chemotherapy. One-half of the patients also received radiation therapy.[46] This finding has not been substantiated by formal studies. In a single-institution study of 245 patients who received etoposide, only 1 patient had acute promyelocytic leukemia after 79 months.[45] Additionally, the Surveillance, Epidemiology, and End Results (SEER) Program calculated standardized incidence rates for secondary hematopoietic malignancies in 34,867 survivors of childhood cancer. The observed-to-expected ratio of secondary AML in patients treated for retinoblastoma was zero.[48]
Survival from SNs is certainly suboptimal and varies widely across studies.[33,49-53] However, with advances in therapy, it is essential that all SNs in survivors of retinoblastoma be treated with curative intent.[54]
Late Effects from Retinoblastoma Therapy
In a report from the Retinoblastoma Survivor Study (N = 470), 87% of survivors of retinoblastoma (mean age, 43 years; median follow-up, 42 years) had at least one medical condition and 71% had a severe or life-threatening condition. The adjusted relative risk of a chronic condition in survivors, compared with nonretinoblastoma controls, was 1.4 (P < .01); the relative risk of a grade 3 or 4 condition was 7.6 (P < .01). After excluding ocular conditions and SNs, this excess risk was found to persist only for those with bilateral disease.[55]
As previously discussed, patients with heritable retinoblastoma have an increased incidence of SNs. (Refer to the Subsequent neoplasms [SNs] section in the Causes of Retinoblastoma-Related Mortality section of this summary for more information.) Other late effects that may occur after treatment for retinoblastoma include the following:
- Diminished orbital growth. Orbital growth is somewhat diminished after enucleation; however, the impact of enucleation on orbital volume may be less after placement of an orbital implant.[56]
- Visual-field deficits. Patients with retinoblastoma demonstrate a variety of long-term visual-field defects after treatment for their intraocular disease. These defects are related to tumor size, location, and treatment method.[57]One study of visual acuity after treatment with systemic chemotherapy and local ophthalmic therapy was conducted in 54 eyes in 40 children. After a mean follow-up of 68 months, 27 eyes (50%) had a final visual acuity of 20/40 or better, and 36 eyes (67%) had final visual acuity of 20/200 or better. The clinical factors that predicted visual acuity of 20/40 or better were a tumor margin of at least 3 mm from the foveola and optic disc and an absence of subretinal fluid.[58]
- Hearing loss. Because systemic carboplatin is now commonly used in the treatment of retinoblastoma (refer to the Treatment of Intraocular Retinoblastoma and Treatment of Extraocular Retinoblastoma sections of this summary for more information), concern has been raised about hearing loss related to therapy. While two large studies that included children treated with six cycles of carboplatin-containing therapy (18.6 mg/kg per cycle) showed an incidence of treatment-related hearing loss of lower than 1%,[59,60] a separate series documented some degree of hearing loss in 17% of patients.[61] In the latter study, age younger than 6 months at the time of treatment and higher carboplatin systemic exposures correlated with an increased risk of ototoxicity.[61,62]
Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.
References
- Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649. Also available online. Last accessed February 07, 2019.
- Rothschild PR, Lévy D, Savignoni A, et al.: Familial retinoblastoma: fundus screening schedule impact and guideline proposal. A retrospective study. Eye (Lond) 25 (12): 1555-61, 2011. [PMC free article: PMC3234459] [PubMed: 21921957]
- Truong B, Green AL, Friedrich P, et al.: Ethnic, Racial, and Socioeconomic Disparities in Retinoblastoma. JAMA Pediatr 169 (12): 1096-104, 2015. [PubMed: 26436436]
- Khurana A, Eisenhut CA, Wan W, et al.: Comparison of the diagnostic value of MR imaging and ophthalmoscopy for the staging of retinoblastoma. Eur Radiol 23 (5): 1271-80, 2013. [PubMed: 23160663]
- Laurent VE, Sampor C, Solernou V, et al.: Detection of minimally disseminated disease in the cerebrospinal fluid of children with high-risk retinoblastoma by reverse transcriptase-polymerase chain reaction for GD2 synthase mRNA. Eur J Cancer 49 (13): 2892-9, 2013. [PubMed: 23721779]
- Kaliki S, Shields CL, Rojanaporn D, et al.: High-risk retinoblastoma based on international classification of retinoblastoma: analysis of 519 enucleated eyes. Ophthalmology 120 (5): 997-1003, 2013. [PubMed: 23399379]
- Castéra L, Sabbagh A, Dehainault C, et al.: MDM2 as a modifier gene in retinoblastoma. J Natl Cancer Inst 102 (23): 1805-8, 2010. [PubMed: 21051655]
- de Oliveira Reis AH, de Carvalho IN, de Sousa Damasceno PB, et al.: Influence of MDM2 and MDM4 on development and survival in hereditary retinoblastoma. Pediatr Blood Cancer 59 (1): 39-43, 2012. [PubMed: 22180099]
- Zajaczek S, Jakubowska A, Kurzawski G, et al.: Age at diagnosis to discriminate those patients for whom constitutional DNA sequencing is appropriate in sporadic unilateral retinoblastoma. Eur J Cancer 34 (12): 1919-21, 1998. [PubMed: 10023315]
- Zhang J, Benavente CA, McEvoy J, et al.: A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature 481 (7381): 329-34, 2012. [PMC free article: PMC3289956] [PubMed: 22237022]
- Rushlow DE, Mol BM, Kennett JY, et al.: Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies. Lancet Oncol 14 (4): 327-34, 2013. [PubMed: 23498719]
- McEvoy J, Nagahawatte P, Finkelstein D, et al.: RB1 gene inactivation by chromothripsis in human retinoblastoma. Oncotarget 5 (2): 438-50, 2014. [PMC free article: PMC3964219] [PubMed: 24509483]
- Ewens KG, Bhatti TR, Moran KA, et al.: Phosphorylation of pRb: mechanism for RB pathway inactivation in MYCN-amplified retinoblastoma. Cancer Med 6 (3): 619-630, 2017. [PMC free article: PMC5345671] [PubMed: 28211617]
- Abramson DH, Mendelsohn ME, Servodidio CA, et al.: Familial retinoblastoma: where and when? Acta Ophthalmol Scand 76 (3): 334-8, 1998. [PubMed: 9686848]
- Clark R: Retinoblastoma: genetic testing and counseling. In: Singh A, Damato B: Clinical Ophthalmic Oncology. Philadelphia, Pa: Saunders Elsevier, 2007, pp 441-6.
- Amitrano S, Marozza A, Somma S, et al.: Next generation sequencing in sporadic retinoblastoma patients reveals somatic mosaicism. Eur J Hum Genet 23 (11): 1523-30, 2015. [PMC free article: PMC4613478] [PubMed: 25712084]
- Richter S, Vandezande K, Chen N, et al.: Sensitive and efficient detection of RB1 gene mutations enhances care for families with retinoblastoma. Am J Hum Genet 72 (2): 253-69, 2003. [PMC free article: PMC379221] [PubMed: 12541220]
- Sagi M, Frenkel A, Eilat A, et al.: Genetic screening in patients with Retinoblastoma in Israel. Fam Cancer 14 (3): 471-80, 2015. [PubMed: 25754945]
- Nichols KE, Houseknecht MD, Godmilow L, et al.: Sensitive multistep clinical molecular screening of 180 unrelated individuals with retinoblastoma detects 36 novel mutations in the RB1 gene. Hum Mutat 25 (6): 566-74, 2005. [PubMed: 15884040]
- Dommering CJ, Mol BM, Moll AC, et al.: RB1 mutation spectrum in a comprehensive nationwide cohort of retinoblastoma patients. J Med Genet 51 (6): 366-74, 2014. [PubMed: 24688104]
- Eloy P, Dehainault C, Sefta M, et al.: A Parent-of-Origin Effect Impacts the Phenotype in Low Penetrance Retinoblastoma Families Segregating the c.1981C>T/p.Arg661Trp Mutation of RB1. PLoS Genet 12 (2): e1005888, 2016. [PMC free article: PMC4771840] [PubMed: 26925970]
- Shinohara ET, DeWees T, Perkins SM: Subsequent malignancies and their effect on survival in patients with retinoblastoma. Pediatr Blood Cancer 61 (1): 116-9, 2014. [PubMed: 23918737]
- Temming P, Arendt M, Viehmann A, et al.: Incidence of second cancers after radiotherapy and systemic chemotherapy in heritable retinoblastoma survivors: A report from the German reference center. Pediatr Blood Cancer 64 (1): 71-80, 2017. [PubMed: 27567086]
- Broaddus E, Topham A, Singh AD: Survival with retinoblastoma in the USA: 1975-2004. Br J Ophthalmol 93 (1): 24-7, 2009. [PubMed: 18718969]
- de Jong MC, Kors WA, de Graaf P, et al.: Trilateral retinoblastoma: a systematic review and meta-analysis. Lancet Oncol 15 (10): 1157-67, 2014. [PubMed: 25126964]
- Blach LE, McCormick B, Abramson DH, et al.: Trilateral retinoblastoma--incidence and outcome: a decade of experience. Int J Radiat Oncol Biol Phys 29 (4): 729-33, 1994. [PubMed: 8040018]
- Rodjan F, de Graaf P, Brisse HJ, et al.: Trilateral retinoblastoma: neuroimaging characteristics and value of routine brain screening on admission. J Neurooncol 109 (3): 535-44, 2012. [PMC free article: PMC3434888] [PubMed: 22802019]
- Kivelä T: Trilateral retinoblastoma: a meta-analysis of hereditary retinoblastoma associated with primary ectopic intracranial retinoblastoma. J Clin Oncol 17 (6): 1829-37, 1999. [PubMed: 10561222]
- Sirin S, de Jong MC, Galluzzi P, et al.: MRI-based assessment of the pineal gland in a large population of children aged 0-5 years and comparison with pineoblastoma: part II, the cystic gland. Neuroradiology 58 (7): 713-21, 2016. [PMC free article: PMC4958131] [PubMed: 27130617]
- Pham TT, Siebert E, Asbach P, et al.: Magnetic resonance imaging based morphologic evaluation of the pineal gland for suspected pineoblastoma in retinoblastoma patients and age-matched controls. J Neurol Sci 359 (1-2): 185-92, 2015. [PubMed: 26671110]
- MacCarthy A, Bayne AM, Brownbill PA, et al.: Second and subsequent tumours among 1927 retinoblastoma patients diagnosed in Britain 1951-2004. Br J Cancer 108 (12): 2455-63, 2013. [PMC free article: PMC3694232] [PubMed: 23674091]
- Dommering CJ, Marees T, van der Hout AH, et al.: RB1 mutations and second primary malignancies after hereditary retinoblastoma. Fam Cancer 11 (2): 225-33, 2012. [PMC free article: PMC3365233] [PubMed: 22205104]
- Fletcher O, Easton D, Anderson K, et al.: Lifetime risks of common cancers among retinoblastoma survivors. J Natl Cancer Inst 96 (5): 357-63, 2004. [PubMed: 14996857]
- Marees T, van Leeuwen FE, de Boer MR, et al.: Cancer mortality in long-term survivors of retinoblastoma. Eur J Cancer 45 (18): 3245-53, 2009. [PubMed: 19493675]
- Kleinerman RA, Yu CL, Little MP, et al.: Variation of second cancer risk by family history of retinoblastoma among long-term survivors. J Clin Oncol 30 (9): 950-7, 2012. [PMC free article: PMC3341108] [PubMed: 22355046]
- Wong FL, Boice JD Jr, Abramson DH, et al.: Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. JAMA 278 (15): 1262-7, 1997. [PubMed: 9333268]
- Temming P, Arendt M, Viehmann A, et al.: How Eye-Preserving Therapy Affects Long-Term Overall Survival in Heritable Retinoblastoma Survivors. J Clin Oncol 34 (26): 3183-8, 2016. [PubMed: 27382102]
- Kleinerman RA, Tucker MA, Tarone RE, et al.: Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol 23 (10): 2272-9, 2005. [PubMed: 15800318]
- Sethi RV, Shih HA, Yeap BY, et al.: Second nonocular tumors among survivors of retinoblastoma treated with contemporary photon and proton radiotherapy. Cancer 120 (1): 126-33, 2014. [PMC free article: PMC3959122] [PubMed: 24122173]
- Kleinerman RA, Tucker MA, Abramson DH, et al.: Risk of soft tissue sarcomas by individual subtype in survivors of hereditary retinoblastoma. J Natl Cancer Inst 99 (1): 24-31, 2007. [PubMed: 17202110]
- Abramson DH, Frank CM: Second nonocular tumors in survivors of bilateral retinoblastoma: a possible age effect on radiation-related risk. Ophthalmology 105 (4): 573-9; discussion 579-80, 1998. [PubMed: 9544627]
- Moll AC, Imhof SM, Schouten-Van Meeteren AY, et al.: Second primary tumors in hereditary retinoblastoma: a register-based study, 1945-1997: is there an age effect on radiation-related risk? Ophthalmology 108 (6): 1109-14, 2001. [PubMed: 11382638]
- Abramson DH, Melson MR, Dunkel IJ, et al.: Third (fourth and fifth) nonocular tumors in survivors of retinoblastoma. Ophthalmology 108 (10): 1868-76, 2001. [PubMed: 11581064]
- Marees T, van Leeuwen FE, Schaapveld M, et al.: Risk of third malignancies and death after a second malignancy in retinoblastoma survivors. Eur J Cancer 46 (11): 2052-8, 2010. [PubMed: 20400293]
- Turaka K, Shields CL, Meadows AT, et al.: Second malignant neoplasms following chemoreduction with carboplatin, etoposide, and vincristine in 245 patients with intraocular retinoblastoma. Pediatr Blood Cancer 59 (1): 121-5, 2012. [PubMed: 21826785]
- Gombos DS, Hungerford J, Abramson DH, et al.: Secondary acute myelogenous leukemia in patients with retinoblastoma: is chemotherapy a factor? Ophthalmology 114 (7): 1378-83, 2007. [PubMed: 17613328]
- Tamboli D, Topham A, Singh N, et al.: Retinoblastoma: A SEER Dataset Evaluation for Treatment Patterns, Survival, and Second Malignant Neoplasms. Am J Ophthalmol 160 (5): 953-8, 2015. [PubMed: 26255575]
- Rihani R, Bazzeh F, Faqih N, et al.: Secondary hematopoietic malignancies in survivors of childhood cancer: an analysis of 111 cases from the Surveillance, Epidemiology, and End Result-9 registry. Cancer 116 (18): 4385-94, 2010. [PubMed: 20549819]
- Yu CL, Tucker MA, Abramson DH, et al.: Cause-specific mortality in long-term survivors of retinoblastoma. J Natl Cancer Inst 101 (8): 581-91, 2009. [PMC free article: PMC2669101] [PubMed: 19351917]
- Aerts I, Pacquement H, Doz F, et al.: Outcome of second malignancies after retinoblastoma: a retrospective analysis of 25 patients treated at the Institut Curie. Eur J Cancer 40 (10): 1522-9, 2004. [PubMed: 15196536]
- Eng C, Li FP, Abramson DH, et al.: Mortality from second tumors among long-term survivors of retinoblastoma. J Natl Cancer Inst 85 (14): 1121-8, 1993. [PubMed: 8320741]
- Dunkel IJ, Gerald WL, Rosenfield NS, et al.: Outcome of patients with a history of bilateral retinoblastoma treated for a second malignancy: the Memorial Sloan-Kettering experience. Med Pediatr Oncol 30 (1): 59-62, 1998. [PubMed: 9371391]
- Marees T, Moll AC, Imhof SM, et al.: Risk of second malignancies in survivors of retinoblastoma: more than 40 years of follow-up. J Natl Cancer Inst 100 (24): 1771-9, 2008. [PubMed: 19066271]
- Moll AC, Imhof SM, Bouter LM, et al.: Second primary tumors in patients with retinoblastoma. A review of the literature. Ophthalmic Genet 18 (1): 27-34, 1997. [PubMed: 9134547]
- Friedman DN, Chou JF, Oeffinger KC, et al.: Chronic medical conditions in adult survivors of retinoblastoma: Results of the Retinoblastoma Survivor Study. Cancer 122 (5): 773-81, 2016. [PMC free article: PMC4764449] [PubMed: 26755259]
- Chojniak MM, Chojniak R, Testa ML, et al.: Abnormal orbital growth in children submitted to enucleation for retinoblastoma treatment. J Pediatr Hematol Oncol 34 (3): e102-5, 2012. [PubMed: 22258347]
- Abramson DH, Melson MR, Servodidio C: Visual fields in retinoblastoma survivors. Arch Ophthalmol 122 (9): 1324-30, 2004. [PubMed: 15364711]
- Demirci H, Shields CL, Meadows AT, et al.: Long-term visual outcome following chemoreduction for retinoblastoma. Arch Ophthalmol 123 (11): 1525-30, 2005. [PubMed: 16286614]
- Lambert MP, Shields C, Meadows AT: A retrospective review of hearing in children with retinoblastoma treated with carboplatin-based chemotherapy. Pediatr Blood Cancer 50 (2): 223-6, 2008. [PubMed: 17278120]
- Batra A, Thakar A, Bakhshi S: Ototoxicity in retinoblastoma survivors treated with carboplatin based chemotherapy: A cross-sectional study of 116 patients. Pediatr Blood Cancer 62 (11): 2060, 2015. [PubMed: 26053139]
- Qaddoumi I, Bass JK, Wu J, et al.: Carboplatin-associated ototoxicity in children with retinoblastoma. J Clin Oncol 30 (10): 1034-41, 2012. [PMC free article: PMC3341147] [PubMed: 22370329]
- Leahey A: A cautionary tale: dosing chemotherapy in infants with retinoblastoma. J Clin Oncol 30 (10): 1023-4, 2012. [PubMed: 22370322]
Tumor Pathology of Retinoblastoma
Cone precursor cells are the cell of origin in retinoblastoma.[1] Microscopically, the appearance of retinoblastoma 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 and are characterized by distinctive arrangements of tumor cells, as follows:
- Flexner-Wintersteiner rosettes are specific to retinoblastoma; these structures consist of a cluster of low columnar cells arranged around a central lumen that is bounded by an eosinophilic membrane analogous to the external membrane of the normal retina. The lumen contains rosettes that are seen in 70% of tumors.
- Homer Wright rosettes are composed of irregular circlets of tumor cells arranged around a tangle of fibrils with no lumen or internal-limiting membrane. Horner Wright rosettes are infrequently seen in retinoblastoma and are most often seen in other neuroblastic tumors, such as neuroblastoma and medulloblastoma.
Retinoblastomas are characterized by marked cell proliferation, as evidenced by high mitosis counts, extremely high MIB-1 labeling indices, and strong diffuse nuclear immunoreactivity for cone-rod homeobox, also known as CRX, a useful marker to discriminate retinoblastoma from other malignant, small, round cell tumors.[2,3]
Cavitary retinoblastoma, a rare variant of retinoblastoma, has ophthalmoscopically visible lucent cavities within the tumor. The cavitary spaces appear hollow on ultrasonography and hypofluorescent on angiography. Histopathologically, the cavitary spaces have been shown to represent areas of photoreceptor differentiation.[4] These tumors have been associated with minimal visible tumor response to chemotherapy, which is thought to be a sign of tumor differentiation.[5]
A pathologist experienced in ocular pathology and retinoblastoma should examine the enucleated specimen. This is particularly relevant to determine risk features of extraocular dissemination (refer to the Treatment of Intraocular Retinoblastoma section of this summary for more information).
References
- Xu XL, Singh HP, Wang L, et al.: Rb suppresses human cone-precursor-derived retinoblastoma tumours. Nature 514 (7522): 385-8, 2014. [PMC free article: PMC4232224] [PubMed: 25252974]
- Terry J, Calicchio ML, Rodriguez-Galindo C, et al.: Immunohistochemical expression of CRX in extracranial malignant small round cell tumors. Am J Surg Pathol 36 (8): 1165-9, 2012. [PubMed: 22790857]
- Schwimer CJ, Prayson RA: Clinicopathologic study of retinoblastoma including MIB-1, p53, and CD99 immunohistochemistry. Ann Diagn Pathol 5 (3): 148-54, 2001. [PubMed: 11436168]
- Palamar M, Pirondini C, Shields CL, et al.: Cavitary retinoblastoma: ultrasonographic and fluorescein angiographic findings in 3 cases. Arch Ophthalmol 126 (11): 1598-600, 2008. [PubMed: 19001231]
- Mashayekhi A, Shields CL, Eagle RC Jr, et al.: Cavitary changes in retinoblastoma: relationship to chemoresistance. Ophthalmology 112 (6): 1145-50, 2005. [PubMed: 15885779]
Staging and Grouping Systems for Retinoblastoma
The staging of patients with retinoblastoma requires close coordination of radiologists, pediatric oncologists, and ophthalmologists. Several staging and grouping systems have been proposed for retinoblastoma.[1] Overall assessment of retinoblastoma extension is documented by staging systems; intraocular extension, which is relevant for ocular salvage, is documented by grouping systems. For treatment purposes, retinoblastoma is categorized into intraocular and extraocular disease.
Intraocular Retinoblastoma
Intraocular retinoblastoma is localized to the eye; it may be confined to the retina or may extend to involve other structures such as the choroid, ciliary body, anterior chamber, and optic nerve head. Intraocular retinoblastoma, however, does not extend beyond the eye into the tissues around the eye or to other parts of the body.
Extraocular Retinoblastoma
Extraocular retinoblastoma extends beyond the eye. It may be confined to the tissues around the eye (orbital retinoblastoma), it may have spread to the central nervous system (CNS), or it may have spread systemically to the bone marrow or lymph nodes (metastatic retinoblastoma).
Staging Systems
American Joint Committee on Cancer (AJCC) staging system
Several staging systems have been proposed over the years. The AJCC clinical and pathological classifications represent a consensus opinion around which a common language is used. However, the AJCC's TNM (tumor, node, metastasis) staging system is not widely used for pediatric retinoblastoma and patients are not stratified on the basis of prognostic stage groups.
International Retinoblastoma Staging System
The more simplified International Retinoblastoma Staging System (IRSS) has been proposed by an international consortium of ophthalmologists and pediatric oncologists;[2] it is more widely used in the clinical setting than the AJCC staging system (refer to Table 1). A retrospective German study found that the IRSS predicted survival in 633 children with heritable retinoblastoma, of which 582 patients presented with IRSS stage 0 or I disease.[3]
Table 1. International Retinoblastoma Staging System
Stage | Description | |
---|---|---|
Stage 0 | Eye has not been enucleated and no dissemination of disease (refer to the International Classification of Retinoblastoma section of this summary for more information). | |
Stage I | Eye enucleated, completely resected histologically | |
Stage II | Eye enucleated, microscopic residual tumor | |
Stage III | Regional extension | a. Overt orbital disease |
b. Preauricular or cervical lymph node extension | ||
Stage IV | Metastatic disease | a. Hematogenous metastasis (without CNS involvement) |
—Single lesion | ||
—Multiple lesions | ||
b. CNS extension (with or without any other site of regional or metastatic disease) | ||
—Prechiasmatic lesion | ||
—CNS mass | ||
—Leptomeningeal and CSF disease |
CNS = central nervous system; CSF = cerebrospinal fluid.
Grouping Systems
Grouping systems are relevant for assessment of intraocular disease extension and are helpful predictors of ocular salvage.
Reese-Ellsworth Classification for Intraocular Tumors
Reese and Ellsworth developed a classification system for intraocular retinoblastoma that has been shown to have prognostic significance for maintenance of sight and control of local disease at a time when surgery and external-beam radiation therapy (EBRT) were the primary treatment options. However, developments in the conservative management of intraocular retinoblastoma have made the Reese-Ellsworth grouping system less predictive for eye salvage and less helpful in guiding treatment.[4] This grouping system is seldom used.
International Classification of Retinoblastoma
The new International Classification of Retinoblastoma staging system has been developed with the goal of providing a simpler, more user-friendly classification that is more applicable to current therapies. This new system is based on the extent of tumor seeding within the vitreous cavity and subretinal space, rather than on tumor size and location. This system seems to be a better predictor of treatment success.[4-7] The International Classification of Retinoblastoma system may also help predict high-risk histopathology. In a study of more than 500 patients with retinoblastoma, histopathologic evidence of high-risk disease was noted in 17% of Group D eyes and 24% of Group E eyes. This can be helpful in counseling parents regarding the potential need for postoperative systemic therapy.[8]
- Group A: Small intraretinal tumors away from foveola and disc.
- -
All tumors are 3 mm or smaller in greatest dimension, confined to the retina and
- -
All tumors are located further than 3 mm from the foveola and 1.5 mm from the optic disc.
- Group B: All remaining discrete tumors confined to the retina.
- -
All other tumors confined to the retina not in Group A.
- -
Tumor-associated subretinal fluid less than 3 mm from the tumor with no subretinal seeding.
- Group C: Discrete local disease with minimal subretinal or vitreous seeding.
- -
Tumor(s) are discrete.
- -
Subretinal fluid, present or past, without seeding involving up to one-fourth of the retina.
- -
Local fine vitreous seeding may be present close to discrete tumor.
- -
Local subretinal seeding less than 3 mm (2 DD) from the tumor.
- Group D: Diffuse disease with significant vitreous or subretinal seeding.
- -
Tumor(s) may be massive or diffuse.
- -
Subretinal fluid present or past without seeding, involving up to total retinal detachment.
- -
Diffuse or massive vitreous disease may include “greasy” seeds or avascular tumor masses.
- -
Diffuse subretinal seeding may include subretinal plaques or tumor nodules.
- Group E: Presence of any one or more of the following poor prognosis features.
- -
Tumor touching the lens.
- -
Tumor anterior to anterior vitreous face involving ciliary body or anterior segment.
- -
Diffuse infiltrating retinoblastoma.
- -
Neovascular glaucoma.
- -
Opaque media from hemorrhage.
- -
Tumor necrosis with aseptic orbital cellulites.
- -
Phthisis bulbi.
References
- Chantada GL, Sampor C, Bosaleh A, et al.: Comparison of staging systems for extraocular retinoblastoma: analysis of 533 patients. JAMA Ophthalmol 131 (9): 1127-34, 2013. [PubMed: 23787805]
- Chantada G, Doz F, Antoneli CB, et al.: A proposal for an international retinoblastoma staging system. Pediatr Blood Cancer 47 (6): 801-5, 2006. [PubMed: 16358310]
- Temming P, Arendt M, Viehmann A, et al.: How Eye-Preserving Therapy Affects Long-Term Overall Survival in Heritable Retinoblastoma Survivors. J Clin Oncol 34 (26): 3183-8, 2016. [PubMed: 27382102]
- Shields CL, Mashayekhi A, Au AK, et al.: The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology 113 (12): 2276-80, 2006. [PubMed: 16996605]
- Murphree L: Staging and grouping of retinoblastoma. In: Singh A, Damato B: Clinical Ophthalmic Oncology. Philadelphia, Pa: Saunders Elsevier, 2007, pp 422-7.
- Zage PE, Reitman AJ, Seshadri R, et al.: Outcomes of a two-drug chemotherapy regimen for intraocular retinoblastoma. Pediatr Blood Cancer 50 (3): 567-72, 2008. [PubMed: 17729249]
- Novetsky DE, Abramson DH, Kim JW, et al.: Published international classification of retinoblastoma (ICRB) definitions contain inconsistencies--an analysis of impact. Ophthalmic Genet 30 (1): 40-4, 2009. [PubMed: 19172510]
- Kaliki S, Shields CL, Rojanaporn D, et al.: High-risk retinoblastoma based on international classification of retinoblastoma: analysis of 519 enucleated eyes. Ophthalmology 120 (5): 997-1003, 2013. [PubMed: 23399379]
Treatment Option Overview for Retinoblastoma
Treatment planning by a multidisciplinary team of cancer specialists—including a pediatric oncologist, ophthalmologist, and radiation oncologist—with experience treating ocular tumors of childhood is required to optimize treatment outcomes.[1] Evaluation at specialized treatment centers is highly recommended before the initiation of treatment to improve the likelihood of ocular salvage and vision preservation.
The goals of therapy are the following:
- Eradicate the disease to save the patient's life.
- Preserve as much vision as possible.
- Decrease risk of late sequelae from treatment, particularly subsequent neoplasms (SNs).
Treatment of retinoblastoma is tailored to the intraocular and extraocular disease burden, disease laterality, germline RB1 gene status, and potential for preserving vision. For patients presenting with intraocular disease, particularly those with bilateral eye involvement, a conservative approach consisting of tumor reduction with intravenous or ophthalmic artery chemotherapy, coupled with aggressive local therapy, may result in high ocular salvage rates.[2] Radiation therapy, one of the most effective treatments in retinoblastoma, is usually reserved for cases of intraocular or extraocular disease progression. Many treatments considered to be standard of care have not been studied in a randomized fashion.
A risk-adapted, judicious combination of the following therapeutic options should be considered:
The treatment options for intraocular, extraocular, and recurrent retinoblastoma are described in Table 2.
Table 2. Treatment Options for Retinoblastoma
CNS = central nervous system; EBRT = external-beam radiation therapy.
Enucleation
Upfront removal of the eye is indicated for large tumors filling the vitreous for which there is little or no likelihood of restoring vision, in cases of extension to the anterior chamber, or in the presence of neovascular glaucoma. Patients must be monitored closely for orbital recurrence of disease, particularly in the first 2 years after enucleation.[3][Level of evidence: 3iiA] Enucleation is also used as a salvage treatment in cases of disease progression or recurrence in patients receiving eye-salvage management. The pathology specimen must be carefully examined to identify patients who are at high risk of extraocular dissemination and who may require adjuvant chemotherapy.
Local Treatment (Cryotherapy, Laser Therapy, and Brachytherapy)
For patients undergoing eye-salvage treatment, aggressive local therapy is always required. Local treatment is administered by the ophthalmologist directly to the tumor.
- Cryotherapy: Cryotherapy is based on the application of a cryoprobe to the sclera in the immediate vicinity of the retinal tumor. Cryotherapy is used as primary therapy or with chemotherapy for tumors smaller than 4 disc diameters (DD) in the anterior portion of the retina.
- Laser therapy: Laser therapy may be used as primary therapy for small tumors or in combination with chemotherapy for larger tumors. Traditional photocoagulation (argon laser), in which the laser was applied around the tumor to target the tumor vasculature, has given way to thermotherapy (diode laser). Thermotherapy is delivered directly to the tumor surface via infrared wavelengths of light.[4,5]
- Brachytherapy (plaque radiation therapy): For larger tumors that are not amenable to cryotherapy or laser therapy, brachytherapy can provide an effective means for local control (refer to the Radiation Therapy section of this summary for more information).
Systemic Chemotherapy
Systemic chemotherapy plays a role in the following:
- Adjuvant setting for patients with high-risk pathology. Different regimens have been used in the management of patients with high-risk pathology in the enucleated specimen. Most regimens include a three-drug combination of vincristine, etoposide, and carboplatin, either alone or alternating with cyclophosphamide and an anthracycline.[6-9]
- Treatment of patients with extraocular and metastatic disease. Patients with extraocular disease benefit from more intensive therapy. While a standard treatment has not been determined, responses to cisplatin-based regimens, with consolidation with high-dose chemotherapy and autologous hematopoietic stem cell rescue for patients with extraorbital disease, have been reported.[10-13]
- Chemoreductive treatment in conjunction with aggressive local treatment for patients undergoing ocular salvage treatments.
During the past two decades, the standard of care has been systemic chemotherapy to reduce tumor volume (chemoreduction) to facilitate the use of local treatments and to avoid the long-term effects of radiation therapy.[14,15]; [16][Level of evidence: 2Di]; [17][Level of evidence: 3iiA]; [18][Level of evidence: 3iiDiii] The success rate for eye salvage varies from center to center, but overall good ocular outcomes are consistently obtained for discrete tumors without vitreous seeding.[14,15,19,20] Chemotherapy may also be continued or initiated with concurrent local control.[21] Eye grouping as defined by the International Classification of Retinoblastoma is the best predictor of ocular salvage using this approach. In a single-institution, nonrandomized study of 345 patients diagnosed with Group D or E tumors, primary enucleation and adjuvant chemotherapy for high-risk pathology was compared with systemic chemotherapy with or without subsequent enucleation as needed. The incidence of local recurrence and metastasis was less than 1%, regardless of the approach. As opposed to 100% enucleation, subsequent enucleation was performed in only 41% of children who received systemic chemoreduction, none of whom were found to have high-risk pathology in the chemoreduced eye.[22][Level of evidence: 3iiDii] In a retrospective study of Group D eyes that were treated primarily with intravenous chemotherapy and never enucleated, more than 50% of patients had visual acuity of less than 20/200 and 75% of patients had strabismus.[23]
Local tumor recurrence is not uncommon in the first few years after treatment [20] and can often be successfully treated with local therapy.[24] Among patients with heritable disease, younger patients and those with a positive family history are more likely to form new tumors. Chemotherapy may treat small, previously undetected lesions by slowing their growth, and this may improve overall salvage with local therapy.[25]
Ophthalmic Artery Infusion of Chemotherapy (Intra-arterial Chemotherapy)
Direct delivery of chemotherapy into the eye via cannulation of the ophthalmic artery is a feasible and effective method for ocular salvage.
Melphalan is the most common and most effective agent used. It is often combined with topotecan or carboplatin when responses are suboptimal or there is very advanced intraocular disease.[26-30]
For patients with treatment-naive eyes, the 2-year radiation-free ocular survival rate is 86% to 90%.[2,26,28,30,31] Outcome after intra-arterial chemotherapy correlates with the extent of intraocular burden, as follows:
- Group D eyes have a worse outcome, with radiation-free ocular survival rates of 80% for eyes with subretinal seeding and 65% for eyes with vitreous seeding.[32,33] Some centers have reported higher ocular salvage rates for unilateral Group D and E eyes using a three-drug chemotherapy regimen.[2] For patients with very advanced intraocular disease, an alternative treatment is the use of systemic chemotherapy followed by consolidation with intra-arterial melphalan.[34]
- Ocular salvage rates when intra-arterial chemotherapy administration is used as salvage treatment for patients with recurrent or progressive disease are consistently lower, with globe survival rates of 50% to 60%.[28,30-32,35,36] However, the use of a more intensive three-drug regimen with melphalan, topotecan, and carboplatin in patients who have progressed after standard systemic and focal therapies has reported radiation-free ocular salvage rates of 75% at 2 years.[37]
Patients with bilateral disease can undergo tandem intra-arterial administration.[38] In those circumstances, patients are at higher risk of systemic toxicity caused by melphalan exposure,[39] and single-agent carboplatin may be used to treat the less-advanced eye during the tandem procedure.[40] For neonates and very young infants where the cannulization of the ophthalmic artery is not feasible, bridge treatment with single-agent systemic carboplatin until the infant is aged 3 months or weighs 6 kg, followed by consolidation with intra-arterial chemotherapy, has been shown to be very effective, with a 1-year radiation-free ocular survival rate of 95%.[41]
While subretinal seeds can be well controlled with intra-arterial chemotherapy,[36] vitreous seeds may be difficult to control with intra-arterial or intravenous chemotherapy alone. Anterior chamber seeding after intra-arterial or intravenous chemotherapy can occur, as detected clinically in one series of 6 of 12 eyes (50%) and histopathologically in 8 of 12 eyes (67%). This finding suggests that intra-arterial chemotherapy may have greater efficacy in posterior segment disease.[42] The addition of intravitreal chemotherapy to intra-arterial chemotherapy appears to markedly improve the overall effectiveness in eyes with vitreous seeds, especially those with vitreous seed clouds (refer to the Intravitreal Chemotherapy section of this summary for more information).[43,44] Similarly, the addition of intravitreal chemotherapy to intravenous chemotherapy is more effective in the treatment of vitreous seeds; as with primary intra-arterial chemotherapy,[44] control of seed dust, spheres, and clouds require progressively more cycles of intravitreal chemotherapy.[45][Level of evidence: 3iiiDiii]
Complications related to intra-arterial chemotherapy include the following:[31]
- Retinal detachment (up to 19.3%).[46]
- Vitreous hemorrhage (18.1%).
- Ptosis (13.6%).
- Dysmotility (6.5%).
- Vascular and ischemic effects (6.2%).
- Optic atrophy (3.4%).
- Phthisis (2.7%).
Major vascular complications related to the procedure are very rare; no strokes or significant acute neurological events have been reported by the most experienced groups.[28,31,47,48] However, stenosis of the ophthalmic artery and occlusion of the retinal artery have been documented;[48] the risk of thrombosis is significantly increased in children with thrombophilia.[49]
The impact of the intraocular vascular changes on vision has not been fully assessed because of the young age of the first cohorts of patients treated. Most patients do not have substantial electroretinographic changes,[50] and preservation of central vision has been reported.[51] A proportion of patients with abnormal electroretinograms (ERGs) with or without retinal detachment may have improved ERGs in the years after intra-arterial chemotherapy.[52] For 72 eyes with advanced retinoblastoma and baseline ERGs indistinguishable from noise (extinguished) or flicker ERG amplitudes less than 25 µV (poor), ERGs were obtained before ophthalmic artery chemosurgery and at 3 months, 1 year, and 2 years after ophthalmic artery chemosurgery. At 3 months, 1 year, and 2 years after ophthalmic artery chemosurgery, extinguished eyes showed 9 of 15, 4 of 11, and 2 of 6 detectable ERGs, respectively; poor eyes showed 19 of 55, 14 of 30, and 8 of 18 ERGs exceeding 25 μV, respectively.[52] However, in patients with heavily pretreated eyes, intensive intra-arterial chemotherapy may result in worsening of retinal function.[37]
Another risk associated with intra-arterial chemotherapy is the exposure to ionizing radiation during fluoroscopy. Radiation doses per procedure can be as high as 191 mGy to the affected eye and 35 mGy to the contralateral eye,[53] although doses as low as 1 mGy per procedure have been reported.[54] After multiple procedures, cumulative doses can reach 0.1 to 0.2 Gy, which can be cataractogenic and potentially carcinogenic in this susceptible population.[53] There is no increase in the incidence of second malignancies;[47,55] however, longer follow-up will be required to fully ascertain the risks associated with the procedure.
The risk of metastatic progression with direct ocular delivery of chemotherapy appears to be very low;[2] however, up to 20 cases of patients treated with intra-arterial chemotherapy who subsequently developed metastases have been reported.[31]
Intravitreal Chemotherapy
Studies suggest that direct intravitreal injection of melphalan or topotecan may be effective in controlling active vitreous seeds.[56,57]; [58][Level of evidence: 3iiDi]; [59][Level of evidence: 3iiiDiii] A retrospective study of 264 eyes (250 children) treated with intravitreal melphalan for vitreous seeds over a two-decade period reported a 68% complete remission rate. There was a low incidence of extraocular spread that occurred in children with high-risk features.[60][Level of evidence: 3iiD] Because of initial concerns about the potential for tumor dissemination, the use of intravitreal chemotherapy was limited. However, a review calculated that the proportion of patients with extraocular tumor spread, potentially as the result of intravitreal injection, is negligible.[61]
A meta-analysis reported that significant side effects are uncommon, although each injection results in a small decrease in retinal function, as measured by ERG.[62][Level of evidence: 3iiiDiv] The current era of retinoblastoma management using intra-arterial chemotherapy plus intravitreal chemotherapy (as needed for vitreous seeding) has improved globe salvage in eyes with advanced retinoblastoma when compared with children who were treated in earlier years with intra-arterial chemotherapy alone.[43][Level of evidence: 3iiDii] A second study, also performed across different eras (2006–2010 vs. 2011–2016), retrospectively addressed 40 eyes presenting with vitreous seed clouds (class 3 seeds). The children treated in the first era received primary treatment with intra-arterial chemotherapy, while the children treated in the later era received simultaneously both intravitreal and intra-arterial chemotherapy. Compared with the children treated in the earlier era, children treated in the later era demonstrated shorter time to regression, fewer recurrences, fewer enucleations, and no increased toxicity, including no difference in loss of retinal function by ERG.[44][Level of evidence: 3iiDiv] Generally, each dose of intravitreal chemotherapy results in a further small decrement of retinal function, as measured by ERG.[63]
Subtenon Chemotherapy (Subconjunctival Chemotherapy)
Periocular delivery of carboplatin results in high intraocular concentrations of the agent, and this treatment is often used in ocular salvage approaches, particularly when there is a high vitreal tumor burden. Carboplatin is administered by the treating ophthalmologist into the subtenon space, and it is generally used in conjunction with systemic chemotherapy and local ophthalmic therapies for patients with vitreous disease.[64,65] Responses have also been noted with subtenon topotecan.[66]
With the development of new treatments for retinoblastoma, such as intra-arterial and intravitreal delivery of chemotherapy, subtenon chemotherapy is being used less often in the clinical setting.
Radiation Therapy
- EBRT: Retinoblastoma is a very radiosensitive malignancy. EBRT doses ranging from 35 Gy to 46 Gy usually result in long-term remissions. Because of the need to sedate young children and the intricacies of field planning, special expertise in pediatric radiation therapy is important. Radiation therapy is used in cases of progression after conservative approaches, in patients with extraocular extension, and as part of the management of patients with metastatic disease.Newer methods of delivering EBRT are being applied in an attempt to reduce adverse long-term effects. This includes intensity-modulated radiation therapy and proton-beam radiation therapy (charged-particle radiation therapy).[67-70] Preliminary data suggest that proton radiation therapy is associated with a lower risk of radiation-induced malignancy in survivors of heritable retinoblastoma. In a nonrandomized study that compared two contemporary cohorts of patients with heritable retinoblastoma who were treated with either photon or proton radiation therapy, the 10-year cumulative incidence of radiation-induced SNs was significantly different between the two groups (0% for proton radiation vs. 14% for photon radiation, P = .015).[71]EBRT in infants causes growth failure of the orbital bones and results in cosmetic deformity. EBRT also increases the risk of SNs in children with heritable retinoblastoma.
- Brachytherapy (plaque radiation therapy): Indications for plaque radiation therapy include solitary tumors with a diameter ranging between 6 mm and 15 mm, tumor thickness of 10 mm or less, and tumor location of more than 3 mm from the optic disc or fovea. The most commonly used radioisotope is iodine I 125, although others such as iridium Ir 192 and ruthenium Ru 106 are also effective. In combination with appropriate use of chemotherapy and other forms of focal consolidation, brachytherapy can be very effective in the treatment of localized retinal tumors that are not amenable to other means of local therapy.[24,72,73]
Special Considerations for the Treatment of Children with Cancer
Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[74] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach is particularly important in the management of retinoblastoma; this approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will provide optimal survival and quality of life:
- An ophthalmologist with extensive experience in the treatment of children with retinoblastoma.
- Primary care physician.
- Pediatric surgical subspecialists.
- Radiation oncologists.
- Pediatric medical oncologists/hematologists.
- Rehabilitation specialists.
- Pediatric nurse specialists.
- Social workers.
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[75] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and their families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
Dramatic improvements in survival have been achieved for children and adolescents with cancer.[74,76,77] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[74,76,77] Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
References
- Chintagumpala M, Chevez-Barrios P, Paysse EA, et al.: Retinoblastoma: review of current management. Oncologist 12 (10): 1237-46, 2007. [PubMed: 17962617]
- Abramson DH, Fabius AW, Issa R, et al.: Advanced Unilateral Retinoblastoma: The Impact of Ophthalmic Artery Chemosurgery on Enucleation Rate and Patient Survival at MSKCC. PLoS One 10 (12): e0145436, 2015. [PMC free article: PMC4692433] [PubMed: 26709699]
- Kim JW, Kathpalia V, Dunkel IJ, et al.: Orbital recurrence of retinoblastoma following enucleation. Br J Ophthalmol 93 (4): 463-7, 2009. [PubMed: 18757474]
- Shields CL, Santos MC, Diniz W, et al.: Thermotherapy for retinoblastoma. Arch Ophthalmol 117 (7): 885-93, 1999. [PubMed: 10408452]
- Francis JH, Abramson DH, Brodie SE, et al.: Indocyanine green enhanced transpupillary thermotherapy in combination with ophthalmic artery chemosurgery for retinoblastoma. Br J Ophthalmol 97 (2): 164-8, 2013. [PubMed: 23143908]
- Chantada GL, Fandiño AC, Guitter MR, et al.: Results of a prospective study for the treatment of unilateral retinoblastoma. Pediatr Blood Cancer 55 (1): 60-6, 2010. [PubMed: 20486172]
- Aerts I, Sastre-Garau X, Savignoni A, et al.: Results of a multicenter prospective study on the postoperative treatment of unilateral retinoblastoma after primary enucleation. J Clin Oncol 31 (11): 1458-63, 2013. [PubMed: 23460706]
- Kaliki S, Shields CL, Rojanaporn D, et al.: High-risk retinoblastoma based on international classification of retinoblastoma: analysis of 519 enucleated eyes. Ophthalmology 120 (5): 997-1003, 2013. [PubMed: 23399379]
- Sullivan EM, Wilson MW, Billups CA, et al.: Pathologic risk-based adjuvant chemotherapy for unilateral retinoblastoma following enucleation. J Pediatr Hematol Oncol 36 (6): e335-40, 2014. [PMC free article: PMC4108566] [PubMed: 24577551]
- Dunkel IJ, Khakoo Y, Kernan NA, et al.: Intensive multimodality therapy for patients with stage 4a metastatic retinoblastoma. Pediatr Blood Cancer 55 (1): 55-9, 2010. [PubMed: 20486171]
- Matsubara H, Makimoto A, Higa T, et al.: A multidisciplinary treatment strategy that includes high-dose chemotherapy for metastatic retinoblastoma without CNS involvement. Bone Marrow Transplant 35 (8): 763-6, 2005. [PubMed: 15750608]
- Rodriguez-Galindo C, Wilson MW, Haik BG, et al.: Treatment of metastatic retinoblastoma. Ophthalmology 110 (6): 1237-40, 2003. [PubMed: 12799253]
- Kremens B, Wieland R, Reinhard H, et al.: High-dose chemotherapy with autologous stem cell rescue in children with retinoblastoma. Bone Marrow Transplant 31 (4): 281-4, 2003. [PubMed: 12621463]
- Friedman DL, Himelstein B, Shields CL, et al.: Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma. J Clin Oncol 18 (1): 12-7, 2000. [PubMed: 10623688]
- Shields CL, Honavar SG, Meadows AT, et al.: Chemoreduction plus focal therapy for retinoblastoma: factors predictive of need for treatment with external beam radiotherapy or enucleation. Am J Ophthalmol 133 (5): 657-64, 2002. [PubMed: 11992863]
- Friedman DL, Krailo M, Villaluna D, et al.: Systemic neoadjuvant chemotherapy for Group B intraocular retinoblastoma (ARET0331): A report from the Children's Oncology Group. Pediatr Blood Cancer 64 (7): , 2017. [PMC free article: PMC5651987] [PubMed: 28019092]
- Brennan RC, Qaddoumi I, Mao S, et al.: Ocular Salvage and Vision Preservation Using a Topotecan-Based Regimen for Advanced Intraocular Retinoblastoma. J Clin Oncol 35 (1): 72-77, 2017. [PMC free article: PMC5455691] [PubMed: 28034080]
- Shields CL, Palamar M, Sharma P, et al.: Retinoblastoma regression patterns following chemoreduction and adjuvant therapy in 557 tumors. Arch Ophthalmol 127 (3): 282-90, 2009. [PubMed: 19273791]
- Rodriguez-Galindo C, Wilson MW, Haik BG, et al.: Treatment of intraocular retinoblastoma with vincristine and carboplatin. J Clin Oncol 21 (10): 2019-25, 2003. [PubMed: 12743157]
- Shields CL, Mashayekhi A, Cater J, et al.: Chemoreduction for retinoblastoma. Analysis of tumor control and risks for recurrence in 457 tumors. Am J Ophthalmol 138 (3): 329-37, 2004. [PubMed: 15364213]
- Lumbroso L, Doz F, Urbieta M, et al.: Chemothermotherapy in the management of retinoblastoma. Ophthalmology 109 (6): 1130-6, 2002. [PubMed: 12045055]
- Berry JL, Kogachi K, Aziz HA, et al.: Risk of metastasis and orbital recurrence in advanced retinoblastoma eyes treated with systemic chemoreduction versus primary enucleation. Pediatr Blood Cancer 64 (4): , 2017. [PMC free article: PMC7034314] [PubMed: 28221729]
- Fabian ID, Naeem Z, Stacey AW, et al.: Long-term Visual Acuity, Strabismus, and Nystagmus Outcomes Following Multimodality Treatment in Group D Retinoblastoma Eyes. Am J Ophthalmol 179: 137-144, 2017. [PubMed: 28501391]
- Shields CL, Mashayekhi A, Sun H, et al.: Iodine 125 plaque radiotherapy as salvage treatment for retinoblastoma recurrence after chemoreduction in 84 tumors. Ophthalmology 113 (11): 2087-92, 2006. [PubMed: 16949158]
- Wilson MW, Haik BG, Billups CA, et al.: Incidence of new tumor formation in patients with hereditary retinoblastoma treated with primary systemic chemotherapy: is there a preventive effect? Ophthalmology 114 (11): 2077-82, 2007. [PubMed: 17628684]
- Abramson DH, Dunkel IJ, Brodie SE, et al.: Superselective ophthalmic artery chemotherapy as primary treatment for retinoblastoma (chemosurgery). Ophthalmology 117 (8): 1623-9, 2010. [PubMed: 20381868]
- Francis JH, Gobin YP, Dunkel IJ, et al.: Carboplatin +/- topotecan ophthalmic artery chemosurgery for intraocular retinoblastoma. PLoS One 8 (8): e72441, 2013. [PMC free article: PMC3749169] [PubMed: 23991112]
- Gobin YP, Dunkel IJ, Marr BP, et al.: Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience. Arch Ophthalmol 129 (6): 732-7, 2011. [PubMed: 21320950]
- Abramson DH, Marr BP, Brodie SE, et al.: Ophthalmic artery chemosurgery for less advanced intraocular retinoblastoma: five year review. PLoS One 7 (4): e34120, 2012. [PMC free article: PMC3335846] [PubMed: 22545080]
- Schaiquevich P, Ceciliano A, Millan N, et al.: Intra-arterial chemotherapy is more effective than sequential periocular and intravenous chemotherapy as salvage treatment for relapsed retinoblastoma. Pediatr Blood Cancer 60 (5): 766-70, 2013. [PubMed: 23024125]
- Yousef YA, Soliman SE, Astudillo PP, et al.: Intra-arterial Chemotherapy for Retinoblastoma: A Systematic Review. JAMA Ophthalmol : , 2016. [PubMed: 26986443]
- Abramson DH, Marr BP, Dunkel IJ, et al.: Intra-arterial chemotherapy for retinoblastoma in eyes with vitreous and/or subretinal seeding: 2-year results. Br J Ophthalmol 96 (4): 499-502, 2012. [PubMed: 22053101]
- Abramson DH, Daniels AB, Marr BP, et al.: Intra-Arterial Chemotherapy (Ophthalmic Artery Chemosurgery) for Group D Retinoblastoma. PLoS One 11 (1): e0146582, 2016. [PMC free article: PMC4710506] [PubMed: 26756643]
- Shields CL, Kaliki S, Al-Dahmash S, et al.: Management of advanced retinoblastoma with intravenous chemotherapy then intra-arterial chemotherapy as alternative to enucleation. Retina 33 (10): 2103-9, 2013 Nov-Dec. [PubMed: 23873161]
- Shields CL, Bianciotto CG, Jabbour P, et al.: Intra-arterial chemotherapy for retinoblastoma: report No. 1, control of retinal tumors, subretinal seeds, and vitreous seeds. Arch Ophthalmol 129 (11): 1399-406, 2011. [PubMed: 21670328]
- Say EA, Iyer PG, Hasanreisoglu M, et al.: Secondary and tertiary intra-arterial chemotherapy for massive persistent or recurrent subretinal retinoblastoma seeds following previous chemotherapy exposure: long-term tumor control and globe salvage in 30 eyes. J AAPOS 20 (4): 337-42, 2016. [PubMed: 27328850]
- Marr BP, Brodie SE, Dunkel IJ, et al.: Three-drug intra-arterial chemotherapy using simultaneous carboplatin, topotecan and melphalan for intraocular retinoblastoma: preliminary results. Br J Ophthalmol 96 (10): 1300-3, 2012. [PubMed: 22863945]
- Abramson DH, Marr BP, Francis JH, et al.: Simultaneous Bilateral Ophthalmic Artery Chemosurgery for Bilateral Retinoblastoma (Tandem Therapy). PLoS One 11 (6): e0156806, 2016. [PMC free article: PMC4892546] [PubMed: 27258771]
- Schaiquevich P, Buitrago E, Taich P, et al.: Pharmacokinetic analysis of melphalan after superselective ophthalmic artery infusion in preclinical models and retinoblastoma patients. Invest Ophthalmol Vis Sci 53 (7): 4205-12, 2012. [PubMed: 22628208]
- Francis JH, Gobin YP, Brodie SE, et al.: Experience of intra-arterial chemosurgery with single agent carboplatin for retinoblastoma. Br J Ophthalmol 96 (9): 1270-1, 2012. [PubMed: 22611138]
- Gobin YP, Dunkel IJ, Marr BP, et al.: Combined, sequential intravenous and intra-arterial chemotherapy (bridge chemotherapy) for young infants with retinoblastoma. PLoS One 7 (9): e44322, 2012. [PMC free article: PMC3445577] [PubMed: 23028521]
- Pavlidou E, Burris C, Thaung C, et al.: Anterior Segment Seeding in Eyes With Retinoblastoma Failing to Respond to Intraophthalmic Artery Chemotherapy. JAMA Ophthalmol 133 (12): 1455-8, 2015. [PubMed: 26334520]
- Shields CL, Alset AE, Say EA, et al.: Retinoblastoma Control With Primary Intra-arterial Chemotherapy: Outcomes Before and During the Intravitreal Chemotherapy Era. J Pediatr Ophthalmol Strabismus 53 (5): 275-84, 2016. [PubMed: 27486728]
- Francis JH, Iyer S, Gobin YP, et al.: Retinoblastoma Vitreous Seed Clouds (Class 3): A Comparison of Treatment with Ophthalmic Artery Chemosurgery with or without Intravitreous and Periocular Chemotherapy. Ophthalmology 124 (10): 1548-1555, 2017. [PubMed: 28545735]
- Berry JL, Bechtold M, Shah S, et al.: Not All Seeds Are Created Equal: Seed Classification Is Predictive of Outcomes in Retinoblastoma. Ophthalmology 124 (12): 1817-1825, 2017. [PubMed: 28655537]
- Shields CL, Say EAT, Pefkianaki M, et al.: RHEGMATOGENOUS RETINAL DETACHMENT AFTER INTRAARTERIAL CHEMOTHERAPY FOR RETINOBLASTOMA: The 2016 Founders Award Lecture. Retina 37 (8): 1441-1450, 2017. [PubMed: 27787452]
- Suzuki S, Yamane T, Mohri M, et al.: Selective ophthalmic arterial injection therapy for intraocular retinoblastoma: the long-term prognosis. Ophthalmology 118 (10): 2081-7, 2011. [PubMed: 21715012]
- Shields CL, Bianciotto CG, Jabbour P, et al.: Intra-arterial chemotherapy for retinoblastoma: report No. 2, treatment complications. Arch Ophthalmol 129 (11): 1407-15, 2011. [PubMed: 21670326]
- Francis JH, Gobin YP, Nagiel A, et al.: Thrombophilia in patients with retinoblastoma receiving ophthalmic artery chemosurgery. Arch Ophthalmol 130 (12): 1605-8, 2012. [PubMed: 23229706]
- Abramson DH: Chemosurgery for retinoblastoma: what we know after 5 years. Arch Ophthalmol 129 (11): 1492-4, 2011. [PubMed: 22084221]
- Brodie SE, Munier FL, Francis JH, et al.: Persistence of retinal function after intravitreal melphalan injection for retinoblastoma. Doc Ophthalmol 126 (1): 79-84, 2013. [PubMed: 23143758]
- Abdelhakim AH, Francis JH, Marr BP, et al.: Retinal reattachment and ERG recovery after ophthalmic artery chemosurgery for advanced retinoblastoma in eyes with minimal baseline retinal function. Br J Ophthalmol 101 (5): 623-628, 2017. [PMC free article: PMC5637273] [PubMed: 27539090]
- Vijayakrishnan R, Shields CL, Ramasubramanian A, et al.: Irradiation toxic effects during intra-arterial chemotherapy for retinoblastoma: should we be concerned? Arch Ophthalmol 128 (11): 1427-31, 2010. [PubMed: 21060044]
- Gobin YP, Rosenstein LM, Marr BP, et al.: Radiation exposure during intra-arterial chemotherapy for retinoblastoma. Arch Ophthalmol 130 (3): 403-4; author reply 404-5, 2012. [PubMed: 22411679]
- Habib LA, Francis JH, Fabius AW, et al.: Second primary malignancies in retinoblastoma patients treated with intra-arterial chemotherapy: the first 10 years. Br J Ophthalmol 102 (2): 272-275, 2018. [PubMed: 28600304]
- Francis JH, Abramson DH, Gaillard MC, et al.: The classification of vitreous seeds in retinoblastoma and response to intravitreal melphalan. Ophthalmology 122 (6): 1173-9, 2015. [PubMed: 25795478]
- Shields CL, Manjandavida FP, Arepalli S, et al.: Intravitreal melphalan for persistent or recurrent retinoblastoma vitreous seeds: preliminary results. JAMA Ophthalmol 132 (3): 319-25, 2014. [PubMed: 24407202]
- Ghassemi F, Shields CL: Intravitreal melphalan for refractory or recurrent vitreous seeding from retinoblastoma. Arch Ophthalmol 130 (10): 1268-71, 2012. [PubMed: 23044940]
- Munier FL, Gaillard MC, Balmer A, et al.: Intravitreal chemotherapy for vitreous disease in retinoblastoma revisited: from prohibition to conditional indications. Br J Ophthalmol 96 (8): 1078-83, 2012. [PubMed: 22694968]
- Suzuki S, Aihara Y, Fujiwara M, et al.: Intravitreal injection of melphalan for intraocular retinoblastoma. Jpn J Ophthalmol 59 (3): 164-72, 2015. [PubMed: 25808017]
- Smith SJ, Smith BD: Evaluating the risk of extraocular tumour spread following intravitreal injection therapy for retinoblastoma: a systematic review. Br J Ophthalmol 97 (10): 1231-6, 2013. [PubMed: 23740960]
- Smith SJ, Smith BD, Mohney BG: Ocular side effects following intravitreal injection therapy for retinoblastoma: a systematic review. Br J Ophthalmol 98 (3): 292-7, 2014. [PubMed: 24187047]
- Francis JH, Brodie SE, Marr B, et al.: Efficacy and Toxicity of Intravitreous Chemotherapy for Retinoblastoma: Four-Year Experience. Ophthalmology 124 (4): 488-495, 2017. [PMC free article: PMC5441308] [PubMed: 28089679]
- Abramson DH, Frank CM, Dunkel IJ: A phase I/II study of subconjunctival carboplatin for intraocular retinoblastoma. Ophthalmology 106 (10): 1947-50, 1999. [PubMed: 10519590]
- Marr BP, Dunkel IJ, Linker A, et al.: Periocular carboplatin for retinoblastoma: long-term report (12 years) on efficacy and toxicity. Br J Ophthalmol 96 (6): 881-3, 2012. [PubMed: 22328819]
- Mallipatna AC, Dimaras H, Chan HS, et al.: Periocular topotecan for intraocular retinoblastoma. Arch Ophthalmol 129 (6): 738-45, 2011. [PubMed: 21670340]
- Krasin MJ, Crawford BT, Zhu Y, et al.: Intensity-modulated radiation therapy for children with intraocular retinoblastoma: potential sparing of the bony orbit. Clin Oncol (R Coll Radiol) 16 (3): 215-22, 2004. [PubMed: 15191011]
- Reisner ML, Viégas CM, Grazziotin RZ, et al.: Retinoblastoma--comparative analysis of external radiotherapy techniques, including an IMRT technique. Int J Radiat Oncol Biol Phys 67 (3): 933-41, 2007. [PubMed: 17293242]
- Lee CT, Bilton SD, Famiglietti RM, et al.: Treatment planning with protons for pediatric retinoblastoma, medulloblastoma, and pelvic sarcoma: how do protons compare with other conformal techniques? Int J Radiat Oncol Biol Phys 63 (2): 362-72, 2005. [PubMed: 16168831]
- Mouw KW, Sethi RV, Yeap BY, et al.: Proton radiation therapy for the treatment of retinoblastoma. Int J Radiat Oncol Biol Phys 90 (4): 863-9, 2014. [PMC free article: PMC4253018] [PubMed: 25227498]
- Sethi RV, Shih HA, Yeap BY, et al.: Second nonocular tumors among survivors of retinoblastoma treated with contemporary photon and proton radiotherapy. Cancer 120 (1): 126-33, 2014. [PMC free article: PMC3959122] [PubMed: 24122173]
- Shields CL, Shields JA, Cater J, et al.: Plaque radiotherapy for retinoblastoma: long-term tumor control and treatment complications in 208 tumors. Ophthalmology 108 (11): 2116-21, 2001. [PubMed: 11713089]
- Merchant TE, Gould CJ, Wilson MW, et al.: Episcleral plaque brachytherapy for retinoblastoma. Pediatr Blood Cancer 43 (2): 134-9, 2004. [PubMed: 15236279]
- Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PMC free article: PMC4136455] [PubMed: 24853691]
- Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004. [PubMed: 15173520]
- Childhood cancer. In: Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2010. Bethesda, Md: National Cancer Institute, 2013, Section 28. Also available online. Last accessed January 31, 2019.
- Childhood cancer by the ICCC. In: Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2010. Bethesda, Md: National Cancer Institute, 2013, Section 29. Also available online. Last accessed January 31, 2019.
Treatment of Intraocular Retinoblastoma
Treatment Options for Unilateral Intraocular Retinoblastoma
Treatment options for unilateral intraocular retinoblastoma include the following:
- Conservative ocular salvage approaches when the eye and vision can be saved.
- Chemoreduction with either systemic or ophthalmic artery infusion chemotherapy with or without intravitreal chemotherapy.
- Local treatments, including cryotherapy, thermotherapy, and plaque radiation therapy.
Enucleation followed by chemotherapy
Because unilateral disease is usually massive and often there is no expectation that useful vision can be preserved, up-front surgery (enucleation) is commonly performed. Careful examination of the enucleated specimen by an experienced pathologist is necessary to determine whether high-risk features for metastatic disease are present. These high-risk features include the following:[1-5]
- Anterior chamber seeding.
- Massive choroidal involvement.
- Tumor beyond the lamina cribrosa.
- Scleral and extrascleral extension.
Pre-enucleation magnetic resonance imaging has low sensitivity and specificity for the detection of high-risk pathology.[6]
High-risk pathology has been associated with the presence of minimal dissemination in bone marrow and cerebrospinal fluid using quantitative polymerase chain reaction for detection of cone-rod homeobox (CRX) or GD2 synthase. In a group of 96 children with nonmetastatic retinoblastoma and high-risk pathology, the 3-year disease-free survival was 78% for patients with detectable minimal dissemination, compared with 98% for those without detectable disease (P = .004).[7]
Systemic adjuvant therapy with vincristine, doxorubicin, and cyclophosphamide or with vincristine, carboplatin, and etoposide has been used to prevent the development of metastatic disease in patients with certain high-risk features assessed by pathologic review after enucleation.[3,8,9]; [10][Level of evidence: 2A]
Conservative ocular salvage approaches
Conservative ocular salvage approaches, such as systemic chemotherapy and local-control treatments, may be offered in an attempt to save the eye and preserve vision.[11] Ocular salvage rates correlate with intraocular grouping. While the possibility of saving the eye without the use of external-beam radiation therapy (EBRT) exceeds 80% for children with early intraocular disease, the ocular outcomes for children with advanced intraocular disease are poor, with less than 40% ocular salvage rates, even after the use of EBRT.[12]
Thus, caution must be exerted with extended systemic chemotherapy administration and delayed enucleation when tumor control does not appear to be possible, particularly for Group E eyes. Pre-enucleation chemotherapy for eyes with advanced intraocular disease may result in downstaging and underestimate the pathological evidence of extraretinal and extraocular disease, thus increasing the risk of dissemination.[13]
The delivery of chemotherapy via ophthalmic artery cannulation as initial treatment for advanced unilateral retinoblastoma appears to be more effective than does systemic chemotherapy for chemoreduction, particularly for Group D eyes.[14,15]; [16][Level of evidence: 3iiDiv] In the setting of a multidisciplinary state-of-the-art center, intra-arterial chemotherapy may result in ocular salvage rates of approximately 80% to 90% for patients with advanced intraocular unilateral retinoblastoma.[15-17]; [18,19][Level of evidence: 3iiiDii]; [20][Level of evidence: 3iiiDiv] (Refer to the Ophthalmic Artery Infusion of Chemotherapy [Intra-arterial Chemotherapy] section of this summary for more information.)
Because a proportion of children who present with unilateral retinoblastoma will eventually develop disease in the opposite eye, these children undergo genetic counseling and testing and periodic examinations of the unaffected eye, regardless of the treatment they receive. Asynchronous bilateral disease occurs most frequently in patients with affected parents and in children diagnosed during the first months of life.
Treatment Options for Bilateral Intraocular Retinoblastoma
Treatment options for bilateral intraocular retinoblastoma include the following:
- Enucleation for large intraocular tumors, followed by risk-adapted chemotherapy when the eye and vision cannot be saved.
- Conservative ocular salvage approaches when the eye and vision can be saved.
- Chemoreduction with either systemic or ophthalmic artery infusion chemotherapy with or without intravitreal chemotherapy.
- Local treatments, including cryotherapy, thermotherapy, and plaque radiation therapy.
- EBRT.
The goal of therapy for bilateral retinoblastoma is ocular and vision preservation and the delay or avoidance of EBRT and enucleation. Intraocular tumor burden is usually asymmetric, and treatment is dictated by the most advanced eye. Systemic therapy is generally selected on the basis of the eye with more extensive disease. Treatment options described for unilateral disease may be applied to one or both affected eyes in patients with bilateral disease. While up-front enucleation of an advanced eye and risk-adapted adjuvant chemotherapy may be required, a more conservative approach using primary chemoreduction with close monitoring for response and aggressive local treatment is usually the treatment of choice. EBRT is now reserved for patients whose eyes do not respond adequately to primary systemic or intra-arterial chemotherapy and local consolidation.[21]
A number of large centers have published trial results that used systemic chemotherapy in conjunction with aggressive local consolidation for patients with bilateral disease.[11,22- 30] The backbone of the chemoreduction has generally been carboplatin, etoposide, and vincristine. While the less toxic combination of vincristine and carboplatin can provide disease control for a significant proportion of patients,[26] ocular salvage appears to be superior when etoposide is included in the regimen.[31][Level of evidence: 1iiDiii] Similar results were achieved in one single-institution study when topotecan was substituted for etoposide in a combination regimen.[32][Level of evidence: 3iiA] Chemotherapy shrinks the tumors (chemoreduction), allowing greater efficacy of subsequent local therapy.[11] Treatment strategies often differ in terms of chemotherapy regimens and local control measures. Using this approach, the International Classification of Retinoblastoma grouping system has been proven to predict ocular salvage.[33,34]; [35][Level of evidence: 3iiDiv]
- Groups C and D: Ocular salvage rates using this approach are 70% to 90% for Group C eyes and 40% to 50% for Group D eyes.[34-36] However, for patients with more advanced intraocular disease (typically Group D eyes), EBRT is frequently required for ocular salvage.[35]; [36][Level of evidence: 3iiDiii]For patients with large intraocular tumor burden with subretinal or vitreous seeds (Groups D eyes), the administration of higher doses of carboplatin, coupled with subtenon carboplatin, and the addition of lower doses of EBRT (36 Gy) for patients with persistent disease have been explored. Using this intensive approach, eye survival may approach a rate of 70% at 60 months.[37][Level of evidence: 2Div]
- Group E: The treatment for Group E eyes is usually up-front enucleation. The use of prolonged systemic chemotherapy for Group E eyes to avoid or delay enucleation has been associated with lower disease-specific survival.[13][Level of evidence: 3iiiB]
Delivery of chemotherapy via ophthalmic artery cannulation has also been shown to be feasible and effective as tandem administration and in the salvage setting in patients with newly diagnosed bilateral disease.[18,19,38,39][Level of evidence: 3iiDii] Bilateral administrations increase the risk of systemic toxicity caused by melphalan exposure.[40] In these circumstances, intra-arterial chemotherapy with single-agent carboplatin may be used to treat the less-advanced eye during the tandem procedure.[41] These treatments should only be performed in an experienced center with a state-of-the-art treatment infrastructure and a dedicated multidisciplinary team.
Treatment Options for Cavitary Retinoblastoma
Treatment options for cavitary retinoblastoma include the following:
- Systemic and/or intra-arterial chemotherapy.
In patients with cavitary retinoblastoma, minimal visual response is seen after intravenous chemotherapy and/or intra-arterial chemotherapy. Despite the blunted clinical response, cavitary retinoblastoma has a favorable long-term outcome, with stable tumor regression and globe salvage. Aggressive or prolonged chemotherapy or adjunctive therapies are generally not necessary. In a retrospective series of 26 cavitary retinoblastomas that were treated with intravenous chemoreduction and/or intra-arterial chemotherapy, the mean reduction in tumor base was 22%, and the mean reduction in tumor thickness was 29%. Despite minimal reduction, tumor recurrence was noted in only one eye, globe salvage was achieved in 22 eyes, and there were no cases of metastasis or death during 49 months (range, 6–189 months) of follow-up.[42]
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
- Chantada GL, Guitter MR, Fandiño AC, et al.: Treatment results in patients with retinoblastoma and invasion to the cut end of the optic nerve. Pediatr Blood Cancer 52 (2): 218-22, 2009. [PubMed: 18937327]
- Eagle RC Jr: High-risk features and tumor differentiation in retinoblastoma: a retrospective histopathologic study. Arch Pathol Lab Med 133 (8): 1203-9, 2009. [PubMed: 19653710]
- Aerts I, Sastre-Garau X, Savignoni A, et al.: Results of a multicenter prospective study on the postoperative treatment of unilateral retinoblastoma after primary enucleation. J Clin Oncol 31 (11): 1458-63, 2013. [PubMed: 23460706]
- Kaliki S, Shields CL, Rojanaporn D, et al.: High-risk retinoblastoma based on international classification of retinoblastoma: analysis of 519 enucleated eyes. Ophthalmology 120 (5): 997-1003, 2013. [PubMed: 23399379]
- Sastre X, Chantada GL, Doz F, et al.: Proceedings of the consensus meetings from the International Retinoblastoma Staging Working Group on the pathology guidelines for the examination of enucleated eyes and evaluation of prognostic risk factors in retinoblastoma. Arch Pathol Lab Med 133 (8): 1199-202, 2009. [PubMed: 19653709]
- Chawla B, Sharma S, Sen S, et al.: Correlation between clinical features, magnetic resonance imaging, and histopathologic findings in retinoblastoma: a prospective study. Ophthalmology 119 (4): 850-6, 2012. [PubMed: 22218144]
- Laurent VE, Torbidoni AV, Sampor C, et al.: Minimal Disseminated Disease in Nonmetastatic Retinoblastoma With High-Risk Pathologic Features and Association With Disease-Free Survival. JAMA Ophthalmol 134 (12): 1374-1379, 2016. [PubMed: 27787537]
- Chantada GL, Dunkel IJ, de Dávila MT, et al.: Retinoblastoma patients with high risk ocular pathological features: who needs adjuvant therapy? Br J Ophthalmol 88 (8): 1069-73, 2004. [PMC free article: PMC1772257] [PubMed: 15258027]
- Cuenca A, Giron F, Castro D, et al.: Microscopic scleral invasion in retinoblastoma: clinicopathological features and outcome. Arch Ophthalmol 127 (8): 1006-10, 2009. [PubMed: 19667337]
- Chantada GL, Fandiño AC, Guitter MR, et al.: Results of a prospective study for the treatment of unilateral retinoblastoma. Pediatr Blood Cancer 55 (1): 60-6, 2010. [PubMed: 20486172]
- Shields CL, Honavar SG, Meadows AT, et al.: Chemoreduction plus focal therapy for retinoblastoma: factors predictive of need for treatment with external beam radiotherapy or enucleation. Am J Ophthalmol 133 (5): 657-64, 2002. [PubMed: 11992863]
- Shields CL, Honavar SG, Meadows AT, et al.: Chemoreduction for unilateral retinoblastoma. Arch Ophthalmol 120 (12): 1653-8, 2002. [PubMed: 12470138]
- Zhao J, Dimaras H, Massey C, et al.: Pre-enucleation chemotherapy for eyes severely affected by retinoblastoma masks risk of tumor extension and increases death from metastasis. J Clin Oncol 29 (7): 845-51, 2011. [PubMed: 21282531]
- Abramson DH, Fabius AW, Issa R, et al.: Advanced Unilateral Retinoblastoma: The Impact of Ophthalmic Artery Chemosurgery on Enucleation Rate and Patient Survival at MSKCC. PLoS One 10 (12): e0145436, 2015. [PMC free article: PMC4692433] [PubMed: 26709699]
- Munier FL, Mosimann P, Puccinelli F, et al.: First-line intra-arterial versus intravenous chemotherapy in unilateral sporadic group D retinoblastoma: evidence of better visual outcomes, ocular survival and shorter time to success with intra-arterial delivery from retrospective review of 20 years of treatment. Br J Ophthalmol 101 (8): 1086-1093, 2017. [PMC free article: PMC5537510] [PubMed: 27927678]
- Shields CL, Jorge R, Say EA, et al.: Unilateral Retinoblastoma Managed With Intravenous Chemotherapy Versus Intra-Arterial Chemotherapy. Outcomes Based on the International Classification of Retinoblastoma. Asia Pac J Ophthalmol (Phila) 5 (2): 97-103, 2016 Mar-Apr. [PubMed: 26765038]
- Abramson DH, Marr BP, Brodie SE, et al.: Ophthalmic artery chemosurgery for less advanced intraocular retinoblastoma: five year review. PLoS One 7 (4): e34120, 2012. [PMC free article: PMC3335846] [PubMed: 22545080]
- Abramson DH, Dunkel IJ, Brodie SE, et al.: Superselective ophthalmic artery chemotherapy as primary treatment for retinoblastoma (chemosurgery). Ophthalmology 117 (8): 1623-9, 2010. [PubMed: 20381868]
- Gobin YP, Dunkel IJ, Marr BP, et al.: Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience. Arch Ophthalmol 129 (6): 732-7, 2011. [PubMed: 21320950]
- Peterson EC, Elhammady MS, Quintero-Wolfe S, et al.: Selective ophthalmic artery infusion of chemotherapy for advanced intraocular retinoblastoma: initial experience with 17 tumors. J Neurosurg 114 (6): 1603-8, 2011. [PubMed: 21294621]
- Orman A, Koru-Sengul T, Miao F, et al.: The modern role of radiation therapy in treating advanced-stage retinoblastoma: long-term outcomes and racial differences. Int J Radiat Oncol Biol Phys 90 (5): 1037-43, 2014. [PubMed: 25442037]
- Beck MN, Balmer A, Dessing C, et al.: First-line chemotherapy with local treatment can prevent external-beam irradiation and enucleation in low-stage intraocular retinoblastoma. J Clin Oncol 18 (15): 2881-7, 2000. [PubMed: 10920136]
- Murphree AL, Villablanca JG, Deegan WF 3rd, et al.: Chemotherapy plus local treatment in the management of intraocular retinoblastoma. Arch Ophthalmol 114 (11): 1348-56, 1996. [PubMed: 8906025]
- Shields CL, Mashayekhi A, Cater J, et al.: Chemoreduction for retinoblastoma. Analysis of tumor control and risks for recurrence in 457 tumors. Am J Ophthalmol 138 (3): 329-37, 2004. [PubMed: 15364213]
- Gallie BL, Budning A, DeBoer G, et al.: Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol 114 (11): 1321-8, 1996. [PubMed: 8906022]
- Rodriguez-Galindo C, Wilson MW, Haik BG, et al.: Treatment of intraocular retinoblastoma with vincristine and carboplatin. J Clin Oncol 21 (10): 2019-25, 2003. [PubMed: 12743157]
- Wilson MW, Haik BG, Billups CA, et al.: Incidence of new tumor formation in patients with hereditary retinoblastoma treated with primary systemic chemotherapy: is there a preventive effect? Ophthalmology 114 (11): 2077-82, 2007. [PubMed: 17628684]
- Rodriguez-Galindo C, Chantada GL, Haik BG, et al.: Treatment of retinoblastoma: current status and future perspectives. Curr Treat Options Neurol 9 (4): 294-307, 2007. [PubMed: 17580009]
- Shields CL, Mashayekhi A, Cater J, et al.: Macular retinoblastoma managed with chemoreduction: analysis of tumor control with or without adjuvant thermotherapy in 68 tumors. Arch Ophthalmol 123 (6): 765-73, 2005. [PubMed: 15955977]
- Qaddoumi I, Billups CA, Tagen M, et al.: Topotecan and vincristine combination is effective against advanced bilateral intraocular retinoblastoma and has manageable toxicity. Cancer 118 (22): 5663-70, 2012. [PMC free article: PMC3413782] [PubMed: 22516936]
- Lumbroso-Le Rouic L, Aerts I, Hajage D, et al.: Conservative treatment of retinoblastoma: a prospective phase II randomized trial of neoadjuvant chemotherapy followed by local treatments and chemothermotherapy. Eye (Lond) 30 (1): 46-52, 2016. [PMC free article: PMC4709527] [PubMed: 26427984]
- Brennan RC, Qaddoumi I, Mao S, et al.: Ocular Salvage and Vision Preservation Using a Topotecan-Based Regimen for Advanced Intraocular Retinoblastoma. J Clin Oncol 35 (1): 72-77, 2017. [PMC free article: PMC5455691] [PubMed: 28034080]
- Zage PE, Reitman AJ, Seshadri R, et al.: Outcomes of a two-drug chemotherapy regimen for intraocular retinoblastoma. Pediatr Blood Cancer 50 (3): 567-72, 2008. [PubMed: 17729249]
- Shields CL, Mashayekhi A, Au AK, et al.: The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology 113 (12): 2276-80, 2006. [PubMed: 16996605]
- Lumbroso-Le Rouic L, Aerts I, Lévy-Gabriel C, et al.: Conservative treatments of intraocular retinoblastoma. Ophthalmology 115 (8): 1405-10, 1410.e1-2, 2008. [PubMed: 18222001]
- Cohen VM, Kingston J, Hungerford JL: The success of primary chemotherapy for group D heritable retinoblastoma. Br J Ophthalmol 93 (7): 887-90, 2009. [PubMed: 18703556]
- Berry JL, Jubran R, Kim JW, et al.: Long-term outcomes of Group D eyes in bilateral retinoblastoma patients treated with chemoreduction and low-dose IMRT salvage. Pediatr Blood Cancer 60 (4): 688-93, 2013. [PubMed: 22997170]
- Abramson DH, Dunkel IJ, Brodie SE, et al.: Bilateral superselective ophthalmic artery chemotherapy for bilateral retinoblastoma: tandem therapy. Arch Ophthalmol 128 (3): 370-2, 2010. [PubMed: 20212212]
- Palioura S, Gobin YP, Brodie SE, et al.: Ophthalmic artery chemosurgery for the management of retinoblastoma in eyes with extensive (>50%) retinal detachment. Pediatr Blood Cancer 59 (5): 859-64, 2012. [PubMed: 22492689]
- Schaiquevich P, Buitrago E, Taich P, et al.: Pharmacokinetic analysis of melphalan after superselective ophthalmic artery infusion in preclinical models and retinoblastoma patients. Invest Ophthalmol Vis Sci 53 (7): 4205-12, 2012. [PubMed: 22628208]
- Francis JH, Gobin YP, Brodie SE, et al.: Experience of intra-arterial chemosurgery with single agent carboplatin for retinoblastoma. Br J Ophthalmol 96 (9): 1270-1, 2012. [PubMed: 22611138]
- Rojanaporn D, Kaliki S, Bianciotto CG, et al.: Intravenous chemoreduction or intra-arterial chemotherapy for cavitary retinoblastoma: long-term results. Arch Ophthalmol 130 (5): 585-90, 2012. [PubMed: 22652844]
Treatment of Extraocular Retinoblastoma
In high-income countries, few patients with retinoblastoma present with extraocular disease. Extraocular disease may be localized to the soft tissues surrounding the eye or to the optic nerve beyond the margin of resection. However, further extension may progress into the brain and meninges, with subsequent seeding of the spinal fluid and as distant metastatic disease involving the lungs, bones, and bone marrow.
Treatment Options for Extraocular Retinoblastoma
Orbital and locoregional retinoblastoma
Treatment options for extraocular retinoblastoma (orbital and locoregional) include the following:
- Chemotherapy.
- Radiation therapy.
Orbital retinoblastoma occurs as a result of progression of the tumor through the emissary vessels and sclera. For this reason, transscleral disease is considered to be extraocular and should be treated as such. Orbital retinoblastoma is isolated in 60% to 70% of cases.
Treatment includes systemic chemotherapy and radiation therapy; with this approach, 60% to 85% of patients can be cured. Because most recurrences occur in the central nervous system (CNS), regimens using drugs with well-documented CNS penetration are used. Different chemotherapy regimens have proven to be effective, including vincristine, cyclophosphamide, and doxorubicin and platinum- and epipodophyllotoxin-based regimens, or a combination of both.[1-3]
For patients with macroscopic orbital disease, delay of surgery until response to chemotherapy is achieved (usually two or three courses of treatment) has been effective. Patients then undergo enucleation and receive an additional four to six courses of chemotherapy. Next, local control is consolidated with orbital irradiation (40 Gy to 45 Gy). Using this approach, orbital exenteration is not indicated.[3]
Patients with isolated involvement of the optic nerve at the transsection level are considered to have extraocular disease and are treated using systemic therapy, similar to that used for macroscopic orbital disease, and irradiation of the entire orbit (36 Gy) with a 10 Gy boost to the chiasm (total of 46 Gy).[2]
CNS disease
Treatment options for extraocular retinoblastoma (CNS disease) include the following:
- Systemic chemotherapy and CNS-directed therapy.
- Systemic chemotherapy followed by myeloablative chemotherapy and stem cell rescue.
Intracranial dissemination occurs by direct extension through the optic nerve, and its prognosis is dismal. Treatment for these patients includes platinum-based, intensive systemic chemotherapy and CNS-directed therapy. Although intrathecal chemotherapy has been used traditionally, there is no preclinical or clinical evidence to support its use. The administration of radiation therapy to these patients is controversial. Responses have been observed with craniospinal radiation using 25 Gy to 35 Gy to the entire craniospinal axis and a boost (10 Gy) to sites of measurable 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.[4][Level of evidence: 3iiA]
Trilateral retinoblastoma
Treatment options for trilateral retinoblastoma include the following:
- Systemic chemotherapy followed by surgery and myeloablative chemotherapy with stem cell rescue.
- Systemic chemotherapy followed by surgery and radiation therapy.
Trilateral retinoblastoma is usually associated with a pineal lesion or, less commonly, a suprasellar lesion.[5-7] In patients with the heritable form of retinoblastoma, CNS disease is less likely the result of metastatic or regional spread than of a primary intracranial focus, such as a pineal tumor. The prognosis for patients with trilateral retinoblastoma is very poor; most patients die of disseminated neuraxis disease in less than 9 months.[8,9] However, with increased surveillance and aggressive therapy, there has been improvement in survival, from 6% (patients treated before 1995) to 44% (patients treated after 1996).[10]
While pineoblastomas occurring in older patients are sensitive to radiation therapy, current strategies are directed towards avoiding radiation by using intensive chemotherapy followed by consolidation with myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue, an approach similar to those being used in the treatment of brain tumors in infants.[11]
(Refer to the Trilateral retinoblastoma section in the Causes of Retinoblastoma-Related Mortality section of this summary for more information about trilateral retinoblastoma, including screening with neuroimaging.)
Extracranial metastatic retinoblastoma
Treatment options for extracranial metastatic retinoblastoma include the following:
- Systemic chemotherapy followed by myeloablative chemotherapy with stem cell rescue and radiation therapy.
Hematogenous metastases may develop in the bones, bone marrow and, less frequently, the liver. Although long-term survival has been reported with conventional chemotherapy, these reports should be considered anecdotal; metastatic retinoblastoma is not curable with conventional chemotherapy. In the last two decades, however, studies of small series of patients have shown that metastatic retinoblastoma can be cured using high-dose, marrow-ablative chemotherapy and autologous hematopoietic stem cell rescue.[12-18]; [19][Level of evidence: 3iiA]
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
- Antoneli CB, Ribeiro KB, Rodriguez-Galindo C, et al.: The addition of ifosfamide/etoposide to cisplatin/teniposide improves the survival of children with retinoblastoma and orbital involvement. J Pediatr Hematol Oncol 29 (10): 700-4, 2007. [PubMed: 17921851]
- Aerts I, Sastre-Garau X, Savignoni A, et al.: Results of a multicenter prospective study on the postoperative treatment of unilateral retinoblastoma after primary enucleation. J Clin Oncol 31 (11): 1458-63, 2013. [PubMed: 23460706]
- Radhakrishnan V, Kashyap S, Pushker N, et al.: Outcome, pathologic findings, and compliance in orbital retinoblastoma (International Retinoblastoma Staging System stage III) treated with neoadjuvant chemotherapy: a prospective study. Ophthalmology 119 (7): 1470-7, 2012. [PubMed: 22463820]
- Dunkel IJ, Chan HS, Jubran R, et al.: High-dose chemotherapy with autologous hematopoietic stem cell rescue for stage 4B retinoblastoma. Pediatr Blood Cancer 55 (1): 149-52, 2010. [PubMed: 20486181]
- Rodjan F, de Graaf P, Brisse HJ, et al.: Trilateral retinoblastoma: neuroimaging characteristics and value of routine brain screening on admission. J Neurooncol 109 (3): 535-44, 2012. [PMC free article: PMC3434888] [PubMed: 22802019]
- Paulino AC: Trilateral retinoblastoma: is the location of the intracranial tumor important? Cancer 86 (1): 135-41, 1999. [PubMed: 10391573]
- Blach LE, McCormick B, Abramson DH, et al.: Trilateral retinoblastoma--incidence and outcome: a decade of experience. Int J Radiat Oncol Biol Phys 29 (4): 729-33, 1994. [PubMed: 8040018]
- Kivelä T: Trilateral retinoblastoma: a meta-analysis of hereditary retinoblastoma associated with primary ectopic intracranial retinoblastoma. J Clin Oncol 17 (6): 1829-37, 1999. [PubMed: 10561222]
- Marcus DM, Brooks SE, Leff G, et al.: Trilateral retinoblastoma: insights into histogenesis and management. Surv Ophthalmol 43 (1): 59-70, 1998 Jul-Aug. [PubMed: 9716194]
- de Jong MC, Kors WA, de Graaf P, et al.: Trilateral retinoblastoma: a systematic review and meta-analysis. Lancet Oncol 15 (10): 1157-67, 2014. [PubMed: 25126964]
- Dunkel IJ, Jubran RF, Gururangan S, et al.: Trilateral retinoblastoma: potentially curable with intensive chemotherapy. Pediatr Blood Cancer 54 (3): 384-7, 2010. [PubMed: 19908299]
- Namouni F, Doz F, Tanguy ML, et al.: High-dose chemotherapy with carboplatin, etoposide and cyclophosphamide followed by a haematopoietic stem cell rescue in patients with high-risk retinoblastoma: a SFOP and SFGM study. Eur J Cancer 33 (14): 2368-75, 1997. [PubMed: 9616283]
- Kremens B, Wieland R, Reinhard H, et al.: High-dose chemotherapy with autologous stem cell rescue in children with retinoblastoma. Bone Marrow Transplant 31 (4): 281-4, 2003. [PubMed: 12621463]
- Rodriguez-Galindo C, Wilson MW, Haik BG, et al.: Treatment of metastatic retinoblastoma. Ophthalmology 110 (6): 1237-40, 2003. [PubMed: 12799253]
- Dunkel IJ, Aledo A, Kernan NA, et al.: Successful treatment of metastatic retinoblastoma. Cancer 89 (10): 2117-21, 2000. [PubMed: 11066053]
- Matsubara H, Makimoto A, Higa T, et al.: A multidisciplinary treatment strategy that includes high-dose chemotherapy for metastatic retinoblastoma without CNS involvement. Bone Marrow Transplant 35 (8): 763-6, 2005. [PubMed: 15750608]
- Jubran RF, Erdreich-Epstein A, Butturini A, et al.: Approaches to treatment for extraocular retinoblastoma: Children's Hospital Los Angeles experience. J Pediatr Hematol Oncol 26 (1): 31-4, 2004. [PubMed: 14707710]
- Palma J, Sasso DF, Dufort G, et al.: Successful treatment of metastatic retinoblastoma with high-dose chemotherapy and autologous stem cell rescue in South America. Bone Marrow Transplant 47 (4): 522-7, 2012. [PubMed: 21602901]
- Dunkel IJ, Khakoo Y, Kernan NA, et al.: Intensive multimodality therapy for patients with stage 4a metastatic retinoblastoma. Pediatr Blood Cancer 55 (1): 55-9, 2010. [PubMed: 20486171]
Treatment of Progressive or Recurrent Retinoblastoma
The prognosis for a patient with progressive or recurrent retinoblastoma depends on the site and extent of the progression or recurrence and previous treatment received. Intraocular and extraocular recurrences have very different prognoses and are treated in distinctly different ways.
Treatment Options for Progressive or Recurrent Intraocular Retinoblastoma
Treatment options for progressive or recurrent intraocular retinoblastoma include the following:
- Enucleation.
- Radiation therapy (external-beam or plaque radiation therapy).
- Local treatments (cryotherapy or thermotherapy).
- Salvage chemotherapy (systemic or intra-arterial chemotherapy).[1]
- Intravitreal administration of chemotherapy, especially for refractory or recurrent vitreous seeding, instead of treatment with intra-arterial or intravenous chemotherapy.[2]
New intraocular tumors can arise in patients with the heritable form of disease whose eyes have been treated with local control measures only, because every cell in the retina carries the RB1 mutation; this should not be considered a recurrence. Even with previous treatment consisting of chemoreduction and local control measures in very young patients with heritable retinoblastoma, surveillance may detect new tumors at an early stage, and additional local control therapy, including plaque radiation therapy, can be successful in eradicating tumor.[3-7]
When the recurrence or progression of retinoblastoma is confined to the eye and is small, the prognosis for sight and survival may be excellent with local therapy only.[8][Level of evidence: 3iiDiv] If the recurrence or progression is confined to the eye but is extensive, the prognosis for sight is poor; however, survival remains excellent. Intra-arterial chemotherapy into the ophthalmic artery has been effective in patients who relapse after systemic chemotherapy and radiation therapy.[9,10] Rescue intra-arterial chemotherapy has been used after primary intra-arterial chemotherapy. However, patients often require other treatment methods because of disease progression after second-line intra-arterial chemotherapy.[1] Radiation therapy should be considered for patients who have not been previously irradiated. Finally, enucleation may be required in cases of progressive disease after all eye-salvaging treatments have failed.
Treatment Options for Progressive or Recurrent Extraocular Retinoblastoma
Treatment options for progressive or recurrent extraocular retinoblastoma include the following:
- Systemic chemotherapy and radiation therapy for orbital disease.
- Systemic chemotherapy followed by myeloablative chemotherapy with stem cell rescue and radiation therapy for extraorbital disease.
If the recurrence or progression is extraocular, the chance of survival is poor.[11] However, the use of intensive systemic chemotherapy and consolidation with high-dose chemotherapy and autologous hematopoietic stem cell rescue may improve the chance of a cure, particularly for patients with extracranial recurrence (refer to the Treatment of Extraocular Retinoblastoma section of this summary for more information). For patients with disease recurrence after those intensive approaches, clinical trials may be considered.
Recurrence in the orbit after enucleation is treated with aggressive chemotherapy in addition to local radiation therapy because of the high risk of metastatic disease.[12][Level of evidence: 3iiA] After enucleation for recurrence, high-resolution magnetic resonance imaging with orbital coils can be helpful in distinguishing orbital recurrence from postsurgical enhancement.[13]
Treatment Options Under Clinical Evaluation for Progressive or Recurrent Retinoblastoma
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
- APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI–Children's Oncology Group Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
- Francis JH, Abramson DH, Gobin YP, et al.: Efficacy and toxicity of second-course ophthalmic artery chemosurgery for retinoblastoma. Ophthalmology 122 (5): 1016-22, 2015. [PMC free article: PMC4994525] [PubMed: 25616769]
- Ghassemi F, Shields CL, Ghadimi H, et al.: Combined intravitreal melphalan and topotecan for refractory or recurrent vitreous seeding from retinoblastoma. JAMA Ophthalmol 132 (8): 936-41, 2014. [PubMed: 24789622]
- Shields CL, Honavar SG, Shields JA, et al.: Factors predictive of recurrence of retinal tumors, vitreous seeds, and subretinal seeds following chemoreduction for retinoblastoma. Arch Ophthalmol 120 (4): 460-4, 2002. [PubMed: 11934319]
- Gombos DS, Kelly A, Coen PG, et al.: Retinoblastoma treated with primary chemotherapy alone: the significance of tumour size, location, and age. Br J Ophthalmol 86 (1): 80-3, 2002. [PMC free article: PMC1770955] [PubMed: 11801509]
- Shields CL, Shelil A, Cater J, et al.: Development of new retinoblastomas after 6 cycles of chemoreduction for retinoblastoma in 162 eyes of 106 consecutive patients. Arch Ophthalmol 121 (11): 1571-6, 2003. [PubMed: 14609913]
- Lee TC, Hayashi NI, Dunkel IJ, et al.: New retinoblastoma tumor formation in children initially treated with systemic carboplatin. Ophthalmology 110 (10): 1989-94; discussion 1994-5, 2003. [PubMed: 14522776]
- Wilson MW, Haik BG, Billups CA, et al.: Incidence of new tumor formation in patients with hereditary retinoblastoma treated with primary systemic chemotherapy: is there a preventive effect? Ophthalmology 114 (11): 2077-82, 2007. [PubMed: 17628684]
- Chan MP, Hungerford JL, Kingston JE, et al.: Salvage external beam radiotherapy after failed primary chemotherapy for bilateral retinoblastoma: rate of eye and vision preservation. Br J Ophthalmol 93 (7): 891-4, 2009. [PubMed: 19329423]
- Schaiquevich P, Ceciliano A, Millan N, et al.: Intra-arterial chemotherapy is more effective than sequential periocular and intravenous chemotherapy as salvage treatment for relapsed retinoblastoma. Pediatr Blood Cancer 60 (5): 766-70, 2013. [PubMed: 23024125]
- Say EA, Iyer PG, Hasanreisoglu M, et al.: Secondary and tertiary intra-arterial chemotherapy for massive persistent or recurrent subretinal retinoblastoma seeds following previous chemotherapy exposure: long-term tumor control and globe salvage in 30 eyes. J AAPOS 20 (4): 337-42, 2016. [PubMed: 27328850]
- Broaddus E, Topham A, Singh AD: Survival with retinoblastoma in the USA: 1975-2004. Br J Ophthalmol 93 (1): 24-7, 2009. [PubMed: 18718969]
- Kim JW, Kathpalia V, Dunkel IJ, et al.: Orbital recurrence of retinoblastoma following enucleation. Br J Ophthalmol 93 (4): 463-7, 2009. [PubMed: 18757474]
- Sirin S, de Jong MC, de Graaf P, et al.: High-Resolution Magnetic Resonance Imaging Can Reliably Detect Orbital Tumor Recurrence after Enucleation in Children with Retinoblastoma. Ophthalmology 123 (3): 635-45, 2016. [PubMed: 26692298]
Changes to This Summary (08/22/2018)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Retinoblastoma
Added text to state that the functional status of the retinoblastoma protein (pRb) is inferred to be inactive in retinoblastoma with MYCN amplification. This suggests that inactivation of RB1 by mutation or inactive pRb is a requirement for the development of retinoblastoma, independent of MYCN amplification (cited Ewens et al. as reference 13).
Treatment Option Overview for Retinoblastoma
Added Say et al. as reference 36.
Revised text to state that while subretinal seeds can be well controlled with intra-arterial chemotherapy, vitreous seeds may be difficult to control with intra-arterial or intravenous chemotherapy alone. Also added text to state that the addition of intravitreal chemotherapy to intravenous chemotherapy is more effective in the treatment of vitreous seeds; as with primary intra-arterial chemotherapy, control of seed dust, spheres, and clouds require progressively more cycles of intravitreal chemotherapy (cited Berry et al. as reference 45 and level of evidence 3iiiDiii).
Added Shields et al. as reference 46.
Treatment of Progressive or Recurrent Retinoblastoma
Added Say et al. as reference 10.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of retinoblastoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
- be discussed at a meeting,
- be cited with text, or
- replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Retinoblastoma Treatment are:
- Christopher N. Frantz, MD (Alfred I. duPont Hospital for Children)
- Karen J. Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
- Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta - Egleston Campus)
- Carlos Rodriguez-Galindo, MD (St. Jude Children's Research Hospital)
- Nita Louise Seibel, MD (National Cancer Institute)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Retinoblastoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/retinoblastoma/hp/retinoblastoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389442]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
Disclaimer
Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
Contact Us
More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.
- General Information About Retinoblastoma
- Tumor Pathology of Retinoblastoma
- Staging and Grouping Systems for Retinoblastoma
- Treatment Option Overview for Retinoblastoma
- Treatment of Intraocular Retinoblastoma
- Treatment of Extraocular Retinoblastoma
- Treatment of Progressive or Recurrent Retinoblastoma
- Changes to This Summary (08/22/2018)
- About This PDQ Summary
- Review Neuroblastoma Treatment (PDQ®): Health Professional Version.[PDQ Cancer Information Summari...]Review Neuroblastoma Treatment (PDQ®): Health Professional Version.PDQ Pediatric Treatment Editorial Board. PDQ Cancer Information Summaries. 2002
- Review Childhood Melanoma Treatment (PDQ®): Health Professional Version.[PDQ Cancer Information Summari...]Review Childhood Melanoma Treatment (PDQ®): Health Professional Version.PDQ Pediatric Treatment Editorial Board. PDQ Cancer Information Summaries. 2002
- Review Childhood Chordoma Treatment (PDQ®): Health Professional Version.[PDQ Cancer Information Summari...]Review Childhood Chordoma Treatment (PDQ®): Health Professional Version.PDQ Pediatric Treatment Editorial Board. PDQ Cancer Information Summaries. 2002
- Review Pediatric Gastric Cancer Treatment (PDQ®): Health Professional Version.[PDQ Cancer Information Summari...]Review Pediatric Gastric Cancer Treatment (PDQ®): Health Professional Version.PDQ Pediatric Treatment Editorial Board. PDQ Cancer Information Summaries. 2002
- Review Childhood Mesothelioma Treatment (PDQ®): Health Professional Version.[PDQ Cancer Information Summari...]Review Childhood Mesothelioma Treatment (PDQ®): Health Professional Version.PDQ Pediatric Treatment Editorial Board. PDQ Cancer Information Summaries. 2002
- Retinoblastoma Treatment (PDQ®) - PDQ Cancer Information SummariesRetinoblastoma Treatment (PDQ®) - PDQ Cancer Information Summaries
Your browsing activity is empty.
Activity recording is turned off.
See more...