Retinoblastoma (Rb) is the most common primary intraocular malignancy of childhood, but an uncommon paediatric cancer, with a constant incidence worldwide of 1:15,000–1:20,000 live births. Despite its rarity, Rb has served as a cornerstone in the field of oncology in many of the aspects that comprise cancer management, including classification schemes, treatment modalities, genetic testing and screening. Until just over half a century ago, the major treatment for Rb was eye removal, and prognosis was poor with outcome fatal for most children. The dramatic evolution, in a short period of time across all fields of Rb management, as well as the development of specialized centres, better infrastructure and introduction of awareness campaigns, has resulted in nearly 100% survival in developed countries and allowed eye salvage in many of the cases. External beam radiotherapy was used as the main treatment choice for four decades, but replaced by chemotherapy at the turn of the century. Initially, and still in many centres, chemotherapy is administered intravenously, but recently is targeted directly into the eye by means of intra-ophthalmic artery and intravitreal chemotherapy. To date, a range of treatments is available to the Rb expert, including enucleation, but there is lack of consensus in a number of scenarios as to what to use and when. In such a rare cancer, treatment outcomes are reported usually via retrospective analyses, with few prospective randomized controlled trials. Classification schemes have also evolved following the introduction of new treatment modalities, but discrepancies exist among centres with respect to the preferred schema and its interpretation. Retinoblastoma management is a remarkable success story, but the future will require a collaborative effort in the form of multicentre randomized controlled trials in order to further improve the quality of care for this subset of young children with ocular cancer.
Subscribe to Journal
Get full journal access for 1 year
only $51.94 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Knudson AG, Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA. 1971;68:820–3.
Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature. 1986;323:643–6.
Comings DE, A general theory of carcinogenesis. Proc Natl Acad Sci USA. 1973;70:3324–8.
Mallipatna A, Gallie BL, Chévez-Barrios P, Lumbroso-Le Rouic L, Chantada GL, Doz F. Retinoblastoma. In: Amin MB, Edge SB, Greene FL, et al. (editors). AJCC Cancer Staging Manual. 8th ed. Springer: New York; 2017.
Gatta G, Capocaccia R, Coleman MP, Gloeckler Ries LA, Berrino F, Childhood cancer survival in Europe and the United States. Cancer. 2002;95:1767–72.
MacCarthy A, Birch JM, Draper GJ, Hungerford JL, Kingston JE, Kroll ME, et al. Retinoblastoma: treatment and survival in Great Britain 1963 to 2002. Br J Ophthalmol. 2009;93:38–39.
Pawius P. Observatio XXIII. Tumor oculorum. In: Observationes Anatomicae Selectiores Appended to: Bartholinus T. Historiarum Anatomicarum Rariorum, Centuria III & IV Copenhagen, Denmark Petrus Morsing; 1657.
Wintersteiner H.Neuroepithelioma Retinae. Eine anatomische und klinsche Studie. Vienna: Franz Deuticke; 1897.
Leber T, Beltrage zur Kenntnis der Struktur desNetzhautglioms. Albr Graefes Arch Ophthalmol. 1911;78:381–411.
Stallard HB, Radiotherapy of malignant intraocular neoplasms. Br J Ophthalmol. 1948;32:618–39.
Moore RF, Stallard HB, Milner JG. Retinal gliomata treated by radon seeds. Br J Ophthalmol. 1931;15:673–96.
Stallard HB, The treatment of retinoblastoma. Ophthalmologica. 1966;151:214–30.
Shields CL, Shields JA, Cater J, Othmane I, Singh AD, Micaily B, Plaque radiotherapy for retinoblastoma: long-term tumor control and treatment complications in 208 tumors. Ophthalmology. 2001;108:2116–21.
Reese AB, Ellsworth RM, The evaluation and current concept of retinoblastoma therapy. Trans Am Acad Ophthalmol Otolaryngol. 1963;67:164–72.
Fletcher O, Easton D, Anderson K, Gilham C, Jay M, Peto J. Lifetime risks of common cancers among retinoblastoma survivors. J Natl Cancer Inst. 2004;96:357–63.
Kleinerman RA, Tucker MA, Tarone RE, Abramson DH, Seddon JM, Stovall M, et al. Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol. 2005;23:2272–9.
Nordling CO, A new theory on cancer-inducing mechanism. Br J Cancer. 1953;7:68–72.
Knudson AG, Strong LC. Mutation and cancer: a model for wilms’ tumor of the kidney. J Natl Cancer Inst. 1972;48:313–24.
Onadim Z, Hungerford J, Cowell JK, Follow-up of retinoblastoma patients having prenatal and perinatal predictions for mutant gene carrier status using intragenic polymorphic probes from the RB1 gene. Br J Cancer. 1992;65:711–6.
Price EA, Price K, Kolkiewicz K, Hack S, Reddy MA, Hungerford JL, et al. Spectrum of RB1 mutations identified in 403 retinoblastoma patients. J Med Genet. 2014;51:208–14.
Richter S, Vandezande K, Chen N, Zhang K, Sutherland J, Anderson J, et al. Sensitive and efficient detection of RB1 gene mutations enhances care for families with retinoblastoma. Am J Hum Genet. 2003;72:253–69.
Soliman SE, Dimaras H, Khetan V, Gardiner JA, Chan HSL, Heon E, et al. Prenatal versus postnatal screening for familial retinoblastoma. Ophthalmology. 2016;123:2610–7.
Rushlow DE, Mol BM, Kennett JY, Yee S, Pajovic S, Thériault BL, et al. Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies. Lancet Oncol. 2013;14:327–34.
Cowell JK, Smith T, Bia B, Frequent constitutional C to T mutations in CGA-arginine codons in the RB1 gene produce premature stop codons in patients with bilateral (hereditary) retinoblastoma. Eur J Hum Genet. 1994;2:281–90.
Kingston JE, Hungerford JL, Madreperla SA, Plowman PN. Results of combined chemotherapy and radiotherapy for advanced intraocular retinoblastoma. Arch Ophthalmol. 1996;114:1339–43.
Murphree AL, Villablanca JG, Deegan WF, Sato JK, Malogolowkin M, Fisher A, et al. Chemotherapy plus local treatment in the management of intraocular retinoblastoma. Arch Ophthalmol. 1996;114:1348–56.
Shields CL, De Potter P, Himelstein BP, Shields JA, Meadows AT, Maris JM, Chemoreduction in the initial management of intraocular retinoblastoma. Arch Ophthalmol. 1996;114:1330–8.
Gallie BL, Budning A, DeBoer G, Thiessen JJ, Koren G, Verjee Z, et al. Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol 1996;114:1321–8.
Fabian ID, Johnson KP, Stacey AW, Sagoo MS, Reddy MA. Focal laser treatment in addition to chemotherapy for retinoblastoma. In: Fabian ID(ed.) Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2017. pCD012366.
Chan HS, DeBoer G, Thiessen JJ, Budning A, Kingston JE, O’Brien JM, et al. Combining cyclosporin with chemotherapy controls intraocular retinoblastoma without requiring radiation. Clin Cancer Res. 1996;2:1499–508.
Linn Murphree A. Intraocular retinoblastoma: the case for a new group classification. Ophthalmol Clin North Am. 2005;18:41–53.
Shields CL, Mashayekhi A, Au AK, Czyz C, Leahey A, Meadows AT, et al. The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology. 2006;113:2276–80.
Yamane T, Kaneko A, Mohri M. The technique of ophthalmic arterial infusion therapy for patients with intraocular retinoblastoma. Int J Clin Oncol. 2004;9:69–73.
Abramson DH, Dunkel IJ, Brodie SE, Kim JW, Gobin YP, A phase I/II study of direct intraarterial (ophthalmic artery) chemotherapy with melphalan for intraocular retinoblastoma initial results. Ophthalmology. 2008;115:1398–404.
Taich P, Requejo F, Asprea M, Sgroi M, Gobin P, Abramson DH, et al. Topotecan delivery to the optic nerve after ophthalmic artery chemosurgery. PLoS One. 2016;11:e0151343.
Abramson DH, Daniels AB, Marr BP, Francis JH, Brodie SE, Dunkel IJ, et al. Intra-arterial chemotherapy (ophthalmic artery chemosurgery) for group D retinoblastoma. PLoS One. 2016;11:e0146582.
Ericson LA, Rosengren BH, Present therapeutic resources in retinoblastoma. Acta Ophthalmol. 1961;39:569–76.
Seregard S, Kock E, af Trampe E, Intravitreal chemotherapy for recurrent retinoblastoma in an only eye. Br J Ophthalmol. 1995;79:194–5.
Kaneko A, Suzuki S, Eye-preservation treatment of retinoblastoma with vitreous seeding. Jpn J Clin Oncol. 2003;33:601–7.
Munier FL, Gaillard M-C, Balmer A, Soliman S, Podilsky G, Moulin AP, et al. Intravitreal chemotherapy for vitreous disease in retinoblastoma revisited: from prohibition to conditional indications. Br J Ophthalmol. 2012;96:1078–83.
Shields CL, Douglass AM, Beggache M, Say EAT. Shields J a. Intravitreous chemotherapy for active vitreous seeding from retinoblastoma: outcomes after 192 consecutive injections. The 2015 Howard Naquin Lecture. Retina. 2015;36:1184–90.
Grigorovski N, Lucena E, Mattosinho C, Parareda A, Ferman S, Catalá J, et al. Use of intra-arterial chemotherapy for retinoblastoma: results of a survey. Int J Ophthalmol. 2014;7:726–30.
Abramson DH, Shields CL, Munier FL, Chantada GL. Treatment of retinoblastoma in 2015: agreement and disagreement. JAMA Ophthalmol. 2015;133:1–7.
Fabian ID, Stacey AW, Johnson KP, Onadim Z, Chowdhury T, Duncan C, et al. Primary intravenous chemotherapy for group D retinoblastoma: a 13-year retrospective analysis. Br J Ophthalmol. 2017;101:82–88.
Munier FL, Mosimann P, Puccinelli F, Gaillard MC, Stathopoulos C, Houghton S, 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. 2017;101:1086–93.
Shields CL, Jorge R, Say EAT, Magrath G, Alset A, Caywood E, et al. Unilateral retinoblastoma managed with intravenous chemotherapy versus intra-arterial chemotherapy. Outcomes based on the International Classification of Retinoblastoma. Asia-Pac J Ophthalmol. 2016;5:97–103.
Yousef YA, Soliman SE, Astudillo PPP, Durairaj P, Dimaras H, Chan HSL et al. Intra-arterial chemotherapy for retinoblastoma: a systematic review. JAMA Ophthalmol. 2016. https://doi.org/10.1001/jamaophthalmol.2016.0244 [Epub ahead of print].
Kaliki S, Shields CL, Shah SU, Eagle RC, Shields JA, Leahey A, Postenucleation adjuvant chemotherapy with vincristine, etoposide, and carboplatin for the treatment of high-risk retinoblastoma. Arch Ophthalmol. 2011;129:1422–7.
Kaliki S, Srinivasan V, Gupta A, Mishra DK, Naik MN, Clinical features predictive of high-risk retinoblastoma in 403 Asian Indian patients a case-control study. Ophthalmology. 2015;122:1165–72.
Fabian ID, Stacey AW, Chowdhury T, Duncan C, Karaa EK, Scheimberg I, et al. High-risk histopathology features in primary and secondary enucleated International Intraocular Retinoblastoma Classification Group D Eyes. Ophthalmology. 2017;124:851–8.
Fabian ID, Stacey AW, Johnson KC, Chowdhury T, Duncan C, Reddy MA et al. Primary enucleation for group D retinoblastoma in the era of systemic and targeted chemotherapy: the price of retaining an eye. Br J Ophthalmol. 2017. bjophthalmol-2017-310624 [Epub ahead of print].
Wilder RT, Flick RP, Sprung J, Katusic SK, Barbaresi WJ, Mickelson C, et al. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology. 2009;110:796–804.
Dimaggio C, Sun LS, Li G, Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth Analg. 2011;113:1143–51.
Novetsky DE, Abramson DH, Kim JW, Dunkel IJ, Published international classification of retinoblastoma (ICRB) definitions contain inconsistencies—an analysis of impact. Ophthalmic Genet. 2009;30:40–44.
Conflict of interest
The authors declare that they have no competing interests.
About this article
Cite this article
Fabian, I.D., Onadim, Z., Karaa, E. et al. The management of retinoblastoma. Oncogene 37, 1551–1560 (2018) doi:10.1038/s41388-017-0050-x
Acta Neuropathologica Communications (2019)
Comparison of ocular pharmacokinetics of etoposide and its nanoemulsion after subtenon administration in rabbits
Journal of Basic and Clinical Physiology and Pharmacology (2019)
Dysregulation of miR-204-3p Driven by the Viability and Motility of Retinoblastoma via Wnt/β-catenin Pathway In Vitro and In Vivo
Pathology & Oncology Research (2019)
Associations among Socioeconomic Factors, Lag Time, and High-Risk Histopathologic Features in Eyes Primarily Enucleated for Retinoblastoma
Current Eye Research (2019)
Revista de la Facultad de Medicina (2019)