Journal of Cancer Research and Therapeutics

: 2011  |  Volume : 7  |  Issue : 1  |  Page : 11--14

Orbital retinoblastoma: Where do we go from here?

Mohammad Javed Ali1, Vijay Anand P Reddy2, Santosh G Honavar1, Milind Naik1,  
1 Ocular Oncology Service, L.V. Prasad Eye Institute, Road No. 2, Banjara Hills, Hyderabad - 500 034, India
2 Apollo Cancer Hospital, Jubilee Hills, Hyderabad - 500 034, India

Correspondence Address:
Santosh G Honavar
Ocular Oncology Service, L.V. Prasad Eye Institute, Road No. 2, Banjara Hills, Hyderabad - 500 034


Diagnosis of orbital retinoblastoma traditionally carries a dismal prognosis. Although its incidence is less in the developed countries, it continues to contribute to an epidemic of extraocular disease at diagnosis in the developing world. Orbital retinoblastoma encompasses a wide range of distinct clinical entities with varying tumor load. There are no standard treatment protocols as of now but the current preferred management is multimodal with a combination of initial high-dose chemotherapy, surgery, external beam radiotherapy and prolonged chemotherapy for 12 cycles. Though orbital retinoblastoma is a catastrophic event, rapid advances on many fronts, especially the genetic, makes the future appear brighter than what it is now. This review looks at all the new frontiers that are in store in the near as well as the distant future. Looking at the ever expanding horizons makes one believe of a definite hope that one day we will conquer this disease as we have conquered many others in the past.

How to cite this article:
Ali MJ, Reddy VP, Honavar SG, Naik M. Orbital retinoblastoma: Where do we go from here?.J Can Res Ther 2011;7:11-14

How to cite this URL:
Ali MJ, Reddy VP, Honavar SG, Naik M. Orbital retinoblastoma: Where do we go from here?. J Can Res Ther [serial online] 2011 [cited 2020 May 31 ];7:11-14
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Full Text


Retinoblastoma is the most common intraocular malignancy in children, with a reported incidence ranging from 1 in 15,000 to 1 in 18,000 live births. [1] It is bilateral in about 25-35% of cases. [2] The average age at diagnosis is 18 months, unilateral cases being diagnosed at around 24 months and bilateral cases before 12 months. [2] Retinoblastoma was associated with near certain death just over a century ago. Early tumor recognition aided by indirect ophthalmoscopy and refined enucleation technique contributed to an improved survival from 5% in 1896 to 81% in 1967. Advances in external beam radiotherapy in the 1970s, followed by the era of chemoreduction in the late 1990s, resulted in further substantial eye salvage. [2],[3],[4],[5]

 Where do we Stand Now?

In neglected or untreated cases, retinoblastoma can demonstrate extraocular spread primarily through optic nerve [6] and also through the sclera. [7] Though it is a rare clinical presentation in developed countries, ranging from 6.3 to 7.6%, [8],[9] it is not an unusual feature in developing and underdeveloped world. Leal-Leal et al. [10] reported an incidence of 18% in a large multicenter study from Mexico. Kao et al.[11] from Taiwan reported the incidence of orbital retinoblastoma to be 36% in a large study. The incidence is even higher (around 40%) from Nepal where Badhu et al. [12] reported proptosis to be the most common presenting feature of retinoblastoma.

Orbital retinoblastoma is one of the major contributors to mortality and carries a poor prognosis for life. [13],[14],[15],[16],[17] The presence of orbital invasion is associated with 10-27 times higher risk of metastasis when compared to cases without orbital extension. [18],[19],[20] The 5-year survival rates of orbital retinoblastoma has been reported to be 88% from the United Kingdom, [21] 91% from Japan [22] and 93% from the United States. [23],[24] However, the mortality in developing countries is still high owing to late presentations compounded by socioeconomic factors, with the mortality reported as high as 50-90%. [12],[17],[25],[26],[27]

There is no proven definitive therapy or management protocol for orbital retinoblastoma. It continues to remain a challenging disease to treat because of its complex nature and usually various combination therapies are needed to achieve reasonable results. Multimodal therapies are probably the next step forward. There are numerous reasons for this, which are as follows:

Systemic chemotherapy alone is unlikely to eradicate residual orbital disease. [28],[29] Orbital exenteration alone is unlikely to achieve surgical clearance. [30],[31] External beam radiotherapy is unlikely to prevent systemic metastasis. [32],[33] Histopathologic evidence of viable tumor cells present even in phthisical eyes following neoadjuvant chemotherapy. [34]

Based on the current evidence, as mentioned above, Honavar et al. [35] developed a treatment protocol comprising initial triple drug high dose chemotherapy (3-6 cycles) followed by appropriate surgery, orbital radiotherapy and an additional 12-cycle standard dose chemotherapy. In this series, six cases of orbital retinoblastoma without intracranial extension and systemic metastasis underwent the protocol as described above and the authors reported dramatic resolution of orbital involvement and a mean event-free survival of 36 months. Most of the eyes following chemotherapy become phthisical. The authors agree that their encouraging protocol needs validation and further studies are needed to know whether fewer cycles are as equally effective since there are concerns of the long-term effects of high dose chemotherapy.

 New Frontiers of the Future

When reviewing the literature, one fact that stands out clearly is the increasing survival of patients with orbital retinoblastoma. Progress has been made and is continuing on all fronts including medical, surgical, diagnostic, genetic, social and rehabilitative. [36],[37]

Medical frontier

Multimodal therapies for advanced retinoblastoma are picking up pace and support from all spheres as amply elucidated in this review. Histopathologic evaluations of eyes following neoadjuvant chemotherapy for orbital retinoblastoma have further vouched for multimodal approaches. [34] The introduction of stem cell rescue along with high dose chemotherapy has added another dimension to the treatment of orbital retinoblastoma. [38],[39] The Children's Oncology Group trials (COG trials), currently taking place, has made a great effort to standardize the treatment protocols worldwide. Their well-designed COG ARET 0321 trial of intensive multimodal therapy for extraocular retinoblastoma will probably lay to rest most of the confusion revolving around management protocols. Other areas being investigated include pharmacologic enhancement of radiotherapy, use of tumor cell targeting techniques, differentiating agents and immunotherapy. [40]

Radiotherapy frontier

Advances in external beam radiotherapy for retinoblastoma with more precise control of the beam through better collimation and tighter isodose curves strongly argue in favor of its continuing supportive role in the management. The modern approaches that are being investigated include stereotactic conformal radiotherapy using a micromultileaf collimator, proton therapy using a fixed horizontal beam and tantalum localization or a rotating gantry with spot scanning. [41]

Surgical frontier

Better survival has led to increasing research and advances on the surgical front. Newer implants with focus on orbital development and, hence, better cosmesis are coming up. [42] Increasing developments in ocularistry with focus on newer materials and techniques are leading to better implant retention and less exposures or extrusions. [43] Upcoming concepts in orbital reconstruction, particularly in children, and newer modalities like free tissue transfer for anophthalmic orbit syndrome may pave way for good cosmesis in patients of orbital retinoblastoma who undergo exenteration and radiotherapy. [44],[45]

Diagnostic frontier

On the diagnostic front, exploring the fetal eye is a new frontier. Fetal magnetic resonance imaging (MRI) and fetal three-dimensional ultrasound are being increasingly explored for prenatal diagnosis. The only two cases reported of in utero diagnosis using fetal ultrasound had massive extraocular extension. [46],[47] MRI is also being increasing used to study the biocolonization of the orbital implant. [48] Whole body bone scans using technetium-99, as shown by Kiratli et al., [49] and flourine-18 flourodeoxyglucose positron emission tomography (PET CT), as demonstrated by Moll et al., [50] reflect a glimpse of what possibly lies in store for early detection of metastasis.

Genetic frontier

On the genetic front, there has been a distressingly little progress in spite of the fact that RB1 was the first human cancer gene to be cloned. Development of an automated, inexpensive screening examination for RB1 mutations has been a long-term need. However, recently, Parsam et al., [51] from the authors group, have developed and published a combinatorial and less expensive approach for the detection of RB1 mutations, which is likely to have applications as a screening tool. Ali et al.[52] have for the first time explored the possible correlations between different types of mutations on the RB1 gene and clinical presentations. It is interesting to note that large deletions were found to correlate with extraocular extension and metastasis at presentation. Further efforts are needed to make it a routine part of patient care. There is also an increasing realization of using a different approach for patients at high risk of metastatic disease. Newer researchers have described a class of genes called the metastasis genes and the metastasis suppressor genes. [53],[54],[55],[56],[57] These genes affect the ability of cancer cells to establish growth foci in locations distant from the primary cancer but do not affect the primary tumor itself. The exploitation of these genes and the pathways to block the growth at distant sites holds promise for precisely targeted therapy to prevent metastasis. [58],[59],[60]

Social frontier

On the social front, awareness through education and outreach to the community has helped to prevent delayed presentations and promote an early referral. Impact of educational programs in certain developing nations of Central America where it was linked with the vaccination programs is continuing to yield encouraging results with the rate of orbital retinoblastoma diagnosis reducing by almost half in the post-campaign period. [61],[62] Similar programs could be cloned to developing countries in Africa and southern Asia, specifically targeting the education of general population and primary care providers.


Orbital retinoblastoma is no doubt still a huge challenge by itself. Although the survival has increased over the last few years, lack of access to medical facilities, lack of education about the need for early medical attention and cultural resistance to enucleation continue to contribute to an epidemic of extraocular disease at diagnosis in the developing world. Multimodal therapies and advancement on all fronts elucidated above appear as rays of light in a dark forest which is providing us with clues to a glittering light ahead to fight the darkness surrounding us at present. There is a definite hope that one day we will conquer this disease as we have conquered many others in the past.


1Bishop JO, Madsen EC. Retinoblastoma: Review of current status. Surv Ophthalmol 1975;19:342-66.
2Shields JA, Shields CL. Retinoblastoma. In: Shields CL, Shields JA, editors. Intraocular tumors - A text and Atlas. 2 nd ed. Philadelphia, United States: Lippincott Williams and Wilkins; 2007. p. 294-318.
3Kingston JE, Hungerford JL, Madreperla SA, Plowman PN. Results of combined chemotherapy and radiotherapy for advanced intraocular retinoblastoma. Arch Ophthalmol 1996;114:1339-43.
4Gallie BL, Budning A, DeBoer G, Thiessen JJ, Koren G, Verjee Z, et al. Chemotherapy with focal therapy can cure retinoblastoma without radiotherapy. Arch Ophthalmol 1996;114:1321-8.
5Shields 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.
6Magramm I, Abramson DH, Ellsworth RM. Optic nerve involvement in retinoblastoma. Ophthalmology 1989;96:217-22.
7Rootman J, Ellsworth RM, Hofbauer J, Kitchen D. Orbital extension of retinoblastoma: A clinicopathological study. Can J Ophthalmol 1978;13:72-80.
8Grabowski EF, Abramson DH. Intraocular and extra ocular retinoblastoma. Hematol Oncol Clin North Am 1987;1:721-35.
9Ellsworth RM. Orbital Retinoblastoma. Trans Am Ophthalmol Soc 1974;72:79-88.
10Leal-Leal C, Flores-Rojo M, Medina-Sanson A, Cerecedo-Diaz F, Sanchez-Felix S, Gonzalez-Ramella O, et al. A multi-centre report from the Mexican retinoblastoma group. Br J Ophthalmol 2004;88:1074-7.
11Kao LY, Su WW, Lin YW. Retinoblastoma in Taiwan: survival and clinical characteristics 1978-2000. Jpn J Ophthalmol 2002;46:577-80.
12Badhu B, Sah SP, Thakur SK, Dulal S, Kumar S, Sood A, et al. Clinical presentation of retinoblastoma in Eastern Nepal. Clin Exp Ophthalmol 2005;33:386-9.
13Stannard C, Lipper S, Sealy R, Sevel D. Retinoblastoma: Correlation of invasion of the optic nerve and choroids with prognosis and metastases. Br J Ophthalmol 1979;63:560-70.
14Hungerford J. Factors influencing metastasis in retinoblastoma. Br J Ophthalmol 1993;77:541.
15Finger PT, Harbour JW, Karcioglu ZA. Risk factors for metastasis in retinoblastoma. Surv Ophthalmol 2002;47:1-16.
16Abramson DH, Beaverson K, Sangani P, Vora RA, Lee TC, Hochberg HM, et al. Screening for retinoblastoma: Presenting signs as prognosticators of patient and ocular survival. Paediatrics 2003;112:1248-55.
17Schvartzman E, Chantada G, Fandino A, de Davila MT, Raslawski E, Manzitti J. Results of a stage-based approach for the treatment of retinoblastoma. J Clin Oncol 1996;14:1532-6.
18Singh AD, Shields CL, Shields JA. Prognostic factors in retinoblastoma. J Pediatr Ophthalmol Strabismus 2000;37:134-41.
19Kopelman JE, McLean IW, Rosenberg SH. Multivariate analysis of risk factors for metastasis in retinoblastoma treated by enucleation. Ophthalmology 1987;94:371-7.
20Khelfaoui F, Validire P, Auperin A, Quintana E, Michon J, Pacquement H, et al. Histopathologic risk factors in retinoblastoma: a retrospective study of 172 patients treated in a single institution. Cancer 1996;77:1206-13.
21Sanders BM, Draper GJ, Kingston JE. Retinoblastoma in Great Britain 1969-80: Incidence, treatment and survival. Br J Ophthalmol 1988;72:576-83.
22Survival rate and risk factors for patients with retinoblastoma in Japan. The committee for the National Registry of Retinoblastoma. Jpn J Ophthalmol 1992;36:121-31.
23Abramson DH, Niksarli K, Ellsworth RM, Servodidio CA. Changing trends in the management of retinoblastoma: 1951-1965 vs 1966-1980. J Pediatr Ophthalmol Strabismus 1994;31:32-7.
24Young J, Smith MA, Roffers SD. Retinoblastoma. In: Ries LA, Smith MA, Gurney JG, editors. Cancer incidence and survival among children and adolescents. SEER Program. United States: NIH Pub; 1999. p. 99-4649.
25Ajaiyeoba IA, Akang EE, Campbell OB, Olurin IO, Aghadiuno PU. Retinoblastomas in Ibadan: Treatment and prognosis. West Africa J Med 1993;12:223-7.
26Chantada G, Fadino A, Manzitti J, Urrutia L, Schvartzman E. Late diagnosis of retinoblastomas in a developing country. Arch Dis Child 1999;80:171-4.
27Kodilinye HC. Retinoblastoma in Nigeria: Problems of treatment. Am J Ophthalmol 1967;63:469-81.
28Antoneli CB, Steinhorst F, de Cassia Braga RK, Novaes PE, Chojniak MM, Arias V, et al. Extra ocular retinoblastoma: A 13-year experience. Cancer 2003;98:1292-8.
29Doz F, Khelfaoui F, Mosseri V, Validire P, Quintana E, Michon J, et al. The role of chemotherapy in orbital involvement of retinoblastoma. The experience of single institution with 33 patients. Cancer 1994;74:722-32.
30Hungerford JL, Kingston JE, Plowman PN. Orbital recurrence of retinoblastoma. Ophthalmic Pediatr Genet 1987;8:63-8.
31Reese AB. Retinoblastoma. In: Reese AB, editor. Tumors of the eye. 1 st ed. New York: Harper and Row; 1963. p. 155-6.
32Amendola BE, Lamm RF, Markoe AM, Karlsson UL, Shields JA, Shields CL, et al. Radiotherapy of retinoblastoma. A review of 63 children treated with different irradiation techniques. Cancer 1990;66:21-6.
33Scott IU, Murray TG, Feuer WJ, Van Quill K, Markoe AM, Ling S, et al. External beam radiotherapy in retinoblastoma. Tumor control and comparison of two techniques. Arch Ophthalmol 1999;117:766-70.
34Ali MJ, Gupta R, Vemuganti GK, Honavar SG. Histopathology of retinoblastoma after primary chemotherapy. Proceedings of the XIV International Congress of Ocular Oncology. Cambridge; 2009. p. 296.
35Honavar SG, Singh AD. Management of advanced retinoblastoma. Ophthalmol Clin North Am 2005;18:65-73.
36Shields CL, Shields JA. Retinoblastoma management: Advances in enucleation, intravenous chemoreduction and intra-arterial chemotherapy. Curr Opin Ophthalmol 2010;21:203-12.
37Bakhshi S, Meel R, Mohanti BK, Hasan Naqvi SG. Treatment and outcomes of non-metastatic extra-ocular retinoblastoma with uniform chemotherapy protocol. J Pediatr Hematol Oncol 2010;32:42-5.
38Kremens B, Wieland R, Reinhart H, Neubert D, Beck JD, Klingebiel T, et al. High dose chemotherapy with autologous stem cell in children with retinoblastoma. Bone Marrow Transplant 2003;31:281-4.
39Lee SH, Yoo KH, Sung KW, Kim JY, Cho EJ, Koo HH, et al. Tandem High-dose chemotherapy and autologous stem cell rescue in children with bilateral advanced retinoblastoma. Bone Marrow Transplant 2008;42:385-91.
40White L. Chemotherapy in retinoblastoma: Current status and future directions. Am J Pediatr Hematol Oncol 1991;13:189-201.
41Munier FL, Verwey J, Pica A, Balmer A, Zografos L, Abouzied H, et al. New developments in external beam radiotherapy in retinoblastoma: From lens to normal tissue-sparing techniques. Clin Exp Ophthalmol 2008;36:78-89.
42Lin HY, Liao SL. Orbital development in survivors of retinoblastoma treated with enucleation with hydroxyapaptite implant. Br J Ophthalmol 2010.
43Williams BK Jr, Schefler AC, Garonzik SN, Gologorsky D, Shi W, Cavalcante LL, et al. Frequent prosthesis refitting to prevent implant exposure in patients with retinoblastoma. J Pediatr Ophthalmol Strabismus 2010;23:1-9.
44Stricker M, Simon E. Orbital reconstruction in children. Neurochirurgie 2010;56:287-93.
45Baj A, Lagana F, Beltramini GA. Anophthalmic socket syndrome: A new free tissue transfer. J Oral Maxillofac Surg 2010;68:2593-7.
46Maat-Kevit JA, Oepkes D, Hartwing NG, Vermeij-Keers C, Van Kamp IL, Van de Kamp JJ. A large retinoblastoma detected in a fetus at 21 weeks of gestation. Prenat Diagn 1993;13:377-84.
47Salim A, Wiknjosastro GH, Danukusumo D, Barnas B, Zalud I. Fetal retinoblastoma. J Ultrasound Med 1998;17:717-20.
48Douira-Khomsi W, Korchane N, Louati H, Bhouri L, Kchaou I, Ben Hassine L, et al. MRI exploration for the evaluation of orbital implant biocolonization in children enucleated for retinoblastoma. J Fr Ophthalmol 2009;32:540-3.
49Kiratli PO, Kiratli H, Ercan MT. Visualization of orbital retinoblastoma with technetium-99m (V) dimercaptosuccinic acid. Ann Nucl Med 1998;12:157-9.
50Moll AC, Hoekstra OS, Imhof SM , Comans EF, Schouten-van Meeteren AY, Van der valk P, et al. Flourine-18 flourodeoxyglucose positron emission tomography (PET) to detect vital retinoblastoma in the eye: Preliminary experience. Ophthalmic Genet 2004;25:31-5.
51Parsam VL, Kannabiran C, Honavar S, Vemuganti GK, Ali MJ. A compréhensive, sensitive and economical approach for the detection of mutations in RB1 gene in retinoblastoma. J Genet 2009;88:517-27.
52Ali MJ, Parsam VL, Honavar SG, Kannabiran C, Reddy VA. RB1 gene mutations in retinoblastoma and its clinical correlation. Saudi J Ophthalmol 2010;24:119-23.
53Zhang G, He B, Weber GF. Growth factor signaling induces metastasis genes in transformed cells: Molecular connections between Akt Kinases and osteopontin in breast cancer. Mol Cell Biol 2003;23:6507-19.
54Wang J, Levenson AS, Satcher RL Jr. Identification of unique sets of genes altered during cell-cell contact in an in-vitro model of prostate cancer bone metastasis. Int J Mol Med 2006;17:849-56.
55Hartl M, Karagiannidis Al, Birster K. Cooperative cell transformation by Myc/Mil(Raf) involves induction of AP-1 and activations of genes implicated in cell motility and metastasis. Oncogene 2006;25:4043-55.
56Weber GF. The metastasis gene osteopontin: A candidate target for cancer therapy. Biochim Biophys Acta 2001;1552:61-85.
57Yu Y, Davicioni E, Triche TJ, Merlino G. The homeoprotein six1 transcriptionally activates multiple protumorigenic genes but requires ezrin to promote metastasis. Cancer Res 2006;66:1982-9.
58Berger JC, Vander Griend DJ, Robinson VL, Hickson JA, Rinker-Schaeffer CW. Metastasis suppressor genes: From gene identification to protein function and regulation. Cancer Biol Ther 2005;4:805-12.
59Keller ET. Metastasis suppressor genes: A role for raf kinase inhibitor protein (RKIP). Anticancer Drugs 2004;15:663-9.
60Kauffman EC, Robinson VL, Stadler WM, Sokoloff MH, Rinker-Schaeffer CW. Metastasis suppression: The evolving role of metastasis suppressor genes for regulating cancer cell growth at the secondary site. J Urol 2003;169:1122-33.
61Leander C, Fu LC, Pena A. Impact of an education programme on the late diagnosis of retinoblastoma in Honduras. Pediatr Blood Cancer 2007;49:817-9.
62Wilimas JA, Wilson MW, Haik BG, Barnoya M, Fu L, Castellanos M, et al. Development of retinoblastoma programs in Central America. Pediatr Blood Cancer 2009;53:42-6.