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Retinoblastoma Treatment (PDQ®)
- General Information
- Cellular Classification
- Stage Information
- Treatment Option Overview
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General Information
Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] 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 incorporates the skills of the primary care physician, an ophthalmologist with extensive experience in the treatment of children with retinoblastoma, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
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.[2] 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/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 Web site.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%.[1] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ Late Effects of Treatment for Childhood Cancer summary for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
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. The estimated annual incidence in the United States is approximately 4 per 1 million children younger than 15 years. Although retinoblastoma may occur at any age, it most often occurs in younger children; the annual incidence is 10 to 14 per 1 million in children aged 0 to 4 years. Ninety-five percent of cases are diagnosed before age 5 years, and two-thirds of these cases occur before age 2 years. Older age is usually associated with more advanced disease and a poorer prognosis.[3]
Hereditary and Nonhereditary Forms of Retinoblastoma
Retinoblastoma is a tumor that occurs in heritable (25% to 30%) and nonheritable (70% to 75%) forms. Hereditary disease is defined by the presence of a positive family history, multifocal retinoblastoma, or an identified germline mutation of the RB1 gene. This germline mutation may have been inherited from an affected progenitor (25%) or may have occurred in utero at the time of conception, in patients with sporadic disease (75%). Hereditary retinoblastoma may manifest as unilateral or bilateral disease. The penetrance of the mutation (laterality, age at diagnosis, and number of tumors) is probably dependent on concurrent genetic modifiers such as MDM2 and MDM4.[4][5] Approximately 85% of patients with unilateral retinoblastoma do not have the hereditary form of the disease, whereas all children with bilateral disease are presumed to have the hereditary form, even though only 20% have an affected parent. In hereditary retinoblastoma, tumors tend to occur at a younger age than in the nonhereditary form of the disease. Unilateral retinoblastoma in children younger than 1 year should raise concern for the hereditary disease, whereas older children with a unilateral tumor are more likely to have the nonhereditary form of the disease.[6][7]
Children with the hereditary form of retinoblastoma may continue to develop new tumors for a few years after diagnosis. For this reason, children with hereditary retinoblastoma need to be examined frequently for the development of new tumors. It is recommended that they be examined every 2 to 4 months for at least 28 months.[8] Following treatment, patients require careful surveillance until age 5 years.[9] The interval between exams is based on both the age of the child (more frequent visits as the child ages) and the stability of the disease.
Early-in-life screening by fundus exams under general anesthesia at regular intervals, according to a schedule based on the absolute estimated risk, can improve prognosis in terms of globe sparing in children with positive family histories of retinoblastoma. Intensive screening decreased the need for enucleation and external-beam radiation therapy in a retrospective review of groups of nonscreened versus differently screened children with positive family histories of retinoblastoma.[10]
The parents and siblings of patients with retinoblastoma should have screening ophthalmic examinations to exclude an unknown familial disease. Siblings should continue to be screened until age 3 to 5 years or until it is confirmed that they do not have a genetic mutation.
Blood and/or tumor samples can be screened to determine if a retinoblastoma patient 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. The RB1 gene is located within the q14 band of chromosome 13. Exon by exon sequencing of the RB1 gene demonstrates germline mutation in 90% of patients with hereditary retinoblastoma.[11][12][13] Although a positive finding with current technology confirms susceptibility, a negative finding cannot absolutely rule it out.[14] The multistep assay includes DNA sequencing to identify mutations within coding exons and immediate flanking intronic regions, Southern blot analysis to characterize genomic rearrangements, and transcript analysis to characterize potential splicing mutations buried within introns. This expanded analysis is showing promise in better defining the functional significance of apparently novel mutations in pilot investigations performed at the University of Pennsylvania. Such testing should be performed only at institutions with expertise in RB1 gene mutation analysis.[14] In cases of somatic mosaicism or cytogenetic abnormalities, the mutations may not be easily detected and more exhaustive techniques such as karyotyping, multiplex ligation-dependent probe amplification, and fluorescence in situ hybridization may be needed. The absence of detectable RB1 mutations in some patients may suggest that alternative genetic mechanisms may underlie the development of retinoblastoma.[15]
Genetic counseling should be an integral part of the management of patients with retinoblastoma and their families, whether unilateral or bilateral.[16] It is of utmost importance to assist parents in understanding the genetic consequences of each form of retinoblastoma and to estimate risk of disease in family members.[13][16] Genetic counseling, however, is not always straightforward. Families with retinoblastoma may have a founder mutation with embryonic mutagenesis causing genetic mosaicism of gametes.[17] A significant proportion (10%–18%) of children with retinoblastoma have somatic genetic mosaicism,[18] [19] making the genetic story more complex and contributing to the difficulty of genetic counseling.[14]
Factors Influencing Mortality
The present challenge for those who treat retinoblastoma is to prevent loss of an eye, blindness, and other serious effects of treatment that reduce the life span or the 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 of retinoblastoma-related mortality in the first decade of life, such as trilateral retinoblastoma and subsequent neoplasms (SNs), have become significant contributors to retinoblastoma-related mortality. In the United States, before the advent of chemoreduction as a means of treating bilateral (hereditary) disease, trilateral retinoblastoma contributed to more than 50% of retinoblastoma-related mortality in the first decade after diagnosis.[20][21]
Trilateral retinoblastoma
Trilateral retinoblastoma is a well-recognized syndrome that occurs in 5% to 15% of patients with hereditary retinoblastoma and is defined by the development of an intracranial midline neuroblastic tumor, which typically develops more than 20 months after the diagnosis of retinoblastoma.[22][23] Patients who are asymptomatic at the time of diagnosis with an intracranial tumor have a better outcome than patients who are symptomatic.[22]
Given the poor prognosis of trilateral retinoblastoma and the short interval between the diagnosis of retinoblastoma and the occurrence of trilateral disease, routine neuroimaging could potentially detect the majority of cases within 2 years of first diagnosis.[22] While it is not clear whether early diagnosis can impact survival, the frequency of screening with magnetic resonance imaging for those suspected of having hereditary disease or those with unilateral disease and a positive family history has been recommended as often as every 6 months for 5 years. It is unclear if this will have an impact on outcome or survival.[23] Computed tomography scans should be avoided for routine screening in these children because of the perceived risk of exposure to ionizing radiation.
Subsequent neoplasms
Patients with hereditary retinoblastoma have a markedly increased frequency of subsequent neoplasms (SNs).[24][25] The cumulative incidence 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.[26] However, more recent studies analyzing cohorts of patients treated with more advanced radiation planning and delivery technology have reported the rates to be about 9.4% in nonirradiated patients and about 30.4% in irradiated patients.[27] The most common SNs are osteosarcomas, soft tissue sarcomas, or melanomas. There is no evidence of an increased incidence of acute myeloid leukemia in children with hereditary retinoblastoma.[28][Level of evidence: 3iiiA]
A cohort study of 963 patients, who were at least 1-year survivors of hereditary retinoblastoma diagnosed at two U.S. institutions from 1914 through 1984, evaluated risk for soft tissue sarcoma overall and by histologic subtype. Leiomyosarcoma was the most frequent subtype, with 78% being diagnosed 30 or more years after the retinoblastoma diagnosis. Risks were elevated in patients treated with or without radiation therapy, and, in those treated with radiation therapy, sarcomas were seen both within and outside the field of radiation. The carcinogenic effect of radiation increased with dose, particularly for secondary sarcomas where a step-wise increase is apparent at all dose categories. In irradiated patients, two-thirds of the SNs occur within irradiated tissue and one-third occur outside the radiation field.[26] The risk for SNs is heavily dependent on the patient's age at the time the external-beam radiation therapy is given, especially in children younger than 12 months, and the histopathologic types of SNs may be influenced by age.[27] [9][29] These data support a genetic predisposition to soft tissue sarcoma, in addition to the risk of osteosarcoma.[30]
It has become apparent that patients with hereditary retinoblastoma 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.[31][32]
Survival from SNs is certainly suboptimal and varies widely across studies.[25][31][33][34][35][36] However, with advances in therapy, it is essential that all SNs be treated with curative intent.[37] Those who survive SNs are at a sevenfold increased risk for developing an SN.[38] The risk further increases threefold when patients are treated with radiation therapy for their retinoblastoma.[39] There is no clear increase in SNs in patients with sporadic retinoblastoma beyond that associated with the treatment.[26] [36]
Late Effects from Retinoblastoma Therapy
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.[40] One study of visual acuity following treatment with systemic chemotherapy and focal 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 at least 3 mm from the foveola and optic disc and an absence of subretinal fluid.[41]
Since systemic carboplatin is now commonly used in the treatment of retinoblastoma (Refer to Intraocular Retinoblastoma and Extraocular Retinoblastoma sections of this summary for more information), concern has been raised about hearing loss related to therapy. However, an analysis of 164 children treated with six cycles of carboplatin-containing therapy (18.6 mg/kg per cycle) showed no loss of hearing among children who had a normal initial audiogram.[42]1Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010.2Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.3de Aguirre Neto JC, Antoneli CB, Ribeiro KB, et al.: Retinoblastoma in children older than 5 years of age. Pediatr Blood Cancer 48 (3): 292-5, 2007.4Castéra L, Sabbagh A, Dehainault C, et al.: MDM2 as a modifier gene in retinoblastoma. J Natl Cancer Inst 102 (23): 1805-8, 2010.5de 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, 2012.6Zajaczek 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, 1998.7Murphree L, Singh A: Heritable retinoblastoma: the RBI cancer predisposition syndrome. In: Singh A, Damato B: Clinical Ophthalmic Oncology. Philadelphia, Pa: Saunders Elsevier, 2007, pp 428-33.8Abramson DH, Mendelsohn ME, Servodidio CA, et al.: Familial retinoblastoma: where and when? Acta Ophthalmol Scand 76 (3): 334-8, 1998.9Abramson 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, 1998.10Rothschild 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, 2011.11Noorani HZ, Khan HN, Gallie BL, et al.: Cost comparison of molecular versus conventional screening of relatives at risk for retinoblastoma. Am J Hum Genet 59 (2): 301-7, 1996.12Lohmann DR, Gerick M, Brandt B, et al.: Constitutional RB1-gene mutations in patients with isolated unilateral retinoblastoma. Am J Hum Genet 61 (2): 282-94, 1997.13Richter 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, 2003.14Clark R: Retinoblastoma: genetic testing and counseling. In: Singh A, Damato B: Clinical Ophthalmic Oncology. Philadelphia, Pa: Saunders Elsevier, 2007, pp 441-6.15Nichols 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, 2005.16Musarella MA, Gallie BL: A simplified scheme for genetic counseling in retinoblastoma. J Pediatr Ophthalmol Strabismus 24 (3): 124-5, 1987 May-Jun.17Munier FL, Thonney F, Girardet A, et al.: Evidence of somatic and germinal mosaicism in pseudo-low-penetrant hereditary retinoblastoma, by constitutional and single-sperm mutation analysis. Am J Hum Genet 63 (6): 1903-8, 1998.18Sippel KC, Fraioli RE, Smith GD, et al.: Frequency of somatic and germ-line mosaicism in retinoblastoma: implications for genetic counseling. Am J Hum Genet 62 (3): 610-9, 1998.19Munier F, Pescia G, Jotterand-Bellomo M, et al.: Constitutional karyotype in retinoblastoma. Case report and review of literature. Ophthalmic Paediatr Genet 10 (2): 129-50, 1989.20Blach 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, 1994.21Broaddus E, Topham A, Singh AD: Survival with retinoblastoma in the USA: 1975-2004. Br J Ophthalmol 93 (1): 24-7, 2009.22Paulino AC: Trilateral retinoblastoma: is the location of the intracranial tumor important? Cancer 86 (1): 135-41, 1999.23Kivelä T: Trilateral retinoblastoma: a meta-analysis of hereditary retinoblastoma associated with primary ectopic intracranial retinoblastoma. J Clin Oncol 17 (6): 1829-37, 1999.24Gallie BL, Dunn JM, Chan HS, et al.: The genetics of retinoblastoma. Relevance to the patient. Pediatr Clin North Am 38 (2): 299-315, 1991.25Marees 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, 2008.26Wong FL, Boice JD Jr, Abramson DH, et al.: Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. JAMA 278 (15): 1262-7, 1997.27Kleinerman 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, 2005.28Gombos DS, Hungerford J, Abramson DH, et al.: Secondary acute myelogenous leukemia in patients with retinoblastoma: is chemotherapy a factor? Ophthalmology 114 (7): 1378-83, 2007.29Moll 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, 2001.30Kleinerman 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, 2007.31Fletcher O, Easton D, Anderson K, et al.: Lifetime risks of common cancers among retinoblastoma survivors. J Natl Cancer Inst 96 (5): 357-63, 2004.32Marees T, van Leeuwen FE, de Boer MR, et al.: Cancer mortality in long-term survivors of retinoblastoma. Eur J Cancer 45 (18): 3245-53, 2009.33Yu CL, Tucker MA, Abramson DH, et al.: Cause-specific mortality in long-term survivors of retinoblastoma. J Natl Cancer Inst 101 (8): 581-91, 2009.34Aerts 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, 2004.35Eng 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, 1993.36Dunkel 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, 1998.37Moll 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, 1997.38Abramson DH, Melson MR, Dunkel IJ, et al.: Third (fourth and fifth) nonocular tumors in survivors of retinoblastoma. Ophthalmology 108 (10): 1868-76, 2001.39Marees 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, 2010.40Abramson DH, Melson MR, Servodidio C: Visual fields in retinoblastoma survivors. Arch Ophthalmol 122 (9): 1324-30, 2004.41Demirci H, Shields CL, Meadows AT, et al.: Long-term visual outcome following chemoreduction for retinoblastoma. Arch Ophthalmol 123 (11): 1525-30, 2005.42Lambert 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.
Cellular Classification
Retinoblastoma is composed mainly of undifferentiated anaplastic cells that arise from the retina. Histology shows similarity to neuroblastoma and medulloblastoma, including aggregation around blood vessels, necrosis, calcification, and Flexner-Wintersteiner rosettes. Retinoblastomas are characterized by marked cell proliferation as evidenced by high mitosis counts and extremely high MIB-1 labeling indices.[1]1Schwimer CJ, Prayson RA: Clinicopathologic study of retinoblastoma including MIB-1, p53, and CD99 immunohistochemistry. Ann Diagn Pathol 5 (3): 148-54, 2001.
Stage Information
Although there are several staging systems available for retinoblastoma, for the purpose of treatment, retinoblastoma is categorized into intraocular and extraocular disease.
Intraocular retinoblastoma is localized to the eye and 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 (metastatic) retinoblastoma has extended beyond the eye. It may be confined to the tissues around the eye (orbital retinoblastoma), or it may have spread to the central nervous system, bone marrow, or lymph nodes (metastatic retinoblastoma).
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.
- Group I: very favorable for maintenance of sight
- Solitary tumor, smaller than 4 disc diameters (DD), at or behind the equator.
- Multiple tumors, none larger than 4 DD, all at or behind the equator.
- Group II: favorable for maintenance of sight
- Solitary tumor, 4 to 10 DD at or behind the equator.
- Multiple tumors, 4 to 10 DD behind the equator.
- Group III: possible for maintenance of sight
- Any lesion anterior to the equator.
- Solitary tumor, larger than 10 DD behind the equator.
- Group IV: unfavorable for maintenance of sight
- Multiple tumors, some larger than 10 DD.
- Any lesion extending anteriorly to the ora serrata.
- Group V: very unfavorable for maintenance of sight
- Massive tumors involving more than one half of the retina.
- Vitreous seeding.
International Classification System for Intraocular Retinoblastoma
There is a new classification system for retinoblastoma, which may offer greater precision in stratifying risk for newer therapies. The International Classification for Intraocular Retinoblastoma that is used in the current Children's Oncology Group treatment studies, as well in some institutional studies, has been shown to assist in predicting those who are likely to be cured without the need for enucleation or EBRT.[1][2] [3][4]
- Group A: Small intraretinal tumors away from foveola and disc.All tumors are 3 mm or smaller in greatest dimension, confined to the retina andAll 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.
Treatment Option Overview
Treatment planning by a multidisciplinary team of cancer specialists, including a pediatric oncologist, ophthalmologist, and radiation oncologist, who have experience treating ocular tumors of childhood is required to optimize treatment planning.[1]
The goals of therapy are threefold:
- 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.
The type of treatment required depends on both the extent of the disease within the eye and whether the disease has spread beyond the eye, either to the brain or to the rest of the body.[2] Eyes with glaucoma and those in which glaucoma resulted in buphthalmia are significantly associated with high-risk pathology risk factors and the occurrence of microscopically residual tumor.[3] Enucleation is reserved for patients with advanced unilateral intraocular disease with no hope for useful vision in the affected eye. Subsequent risk of extraocular recurrence may be increased in the presence of high-risk histopathologic features such as massive choroid invasion, scleral invasion, and optic nerve invasion.[4][5]; [6][Level of evidence: 3iiDi] Clinical features predictive of these histological findings include eyes with glaucoma, especially those that have become buphthalmic. Routine bone marrow biopsy and lumbar puncture are not indicated, except when there is a high level of suspicion that the tumor has spread beyond the globe.[7][8] Examples include patients with an abnormal complete blood count or those whose tumors show massive choroidal involvement and which extend beyond the lamina cribrosa on pathologic examination of the enucleated specimen.
It is not uncommon for patients with retinoblastoma to have extensive disease within one eye at diagnosis, with either massive tumors involving more than one-half of the retina, multiple tumors diffusely involving the retina, or obvious seeding of the vitreous. For those with bilateral disease, systemic therapy may be used to treat the more severe eye.[9][10] There are data suggesting that the use of systemic chemotherapy may decrease the risk of development of trilateral retinoblastoma.[11]1Chintagumpala M, Chevez-Barrios P, Paysse EA, et al.: Retinoblastoma: review of current management. Oncologist 12 (10): 1237-46, 2007.2Kopelman JE, McLean IW, Rosenberg SH: Multivariate analysis of risk factors for metastasis in retinoblastoma treated by enucleation. Ophthalmology 94 (4): 371-7, 1987.3Chantada GL, Gonzalez A, Fandino A, et al.: Some clinical findings at presentation can predict high-risk pathology features in unilateral retinoblastoma. J Pediatr Hematol Oncol 31 (5): 325-9, 2009.4Cuenca A, Giron F, Castro D, et al.: Microscopic scleral invasion in retinoblastoma: clinicopathological features and outcome. Arch Ophthalmol 127 (8): 1006-10, 2009.5Gupta R, Vemuganti GK, Reddy VA, et al.: Histopathologic risk factors in retinoblastoma in India. Arch Pathol Lab Med 133 (8): 1210-4, 2009.6Chantada GL, Dunkel IJ, Antoneli CB, et al.: Risk factors for extraocular relapse following enucleation after failure of chemoreduction in retinoblastoma. Pediatr Blood Cancer 49 (3): 256-60, 2007.7Moscinski LC, Pendergrass TW, Weiss A, et al.: Recommendations for the use of routine bone marrow aspiration and lumbar punctures in the follow-up of patients with retinoblastoma. J Pediatr Hematol Oncol 18 (2): 130-4, 1996.8Pratt CB, Meyer D, Chenaille P, et al.: The use of bone marrow aspirations and lumbar punctures at the time of diagnosis of retinoblastoma. J Clin Oncol 7 (1): 140-3, 1989.9Abramson DH, Beaverson K, Sangani P, et al.: Screening for retinoblastoma: presenting signs as prognosticators of patient and ocular survival. Pediatrics 112 (6 Pt 1): 1248-55, 2003.10Shields CL, Mashayekhi A, Demirci H, et al.: Practical approach to management of retinoblastoma. Arch Ophthalmol 122 (5): 729-35, 2004.11Shields CL, Meadows AT, Shields JA, et al.: Chemoreduction for retinoblastoma may prevent intracranial neuroblastic malignancy (trilateral retinoblastoma). Arch Ophthalmol 119 (9): 1269-72, 2001.
Intraocular Retinoblastoma Treatment
Treatment of retinoblastoma is individualized and considers the age of the patient, laterality, potential for vision, and intraocular tumor burden. Treatment options consider both cure of the disease and preservation of sight.[1][2][3] Different combinations of the following approaches may be applied to the individual patient, considering the two main scenarios, unilateral and bilateral disease.
Treatment options for the involved eye include the following:
- Enucleation: If the tumor is massive and there is little expectation for useful vision in the affected eye, up-front enucleation may be indicated, depending on laterality. Patients must be monitored closely for orbital recurrence of disease, particularly in the first 2 years after enucleation.[4][Level of evidence: 3iiA] Recurrence in the orbit is often associated with systemic disease (85%) and should be treated with aggressive therapy.
- Radiation therapy: External-beam 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. Newer methods of delivering EBRT are being used at many centers in an attempt to reduce adverse long-term effects. This includes intensity-modulated radiation therapy, stereotactic radiation therapy, and proton-beam radiation therapy (charged-particle radiation therapy).[5][6][7] EBRT in infants causes growth failure of the orbital bones and results in cosmetic deformity. It also increases the risk of subsequent neoplasms in children with hereditary retinoblastoma.Brachytherapy: Brachytherapy with radioactive plaques is very effective in the treatment of localized retinal tumors that are not amenable to other means of local therapy.[8][9][10]
- Local treatments: For patients undergoing eye salvage treatment, aggressive local therapy is required.Cryotherapy: Cryotherapy is based on the application of a cryoprobe to the sclera in the immediate vicinity of the retinal tumor. It 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 (thermotherapy): Laser therapy may be used as primary therapy for small tumors or in combination with chemotherapy for larger tumors. Traditional photocoagulation, in which the laser was applied around the tumor, has given way to thermotherapy. Thermotherapy is delivered directly to the tumor surface via infrared wavelengths of light.[11]
- Systemic chemotherapy: Systemic chemotherapy plays a role both in the adjuvant setting for patients with high-risk pathology, and in the eye-salvage regimens, where it is used in conjunction with aggressive focal treatments. During the past 15 years, systemic chemotherapy to reduce tumor volume (chemoreduction) and to avoid the long-term effects of radiation therapy for patients with intraocular tumors has succeeded in rendering many eyes amenable to treatment with cryotherapy or laser therapy.[1][12][13]; [14][Level of evidence: 3iiDiii] Chemotherapy may also be continued or initiated with concurrent local control interventions.[15] Factors such as tumor location (macula), patient age (patient older than 2 months), and tumor size correlate with responsiveness to chemotherapy.[15][16] Multiagent chemotherapy is generally used, although carboplatin as a single agent causes shrinkage of retinoblastoma tumors.[17]; [18][Level of evidence: 3iiiDiii] Most standard regimens incorporate vincristine, carboplatin, and etoposide, although a two-drug regimen without etoposide may also be effective for early intraocular stages.[1][12][13][16][19][20][21][22] The success rate of these trials varies from center to center, but overall, the rate is highest for discrete tumors without vitreous seeding. Local tumor recurrence is not uncommon in the first few years after treatment [23] and can often be successfully treated with focal therapy.[10] Among patients with hereditary disease, younger patients and those with positive family histories 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 focal therapy.[24]There are data suggesting that the use of systemic chemotherapy may decrease the risk of development of trilateral retinoblastoma.[25]
- Subtenon (subconjunctival) chemotherapy: Periocular delivery of carboplatin results in high intraocular concentrations of the agent, and this approach is often used in ocular salvage approaches, particularly when there is a high intravitreous 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.[26][27][28] Responses have also been noted with subtenon topotecan.[29]
- Ophthalmic artery infusion of chemotherapy: Direct delivery of chemotherapy into the eye globe via cannulation of the ophthalmic artery is a feasible and effective method for ocular salvage. Melphalan was the chemotherapeutic agent used in the first studies, although it can be associated with significant local side effects, including third cranial nerve palsy, orbital edema, permanent retinal detachment, vitreous hemorrhage, and retinal pigment epithelium changes.[30] Other agents such as topotecan and carboplatin are also being tested. Ocular salvage rates are greater than 70% when ophthalmic artery infusion of chemotherapy is used as primary treatment, although success rates are inferior when this approach is used after failure of systemic chemotherapy or radiation.[31][32][33] Retinal and choroidal vasculopathy may occur in 10% to 20% of patients.[34] This modality continues to undergo study at very specialized retinoblastoma treatment centers, but preliminary data appear to indicate that this treatment modality results in satisfactory ocular salvage rates in patients with intraocular unilateral retinoblastoma.[31][33][34][35][36][37][38]This treatment is not without complications in some cases.[31][37][39]
Unilateral Disease
Standard treatment options
Because unilateral disease is usually massive and there is often no expectation that useful vision can be preserved, up-front surgery (enucleation) is usually recommended. Careful examination of the enucleated specimen by an experienced pathologist is necessary to determine whether high-risk features for metastatic disease are present. These features include anterior chamber seeding, choroidal involvement, tumor beyond the lamina cribrosa, or scleral and extrascleral extension.[40][41][42] Systemic adjuvant therapy with vincristine, doxorubicin, and cyclophosphamide or with vincristine, carboplatin, and etoposide has been used in patients with certain high-risk features assessed by pathologic review after enucleation to prevent the development of metastatic disease,[43][44][45][46]; [47][Level of evidence: 2A] with the suggestion of success compared with historical controls.[48][Level of evidence: 3iiDiii]
Patients with unilateral disease may also be offered chemotherapy and aggressive focal treatments in an attempt to save the eye and preserve vision.[1][49][50] Ocular salvage rates correlate with intraocular stage.[51] In selected children with unilateral disease, R-E Group correlated with successful chemoreduction: 11% of children classified as having R-E Group II or III disease; 60% of children having R-E Group IV disease; and 100% of children having R-E Group V disease required enucleation or EBRT within 5 years of treatment.[52] Caution must be exerted with extended chemotherapy and delayed enucleation when tumor control does not appear to be possible. 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.[53]
Pilot studies have evaluated the delivery of chemotherapy via ophthalmic artery cannulation as initial treatment for advanced unilateral and bilateral intraocular retinoblastoma. In the setting of a multidisciplinary, state-of-the-art center, intra-arterial chemotherapy may result in ocular salvage rates in excess of 80% for patients with advanced intraocular unilateral retinoblastoma.[31][35][Level of evidence: 3iiiDii]; [32][Level of evidence: 3iiiDiv]
Because a proportion of children who present with unilateral retinoblastoma will eventually develop disease in the opposite eye, it is very important that children with unilateral retinoblastoma receive periodic examinations of the unaffected eye, regardless of the treatment they received. Asynchronous bilateral disease occurs most frequently in patients with affected parents and in children diagnosed during the first months of life. Pre-enucleation magnetic resonance imaging has low sensitivity and specificity for the detection of high-risk pathology.[54] As discussed, genetic counseling and testing at the time of diagnosis is the key to defining risk and planning follow-up.
Bilateral Disease
The management of bilateral disease depends on the extent of the disease in each eye. Systemic therapy should be chosen based on the eye with more extensive disease. Treatment modality options described for unilateral disease may be applied to one or both affected eyes in patients with bilateral disease.
Standard treatment options
Usually the disease is more advanced in one eye, with less involvement in the other eye. Overall treatment management is dictated by the most advanced eye. 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 follow-up for response and focal treatment (e.g., cryotherapy or laser therapy) may be indicated. EBRT is now reserved for patients whose eyes do not respond adequately to primary systemic chemotherapy and focal consolidation.
A number of large centers in Europe and North America have published trial results using systemic chemotherapy in conjunction with aggressive focal consolidation for patients with bilateral disease.[1][20][23][24][50][51][55][56][57][58][59][60][61][62] [63]; [22][Level of evidence: 3iiDiv] Chemotherapy may shrink the tumors (chemoreduction), allowing greater efficacy of subsequent focal therapy.[1][40] Treatment strategies often differ in terms of chemotherapy regimens and local control measures.
Centers using the R-E classification have demonstrated that the goal to save eyes may be achievable for tumors that are R-E Group IV or lower. The backbone of the chemoreduction protocols has generally been carboplatin, etoposide, and vincristine (CEV). Studies from The Children's Hospital of Philadelphia and Wills Eye Hospital reported that enucleation or EBRT may be avoided in R-E Group I, II, and III eyes when patients were treated with six cycles.[1][12][21] Tumors associated with massive vitreous or subretinal seeds have proven problematic.[64] Local control was often transient in patients with vitreous seeding or very large tumors (R-E Group V), and fewer than half of patients were treated successfully without requiring EBRT and/or enucleation.[1][12]
Other researchers reported the use of nine courses of CEV with the addition of high-dose cyclosporine A (a modulator of the p-glycoprotein) for eight R-E Group V eyes with an 88% (7 out of 8 eyes) success rate without the use of EBRT or enucleation.[58][59] However, conflicting results were seen in another study using the cyclosporine regimen in ten R-E Group V eyes, which reported only a 20% (2 out of 10 eyes) success rate.[60]
The International Classification system for staging intraocular retinoblastoma is a better predictor of treatment success for the use of systemic chemotherapy in combination with local control. (Refer to the Treatment Options Under Clinical Evaluation section of this summary for a more complete description of the International Classification system.) The combinations of carboplatin and etoposide (CE) [22][65] or CEV [66][67] in conjunction with local control have resulted in ocular salvage rates above 90% for early intraocular disease (Groups A and B eyes), 70% to 90% for Group C eyes, and 40% to 50% for Group D eyes.[22][65][67]; [65][Level of evidence: 3iiDiv] However, for patients with advanced intraocular disease (typically Group D eyes), EBRT is frequently required for ocular salvage.[65]; [66][Level of evidence: 3iiDiii]
For patients with large intraocular tumor burden or with subretinal or vitreous seeds (Groups C and D eyes), the use of periocular chemotherapy, usually in combination with systemic therapy, has been explored.[26][68] However, the outcome of this approach on ocular salvage is not well defined.
The treatment recommendation for Group E eyes is 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 (P < .001).[53][Level of evidence: 3iiiB]
Delivery of chemotherapy via ophthalmic artery cannulation has also been shown to be feasible and effective in patients with bilateral disease, in both the up-front and salvage settings.[31][35][Level of evidence: 3iiDii] However, this treatment should only be performed in an experienced center with a state-of-the-art treatment infrastructure and a dedicated multidisciplinary team.
The unresolved issues are long-term tumor control and the consequences of chemotherapy. Most of these patients are exposed to etoposide, which has been associated with secondary leukemia in patients without predisposition to cancer, but at modest rates when compared to the risk of EBRT in hereditary retinoblastoma. In a retrospective database and literature review, cases of secondary acute myeloid leukemia were identified among children who received epipodophyllotoxins. The actuarial risk for leukemia is not known and it is unclear whether the risk for children with retinoblastoma receiving topoisomerase II inhibitors exceeds the risk that exists for other children.[69]
Treatment Options Under Clinical Evaluation
Studies are planned for a variety of patient groups. The International Classification system is being utilized for these trials. This classification schema is based on the extent and location of intraocular retinoblastoma and is being used in the ongoing series of protocols from the COG. The preliminary version of this system was verified to be reproducible with preliminary data from five centers that staged their patients on an Internet site in August 2000. Experience with a closely related grouping system has been published.[2] Data have been published using this system in a study of chemotherapy for intraocular retinoblastoma, where stage appeared to assist in prognosis for successful treatment without enucleation or EBRT.[67]
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
- Delivery of chemotherapy via ophthalmic artery cannulation is being evaluated as an initial treatment for advanced unilateral and bilateral disease.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with intraocular retinoblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.1Shields 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, 2002.2Shields CL, Mashayekhi A, Demirci H, et al.: Practical approach to management of retinoblastoma. Arch Ophthalmol 122 (5): 729-35, 2004.3Shields CL, Meadows AT, Leahey AM, et al.: Continuing challenges in the management of retinoblastoma with chemotherapy. Retina 24 (6): 849-62, 2004.4Kim JW, Kathpalia V, Dunkel IJ, et al.: Orbital recurrence of retinoblastoma following enucleation. Br J Ophthalmol 93 (4): 463-7, 2009.5Krasin 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, 2004.6Reisner 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, 2007.7Lee 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, 2005.8Shields 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, 2001.9Merchant TE, Gould CJ, Wilson MW, et al.: Episcleral plaque brachytherapy for retinoblastoma. Pediatr Blood Cancer 43 (2): 134-9, 2004.10Shields 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, 2006.11Shields CL, Santos MC, Diniz W, et al.: Thermotherapy for retinoblastoma. Arch Ophthalmol 117 (7): 885-93, 1999.12Friedman DL, Himelstein B, Shields CL, et al.: Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma. J Clin Oncol 18 (1): 12-7, 2000.13Gündüz K, Shields CL, Shields JA, et al.: The outcome of chemoreduction treatment in patients with Reese-Ellsworth group V retinoblastoma. Arch Ophthalmol 116 (12): 1613-7, 1998.14Shields CL, Palamar M, Sharma P, et al.: Retinoblastoma regression patterns following chemoreduction and adjuvant therapy in 557 tumors. Arch Ophthalmol 127 (3): 282-90, 2009.15Lumbroso L, Doz F, Urbieta M, et al.: Chemothermotherapy in the management of retinoblastoma. Ophthalmology 109 (6): 1130-6, 2002.16Gombos 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, 2002.17Abramson DH, Lawrence SD, Beaverson KL, et al.: Systemic carboplatin for retinoblastoma: change in tumour size over time. Br J Ophthalmol 89 (12): 1616-9, 2005.18Dunkel IJ, Lee TC, Shi W, et al.: A phase II trial of carboplatin for intraocular retinoblastoma. Pediatr Blood Cancer 49 (5): 643-8, 2007.19Wilson MW, Rodriguez-Galindo C, Haik BG, et al.: Multiagent chemotherapy as neoadjuvant treatment for multifocal intraocular retinoblastoma. Ophthalmology 108 (11): 2106-14; discussion 2114-5, 2001.20Rodriguez-Galindo C, Wilson MW, Haik BG, et al.: Treatment of intraocular retinoblastoma with vincristine and carboplatin. J Clin Oncol 21 (10): 2019-25, 2003.21Kingston JE, Hungerford JL, Madreperla SA, et al.: Results of combined chemotherapy and radiotherapy for advanced intraocular retinoblastoma. Arch Ophthalmol 114 (11): 1339-43, 1996.22Zage PE, Reitman AJ, Seshadri R, et al.: Outcomes of a two-drug chemotherapy regimen for intraocular retinoblastoma. Pediatr Blood Cancer 50 (3): 567-72, 2008.23Shields 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, 2004.24Wilson 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, 2007.25Shields CL, Meadows AT, Shields JA, et al.: Chemoreduction for retinoblastoma may prevent intracranial neuroblastic malignancy (trilateral retinoblastoma). Arch Ophthalmol 119 (9): 1269-72, 2001.26Abramson DH, Frank CM, Dunkel IJ: A phase I/II study of subconjunctival carboplatin for intraocular retinoblastoma. Ophthalmology 106 (10): 1947-50, 1999.27Villablanca JG, Jubran R, Murphree AL: Phase I study of subtenon carboplatin I with systemic high dose carboplatin/etoposide/vincristine (CEV) for eyes with disseminated intraocular retinoblastoma (RB). [Abstract] Proceedings of the XIII Biannual Meeting of ISGED and the X International Symposium on Retinoblastoma, May 4, 2001, Fort Lauderdale, Fla. USA .28Marr 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, 2012.29Mallipatna AC, Dimaras H, Chan HS, et al.: Periocular topotecan for intraocular retinoblastoma. Arch Ophthalmol 129 (6): 738-45, 2011.30Muen WJ, Kingston JE, Robertson F, et al.: Efficacy and complications of super-selective intra-ophthalmic artery melphalan for the treatment of refractory retinoblastoma. Ophthalmology 119 (3): 611-6, 2012.31Gobin YP, Dunkel IJ, Marr BP, et al.: Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience. Arch Ophthalmol 129 (6): 732-7, 2011.32Peterson 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, 2011.33Abramson 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, 2012.34Bianciotto C, Shields CL, Iturralde JC, et al.: Fluorescein angiographic findings after intra-arterial chemotherapy for retinoblastoma. Ophthalmology 119 (4): 843-9, 2012.35Abramson DH, Dunkel IJ, Brodie SE, et al.: Superselective ophthalmic artery chemotherapy as primary treatment for retinoblastoma (chemosurgery). Ophthalmology 117 (8): 1623-9, 2010.36Shields 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, 2011.37Shields CL, Bianciotto CG, Jabbour P, et al.: Intra-arterial chemotherapy for retinoblastoma: report No. 2, treatment complications. Arch Ophthalmol 129 (11): 1407-15, 2011.38Shields CL, Kaliki S, Shah SU, et al.: Minimal exposure (one or two cycles) of intra-arterial chemotherapy in the management of retinoblastoma. Ophthalmology 119 (1): 188-92, 2012.39Suzuki S, Yamane T, Mohri M, et al.: Selective ophthalmic arterial injection therapy for intraocular retinoblastoma: the long-term prognosis. Ophthalmology 118 (10): 2081-7, 2011.40Levy C, Doz F, Quintana E, et al.: Role of chemotherapy alone or in combination with hyperthermia in the primary treatment of intraocular retinoblastoma: preliminary results. Br J Ophthalmol 82 (10): 1154-8, 1998.41Chantada 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, 2009.42Eagle RC Jr: High-risk features and tumor differentiation in retinoblastoma: a retrospective histopathologic study. Arch Pathol Lab Med 133 (8): 1203-9, 2009.43Uusitalo MS, Van Quill KR, Scott IU, et al.: Evaluation of chemoprophylaxis in patients with unilateral retinoblastoma with high-risk features on histopathologic examination. Arch Ophthalmol 119 (1): 41-8, 2001.44Honavar SG, Singh AD, Shields CL, et al.: Postenucleation adjuvant therapy in high-risk retinoblastoma. Arch Ophthalmol 120 (7): 923-31, 2002.45Chantada 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, 2004.46Cuenca A, Giron F, Castro D, et al.: Microscopic scleral invasion in retinoblastoma: clinicopathological features and outcome. Arch Ophthalmol 127 (8): 1006-10, 2009.47Chantada 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, 2010.48Kaliki S, Shields CL, Shah SU, et al.: Postenucleation adjuvant chemotherapy with vincristine, etoposide, and carboplatin for the treatment of high-risk retinoblastoma. Arch Ophthalmol 129 (11): 1422-7, 2011.49Shields CL, Shields JA: Editorial: chemotherapy for retinoblastoma. Med Pediatr Oncol 38 (6): 377-8, 2002.50Schouten-Van Meeteren AY, Moll AC, Imhof SM, et al.: Overview: chemotherapy for retinoblastoma: an expanding area of clinical research. Med Pediatr Oncol 38 (6): 428-38, 2002.51Shields CL, Gorry T, Shields JA: Outcome of eyes with unilateral sporadic retinoblastoma based on the initial external findings by the family and the pediatrician. J Pediatr Ophthalmol Strabismus 41 (3): 143-9; quiz 172-3, 2004 May-Jun.52Shields CL, Honavar SG, Meadows AT, et al.: Chemoreduction for unilateral retinoblastoma. Arch Ophthalmol 120 (12): 1653-8, 2002.53Zhao 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, 2011.54Chawla 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, 2012.55Beck 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, 2000.56Murphree AL, Villablanca JG, Deegan WF 3rd, et al.: Chemotherapy plus local treatment in the management of intraocular retinoblastoma. Arch Ophthalmol 114 (11): 1348-56, 1996.57Jubran RF, Murphree AL, Villablanca JG: Low dose carboplatin/etoposide/vincristine (CEV) and local therapy (LT) for intraocular retinoblastoma group II-IV eyes. [Abstract] Proceedings of the XIII Biannual Meeting of ISGED and the X International Symposium on Retinoblastoma, May 4, 2001, Fort Lauderdale, Fla. USA .58Gallie BL, Budning A, DeBoer G, et al.: Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol 114 (11): 1321-8, 1996.59Chan HSL, Heon E, Budning A, et al.: Improvement of the cure rate of intraocular retinoblastoma without significantly increasing toxicity with higher dose carboplatin-teniposide in a cyclosporine multidrug resistance-reversal regimen. [Abstract] Proceedings of the XIII Biannual Meeting of ISGED and the X International Symposium on Retinoblastoma, May 4, 2001, Fort Lauderdale, Fla. USA .60Villablanca JG, Atchaneeyasakul L, Murphree AL: Clinical outcome of group V eyes treated with cyclosporin A (CSA)/carboplatin/etoposide/vincristine (CEV). [Abstract] Proceedings of the XIII Biannual Meeting of ISGED and the X International Symposium on Retinoblastoma, May 4, 2001, Fort Lauderdale, Fla. USA .61Chan HS, Gallie BL, Munier FL, et al.: Chemotherapy for retinoblastoma. Ophthalmol Clin North Am 18 (1): 55-63, viii, 2005.62Rodriguez-Galindo C, Chantada GL, Haik BG, et al.: Treatment of retinoblastoma: current status and future perspectives. Curr Treat Options Neurol 9 (4): 294-307, 2007.63Shields 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, 2005.64Shields 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, 2002.65Lumbroso-Le Rouic L, Aerts I, Lévy-Gabriel C, et al.: Conservative treatments of intraocular retinoblastoma. Ophthalmology 115 (8): 1405-10, 1410.e1-2, 2008.66Cohen VM, Kingston J, Hungerford JL: The success of primary chemotherapy for group D heritable retinoblastoma. Br J Ophthalmol 93 (7): 887-90, 2009.67Shields CL, Mashayekhi A, Au AK, et al.: The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology 113 (12): 2276-80, 2006.68Chantada GL, Fandino AC, Carcaboso AM, et al.: A phase I study of periocular topotecan in children with intraocular retinoblastoma. Invest Ophthalmol Vis Sci 50 (4): 1492-6, 2009.69Gombos 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.
Extraocular Retinoblastoma Treatment
In developed 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 occur into the brain and meninges with subsequent seeding of the spinal fluid, as well as distant metastatic disease involving the lungs, bones, and bone marrow.
Standard Treatment Options
Orbital and loco-regional retinoblastoma
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; lymphatic, hematogenous, and central nervous system (CNS) metastases occur in the remaining patients. Treatment should include systemic chemotherapy and radiation therapy; with this approach, 60% to 85% of patients can be cured. Since most recurrences occur in the CNS, regimens using drugs with well-documented CNS penetration are recommended. 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] For patients with macroscopic orbital disease, it is recommended that surgery is delayed until response to chemotherapy has been obtained (usually two or three courses of treatment). Enucleation should then be performed and an additional four to six courses of chemotherapy administered. Local control should then be consolidated with orbital irradiation (40 Gy to 45 Gy). Using this approach, orbital exenteration is not indicated. Patients with isolated involvement of the optic nerve at the transsection level should also receive similar systemic treatment, and irradiation should include the entire orbit (36 Gy) with 10 Gy boost to the chiasm (total 46 Gy).
Central nervous system disease
Intracranial dissemination occurs by direct extension through the optic nerve and its prognosis is dismal. Treatment for these patients should include platinum-based intensive systemic chemotherapy and CNS-directed therapy. Although intrathecal chemotherapy has been traditionally used, there is no preclinical or clinical evidence to support its use. Although the use of irradiation in these patients is controversial, responses have been observed with craniospinal irradiation, 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.[2][Level of evidence: 3iiA]
Trilateral retinoblastoma
Trilateral retinoblastoma is usually associated with a pineal or, less commonly, a suprasellar lesion. In patients with the hereditary form of retinoblastoma, CNS disease is less likely the result of metastatic or regional spread than 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. While pineoblastomas occurring in older patients are sensitive to radiation therapy, current strategies are directed towards avoiding irradiation 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.[3]
Because of the poor prognosis of trilateral retinoblastoma, screening neuroimaging is a common practice. While it is not clear whether early diagnosis can impact survival, the frequency of screening with magnetic resonance imaging for those suspected of having hereditary disease or those with unilateral disease and a positive family history has been recommended as often as every 6 months for up to 5 years. Given the short interval between the diagnosis of retinoblastoma and the occurrence of trilateral retinoblastoma, routine screening might detect the majority of cases within 2 years. However, it is not clear that screening by neuroimaging improves survival.[4] Computed tomography scans should be avoided for routine screening in these children because of the perceived risk of exposure to ionizing radiation.
Extracranial metastatic retinoblastoma
Hematogenous metastases may develop in the bones, bone marrow, and less frequently, in the liver. Although long-term survivors have been reported with conventional chemotherapy, these reports should be considered anecdotal; metastatic retinoblastoma is not curable with conventional chemotherapy. In recent years, 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.[5][6][7][8][9][10]; [11][Level of evidence: 3iiA]
There is no clearly proven effective or standard therapy for the treatment of extraocular retinoblastoma, although orbital irradiation and chemotherapy have been used. In the past, palliative therapy with radiation therapy (including craniospinal irradiation when there is meningeal involvement) and/or intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone, plus supportive care has been used.[12] A retrospective study showed that extraocular disease, manifested by gadolinium enhancement on magnetic resonance imaging of the proximal optic nerve, might respond to treatment with neoadjuvant chemotherapy prior to enucleation.[13][Level of evidence: 3iiDi]
Treatment Options Under Clinical Evaluation
Two reports suggest that there may be a role for intensive multimodality therapy with autologous stem cell rescue for patients with metastatic retinoblastoma.[2][11][Level of evidence: 3iiA] A few responses were noted in both CNS (including trilateral) and systemic metastases. However, these strategies remain under clinical investigation.
The following is an example of national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
- COG-ARET0321 (Combination Chemotherapy, Autologous Stem Cell Transplant [SCT], and/or Radiation Therapy in Treating Young Patients With Extraocular Retinoblastoma): Patients with metastatic or recurrent retinoblastoma that is beyond the globe are eligible for treatment with combined conventional chemotherapy, high-dose chemotherapy, and SCT with conventional radiation.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with extraocular retinoblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.1Antoneli 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, 2007.2Dunkel 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, 2010.3Dunkel IJ, Jubran RF, Gururangan S, et al.: Trilateral retinoblastoma: potentially curable with intensive chemotherapy. Pediatr Blood Cancer 54 (3): 384-7, 2010.4Kivelä T: Trilateral retinoblastoma: a meta-analysis of hereditary retinoblastoma associated with primary ectopic intracranial retinoblastoma. J Clin Oncol 17 (6): 1829-37, 1999.5Namouni 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, 1997.6Kremens 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, 2003.7Rodriguez-Galindo C, Wilson MW, Haik BG, et al.: Treatment of metastatic retinoblastoma. Ophthalmology 110 (6): 1237-40, 2003.8Dunkel IJ, Aledo A, Kernan NA, et al.: Successful treatment of metastatic retinoblastoma. Cancer 89 (10): 2117-21, 2000.9Matsubara 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, 2005.10Jubran 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, 2004.11Dunkel IJ, Khakoo Y, Kernan NA, et al.: Intensive multimodality therapy for patients with stage 4a metastatic retinoblastoma. Pediatr Blood Cancer 55 (1): 55-9, 2010.12Rootman J, Hofbauer J, Ellsworth RM, et al.: Invasion of the optic nerve by retinoblastoma: a clinicopathological study. Can J Ophthalmol 11 (2): 106-14, 1976.13Armenian SH, Panigrahy A, Murphree AL, et al.: Management of retinoblastoma with proximal optic nerve enhancement on MRI at diagnosis. Pediatr Blood Cancer 51 (4): 479-84, 2008.
Recurrent Retinoblastoma Treatment
The prognosis for a patient with recurrent or progressive retinoblastoma depends on the site and extent of the recurrence or progression, as well as previous treatment. New intraocular tumors can arise in patients with the hereditary form of disease whose eyes have been treated with focal measures only, since every cell in the retina carries the RB1 mutation; this is not technically recurrence. Even with prior treatment consisting of chemoreduction and focal measures in very young patients with hereditary retinoblastoma, surveillance may detect new tumors at an early stage and additional focal therapy, including plaque brachytherapy, can be successful in eradicating tumor.[1][2][3][4][5] 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.[6][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. Recurrence in the orbit after enucleation should be treated with aggressive chemotherapy in addition to local radiation therapy because of the high risk of metastatic disease.[7][Level of evidence: 3iiA] If the recurrence or progression is extraocular, the chance of survival is probably less than 50%. In this circumstance, the treatment depends on many factors and individual patient considerations and clinical trials may be appropriate and should be considered.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent retinoblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.1Shields 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, 2002.2Gombos 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, 2002.3Shields 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, 2003.4Lee 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, 2003.5Wilson 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, 2007.6Chan 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, 2009.7Kim JW, Kathpalia V, Dunkel IJ, et al.: Orbital recurrence of retinoblastoma following enucleation. Br J Ophthalmol 93 (4): 463-7, 2009.
Changes to This Summary (10/05/2012)
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
Revised text to state that the RB1 germline mutation may have been inherited from an affected progenitor or may have occurred in utero at the time of conception, in patients with sporadic disease. Also revised text to state that the penetrance of the mutation is probably dependent on concurrent genetic modifiers such as MDM2 and MDM4 (cited de Oliveira et al. as reference 5).
Added text about how early-in-life screening by fundus exams under general anesthesia at regular intervals can improve prognosis in terms of globe sparing in children with positive family histories of retinoblastoma (cited Rothschild et al. as reference 10).
The Subsequent neoplasms subsection was renamed from Second malignant neoplasms.
Revised text to state that more recent studies analyzing cohorts of patients treated with more advanced radiation planning and delivery technology have reported the incidence to be about 9.4% in nonirradiated patients and about 30.4% in irradiated patients.
Stage Information
Revised text to state that extraocular retinoblastoma may be confined to the tissues around the eye (orbital retinoblastoma), or it may have spread to the central nervous system, bone marrow, or lymph nodes (metastatic retinoblastoma).
Intraocular Retinoblastoma Treatment
This section was extensively revised.
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:
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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 Jean Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
- Thomas A. Olson, MD (AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus)
- Carlos Rodriguez-Galindo, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
- Nita Louise Seibel, MD (National Cancer Institute)
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. 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.
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National Cancer Institute: PDQ® Retinoblastoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/retinoblastoma/HealthProfessional. Accessed <MM/DD/YYYY>.
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This information was last updated on 2012-10-05


text:
Bots Overview
Acclaim's Bot is a simple Robo beat 'em up that offers both cooperative and versus gameplay modes. Players can clear 31 stages with up to 8 other players in Sector Mode. In Base mode, two teams of players must destroy the enemy team's base while defending their own. Player Battle mode is a simpler PvP experience, the last man standing wins. There are only three starting Bots to chose from but the item shop is full of equipment with which to customize your character! The three Bots are:
Patch - Originally designed as a heavy construction machine, Patch was remodeled for combat purposes.
Surge - Armed with powerful lasers and an anti gravity core, Surge was built for combat.
Ram - Equipped with a large, powerful arm capable of crushed most objects, Ram is a multi purpose Bot with good utility.
Bots Screenshots
Bots Feature Video
Bots Review
By Erhan Altay
Bots is Acclaim's take on the popular mech genre but rather than a full fledged MMORPG like Age of Armor, Bots is closer to Exteel, by NCsoft. Players chose a mech during character creation, join player hosted rooms and gain experience and currency based on their performance. The graphic style in Bots is more cartoonish than Exteel's and looks something like Nintendo's Custom Robo.
Robo Choice
I'm not sure how old of a game Bots is but it certainly is not recent. The game's graphic look and feel aged. Technically, it's a 3D game but looks worse than many recent 2D releases. Character customization is a letdown – there are a grand total of 3 Bots to choose from; Patch, Surge or Ram. There's not much to explain about them except that Surge levitates. After selecting your Bot type and name, you're taken to the game lobby. There are several channels but the only one with any players seems to be the free channel. This means new players will likely end up playing with others much higher level then themselves. This isn't a problem in the game's most popular mode – Sector. In Sector, players work together (up to 8 per room) to complete various stages, each with a boss at the end. In total there are 31 sector stages and running them is the best way for beginners to gain experience and Gigas, the game's currency. Sadly, most players host high level maps and have a tendency to kick out low level players. If you want to get ahead in Bots, you'll either have to grind through the same sector maps solo or with friend who started at the same time as you. Fortunately, the controls in Bots are easy enough and can be customized to your liking. By default, the arrow keys move while V attacks, C jumps, X blocks and Z activates 'trance' mode which transforms the player into a more powerful bot for a short time.
Bot on Bot Action
Bots two other game modes; Base and 'Players' are competitive rather than cooperative. Base is the more interesting of the two, players are divided into two teams and must destroy the opposing team's core while defending their own. Player mode is a simple free for all death match with the last man standing as the victor.From my experience, playing either of these games modes during your first few levels is futile. The random rooms I joined put me against level 50+ Bots that completely demolished me. New players are better off sticking with Sector mode until they can afford better gear. From what I experienced, combat in Bots has a lot of technique involved. Players have to know when to attack, use their trance mode, and when to use special attacks. There's plenty of equipment available for purchase at the item shop but sadly most of it is only available with the use of coins which can only be obtained with real money. The stuff that is priced in Gigas is often expensive and has minimum level requirements.
My Bot has a Virus…
Despite being an old game, Bots continues to suffer from some bugs. When you purchase new gear from the shop, with Gigas or real money, they have a tendency to disappear. There is a guide on how to avoid this on the forums but it really shouldn't be necessary. I also found the number of in-game ads annoying. Before every match begins players must stare at an ad. This would make sense if the ads were advertising something other than Bots – the game we're playing! On the bright side, Bots has a high level cap (100.) It takes about a month and a half to get to level 50 so there's enough here to keep the dedicated player coming back for a long time. The trouble is, can it attract new players? The lighter graphic style and easier controls do make it more appealing than Exteel at first glance, especially for younger players, but I can't recommend this game when Exteel is better on almost all counts.
Final Verdict: Fair
Bots has a small but dedicated following and offers enough to keep fans coming back but not enough to appeal to a broad audience. With only three characters to chose from, aging graphics, and several bugs, Bots is a difficult game to get into.
Bots Videos
Bots Character Creation
Bots PvP Trailer
Bots Gameplay Trailer
Bots Arena Video
Bots Pro Gameplay Trailer
Bots Links
Bots System Requirements
Minimum Requirements:
OS: Windows XP / 2000 / Vista
CPU: Pentium III
HDD: 800 MB Free
Graphics Card: 32 MB Video card
DirectX: 9.0c
Recommended Specification:
OS: Windows XP/ Vista
CPU: Pentium IV or better
RAM: 512 MB or more
HDD: 1.0 GB or more
Graphics Card: 64 MB Video card or better
DirectX: 9.0c or better

subset: commoncrawl