Eye, retinoblastoma: Treatment - Health Professional Information [NCI PDQ]

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Retinoblastoma Treatment (PDQ®)

General Information

This cancer treatment information summary provides an overview of the prognosis, diagnosis, classification, and treatment of retinoblastoma.

The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public. These summaries are updated regularly according to the latest published research findings by an Editorial Board of pediatric oncology specialists.

Cancer in children and adolescents is rare. 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 in order to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive 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.[1] 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.

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. 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.[2] The estimated annual incidence is approximately 4 per million children. Although retinoblastoma may occur at any age, it most often occurs in younger children, usually before the age of 2 years. Ninety-five percent of cases are diagnosed before the age of 5 years. The tumor may be either unilateral (75%) or bilateral (25%). Retinoblastoma is usually confined to the eye, and as a result, more than 90% of children with retinoblastoma will be cured. The present challenge for those who treat retinoblastoma is to prevent blindness and other serious effects of treatment that reduce the life span or the quality of survival.

Retinoblastoma is a tumor that occurs in germline (40%) and sporadic (60%) forms. Germline disease includes those patients with a positive family history (hereditary disease) and those patients who have sustained a new germline mutation at the time of conception. The genetic locus responsible for a predisposition to retinoblastoma is located within the q14 band of chromosome 13.

The germline form of retinoblastoma may manifest as unilateral or bilateral disease. Most unilateral disease is sporadic or nongermline, whereas all children with bilateral disease have the germline form. Germline tumors tend to occur at a younger age than sporadic tumors. Unilateral tumors in infants are more likely to have germline mutations, whereas older children with unilateral tumors are more likely to have sporadic tumors.[3] Unilateral tumors in younger children have fewer genetic abnormalities than those in older children.[4] Children with the germline form (positive family history and/or bilateral retinoblastoma or mutations in the RB gene) who have a normal examination in at least one eye on initial presentation need to be examined frequently for the development of new retinoblastoma tumors. It is recommended that they be examined every 2 to 4 months for at least 28 months.[5] Following treatment, patients require careful surveillance until age 7 years.[6]

Genetic counseling should be an integral part of the therapy for a patient with retinoblastoma, whether unilateral or bilateral. Genetic counseling, however, is not always straightforward. Families with retinoblastoma may have a founder with embryonic mutagenesis causing genetic mosaicism of gametes.[7] A significant proportion (10%-18%) of children with retinoblastoma have somatic genetic mosaicism,[8] [9] making the genetic story more complex and contributing to the difficulty of genetic counseling.

Trilateral retinoblastoma is a well-recognized syndrome that consists of unilateral or bilateral germline retinoblastoma associated with an intracranial neuroblastic tumor. It has been observed that 5% to 15% of children with either familial, multifocal, or bilateral retinoblastoma may develop an intracranial neuroblastic tumor as well.[10] Children with germline retinoblastoma have a particularly high incidence of trilateral retinoblastoma, which is nearly always fatal.[11] It also has been found that patients who are asymptomatic at the time of diagnosis with an intracranial tumor have a better overall survival than patients who are symptomatic.[10] Screening by neuroimaging may improve the cure rate. It has been recommended that children with germline retinoblastoma should be screened using magnetic resonance neuroimaging every 6 months after diagnosis for the next 4 years, since these tumors are not likely to occur after the age of 5 years.[11] The current practice of using chemotherapy to reduce the extent of intraocular tumor in bilateral cases may prevent the development of pineal tumors.[12]

Patients with the germline type of retinoblastoma have a markedly increased frequency of second malignant neoplasms (SMN).[13] The cumulative incidence is about 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.[14] Most of the SMN are osteosarcomas, soft tissue sarcomas, or melanomas. However, a markedly increased mortality from lung, bladder, and other epithelial cancers occurs in patients with germline retinoblastoma who were spared radiation. Tobacco use is associated with these cancers in this uniquely susceptible population.[15] The carcinogenic effect of radiation increases with dose. In irradiated patients, two thirds of the second cancers occur within irradiated tissue and one third outside the radiation field.[14] The risk for SMN in the field of radiation is heavily dependent on the patient’s age at the time the external-beam radiation is given. This risk may be less for patients older than 12 months.[6,16]

A study from the United Kingdom following patients treated with high doses of radiation therapy from 1873 until 1950 found that among 144 survivors, 58 subsequent cancers developed between age 25 and 84 years, for a cumulative cancer incidence of 68.8%. Of note, only 8 of those cancers were of bone and soft tissue, and epithelial cancers were more common, with survival from same being quite poor.[15]

Survival from second malignancies is certainly suboptimal and varies widely across studies.[15,17,18,19] However, with advances in therapy, it is essential that all second malignancies should be treated with curative intent.[20] Those who survive SMN are at increased risk for developing additional malignancies at a rate of about 2% per year.[21] There is no clear increase in second malignancies in patients with sporadic retinoblastoma beyond that associated with the treatment.[14] [19]

All siblings of patients with retinoblastoma should be examined, and studies suggest that DNA polymorphism analysis may help predict which persons are at risk and warrant close follow-up. Cytogenetic abnormalities (e.g., deletion on the long arm of chromosome 13) are sometimes observed.[22] Clinical laboratory service is now becoming available in some centers for performing genetic testing of relatives of retinoblastoma patients to determine risk of hereditary susceptibility to the disease. Although confined to use in research, exon by exon sequencing of the RB1 gene demonstrates germline mutation in 90% of patients with germline retinoblastoma.[23,24] Although a positive finding with current technology confirms susceptibility, a negative finding cannot absolutely rule it out.

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.[25] 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.[26,27] Examples include patients with an abnormal complete blood count (CBC) or those whose tumors extend beyond the lamina cribrosa on pathologic examination of the enucleated specimen.

Most patients with retinoblastoma have extensive disease within the 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. [28] The goals of therapy are 3-fold: eradicate the disease, preserve as much vision as possible, and decrease risk of late sequelae from treatment, particularly SMN. 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.[29]

References:

1. Guidelines 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.
2. Hurwitz RL, Shields CL, Shields JA: Retinoblastoma. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 4th ed. Philadelphia, Pa: Lippincott, Williams and Wilkins, 2002, pp 825-46.
3. Zajaczek S, Jakubowska A, Kurzawski G, et al.: Age at diagnosis to discriminate those patients for whom constitutional DNA sequencing is appropriate in sporadic unilateral retinoblastoma. Eur J Cancer 34 (12): 1919-21, 1998.
4. Herzog S, Lohmann DR, Buiting K, et al.: Marked differences in unilateral isolated retinoblastomas from young and older children studied by comparative genomic hybridization. Hum Genet 108 (2): 98-104, 2001.
5. Abramson DH, Mendelsohn ME, Servodidio CA, et al.: Familial retinoblastoma: where and when? Acta Ophthalmol Scand 76 (3): 334-8, 1998.
6. Abramson DH, Frank CM: Second nonocular tumors in survivors of bilateral retinoblastoma: a possible age effect on radiation-related risk. Ophthalmology 105 (4): 573-9; discussion 579-80, 1998.
7. Munier 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.
8. Sippel 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.
9. Munier 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.
10. Paulino AC: Trilateral retinoblastoma: is the location of the intracranial tumor important? Cancer 86 (1): 135-41, 1999.
11. Kivelä T: Trilateral retinoblastoma: a meta-analysis of hereditary retinoblastoma associated with primary ectopic intracranial retinoblastoma. J Clin Oncol 17 (6): 1829-37, 1999.
12. Shields CL, Meadows AT, Shields JA, et al.: Chemoreduction for retinoblastoma may prevent intracranial neuroblastic malignancy (trilateral retinoblastoma). Arch Ophthalmol 119 (9): 1269-72, 2001.
13. Gallie BL, Dunn JM, Chan HS, et al.: The genetics of retinoblastoma. Relevance to the patient. Pediatr Clin North Am 38 (2): 299-315, 1991.
14. Wong FL, Boice JD Jr, Abramson DH, et al.: Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. JAMA 278 (15): 1262-7, 1997.
15. Fletcher O, Easton D, Anderson K, et al.: Lifetime risks of common cancers among retinoblastoma survivors. J Natl Cancer Inst 96 (5): 357-63, 2004.
16. Moll AC, Imhof SM, Schouten-Van Meeteren AY, et al.: Second primary tumors in hereditary retinoblastoma: a register-based study, 1945-1997: is there an age effect on radiation-related risk? Ophthalmology 108 (6): 1109-14, 2001.
17. Aerts I, Pacquement H, Doz F, et al.: Outcome of second malignancies after retinoblastoma: a retrospective analysis of 25 patients treated at the Institut Curie. Eur J Cancer 40 (10): 1522-9, 2004.
18. Eng C, Li FP, Abramson DH, et al.: Mortality from second tumors among long-term survivors of retinoblastoma. J Natl Cancer Inst 85 (14): 1121-8, 1993.
19. Dunkel IJ, Gerald WL, Rosenfield NS, et al.: Outcome of patients with a history of bilateral retinoblastoma treated for a second malignancy: the Memorial Sloan-Kettering experience. Med Pediatr Oncol 30 (1): 59-62, 1998.
20. Moll AC, Imhof SM, Bouter LM, et al.: Second primary tumors in patients with retinoblastoma. A review of the literature. Ophthalmic Genet 18 (1): 27-34, 1997.
21. Abramson DH, Melson MR, Dunkel IJ, et al.: Third (fourth and fifth) nonocular tumors in survivors of retinoblastoma. Ophthalmology 108 (10): 1868-76, 2001.
22. Wiggs J, Nordenskjöld M, Yandell D, et al.: Prediction of the risk of hereditary retinoblastoma, using DNA polymorphisms within the retinoblastoma gene. N Engl J Med 318 (3): 151-7, 1988.
23. Noorani 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.
24. Lohmann 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.
25. Kopelman JE, McLean IW, Rosenberg SH: Multivariate analysis of risk factors for metastasis in retinoblastoma treated by enucleation. Ophthalmology 94 (4): 371-7, 1987.
26. Moscinski 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.
27. Pratt 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.
28. Abramson 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.
29. Abramson DH, Melson MR, Servodidio C: Visual fields in retinoblastoma survivors. Arch Ophthalmol 122 (9): 1324-30, 2004.

Cellular Classification

The tumor is composed mainly of undifferentiated anaplastic cells that arise from the nuclear layers of 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]

References:

1. Schwimer 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 currently available for retinoblastoma, for the purpose of treatment, retinoblastoma is categorized into intraocular and extraocular disease.

Intraocular

5-year disease-free survival: >90%

Intraocular retinoblastoma is localized to the eye and may be confined to the retina or may extend to involve the globe; however, it does not extend beyond the eye into the tissues around the eye or to other parts of the body.

Extraocular

5-year disease-free survival: <10%

Extraocular retinoblastoma has extended beyond the eye. It may be confined to the tissues around the eye, or it may have spread, typically to the central nervous system (CNS) or to other parts of the body.

Reese-Ellsworth classification for intraocular tumors

Reese and Ellsworth have developed a generally adopted 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 were the only treatment options. The Reese-Ellsworth system is relevant to decisions regarding the use of local treatment modalities and chemoreduction, but another system has since evolved which may offer greater precision in stratifying risk for newer therapies. (See International Classification System in the Future Directions section of this summary.)

Group I: very favorable for maintenance of sight

1. Solitary tumor, smaller than 4 disc diameters, at or behind the equator.
2. Multiple tumors, none larger than 4 disc diameters all at or behind the equator.

Group II: favorable for maintenance of sight

1. Solitary tumor, 4-10 disc diameters at or behind the equator.
2. Multiple tumors, 4-10 disc diameters behind the equator.

Group III: possible for maintenance of sight

1. Any lesion anterior to the equator.
2. Solitary tumor, larger than 10 disc diameters behind the equator.

Group IV: unfavorable for maintenance of sight

1. Multiple tumors, some larger than 10 disc diameters.
2. Any lesion extending anteriorly to the ora serrata.

Group V: very unfavorable for maintenance of sight

1. Massive tumors involving more than one half the retina.
2. Vitreous seeding.

Treatment Option Overview

Treatment planning by a multidisciplinary team of cancer specialists who have experience treating ocular tumors of childhood is required to determine and implement optimum treatment. Because of the complexity of therapy, expertise in pediatric radiation therapy and ophthalmology should be available.

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

Intraocular Retinoblastoma

Treatment of retinoblastoma should be planned after the extent of the tumor within and outside the eye is known. Treatment options consider both cure and preservation of sight.[1,2]

Treatment options for the involved eye include the following:

1. Enucleation, if the tumor is massive or if there is little expectation for useful vision.
2. External-beam radiation with doses ranging from 3,500 to 4,600 cGy. 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 external-beam radiation are being used at many centers in an attempt to reduce adverse long-term effects. This includes intensity-modulated radiation therapy (IMRT),[3] stereotactic radiation therapy, and proton-beam radiation therapy. The Children's Oncology Group (COG) is conducting a clinical trial in which reduced-dose (2,600 cGy) IMRT is being used in combination with chemoreduction.
3. Cryotherapy, used in addition to radiation or in place of photocoagulation for lesions smaller than 4 disc diameters in the anterior portion of the retina.
4. Light coagulation (photocoagulation), occasionally used alone with small tumors. In patients with early-stage disease, light coagulation is usually used in addition to radiation therapy or when there is limited recurrence following radiation therapy. Photocoagulation is used for posteriorly located tumors that are smaller than 4 disc diameters, distinct from the optic nerve head and macula, and without involvement of large nutrient vessels or choroid involvement. Thermotherapy delivered via infrared radiation is an alternative to laser photocoagulation.[4]
5. Brachytherapy with radioactive plaques for either focal unilateral presentations or recurrent disease following previous external-beam radiation.[5,6]
6. Systemic chemotherapy: During the past 10 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 photocoagulation.[1,2,7] Chemotherapy may also be continued or initiated with concurrent local control interventions.[8] Factors such as tumor location (macula), patient age (patient older than 2 months), and tumor size correlate with responsiveness to chemotherapy.[8,9] Multiagent chemotherapy is generally used although carboplatin as a single agent causes shrinkage of retinoblastoma tumors.[10]Most tumors treated with vincristine and carboplatin require additional local therapy;[1,2,7,11,12] the addition of etoposide to the chemotherapy regimen may improve outcome.[9,13] With the use of etoposide, there is a risk of developing secondary leukemia, though no cases have yet been reported from the clinical trials undertaken over the past 10 years. The success rate of these trials varies from center to center, but overall, the rate is highest for tumors that are unilateral or unifocal and without vitreous seeding (see below). There are emerging data suggesting that the use of systemic chemotherapy may decrease the risk of development of trilateral retinoblastoma.[14] Local tumor recurrence is not uncommon in the first few years after treatment,[15] and can often be successfully treated with local interventions.
7. Subtenon (subconjunctival) chemotherapy: Carboplatin is administered by the treating ophthalmologist into the subconjunctival space. This modality is undergoing testing in phase I and II trials and is generally used in conjunction with systemic chemotherapy and local ophthalmic therapies for retinoblastoma with vitreous seeding. This approach offers some promise in this group of patients.[16,17]

Unilateral disease

Standard treatment options

Because most unilateral disease is usually massive and there is often no expectation that useful vision can be preserved, surgery (enucleation) is usually undertaken and radiation therapy is not given to the tumor bed. Even this is being tested, however, as patients with unilateral disease have been treated with chemotherapy in an attempt to preserve vision in the affected eye.[2,18,19]

When there is potential for preservation of sight because the tumors are smaller, treatment with other modalities (radiation therapy, photocoagulation, cryotherapy, thermotherapy, chemoreduction, and brachytherapy) instead of surgery should be considered. In selected children with unilateral disease, chemoreduction reduced the need for enucleation or external-beam radiation to 68% within 5 years of treatment. RE group correlated with successful chemoreduction: 11% of children classified as having RE group II or III disease, 60% of children having RE group IV disease, and 100% of children having RE group V disease required enucleation or external-beam radiation within 5 years of treatment.[20]

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. Asynchronous bilateral disease occurs most frequently in families with affected parents.

Careful examination of the enucleated specimen by an experienced pathologist is necessary to determine whether high-risk features for metastatic disease are present. These include anterior chamber seeding, choroidal involvement, tumor beyond the lamina cribrosa, intraocular hemorrhage, or scleral and extrascleral extension.[21] Systemic adjuvant therapy with vincristine, doxorubicin, and cyclophosphamide, or 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.[22,23,24] Clinical trials are needed to determine precisely what features are truly high risk.

Bilateral disease

The management of bilateral disease depends on the extent of the disease in each eye.

Standard treatment options

Usually the disease is more advanced in one eye, with less involvement in the other eye. The standard of care in the past has been to enucleate the more involved eye; however, if there is potential for vision in both eyes, bilateral irradiation or chemoreduction with close follow-up for response and focal treatment (e.g., cryotherapy or laser therapy) is indicated.

A number of large centers in Europe and North America have published trial results using systemic chemotherapy for patients whose intraocular tumors are not initially amenable to local management.[2,7,12,13,15,18,19,25,26,27,28,29,30] Examples of such tumors are those that are too large to be treated with either cryotherapy, laser photocoagulation, or plaque radiation therapy (brachytherapy). Another example is the newborn with a tumor over the optic nerve head. All these situations share the likelihood that local therapy would limit vision as to offer little improvement over enucleation. Most centers have limited this approach to patients with bilateral disease, reasoning that for patients with unilateral disease, the morbidity of enucleation is modest. When disease is massive and there is no expectation that useful vision can be preserved, surgery is usually undertaken and radiation therapy is not given.

In all cases, the goal of chemotherapy is the reduction (hence the term chemoreduction) of tumor volume, making possible the use of local therapy (cryotherapy, photocoagulation, thermotherapy, plaque radiation therapy).[2,21] All centers reporting to date have demonstrated the short-term goal is achievable, especially for tumors that are Reese-Ellsworth (RE) group IV or lower, reporting responses in nearly 75% of eyes. Group V tumors, particularly those with vitreous seeding, have proven problematic.[18,19] Subretinal seeds have a recurrence rate of 5% following chemotherapy.[31]

The backbone of the chemoreduction protocols has generally been carboplatin, etoposide, and vincristine (CEV). Studies from The Children’s Hospital in Philadelphia and Wills Eye Hospital reported complete success in the avoidance of enucleation or external-beam radiation therapy in RE group I, II, and III eyes when patients were treated for 6 cycles.[1,2] Other available data have been published in abstract form, and larger studies with more mature data are still required to make definitive conclusions. A similar study at Children’s Hospital of Los Angeles reported 13 group B (RE groups I-IV) eyes treated with only 3 courses of this chemotherapy with 6 of 11 patients successfully treated. Three patients were salvaged with further chemotherapy only, for a total of 9 of 11 (82%) patients who did not require enucleation and/or external-beam radiation therapy.[27] However, local control was often transient in patients with vitreous seeding or very large tumors (RE group V), and fewer than half of patients were treated successfully without requiring external-beam radiation therapy and/or enucleation.[1,2] Several strategies have been used in an attempt to overcome this problem. Researchers reported the use of 9 courses of CEV with the addition of high-dose cyclosporine A as a modulator of the p-glycoprotein for 8 group RE V eyes with an 88% (7/8 eyes) success rate without the use of external-beam radiation therapy or enucleation.[28,29] However, researchers, using the Gallie regimen in 10 RE Group V eyes, reported only a 20% (2/10 eyes) success rate.[30]

When the International Classification system (a classification system currently being evaluated in clinical trials by the COG) was applied to these data retrospectively, approximately 30% of Group C and 70% of Group D eyes failed systemic chemotherapy alone and achieved responses in pilot studies. (Refer to the Future Directions section of this summary for a more complete description of the International Classification system.)

This has led to newer adjuvant therapies, including subtenon (subconjunctival) carboplatin in pilot studies that also use higher doses of carboplatin or etoposide.[16,17]

The unresolved issues are long-term tumor control and the consequences of chemotherapy. All 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 external-beam irradiation in germline retinoblastoma.[32,33] Whether patients with germline retinoblastoma will have greater susceptibility to chemotherapy-induced second tumors is not known. Some patients will progress, and the risk of exposure both to chemotherapy and irradiation in this population has not been determined.

Future directions

Studies are planned for a variety of patient groups. The International Classification system, which is still under modification 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 upcoming series of protocols from COG. The preliminary version of this system was verified to be reproducible with preliminary data from 5 centers that staged their patients on an Internet site in August 2000. Experience with a closely related grouping system has been published.[34]

For patients without large tumors or retinal/subretinal seeding, COG is investigating the use of vincristine and carboplatin chemoreduction combined with local ophthalmic therapies, without the use of etoposide. For patients with large tumors and retinal/subretinal seeding, COG is investigating use of higher doses of systemic carboplatin, combined with subconjunctival carboplatin and lower doses of external-beam radiation therapy, using intensity-modulated approaches. Also under investigation is the use of adenovirus-mediated gene therapy for treatment of vitreous tumor seeding.[35]

References:

1. Friedman DL, Himelstein B, Shields CL, et al.: Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma. J Clin Oncol 18 (1): 12-7, 2000.
2. Shields CL, Honavar SG, Meadows AT, et al.: Chemoreduction plus focal therapy for retinoblastoma: factors predictive of need for treatment with external beam radiotherapy or enucleation. Am J Ophthalmol 133 (5): 657-64, 2002.
3. Krasin MJ, Crawford BT, Zhu Y, et al.: Intensity-modulated radiation therapy for children with intraocular retinoblastoma: potential sparing of the bony orbit. Clin Oncol (R Coll Radiol) 16 (3): 215-22, 2004.
4. Shields CL, Santos MC, Diniz W, et al.: Thermotherapy for retinoblastoma. Arch Ophthalmol 117 (7): 885-93, 1999.
5. Shields CL, Shields JA, Cater J, et al.: Plaque radiotherapy for retinoblastoma: long-term tumor control and treatment complications in 208 tumors. Ophthalmology 108 (11): 2116-21, 2001.
6. Merchant TE, Gould CJ, Wilson MW, et al.: Episcleral plaque brachytherapy for retinoblastoma. Pediatr Blood Cancer 43 (2): 134-9, 2004.
7. Gündüz 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.
8. Lumbroso L, Doz F, Urbieta M, et al.: Chemothermotherapy in the management of retinoblastoma. Ophthalmology 109 (6): 1130-6, 2002.
9. Gombos DS, Kelly A, Coen PG, et al.: Retinoblastoma treated with primary chemotherapy alone: the significance of tumour size, location, and age. Br J Ophthalmol 86 (1): 80-3, 2002.
10. Abramson 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.
11. Wilson 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.
12. Rodriguez-Galindo C, Wilson MW, Haik BG, et al.: Treatment of intraocular retinoblastoma with vincristine and carboplatin. J Clin Oncol 21 (10): 2019-25, 2003.
13. Kingston JE, Hungerford JL, Madreperla SA, et al.: Results of combined chemotherapy and radiotherapy for advanced intraocular retinoblastoma. Arch Ophthalmol 114 (11): 1339-43, 1996.
14. Shields CL, Meadows AT, Shields JA, et al.: Chemoreduction for retinoblastoma may prevent intracranial neuroblastic malignancy (trilateral retinoblastoma). Arch Ophthalmol 119 (9): 1269-72, 2001.
15. Shields CL, Mashayekhi A, Cater J, et al.: Chemoreduction for retinoblastoma. Analysis of tumor control and risks for recurrence in 457 tumors. Am J Ophthalmol 138 (3): 329-37, 2004.
16. Abramson DH, Frank CM, Dunkel IJ: A phase I/II study of subconjunctival carboplatin for intraocular retinoblastoma. Ophthalmology 106 (10): 1947-50, 1999.
17. Villablanca 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 .
18. Shields CL, Shields JA: Editorial: chemotherapy for retinoblastoma. Med Pediatr Oncol 38 (6): 377-8, 2002.
19. Schouten-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.
20. Shields CL, Honavar SG, Meadows AT, et al.: Chemoreduction for unilateral retinoblastoma. Arch Ophthalmol 120 (12): 1653-8, 2002.
21. Levy 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.
22. Uusitalo 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.
23. Honavar SG, Singh AD, Shields CL, et al.: Postenucleation adjuvant therapy in high-risk retinoblastoma. Arch Ophthalmol 120 (7): 923-31, 2002.
24. Chantada GL, Dunkel IJ, de Dávila MT, et al.: Retinoblastoma patients with high risk ocular pathological features: who needs adjuvant therapy? Br J Ophthalmol 88 (8): 1069-73, 2004.
25. Beck MN, Balmer A, Dessing C, et al.: First-line chemotherapy with local treatment can prevent external-beam irradiation and enucleation in low-stage intraocular retinoblastoma. J Clin Oncol 18 (15): 2881-7, 2000.
26. Murphree AL, Villablanca JG, Deegan WF 3rd, et al.: Chemotherapy plus local treatment in the management of intraocular retinoblastoma. Arch Ophthalmol 114 (11): 1348-56, 1996.
27. Jubran 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 .
28. Gallie BL, Budning A, DeBoer G, et al.: Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol 114 (11): 1321-8, 1996.
29. Chan 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 .
30. Villablanca 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 .
31. Shields CL, Honavar SG, Shields JA, et al.: Factors predictive of recurrence of retinal tumors, vitreous seeds, and subretinal seeds following chemoreduction for retinoblastoma. Arch Ophthalmol 120 (4): 460-4, 2002.
32. Abramson DH, Frank CM: Second nonocular tumors in survivors of bilateral retinoblastoma: a possible age effect on radiation-related risk. Ophthalmology 105 (4): 573-9; discussion 579-80, 1998.
33. Mohney BG, Robertson DM, Schomberg PJ, et al.: Second nonocular tumors in survivors of heritable retinoblastoma and prior radiation therapy. Am J Ophthalmol 126 (2): 269-77, 1998.
34. Shields CL, Mashayekhi A, Demirci H, et al.: Practical approach to management of retinoblastoma. Arch Ophthalmol 122 (5): 729-35, 2004.
35. Chévez-Barrios P, Chintagumpala M, Mieler W, et al.: Response of retinoblastoma with vitreous tumor seeding to adenovirus-mediated delivery of thymidine kinase followed by ganciclovir. J Clin Oncol 23 (31): 7927-35, 2005.

Extraocular Retinoblastoma

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. In patients with the genetic form of retinoblastoma, central nervous system (CNS) disease is less likely the result of metastatic or regional spread than a primary intracranial focus, such as a pineal tumor. Early diagnosis may be helpful; it has been recommended that cranial computerized tomography or magnetic resonance imaging be done twice a year until age 5 years for those who carry the gene (bilateral and unilateral germline cases).

Standard treatment options

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 (including craniospinal irradiation when there is meningeal involvement) and/or intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone, plus supportive care has been used.[1]

Treatment options under clinical evaluation

1. With emerging dose-intensive chemotherapy regimens and the use of high-dose chemotherapy with autologous stem cell rescue, clinical trials are ongoing to improve the dismal outcome for this relatively small group of patients. The agents used in the past included vincristine, cyclophosphamide, and doxorubicin; although they produce an initial response, overall survival has been less than optimal. Carboplatin, ifosfamide, and etoposide have shown more promise for remission and may be used in conjunction with high-dose chemotherapy followed by stem cell rescue.[2,3,4] Patients presenting with extensive non-CNS metastases have been treated successfully with myeloablative chemotherapy with stem cell rescue.[4,5,6]

References:

1. Rootman 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.
2. Namouni F, Doz F, Tanguy ML, et al.: High-dose chemotherapy with carboplatin, etoposide and cyclophosphamide followed by a haematopoietic stem cell rescue in patients with high-risk retinoblastoma: a SFOP and SFGM study. Eur J Cancer 33 (14): 2368-75, 1997.
3. Kremens B, Wieland R, Reinhard H, et al.: High-dose chemotherapy with autologous stem cell rescue in children with retinoblastoma. Bone Marrow Transplant 31 (4): 281-4, 2003.
4. Rodriguez-Galindo C, Wilson MW, Haik BG, et al.: Treatment of metastatic retinoblastoma. Ophthalmology 110 (6): 1237-40, 2003.
5. Dunkel IJ, Aledo A, Kernan NA, et al.: Successful treatment of metastatic retinoblastoma. Cancer 89 (10): 2117-21, 2000.
6. Matsubara H, Makimoto A, Higa T, et al.: A multidisciplinary treatment strategy that includes high-dose chemotherapy for metastatic retinoblastoma without CNS involvement. Bone Marrow Transplant 35 (8): 763-6, 2005.

Recurrent Retinoblastoma

The prognosis for a patient with recurrent or progressive retinoblastoma depends on the site and extent of the recurrence or progression. With the use of systemic chemotherapy, without radiation therapy or enucleation, recurrence is not uncommon and generally occurs in the first 6 months following therapy. Risk factors for recurrence include larger tumor size or thickness at original diagnosis, Reese-Ellsworth group V disease, younger age at diagnosis, and family history of retinoblastoma.[1,2,3,4] 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. If the recurrence or progression is confined to the eye but is extensive, the prognosis for sight is poor; however, the survival remains excellent. 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; clinical trials may be appropriate and should be considered.

References:

1. Shields CL, Honavar SG, Shields JA, et al.: Factors predictive of recurrence of retinal tumors, vitreous seeds, and subretinal seeds following chemoreduction for retinoblastoma. Arch Ophthalmol 120 (4): 460-4, 2002.
2. Gombos DS, Kelly A, Coen PG, et al.: Retinoblastoma treated with primary chemotherapy alone: the significance of tumour size, location, and age. Br J Ophthalmol 86 (1): 80-3, 2002.
3. Shields CL, Shelil A, Cater J, et al.: Development of new retinoblastomas after 6 cycles of chemoreduction for retinoblastoma in 162 eyes of 106 consecutive patients. Arch Ophthalmol 121 (11): 1571-6, 2003.
4. Lee TC, Hayashi NI, Dunkel IJ, et al.: New retinoblastoma tumor formation in children initially treated with systemic carboplatin. Ophthalmology 110 (10): 1989-94; discussion 1994-5, 2003.

Changes to This Summary (8/20/2007)

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.

INTRAOCULAR RETINOBLASTOMA

Added text to state that multiagent chemotherapy is generally used, although carboplatin as a single agent causes shrinkage of retinoblastoma tumors.

Added Abramson et al. as reference 10.

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Date Last Modified: 2007-08-20