Retinoblastoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]
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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.
Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. 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. 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%. 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.
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 be known in those patients with a positive family history (25%) or may have occurred in utero at the time of conception, in those 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. Most patients with unilateral diseases do not have the hereditary form of the disease, whereas all children with bilateral diseases are presumed to have the hereditary form of the disease, 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.[5,6]
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 who have a normal examination in at least one eye on initial presentation 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. Following treatment, patients require careful surveillance until age 5 years. 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.
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. Commercial laboratories are now available to perform this service. 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.[9,10,11] Although a positive finding with current technology confirms susceptibility, a negative finding cannot absolutely rule it out. 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. 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 (MLPA), and fluorescence in situ hybridization (FISH) may be needed. The absence of detectable RB1 mutations in some patients may suggest that alternative genetic mechanisms may underlie the development of retinoblastoma.
Genetic counseling should be an integral part of the therapy for a patient with retinoblastoma, whether unilateral or bilateral. 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.[11,14] Genetic counseling, however, is not always straightforward. Families with retinoblastoma may have a founder mutation with embryonic mutagenesis causing genetic mosaicism of gametes. A significant proportion (10%–18%) of children with retinoblastoma have somatic genetic mosaicism,[16,17] making the genetic story more complex and contributing to the difficulty of genetic counseling.
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 second malignant neoplasms, 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.[18,19]
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.[20,21] Patients who are asymptomatic at the time of diagnosis with an intracranial tumor have a better outcome than patients who are symptomatic.
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. 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. Computed tomography scans should be avoided for routine screening in these children because of the perceived risk of exposure to ionizing radiation.
Second malignant neoplasms
Patients with hereditary retinoblastoma have a markedly increased frequency of second malignant neoplasms (SMN).[22,23] 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. However, more recent studies have reported the rates to be about 9.4% in nonirradiated patients and about 30.4% in irradiated patients. Most of the SMN are osteosarcomas, soft tissue sarcomas, or melanomas. There is no evidence of an increased incidence of acute myeloid leukemia in children with hereditary retinoblastoma.[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 second cancers occur within irradiated tissue and one-third occur outside the radiation field. The risk for SMN 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 type of SMN may be influenced by age.[25,8,27] These data support a genetic predisposition to soft tissue sarcoma, in addition to the risk of osteosarcoma.
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.[29,30]
Survival from second malignancies is certainly suboptimal and varies widely across studies.[23,29,31,32,33,34] However, with advances in therapy, it is essential that all second malignancies be treated with curative intent. Those who survive SMN are at a 7-fold increased risk for developing a subsequent malignancy. The risk further increases 3-fold when patients are treated with radiation therapy for their retinoblastoma. There is no clear increase in second malignancies in patients with sporadic retinoblastoma beyond that associated with the treatment.[24,34]
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. 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.
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.
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.||Schwimer CJ, Prayson RA: Clinicopathologic study of retinoblastoma including MIB-1, p53, and CD99 immunohistochemistry. Ann Diagn Pathol 5 (3): 148-54, 2001.|
Although there are several staging systems available for retinoblastoma, for the purpose of treatment, retinoblastoma is categorized into intraocular and extraocular disease.
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 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.
5-year disease-free survival: <10%
Extraocular (metastatic) retinoblastoma has extended beyond the eye. It may be confined to the tissues around the eye, or it may have spread to the central nervous system, bone marrow, or lymph nodes.
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
|1.||Solitary tumor, smaller than 4 disc diameters (DD), at or behind the equator.|
|2.||Multiple tumors, none larger than 4 DD, all at or behind the equator.|
Group II: favorable for maintenance of sight
|1.||Solitary tumor, 4 to 10 DD at or behind the equator.|
|2.||Multiple tumors, 4 to 10 DD behind the equator.|
Group III: possible for maintenance of sight
|1.||Any lesion anterior to the equator.|
|2.||Solitary tumor, larger than 10 DD behind the equator.|
Group IV: unfavorable for maintenance of sight
|1.||Multiple tumors, some larger than 10 DD.|
|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 of the retina.|
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]
Small intraretinal tumors away from foveola and disc.
- All tumors are 3 mm or smaller in greatest dimension, confined to the retina and
- All tumors are located further than 3 mm from the foveola and 1.5 mm from the optic disc.
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.
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.
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.
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.
The goals of therapy are threefold:
|1.||Eradicate the disease to save the patient's life.|
|2.||Preserve as much vision as possible.|
|3.||Decrease risk of late sequelae from treatment, particularly second malignant 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. 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. 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]; [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.
Intraocular Retinoblastoma Treatment
Treatment options for the involved eye include the following:
|1.||Enucleation: Enucleation, if the tumor is massive or if there is little expectation for useful vision in the affected eye. Patients must be followed closely to monitor the remaining eye and assure there is no orbital recurrence of disease, particularly in the first 2 years after enucleation.[Level of evidence: 3iiA] Recurrence in the orbit is often associated with systemic disease (85%) and should be treated with aggressive therapy.|
|3.||Cryotherapy: Cryotherapy, used as primary therapy or with chemotherapy for tumors smaller than 4 disc diameters (DD) in the anterior portion of the retina.|
|4.||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.|
Systemic chemotherapy: 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.[1,2,13]; [Level of evidence: 3iiDiii] Chemotherapy may also be continued or initiated with concurrent local control interventions. 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.; [Level of evidence: 3iiiDiii] Most tumors treated with vincristine and carboplatin require additional local therapy;[1,2,13,19,20] the addition of etoposide to the chemotherapy regimen may improve outcome.[16,21] One study utilized carboplatin and etoposide with focal therapy, without vincristine, and found acceptable vision salvage rates for Reese-Ellsworth (R-E) Groups I through IV and International Classification Groups A and B retinoblastoma. The success rate of these trials varies from center to center, but overall, the rate is highest for discrete tumors without vitreous seeding (see below). Local tumor recurrence is not uncommon in the first few years after treatment, and can often be successfully treated with focal therapy. Among patients with hereditary disease, younger patients and those with a positive family history are more likely to form new tumors. Chemotherapy may treat small previously undetected lesions by slowing their growth and this may improve overall salvage with focal therapy.
There are data suggesting that the use of systemic chemotherapy may decrease the risk of development of trilateral retinoblastoma.
|6.||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.[26,27] Periocular topotecan administered in fibrin sealant has shown activity in patients with recurrent intraocular retinoblastoma. This approach offers some promise in this group of patients.|
|7.||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 other agents such as topotecan and carboplatin are also being tested. Ocular salvage rates are greater than 70% when used as primary treatment, although success rates are inferior when used after failure of systemic chemotherapy or radiation.[29,30] This modality continues to undergo study at very specialized retinoblastoma treatment centers.[29,31]|
Standard treatment options
Because 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. However, patients with unilateral disease have been treated with chemotherapy in an attempt to preserve vision in the affected eye.[2,32,33] One study revealed that children with retinoblastoma who present with obvious external findings of leukocoria, strabismus, or red eye detectable by their family or pediatrician most often require enucleation. Children who manifest no obvious external findings can often avoid enucleation.
When there is potential for preservation of sight because the tumors are smaller, treatment with other modalities (radiation therapy, laser therapy [thermotherapy], cryotherapy, chemoreduction, and brachytherapy) instead of surgery should be considered. In selected children with unilateral disease, chemoreduction reduced the need for enucleation or EBRT to 68% within 5 years of treatment. 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. Pilot studies have evaluated the delivery of chemotherapy via ophthalmic artery cannulation as initial treatment of advanced unilateral and bilateral intraocular retinoblastoma.[29,31][Level of evidence: 3iiiDii]; [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. Asynchronous bilateral disease occurs most frequently in patients 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, or scleral and extrascleral extension.[36,37,38] 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.[39,40,41,42]; [Level of evidence: 2A]
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 above 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. In the past, the standard of care has been to enucleate the more involved eye. 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. However, if there is potential for vision in both eyes, 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 for patients whose intraocular tumors are not initially amenable to local management.[2,20,23,24,33,34,44,45,46,47,48,49,50,51,52]; [Level of evidence: 3iiDiv] Examples of such tumors are those that are too large to be treated with either cryotherapy, laser therapy, or plaque brachytherapy, or those located adjacent to visually sensitive areas such as the optic nerve and macula. Chemotherapy may shrink the tumors (chemoreduction) allowing greater efficacy of subsequent focal therapy.[2,36] Most centers have limited this approach to patients with bilateral disease, reasoning that for patients with unilateral disease, the morbidity of enucleation is modest. Also, most centers use one of two staging systems. Treatment strategies often differ in terms of chemotherapy regimens and local control measures.
Centers using the R-E classification have demonstrated 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 for six cycles.[1,2,21] Other available data have been published in abstract form, and larger studies with more mature data are still required to make definitive conclusions. Group V tumors, particularly those with vitreous seeding, have proven problematic. Subretinal microscopic tumor has a recurrence rate of 5% following chemotherapy.[24,53]; [Level of evidence: 3iiDiv] 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.[1,2]
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.[47,48] 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.
The International Classification system for staging intraocular retinoblastoma has also been used 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 addition of carboplatin and etoposide (CE) [22,54] or CEV [55,56] have been used in combination with local control. All of these studies are single institution studies that report some salvage of Group C and Group D eyes.[22,56]; [Level of evidence: 3iiDiv] However, in another study with carboplatin, etoposide, and local ophthalmic treatment, Group D eyes were at high risk for enucleation.; [Level of evidence: 3iiDiii] This has led to newer adjuvant therapies, including subtenon (subconjunctival) carboplatin in pilot studies that also use higher doses of carboplatin or etoposide.[26,27] This therapy has also been studied via the periocular route in a phase I study.
The question of whether eyes classified as Group E can be salvaged is under study. A pilot study evaluated the delivery of chemotherapy via ophthalmic artery cannulation as initial treatment of advanced unilateral and bilateral intraocular retinoblastoma. Patients with Group V disease (usually enucleated) without high-risk features such as metastatic disease or anterior chamber disease were enrolled on the study. The ophthalmic artery was safely cannulated and 27 of 28 eyes avoided enucleation.
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.
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. 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.
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.
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. 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.[Level of evidence: 3iiA]
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.
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. 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]; [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. 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.[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.
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.[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.[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.
Changes to This Summary (03 / 08 / 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.
Editorial changes were made to this summary.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of retinoblastoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
- be discussed at a meeting,
- be cited with text, or
- replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Retinoblastoma Treatment are:
- Christopher N. Frantz, MD (Alfred I. duPont Hospital for Children)
- 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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The preferred citation for this PDQ summary is:
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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Last Revised: 2012-03-08
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