Pediatrics

Retinoblastoma

OVERVIEW: What every practitioner needs to know

The management of retinoblastoma has seen striking advances in the past two decades. These advances include the now widespread use of chemotherapy, with or without conventional radiation therapy, for intraocular tumors; the identification of children who, based upon globe and optic nerve pathology, are at high risk for micrometastases; the successful use of chemotherapy for localized bulky tumor (orbital recurrence, optic nerve tumor at the margin of surgical section of the optic nerve at time of an enucleation) or cerebrospinal fluid tumor only; and the successful application of combination chemotherapy followed by autologous stem cell rescue for bone and bone marrow disease.

For intraocular tumor, a new staging system is gaining widespread acceptance and has been adopted internationally as well as by the Children's Oncology Group: the International Classification System for Intraocular Retinoblastoma (Table I). For extraocular tumor, a staging system based on clinical presentation as well as any globe and optic nerve pathology has previously been described.

Table I.

International Classification System for Intraocular Retinoblastoma
Group ASmall intraretinal tumors away from foveola and discAll 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 BAll remaining discrete tumors confined to the retinaAll other tumors confined to the retina not in Group ATumor-associated subretinal fluid less than 3 mm from the tumor with no subretinal seeding
Group CDiscrete local disease with minimal subretinal or vitreous seedingTumor(s) are discreteSubretinal fluid, present or past, without seeding involving up to 1/4 retinaLocal fine vitreous seeding may be present close to discrete tumorLocal subretinal seeding less than 3 mm (2 disk diameters) from the tumor
Group DDiffuse disease with significant vitreous or subretinal seedingTumor(s) may be massive or diffuseSubretinal fluid present or past without seeding, involving up to total retinal detachmentDiffuse or massive vitreous disease may include "greasy" seeds or avascular tumor massesDiffuse subretinal seeding may include subretinal plaques or tumor nodules
Group EPresence of any one or more of these poor prognosis featuresTumor touching the lensTumor anterior to anterior vitreous face involving ciliary body or anterior segmentDiffuse infiltrating retinoblastomaNeovascular glaucomaOpaque media from hemorrhageTumor necrosis with aseptic orbital cellulitesPhthisis bulbi

This system recognizes the following stages of disease, which are elaborated upon in succeeding sections:

I. Intraocular tumor

II. Tumor with high-risk of micrometastases based on globe and optic nerve histopathology following an enucleation

III. Regionally metastatic tumor

IV. Tumor with extension to the central nervous system, and/or bone and bone marrow.

Are you sure your patient has retinoblastoma? What are the typical findings for this disease?

The most common presenting symptoms are: 1) leukocoria (white eye reflex) caused by tumor within the vitreous or by retinal detachment (56%); 2) strabismus (20%); 3) painful eye with glaucoma (7%); and 4) poor vision (5%).

What other disease/condition shares some of these symptoms?

Strabismus is also seen as a developmental disorder ("lazy eye"), while a white reflex can be caused by any of several non-tumor conditions: astrocytic hamartoma, persistent hyperplastic primary vitreous, advanced Coats' disease, and retinopathy of prematurity. Coats' disease is a condition in which abnormal, telangiectatic, permeable blood vessels of the retina exude subretinal fluid, at first causing localized and later total retinal detachment.

What caused this disease to develop at this time?

Retinoblastoma is believed to be a disorder caused by a mutation (most commonly) in the RB1 gene, which gives rise to a dysfunctional retinoblastoma protein which normally serves as a tumor suppressor. The RB1 gene is located on the q14.1-q14.2 band of chromosome 13, and gives rise to retinoblastoma when both alleles are affected.

Retinoblastoma, however, can develop as germinal and nongerminal types. In the germinal form, tumors are generally bilateral and multiple, and a prezygotic mutation is believed to be present in all the cells of the body. About 15% of unilateral cases are also germinal. Tumors develop when a second mutation (the other allele of the RB1 gene) occurs, which is postzygotic and generally within the first year of life. Since the probability is high that two or more different retinal cells are affected, tumors are generally multiple and bilateral, although 15% of unilateral tumors are also germinal. In fact, the median number of observed tumors in a given eye is 5.3 (range 2 to 20), with the actual number following a Poisson distribution.

In the nongerminal form, both chromosomal events are postzygotic, with the loss of both alleles of the RB1 gene being postzygotic, or somatic. Tumors tend to be solitary and unilateral (85% of all unilateral retinoblastoma) and tend to develop later than germinal tumors; that is, between the first and third years of life. This is due to the low probability that even a single retinal cell will be affected by two postzygotic events. Mutations are inherited in about 12% of germinal cases; the other 88% involve new mutations. The cause of nongerminal retinoblastoma remains unknown, although one suspect has been human papillomavirus.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • Important studies to obtain in suspected germinal cases (based on age <18 months, family history of retinoblastoma, bilaterality, and/or multiplicity of tumors) include study of tumor tissue for the RB1 gene, peripheral blood for the RB1 gene (if tumor tissue not available), and examination of the retinae of both parents to look for evidence of a regressed form of retinoblastoma, known as retinoma or retinocytoma. The latter is analogous to the ganglioneuroma of neuroblastoma. In this fashion, the treating physician can better determine the risk for non-ocular tumors (1%-1.5% per year in germinal cases, vs no more than those due to chemotherapy and/or radiation therapy in nongerminal cases), as well as offer genetic counseling regarding the risk of retinoblastoma to subsequent offspring.

Would imaging studies be helpful? If so, which ones?

Useful imaging studies include an MR of the brain and orbits, to identify the presence of any orbital or extraorbital tumor and also to exclude a pineal or suprasellar tumor. The latter has been described as "trilateral retinoblastoma," since tumor in these areas has been found to contain primitive photoreceptors and represents additional primary tumor foci.

Imaging of the neuroaxis is indicated only if there is suspicion based on neurological examination of leptomeningeal disease or if leptomeningeal disease is evident already on brain MR.

CT scans may confirm the diagnosis of retinoblastoma in equivocal cases since they can detect intraocular calcifications characteristic of this tumor. However, we generally try to minimize radiation exposure in the very young, especially the child with germinal retinoblastoma, for whom radiation therapy is known to augment the risk of second, non-ocular tumors.

A bone scan is indicated if there is suspicion of bone and/or bone marrow tumor. Reasons to have such suspicion include unexplained bone pain, palpable firm masses overlying bony sites (e.g., calvarium, long bones), cytopenias involving two or more cell lines (leukopenia, anemia, and/or thrombocytopenia), and plain radiographs or other imaging modalities showing unexplained bone lesions.

MIBG (iodine-131-meta-iodobenzylguanidine) scans may also be useful, as these scans are sensitive to the presence of retinoblasts.

Confirming the diagnosis

The diagnosis of retinoblastoma is generally a visual one made by a retinal specialist, since biopsy of tumor, unless to perform an enucleation, carries with it risk of extraocular spread of tumor, and is generally to be avoided. Even with enucleation, great care is taken not to spill tumor contents and also to take at least 10 mm of optic nerve to maximize chances of excision of early tumor invasion of the optic nerve.

The determination of stage of disease (intraocular vs extraocular) rests with the pediatric hematologist/oncologist, and is made based on the findings of the MR of the brain and orbits, and globe and optic nerve pathology (if a severely involved globe is enucleated). If indicated by clinical symptoms, determination of stage is also based on the results of a lumbar puncture for tumor cells in the cerebrospinal fluid, bilateral bone marrow aspirates and biopsies, and bone scan.

If you are able to confirm that the patient has retinoblastoma, what treatment should be initiated?

Treatment is tailored to whether the child has germinal vs nongerminal tumor, and whether tumor is unilateral or bilateral.

Unilateral cases lacking a positive family history for retinoblastoma, and which are negative for the Rb1 gene when test results on tumor tissue are available, are treated with radiation and/or enucleation. Use of radiation in such children does not carry with it any greater risk of second, nonocular tumors than that for other solid tumors of childhood, in contrast to the case with germinal tumors. Further, enucleation of an eye containing very advanced stage tumor can frequently be a definitive therapy when there is no risk of the remaining eye developing retinoblastoma.

Conversely, the increased risk of second, nonocular tumors seen in germinal tumors makes chemotherapy more attractive for this group than radiation therapy. (There is, however, likely to be some small effect of even chemotherapy in enhancing the inherent second tumor risk in germinal patients.) Consequently, chemotherapy for advanced intraocular disease is generally offered only to children with bilateral (clearly germinal) retinoblastoma. Exceptions are therapies offered via innovative protocols (new chemotherapeutic agents, agents with novel molecular targets, and/or new forms of delivery of these agents) which may become available in the near future and which may be directed iniitally at unilateral tumor.

For extraocular tumor, children with both germinal and nongerminal tumor are treated aggressively with chemotherapy and radiation.

The following sections describe more specific treatments offered by tumor Stage (I, II, II, or IV) and, for tumor Stage I, intraocular tumor Group (A, B, C, D, and/or E). These treatments are summarized in Table II.

Table II.

Stage I: Intraocular tumor.

Bilateral or unilateral intraocular tumor, Group A eyes. Children with Group A tumor(s) can generally be managed by local measures carried out by an ophthalmologist, and do not need chemotherapy. These measures include photocoagulation, cryotherapy, and diathermy. Chemotherapy is not indicated.

Bilateral intraocular tumor, with at least one Group B eye. We currently recommend a three-agent regimen for Group B tumors with vincristine, carboplatin, and etoposide at three week intervals for 4 to 6 cycles. See Table III for dosing. Twenty-four hours after completion of a course of chemotherapy, G-CSF is started at 5 mg/kg SC daily until the ANC > 1000/µL, or PEG-G-CSF at 100μg/kg SC x 1. This regimen has as a major aim the elimination, where possible, of radiation therapy altogether. Non-proton beam radiation therapy has a recognized contribution to secondary nonocular malignancies in children with germline RB1 mutations.

Table III.

Bilateral intraocular tumor, with at least one Group C or D eye. Where proton beam radiation is available, our group believes that the chemotherapy treatment plan above for Group B eyes is also to be recommended for Group C and D eyes, given that proton radiation therapy can be made available as "consolidation" therapy should additional treatment be needed. Three of 3 group C and D eyes have had no active tumor after 18 or more months of follow-up (and have not required enucleation).

The Children's Oncology Group recently piloted a protocol that utilized courses of vincristine, carboplatin, and etoposide given every 28 days for a total of six courses for Group C eyes, and for eight courses (with a dose escalation) for Group D eyes. For each Group C or D eye and for courses 2-4, subtenon carboplatin was also given, at a dose of 1 cc of 10 mg/ml at each of two sites in two quadrants of each Group C or D eye. G-CSF was used as above. Children with eyes that failed to respond to this chemotherapy were considered “off study,” and went on to either enucleation of a failed eye or radiation therapy to that eye. Twelve of 22 eyes after 24 months or more of follow-up had not required enucleation and/or external beam radiation. Unfortunately, this study was recently closed for lack of patient accrual; study patients, however, continue to be followed for late effects.

Much current interest has been directed towards intra-arterial chemotherapy (IAC), usually melphalan, for retinoblastoma. This has been considered a novel approach to the delivery of a small dose of chemotherapy into the ophthalmic artery, thereby minimizing systemic toxicities of chemotherapy. Japanese collaborators (Yamane et al., 2004) improved upon the technique of Reese et al. (1958) by entering the carotid region from a remote femoral artery access and delivering chemotherapy into the internal carotid artery at the branch point of the ophthalmic artery without entering the ophthalmic artery itself. They accomplished this by occluding additional distal flow in the internal carotid artery via balloon obstruction. Abramson and co-workers (2010) report impressive and durable responses. Shields et al. (2011) have also obtained promising tumor responses, yet express great concern for acute and chronic vascular insults which, they point out, are detected only when fluorescein angiography is used. These insults include occlusion and stenoses of the ophthalmic artery and attenuation of retinal vessels. Most other groups have not employed fluorescein angiography. A COG protocol is currently under development for IAC for unilateral tumors only. The long-term outlook for IAC is controversial.

Group E eyes: These are usually treated by enucleation, although retina specialists have occasionally recommended chemotherapy for bilaterally advanced tumors, on a case-by-case basis.

Stage II: Tumor with high-risk features on histopathologic examination.

In this category are children with one or both eyes enucleated who have tumor involvement of the optic nerve beyond the lamina cribrosa, but not to the line of surgical section; massive choroidal tumor defined as posterior uveal invasion; and any posterior uveal involvement with any optic nerve disease (optic nerve head, pre-lamina and post-lamina cribrosa). Excluded from this category are those with extraocular tumor, including disease at the surgical margin and tumor in an emissary vein and/or on the episcleral surface. The former children have an estimated 10%-15% mortality from recurrent tumor and, therefore, should receive chemotherapy which includes vincristine, carboplatin, and etoposide given every 28 days for six courses (see Table III for dosing).

In view of our experience in having seen four cases of tumor involving the cerebrospinal fluid only (each case had a repeat positive CSF cytology), we recommend a diagnostic lumbar puncture in cases of retinoblastoma involving or obscuring the optic nerve. If the CSF cytology is positive (preferably confirmed by means of a repeat lumbar puncture for CSF cytology), we recommend including intrathecal chemotherapy with methotrexate and cytosine arabinoside at weeks 0,1, 2, and 3 with age-related (and therefore, CSF volume-related) dosing: doses for methotrexate are 6, 8, 10, and 12 mg for ages 4 to 11, 12 to 23, 24 to 36, and > 37 months, respectively. Corresponding doses for cytosine arabinoside are 20, 30, 50, and 70 mg. For ages 0 to 3 months, we recommend half-doses of methotrexate and cytosine arabinoside of 3 and 10 mg, respectively. (In this situation, the extraocular tumor is technically no longer regional.)

We consider radiation therapy to be unnecessary. Of 12 children we have treated in this manner, none developed extraocular tumor after 48 months or more of follow-up.

Stage III: Regional extraocular tumor.

Children in this category, for whom mortality is in the range of 20%, are those with measurable or microscopic extraocular tumor which may include:

a. orbital recurrence (orbital mass)

b. presence of episcleral tumor following enucleation

c. positive preauricular lymph nodes

Excluded are children with CNS, and/or bone and bone marrow disease. An exception appears to be the rare case of a child with isolated CSF tumor (rare). Such cases have been treated effectively by us as above for tumor with high-risk features.

All patients should receive an induction, according to a currently open COG protocol for extraocular tumor, with four courses of vincristine, cisplatin, cyclophosphamide with mesna, and etoposide. G-CSF is given as above. Orbital RT (stereotactic or proton beam) should begin at week 6 for orbital recurrence. A good outcome in 5 of 6 patients following orbital recurrence has been reported by Goble et al. (1990), who used vincristine-carboplatin-etoposide alternating with vincristine-doxorubicin-ifosfamide for a total of three courses of each, with orbital radiation and with or without intrathecal chemotherapy. G-CSF was used as above. Our group has had a similarly good outcome in 2 of 2 patients with orbital recurrence using the same chemotherapy combined with proton beam radiation.

Stage IV: Extraocular tumor with CNS and/or bone and bone marrow involvement.

While extraocular retinoblastoma is usually very chemosensitive, durable remission rates (at 3 to 5 years) with bone and bone marrow disease at most centers are only 20%-30%, indicating the need to offer myeloablative chemotherapy followed by stem cell rescue to this subgroup. All patients should receive the same induction with four courses of vincristine, cisplatin, cyclophosphamide with mesna, and etoposide as for regional extraocular tumor above.

In addition and according to the same Children's Oncology Group extraocular tumor protocol as above, patients in this category should go on to consolidation with myeloablative chemotherapy with carboplatin, thiotepa, and etoposide, followed by autologous stem cell rescue. G-CSF is used as above. This approach can be taken, provided a child has: a) adequate stem cell yield upon collection of stem cells following induction chemotherapy, and b) adequate remission status. Children with regional extraocular tumor should not receive consolidation, since they have a good prognosis with induction chemotherapy alone. External beam (or proton beam) radiation therapy should be administered to sites that initially harbored bulky disease on or about day +42 post-stem cell rescue.

All patients should be followed with audiograms or BAER (brainstem auditory evoked response) studies, and echocardiograms, in addition to CNS imaging and follow-up CSF and/or bone marrow studies.

For tumors that are ≥ 3 mm or for any smaller tumors if the macula is involved or the tumors are peripapillary, we also recommend vincristine, carboplatin, and etoposide at three-week intervals, but for 6 cycles, followed by G-CSF or PEG-G-CSF as above. Again, see Table III for dosing. The reason for including in this approach tumors that involve the maculae or are peripapillary is that the maculae are susceptible to injury from focal measures, while peripapillary tumors lack pigment, which makes them relatively poorly responsive to photocoagulation. All smaller tumors 3 mm or more away from the macula are treated by local measures, as for Group A eyes. In the event any tumors fail to fully respond, defined as reduction in size to < 3 mm before the completion of chemotherapy at week 18, or failure of any tumors to continue to respond at or after week 6, the child should go on to have proton beam radiation therapy, which largely spares the orbital bones and thereby permits better growth and development of these structures while minimizing the risks of radiation-induced bone tumors and radiation-associated impairment of orbital bone growth.

In addition, radiation therapy has been recognized to cause and/or contribute to transient retinopathy (incidence, 15%-25%), vitreous hemorrhage (10%-20%), neovascular glaucoma (0%-5%), lacrimal gland/duct injury (diminished tear production with dry and sometimes photophobic eyes; 2%-50%), cataracts (10%-25%), and impaired orbital bone growth (up to 100%). Toward this end, Friedman et al. (2000) used six cycles of vincristine, carboplatin, and etoposide to treat 39 eyes, which were chiefly Group B eyes, and avoided enucleation or external beam radiation in all. G-CSF was used as above. Jubran et al. (2001) treated 11 eyes in this fashion, and avoided enucleation and external beam radiation in nine. The Children’s Oncology Group (COG) recently studied a two-agent (vincristine-carboplatin) regimen for Group B eyes with the same aim of avoiding radiation, but failed to confirm earlier promising results.

Previously our group had sought to avoid the use of etoposide in Group B eyes, since we believed that doing so would reduce the risk of hospitalizations for fever and neutropenia, and eliminate a small risk of myelodysplasia, a potentially fatal condition. However, we cannot justify omitting etoposide at this time.

What are the adverse effects associated with each treatment option?

Radiation therapy has the potential, as noted, to augment the risk of second, nonocular tumors in germinal retinoblastoma. There may be a modest effect of chemotherapy in this regard, although studies are not definitive on this point. More commonly, radiation therapy can lead to poor growth of orbital bones, cataracts, and/or loss of tear production.

Carboplatin has the potential to cause protracted bone marrow suppression, which most groups mitigate by use of G-CSF or pegylated G-CSF (PEG-G-CSF). Carboplatin has also been shown to cause significant hearing loss in infants with retinoblastoma, for dosing based on surface area rather than on a per kg basis. The latter dosing provides a significantly lower absolute dose when weight is less than 10 kg (or age is less than 36 months). Etoposide has some risk of secondary acute myeloid leukemia (AML), but doses are generally held to below the threshold above which such leukemias are usually seen. Vincristine is associated with its known neurotoxicities, as well as constipation and temporary hair loss.

What are the possible outcomes of retinoblastoma?

In contrast to much of the developing world, where retinoblastoma is often fatal, only 2%-5% of children in developed countries lose their lives. Many suffer long-term visual impairment and, sometimes, some degree of facial asymmetry. Plastic surgery can help in more severely affected cases. Most children adapt well, nonetheless. A special concern, especially in germinal cases, is the lifelong risk of second, nonocular tumors.

What causes this disease and how frequent is it?

Retinoblastoma, while being a tumor arising from deletion of both alleles of the RB1 gene, which normally produces a tumor suppressor protein, has no known specific cause, other than about 12% of germinal cases are inherited from parents who either have had the disease themselves, or who have a regressed form of the tumor, or, rarely, for whom expression of the tumor may have skipped a generation. The frequency is about 1 in 18,000 live births, with about 40% being germinal and 30% bilateral. The remaining 10% of germinal cases involve 15% of the 60% of cases that are nongerminal.

How do these pathogens/genes/exposures cause the disease?

N/A

Other clinical manifestations that might help with diagnosis and management

Germinal retinoblastoma can, uncommonly, present as a somatic disorder. The combination of germinal retinoblastoma with developmental delay and/or microcephaly is known as the chromosome 13 deletion syndrome, and affects about 5% of germinal cases. Other somatic abnormalities reported in germinal retinoblastoma include broad prominent nasofrontal bones, hypertelorism, microphthalmos, epicanthus, ptosis, protruding upper incisors, micrognathia, a short neck with lateral folds, malformed and malrotated ears with deep helical sulci, imperforate anus or perineal fistula, and hypoplastic or absent thumbs. Still other features can sometimes include mental retardation, failure to thrive, cleft palate, and supernumerary fingers or toes.

These have been known to precede the diagnosis of retinoblastoma.

What complications might you expect from the disease or treatment of the disease?

In germinal retinoblastoma, there is a significant risk, about 1% to 1.5% per year, of the development of a second, nonocular tumor. Such second tumors may include pineal or suprasellar "trilateral retinoblastoma" in the first decade of life, soft tissue and bone tumors, especially osteogenic sarcoma, in the second decade, and melanomas starting in the third decade. A variety of other tumors have also been described, including acute myelogenous leukemia and breast cancer. It is important to inform parents and patients (when old enough) of this risk and to investigate thoroughly any new complaint of pain, swelling, irritability, or other systemic illness.

Are additional laboratory studies available; even some that are not widely available?

N/A

How can retinoblastoma be prevented?

N/A

What is the evidence?

Grabowski, EF, Abramson, DH. "Intraocular and extraocular retinoblastoma". Hematol Oncol Clin North Am. vol. 1. 1987. pp. 721-35.

(This work outlines a clinical and histopathologic staging system for extraocular tumor, reports successful treatment of tumor extending into the optic nerve, and also reports a group of long-term survivors with bone and bone marrow tumor.

Wong, FL, Boice, JD, Abramson, DH. "Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk". JAMA. vol. 278. 1997. pp. 1262-7.

(This is a good review of second, nonocular tumors seen with germinal retinoblastoma.)

Imhof, SM, Mourits, MP, Hofman, P. "Quantification of orbital and mid-facial growth retardation after megavoltage external beam irradiation in children with retinoblastoma". Ophthalmology. vol. 103. 1996. pp. 263-8.

(This paper describes impairment of orbital bone growth associated with external beam radiation.)

Kaste, SC, Chen, G, Fontanesi, J. "Orbital development in long-term survivors of retinoblastoma". J Clin Oncol. vol. 15. 1997. pp. 1183-9.

(This article is a good companion to the preceding article.)

Friedman, DL, Himelstein, B, Shields, CL. "Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma". J Clin Oncol. vol. 18. 2000. pp. 12-7.

(This paper summarizes success in using chemotherapy to avoid external beam radiation in principally Stage B intraocular tumors.)

Jubran, RF, Murphree, AL, Villablanca, JG. "Low dose carboplatin/etoposide/vincristine and local therapy for intraocular retinoblastoma group II-IV eyes".

(This report supports the preceding article.)

Yamane, T, Kaneko, A, Mohri, M. "The technique of ophthalmic arterial infusion therapy for patients with intraocular retinoblastoma". Int J Clin Oncol. vol. 9. 2004. pp. 69-73.

(This article summarizes the work of Japanese investigators in initiating a modern approach of intra-arterial chemotherapy.)

Reese, AB, Hyman, GA, Tapley, ND, Forrest, AW. "The treatment of retinoblastoma by x-ray and triethylene melamine". AMA Arch Ophthalmol. vol. 60. 1958. pp. 897-906.

Abramson, DH, Dunkel, IJ, Brodie, SE. "Superselective ophthalmic artery chemotherapy as primary treatment for retinoblastoma (chemosurgery)". Ophthalmology. vol. 117. 2010. pp. 1623-9.

(Later modern experience with intra-arterial chemotherapy is described here.)

Shields, CL, Bianciotto, CG, Jabbour, P. "Intra-arterial chemotherapy for retinoblastoma: report No. 1, control of retinal tumors, subretinal seeds, and vitreous seeds". Arch Opthalmol. vol. 129. 2011. pp. 1399-1406.

(This article summarizes work with intra-arterial chemotherapy at the Wills Eye Institute.)

Shields, CL, Bianciotto, CG, Jabbour, P. "Intra-arterial chemotherapy for retinoblastoma: report No. 2, treatment complications". Arch Ophthalmol. vol. 129. 2011. pp. 1407-15.

(Shields et al., while finding promising results with intra-arterial chemotherapy, also caution in this work against serious vascular events not observed unless one uses fluorescein angiography.)(This paper describes early success in managing orbital recurrence of tumor.)

Goble, RR, McKenzie, J, Kingston, JE. "Orbital recurrence of retinoblastoma successfully treated by combined therapy". Brit J Ophthalmol. vol. 74. 1990. pp. 97-8.

Chantada, G, Fandiño, A, Casak, S. "Treatment of overt extraocular retinoblastoma". Med Pediatr Oncol. vol. 40. 2003. pp. 158-61.

(This article points out a poor outcome with CNS tumor and bone and bone marrow tumor when treated with conventional combination chemotherapy.)

Dunkel, IJ, Aledo, A, Kernan, NA. "Successful treatment of metastatic retinoblastoma". Cancer. vol. 89. 2000. pp. 2117-21.

(This paper describes a series of patients with bone and bone marrow tumor who did well with intensive chemotherapy combined with autologous stem cell rescue.)

Qaddoumi, I, Bass, JK, Wu, J. "Carboplatin-associated ototoxicity in children with retinoblastoma". J Clin Oncol. vol. 30. 2012. pp. 1034-41.

(In this work, carboplatin is shown to cause significant hearing loss when given in doses based on body surface area rather than body mass when body weight is less than 10 kg (or age is less than 36 months.)(The work of Reese et al. pioneered intra-arterial chemotherapy in the 1950s.
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