|Year : 2019 | Volume
| Issue : 2 | Page : 69-79
Contemporary management of retinoblastoma in the context of a low-resource country
Dupe S Ademola-Popoola1, Enrico Opocher2, M Ashwin Reddy3
1 Department of Ophthalmology (Paediatric, Strabismus and Oncology Services), University of Ilorin, University of Ilorin Teaching Hospital, Ilorin, Kwara, Nigeria
2 Azienda Ospedaliera di Padova, Italy; Paediatric Oncology-Great Ormond Street (GOS) Hospital, London, UK
3 Retinoblastoma Unit, Royal London Hospital, Barts Health NHS Trust; Department of Paediatrics, Moorfields Eye Hospital NHS Foundation Trust, London, UK
|Date of Web Publication||10-Jun-2019|
Dr. Dupe S Ademola-Popoola
Department of Ophthalmology (Paediatric, Strabismus and Oncology Services), University of Ilorin, University of Ilorin Teaching Hospital, GPO Box: 4718, 240001, Ilorin, Kwara
Source of Support: None, Conflict of Interest: None
Retinoblastoma (RB) is the most common ocular cancer, and it typically presents before the age of 5 years in over 90% of cases. In high resource countries, RB patients tend to survive and retain their sight. This is not the case in low-resource countries because of late presentation and delayed intervention arising mostly from sociocultural and socioeconomic challenges. RB has no gender or racial predilection; the incidence is estimated as 1:16,000–1:18,000 live-births or 11/1 million children under 5 years. Most of the world's RB cases are found in Asia and Africa while most RB treatment centres are in America and Europe. RB is easy to detect by caregivers as a glowing white 'cat eye reflex' at night or when captured on camera. Health workers at primary care level can detect RB in early life if red reflex test and/or squint (Hirschberg) tests are deployed as part of wellness checks done especially during routine immunisation and well-baby clinics in the first 24 months of life. In most cases of RB, biopsies for histological confirmation are not required for diagnosis and treatment decisions to be made. Clinical information, ophthalmic evaluation and imaging modalities are typically used. There have been significant changes in the management of RB using various treatment modalities such as enucleation with orbital implant, use of chemotherapy delivered through intravenous, intravitreal, periocular and intra-arterial routes and targeted treatment with laser, cryotherapy and brachytherapy. Algorithm for management and development of the national RB program within the context of a low-resource country is presented from review of data extracted from Mendeley library, PubMed library, Google Scholar and One Network; full-text articles were mostly retrieved through the American Academy of Ophthalmology.
Keywords: Early detection, Leukocoria, low-resource countries, primary eye care, retinoblastoma
|How to cite this article:|
Ademola-Popoola DS, Opocher E, Reddy M A. Contemporary management of retinoblastoma in the context of a low-resource country. Niger Postgrad Med J 2019;26:69-79
|How to cite this URL:|
Ademola-Popoola DS, Opocher E, Reddy M A. Contemporary management of retinoblastoma in the context of a low-resource country. Niger Postgrad Med J [serial online] 2019 [cited 2019 Sep 17];26:69-79. Available from: http://www.npmj.org/text.asp?2019/26/2/69/259912
| Retinoblastoma Incidence, Presentation and Diagnosis|| |
Retinoblastoma (RB) is the most common ocular cancer., It is responsible for about 3%–5% of all childhood cancers., It occurs in about 1:16,000–18,000 live births or 11/1 million children under 5 years, with 200–300 new cases seen in the United States each year, followed by 40–50 in the United Kingdom, 1500 in India and an estimate of 339 cases in Nigeria where children under the age of 5 years are estimated as 30,780,000 (17.1%) of the 180 million population, and it has no sex predilection.,,
Worldwide, an estimated 8000 cases present yearly, 89% of these are in medium-resource countries with survival about 30%. Whereas, most RB treatment centres are in high-resource countries with survival >95%.,, This is especially important in low-resource countries in Africa such as Nigeria where children aged 0–14 years constitute about 44% of the growing population.
Although 90% of children affected by RB are <5 years, few cases in older children and adults up to 45 years old have been reported. RB (unpublished report) cases have been reported among children between 3 weeks and 9 years at Ilorin, Nigeria. About 66% of RBs are unilateral and the others bilateral. Heritable RB is found in 40% of cases including all the bilateral and unilateral multifocal disease.
In high-resource nations, presentation is typically at the stage of leucocoria and/or strabismus, [Figure 1] when it is still very manageable. At this stage, it is easy to detect by caregivers, especially as glowing white 'cat eye reflex' at night or when captured on camera. Health workers at primary care level can detect RB in early life if the red reflex test and misalignment of visual axis for squint (Hirschberg) test are deployed as part of wellness checks; this can be done during routine immunisation and well-baby clinics scheduled in the first 24 months of life in Nigeria.
However, most healthcare workers at the health centres typically would have had little or no contact with eye care during training. It is therefore essential to incorporate this simple but essential skill into their curriculum, enhance the capacity of the primary care health workers through targeted trainings in order to ensure early detection and appropriate referral of cases of RB and other vision-threatening eye disorders of childhood.
Whenever cat eye reflex is neglected as is often the case in low-resource countries, delay in presentation is typical. The presentation then gradually takes on a more relentless course with destructive ocular and orbital manifestations such as proptosis and masquerade syndromes leading to intracranial and extensive systemic spread,, [Figure 2], with predictable consequences culminating in death.
The diagnosis and treatment decisions in RB typically require only ophthalmic history, evaluation and imaging. There is typically no positive family history in 85% of cases. Fine-needle cytology or tissue biopsies for histological diagnosis and confirmation, respectively, as required in most other cancers are undesirable, since this practically converts an intraocular disease through 'needle track effect' to an extraocular one with resultant morbidity, extraocular spread and tumour metastases throughout the body.,
The tumour arises from the retina and therefore could be viewed directly with the pupils adequately dilated using wide-field retinal camera systems which are capable of recording and documenting the details of each tumour. Unfortunately, in low-resource countries, this camera is typically not affordable. Therefore, indirect ophthalmoscopy is critical to diagnosis. It is essential to examine both eyes as the presence of unilateral or bilateral disease dictates the treatment plan. Retinal imaging captured under sedation or anaesthesia using smartphone [Figure 3] provides a more readily available tool for image documentation, caregiver education, teleophthalmology and follow-up in even low-resource countries.
|Figure 3: Smartphone imaging of a small retinal periphery retinoblastoma seen on retinal indentation|
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As part of tumour workup, required imaging modality before treatment include scanning orbito-ocular A and B-ultrasound using high-resolution probes (7.5–12 MHz), which typically shows the tumour mass arising from the retina with areas of speckled calcification depicted by high ultrasound spikes and orbital shadowing. It helps to evaluate optic nerve invasion, extrascleral invasion and orbital invasion [Figure 4]. It also helps to rule out mimics of RB including persistent hyperplastic primary vitreous (persistent foetal vasculature), Coats disease and myelinated nerve fibres. In the presence of clear ocular media, fundoscopy combined with ultrasound was found to have a specificity of 100% and a sensitivity of 95.4% with diagnostic accuracy as using a CT.
|Figure 4: Ultrasound in retinoblastoma showing intraocular mass with high spike|
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On magnetic resonance imaging (MRI) which typically requires deep sedation or anaesthesia, the tumour is hyperintense on T1. This is enhanced with gadolinium (with or without fat saturation). In a study, fat saturation was found to improve tumour enhancement and detection of post-laminar optic nerve infiltration whereas image quality and detection of choroidal invasion were better without fat saturation and hypointense on T2-weighted images.
MRI is useful in determining intraocular tumour size in RB, and the size was found to show a strong and predictive association with post-laminar and massive choroidal invasion by tumour cells., The sensitivity of MRI at 95% confidence interval in a meta-analysis of 574 eyes was between 59% and 88% and specificity between 72% and 99%., Nevertheless, a pre-operative normal-size optic nerve on MRI may not be useful in predicting optic nerve invasion.,
MRI has an essential role for patients with orbital RB; if there is evidence of optic nerve involvement, treatment of the disease with chemotherapy can begin, and it is also beneficial in monitoring recurrence from 3 months after enucleation. In addition, MRI is particularly used to rule out trilateral/intracranial disease with involvement of pineal gland known to have poor prognosis and treatment strategy will change accordingly.,
Computed tomography (CT) is discouraged in order to avoid ionising irradiation and the consequence of other non-ocular malignancies, especially in children aged within 1 year who typically have heritable RB (germline mutations) and potential for soft-tissue sarcomas.
Delays in imaging may delay treatment; it is therefore not uncommon for treatment to be started in developing countries based on clinical and ultrasound findings before MRI is done if intracranial disease is not suspected and mostly due to late presentation and the tendency for catastrophic health expenditure attributable to out-of-pocket payment for treatment, ignorance and poverty.
After the tumour workup, decision is taken based on the grouping which reflects the extent of intraocular involvement or the staging if extraocular or metastatic. In intraocular RB, the Reese and Ellsworth classification was used for many years from the 1960s to predict ocular salvage with external beam radiation therapy (EBRT). With the availability of effective chemotherapy with focal treatment, one of the newer classifications such as the International Classification of Retinoblastoma (ICRB) or International Intraocular Retinoblastoma, are used to plan counselling and treatment with caregivers. The American Joint Committee on Cancer tumour, node, metastasis, heritable trait staging system may soon supersede both of these classifications as there is confusion regarding the most advanced form of intraocular disease: Group E RB.
In extraocular RB which is not unusual in low-resource countries, staging of the disease is essential. The International Retinoblastoma Staging System can be used; it depends on clinical, surgical and pathological findings. Stage 0 is an intraocular disease, eye not enucleated; Stage I – eye enucleated, no microscopic residual tumour; Stage II – eye enucleated, microscopic residual tumour; Stage III – Regional extension, a – orbital and b – pre-auricular/cervical lymph node involvement and Stage IV – metastatic disease, a – no central nervous system (CNS) involvement and b – CNS involvement. The more recent TNM8 (updated TNM classification for RB) classification is more detailed and requires the presence or otherwise of history suggestive of heritable disease/outcome of genetic testing in addition to describing the extent of the primary tumour, regional spread to the orbits and optic nerve, involvement of lymph nodes and distant metastasis.
| Histological Findings|| |
It is important to observe the enucleated eye grossly and microscopically for features of either scleral / extrascleral nodules, presence of anterior chamber seeds, iris infiltration, ciliary body infiltration, massive (≥3 mm) choroidal invasion, post-laminar optic nerve invasion, tumour at cut end of optic nerve or a combination of non-massive < 3 mm choroidal invasion plus non-post-laminar optic nerve involvement, which are high risk histological findings.
Histopathologic grading of anaplasia in RB considers the degree of pleomorphism, frequency of mitotic figures and level of differentiation as defined by the development of rosettes and fleurettes. The neuroblastic Homer–Wright rosette is the least differentiated, followed by Flexner–Wintersteiner rosette, and fleurette is the most differentiated.
Increased grade of anaplasia tends to correlate with patient age at diagnosis, high-risk histologic features, decreased survival and increased probability of metastasis. Specifically, diffuse severe anaplasia had worse clinical outcomes compared to those with focal severe anaplasia. However, some RB cases with severe anaplasia without high-risk histologic features developed distant metastasis. It was postulated that other factors influencing metastasis unrelated to local tumour invasion such as tumour microenvironment, remodelling and mesenchymal transformation might be implicated.
| Management|| |
RB is a disease which contributes to under-5 mortality, especially in developing countries. The greatest reason for this is the time to diagnosis or lag time between symptoms and treatment. Significant cost would have been expended as the parents/caregivers would have to go from one healthcare provider and facilities to the other.
It requires a multidisciplinary team of specialists including paediatric, ocular, medical and radiation oncologists, nurses, geneticists and social workers. Several other critical stakeholders include ophthalmologists, paediatricians, anaesthetists, family physicians, students of health institutions, allied health workers, health educators (communicators), mass media workers, telephone service providers, religious and community leaders. In particular, senior family members may contribute significantly to uptake of treatment and outcome, especially in low-resource countries.
| Challenges to Retinoblastoma Diagnosis and Care|| |
In low-resource countries, patients with advanced RB present to the few hospitals that have adequate facilities for treatment of this lesion., Factors that mitigate against the provision of high quality care include poor awareness by parents and healthcare providers, failure of religious/cultural systems that promotes optimism, inadequate transportation system, poor health insurance coverage and collapse of the social support system.
When the patient present early for care, poor treatment uptake results from inadequate counselling by healthcare providers mostly leading to refusal of enucleation when this is the appropriate treatment for the child. Other challenges encountered by caregivers include inability to afford cost of treatment and hospital visits. At the hospitals, absence of multidisciplinary team system of providing care, genuine chemotherapy and focal treatment modalities (cryotherapy, laser and brachytherapy) further compound the situation.
It is therefore believed that RB outcomes may improve not by technological improvement alone but by the need to specifically identify and tackle each of the highlighted sociocultural and economic challenges., Kodinliye in the 1960s advocated for the provision of cobalt-60 external beam radiation facilities but the ocular morbidity and mortality attributable to RB did not decline despite its availability in the West African region.
| Goal of Retinoblastoma Treatment|| |
The goals of RB treatment include, to save life, salvage the eye, and salvage vision, in that order. The attainable objectives would depend on the stage of presentation, which is determined at the onset and may be reviewed in the course of treatment. Counselling is often central to the success and outcome of RB care and must be given adequate priority, time and attention.
Counselling with empathy and firmness providing only as much information as required at the first contact and at different times in the care of the child is invaluable in ensuring acceptance and compliance with care. The goal of therapy in the child, care process and options, cost implications and scheduled follow-up care are discussed. Genetics is discussed at the appropriate time. It is sometimes essential to admit the child/family who have probably travelled long distances. This helps to accomplish the required understanding and to facilitate the active involvement of other care providers in counselling.
Even though individual counselling and confidentiality is promoted, involving caregivers of other children with RB in one on one or group counselling after obtaining consent has been found to strengthen RB care processes, treatment uptake and compliance with treatment; this is especially important because parents/caregivers of children at different stages of RB become advocates for treatment. Caregivers tend to lend support to one another, the much-needed psychosocial support which is non-medical.
In developing countries, it is sometimes impossible to give each caregiver the needed written information handbills and documents, so other methods can be used. For instance, posters on RB in local languages are placed on walls for caregivers to read before counselling sessions. Pictures [Figure 5] of previously managed children who have had enucleation with orbital implant and ocular prostheses are used to encourage new families to take the safest decision for their child, especially in advanced diseases.
|Figure 5: Retinoblastoma enucleated left eye with orbital implant and ocular prosthesis|
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| Treatment Plans|| |
Documentation using specific proforma is preferred. This contains information on specific presentation, social issues, laterality and tumour characteristics including size, number, location and morphology. Tumour staging – ocular/extraocular germline versus somatic mutation, status of other eye, vitreous seeding, religion, family and socioeconomic issues and available resources for systemic and targeted focal treatment are important considerations essential in the complex and individualised treatment decisions for each child. The management of RB is then tailored to the individual with the following considerations; Age of patient at detection and presentation which are likely to be significantly different in developing countries, the group and stage of the disease, laterality – unilateral, bilateral or trilateral (bilateral intraocular RB associated with a histologically similar midline intracranial tumour usually affecting the pineal glands), extraocular local, regional or distant metastasis, visual potential and the size of tumour.
Bilateral RB usually presents with asymmetrical tumour sizes in both eyes within the 1st year of life, and all bilateral cases are heritable; therefore, detection within infancy will suggest bilateral, heritable disease in which visual potential is often better in one eye with the smaller tumour size. They typically require chemotherapy and focal treatment while EBRT usually delivered used as a cumulative dose of 4000–4500 cGy delivered in 200 cGy fractions. This is avoided because of the higher risk of second non-ocular malignancies if used in this group of cases., EBRT significantly affects bone growth resulting in hemifacial hypoplasia and asymmetry and may also cause eye dryness, keratitis, neovascularisation and glaucoma. EBRT was associated with a six times risk for second non-ocular malignancies.,
It is particularly essential to examine both eyes with binocular indirect ophthalmoscopy up to the periphery, as a small tumour in the 'normal' looking eye can be treated and vision salvaged; ignoring this eye may result in the loss of the presumably normal eye as the tumour continues to grow.
Examination under Anaesthesia (EUA) is the gold standard; nevertheless, in developing countries, in order to reduce the number of EUAs on account of cost and for optimal utilisation of theatre space, examinations are sometimes performed under monitored sedation with chloral hydrate syrup. Enucleation, orbital implant and subsequent prosthesis fitting are often indicated in Group D and E diseases by the International Intraocular Retinoblastoma Classification or ICRB.
Genetic testing strongly influences follow-up protocol. Unilateral non-heritable diseases require fewer follow-up appointments, especially in the first 5 years of life when compared to heritable disease where, after regression of the RB, 3 monthly follow-up is scheduled up to 3 years, 6 monthly till 5 years and yearly for life thereafter. The algorithm typically deployed in decision-making in a low-resource country is shown in [Figure 6].
|Figure 6: Algorithm for retinoblastoma management in a low-resource country|
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| Treatment of Intraocular Retinoblastoma|| |
Enucleation with acrylic orbital implants is offered in unilateral Group D or E diseases except if enucleation is declined by caregivers. The procedure is carried out with utmost care to avoid perforation of the globe and to obtain a long optic nerve (15 mm) excision along with the globe [Figure 7]. It is essential to look at the enucleated eye grossly for high-risk signs: optic nerve thickening, irregularities and enlargement, sclera/extrascleral invasion nodules and anterior chamber seeding. When any of these is present, chemotherapy is commenced promptly.
|Figure 7: Enucleated eyes. (a) Long optic nerve; (b) thickened optic nerve|
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In the grossly normal enucleated eye, pathological reporting of extension of tumour cells beyond the cut end of the optic nerve and reporting of high-risk signs are indications for adjunct chemo/radiation therapy.,
The myoconjunctival technique of enucleation which is believed to improve prosthesis movement,, is typically done at the University of Ilorin Teaching Hospital, Ilorin, Nigeria. Appropriately sized orbital implant and conformers are fitted at surgery, while prosthesis/artificial eye (AE) replaces the conformers 4–6 weeks after.
Focal laser/cryotherapy treatment
This can be used alone in Group A or following chemoreduction in Group B and C. Focal treatment is rarely used as an adjunct treatment to improve chemopenetration in Group D and E disease in special circumstances in one eye patient and bilateral Group E in which ocular salvage is desirable. It involves the use of laser, which can be diode (810 nm), 1064 nm which was used mainly for thick and recurrent tumours after chemotherapy or green (532 nm) and/or cryotherapy alone or in conjunction with chemotherapy. Rarely, brachytherapy which entails suturing on the sclera over the area of tumour of radioactive plaque most commonly iodine 125 and in some cases 192 Ir (iridium) or radioactive 106 Ru (ruthenium) is used for intraocular tumour that is resistant to other treatments and recurrences, but the resources are unlikely to be available in low-resource countries.
The emphasis should be on regular follow-up for dilated ophthalmoscopy and tissue regression monitoring due to the possibility for tumour regrowth.
| Chemotherapy|| |
Retinoblastoma is an extremely chemosensitive tumour. The role and contribution of chemotherapy in the multidisciplinary management of children with RB have been well established and vary according to age, staging, bilateral disease, supportive care facilities and expertise.,
Systemic chemotherapy is routinely recommended in children with RB in the following scenarios: 1) as part of a conservative upfront strategy in eyes with residual functional vision and non advanced group (not group E), or 2) in bilateral cases in attempt to preserve at least one eye, or 3) after enucleation in the presence of histological risk factors with the aim to minimise the risk of extraocular disease spread. upfront, as part of a conservative strategy in non-advanced RB cases (Groups A–D), with useful vision in the affected eye, or as initial management of bilateral RB or after eye enucleation, when histopathological risk factors are present in order to reduce the risk of metastasis.,
Carboplatin-based regimens are nowadays considered standard of care worldwide; the final decision on which chemotherapy regimen to use however depends on the local availability of chemotherapy drugs and the supportive care facilities. The most commonly used regimen includes a combination of carboplatin 560 mg/m2, etoposide 300 mg/m2 dose and vincristine 1.5 mg/m2, given intravenously in 1–2 days, every 21–28 days, for 4 to 6 courses – [Table 1] contains a summary of recommended chemotherapy regimen.
The eye salvage rate with the addition of systemic chemotherapy in the multidisciplinary management of intraocular RB varies by initial stage and can be as high as 80% in Group C but often < 50% in these cases (group D), the role and benefit of conservative management should be balanced against the risk of extraocular spread due to a delayed enucleation. Furthermore, only <20% of Group D are associated with high-risk histological feature, indicating the need for adjuvant chemotherapy only in selected cases. Enucleation may still be a sufficiently curative treatment option in many cases if RB is diagnosed on time.
Systemic chemotherapy can be used also in bilateral cases, with the aim to avoid bilateral enucleation, by attempting salvage of at least one eye and ultimately reduces the need for radiotherapy, which is well known to be associated with significant risk of the second non-ocular tumours particularly in the genetic forms of RB. Systemic chemotherapy should be also considered in newborns with limited disease but with heritable forms of RB, as the risk of multifocal and/or bilateral disease is considerable over time.
| Other Conservative Strategies|| |
Periocular carboplatin is used to improve local availability of chemotherapy in advanced Group D and E eyes and in eyes with secondary vitreous seeds in which about 30% were salvaged without EBRT.
Intravitreal route chemotherapy can be given in low-resource settings; it is indicated in RB with vitreous seeding which is often not responsive to systemic chemotherapy. Melphalan and topotecan are the most used drugs [Table 2]. Fewer injections and better outcomes were obtained in dust-like vitreous seeds, than spheres and worse with cloud-like seeds. It is fundamental to follow the intravitreal technique recommendations to avoid risks of spreading tumour out of the eye.,,,
In the recent decades, intra-arterial chemotherapy involves delivery of chemotherapy (melphalan or topotecan) to the affected eye typically under fluoroscopy and catheterisation of the ophthalmic artery, and if considered unsuitable on account of poor development or spasm of the ophthalmic artery, the orbital branch of the middle meningeal artery is used; this modality of treatment has emerged as a potential alternative to systemic chemotherapy,, with limited systemic exposure and high efficacy to control localised disease [Table 2]; however, several technical issues limit its wider use in many countries.
| Chemotherapy Before and After Enucleation|| |
In advanced orbital disease without intracranial extension, combined 12 cycles of chemotherapy before and after enucleation followed by EBRT showed improved survival of 18/20 (90%) in India. After eye enucleation in locally advanced RB, adjuvant chemotherapy may be necessary in the presence of histological risk factors, including retrolaminar optic nerve involvement, with or without tumour in the resection margin, massive anterior chamber or choroidal invasion or any degree of scleral involvement, with the aim to control or prevent potential extraocular metastatic spread [Table 3]. The overall survival is still excellent in the absence of central nervous system involvement with such strategies.
| Chemotherapy at Relapse|| |
In cases of recurrence after conservative treatment, secondary enucleation or intravitreal chemotherapy can be used as effective strategies, with or without additional adjuvant systemic chemotherapy. Second-line chemotherapy adding cyclophosphamide, ifosfamide (with Mesna infusion) and doxorubicin may be good options at relapse. However, these regimens often have potentially severe side effects and should be administered only in those centres with sufficient expertise and facilities to manage these life-threatening toxicities.
| High-Dose Chemotherapy|| |
High-dose (HD) chemotherapy followed by autologous stem cell rescue is the only effective therapy for patients with Stage IV extraocular RB; the cure rate may be as high as 70% if there is no CNS involvement where cure rate is lower than thirty per cent.
| Treatment of Extraocular and Metastatic Disease|| |
Extraocular RB typically extends from the optic nerve to the CNS but also can spread to the orb it from the sclera and to regional lymph nodes. It later spreads to the cranium, bone marrow and the liver. The outcome in extracranial and metastatic disease is usually very poor, and it has however been found to be improved with chemotherapy including thiotepa as part of HD myeloablative regimens, in those centres where sufficient expertise is present.
Chemotherapy can be given before enucleation also in extensive unilateral RB with buphthalmos and/or radiological optic nerve invasion at diagnosis, possibly allowing for less mutilating surgery as chemoreduction modality to reduce tumour size and assist surgeons in tissue delineation during exenteration. However, it should be noted that delaying or omitting enucleation might result in disseminated disease as chemotherapy is not sufficient to treat advanced disease, and chemoresistance may also occur at some point.,
| Intrathecal Chemotherapy|| |
Due to the limited ability of most of the intravenous drugs to cross the blood–brain barrier at standard doses, CNS is a possible site of relapse, especially after systemic chemotherapy. However, at present stage, there is limited evidence to support the role of intrathecal chemotherapy in the overall survival in children with RB and leptomeningeal dissemination. Various drugs, including topotecan or aracytin, have proven to be effective, at least on the short term, to reduce the tumour burden and should be considered in palliative settings, if there are no concerns of obstructive or communicative hydrocephalus from intracerebral tumour masses causing obstruction to cerebrospinal fluid flow.
Before each systemic chemotherapy session, adequate haematologic parameters, electrolytes, urea and creatinine are ensured. In general, a neutrophil count >1.000/uL should be documented prior to the commencement of each course of chemotherapy. In our hospital, cases in which the blood profiles (platelet <100 × 106 and packed cell volume <30%) are subnormal chemotherapy are skipped for about 2 weeks before a review is done. Nutritional and haematinic support (without folic acids) are provided in the course of chemotherapy. Management of febrile neutropenia is at the physician's discretion according to institutional guidelines. The use of granulocyte colony-stimulating factors is not routinely recommended.
| Pinealoblastoma|| |
Trilateral RB is a midline pineal/suprasellar CNS tumour arising in the context of bilateral RB with germline RB1 gene mutations. It has been found in approximately 3.8% of bilateral RB cases and in 3.1% of hereditary RB forms, and it occurs most in the pineal gland region.,
The cure rate is extremely low, especially in the presence of metastatic dissemination in the cerebrospinal fluid or to the leptomeninges. Some children, up to 44%, survived after HD intensive chemotherapy with stem cell rescue which is often not available in low-resource countries. Radio imaging screening in bilateral RB to detect trilateral cases is therefore advocated in order to guide treatment choices.
| Palliative Care|| |
Chemotherapy with an intention of life prolongation should be discussed with caregivers and given to children with Stage IV disease in settings where treatment with high-dose chemotherapy and autologous stem cell rescue is not available. With unsightly proptosis and metastatic disease to the cranium, parents have expressed desire to receive chemotherapy to improve the psychological impact of RB even when prognosis is known to be extremely poor.
Furthermore, in the presence of advanced disease not responsive to chemotherapies, supportive treatment to control tumour-related symptoms, in particular effective cancer pain management, is advocated as an integral part of the treatment plan.
| Response to Chemotherapy|| |
With chemotherapy, a significant regression up to 50% reduction in tumour/oedema is expected after the second course [Figure 8]. Different regression patterns including flat scar, hill of calcium, fleshy regression and mixed calcific and fleshy regression should be documented depending on the tumour mass. Phthisis bulbi may develop with chemotherapy use for advance RB when enucleation is declined. This unsightly eye is often a reason for family to accept enucleation.
|Figure 8: Orbital retinoblastoma, before and after two courses of chemotherapy|
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| Genetic Testing|| |
RB gene RB1 is a tumour suppressor gene or oncogene located on 13q14 (position 14.2 on long arm of chromosome 13). The gene produces protein, which prevents unregulated cell division and influences cell survival, differentiation and apoptosis.,, Genetic testing is done on peripheral blood samples and on tumour cells following enucleation. Although all bilateral RB are heritable, RB1 mutation was found in about 95% of cases. Because of discovery of new mutations, gene testing in bilateral cases is encouraged. About 15% of unilateral RB are heritable disease, and gene testing is useful to avoid unnecessary examinations under anaesthesia with its attendant risk and costs. Molecular testing of at-risk individuals may reduce screening schedules if RB1 genetic mutations are not detected; in familiar cases, at subsequent pregnancy, ultrasound can be used for prenatal diagnosis at 32 weeks; if positive, early delivery at 36 weeks in a centre with good neonatal care has been suggested. It is also used to determine which embryo to implant for in vitro fertilisation. Gene testing project on likely severity of RB, large deletions were found mostly in group E diseases and to avoid EBRT, as a treatment option because of the increased risk of secondary non-ocular malignancies such as soft-tissue sarcomas following radiation in such patients. Genetic testing suggested that retinomas are pre-malignant lesions.
As genetic testing for RB may not be available in low-resource countries, collaboration with a better resource RB centre provides opportunity for it to be offered.
| Follow-Up Schedule|| |
This is typically influenced by age at presentation and laterality. Diagnosis in the 1st year suggests the possibility of bilateral disease which may not be present at diagnosis and the need for treatment, which requires a monthly follow-up until about year. Once the disease has regressed, it is monitored 3 monthly until 3 years, then 6 monthly till 5 years and yearly for life.
| Retinoblastoma Program Strategy|| |
RB program must be comprehensive with focus on early detection, development of referral chains and early intervention delivered within a multidisciplinary team with effective counselling and follow-up program. Education of parents and training of allied health workers, physicians, paediatricians, nurses and ophthalmologists and research are key to improvement in survival.
Early detection within the first 2 years of life includes strategies for examination of newborn eyes looking for red reflexes and squint from the eyes in the labour room, postnatal wards, during immunisation and well-baby clinics, public education through mass media, handbills, placement of large format materials in antenatal clinics and public places and on 15 February yearly WHO International Childhood Cancer Day.
Targeting primary, secondary and tertiary levels of health systems for level appropriate referral/care and public education to encourage appropriate response to child eye health symptoms in addition to seeking support of other stakeholders for RB have significant roles to play in early diagnosis, referral and comprehensive intervention to reverse the abysmally low survival in RB in low-resource countries. At the primary care level, incorporating child eye health in services is essential. Antenatal immunisation and well-baby clinics provide good opportunities for awareness campaigns, early detection and referral to a RB care centre. Use of information posters, interview of caregivers and red reflex examination, that reveals history of eye glow in the dark, abnormal red reflex and strabismus should lead to prompt referral.,, Up to 10% of all RBs and about 70% of those with a family history are diagnosed in the neonatal period in high-resource countries where nurses have been invaluable in ensuring screening, follow-up care and practical support for patients.
RB requires a multidisciplinary team care. At the secondary healthcare level in low-resource countries, RB detected after 18 months of life should be assessed to rule out bilateral disease beyond any reasonable doubt. If confirmed to be unilateral and there are facilities for counselling, enucleation and insertion into the posterior Tenon's space during the primary surgery of orbital implant is recommended the material is made from silicone or polymethylmethacrylate if silicone is not available. At follow-up 6 week post-enucleation, ocular prosthesis (AE) to match the colour of the other eye is fitted for good cosmetic appearance.
In order to strengthen and improve RB care and patient survival in low-resource countries such as Nigeria, a national RB program is required; there must be deliberate efforts for capacity building and inclusion of child eye health in the curriculum and practice of all cadres of primary healthcare workers. Creation of public awareness for behavioural change requires government and stakeholder support.
Because the disease is not so common and there can be challenges with expertise and availability of equipment for comprehensive RB care, some regional centres should be designated for RB care in each country such as the two centres in the United Kingdom where all RB cases are referred. This is essential for saving life, eyes or vision due to pooling of required resources and good potential for sustainable and equitable care for RB.,
In order to strengthen and improve RB care and patient survival in low-resource countries, a national RB program is required; there must be deliberate efforts for capacity building and inclusion of child eye health in the curriculum and practice of all cadres of primary healthcare workers. Creation of public awareness for behavioural change requires government and all other stakeholder support.
Currently, in Nigeria, comprehensive RB services are available at the University of Ilorin Teaching Hospital, in Ilorin, where a clinic is dedicated to RB care having being recognised as a referral centre. Likewise, University College Ibadan provides RB care. Other centres such as the National Eye Centre and one each from the other geopolitical zones of Nigeria should be strengthened to provide comprehensive RB care. Such a centre should be able to safely provide chemotherapy, focal laser/cryotherapy, counselling, RB support group, RB specialist, social workers, pathologists with RB expertise, imaging expertise, paediatric anaesthesia, counsellor and access to genetic evaluation. Because of the geographical peculiarity of Nigeria and consideration for disease severity, secondary RB centres could be developed to provide high-quality care for cases that are confirmed to be advance unilateral in which enucleation might be the main treatment while they refer bilateral cases and complicated unilateral cases to the tertiary RB centres as is done in Canada.
Globalisation should be utilised to tap from national and international resources for RB care including capacity building for human, equipment and supplies of medication resulting in strengthening of RB team, consultations, telemedicine and twinning, such as obtains in Jordan and Kenya., These are accomplished through twinning and collaboration between RB centres/governments of high- and low-resource countries. Countries that develop strong primary eye care services and referral chain to designated centres will improve survival of children who develop this highly treatable cause of under-5 mortality – RB.
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Conflicts of interest
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| References|| |
Kivelä T. The epidemiological challenge of the most frequent eye cancer: Retinoblastoma, an issue of birth and death. Br J Ophthalmol 2009;93:1129-31.
Owoeye JF, Afolayan EA, Ademola-Popoola DS. Retinoblastoma – A clinico-pathological study in Ilorin, Nigeria. Afr J Health Sci 2006;13:117-23.
Yun J, Li Y, Xu CT, Pan BR. Epidemiology and Rb1 gene of retinoblastoma. Int J Ophthalmol 2011;4:103-9.
Dimaras H, Kimani K, Dimba EA, Gronsdahl P, White A, Chan HS, et al.
Retinoblastoma. Lancet 2012;379:1436-46.
Grossniklaus HE. Retinoblastoma. Fifty years of progress. The LXXI Edward Jackson memorial lecture. Am J Ophthalmol 2014;158:875-91.
Jenkinson H. Retinoblastoma: Diagnosis and management – The UK perspective. Arch Dis Child 2015;100:1070-5.
Seth R, Singh A, Guru V, Chawla B, Pathy S, Sapra S. Long-term follow-up of retinoblastoma survivors: Experience from India. South Asian J Cancer 2017;6:176-9.
] [Full text]
United Nations Children's Fund. The Economic and Social Council. Country Programme Document – Nigeria; 2017. p. 500-706.
Solebo AL, Cumberland PM, Rahi JS. Whole-population vision screening in children aged 4-5 years to detect amblyopia. Lancet 2015;385:2308-19.
Fabian ID, Sagoo MS. Understanding retinoblastoma: Epidemiology and genetics. Community Eye Health 2018;31:7.
Chantada G, Luna-Fineman S, Sitorus RS, Kruger M, Israels T, Leal-Leal C, et al.
SIOP-PODC recommendations for graduated-intensity treatment of retinoblastoma in developing countries. Pediatr Blood Cancer 2013;60:719-27.
Dimaras H, Corson TW, Cobrinik D, White A, Zhao J, Munier FL, et al.
Retinoblastoma. Nat Rev Dis Primers 2015;1:15021.
Lim FP, Soh SY, Iyer JV, Tan AM, Swati H, Quah BL. Clinical profile, management, and outcome of retinoblastoma in Singapore. J Pediatr Ophthalmol Strabismus 2013;50:106-12.
Sengupta S, Pan U, Khetan V. Adult onset retinoblastoma. Indian J Ophthalmol 2016;64:485-91.
] [Full text]
Balmer A, Zografos L, Munier F. Diagnosis and current management of retinoblastoma. Oncogene 2006;25:5341-9.
Bell AL, Rodes ME, Collier Kellar L. Childhood eye examination. Am Fam Physician 2013;88:241-8.
Abdu L, Malami S. Clinicopathological pattern and management of retinoblastoma in Kano, Nigeria. Ann Afr Med 2011;10:214-9.
] [Full text]
Karcioglu ZA. Fine needle aspiration biopsy (FNAB) for retinoblastoma. Retina 2002;22:707-10.
Chawla B, Tomar A, Sen S, Bajaj MS, Kashyap S. Intraocular fine needle aspiration cytology as a diagnostic modality for retinoblastoma. Int J Ophthalmol 2016;9:1233-5.
Ademola-Popoola DS, Olatunji VA. Retinal imaging with smartphone. Niger J Clin Pract 2017;20:341-5.
] [Full text]
Finger PT, Khoobehi A, Ponce-Contreras MR, Rocca DD, Garcia JP Jr. Three dimensional ultrasound of retinoblastoma: Initial experience. Br J Ophthalmol 2002;86:1136-8.
Ghosh S, Mukhopadhyay S, Dutta SK, Chattopadhyay D, Biswas K. Diagnostic accuracy in retinoblastoma. J Indian Med Assoc 2010;108:509, 512-3.
Razek AA, Elkhamary S. MRI of retinoblastoma. Br J Radiol 2011;84:775-84.
De Jong MC, van der Meer FJ, Göricke SL, Brisse HJ, Galluzzi P, Maeder P, et al.
Diagnostic accuracy of intraocular tumor size measured with MR imaging in the prediction of postlaminar optic nerve invasion and massive choroidal invasion of retinoblastoma. Radiology 2016;279:817-26.
Galluzzi P, Hadjistilianou T, Cerase A, Toti P, Leonini S, Bracco S, et al.
MRI helps depict clinically undetectable risk factors in advanced stage retinoblastomas. Neuroradiol J 2015;28:53-61.
Chou R, Dana T, Bougatsos C. Screening for visual impairment in children ages 1-5 years: Update for the USPSTF. Pediatrics 2011;127:e442-79.
de Jong MC, de Graaf P, Noij DP, Göricke S, Maeder P, Galluzzi P, et al.
Diagnostic performance of magnetic resonance imaging and computed tomography for advanced retinoblastoma: A systematic review and meta-analysis. Ophthalmology 2014;121:1109-18.
Song KD, Eo H, Kim JH, Yoo SY, Jeon TY. Can preoperative MR imaging predict optic nerve invasion of retinoblastoma? Eur J Radiol 2012;81:4041-5.
Cui Y, Luo R, Wang R, Liu H, Zhang C, Zhang Z, et al.
Correlation between conventional MR imaging combined with diffusion-weighted imaging and histopathologic findings in eyes primarily enucleated for advanced retinoblastoma: A retrospective study. Eur Radiol 2018;28:620-9.
Sirin S, de Jong MC, de Graaf P, Brisse HJ, Galluzzi P, Maeder P, et al.
High-resolution magnetic resonance imaging can reliably detect orbital tumor recurrence after enucleation in children with retinoblastoma. Ophthalmology 2016;123:635-45.
Cozza R, De Ioris MA, Ilari I, Devito R, Fidani P, De Sio L, et al.
Metastatic retinoblastoma: Single institution experience over two decades. Br J Ophthalmol 2009;93:1163-6.
Gündüz K, Müftüoglu O, Günalp I, Unal E, Taçyildiz N. Metastatic retinoblastoma clinical features, treatment, and prognosis. Ophthalmology 2006;113:1558-66.
Galluzzi P, Hadjistilianou T, Cerase A, De Francesco S, Toti P, Venturi C. Is CT still useful in the study protocol of retinoblastoma? AJNR Am J Neuroradiol 2009;30:1760-5.
Ortiz MV, Dunkel IJ. Retinoblastoma. J Child Neurol 2016;31:227-36.
Shields CL, Shields JA. Basic understanding of current classification and management of retinoblastoma. Curr Opin Ophthalmol 2006;17:228-34.
Fabian ID, Onadim Z, Karaa E, Duncan C, Chowdhury T, Scheimberg I, et al.
The management of retinoblastoma. Oncogene 2018;37:1551-60.
Fabian ID, Reddy A, Sagoo MS. Classification and staging of retinoblastoma. Community Eye Health 2018;31:11-3.
PDQ Pediatric Treatment Editorial Board. Retinoblastoma Treatment (PDQ®): Health Professional Version. [Table 1]. International Retinoblastoma Staging System. In: PDQ Cancer Information Summaries. Bethesda (MD): National Cancer Institute (US); [In press].
TNM8: The updated TNM classification for retinoblastoma. Community Eye Health 2018;31:34.
Sastre X, Chantada GL, Doz F, Wilson MW, de Davila MT, Rodríguez-Galindo C, et al.
Proceedings of the consensus meetings from the International Retinoblastoma Staging Working Group on the pathology guidelines for the examination of enucleated eyes and evaluation of prognostic risk factors in retinoblastoma. Arch Pathol Lab Med 2009;133:1199-202.
Mendoza PR, Specht CS, Hubbard GB, Wells JR, Lynn MJ, Zhang Q, et al.
Histopathologic grading of anaplasia in retinoblastoma. Am J Ophthalmol 2015;159:764-76.
Posner M, Jaulim A, Vasalaki M, Rantell K, Sagoo MS, Reddy MA. Lag time for retinoblastoma in the UK revisited: A retrospective analysis. BMJ Open 2017;7:e015625.
Bekibele CO, Ayede AI, Asaolu OO, Brown BJ. Retinoblastoma: The challenges of management in Ibadan, Nigeria. J Pediatr Hematol Oncol 2009;31:552-5.
Meel R, Radhakrishnan V, Bakhshi S. Current therapy and recent advances in the management of retinoblastoma. Indian J Med Paediatr Oncol 2012;33:80-8.
] [Full text]
Kodilinye HC. Retinoblastoma in Nigeria: Problems of treatment. Am J Ophthalmol 1967;63:469-81.
Karkhaneh R, Pourmostadam B, Nili AhmadAbadi M, Roohipoor R, Ghassemi F, Chams H, et al
. Chemoreduction in the Management of Intraocular Retinoblastoma Using New International Classification. Iran J Ophthalmol 2010;22:31-35.
Kim JY, Park Y. Treatment of retinoblastoma: The role of external beam radiotherapy. Yonsei Med J 2015;56:1478-91.
Bakhshi S, Bakhshi R. Genetics and management of retinoblastoma. J Indian Assoc Pediatr Surg 2007;12:109. [Full text]
Abramson DH, Shields CL, Munier FL, Chantada GL. Treatment of retinoblastoma in 2015: Agreement and disagreement. JAMA Ophthalmol 2015;133:1341-7.
Rao R, Honavar SG. Retinoblastoma. Indian J Pediatr 2017;84:937-44.
Yadava U, Sachdeva P, Arora V. Myoconjunctival enucleation for enhanced implant motility. Result of a randomised prospective study. Indian J Ophthalmol 2004;52:221-6.
] [Full text]
Shome D, Honavar SG, Raizada K, Raizada D. Implant and prosthesis movement after enucleation: A randomized controlled trial. Ophthalmology 2010;117:1638-44.
Shields CL, Kaliki S, Al-Dahmash S, Rojanaporn D, Leahey A, Griffin G, et al.
Management of advanced retinoblastoma with intravenous chemotherapy then intra-arterial chemotherapy as alternative to enucleation. Retina 2013;33:2103-9.
National Retinoblastoma Strategy Canadian Guidelines for Care: NRbS Canadian Guidelines for Care. Can J Ophthalmol 2009;44;S9-S47.
Hernandez JC, Brady LW, Amendola BE, Shields JA, Shields CL. Plaque Brachytherapy in the Treatment of Retinoblastoma. Berlin:Springer, Berlin, Heidelberg; 1993. p. 147-51.
Kaliki S, Shields CL. Retinoblastoma: Achieving new standards with methods of chemotherapy. Indian J Ophthalmol 2015;63:103-9.
] [Full text]
Shields CL, Lally SE, Leahey AM, Jabbour PM, Caywood EH, Schwendeman R, et al.
Targeted retinoblastoma management: When to use intravenous, intra-arterial, periocular, and intravitreal chemotherapy. Curr Opin Ophthalmol 2014;25:374-85.
Brichard B, De Bruycker JJ, De Potter P, Neven B, Vermylen C, Cornu G. Combined chemotherapy and local treatment in the management of intraocular retinoblastoma. Med Pediatr Oncol 2002;38:411-5.
Kaliki S, Srinivasan V, Gupta A, Mishra DK, Naik MN. Clinical features predictive of high-risk retinoblastoma in 403 Asian Indian patients: A case-control study. Ophthalmology 2015;122:1165-72.
Gupta R, Vemuganti GK, Reddy VA, Honavar SG. Histopathologic risk factors in retinoblastoma in India. Arch Pathol Lab Med 2009;133:1210-4.
Said AMA, Aly MG, Rashed HO, Rady AM. Safety and efficacy of posterior sub-Tenon's carboplatin injection versus intravitreal melphalan therapy in the management of retinoblastoma with secondary vitreous seeds. Int J Ophthalmol 2018;11:445-55.
Munier FL, Gaillard MC, Balmer A, Soliman S, Podilsky G, Moulin AP, et al
. Intravitreal chemotherapy for vitreous disease in retinoblastoma revisited: From prohibition to conditional indications. Br J Ophthalmol 2012;96:1078-83. doi:10.1136/bjophthalmol-2011-301450.
Shields CL, Douglass AM, Beggache M, Say EAT, Shields JA. Intravitreous chemotherapy for active vitreous seeding from retinoblastoma. Retina. 2016;36:1184-90. Doi:10.1097/iae.0000000000000903.
Shields CL, Kaliki S, Shah SU, Bianciotto CG, Liu D, Jabbour P, et al
. Minimal exposure (one or two cycles) of intra-arterial chemotherapy in the management of retinoblastoma. Ophthalmol 2012; 119(1):188-92 doi:10.1016/j.ophtha.2011.06.036.
Francis JH, Abramson DH, Gaillard MC, Marr BP, Beck-Popovic M, Munier FL. The classification of vitreous seeds in retinoblastoma and response to intravitreal melphalan. Ophthalmology 2015;122:1173-9.
Lee JH, Han JW, Hahn SM, Lyu CJ, Kim DJ, Lee SC. Combined intravitreal melphalan and intravenous/intra-arterial chemotherapy for retinoblastoma with vitreous seeds. Graefes Arch Clin Exp Ophthalmol 2016;254:391-4.
Berry JL, Shah S, Bechtold M, Zolfaghari E, Jubran R, Kim JW. Long-term outcomes of group D retinoblastoma eyes during the intravitreal melphalan era. Pediatr Blood Cancer 2017;64:e26696.
Berry JL, Shah S, Kim F, Jubran R, Kim JW. Integrated treatment during the intravitreal melphalan era: Concurrent intravitreal melphalan and systemic chemoreduction. Ocul Oncol Pathol 2018;4:335-40.
Friedman DN, Sklar CA, Oeffinger KC, Kernan NA, Khakoo Y, Marr BP, et al
. Long-term medical outcomes in survivors of extra-ocular retinoblastoma: The Memorial Sloan-Kettering Cancer Center (MSKCC) experience. Pediatric Blood and Cancer. 2013;60:694-9. doi:10.1002/pbc.24280.
Kaliki S, Patel A, Iram S, Palkonda VAR. Clinical Presentation and Outcomes of Stage III or Stage IV Retinoblastoma in 80 Asian Indian Patients. Journal of pediatric ophthalmology and strabismus. 2017;54:177-84. doi:10.3928/01913913-20161019-01.
de Jong MC, Kors WA, de Graaf P, Castelijns JA, Moll AC, Kivelä T. The incidence of trilateral retinoblastoma: A systematic review and meta-analysis. Am J Ophthalmol 2015;160:1116-26.e5.
Abramson DH, Dunkel IJ, Marr BP, Francis J, Gobin YP. Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era. Am J Ophthalmol 2013;156:1319-20.
de Jong MC, Kors WA, de Graaf P, Castelijns JA, Kivelä T, Moll AC. Trilateral retinoblastoma: A systematic review and meta-analysis. Lancet Oncol 2014;15:1157-67.
Pradhan MA, Ng Y, Strickland A, George PM, Raizis A, Warrington J, et al.
Role of genetic testing in retinoblastoma management at a tertiary referral centre. Clin Exp Ophthalmol 2010;38:231-6.
Nichols KE, Walther S, Chao E, Shields C, Ganguly A. Recent advances in retinoblastoma genetic research. Curr Opin Ophthalmol 2009;20:351-5.
Ali MJ, Parsam VL, Honavar SG, Kannabiran C, Vemuganti GK, Reddy VA. RB1 gene mutations in retinoblastoma and its clinical correlation. Saudi J Ophthalmol 2010;24:119-23.
de Bree R, Moll AC, Imhof SM, Buter J, Leemans CR. Subsequent tumors in retinoblastoma survivors: The role of the head and neck surgeon. Oral Oncol 2008;44:982-5.
Jarvis SN, Tamhne RC, Thompson L, Francis PM, Anderson J, Colver AF. Preschool vision screening. Arch Dis Child 1991;66:288-94.
Mema SC, McIntyre L, Musto R. Childhood vision screening in Canada: Public health evidence and practice. Can J Public Health 2012;103:40-5.
Shoamanesh A, Pang NK, Oestreicher JH. Complications of orbital implants: A review of 542 patients who have undergone orbital implantation and 275 subsequent PEG placements. Orbit 2007;26:173-82.
Qaddoumi I, Nawaiseh I, Mehyar M, Razzouk B, Haik BG, Kharma S, et al.
Team management, twinning, and telemedicine in retinoblastoma: A 3-tier approach implemented in the first eye salvage program in Jordan. Pediatr Blood Cancer 2008;51:241-4.
He LQ, Njambi L, Nyamori JM, Nyenze EM, Kimani K, Matende I, et al.
Developing clinical cancer genetics services in resource-limited countries: The case of retinoblastoma in Kenya. Public Health Genomics 2014;17:221-7.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
[Table 1], [Table 2], [Table 3]