Retinoblastoma: Exploring New Horizons

Experts Corner Retinoblastoma: Exploring New Horizons Retinoblastoma is the most common intraocular malignancy of childhood, with an incidence of 1 in 15,000 to 20,000 live births. The goal of treatment includes saving life, conserving the globe and preserving functional vision. The prognosis for life has improved significantly in the past few decades, due to a better understanding of the disease, early diagnosis and improved management. Therapy for retinoblastoma has evolved from enucleation to globe salvage measures like systemic chemotherapy, plaque brachytherapy, intra-vitreal and intraarterial chemotherapy. Extra-ocular retinoblastoma remains a challenge in the developing world. We will discuss the preferred practice pattern with the leading experts of this field. The questions have been prepared by Dr. Abhijit Rasal (A. Rasal): MS, DNB, FAICO Senior Resident, Ocular Oncology & Pediatric Ophthalmology Services, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi. Dr. Arun D. Singh (ADS): MD is the Director of the Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, USA. He has published more than 280 scientific articles and has edited several textbooks (Clinical Ophthalmic Oncology, Ophthalmic Ultrasonography, Ophthalmic Radiation therapy and, FNA cytology of Ophthalmic Tumors). He is Editor of the Ocular Oncology and Pathology. Dr. Bhavna Chawla (BC): MS, Additional Professor of Ophthalmology, Ocular Oncology & Pediatric Ophthalmology Services, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India. Dr. Ashwin Reddy (AR): MA, MBBChir,MD FRCOphth, Consultant Paediatric Ophthalmologist and Retinoblastoma Surgeon, Lead for Retinoblastoma Barts Health NHS Trust, Paediatric Service Director Moorfields Eye Hospital NHS Foundation Trust, London, U.K. Dr. Santosh G. Honavar (SGH): MD, FACS, Director, Ocular Oncology, and National Retinoblastoma Foundation, Centre for Sight, Road No 2, Banjara Hills, Hyderabad, India. Dr. Gangadhara Sundar (GS): DO, FRCSEd, FAMS, Diplomate, The American Board of Ophthalmology, Head & Senior Consultant, Orbit & Oculofacial Surgery, Dept of Ophthalmology, Adjunct Faculty, Dept of Pediatrics, National University Hospital, Singapore Dr. Ashwin Mallipatna (AM): Paediatric Ophthalmology and Strabismus, In-charge of Retinoblastoma Service, Bangalore, India. Arun D. Singh Bhavna Chawla Ashwin Reddy Santosh G. Honavar A. Rasal: How do you evaluate a child presenting with leucocoria? ADS: A practical stepwise approach to evaluate a child suspected to have retinoblastoma includes a detailed history, thorough office examination, focused ophthalmic ultrasonography, and an examination under anesthesia (Figure 1). BC: Leucocoria is an important sign that can result from several conditions. After obtaining a detailed history, a child with leucocoria should undergo a meticulous clinical examination, which includes assessment of vision, anterior segment evaluation and fundus examination. If retinoblastoma is suspected, examination under general anesthesia is usually required for a thorough evaluation and must include examination of the fellow eye. B-scan ultrasonography of the posterior segment should be done in all cases.mri of the orbits is useful in certain situations when the fundus cannot be visualized. Gangadhara Sundar Ashwin Mallipatna www. dosonline.org l 13

Experts Corner: Retinoblastoma: Exploring New Horizons Figure 1: Stepwise evaluation for retinoblastoma. This approach is merely a guide that can be modified as needed based upon clinical setting. Reproduced with permission from Marr BP, Singh AD. Retinoblastoma diagnosis and management.clinical Ophthalmic Oncology.Retinoblastoma. Singh AD, AL Murphree, BE Damato. (Eds). Springer, Heidelberg 2014. AR: History, awake assessment and orthoptic evaluation.dilated examination of parents.if the problem is retinal, for examination under anaesthesia with ultrasonography. SGH: A child would leucocoria would undergo a complete ophthalmic and relevant physical examination. Specifically, we would look at the type of leucocoria: (is it typical leucocoria or xanthocoria, diffuse or eccentric, dull or shiny, anterior or deeper etc), visual response, squint, proptosis, relative microphthalmia, intraocular pressure, conjunctival congestion, corneal diameter, corneal oedema, anterior chamber depth, presence of hypopyon, hyphema or anterior chamber seeds, neovascularisation of the iris, iris hypoplasia, iris heterochromia, synechiae, cataract, zonular coloboma, dragging of ciliary processes, fibrovascular vitreous proliferation, vitreous seeds, vitreous haemorrhage, and vitritis, followed by a thorough fundus evaluation, and of course, a complete examination of the contra-lateral eye. In a young child, most of this information is gathered under GA. Imaging would include ultrasound B-scan, UBM if needed, and a CT scan or an MRI only if mandatory. FNAC is generally avoided. GS: Primarily history and clinical examination, investigations as indicated, with either an Examination under sedation or Anesthesia as appropriate. AM: A child with leukocoria would be evaluated with a full ophthalmology examination, first in clinic and then under anesthesia if the possibility of retinoblastoma exists. A detailed history, and family history is obtained followed by a systematic ocular examination and general systemic examination in all children suspected to have retinoblastoma. A B-mode ultrasonography and appropriate neuroimaging is an adjunct to the clinical features in considering the diagnosis of retinoblastoma and the evaluation of its extent of involvement. A. Rasal: What is the standard protocol for imaging a case of suspected retinoblastoma? ADS: Fundus photography is highly recommended at baseline and follow up examinations. Fluorescein angiography is useful particularly for imaging small intraretinal tumors. It may show minimally dilated feeding vessels with mild hypervascularity and staining in the venous phase. Larger tumors usually demonstrate more significant hypervascularity and late staining. Ultrasonography is extremely useful because it can easily demonstrate characteristic calcifications within the tumor. A-scan typically shows high internal echoes within the tumor and rapid attenuation. B-scan may show a rounded or irregular intraocular mass with numerous highly reflective granules consistent with intraocular calcification. Ultrasonography may also be used in combination with fundus photography/ophthalmoscopy to document tumor response after treatment. MRI is the preferred imaging modality, offering better soft tissue resolution while avoiding radiation exposure. Retinoblastoma usually appears in T2-weighted images as a lesion that is moderately hypo intense compared to the vitreous. BC: B-scan ultrasonography is routinely used as the baseline imaging modality for detection of an intraocular mass with calcification.retcam imaging is very important to document the tumor and should be done for all cases. RetCam Fundus fluorescein angiography can be done if required. UBM is a useful imaging modality if there is evidence of anterior segment seeding and helps to ascertain the anterior extent of the tumor. For staging of tumors in advanced disease (Group D/E or orbital invasion) and to rule out trilateral retinoblastoma, neuroimaging is indicated. MRI of the orbits and brain is preferred over CT scan as it has a superior soft tissue resolution as compared with CT and does not expose the child to hazards of radiation. CT scan should be particularly avoided in heritable cases. AR: Ultrasound examination, MRI of orbits and optic nerves including pineal gland. SGH: I would begin with a standard ultrasound 14 l DOS Times - Vol. 20, No. 6 December, 2014

Ocular Malignancies B-scan and it gives most of the necessary information. I would do a UBM under GA if the lesion is very anterior and in a child with hypopyon or hyphema, to determine the invasion of the ciliary body. I would avoid neuroimaging in a nonheritable retinoblastoma unless there are clinical risk factors such as proptosis. An MRI (preferable) or a CT scan helps determine extraocular extension or optic nerve invasion. In bilateral heritable retinoblastoma, a baseline screening MRI is indicated to rule out pinealoblastoma. I would document every child with detailed external photographs and supplementary high magnification documentation of the anterior segment if there are positive findings. RetCam fundus photograph is mandatory and RetCam FFA when needed. GS: Not for all cases. Ultrasound B Scan (not always), Retcam Imaging (Standard), MRI Brain & Orbits ( only for Group D(peripapillary)/E disease to r/o post laminar invasion, trilateral retinoblastoma (bilateral or multifocal disease). Seldom order CT Scan unless patients present with metastatic disease or MRI unavailable /unaffordable. AM: Any child with retinoblastoma undergoes neuroimaging either before or soon after the diagnosis of retinoblastoma to rule out the possibility of a primitive neuroectodermal tumor (especially in the pineal region). Orbital imaging is suggested if there is suspected extraocular involvement, or if the optic nerve head is suspected to be involved or not visible during clinical examination. An MRI scan tends to describe optic nerve involvement and intracranial involvement better than CT scan. A. Rasal: Which classification system do you follow for Retinoblastoma? ADS: International Classification for Intraocular Retinoblastoma BC: For intraocular tumors, I follow The International Classificationof Intraocular Retinoblastoma (Murphree et al) and for extraocular tumors, the International Retinoblastoma Staging System (Chantada et al). AR: International Intra-ocular Retinoblastoma Classification. SGH: I follow the International Classification of Intraocular Retinoblastoma and International Staging of Retinoblastoma (Chantada) as a routine. GS: International Classification. AM: For the management of intraocular retinoblastoma, I use the International Intraocular Retinoblastoma Classification described by Murphree in 2005. Other versions of the classification system exist, which have caused differences in interpreting papers published in the subject (as described by Novetsky et al in 2009). To help make a distinction in discussions, I use the clinical TNM classification (published in the 7th edition of the American Joint Committee on Cancer in 2009). The clinical TNM classification also takes into consideration extraocular retinoblastoma, lymph node involvement and metastatic tumors. When required to take a combination of clinical and pathological risks to a patient, I use the International Retinoblastoma Staging System described by Chantada et al in 2006. A. Rasal: What are the indications for primary chemotherapy? Which drugs are most commonly used at your centre? ADS: Group B, C, D eye are treated with primary chemotherapy. The foundation of systemic chemotherapy protocols has generally been carboplatin, vincristine with etoposide. BC: Broadly speaking, primary chemotherapy is indicated in the following situations. a) As globe salvage therapy for intraocular tumors Groups B-D, in combination with focal therapy. b) As neoadjuvant chemotherapy in children with orbital invasion. High dose chemotherapy is given. c) In a child with a staphylomatous globe where there is a risk of perforation during enucleation surgery, primary chemotherapy can be given prior to enucleation. Vincristine, Etoposide and Carboplatin (VEC) are the most commonly used drugs at our centre. AR: Group D eye or better in bilateral disease. Group D eye or better in unilateral disease. Carboplatin/Etoposide/ Vincristine as 6 cycles. SGH: Indications for primary chemotherapy are: a. Group B and higher intraocular retinoblastoma for chemoreduction b. Neoadjuvant systemic chemotherapy in unilateral Group E retinoblastoma when primary enucleation is unsafe specifically if there is spontaneous tumour necrosis with orbital cellulitis, or if the eyeball is buphthalmic, thus precluding excision of a long optic nerve stump. Another special situation is when the family refuses enucleation or wants time to mourn the eye. Most of these families can ultimately be convinced for surgery c. High-dose neoadjuvant chemotherapy in orbital retinoblastoma. We use a combination of vincristine, carboplatin and etoposide. GS: All cases where there is suspected extraocular extension, intraocular tumor where globe salvage is preferred (physician or parents), metastatic disease. VEC for intraocular disease, VETOPEC for metastatic disease. www. dosonline.org l 15

Experts Corner: Retinoblastoma: Exploring New Horizons AM: Usually, children with intraocular retinoblastoma with no clinical risk of metastasis get selected for primary chemotherapy. Each child diagnosed with retinoblastoma gets discussed in a tumor board meeting with the pediatric oncologists and the ideal treatment plan or a change in its course is decided there. Carboplatin, etoposide, and vincristine are usually our drugs of choice. A. Rasal: What is the role of intra-arterial chemotherapy as a globe-saving treatment? ADS: Typically in Group C or D eye with multifocal retinal recurrence (with visual potential). BC: Intra-arterial chemotherapy is gaining popularity as a globe conserving therapy due to its main advantage of providing targeted drug delivery to the tumor, without exposing the body to risks of systemic chemotherapy. In the current scenario, we reserve IAC for eyes that have failed to respond to systemic chemotherapy and have visual potential, usually Group C or D retinoblastoma. In exceptional circumstances, when systemic chemotherapy is not tolerated or is contra-indicated, Intra-arterial chemotherapy is another option.it is an expensive treatment and hence, affordability is an added factor in our patients. AR: Salvage if unable to control with systemic chemotherapy and local treatment.useful in 13q deletion syndrome to avoid use of systemic chemotherapy. SGH: There is a definite role of intra-arterial chemotherapy as a globe -saving treatment. However, at this stage, I would reserve it to only those cases where there are no clinical risk factors, where vision salvage may be possible, failed systemic chemotherapy in a child with the only potentially seeing eye, and if the family can afford this form of expensive treatment. GS: Limited experience only. Only when systemic chemoreduction has failed or not tolerated or parent preference. AM: Intra-arterial chemotherapy is one of the novel options for the delivery of chemotherapy in children with retinoblastoma, gaining popularity in the field. As with any of the treatment modalities, it carries risks and benefits, best described by prospective clinical trials. The true clinical indications of this method of treatment will be realized from an understanding of its strengths, limitations and cost effectiveness. A. Rasal: When do you advise enucleation? What are the basic precautions to be taken during surgery? ADS: Enucleation continues to be the treatment of choice for significantly advanced retinoblastoma (Group E) and eyes without visual potential. This is particularly true in the setting of unilateral and non-germ line disease since enucleation is curative in the majority of such cases. During enucleation, particular care should be taken to avoid perforation or penetration of the globe to minimize the risk of extraocular extension and to obtian about 15 mm of opticnerve stump. BC: I usually advise enucleation as a primary treatment for eyes with advanced intraocular tumors. In Group E disease where one or more of the following factors are present- secondary glaucoma, anterior chamber invasion, phthisis bulbi, aseptic orbital cellulitis, diffuse infiltrating retinoblastoma, massive intraocular haemorrhage or tumor touching the lens, enucleation is the treatment of choice. After failure of conservative therapy, enucleation is advised as a secondary treatment when the risk involved in saving the eye outweighs the benefits. In extraocular cases, after tumor shrinkage with neoadjuvant chemotherapy, enucleation is advised, followed by orbital radiotherapy and adjuvant chemotherapy cycles. Important precautions to be taken during surgery are avoidance of perforation of the globe and ensuring a long optic nerve stump ( >15mm). Gentle handling of the globe with minimal manipulation should be practised. Prior to sending the eyeball for histopahological examination, it is important for the surgeon to inspect the globe externally including the optic nerve for any suspicious area of tumor invasion. AR: Group E eyes at presentation or if salvage treatment is ineffective. Avoid perforation. SGH: Primary enucleation continues to be the treatment of choice for advanced intraocular retinoblastoma with neovascularization of iris, secondary glaucoma, anterior chamber tumour invasion, tumours occupying >75% of the vitreous volume, necrotic tumours with secondary orbital inflammation, and tumours associated with hyphema or vitreous haemorrhage where the tumour characteristics can not be visualized, especially when only one eye is involved. Secondary enucleation is advised in those who fail reasonable and standard treatment where continuation of further conservative treatment may entail risk to life. There are specific considerations while enucleating an eye with retinoblastoma. Minimum-manipulation surgical technique should be necessarily practiced. It is important to take due precautions not to accidentally perforate the eye. The sclera is thin at the site of muscle insertions and the rectus muscles have to be hooked delicately. It is mandatory to obtain a long optic nerve stump, ideally more than 15 mm, but never less than 10 mm. Certain steps can be taken to obtain about 15 mm long optic nerve stump in all cases of advanced retinoblastoma. Gentle traction can be applied by the traction sutures applied to recti muscle stumps prior to transecting the optic nerve. As an alternative to the traction sutures, medial or lateral rectus 16 l DOS Times - Vol. 20, No. 6 December, 2014

Ocular Malignancies muscle stumps may be kept long and traction exerted with an artery clamp. It is best to prolapse the eyeball through the blades of the wire speculum. A 15-degree curved and blunt-tipped tenotomy scissors is introduced from the lateral aspect (or a straight scissors from the medial aspect) and the optic nerve is palpated with the closed tip of the scissors while maintaining gentle anteroposterior traction on the eyeball. The scissors is moved posteriorly to touch the orbital apex while gently strumming the optic nerve. The scissors is lifted by 2 or 3 millimetres off the orbital apex (to prevent accidental damage to the contents of the superior orbital fissure), the blades of the scissors are opened to engage the optic nerve, and the nerve is transected with one bold cut. This manoeuvre easily provides at least 15 mm long optic nerve stump. Enucleation spoon and heavy enucleation scissors limit space for manoeuvrability and may result in a shorter optic nerve stump. In addition, one should be careful not to accidentally perforate the eye during enucleation. The enucleated eyeball is thoroughly inspected for optic nerve or extraocular extension of the tumour and suspicious areas (sclera thinning, induration, discoloration, vascularilty, and nodularity and, dilated vortex veins) are marked for histoapthogic examination to evaluate scleral or extrascleral extension of the tumour. GS: Unilateral advanced disease (Group D/E) with poor visual potential, > 2 yrs of age at presentation. Failed conservative management, massive tumor necrosis, etc Only when absolutely indicated or parent desire, Retrobulbar Lido with adrenaline block, Long optic nerve stump, Frozen section to be available for cut end of optic nerve. AM: We would advice enucleation to a child when the risks of keeping an eye with retinoblastoma outweight its benefits. A full discussion with parents about the potential risks and benefits is made prior to making the final decision. If treatment compliance for globe salvage is a concern, or repeated examinations under anesthesia is considered a risk, enucleation might be suggested before other methods. We advocate minimal handling of the globe during the enucleation procedure, and using proper procedures and equipment that help to getting the longest possible optic nerve stump. A. Rasal: What important features would you like your pathologist to mention while reporting on the enucleated eyeball? ADS: Extent of choroidal invasion and optic nerve extension. BC: The histopathological factors that define high risk for metastasis and require the child to be treated with adjuvant chemotherapy must be mentioned such as the extent of choroidal invasion (focal/massive), retro-laminar optic nerve invasion, optic nerve transection end invasion, anterior segment involvement (iris/ciliary body/trabecular meshwork/ anterior chamber), and scleral or extra-scleral invasion. In addition, the degree of tumor differentiation and extent of necrosis are also usually reported. It is important to bear in mind that in children with history of prior chemotherapy, histopathology may be down-staged and has to be interpreted with caution. AR: Optic nerve invasion( particularly post-laminar invasion), choroidal invasion (whether massive or not), cutend disease, anterior segment involvement. SGH: The identification of frequency and significance of high-risk histopathologic factors that can reliably predict metastasis is vital for patient selection for adjuvant therapy. It is now generally agreed that massive choroidal infiltration, retrolaminar optic nerve invasion (intraneuritis or perineuritic), invasion of the optic nerve to transection, scleral infiltration, and extrascleral extension are the risk factors that are predictive of metastasis. I would like my pathologist to not just evaluate the pupillo-optic calotte, but also lateral calotte, and section specifically through clinically suspicious areas marked out by the surgeon and objectively report on high-risk factors. GS: Frozen section of cut end of optic nerve. Extent of tumor necrosis (if chemoreduced), choroidal invasion, post laminar invasion, anterior segment invasion. Differentiation. AM: Proper processing of an eyeball after enucleation is essential in being able to find the histopathological risk of metastasis. I look at histopathology slides myself, and specifically look for signs of the tumor involving the choroid, sclera, anterior segment or past lamina cribrosa. I discuss my findings on the histopathology slide with the pathologists, and clarify my doubts about the extent of involvement of the tumor prior to us making a treatment decision. Reading pathology reports of eyes that have previously been exposed to chemotherapy would require caution in its interpretation, with the understanding that chemotherapy might mask the signs that usually predict possible metastasis. A. Rasal: What are the indications for adjuvant chemotherapy after enucleation at your centre? ADS: Patients with the high-risk features listed in (Table 1) receive chemotherapy consisting of 6 cycles of standard dose carboplatin, vincristine and etoposide given once every 4 weeks as per the COG ARET 0332 Histopathologic Risk Factors Protocol (A Study of Unilateral Retinoblastoma with and without Histopathologic High- Risk Features and the Role of Adjuvant Chemotherapy). BC: At our centre, we follow the guidelines recommended by the Children s Oncology Group for high risk histopathological features predictive of metastasis in children undergoing primary enucleation. These include www. dosonline.org l 17

Experts Corner: Retinoblastoma: Exploring New Horizons Table 1: High Risk Histopathologic Features in an Enucleated Eye that Qualified for Adjuvant Chemotherapy under COG ARET-0332 Feature Details Massive choroidal invasion Posterior uveal invasion grades IIC and IID (as defined in pathology guidelines of the protocol) Any posterior uveal invasion with any optic nerve involvement (optic nerve head, pre-lamina and post lamina cribrosa) Both posterior uveal invasion AND optic nerve involvement are required Optic nerve involvement posterior to the lamina cribrosa as an independent finding. Modified with permission from: Children s Oncology Group Trials. DS Gombos, AT Meadows, M Chintagumpala, IJ Dunkel, D Friedman, JA Stoner, R Jubran, JG Villablanca. Retinoblastoma. Singh AD, Murphree AL, Damato BE. Clinical Ophthalmic Oncology. Springer 2014. massive choroidal invasion, scleral invasion, anterior segment invasion and retrolaminar optic nerve invasion. Children with one or more of these high-risk features are treated with 6 cycles of standard dose VEC. In children with tumor invasion to the transection end of the optic nerve or extra-scleral invason, orbital radiotherapy is advised in addition to high dose adjuvant chemotherapy. Adjuvant chemotherapy after enucleation is also given in rare instances when a child presents with a history of surgical intervention like intra-vitral injection or hyphaema drainage elsewhere for unsuspected RB. AR: Massive choroidal invasion, post-laminar optic nerve invasion, anterior segment involvement. SGH: If primary enucleation is performed, histopathological high risk factors govern further treatment. If there is iris, ciliary body or choroidal (>3mm in thickness or diameter) invasion, invasion of the optic nerve beyond the lamina cribrosa, or lamellar invasion of the sclera, 6 cycles of standard dose adjuvant chemotherapy with a combination of carboplatin, etoposide and vincristine is indicated. If there is full-thickness sclera invasion, extraocular extension or optic nerve invasion to the level of transaction, then we would provide adjuvant high-dose chemotherapy for 6 cycles and external beam radiotherapy to the orbit. GS: Postlaminar or significant choroidal invasion, bilateral / trilateral disease, previous inadvertent biopsy/ intravitreal injection (elsewhere). AM: We have adopted guidelines based on the Children s Oncology Group in describing histopathological features that define high-risk for metastasis. Involvement of the iris, ciliary body, massive choroidal invasion and invasion of the optic nerve beyond lamina cribrosa or in the cut section of the optic nerve would necessitate adjuvant chemotherapy. A. Rasal: What is the role of intra-vitreal chemotherapy in the current scenario? When should it be considered? ADS: Intravitreal chemotheraphy is considered only as salvage therapy in eyes with persistent or recurrent intravitreal seeding following intra-arterial or intravenous chemotherapy (Group C, Deyes) in combination with treatment of the retinal tumor (source). BC: Intra-vitral chemotherapy has shown promising results in carefully selected cases. For persistent or recurrent vitreous seeds that have failed to respond to systemic chemotherapy and/or intra-arterial chemotherapy, intravitreal chemotherapy can be considered for globe salvage. Simultaneous control of tumor source is very important and the procedure must be performed with utmost caution. A UBM evaluation prior to the procedure is recommended. AR: Resistant vitreous seeds not successfully treated with systemic chemotherapy or intra-arterial chemotherapy. We now tend to use it specifically for vitreous seeding after systemic chemotherapy is ineffective. SGH: I would do intra-vitreal chemotherapy in those where there are residual or recurrent viable vitreous seeds following completion of 6 cycles of high-dose chemotherapy with concurrent periocular chemotherapy. GS: Havent offered it yet. AM: Intra-vitreal chemotherapy is being reintroduced as one of the options for the delivery of chemotherapy in children with retinoblastoma with vitreous seeds. It has found success when standard chemotherapy fails to reach the vitreous at sufficient concentrations. The response of vitreous seeds has been encouraging in those seeds that continue to be active despite standard chemotherapy. We always ensure that an ultrasound bio-microscopy of the injection site is performed prior to every injection, to confirm that the vitreous adjacent to the injection site does not show visible seeding. Like with intra-arterial chemotherapy, the true clinical value of this method of treatment will be realized from a further understanding of its indications and limitations. A. Rasal: Do you advise external beam radiotherapy? If so, in which situations? ADS: We currently do not use external radiation therapy for management of intraocular retinoblastoma. Radiation therapy is still used used for orbital retnoblastoma, an extremely uncommon scenario in the United States. BC: I advise external beam radiotherapy in the following situations: 18 l DOS Times - Vol. 20, No. 6 December, 2014

Ocular Malignancies a) In all cases with extra-ocular disease, as a part of multi-modal treatment protocol b) After primary enucleation, when there is evidence of tumor invasion upto the optic nerve transection end or into extrascleral tissue on histopathology. Rarely in intraocular cases, after failure of systemic chemotherapy and intra-arterial chemotherapy, external beam radiotherapy has a role in globe salvage. AR: Yes for salvage. SGH: Very rarely in intraocular retinoblastoma when all else has failed, or as adjuvant treatment in orbital retinoblastoma as part of the planned multi-modal treatment. GS: Only when extraocular (orbital/intracranial disease) exists at presentation, only seeing eye failing conservative chemoreduction, intraarterial. AM: Although increasingly rare, we sometimes use stereotactic external beam radiation for the treatment of extraocular retinoblastoma after chemotherapy. Its use for intraocular retinoblastoma has been limited to children with an only seeing eye with active tumor that is resistant to all other forms of treatment. A. Rasal: How common is it to find extra-ocular retinoblastoma in your clinical practice? ADS: Extremely rare. BC: Unfortunately, its very common in our clinical setting. One fourth of children who present to the Retinoblastoma clinic of our centre already have extraocular spread at the time of initial diagnosis, some also have CNS disease. Around 200 new cases are diagosed with RB every year at AIIMS, so the burden of extraocular RB is fairly large. AR: Very uncommon. SGH: Around 5%. GS: 1 in 6 pts approx. annually. AM: Retinoblastoma with overt extraocular involvement is thankfully getting less common in our practice, probably due to improving awareness and access to care. We do still get children with intraocular retinoblastoma presenting with aseptic orbital cellulitis, but they are not considered to have extraocular tumor. A. Rasal: Do you advise metastatic work up for all cases? What are the investigations to be done? ADS: A systemic metastatic evaluation is not indicated in children without evidence of neurologic abnormalities, extrascleral extension or high risk features of massive choroidal invasion or retrolaminar optic nerve extension on histopathologic examination of the enucleated globe. If extraocular extension is present, systemic workup should include a bone marrow biopsy as well as lumbar puncture. BC: Metastatic work up is indicated for cases with high risk histopathology after primary enucleation and in all cases with extraocular spread. This consists of clinical examination by a pediatric oncologist, neuroimaging, blood biochemistry, liver and kidney function tests, Chest X-ray, Ultrasound of the abdomen, Bone marrow examination and lumbar puncture for CSF cytology. Bone scan and PETscan can be done for orbital cases, if the facility is available. AR: No, only if having systemic chemotherapy. SGH: Baseline metastatic work-up in intraocular retinoblastoma with clinical risk factors, histopathological risk factors following enucleation, and in all cases of orbital retinoblastoma. It includes neuroimaging, bone marrow biopsy, CSF cytology, a thorough physical evaluation by a paediatric oncologist, and a PET scan where indicated. GS: Only when secondary glaucoma, known extraocular disease (orbital or post laminar disease) or previous invasive procedures performed elsewhere. Bone marrow Trephine (not needle) biopsy, lumbar puncture, clinical exam. AM: A metastatic workup is suggested for every child with overt extra-ocular tumor, and those discovered to have a high-risk histopathology after enucleation. Metastatic work-up is sometimes suggested for patients with high-risk clinical features (ie; Group E tumor) of intraocular retinoblastoma, especially those in whom we are unable to confirm the health of optic nerve head during an examination under anesthesia. A. Rasal: How often and till what age do you follow up your cases? ADS: Depends upon the status of the tumor and how much time has elapsed since active therapy. During active therapy EUA is perfomred very 4 weeks. Once off therapy, the interval can be gradually prolonged based upon clinical judgement. For stable cases, following outline is used (with modifications as clinically necessary): Germline cases (based upon genetic testing), EUA(every 4 months) until age 3 years followed by office exams (every 6 months) from ages 3-5 years, followed by annual exams after that. Sporadic cases (based upon genetic testing), we recommend office exams (every 4 months) until age 3 years followed by office exams (every 6 months) from ages 3-5 years followed by annula exams after that. BC: After completion of therapy, we perform EUA at 3 monthly intervals for the first two years, thereafter, the www. dosonline.org l 19

Experts Corner: Retinoblastoma: Exploring New Horizons interval is gradually increased to 4 monthly, 6 monthly and finally, annually. In older children, office examinations can be done. If genetic testing shows a germline mutation, a more rigorous follow up is warranted. Follow up visits should include both ophthalmic and systemic examination. It is important to look for recurrence or reactivation of the tumor and development of new tumors for visual rehabilitation or care of the anophthalmic socket, for side effects of treatment and development of secondary cancers. Ideally, life long follow-up should be done. AR: Bilateral or unilateral genetic until 16, others until 10. SGH: The usual protocol is to schedule the first examination 3 6 weeks after the initial therapy. In cases where chemoreduction has been administered, the examination should be done every 3-4 weeks along with each cycle of chemotherapy. Patients under focal therapy are evaluated and treated every 4-8 weeks until complete tumour regression. Following tumour regression, subsequent examination should be 3 monthly for the first year, 6 monthly for three years or until the child attains 6 years of age, and yearly thereafter. GS: All patients are advised life long follow up, with reducing frequency as they grow older, eventually annually. Every 2-3 months until 2-3 yrs of age, every 4-6 months until 5 yrs of age and annually thereafter (partly for RB recurrence, partly for anophthalmic socket review). AM: Active follow-up is suggested to discover new and recurrent tumors, for visual rehabilitation, and for monitoring of late effects of treatments occurs until 9 years of age, or for 5 years after the last treatment was performed. Beyond that, long-term follow-up goes on, with a focus on survivorship, monitoring of late effects of cancer treatments, ongoing ophthalmological care, genetic counseling, and surveillance for secondary malignancies. A. Rasal: How do you rehabilitate the anophthalmic socket? Which implant do you prefer? ADS: We insert inegrated orbtal implant (Medpor, porous polyethylene implant, unwrapped) at thetime of enucletaion with insertion of all 4 rectii muscles into anatomical position. BC: A primary implant is usually preferred at the time of enucleation surgery. Both non-integrated (PMMA, silicone) or integrated (hydroxyapatite, porous polyethylene) implants can be used after a primary enucleation. In those cases planned for external beam radiotherapy after enucleation, integrated implants are avoided as they are more likely to extrude due to hampering of vascularization. In such cases, I prefer PMMA implants. AR: Acrylic implant via myo-conjunctival technique. SGH: Placement of a primary orbital implant following enucleation for retinoblastoma is the current standard of care. The orbital implant promotes orbital growth, provides better cosmesis and enhances prosthesis motility. The implant could be non-integrated (polymethyl methacrylate or silicon) or bio-integrated (hydroxyapatite or porous polyethylene). Placement of a biointegrated implant is generally avoided if post-operative adjuvant radiotherapy is considered necessary. Although most implants structurally tolerate radiotherapy well, implant vascularization may be compromised by radiotherapy thus increasing the risk of implant exposure. Use of an inexpensive PMMA/silicone implant with myoconjunctival technique and custom ocular prosthesis have optimized prosthesis motility and static cosmesis. GS: Primary orbital implantation. Acrylic sphere(18mm) wrapped in donor sclera if enucleated < 1 yr of age. If > 1-2 yrs of age, Medpor sphere (20mm) wrapped in Donor sclera. AM: We introduce an orbital implant during the time of enucleation. A silicone sphere or a PMMA implant is most commonly used. We also suture the extraocular muscles to the conjunctival fornix to improve mobility of the ocular prosthesis. A. Rasal: How important is Genetic testing? Should it be done for all cases? ADS: Genetic testing and counseling are integral to efficient management of retinoblastoma. It is performed for every case case managed in our cclinic. BC: Genetic testing is very important for genetic counselling to parents for predicting the risk of retinoblastoma to siblings. Patients who carry a germline mutation are at a higher risk of developing secondary cancers and require lifelong clinical surveillance. Genetic testing also helps in identifying which unilateral cases carry a germline mutation. Ideally, genetic testing should be done for all cases, if available. AR: Very important. Always assessed. SGH: Genetic testing should be ideally done in all heritable retinoblastoma where facilities are available. GS: Partly for completeness of work up and partly for counseling purpose. AM: Testing for a mutation in the RB1 gene helps determine the germline mutation that could be carried in the family. A germline mutation predisposes the patient to second malignancies, and monitoring for those is essential in those that carry the germline mutation. Knowing this also helps the family plan for future children. We can also prenatally determine the risks of a sibling carrying the tumor, and increase the chances of good vision in an affected sibling. With improving affordability of testing, we have started to suggest genetic testing for all of our patients. 20 l DOS Times - Vol. 20, No. 6 December, 2014

Ocular Malignancies A. Rasal: Do you recommend screening for siblings and parents of all affected children? ADS: Parents of all affected chideren are examined, usually at initial presentation for a possibility of retinona/ retinocytoma. The siblings undergo age appropriate EUA (see above) only if the the child (porband), one of the parents, and the sibling in question have a mutation identified by genetic testing. If the genetic testing is negative,in approriate clinical scenario (presumed sporadic), then office exams are sufficient. BC: Yes, at initial examination, we perform screening of parents and siblings of all affected children. In cases of heritable retinoblastoma, siblings are screened on a regular basis. AR: If mutation is found, yes. SGH: Yes, a baseline screening of all, and empirical/ genetic risk-based target screening thereafter. GS: Yes whenever possible and siblings are available. AM: We suggest genetic screening for more accurately predicting the risk of developing retinoblastoma in siblings and the risk of second primary tumors in the parents of the affected child. Until that is possible, we clinically screen the siblings with repeated retinal examinations until they are 7 years old, while parents usually undergo a single detailed retinal examination. A. Rasal: Any suggestions to improve awareness on retinoblastoma? ADS: The biggest challenge in managment of retinoblastoma is the delay in diagnosis. Hence awareness campaigns should be targeted to pediatricians or other primary care providers. BC: With many of our children presenting to us with orbital spread, delay in diagnosis is a matter of concern. A nationwide awareness campaign about early signs of retinoblastoma would be very effective in educating the community as well as ophthalmologists, pediatricians, public health professionals and medical practitioners to ensure early referrals. The electronic and print media are powerful tools that can spread awareness about the significance of early detection and should take up the cause. No child should lose his or her life or sight from a tumor that is potentially curable. AR: We work closely with a family support group (childhood eye cancer trust in UK) to increase awareness amongst professionals and the general public. SGH: Multi-pronged approach to sensitize the society about the importance of seeing an ophthalmologist when they notice a white reflex or squint in a child, paediatricians to screen for white reflex or squint and refer to an ophthalmologist, and ophthalmologists to keep retinoblastoma as a consideration in a child with leucocoria, squint, atypical buphthalmos/hypopyon/hyphema/vitreous hemorrhage/inflammed eye/proptosis in a child. Most importantly, the message should clearly go through that retinoblastoma is now curable with >98% life salvage, and excellent chance for eye and vision salvage. GS: Educate our own ophthalmology colleagues, pediatrician colleagues and finally community. AM: Improving leukocoria and strabismus awareness is essential in improving survival of children with retinoblastoma. Creative and impactful public campaigns involving the print, broadcast and digital media will help in making our public aware of the cancer. Awareness about early signs of retinoblastoma would require to be stressed amongst pediatricians and ophthalmologists as well. The work of NGO s like Iksha Foundation (www. ikshafoundation.org) and Can Kids (www.cankidsindia.org) require to be promoted to improve awareness of this cancer in India. DOS Correspondent Abhijit Rasal MS, DNB, FAICO Ocular Oncology & Pediatric Ophthalmology Services, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi. www. dosonline.org l 21