Retinoblastoma - Ocular Oncology and Intra-Arterial Chemotherapy

Quick Answer

What is retinoblastoma?

Retinoblastoma is the most common primary intraocular malignancy in children, with an incidence of 1 in 15,000-20,000 live births (approximately 300 new cases per year in the USA, 8-10 per year in Australia). [1,2] It is caused by mutations in the RB1 tumor suppressor gene located on chromosome 13q14. [3]

Key features:

• Age: 90% diagnosed before 5 years; median age 18 months (unilateral), 12 months (bilateral)
• Presentation: Leukocoria (white pupillary reflex) 50-60%, strabismus 20%, visual loss, rarely orbital cellulitis picture
• Genetics:
  • Heritable (germline): 40% - RB1 mutation in all cells, bilateral, earlier onset, increased lifetime risk of other tumors (osteosarcoma, melanoma)
  • Non-heritable (somatic): 60% - RB1 mutation only in retina, usually unilateral, later onset

Treatment goals:

1. Save the child's life (prevent metastasis)
2. Preserve the eye (if possible)
3. Preserve vision (if possible)

Modern treatment modalities:

Intra-arterial chemotherapy (IAC) - Anesthetic considerations:

• Long procedure (2-4 hours)
• Neurovascular access (femoral artery, microcatheter to ophthalmic artery)
• Minimal blood loss but potential for significant hemodynamic shifts
• Post-procedure recovery considerations
• Requires specialized pediatric oncology/ophthalmology center

Key principle: Retinoblastoma is curable in >95% of cases in developed countries, but diagnosis delay is common. Early detection through "red reflex" screening in infants is critical. Anaesthetic management focuses on safe provision of repeated examinations under anesthesia (EUA) and interventional procedures.

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Clinical Overview

Definition and Pathophysiology

Definition: Malignant tumor arising from the immature retinal cells (retinoblasts) of the developing retina.

Genetics:

RB1 Tumor Suppressor Gene:

• Located on chromosome 13q14
• "Two-hit" hypothesis (Knudson model):
  • Heritable: One mutated RB1 allele in all cells (germline), second hit occurs in retina → bilateral, earlier
  • Non-heritable: Both mutations occur somatically in same retinal cell → unilateral, later
• Normal function: Cell cycle regulation, blocks G1-S transition
• Loss of function: Uncontrolled cellular proliferation, tumor formation

Genetic testing:

• Identifies germline vs. somatic mutations
• Critical for family screening, counseling, surveillance
• Testing of tumor tissue and blood

Classification Systems

International Classification of Retinoblastoma (ICRB) - 2005:

Reese-Ellsworth Classification (historical, pre-chemotherapy era):

• Based on tumor size, location, multifocality
• Used for external beam radiotherapy (largely replaced)

Epidemiology

Risk factors:

• Family history (10-15% of cases have positive family history)
• Previous child with retinoblastoma (50% risk for subsequent children if heritable)
• 13q deletion syndrome (includes RB1 gene)
• No environmental risk factors identified

Clinical Presentation

Common presentations:

Differential diagnosis of leukocoria:

• Retinoblastoma (most important to exclude)
• Persistent fetal vasculature (PFV)
• Cataract
• Coats disease (retinal telangiectasia)
• Toxocariasis
• Retinal astrocytic hamartoma
• Retinopathy of prematurity (advanced)
• Coloboma
• Norrie disease
• Familial exudative vitreoretinopathy

Diagnostic delay:

• Average delay from first sign to diagnosis: 3-6 months
• Parents may notice leukocoria in photos ("photographic red reflex" absent)
• Lack of awareness among primary care providers
• "Don't know, don't miss" - important condition

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Diagnosis and Staging

Examination Under Anesthesia (EUA)

Purpose:

• Definitive diagnosis
• Tumor mapping (size, location, number, extent)
• Retinal drawings/photography
• Classification
• Treatment planning
• Surveillance after treatment

Frequency:

• Active treatment: Every 3-4 weeks (with chemotherapy cycles)
• Post-treatment: Every 3-6 months for years, then annually
• Lifetime surveillance for heritable cases (second tumors)

Components:

1. External examination (proptosis, ptosis, strabismus)
2. Pupillary examination (red reflex)
3. Slit lamp examination (anterior segment, tumor seeds)
4. Dilated fundus examination (indirect ophthalmoscopy)
5. Drawing/photography of all tumors
6. A-scan/B-scan ultrasonography (tumor dimensions, calcification)
7. Intraocular pressure measurement
8. Examination of fellow eye (if unilateral suspected)

Anesthetic considerations for EUA:

• Short procedure (30-60 minutes)
• No significant pain post-procedure
• Smooth emergence important (coughing/straining ↑ IOP)
• May require multiple EUAs over months/years
• Parents highly anxious - sensitive communication

Imaging

Ocular imaging:

• Ultrasonography: A-scan (tumor height), B-scan (location, calcification)
• Wide-field fundus photography: Retcam (documentation)
• Optical coherence tomography (OCT): Macular involvement, tumor detail
• Fluorescein angiography: Vascular patterns

Systemic staging (if high-risk features):

• MRI orbits and brain (optic nerve, extraocular extension, pineal tumor - trilateral retinoblastoma)
• Bone marrow biopsy (if suspicious)
• Lumbar puncture (if CNS involvement suspected)
• Bone scan (rarely)
• Liver function tests

Genetic testing:

• RB1 mutation analysis
• Determines heritability
• Guides family screening
• Karyotype if dysmorphic features (13q deletion)

Staging

Intraocular disease (AJCC 8th edition):

• cT1: Tumors ≤3mm, macula/optic disc clear
• cT2: Tumors >3mm or involving macula/optic disc
• cT3: Subretinal/vitreous seeds, retinal detachment
• cT4: Advanced intraocular disease (glaucoma, hemorrhage)

Extraocular extension:

• Optic nerve invasion (post-laminar)
• Scleral invasion
• Orbital extension

Metastatic disease:

• Regional lymph nodes
• Distant metastases (CNS, bone, liver)
• Trilateral retinoblastoma (bilateral RB + pineal tumor)

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Treatment

Multimodal Approach

Treatment selection based on:

• Laterality (unilateral vs. bilateral)
• Tumor classification (group A-E)
• Vision potential
• Genetic status
• Family preferences

Goals in order:

1. Save life (prevent metastasis)
2. Preserve eye
3. Preserve vision

Intravenous Chemotherapy (IVC)

Regimen:

• VEC protocol: Vincristine, Etoposide, Carboplatin
• 6 cycles typically
• 3-4 week intervals

Indications:

• Bilateral retinoblastoma
• High-risk unilateral (advanced groups)
• Extraocular disease
• Neoadjuvant before focal therapy

Response:

• Tumor shrinkage (chemoreduction)
• Facilitates focal therapy
• Treats microscopic metastases

Side effects:

• Myelosuppression (monitor CBC)
• Ototoxicity (carboplatin - hearing monitoring required)
• Nephrotoxicity
• Secondary leukemia (etoposide - rare but serious)

Intra-Arterial Chemotherapy (IAC)

Revolution in treatment - developed by Abramson and Gobin (2010s)

Principle:

• Super-selective delivery of chemotherapy to ophthalmic artery
• High intraocular drug concentration
• Minimal systemic exposure
• Preserves systemic treatment options

Procedure:

Access:

• Femoral artery puncture (usually right common femoral)
• 4F sheath placement
• Guidewire and catheter to internal carotid artery
• Microcatheter (1.5-2.0F) advanced to ostium of ophthalmic artery

Angiography:

• Confirm ophthalmic artery anatomy
• Identify dangerous anastomoses (to CNS)
• Test injection with fluorescein

Drug delivery:

• Melphalan (primary agent) - 3-7.5 mg (age-dependent dosing)
• ± Carboplatin (topical ophthalmic solution)
• ± Topotecan
• Infused over 30 minutes with pulsatile flow
• Totals 1-2 hours for single eye; 3-4 hours for bilateral sequential

Anesthetic considerations (detailed below)

Outcomes:

• Globe salvage rates 60-90% depending on group
• Vision preservation in many
• Reduced systemic side effects compared to IVC

Complications:

• Ophthalmic artery occlusion (rare, severe)
• Choroidal ischemia (common, usually transient)
• Retinal detachment
• Vitreous hemorrhage
• Neutropenia (mild, transient)
• Stroke (rare, from reflux or anastomosis)
• Femoral artery complications

Intravitreal Chemotherapy (IVitC)

Indication:

• Persistent or recurrent vitreous seeds
• Subretinal seeds
• Failed other therapies

Agent:

• Melphalan 20-30 mcg in 0.1 mL
• Topotecan alternative

Technique:

• Injection via pars plana
• Low dose to avoid systemic toxicity
• Repeated injections may be needed

Risk:

• Tumor dissemination via needle track (rare with proper technique)
• Retinal detachment
• Endophthalmitis

Focal Therapy

Laser photocoagulation:

• 532 nm or 810 nm laser
• Direct tumor coagulation
• Used for small tumors (groups A-B)
• Combined with chemotherapy (chemoreduction + laser)

Cryotherapy:

• Trans-scleral freezing
• For anterior tumors
• Can be primary or adjunctive

Plaque Radiotherapy

Indications:

• Solitary tumors
• Recurrent tumors after chemotherapy
• Tumors near optic disc or fovea

Isotopes:

• Iodine-125 (most common)
• Ruthenium-106

Dose:

• 40-45 Gy to tumor apex
• 3-7 day inpatient stay

Complications:

• Cataract
• Radiation retinopathy
• Optic neuropathy
• Dry eye
• Orbital hypoplasia (in growing children)

Enucleation

Indications:

• Group E tumors (advanced, no vision potential)
• Failed all conservative therapies
• Neovascular glaucoma with pain
• Optic nerve involvement (high-risk for metastasis)

Technique:

• Remove globe with longest possible optic nerve segment (>10 mm if possible)
• Implant placement (hydroxyapatite, porous polyethylene)
• Postoperative prosthesis fitting

Prognosis:

• Excellent if no extraocular extension
• No adjuvant chemotherapy needed if low-risk pathology

Treatment by Group

Bilateral Disease Management

• Treat worse eye first (IAC) or both eyes with systemic chemotherapy
• Attempt to preserve at least one eye with vision
• Staggered treatment if sequential IAC (1-2 weeks apart)
• Lifetime surveillance for second malignancies (heritable)

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Anesthetic Management

Preoperative Assessment

Specific considerations:

Genetic counseling and family issues:

• Parents often highly distressed
• Sibling screening required
• Genetic testing implications
• May be dealing with diagnosis crisis

Prior treatments:

• Number of prior EUAs/procedures
• Response to previous anesthetics
• Current systemic therapy (chemotherapy effects)
• Current medications

Ocular status:

• Vision in fellow eye (bilateral?)
• Intraocular pressure (glaucoma risk)
• Current treatment plan

Systemic issues:

• Anemia (chemotherapy-related)
• Hearing status (carboplatin ototoxicity)
• Immune status (chemotherapy)
• Nutrition (failure to thrive with cancer)

Examination Under Anesthesia (EUA)

Procedure characteristics:

• Duration: 30-60 minutes
• No significant surgical stimulus
• Minimal blood loss
• Smooth emergence critical

Anesthetic options:

1. Mask induction with sevoflurane:

• Suitable for cooperative children
• IV access established after induction
• LMA or mask maintenance

2. IV induction (propofol):

• If IV already in place
• Rapid onset, smooth

Maintenance:

• TIVA (propofol + remifentanil) or volatile
• Avoid nitrous oxide (may increase IOP slightly)
• Paralysis optional ( atracurium/rocuronium if needed)

Emergence:

• Deep extubation or LMA removal to avoid coughing/straining
• Coughing significantly increases IOP
• Consider lidocaine 1-2 mg/kg IV before emergence

Monitoring:

• Standard ASA monitors
• Temperature (pediatric)
• If repeated EUAs, document anesthetic course

Postoperative:

• Minimal pain
• Eye patch often placed
• Observe for oculocardiac reflex if manipulation occurred
• Discharge home same day (usually)

Intra-Arterial Chemotherapy (IAC)

Procedure characteristics:

• Duration: 2-4 hours (bilateral sequential longer)
• Vascular access and interventional radiology
• Minimal surgical stimulus, but long immobility required
• Hemodynamic shifts possible
• Post-procedure groin observation required

Preoperative preparation:

• Fasting: Standard pediatric fasting guidelines (clear fluids 2 hrs, breast milk 4 hrs, solids 6 hrs)
• Consent: Parents for EUA + IAC; risks explained by oncology team
• Premedication: Midazolam 0.5 mg/kg PO (max 15 mg) if anxious
• IV access: 2 large-bore IVs (20-22G); blood available if needed
• Groin preparation: Shave if needed, chlorhexidine prep

Anesthetic technique:

Induction:

• Propofol 2-3 mg/kg or sevoflurane mask
• Fentanyl 2-3 mcg/kg for analgesia
• Rocuronium 0.6 mg/kg for intubation

Airway:

• ETT (cuffed, appropriate size) - secure airway for long procedure, prone positioning concern
• Position: Supine, arms secured, groin exposed
• Eye protection (tape closed)

Maintenance:

• TIVA preferred: Propofol 100-200 mcg/kg/min + Remifentanil 0.1-0.2 mcg/kg/min
• Or balanced: Sevoflurane + remifentanil infusion
• Benefits of TIVA: Smooth, predictable, less PONV, rapid emergence

Why TIVA preferred for IAC:

• Long procedure (2-4 hours)
• Minimal movement critical (microcatheter manipulation)
• Smooth emergence important
• Reduced PONV
• No volatile-related issues

Monitoring:

• Standard ASA + arterial line (optional but preferred for long cases, BP monitoring)
• Temperature (forced air warming - risk of hypothermia in infants)
• Urinary catheter if >3 hours
• Neuromuscular monitoring
• BIS (optional, helps titrate anesthesia)

Hemodynamic management:

• Maintain normotension
• Treat hypertension (pain, light anesthesia)
• Hypotension rare but treat aggressively
• Blood loss minimal but have cross-matched blood available

Fluid management:

• Maintenance: 4-2-1 rule
• Replace urine output if catheterized
• Consider NPO duration + contrast load
• Avoid overload (cardiac reserve in infants)

Anticoagulation:

• Heparin 50-100 units/kg during catheterization (discuss with interventionalist)
• Monitor ACT if prolonged procedure
• Protamine reversal at end if needed

Positioning:

• Supine, legs slightly abducted for groin access
• Pressure points padded
• Eye protection
• Temperature management

Emergence:

• Ensure neuromuscular blockade reversed (sugammadex preferred)
• Smooth extubation (avoid coughing - groin hematoma risk)
• Transfer to recovery with leg straight (groin compression)

Postoperative care:

• Groin observation (hematoma, bleeding, pulse)
• 4-6 hours flat (groin hemostasis)
• Analgesia: Paracetamol, ibuprofen (if not contraindicated), low-dose morphine if needed
• Antiemesis: Ondansetron
• Observation for 24 hours typical (groin, systemic effects)
• Discharge criteria: Eating, drinking, ambulating, groin stable

Potential complications during IAC:

• Hemodynamic instability: Hypotension from sedation/anesthesia, hemorrhage (rare)
• Vascular complications: Arterial dissection, thrombosis, spasm
• Neurological: Stroke (very rare, from reflux), seizure
• Contrast reactions: Anaphylaxis, nephrotoxicity
• Airway: Kinked ETT (long procedure, positioning)
• Hypothermia: Especially in infants
• Ocular: Sudden IOP changes if globe manipulated

Special considerations for infants:

• Temperature control critical
• Blood glucose monitoring (fasting infant)
• Fluid management precise
• Drug doses calculated carefully by weight
• Consider blood transfusion threshold (higher Hb acceptable)
• Parents extremely anxious

Enucleation

Procedure characteristics:

• Duration: 1-2 hours
• Moderate surgical stimulus
• Some blood loss (moderate)
• Postoperative pain

Anesthetic management:

• Standard pediatric GA
• Consider antiemetic prophylaxis
• Plan for postoperative pain (morphine, local anesthetic infiltration)
• Smooth emergence (eye patch will be in place)
• Postoperative admission usually overnight

Repeated Anesthetics

Considerations:

• These children may have 10-20+ EUAs over years
• Anesthetic exposure concerns (developing brain)
• Use lowest effective doses
• Document each exposure
• TIVA may be neuroprotective vs. some volatiles (debatable)
• Regional anesthesia when appropriate to reduce GA requirements

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Postoperative Care and Follow-up

Immediate Post-IAC

Groin care:

• Compression device or manual pressure
• 4-6 hours flat
• Check pedal pulses (femoral artery patency)
• Watch for hematoma, pseudoaneurysm

Systemic monitoring:

• CBC (neutropenia usually mild, transient)
• Electrolytes
• Renal function (contrast)
• Temperature (fever common, usually mild)

Ocular monitoring:

• Pain (retrobulbar block may have been given by ophthalmologist)
• Vision (if possible to assess)
• Swelling, proptosis
• Follow-up EUA schedule

Long-term Follow-up

Schedule:

• Active treatment: EUA every 3-4 weeks
• Post-treatment: Every 3-6 months for years
• Then annually for life (heritable)

Surveillance for:

• Tumor recurrence
• New tumors (fellow eye in unilateral, second tumors in heritable)
• Second malignancies (osteosarcoma, melanoma, soft tissue sarcoma in heritable)
• Vision development
• Orbital growth (if enucleated)
• Psychological support

Prognosis

Overall survival (developed countries):

• 95% survival

• Deaths usually from metastatic disease or second malignancies

Vision outcomes:

• Variable depending on tumor location, treatment
• Many achieve useful vision in at least one eye
• Bilateral cases: may have reduced but functional vision

Second malignancies (heritable):

• Lifetime risk 50-60%
• Osteosarcoma most common
• Melanoma (cutaneous and uveal)
• Soft tissue sarcomas
• Screening: Regular physical exams, imaging as indicated

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Indigenous Health Considerations

Disparities:

• Higher mortality rates in developing countries due to delayed diagnosis
• Remote communities may lack pediatric ophthalmology access
• Genetic testing and family counseling may be less accessible

Cultural considerations:

• Eye has cultural significance in many Indigenous cultures
• Loss of eye may have particular psychological impact
• Family decision-making regarding enucleation
• Traditional healing alongside Western treatment

Management approaches:

• Telemedicine for consultations with pediatric ophthalmology centers
• Support for travel to specialized centers (IAC requires specific expertise)
• Genetic counseling with cultural sensitivity
• Psychological support for child and family
• Coordination with local services for follow-up EUAs

Key principle: Early diagnosis through awareness and screening programs in all communities; access to specialized care (IAC) in major centers with support for families traveling from remote areas.

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ANZCA Exam Focus

High-Yield Topics

Written Examination:

• Pathophysiology (RB1 gene, two-hit hypothesis)
• Presenting features (leukocoria, strabismus)
• Treatment modalities (IAC, IVC, focal therapy)
• Anesthetic management for EUA and IAC
• Complications of IAC

Viva Voce:

• Anesthetic plan for IAC
• Management of repeated anesthetics in children
• Complications during IAC
• Ethical scenario: Enucleation vs. globe salvage attempt

Common Exam Scenarios

Scenario 1: IAC Procedure

• 18-month-old with unilateral group C retinoblastoma
• Scheduled for intra-arterial melphalan

Key points:

• Long procedure, vascular access
• TIVA preferred
• Temperature control, fluid management
• Groin postoperative care
• Hemodynamic stability

Scenario 2: Repeated EUAs

• Child had 12 EUAs over 18 months
• Parents concerned about anesthetic effects

Key points:

• Acknowledge concerns
• Use lowest effective doses
• TIVA may have advantages
• Document exposures
• Benefits of treatment outweigh risks

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Assessment Content

SAQ: Retinoblastoma and IAC (20 marks)

Question:

An 18-month-old child with unilateral group D retinoblastoma is scheduled for intra-arterial chemotherapy (IAC) with melphalan via the ophthalmic artery. The procedure is expected to take 2-3 hours.

a) Outline your anesthetic plan for this procedure, including induction, maintenance, monitoring, and specific considerations for this specialized procedure. (10 marks)

b) What are the potential intraoperative and postoperative complications specific to IAC that you should be prepared to manage? (6 marks)

c) The child has had 10 prior examinations under anesthesia (EUA) over the past year. The parents are concerned about the effects of repeated anesthetic exposure on their child's developing brain. How would you address their concerns? (4 marks)

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Model Answer:

a) Anesthetic plan (10 marks):

Preoperative:

• Fasting: Clear fluids 2 hrs, solids 6 hrs
• IV access: 2 peripheral IVs (20-22G)
• Premedication: Midazolam 0.5 mg/kg PO if anxious
• Blood: Type and screen, cross-match available
• Consent: Explain anesthetic risks

Induction:

• Propofol 2-3 mg/kg IV or sevoflurane mask induction
• Fentanyl 2-3 mcg/kg
• Rocuronium 0.6 mg/kg for intubation

Airway:

• Cuffed ETT (size appropriate for age)
• Secure airway essential for long procedure

Monitoring:

• Standard ASA monitors
• Arterial line (recommended for 2-3 hour procedure, BP monitoring, blood sampling)
• Temperature (esophageal or nasopharyngeal)
• Urine output (catheter if >3 hours)
• Neuromuscular monitoring
• BIS (optional)

Maintenance (TIVA preferred):

• Propofol 100-200 mcg/kg/min
• Remifentanil 0.1-0.2 mcg/kg/min
• Benefits: Smooth, predictable, no movement, rapid emergence

Positioning:

• Supine, legs abducted for femoral access
• Pressure points padded
• Eye protection (tape closed)
• Forced air warming (infant at risk for hypothermia)

Fluid management:

• Maintenance per 4-2-1 rule
• Consider NPO deficit + contrast load
• Avoid fluid overload

Hemodynamics:

• Maintain normotension
• Avoid hypertension (groin bleeding risk)
• Treat hypotension promptly

Emergence:

• Reverse neuromuscular blockade (sugammadex preferred)
• Smooth extubation (avoid coughing → groin hematoma)
• Transfer to recovery with leg straight

b) IAC complications (6 marks):

Intraoperative:

Postoperative:

c) Addressing parental concerns about repeated anesthesia (4 marks):

Key points to communicate:

1. Acknowledge concern: Valid concern about developing brain and anesthetic exposure

2. Evidence-based reassurance:

   • Large studies (GAS, PANDA, MASK) show no significant neurodevelopmental difference between single short anesthetic vs. no anesthetic in infants
   • Evidence for repeated/multiple exposures less clear, but EUAs are brief (30-60 min) and not prolonged
   • No practical alternative for necessary treatment

3. Risk-benefit discussion:

   • Retinoblastoma is life-threatening if untreated
   • EUAs are essential for diagnosis and monitoring
   • Benefits of cancer treatment far outweigh theoretical anesthetic risks

4. Mitigation strategies:

   • Use lowest effective anesthetic doses
   • TIVA may have advantages over volatiles (debatable but some evidence)
   • Optimize all other factors (oxygenation, perfusion, glucose)
   • Document all exposures

5. Reassurance:

   • Most children treated for retinoblastoma develop normally
   • Will monitor developmental milestones
   • Long-term follow-up studies ongoing

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References

1. Kivela T. The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an issue of birth and death. Br J Ophthalmol. 2009;93(9):1129-1131. PMID: 19635719

2. Broaddus E, Topham A, Singh AD. Incidence of retinoblastoma in the USA: 1975-2004. Br J Ophthalmol. 2009;93(1):21-23. PMID: 18838476

3. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA. 1971;68(4):820-823. PMID: 5279522

4. Abramson DH, Schefler AC. Update on retinoblastoma. Retina. 2004;24(6):828-838. PMID: 15579953

5. Shields CL, Shields JA. Retinoblastoma management: advances in enucleation, intravenous chemoreduction, and intra-arterial chemotherapy. Curr Opin Ophthalmol. 2010;21(3):203-212. PMID: 20216408

6. Abramson DH, Dunkel IJ, Brodie SE, et al. A phase I/II study of direct intraarterial (ophthalmic artery) chemotherapy with melphalan for intraocular retinoblastoma initial results. Ophthalmology. 2008;115(8):1398-1404. PMID: 18466959

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