Retinoblastoma..Retinoblastoma..a brief overview !a brief overview !

ByByOsama El-ZaafaranyOsama El-Zaafarany

Assistant lecturer of clinical oncologyAssistant lecturer of clinical oncologyMedical Research instituteMedical Research institute

Alexandria UniversityAlexandria UniversityApril 2013April 2013

BackgroundBackground• Retinoblastoma is the most common Retinoblastoma is the most common intraocularintraocular

tumor and the Seventh most common solid tumor tumor and the Seventh most common solid tumor in childhood.in childhood.

• Occurring in approximately 1 in 15,000 live births Occurring in approximately 1 in 15,000 live births in the United States.in the United States.

• Approximately 95 % before the age of five.Approximately 95 % before the age of five.• The incidence is similar in boys and girls and The incidence is similar in boys and girls and

among blacks and whites.among blacks and whites.• bilateral in 30% ;bilateral in 30% ; < 12 months.< 12 months.

SPORADIC SPORADIC (Non-hereditary)(Non-hereditary)

FAMILIALFAMILIAL

(Hereditary)(Hereditary) Unilateral, unifocal. Unilateral, unifocal. 85% bilateral, multifocal.85% bilateral, multifocal.

60% of all cases. 60% of all cases. 40% of all cases.40% of all cases.

Present later. Present later. Present earlierPresent earlier..

Children of the affected are Children of the affected are normal.normal.

Children of the affected have 45% Children of the affected have 45% chance of inheritance.chance of inheritance.

Chromosomal anomaly is a Chromosomal anomaly is a somatic mutation.somatic mutation.

Chromosomal anomaly is a germline Chromosomal anomaly is a germline mutation.mutation.

Relatives have a low risk of RB Relatives have a low risk of RB development.development.

Relatives have a high risk of RB Relatives have a high risk of RB development.development.

Increased risk for second Increased risk for second malignancies malignancies ⇒ ⇒ sarcomas, melanoma, and sarcomas, melanoma, and

cancers of the brain and nasal cavities.cancers of the brain and nasal cavities.

Autosomal dominant with high Autosomal dominant with high penetrance.penetrance.

PathogenesisPathogenesis::

• Mutational inactivation of Mutational inactivation of both allelesboth alleles of of the retinoblastoma (RB1) gene.the retinoblastoma (RB1) gene.

• On chromosome 13q14.On chromosome 13q14.• Encodes a nuclear protein that acts as a Encodes a nuclear protein that acts as a

tumor suppressor and cell cycle regulator; tumor suppressor and cell cycle regulator; checkpoint between G1 & S-phase. checkpoint between G1 & S-phase.

• Normal individual inherits two copies of Normal individual inherits two copies of this gene one from each parent.this gene one from each parent.

A "two-hit" modelA "two-hit" model

Sporadic retinoblastoma:Sporadic retinoblastoma: First hit occurs after conception in First hit occurs after conception in

utero or in early childhood in retinal utero or in early childhood in retinal cells. cells.

All cells in body are not affected as All cells in body are not affected as germ cells are notgerm cells are not involvedinvolved. .

Second somatic mutation results in Second somatic mutation results in loss of other normal allele. loss of other normal allele.

Hereditary retinoblastomaHereditary retinoblastoma Child starts with heterozygous alleles Child starts with heterozygous alleles

(RB/RB+).(RB/RB+). Only one mutation is required to Only one mutation is required to

produce disease.produce disease. First hit occurs in utero in germ cells First hit occurs in utero in germ cells

before conception or is inherited from before conception or is inherited from a parent.a parent.

All cells of body affected.All cells of body affected. Second hit occurs in any retinal cell.Second hit occurs in any retinal cell.

Natural history & Natural history & PrognosisPrognosis::

If untreated:If untreated: Retinoblastoma grows to fill the eye (Retinoblastoma grows to fill the eye (within 6 within 6

monthsmonths) and destroys the internal ) and destroys the internal architecture of the globe.architecture of the globe.

Metastatic spread usually begins after six Metastatic spread usually begins after six months. => months. => BM, bone, cx LNs, liverBM, bone, cx LNs, liver

Death occurs within a matter of yearsDeath occurs within a matter of years

The 5-year OS rate for children with retinoblastoma in The 5-year OS rate for children with retinoblastoma in the United States is 93 %.the United States is 93 %.

A child who remains recurrence free for 5 years after A child who remains recurrence free for 5 years after diagnosis is considered cured.diagnosis is considered cured.

5-year DFS for Intraocular RB >90%.5-year DFS for Intraocular RB >90%. (extraocular <10%)(extraocular <10%)

1-year survival rate for patients with hematogenous 1-year survival rate for patients with hematogenous metastases are approximately 50 %.metastases are approximately 50 %.

The risk of a The risk of a second malignancysecond malignancy is 40 % at 50 ≃ is 40 % at 50 ≃years after the original treatment in patients with years after the original treatment in patients with hereditaryhereditary retinoblastoma. retinoblastoma.

This risk is markedly increased in those who were This risk is markedly increased in those who were treated with radiation therapy when they were treated with radiation therapy when they were younger than one year of age.younger than one year of age.

Child with RB who receive carboplatin are at risk Child with RB who receive carboplatin are at risk for hearing loss and require long-term audiometric for hearing loss and require long-term audiometric follow-up.follow-up.

The preservation of vision is better if the tumors are The preservation of vision is better if the tumors are small and do not involve the fovea.small and do not involve the fovea.

Eye preservations rates range among series from Eye preservations rates range among series from ~60 to 90% when using EBRT and depend on ~60 to 90% when using EBRT and depend on extent of disease.extent of disease.

Group E patients have eye preservation rates of Group E patients have eye preservation rates of only 2%.only 2%.

Visual preservation rates range among series from Visual preservation rates range among series from ~65 to 100% for Groups I–III but are lower for ~65 to 100% for Groups I–III but are lower for Groups IV–V.Groups IV–V.

Median survival of trilateral RB was 9 months.Median survival of trilateral RB was 9 months.

Poor prognostic factorsPoor prognostic factors:: Optic nerveOptic nerve, , choroidal or orbital invasion ⇒choroidal or orbital invasion ⇒

risk of metastatic disease.risk of metastatic disease. Delay in diagnosis of more than Delay in diagnosis of more than six monthssix months.. intraocular surgery intraocular surgery ⇒⇒ vitreous seeding and vitreous seeding and

extraocular spread.extraocular spread. Cataract.Cataract. EBRTx EBRTx ⇒⇒ secondary cancers; particularly in secondary cancers; particularly in

patients with the heritable form of RB.patients with the heritable form of RB.

Risk factors for extension into the optic N:Risk factors for extension into the optic N:• Exophytic growth pattern.Exophytic growth pattern.• Elevated intraocular pressure.Elevated intraocular pressure.• Tumor thickness ≥15 mm.Tumor thickness ≥15 mm.

Risk factors for extension into the choroid:Risk factors for extension into the choroid:• Elevated I.O. pressure.Elevated I.O. pressure.• Iris neovascularization.Iris neovascularization.

DiagnosisDiagnosis::

The diagnosis of retinoblastoma can usually The diagnosis of retinoblastoma can usually be made during a dilated indirect be made during a dilated indirect ophthalmoscopic examinationophthalmoscopic examination that is that is performed under anesthesia;performed under anesthesia;

the characteristic findingthe characteristic finding

is a chalky, white-grayis a chalky, white-gray

retinal mass withretinal mass with

a soft, friable consistency a soft, friable consistency

• Leukocoria (60%) Strabismus (20%) Secondary glaucoma

Anterior segment invasion •Orbital inflammat. • Orbital invasion

Presentations of retinoblastoma

Pattern of growthPattern of growth::

To confirm the diagnosisTo confirm the diagnosis:: Ocular U/S: Ocular U/S:

• Demonstrates a mass more echogenic than the Demonstrates a mass more echogenic than the vitreous on B mode. vitreous on B mode.

• Highly reflective intrinsic Highly reflective intrinsic echoes of fine calcificationsechoes of fine calcifications on A mode.on A mode.• Accuracy 80 %.Accuracy 80 %.

computed tomography:computed tomography:• may demonstrate a solidmay demonstrate a solidintraocular tumor withintraocular tumor withcharacteristic intratumoralcharacteristic intratumoralcalcifications.calcifications.

Magnetic resonance imaging (MRI)Magnetic resonance imaging (MRI)::• tumor size.tumor size.• optic nerve involvement. optic nerve involvement. • the presence of an associated intracranial the presence of an associated intracranial

lesionlesion→→ Tri-lateral RB.Tri-lateral RB.

• preferred in children younger than one year of preferred in children younger than one year of age age →→ avoid cancer risk that increase with CTavoid cancer risk that increase with CT

C T MRIC T MRI

FNACFNAC from tumor should be avoided from tumor should be avoided => => increase risk of vitreous seeding.increase risk of vitreous seeding.

if there is clear evidence of tumor outside if there is clear evidence of tumor outside the eye, the full the eye, the full metastatic evaluationmetastatic evaluation should be done:should be done:• bone marrow examination (aspiration and bone marrow examination (aspiration and

biopsy). biopsy). • lumbar puncture.lumbar puncture.• bone scan. bone scan.

Differential diagnosis of leukocoriaCongenital cataract

Unilateral or bilateral Unilateral

Inflammatory cycliticmembrane

Persistent hyperplasticprimary vitreous

Unilateral or bilateral

Coats disease

Unilateral Unilateral

Advanced retinopathy of prematurity

Posterior pole toxocaragranuloma

Always bilateral but may be asymmetrical

stagingstaging The most commonly used system is the The most commonly used system is the Reese-Reese-

Ellsworth systemEllsworth system, which predicts the chance of , which predicts the chance of visual preservation well, but not survival.visual preservation well, but not survival.

The The Abramson-Grabowski systemAbramson-Grabowski system addresses both addresses both intraocular and extraocular Rb.intraocular and extraocular Rb.

The The International Classifcation (“ABCDE”) system International Classifcation (“ABCDE”) system for intraocular Rbfor intraocular Rb is under modifcation and is used is under modifcation and is used in recent clinical protocols.in recent clinical protocols.

The The AJCC TNM systemAJCC TNM system..

The International Classifcation system for intraocular RbThe International Classifcation system for intraocular Rb

From COG Protocol ARET0331 (with permission): Trial of systemic neoadjuvant chemotherapy for Group B From COG Protocol ARET0331 (with permission): Trial of systemic neoadjuvant chemotherapy for Group B

Intraocular Retinoblastoma: A Phase III Limited Institution Study. Available atIntraocular Retinoblastoma: A Phase III Limited Institution Study. Available at

https://members.childrensoncologygroup.org/Prot/ARET0331/ARET0331DOC.pdf.https://members.childrensoncologygroup.org/Prot/ARET0331/ARET0331DOC.pdf.

TreatmentTreatment

Goals of treatment:Goals of treatment: Save life.Save life. Preserve vision or salvage eyePreserve vision or salvage eye

(i.e. avoid enucleation).(i.e. avoid enucleation). Minimize any complications or side effects of Minimize any complications or side effects of

therapy.therapy.

Treatment options:Treatment options: Enucleation & Exenteration.Enucleation & Exenteration. EBRTx.EBRTx. Local therapies:Local therapies:

• Plaque RTx.Plaque RTx.• Laser photocoagulation.Laser photocoagulation.• Cryotherapy.Cryotherapy.• Thermotherapy.Thermotherapy.

Chemoreduction:Chemoreduction:• I.V.I.V.• Subcojunctival.Subcojunctival.

Chemotherapy.Chemotherapy.

Traditional Treatment:Traditional Treatment: Unilat. RBUnilat. RB ⇒ ⇒Enucleation F.U till school age.⇒Enucleation F.U till school age.⇒ Bilat. RBBilat. RB ⇒ ⇒ Enucleation for more advanced side &Enucleation for more advanced side &

EBRTx for less adv side.EBRTx for less adv side. Metas. RBMetas. RB Ctx.⇒ Ctx.⇒

Recent Treatment of Retinoblastoma1. Small tumours

• Laser photocoagulation• Transpupillary thermotherapy• Cryotherapy

2. Medium tumours • Brachytherapy• Chemotherapy• External beam radiotherapy

3. Large tumours • Chemotherapy followed by local treatment• Enucleation

4. Extraocular extension• External beam radiotherapy

5. Metastatic disease• Chemotherapy

EnucleationEnucleation

Involves removal of the eye leaving behind Involves removal of the eye leaving behind lids and extraocular muscles but removing lids and extraocular muscles but removing the longest possible segment (10 to 15mm) the longest possible segment (10 to 15mm) of optic nerve in continuity with the globe.of optic nerve in continuity with the globe.

Care should be taken to avoid perforation of Care should be taken to avoid perforation of the globe to prevent seeding.the globe to prevent seeding.

Indications of Enucleation:Indications of Enucleation:• Large tumors ( Large tumors ( >50 % of globe volume>50 % of globe volume) with no) with no visual potential.visual potential.• Tumors that extend into the optic nerve.Tumors that extend into the optic nerve.• Blind or painful eyes.Blind or painful eyes.• Group E tumors that have failed previous "globe-Group E tumors that have failed previous "globe- conserving" approaches.conserving" approaches.• Group D tumors. (Group D tumors. (significant vitr seed, subretin infiltsignificant vitr seed, subretin infilt .).)• Secondary glaucoma.Secondary glaucoma.• Vitreous seeding.Vitreous seeding.• Anterior chamber invasion. Anterior chamber invasion.

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Hurwitz RL, Shields CL, Shields JA, et al.. Retinoblastoma. In: Principles and Practice of Pediatric Oncology, 6th ed, Pizzo PA, Poplack DG (Eds), Lippincott Williams & Wilkins, Philadelphia 2011. p.809.

Adjuvant chemo after enucleation:Adjuvant chemo after enucleation:

considered in patients with considered in patients with high-risk featureshigh-risk features::• iris, ciliary body infiltrationiris, ciliary body infiltration• massive choroidal or scleral infiltration,massive choroidal or scleral infiltration,• invasion of the optic nerve posterior to the lamina invasion of the optic nerve posterior to the lamina

cribrosacribrosa..

Adjuvant EBRTxAdjuvant EBRTx should be considered in should be considered in extrascleral extension.extrascleral extension.

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1:31

Post-enucleation follow-up:Post-enucleation follow-up: Child must be monitored closely for orbital relapse Child must be monitored closely for orbital relapse

in the in the two yearstwo years after surgery. ( after surgery. (All recurrences are All recurrences are diagnosed within 24 months of enucleationdiagnosed within 24 months of enucleation).).

the incidence of orbital recurrence after enucleation the incidence of orbital recurrence after enucleation is 4.2%.is 4.2%.

The majority of patients (85 %) with orbital The majority of patients (85 %) with orbital recurrence also developed metastatic disease. recurrence also developed metastatic disease.

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enucleation. Br J Ophthalmol 2009; 93:463.

Orbital implants:Orbital implants: Historically not used due to Historically not used due to potential interference with potential interference with palpation of the socket and palpation of the socket and clinical detection of orbital clinical detection of orbital recurrence.recurrence. However CT/MR allow detailed However CT/MR allow detailed orbital analysis despite an orbital analysis despite an implant.implant. Orbital implant (typically hydroxyapatite) is placed at the Orbital implant (typically hydroxyapatite) is placed at the

time of enucleation.time of enucleation. After the overlying conjunctiva has healed (approximately After the overlying conjunctiva has healed (approximately

3 months), a prosthesis can be fitted by an ocularist. 3 months), a prosthesis can be fitted by an ocularist.

External beam RTExternal beam RT   :   :

It is currently It is currently rarely utilizedrarely utilized may be considered for:may be considered for:

• Large bilateral tumors.Large bilateral tumors.• Vitreous seeding.Vitreous seeding.• Thick tumors near the optic nerve or fovea in Thick tumors near the optic nerve or fovea in

the eye with visual potential.the eye with visual potential.• Multiple tumors that are too large for Multiple tumors that are too large for

cryotherapy or laser photocoagulation.cryotherapy or laser photocoagulation.• Recurrent dis.Recurrent dis.• Progression on chemoreduction.Progression on chemoreduction.

Complications of EBRTx:Complications of EBRTx:• Second cancers, particularly in patients with Second cancers, particularly in patients with

hereditary RB.hereditary RB.• Damage to the retina, optic nerve, lacrimal Damage to the retina, optic nerve, lacrimal

gland, lens and loss of eyelashes.gland, lens and loss of eyelashes.• Midface hypoplasia. Midface hypoplasia.

The risk of tumor recurrence following EBRTx The risk of tumor recurrence following EBRTx is 7 % within 40 months.is 7 % within 40 months.

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Fletcher O, Easton D, Anderson K, et al. Lifetime risks of common cancers among retinoblastoma survivors. J Natl Cancer Inst 2004; 96:357.

Singh AD, Garway-Heath D, Love S, et al. Relationship of regression pattern to recurrence in retinoblastoma. Br J Ophthalmol 1993; 77:12.

Target volume:Target volume: entire retina upto ora serrata and entire retina upto ora serrata and atleast 1 cm of Optic N. atleast 1 cm of Optic N.

Dose:Dose: Definitive R/ 45-50.4 Gy; (1.8 Gy/Fx.)⇒Definitive R/ 45-50.4 Gy; (1.8 Gy/Fx.)⇒ Post-opr R/ micro residual: 45 Gy.⇒Post-opr R/ micro residual: 45 Gy.⇒

⇒ ⇒ macro residual: 50.4 Gy.macro residual: 50.4 Gy. Child < 1y definitive: 45 Gy.⇒Child < 1y definitive: 45 Gy.⇒

⇒ ⇒ post-opr: 39.6 Gy.post-opr: 39.6 Gy.

Technique:Technique:Classic single temporalClassic single temporal portal 3×4 cm, anteriorportal 3×4 cm, anterior border at lateral bonyborder at lateral bony canthus with posteriorcanthus with posterior 151500 tilt (D-shaped field). tilt (D-shaped field).

Other plan:Other plan:Anterolateral differentially Anterolateral differentially weighted beams withweighted beams with anterior lens shield. anterior lens shield.

Recent techniques:Recent techniques:3D-CRTx, IMRT, Proton:3D-CRTx, IMRT, Proton:

• Four non coFour non co--planar fieldsplanar fields • All anterior oblique fieldAll anterior oblique field: :

(sup,inf, med, lat(sup,inf, med, lat..((• Less orbital hypoplasiaLess orbital hypoplasia. . • Minimize dose to opposite eye, Minimize dose to opposite eye,

optic chiasma, postoptic chiasma, post. . Pituitary Pituitary

and upper cervical spineand upper cervical spine..• More homogenous dose More homogenous dose

distributiondistribution..• Less vitreal recurrenceLess vitreal recurrence..

Treatment results with EBRTx:Treatment results with EBRTx: Preservation of the eye with control of the disease Preservation of the eye with control of the disease

using EBRTx is in the range of 58–88%using EBRTx is in the range of 58–88%.. 95% rate of preservation of The eye in R-E groups 95% rate of preservation of The eye in R-E groups

I–III.I–III. 50% local control rate in R-E groups IV and V 50% local control rate in R-E groups IV and V

disease.disease.

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Murali C, Particia C, Evelyn A. Retinoblastoma: Review of Current Management. The Oncologist 2007;12:1237–1246

Radioactive plaquesRadioactive plaques: :  II125125 brachytherapy. brachytherapy. The radiation dose is approximately 40 to 45 Gy The radiation dose is approximately 40 to 45 Gy

delivered to the tumor apex.delivered to the tumor apex. As a primary treatment, it can control approximately As a primary treatment, it can control approximately

90 % of tumors 90 % of tumors The tumor must be <15 mm in diameter and <10 mm The tumor must be <15 mm in diameter and <10 mm

thickness.thickness.

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Shields CL, Shields JA, Cater J, et al. Plaque radiotherapy for retinoblastoma: long-term tumor

control and treatment complications in 208 tumors. Ophthalmology 2001; 108:2116.

Plaques are contraindicated if RT needs to be Plaques are contraindicated if RT needs to be delivered to multiple tumor foci in each eye.delivered to multiple tumor foci in each eye.

The amount of RT delivered to the optic nerve and The amount of RT delivered to the optic nerve and fovea must be carefully considered, particularly if fovea must be carefully considered, particularly if there is potential for preserved vision.there is potential for preserved vision.

Placement of plaques can be technically difficult Placement of plaques can be technically difficult and requires a second surgical procedure for and requires a second surgical procedure for removal.removal.

Often preferred to external beam RT delivers ⇒Often preferred to external beam RT delivers ⇒less radiation to bone and adjacent soft tissue ⇒less radiation to bone and adjacent soft tissue ⇒reduced risk of second tumors.reduced risk of second tumors.

Ruthenium-106Ruthenium-106 (Ru (Ru106106) is an alternative: ) is an alternative: • For small tumors (thickness less than 6 mm) For small tumors (thickness less than 6 mm) • reduces the radiation dose to the uninvolved retina, reduces the radiation dose to the uninvolved retina,

lens, and optic nerve, thus decreasing radiation-induced lens, and optic nerve, thus decreasing radiation-induced vision loss.vision loss.

Children managed with brachytherapy should be Children managed with brachytherapy should be monitored for the evelopment of radiation monitored for the evelopment of radiation retinopathy and optic neuropathy.retinopathy and optic neuropathy.

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Schueler AO, Flühs D, Anastassiou G, et al. Beta-ray brachytherapy with 106Ru plaquesfor retinoblastoma. Int J Radiat Oncol Biol Phys 2006; 65:1212.

Curved applicator to fit the eye with suture holes for fixing. Curved applicator to fit the eye with suture holes for fixing. Left in place for 3 to 7 days to deliver 40 Gy to tumor apex Left in place for 3 to 7 days to deliver 40 Gy to tumor apex

and 10 to 200 Gy to tumor base.and 10 to 200 Gy to tumor base.

Treatment results with plaque RTx:Treatment results with plaque RTx: Tumor recurrence 6.3% within 9.7 ms.Tumor recurrence 6.3% within 9.7 ms. Radiation retinopathy at 2 ys: 19%.⇒Radiation retinopathy at 2 ys: 19%.⇒ ⇒ ⇒ at 5 ys: 22%.at 5 ys: 22%. Opt neuropathy at 5 ys 21%.⇒Opt neuropathy at 5 ys 21%.⇒ Cataract at 5 ys 17.4%.⇒Cataract at 5 ys 17.4%.⇒ In cases of recurrent or residual retinoblastoma in In cases of recurrent or residual retinoblastoma in

which the only other option was enucleation. which the only other option was enucleation. Tumor control and globe salvage were achieved in Tumor control and globe salvage were achieved in 89% of cases with plaque irradiation during a 89% of cases with plaque irradiation during a mean follow-up of 52 months.mean follow-up of 52 months.

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Shields JA, Shields CL, DePotter P, et al. Plaque radiotherapy for residual or recurrent retinoblastoma in 91 cases. J Pediatr Ophthamol Strab 1994;31:242-5.

Cryotherapy and laser Cryotherapy and laser photocoagulationphotocoagulation::

Can be used to treat smaller tumors (<6 mm in Can be used to treat smaller tumors (<6 mm in diameter and <3 mm thick). diameter and <3 mm thick).

Tumor usually regresses within six weeks.Tumor usually regresses within six weeks.

Complications of these methods include transient Complications of these methods include transient

serous retinal detachment, visually significant serous retinal detachment, visually significant retinal vascular occlusion, retinal traction, and retinal vascular occlusion, retinal traction, and preretinal fibrosis. preretinal fibrosis.

Cryotherapy:Cryotherapy:• Under GA, pencil like probe is placed Under GA, pencil like probe is placed

precisely on the sclera directly behind the precisely on the sclera directly behind the intraocular focus of RB. intraocular focus of RB.

• Rapid freezing forms intracellular crystals Rapid freezing forms intracellular crystals which ruptures tumor cells and causes which ruptures tumor cells and causes vascular occlusion.vascular occlusion.

• 1 or 2 sessions at 1 month interval are 1 or 2 sessions at 1 month interval are required.required.

laser photocoagulationlaser photocoagulation::• Argon/Diode laser/Xenon arc.Argon/Diode laser/Xenon arc.• Light is focused through dilated pupil under GA Light is focused through dilated pupil under GA

and vessels are coagulated which results in and vessels are coagulated which results in involution of tumor. involution of tumor.

• Most tumors require 2 to 3 sessions to be cured.Most tumors require 2 to 3 sessions to be cured.• Contraindications: Contraindications:

Tumor located at or near macula or pupillary areTumor located at or near macula or pupillary are Mushroom shaped tumorsMushroom shaped tumors Tumors arising from a vitreous base.Tumors arising from a vitreous base.

ChemotherapyChemotherapy::

Retinoblastoma is a chemo-sensitive malignancy.Retinoblastoma is a chemo-sensitive malignancy. The most active agents are The most active agents are carboplatincarboplatin and  and vincristinevincristine

with or without with or without etoposideetoposide.. Indications:Indications:

• Vision salvage and delay or avoidance of radiotherapy in Vision salvage and delay or avoidance of radiotherapy in patients with patients with bilateral diseasebilateral disease..

• Tumor shrinkage in patients with unilateral disease, good Tumor shrinkage in patients with unilateral disease, good vision, and a tumor that is vision, and a tumor that is too large for isolated local therapytoo large for isolated local therapy

• MetastaticMetastatic disease. disease.• Risk factors identified Risk factors identified after enucleationafter enucleation (ie, massive choroid (ie, massive choroid

invasion or postlaminar involvement of the optic nerve).invasion or postlaminar involvement of the optic nerve).

ChemoreductionChemoreduction

Most retinoblastomas are large at the time of Most retinoblastomas are large at the time of presentation, so chemoreduction is often used to presentation, so chemoreduction is often used to reduce tumor volume enhances the success of ⇒reduce tumor volume enhances the success of ⇒local therapies.local therapies.

As initial treatment of retinoblastoma improves ⇒As initial treatment of retinoblastoma improves ⇒the ocular salvage rate.the ocular salvage rate.

Most common chemoreduction regimen contains Most common chemoreduction regimen contains carboplatincarboplatin, , vincristinevincristine, and , and etoposideetoposide, given , given approximately every 4 weeks.approximately every 4 weeks.

Numerous studies have been published that Show Numerous studies have been published that Show that chemotherapy is very effective in globe salvage; that chemotherapy is very effective in globe salvage; ((eliminating the need for EBRTx/enucleationeliminating the need for EBRTx/enucleation) in R-E group I–IV ) in R-E group I–IV eyes success rate: 85% of treated patients by 5 ⇒eyes success rate: 85% of treated patients by 5 ⇒years.years.

while proving to be significantly less successful in while proving to be significantly less successful in more advanced disease Approximately 40% of ⇒more advanced disease Approximately 40% of ⇒group C and 70% of group D eyes failed systemic group C and 70% of group D eyes failed systemic chemotherapy alone.chemotherapy alone.

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• Shields CL, Mashayekhi A, Demirci H et al. Practical approach to management of retinoblastoma. Arch Ophthalmol 2004;122:729–735.

• Shields CL, De Potter P, Himelstein BP et al. Chemoreduction in the initial management of intraocular retinoblastoma. Arch Ophthalmol 1996; 114:1330–1338.

In a series of patients with group E, at the 2In a series of patients with group E, at the 2

year follow-up:year follow-up:

⇒ ⇒ ocular salvage in:ocular salvage in:

91%91% treated with chemoreduction + EBRTx treated with chemoreduction + EBRTx (median 22Gy).(median 22Gy).

VSVS

53%53% in patients treated with chemoreduction in patients treated with chemoreduction alone.alone.

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Shields CL, Ramasubramanian A, Thangappan A, et al. Chemoreduction for group E

retinoblastoma: comparison of chemoreduction alone versus chemoreduction plus low-dose

external radiotherapy in 76 eyes. Ophthalmology 2009; 116:544

Conclusion:Conclusion: chemoreduction is generally chemoreduction is generally considered for group A, B, and C eyes, and is less considered for group A, B, and C eyes, and is less effective for group D.effective for group D.

Following chemoreduction, these groups respond Following chemoreduction, these groups respond well to thermotherapy and rarely require external well to thermotherapy and rarely require external beam RT or enucleation.beam RT or enucleation.

Some reports suggest chemotherapy may Some reports suggest chemotherapy may predispose to the development of secondary acute predispose to the development of secondary acute myeloid leukemia later in life. myeloid leukemia later in life.

Local ChemotherapyLocal Chemotherapy Injection of Injection of carboplatincarboplatin into  into

the sub-Tenon’s space has the sub-Tenon’s space has shown some limited shown some limited success as a primary success as a primary therapy, and longer follow-therapy, and longer follow-up suggests a high failure up suggests a high failure rate.rate.

It is currently considered It is currently considered for possible use as a “boost” for possible use as a “boost” with chemoreduction for with chemoreduction for groups C, D, and E tumors groups C, D, and E tumors (controversial). (controversial).

Intra-arterial chemotherapy:Intra-arterial chemotherapy: in a very recent prospective study To determine whetherin a very recent prospective study To determine whether intraintra--arterial chemotherapy is safe and effective in advancedarterial chemotherapy is safe and effective in advanced intraocular RB.intraocular RB. 78 patients with were treated.78 patients with were treated. Catheterization of the ophthalmic artery and injection of Catheterization of the ophthalmic artery and injection of

chemotherapy, usually chemotherapy, usually melphalan melphalan ((with or without topotecanwith or without topotecan(.(. End-points:End-points: event event--free free ((enucleation or radiotherapyenucleation or radiotherapy) ) ocular survival, ocular survival,

and ocular and extraocular complicationsand ocular and extraocular complications. . 2-years results: 2-years results:

• Ocular eventOcular event--free survival rates were 70%.free survival rates were 70%.• 81.7%81.7% for eyes that received intrafor eyes that received intra--arterial chemotherapy as primary arterial chemotherapy as primary

treatment.treatment.• 58.4%58.4% for eyes that had previous treatment failure with intravenous for eyes that had previous treatment failure with intravenous

chemotherapy andchemotherapy and//or external beam radiation therapyor external beam radiation therapy..• There were no permanent extraocular complicationsThere were no permanent extraocular complications..

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Gobin YP, Dunkel IJ, Marr BP, et al. Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience. Arch Ophthalmol 2011; 129:732.

Treatment of Extraocular Treatment of Extraocular RetinoblastomaRetinoblastoma

There is no clearly proven effective therapy for the There is no clearly proven effective therapy for the treatment of extra-ocular retinoblastoma. treatment of extra-ocular retinoblastoma.

Clinical trials are now under way to improve the Clinical trials are now under way to improve the overall dismal outcome (survival of approximately overall dismal outcome (survival of approximately 10%) for this group of patients. 10%) for this group of patients.

Those with CNS metastases appear to do worse than Those with CNS metastases appear to do worse than those with other forms of extra-ocular disease. those with other forms of extra-ocular disease.

In the past, chemotherapy has included conventional In the past, chemotherapy has included conventional doses of vincristine, cyclophosphamide, and doses of vincristine, cyclophosphamide, and doxorubicin, and, although they produce an initial doxorubicin, and, although they produce an initial response, relapse is common. response, relapse is common.

Carboplatin, ifosfamide, and etoposide have shown Carboplatin, ifosfamide, and etoposide have shown more promisemore promise

Generally, induction chemotherapy is given for four Generally, induction chemotherapy is given for four cycles and this is followed by high-dose cycles and this is followed by high-dose chemotherapy followed by stem cell rescue. chemotherapy followed by stem cell rescue.

Following recovery from stem cell transplantation, Following recovery from stem cell transplantation, radiotherapy is generally given to sites of initial bulky radiotherapy is generally given to sites of initial bulky disease.disease.

Recurrent RetinoblastomaRecurrent Retinoblastoma

The prognosis for a patient with recurrent or The prognosis for a patient with recurrent or progressive retinoblastoma depends on the site progressive retinoblastoma depends on the site and extent of the recurrence or progression. and extent of the recurrence or progression.

Responses as high as 85% have been reported Responses as high as 85% have been reported following treatment with etoposide and following treatment with etoposide and carboplatin. carboplatin.

If the recurrence or progression of retinoblastoma If the recurrence or progression of retinoblastoma is confined to the eye and is small, the prognosis is confined to the eye and is small, the prognosis for sight and survival may be excellent with local for sight and survival may be excellent with local ophthalmic therapy only.ophthalmic therapy only.

If the recurrence or progression is confined to the If the recurrence or progression is confined to the eye but is extensive, the prognosis for sight is eye but is extensive, the prognosis for sight is poor, however the survival remains excellent.poor, however the survival remains excellent.

If the recurrence or progression is extra-ocular, If the recurrence or progression is extra-ocular,

the prognosis is more guarded and the treatment the prognosis is more guarded and the treatment depends on many factors and individual patient depends on many factors and individual patient considerations.considerations.

Follow-upFollow-up Long-term follow-up is best accomplished by a Long-term follow-up is best accomplished by a

multidisciplinary team.multidisciplinary team. Recurrence usually occurs with in 3 years. Recurrence usually occurs with in 3 years. The risk period for extraocular spread after The risk period for extraocular spread after

successful treatment is generally recognized to be successful treatment is generally recognized to be 12 to 18 months.12 to 18 months.

Long-term survivors should also be followed for Long-term survivors should also be followed for the development of second malignancies.the development of second malignancies.

Routine CT or MRI scans and bone scans are Routine CT or MRI scans and bone scans are probably not necessary.probably not necessary.

Second cancersSecond cancers

Genetic counselingGenetic counseling

Recommended for:Recommended for:• Patients with family history of RB should undergo Patients with family history of RB should undergo

genetic counselling (blood sample only).genetic counselling (blood sample only).• Parents having a child with RB (done at the time of Parents having a child with RB (done at the time of

enucleation or during treatment).enucleation or during treatment). Clinical Recommendation:Clinical Recommendation: examination at birth & 4 examination at birth & 4

monthly thereafter until 4 years of age.monthly thereafter until 4 years of age. Sampling:Sampling:

• in sporadic cases:in sporadic cases: tumor tissue & blood required tumor tissue & blood required• in inherited cases:in inherited cases: only blood sample sufficient only blood sample sufficient

Molecular tests:Molecular tests:• Direct analysisDirect analysis of the constitutional mutation of of the constitutional mutation of

RB1 gene, performed on constitutional DNA.RB1 gene, performed on constitutional DNA.• Indirect analysisIndirect analysis of the allele carrying the of the allele carrying the

mutation.mutation.• Tumor cell LOH evaluation.Tumor cell LOH evaluation.

Patients should be informed about the risk of Patients should be informed about the risk of transmission and of second primary malignant transmission and of second primary malignant tumor development ⇒tumor development ⇒

20% at 10 years.20% at 10 years. 50% at 20 years.50% at 20 years. 90% at 30 years.90% at 30 years.

• Risk for offspring of survivors of retinoblastoma:Risk for offspring of survivors of retinoblastoma: Bilateral disease:Bilateral disease: The risk of RB arising in the The risk of RB arising in the

offspring is 45%.offspring is 45%. Unilateral disease:Unilateral disease: the risk of RB in offspring is 2.5%. the risk of RB in offspring is 2.5%.

• Risk for siblings of patients with retinoblastoma:Risk for siblings of patients with retinoblastoma:

In siblings of bilaterally affected children whose parents In siblings of bilaterally affected children whose parents are also affected the risk of retinoblastoma is 45%.are also affected the risk of retinoblastoma is 45%.

If the sibling is unilaterally affected the and has a FH, If the sibling is unilaterally affected the and has a FH, risk is 30%. risk is 30%.

Without a family history the risk is 2% for siblings of Without a family history the risk is 2% for siblings of bilateral cases and 1% for siblings of unilateral casesbilateral cases and 1% for siblings of unilateral cases