MANAGEMENT OF RETINOBLASTOMA

MANAGEMENT OF RETINOBLASTOMA & CURRENT TRENDS

Dr samarth mishra

CLINICAL EVALUATIONVA assessmentPupillary examinationSlit-lamp examination iris neovascularization hyphema / hypopyoniris nodules Indirect ophthalmoscopy (EUA)IOP measurement (portable tonometer)360 degrees of scleral depression; andFundus photographs (RETCAM) documenting site, size and numbers of retinal tumorsvitreous and subretinal seeds RD

IMAGINGADV:confirmation of diagnosis when there is opaque mediato evaluate the presence of extraocular extension or associated cerebral lesion in trilateral cases.Ultrasound : mass with calcificationCT scan MRI: is more sensitive for extraocular extensiondistinguishing tumor with secondary retinal detachment from other causes of subretinal effusion or detachment, like coat's disease, primary hyperplastic vitreous and retinopathy of prematurityCurrently, MRI is the standard imaging modality used to rule out extraocular extension.

CLASSIFICATION OF RETINOBLASTOMAIdeal classification system of retinoblastoma include two componentsGrouping: A clinical systems of prognosticating organ salvage.Staging: System of prognosticating survival

Reese-Ellsworth classification

International classification of intraocular RetinoblastomaPrognosticate pts treated with newer therapeutic modalities

INTERNATIONAL STAGING SYSTEM FOR RETINOBLASTOMAStage 0No enucleation (one or both eyes may have intraocular disease)Stage IEnucleation, tumor completely resectedStage IIEnucleation with microscopic residual tumorStage IIIRegional extensionA. Overt orbital diseaseB. Preauricular or cervical lymph node extensionStage IVMetastatic diseaseA. Hematogenous metastasis1. Single lesion2. Multiple lesionB. CNS Extension1. Prechiasmatic lesion2. CNS mass3. Leptomeningeal disease

Based on clinical evaluation, imaging, systemic survey & histopathology

Metastatic work-upLP for CSF analysisBone marrow evaluation and bone scanPET Scan

Screening for retinoblastoma

Parents and siblings of the affected child should be screened for evidence of retinoblastoma in all cases of retinoblastoma in order to identify the hereditary cases of retinoblastoma.

MANAGEMENT OF RETINOBLASTOMAGOAL OF MANAGEMENTSave lifeSalvage of the organ (eye) & Function (Vision)Avoidance of side effects sec.malignancies, facial bony deformities, or oter physical changes that can affect functional well-beingManagement strategies depends on stage of the diseaseIntra ocular retinoblastoma Retinoblastoma with high risk characteristic Orbital retinoblastomaMetastatic retinoblastoma

LASER PHOTOCOAGULATION < 2mm ht. & post to equatorTo delimit the tumor and coagulate the blood supplyContraindicated in patients on active chemo reduction protocolComplications: Transient serous RD, Retinal vascular occlusion, Retinal hole, Retinal traction and Pre-retinal fibrosis.

CRYOTHERAPY

For small equitorial and peripheral tumors 15 mm) optic nerve stumpInspect the enucleated eye for macroscopic extraocular extension & optic nerve involvementHarvest fresh tissue for genetic studiesAvoid biointegrated implant if postoperative radiotherapy is necessary

(Contd.)Enucleated eye ball with 18mm optic nerve stumpEnucleated eye ball with extrascleral tumor extension

Placement of orbital implant following enucleation promotes orbital growth provided better cosmesis & enhances prosthesis motility

Retinoblastoma in RE following enucleation with orbital implantExcellent cosmesis following fitting of a custom ocular prosthesis

ORBITAL IMPLANT FOLLOWING ENUCLEATION Orbital implants can be Integrated or nonintigrated Buried or nonburied Buried integrated implants have greater cosmesis & safety. Nonburied implants have a potential problems of migration, extension & infectionImplants used are plastic, silicon & hydroxy apatite

CHEMOTHERAPYCommonly used are VECDAY 1 : Vincristine + Etoposide + CarboplatinDAY 2 : Etoposide Standard dose : ( 3 weekly, 6 cycles): Vincristine 1.5 mg/m2 (0.05 mg/kg for children 36 month of age and maximum dose 2 mg), Etoposide 150 mg/m2 (5 mg/kg for children 36 months of age), carboplatin 560 mg/m2 (18.6 mg/kg for children 36 months of age)

Others are cyclophosphamide, mephalan & thiotepa

CHEMOREDUCTIONAim is to reduce the tumor volume in large intraocular tumors (ICRB Group B to D) before consolidative therapyrequires two to six cycles

PERIOCULAR CHEMOTHERAPY helps in better penetration to avascular spaces like aq & vitreousUse of carboplatin in an aqueous vehicle benefit in the treatment of groups C and D retinoblastoma Adverse effects: ocular motility changes, orbital fat necrosis, severe pseudopreseptal cellulitis and ischemic necrosis with atrophy of the optic nerve resulting in blindness periocular carboplatin delivered in a fibrin sealant that allows for a controlled-release of the drug in the periocular spaceTopotecan in fibrin sealant has also been tried subconjunctivally to treat retinoblastoma

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PATTERNS OF REGRESSION OF THE TUMORTYPE ONo visible remnant NoTYPE ICompletely calcified remnant ( rock salt)Probably yesTYPE IICompletely non calcified remnant (fish fresh)YesTYPE IIIPartially calcified remnantYesTYPE IVAtrophic chorioratianal flat scarYes three complete laser coverages

INTRARTERIAL CHEMOTHERAPYMelphalan used intracarotid administration / direct intraophthalmic artery toxic effects following multiple sessions of intraarterial chemotherapy could be cataractogenic and possibly carcinogenic

CHEMOPROPHYLAXIS

Indicated in presence of 1 or more of the following features on HP study in enucleated eyes to prevent a higher risk of systemic metastasis and/or local recurrenceHP features (6 cycles) invasion of anterior chamber, iris, ciliary bodymassive choroidal invasionInvasion of sclera Post laminar optic nerve invasionAdjuvant chemotherapy for microscopic residual disease (12 cycles )extrascleral and optic nerve cut-end involvement is treated with 12 cycles of adjuvant chemotherapy and EBRT.

NEOADJUVANT CHEMOTHERAPYNACT is used to reduce the tumor size, followed by enucleation, local radiotherapy and adjuvant chemotherapy, to complete a total of 12 cycles

leads to rapid reduction in tumor bulk and also controls micrometastatic disease

enables most patients to undergo enucleation instead of cosmetically disfiguring and more complex exenteration.

Indicated in : stage III RB like extraocular extension into orbit on imaging seen as orbital mass / optic nerve thickening anterioroly fungating mass on clinical exam.

High-dose chemotherapy and autologous stem cell transplant

Indicated for metastatic diseaseChildren with noncentral nervous system disease (bone or bone marrow) have had better outcomes when compared with patients with central nervous system metastasisDrugs commonly used as part of high-dose chemotherapy include combinations of carboplatin, etoposide, cyclophosphamide, melphalan and thiotepa

EBRT in extraocular retinoblastomaLocal EBRT is an important component of the treatment protocol for eradication of residual disease in the orbit. The usual dose of radiotherapy given to the involved orbit is 40-45 Gray over 4-5 weeks The inclusion of optic chiasma in the radiation field is not clear and is practiced by few centers

METASTATIC RETINOBLASTOMAThe common sites for local spread and metastasis include orbital & regional lymph node extension, central nervous system metastasis & systemic metastasis to bone & bone marrow. Metastasis usually occurs within 1 year of diagnosis Prognosis is poorConventional dose chemotherapy using vincristine, doxorubicin, cyclophosphamide, cisplatin & etoposide with radiation therapy. Followed by hematopoietic stem cell rescue.

NEW FRONTIERSGene therapyPriliminary results of intravitreal inj. Of Adenovirus carring coding sequence of thymidine kinase followed by Ganciclovir inj. Are promising

Arsenic trioxide causes regression of RB as cauases cell damage by O2 free radical formationExperimental t/tRole of Cox 2 inhibitor is under trail as it is expressed in RB & promotes angiogenesis

MOLECULAR THERAPYThe molecular signaling pathways in retinoblastoma and potential clinical applications

The normal retinoblastoma protein binds to and inhibits the transcription factor E2F, thereby halting transcription of E2F target genes, which are responsible for cell cycle progression. It also binds to histone deacetylase (HDAC), which results in silencing of transcription. Mutated or absent retinoblastoma protein results in uncontrolled cellular proliferation and, ultimately, cancer.

Nutlin 3A

Nutlin 3A is a small molecule inhibitor of the MDM2/MDMX and p53 interaction, which was found to be able to induce cell death in human retinoblastoma cell linesused in combination with topotecan, it killed human retinoblastoma cell linesNutlin 3A was injected subconjunctivally with topotecan.

Inhibitors of HDAC

HDAC inhibitors may be particularly useful because they induce cytotoxicity to tumors selectively

Molecule inhibitors of the oncogene N-myc

N-myc is amplified in 10% of human retinoblastoma cases

SUPERSELECTIVE INTRA-ARTERIAL CHEMOTHERAPY

Japanese physicians introduced the technique of ophthalmic arterial infusion therapy for patients with intraocular RBThe study technique consisted of selective catheterization of the internal carotid artery, followed by the occlusion of a balloon distal to the ophthalmic artery. Melphalan (Alkeran, Celgene, Summit, NJ) was infused into the catheter tip and into the ophthalmic artery.Complications were mild, transient bradycardia, periorbital erythema, and swelling

VEGF plays multiple roles during various steps of tumor progression by stimulating vessel growth to provide the necessary metabolic needsGrowing evidence also exists that the p53 tumor suppressor downregulates VEGF expressionGlycolytic InhibitorsInhibition of glucose metabolism byGlycolytic inhibitors, such as 2-deoxy-d-glucose (2-DG), target the cellular mechanism that hypoxic tumoral cells utilize for survival.Antiangiogenic Agentsantiangiogenic agent anecortave acetate (Retaane, Alcon, Fort Worth, TX) & Bevacizumab (Avastin, Genentech, South San Francisco, CA) has also been shown to decrease tumor burden Combination therapy with angiogenic and glycolytic inhibitors significantly enhanced tumor control

Current suggested protocol A. Intraocular tumor, international classification Group A to C, unilateral or bilateral1.Focal therapy (cryotherapy or transpupillary thermotherapy) alone for smaller tumors ( 6 cycles.4Focal therapy for small residual tumor, and plaque brachytherapy / external beam radiotherapy (>12 months age) for large residual tumor if bilateral, and enucleation if unilateral.

B. Intraocular tumor, international classification group D, unilateral or bilateral1.High dose chemotherapy & sequential aggressive focal therapy2.Periocular carboplatin for vitreous seeds3.Consider primary enucleation if unilateral, specially in eye with no visual prognosisC. Intraocular tumor, international Classification Group E, Unilateral or Bilateral1.Primary enucleation2.Evaluate histopathology for high risk factorsD. High risk factors on histopathology, international staging, stage 21.Baseline systemic evaluation for metastasis2.Standard 6 cycle adjuvant chemotherapy 3.High dose adjuvant chemotherapy and orbital external beam radiotherapy in patients with scleral infiltration, extraocular extension, and optic nerve extension to transection.

E. Extraocular tumor, international Staging, Stage 3A1.Baseline systemic evaluation for metastasis 2.High dose chemotherapy for 3-6 cycles, followed by enucleation or extended enucleation, external beam radiotherapy, and continued chemotherapy for 12 cycles F. Regional Lymph Node Metastasis, International Staging, Stage 3B1.Baseline evaluation for systemic metastasis 2.Neck dissection, high dose chemotherapy for 6 cycles, followed by external beam radio-therapy, and continued chemotherapy for 12 cycles G. Hematogenous or Central Nervous System Metastasis, International Staging, Stage 4 1.Intent-to-cure or Palliative therapy in discussion with the family

SECOND TUMOR IN RETINOBLASTOMARisk of developing of non-ocular second primary tumor following irradiationOsteogenic sarconma is the commonestFibrosarcoma malignant melanoma, chondro-sarcoma, leukemia, renal cell carcinoma, Ewings sarcoma, Thyroid carcinoma, Rhabdomyosarcoma may also develop.TRILATERAL RETINOBLASTOMThe association of midline intra-cranial pineal tumor of supra sellar and para sellar neuroblastic tumors with bilateral retinoblastoma. Pinealo blastomas occurs during first 4 years of life & invariably fatal.

PROGNOSISRetinoblastoma is fatal if untreated.95% of pts survive if treated before extra-ocular spread.Relation of mortality with extent of involvement of optic nerve

Extent of involvement5 yrs mortality rateGrade I: Superficial invasion of optic nerve head only10%Grade II: Involvement up to & including the lamina cribrosa29%Grade III: Involvement beyond lamina cribrosa42%Grade IV: Involvement & up to surgical margin78%

GENETIC COUNSELING Using molecular genetic technique such as PCR & DNA sequencing it is now possible to find the exact retinoblastoma gene mutation prenataly.