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Management of Extraocular Retinoblastoma

Management of Extraocular Retinoblastoma. Nurdan TAÇYILDIZ MD , Prof. of Pediatric Oncology Ankara University Medical School Department of Pediatric Oncology. Extraocular RB is a common problem in pediatric oncology in developing countries (9% - 12%)

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Management of Extraocular Retinoblastoma

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  1. Management of Extraocular Retinoblastoma Nurdan TAÇYILDIZ MD, Prof. of Pediatric Oncology Ankara University Medical School Department of Pediatric Oncology

  2. Extraocular RB is a common problem in pediatric oncology in developing countries (9% - 12%) • Late diagnosis is a determinant factor for advenced disease in our population • Associated with poor prognosis

  3. Education programs Questionnaire

  4. Presenting symptoms of patients with Rb in Ankara University Medical School Department of Pediatric Oncology *with screening 19 of 91 patients have metastatic Rb

  5. Patterns of Spread Intraocular 1. With endophytic growth, there is a white hazy mass 2. With exophytic growth, there is retinal detachment 3. Most tumors have combined growth 4. Retinal cells frequently break off from the main mass and seed the vitreousor new locations on the retina 5. Glaucoma may result from occlusion of the trabecular network or from iris neovascularization

  6. Patterns of Spread Extraocular 1. Retinoblastoma spreads first to surrounding structures and then by hematogenous or lymphatic extension 2. Lymphatic spread is rare because there is minimal lymphatic drainage of the orbit. Occasionally, retinoblastoma spreads lymphatically to the preauricular and submandibular nodes.

  7. Patterns of Spread Extraocular 3. Retinoblastoma invades the optic nerve. From there it can spread directly along the axons to the brain or may cross into the subarachnoid space and spread via the cerebrospinal fluid to the brain 4. Hematogenous spread leads to metastatic disease, most commonly to brain, bone marrow, or bone Retinoblastoma cells in CSF Retinoblostoma Optic nerve

  8. Investigations for Diagnosis of Retinoblastoma Risk assesment for metastatic disease

  9. Risk assesment for metastatic disease Prognostic Factors Pre-lamina cribrosa Optic Nerve Lamina cribrosa Involvement beyond lamina cribrosa, Optic cut end (-) Beyond lamina cribrosa Optic cut end Massive involvement of Choroid and optic nerve Optic cut end (+) Focal involvement of subretinal area Minimal involvement of coroid

  10. Grabowski-Abramson Clinicopathologic Classification I. Intraocular disease • Retinal tumors • Extension into to the lamina cibrosa • Uveal extension II. Orbital disease • Orbital tumor • Scattered episcleral cells • Orbital invasion b. Optic nerve • Tumor beyond the lamina but not up to cut section • Tumor at the cut section of the optic nerve III. Intracranial metastasis • Postivite CSF only • Mass CNS lesion IV. Hematogenous metastasis • Postive bone marrow alone • Focal bone lesions with or without positive bone marrow • Other organ involvement CFS: cerebrospinal fluid; CNS: central nervous system

  11. A proposal for an international retinoblastoma staging system • Stage 0: Patients treated conservatively (subject to presurgical ophthalmologic classifications); • Stage I: Eye enucleated, completely resected histologically; • Stage II: Eye enucleated, microscopic residual tumor; • Stage III: Regional extension • a) overt orbital disease, • b) preauricular or cervical lymph node extension • Stage IV: Metastatic disease • a) hematogenous metastasis: • 1) single lesion, • 2) multiple lesions; • b) CNS extension: • 1) prechiasmatic lesion, • 2) CNS mass, • 3) leptomeningeal disease]. Guillermo Chantada, MD, François Doz, MD, Celia B.G. Antoneli, PhD, Richard Grundy, PhD, F.F. Clare Stannard, Rad Onc (SA), Ira J. Dunkel, MD, Eric Grabowski, MD, Carlos Leal-Leal, MD, Carlos Rodríguez-Galindo, MD, Enrique Schvartzman, MD, Maja Beck Popovic, MD, Bernhard Kremens, MD, Anna T. Meadows, MD, Jean-Michel Zucker, MD Pediatric Blood & Cancer 2005; 47: 6; 801-805.

  12. Retinoblastoma Team The diagnosis and treatment of patients with retinoblastoma involve a team approach requiring: • Pediatric oncologist • Ophthalmologist (ocular oncologist) • Radiologist • Radiotherapist • Child psychologist • Social worker • Nurse • Genetic counselors

  13. The Goals of Treatment 1) To save child’s life 2) To salvage the eye of vision Tailored to each individual case Based on, • Laterally of disease • Size and location of tumor • Visual prognosis • Treatment of metastatic disease • Risks for second cancers

  14. Prognostic Factors for success of therapy • Prognosis for vision in bilateral retinoblastoma • Extend of tumor involvement • Effectiveness of treatment modalities • Survival rate has improved dramatically over the last century • 1897 Wintersteiner ®13% survival rate • Today ®90% 5 year survival Due to improved ability to detect retinoblastoma before metastasis Development of alternative treatment strategies

  15. Treatment Methods • Enucleation • External beam radiotherapy (EBRT) • Plaque radiotherapy • Laser photocoagulation • Cryotherapy • Thermotherapy • Chemo-thermotherapy • Intravenous chemoreduction • Subconjunctival chemoreduction • Systemic chemotherapy for possible metastatic disease • Orbital exenteration ? • Treatment of systemic retinoblastoma

  16. Treatment Methods Chemotherapy for Possible Metastatic Disease Patients with; pathologic evidence of disease • With extensive choroidal involvement • Extending to the sclera • Extending beyond lamina cribrosa but not cut end of the optic nerve prophylactic adjuvant therapy is indicated • cyclophosphamide + doxorubicin • VEC to minimize the risk of metastases (there is no randomized study)

  17. The Role of Adjuvant Chemotherapy in Preventing Metastasis in High- Risk Retinoblastoma: Survey of the Published Literature* Honavar SG. et al. Arch Ophthalmol 2002; 120:923-931

  18. Chemotherapy Regimens in 46 Patients of Retinoblastoma With High-Risk Characteristics Chemotherapy Regimen No. of Patients Vincristine sulfate + doxorubicin 21 hydrochloride + cyclophosphamide* Vincristine + etoposide + carboplatin† 25 Honavar SG. et al. Arch Ophthalmol 2002; 120:923-931

  19. Chemotherapy Regimens in 46 Patients of Retinoblastoma With High-Risk Characteristics Kaplan-Meier estimates of the proportion of patients free of metastasis in the group that received adjuvant therapy (triangle line) and the group that did not (open circle line). Honavar SG. et al. Arch Ophthalmol 2002; 120:923-931

  20. Patient distribution according to histopathology and centre Retinoblastoma patients with high risk ocular pathological features: who needs adjuvant therapy? NYPH: NewYork Presbyterian Hospital , HPG: Hospital JP Garrahan Chantada GL, Dunkel IJ, de Davila MTG, Abramson DH. Retinoblastoma patients with high risk ocular pathological features : who needb adjuvant therapy? Br J Ophthalmol 2004; 88:1069-1073

  21. Treatment and outcome of patients according to risk factors detected histopathological examination Chantada GL, Dunkel IJ, de Davila MTG, Abramson DH. Retinoblastoma patients with high risk ocular pathological features : who needb adjuvant therapy? Br J Ophthalmol 2004; 88:1069-1073

  22. Treatment Methods Treatment of Systemic Retinoblastoma • Requires both chemotherapy and radiotherapy • Scleral involvement • Orbital or bony involvement • Involvement beyoned the cut end of the optic nerve • Metastatic disease involving CNS or other sides • Trilateral Rb • Vincristine, Carboplatin, Etoposide (6 to 18 months) • Cyclophosphamide, Etoposide, Vincristine + peripheral stem cell rescue

  23. Treatment of Metastatic Retinoblastoma: Survey of the published literature Doz F et al. J Clin Oncol 1995; 13: 902-9 Namouni et al. Eur J Cancer 1997; 33 (14): 2368-78 Sandri et al. Pediatr Hematol Oncol 1998; 15: 557-61 Advani et al. Med Pediatr Oncol 1999; 22:125-8 Goble et al. Br J Ophthalmol 1990, 74: 97-8

  24. Treatment of Metastatic Retinoblastoma: Survey of the published literature Marec-Berard et al. Antonelli CBG et al. Med Pediatr Oncol 2001; 37: 234 Chantada G et al. Med Pediatr Oncol 2001; 37: 236

  25. Treatment of Metastatic Retinoblastoma: Survey of the published literature Chantada et al. Treatment of overt extraocular retinoblastoma. Med Pediatr Oncol 2003; 40:158-161. Antonelli et al. Extraocular retinoblastoma: a 13-year experience. Cancer 2003; 15(6):1292-8. Matsubara et al. A multidisciplinary treatment strategy that includes high-dose chemotherapy for metastatic retinoblastoma without CNS involvement. Bone Marrow Transp 2005; 35:763-6 Dunkel et al. Successful treatment of metastatic retinoblastoma. Cancer. 2000;89:2117-21

  26. Treatment Methods - Treatment of Systemic Retinoblastoma Metastatic Retinoblastoma in Retinoblastoma in Ankara University Medical School Departments of Pediatric Oncology & Ophthalmology Demographics and Examination Results of Metastatic Retinoblastoma Patients at Presentation Gunduz et al. Ophthalmology 2006; 113: 1558-1566

  27. Treatment Methods - Treatment of Systemic Retinoblastoma Metastatic Retinoblastoma in Retinoblastoma in Ankara University Medical School Departments of Pediatric Oncology & Ophthalmology Demographics and Examination Results of Metastatic Retinoblastoma Patients at Presentation Gunduz et al. Ophthalmology 2006; 113: 1558-1566

  28. Treatment Methods - Treatment of Systemic Retinoblastoma Metastatic Retinoblastoma in Retinoblastoma in Ankara University Medical School Departments of Pediatric Oncology & Ophthalmology Chemotherapy Regimens Used in Metastatic Retinoblastoma Regiman A Weeks 0, 6, 12, 18, 24, 27, 30, 33 Cyclophosphamide (20 mg/kg, day 1) Doxorubicin (0.67 mg/kg, days 1-3) Weeks 3, 9, 15, 21 Carboplatin (560 mg/m2, day 1) Etoposide (3.3 mg/kg, days 1-3) Weeks 36, 39, 42, 45, 48, 51, 54, 57 Cyclophosphamide (30 mg/kg, day 1) Vincristine (0.05 mg/kg, day 1) Intrathecal chemotherapy* (weeks 0, 1, 2, 3, 4, 5, 6, and at every 3 week chemotherapy cycle after week 6) * In patients with central nervous system involvement. Gunduz et al. Ophthalmology 2006; 113: 1558-1566

  29. Treatment Methods - Treatment of Systemic Retinoblastoma Metastatic Retinoblastoma in Retinoblastoma in Ankara University Medical School Departments of Pediatric Oncology & Ophthalmology Chemotherapy Regimens Used in Metastatic Retinoblastoma Regiman B (ICE = ifosfamide, carboplatin, etoposide) Weeks 1, 4, 7, 10, 13, 16 Ifosfamide (1.8 g/m2/day, days 1-5) Carboplatin (560 mg/m2/day, day 1) Etoposide (100 mg/m2/day, days 1-5) (No intrathecal chemotherapy) (Regimen B developed by INCTR Retinoblastoma strategy group) Gunduz et al. Ophthalmology 2006; 113: 1558-1566

  30. Treatment Methods - Treatment of Systemic Retinoblastoma Metastatic Retinoblastoma in Retinoblastoma in Ankara University Medical School Departments of Pediatric Oncology & Ophthalmology Treatment methods, Final Outcomes, and Duration of Follow-up in Metastatic Retinoblastoma Patients Gunduz et al. Ophthalmology 2006; 113: 1558-1566

  31. Retinoblastoma cells in Cerebro- Spinal Fluid

  32. Regression of orbital mass and pre-auricular metastasis after one cycle of ICE chemotherapy

  33. Treatment Methods Orbital Exenteration • Most often used for orbital recurrence after the child has received a maximum acceptable dose of irradiation and chemotherapy Trilateral Retinoblastoma • Bilateral Rb + neuroblastic tumor in the pineal gland or other midline structures • Occurs in children 4 years of age or younger • MRI or CT is essential to the diagnosis • Highly fatal • Chemoreduction may reduce the risk for development of pineoblastoma

  34. Treatment Methods Trilateral Retinoblastoma • Jan 1986 – Dec 2003 • AC Camargo Hospital , Sao Paulo, Brazil 4/470 children with trilateral retinoblastoma, 2 had (+) familial history • 1 pts, unilat, enucleated • 3 pts, bilat, one eye enucleated • Age at diagnosis Rb4, 6, 10, 24 months • All patients died 7, 8, 12 and 12 months after diagnosis • Age at diagnosis of trilateral Rb10, 25, 57, 72 months • Early diagnosis • New therapatic approaches Antonelli CB et al. Ped. Blood &Cancer 2007 Mar;48;306-10

  35. Potential Preparative Chemotherapy Regimens for Stem Cell Transplant for Metastatic Retinoblastomaa All are followed by infusion of autologous stem cells. aMany alternative preparative regimens are available and no current data to support any one as a standard of care.

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