Management of Extraocular Retinoblastoma Nurdan TA YILDIZ

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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

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Education programs
Questionnaire
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Presenting symptoms of patients with Rb in Ankara
University Medical School Department of Pediatric
Oncology
with screening
19 of 91 patients have metastatic Rb
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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

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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.

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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
Retinoblostoma
Retinoblastoma cells in CSF
Optic nerve
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Investigations for Diagnosis of Retinoblastoma
Risk assesment for metastatic disease
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Prognostic Factors
Risk assesment for metastatic disease

• Optic Nerve

Pre-lamina cribrosa
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
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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
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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.
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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

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The Goals of Treatment

• 1) To save childs 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

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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
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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

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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)
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The Role of Adjuvant Chemotherapy in Preventing
Metastasis in High- Risk Retinoblastoma Survey
of the Published Literature
Honavar SG. et al. Arch Ophthalmol 2002
120923-931
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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
120923-931
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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
120923-931
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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 881069-1073
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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 881069-1073
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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

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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
22125-8 Goble et al. Br J Ophthalmol 1990, 74
97-8
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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
40158-161. 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 35763-6 Dunkel et al.
Successful treatment of metastatic
retinoblastoma. Cancer. 2000892117-21
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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
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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
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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
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Retinoblastoma cells in Cerebro- Spinal Fluid
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Regression of orbital mass and pre-auricular
metastasis after one cycle of ICE chemotherapy
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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

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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
Mar48306-10
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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.