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IdealizaçãoRealização
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Célia Beatriz Gianotti Antoneli
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Comitê do Protocolo Brasileiro de Retinoblastoma 2020
Carla Macedo IOP-GRAACC
Célia Beatriz Gianotti Antoneli Universidade 9 de julho
Karina de Cassia Braga Ribeiro Casa de Saúde Santa Marcelina / TUCCA
Maristela Bergamo HC Ribeirão Preto
Maristela Palazzi Centro Infantil Boldrini
Nathalia Grigorovski INCA-RJ
Neviçolino P. de Carvalho Filho A C Camargo Cancer Center
Simone Aguiar Casa de Saúde Santa Marcelina / TUCCA
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Comitê do Protocolo Brasileiro de Retinoblastoma 2020
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Tópicos
Resultados do SurveyInfra-estrutura para tratamento do RB no Brasil (21 respostas)
Baixa adesão
82 instituições credenciadas para atendimento em Oncologia Pediátrica pelo SUS
Proposta de estudo epidemiológicoFatores de risco para desenvolvimento de RB
Idade paterna/materna
Tabagismo materno
Poluição associada ao trânsito
Nível socioeconômico
Raça/etnia
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Objetivos principais
Avaliação global dos casos de retinoblastoma no Brasil
Avaliar a resposta do uso de ciclofosfamida, doxorrubicina e vincristina em
pacientes classificados com grupo Murphree C e D sem resposta após 4 ciclos de
CEV (Carboplatina, Etoposide, Vincristina)
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Objetivos principais
Avaliação da sobrevida global e livre de evento em pacientes com doença
metastática IRSS- IV submetidos a transplante de células tronco hematopoiéticas .
Identificar as dificuldades regionais dos centros de tratamento de retinoblastoma e
promover educação e capacitação da equipe interdisciplinar envolvida no tratamento
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Objetivos secundários
• Avaliar a correlação entre variáveis demográficas e sócio-econômicas (procedência,
idade dos pais, tabagismo, nível de escolaridade dos pais, raça/etnia) com atraso
diagnóstico e extensão de doença
• Avaliação fatores histopatológicos para recaída locorregional e à distância pós
enucleação com e sem tratamento prévio
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Fatores de risco histopatológico
Infiltração do nervo óptico
Infiltração de coroide
Infiltração de esclera
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0
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Desafios na Identificação dos fatores de risco
▪Variações no processamento das amostras e interpretação da patologia
▪Falta de critérios uniformes universalmente aceitos para definição dos fatores derisco
▪Número de pacientes que desenvolvem doença metastática após enucelação épequeno; estudos randomizados não são factíveis
Chintagumpala M., 2017
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Fatores de risco
▪Invasão uveal posterior (incluindo invasão da coroide)
▪Qualquer grau de comprometimento de coroide e nervo óptico
▪Invasão pós laminar do nervo óptico – fator independente
▪Invasão de esclera
▪Sementes na câmara anterior
▪Infiltração do corpo ciliar
▪Infiltração da íris
Somente alguns desses fatores de
risco são candidatos a tratamento
adjuvante
Chintagumpala M., 2017
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Fatores de risco histopatológicos de acordo com as estruturas oculares
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Infiltração pós laminar do nervo óptico
Estados Unidos (COG) – 6 ciclos de CEV
França – 4 ciclos de quimioterapia
Argentina
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Infiltração maciça da coróide
França – 4 ciclos de quimioterapia
Estados Unidos – qt adjuvante
Argentina – se associado PLONI
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PLONI
Esclera
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Nenhum tratamento adjuvante
Infiltração focal da coróide Infiltração pré laminar/laminar
do nervo óptico
Infiltração de câmara anterior
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Retinoblastoma
Gender - male: 54.6%
Age - mean : 28.8 mo (0 – 219 mo)
Race: white 71%
Familial history : 9%
Laterality: unilateral = 65.8% bilateral = 34.2%
Extension: intraocular = 72% extraocular = 28%
Lag time: mean: 5.5 months (0- 48 months)
1986-2005 = 923 cases
Ciope - Central Informatizada de Oncologia
Pediátrica
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85.4%
Retinoblastoma
5-year overall survival
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Cases – 923 / 1986-2005
60%
94.2%
p < 0.001
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AHOPCA
GALOP
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Setting 1 – Registry and Counseling AHOPCA II
cT2-cT3a,b, d, e IRSS III (cT4a and T4b)
Enucleation
cT3c [buphthalmia] or any cTwith risk of abandonment)
Neoadjuvant chemo
Pathology
Low riskIRSS Stage I (pT1-pT2a)
Adjuvant: 6 cycles CEV + Orbital EBRT
Observation
Chemotherapy: CEV (carboplatin/etoposide/vincristine)Palliative chemo (morphine/steroids/oral etoposide or
cyclophosphamide/NSAIDS)
Adjuvant: 6 cycles CEV
IRSS Stage II (pT4)
High risk IRSS stage I(pT2b, pT3a, pT3b, pT3c,
pT3d)
2-3 cycles CEV
Enucleation
Pathology
IRSS Stage II (pT3d,pT4)
IRSS Stage I
Complete 6 cycles of CEV
Adjuvant : complete 6 cycles CEV + EBRT^
Neoadjuvant chemo CEV x 3 cycles
Enucleation
Adjuvant: complete 6 cycles CEV + EBRT
IRSS IV(outside orbit, CNS, lung BM
and/or bone)
Palliative Care
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Setting 2 – AHOPCA III
cT2-cT3a,b, d, e)IRSS III-IVa(cT4a and T4b)
Enucleation
cT3 c(massive buphthalmus)
Neoadjuvant chemo
Pathology
IRSS I Low risk(pT1-pT2a)
Adjuvant: CEV/VDC+ EBRT
Observation
* pT3d will receive orbital EBRTChemotherapy: CEV (carboplatin/etoposide/vincristine)/VDC (vincristine/doxorubicin/cyclophosphamide)EBRT (external beam radiation therapy)
Palliative chemo (morphine/steroids/oral etoposide or cyclophosphamide/NSAIDS)
Adjuvant: 6 cycles CEV
IRSS Stage II(pT4)
IRSS I High risk (St A)
(pT2b, pT3a, pT3b, pT3c,
PT3d*)
2-3 cycles CEV
Enucleation
Pathology
IRSS II (pT3d,pT4) IRSS I
Complete 6 cycles of CEV/VDC
Adjuvant: complete 6 cycles CEV/VDC +
EBRT
Neoadjuvant chemo x 3 CEV cycles
Enucleation
Adjuvant: complete 6 cycles CEV/VDC + EBRT
IRSS IVb
Palliative Care^^
Any cT IRSS I (risk of abandonment)
Neoadjuvant chemo
2-3 cycles CEV
Enucleation
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Setting 3 – GALOP II
cT3a-cT3b-cT3d
cT1b-cT2b
Enucleation
cT3c(massive buphthalmus)
Neoadjuvant chemotherapy
Pathology
IRSS I Low risk
(pT1-pT2, pT3a)
Adjuvant: 8 cycles JET-VIC +IT + EBRT
Observation
#: EBRT: Only patients with tumor at the resection margin at the optic nerve stump. Those stage II because of trans-scleral invasion will be treated with chemotherapy onlyJet: Carboplatin 400 mg/m2/days 1-2, etoposide 100 mg/m2/days 1-3. VIC: Vincristine 1.5 mg/m2/day1, idarubicin 10 mg/m2/day 1, cyclophosphamide 65 mg/kg/day 1 (+MESNA)JET: Carboplatin 500 mg/m2/days 1-2, etoposide 100 mg/m2/days 1-3. IT: Topotecan 0.4 mg weeks 0,3,6,9
Adjuvant: 6 cycles Jet-VIC + IT
IRSS Stage II(pT4 #)
IRSS I High risk
(pT3b, pT3c, pT3d)
2 cycles JET-VIC + IT
Enucleation
Pathology
IRSS II (pT4) IRSS I
Adjuvant: Complete 8 cycles of JET-VIC +IT
Adjuvant: Complete 8 cycles of JET-VIC +IT
+ EBRT
Intra-arterial chemotherapy
IRSS III-IV
INDIVIDUALIZED THERAPY
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Pathology Criteria
Setting 3. Pathology Criteria
The path report must explicitly mention the state and presence of tumor in the following ocular structures and coats, including the optic nerve Histopathologic definitions:
Optic Nerve involvement:Prelaminar: if the tumor touches but does not cross the lamina cribrosaLaminar: if the tumor penetrates but does not cross the la lamina cribrosaPost-laminar: if the tumor crosses the lamina cribrosa but negative at optic nerve cut end Level of the post optic never cut: describe if positive or negative and if meninges included or not.
Sclera: if it invades or not the sclera, if it crosses the entire sclera it is considered orbital disease. Episcleral veins: if invasion or thrombus in the vein. Ciliary body or iris: tumor in the ciliary body, disruption of the membrane (does NOT include neovascularization). Anterior chamber: tumor inside the anterior chamber (cells or mass)
Choroid: Focal invasion: any tumor in the choroid that is Not massive as described below.. Massive Invasion: When any area of the choroid has 3mm or more of invasion, in diameter or along the thickness of
the choroid without invading the sclera.
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PROPOSTAS
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Retinoblastoma intra-ocular
Unilateral Unifocal
A B C D E
Classificação de Murphree
Terapia local EnucleaçãoQuimioterapia
Intra-arterial
Melfalan
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Idade
Droga
3-6 meses 6-12 meses 1-3 anos > 3 anos Dose máxima
Melfalan 2,5 mg 3 mg 4 mg 5 mg 0,5 mg/kg
Topotecan 0,5 mg 1 mg 1 mg 1 mg 1 mg
Carboplatina Não recomendado 40 mg 50 mg 50 mg 50 mg
Retinoblastoma intra-ocular
Unilateral Unifocal
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Femoral comum > Ilíaca externa > Ilíaca comum > Aorta abdominal > Aorta torácica > Arco aórtico > Carótidacomum > Carótida interna > Oftálmica
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TUMORES INTRA-OCULARES
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Murphree B
Reavaliação com fundo de olho a cada 2 ciclos
6 ciclos de
Carboplatina e
Vincristina
Tratamento
oftalmológico local
(TTT/crio)
DE – associar Etoposide
PD – indicar QT-ia/enucleação
Braquiterapia
Carboplatina – 540 mg/m2 d1
Vincristina – 1,5 mg/m2 d1
Etoposide – 150 mg/m2 d1 e d2
Retinoblastoma intra-ocular unilateral unifocal
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Murphree C
Reavaliação com fundo de olho a cada 2 ciclos
6 ciclos de
Carboplatina,
Vincristina e
Etoposide
Tratamento
oftalmológico local
(TTT/crio)
DE – Ciclofasfamida, Doxorrubicina, Vincristina
PD – indicar QT-ia/enucleação
QT intra-vítrea
Braquiterapia
Carboplatina – 540 mg/m2 d1
Vincristina – 1,5 mg/m2 d1
Etoposide – 150 mg/m2 d1 e d2
Ciclofosfamida
Vincristina
Doxorrubicina
Retinoblastoma intra-ocular unilateral unifocal
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Murphree D
Reavaliação com fundo de olho a cada 2 ciclos
6 ciclos de
Carboplatina,
Vincristina e
Etoposide
Tratamento
oftalmológico local
(TTT/crio)
DE – Ciclofasfamida, Doxorrubicina, Vincristina
PD – indicar QT-ia/enucleação
QT intra-vítrea
Carboplatina – 540 mg/m2 D1
Vincristina – 1,5 mg/m2 D1
Etoposide – 150 mg/m2 D1 e D2
Ciclofosfamida
Vincristina
Doxorrubicina
Retinoblastoma intra-ocular unilateral unifocal
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Murphree E Enucleação
IRSS I
sem fator de risco
IRSS I
com fator de risco
Carboplatina – 540 mg/m2 d1
Vincristina – 1,5 mg/m2 d1
Etoposide – 150 mg/m2 d1 e d2
Follow-up
6 ciclos de Carboplatina, Vincristina
e Etoposide
• Infiltração de nervo óptico
pós laminar
• Coroide mais nervo pos
laminar
• Esclera sem traspor
IRSS II• Margem de secção do coto
do nervo óptico positiva
• Invasão trans-escleral
4 ciclos de Cisplatina, Vincristina,
Ciclofosfamida e Etoposide Radioterapia
externa 4.600 cGy
Retinoblastoma intra-ocular unilateral unifocal
Cisplatina – 105 mg/m2 d1
Vincristina – 1,5 mg/m2 d1
Ciclofosfamida – 1950 mg/m2 d2 e d3
Mesna – 1950 mg/m2 d2 e d3
Etoposide – 150 mg/m2 d2 e d3
Filgrastim – a partir do d4 ate N > 1.000
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Retinoblastoma
Bilateral / Multifocal
• Classificar conforme estadiamento de Murphree / IRSS
• Menores de 3m ou < 6Kg iniciar com quimioterapia sistêmica
• Sempre iniciar o tratamento conforme maior estadiamento
• QT-ia a partir 3 meses de vida ou > 6Kg; bilateral/concomitante
• A prosposta de quimioterapia EV (drogas e doses) é a mesma dos unilaterais
na impossibilidade de qt-ia
• Radioterapia sempre que possível deve ser proscrita
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TUMORES EXTRA-OCULARES
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Disseminação Local Calota Craniana
Gânglios Cervicais
Retro Auricular
Mandíbula
Parótidas
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Disseminação SNC
Extensão direta do tumor pelo NO
Espaço subaracnoideo (disseminação leptomeníngea)
Disseminação hematogênica para parênquima ou para vertebral
Raramente ao SNC por via óssea
TRILATERAL: pode se disseminar pelo LCR, disseminação leptomeníngea
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Disseminação Hematogênica
Medula Óssea
Fígado
Ossos
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Exames de Estadiamento
Fundo de olho sob anestesia
RNM de crânio, órbita, pescoço e coluna total
Mielograma e BMO bilaterais
Cintilografia óssea com Tecnécio
LCR
US abdome total
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Fundo olho sob narcose
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RNM crânio e órbita
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RNM crânio, órbita e pescoço
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RNM crânio e órbitaRNM corpo total
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RNM de coluna total
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Cintilografia Óssea com Tecnésio
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LCR
• IMUNOCITOLOGIA • GD2 ou • CRX (RNA mensageiro do fator de
transcrição cone-rode homeobox)
• CITOMETRIA DE FLUXO • CD45 negativo• CD56 positivo.
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Medula Óssea• Mielograma - MO bilateralmente infiltrada
77,2% por células anômalas à medula, de linhagem não hematopoiética
• Bx MO - Comprometimento maciço bilateralmente por células de Retinoblastoma.
• IMH - infiltração neoplásica bilateral
(enolase, sinaptofisina +)
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Buftalmo
IRSS I
Carboplatina – 540 mg/m2 d1
Vincristina – 1,5 mg/m2 d1
Etoposide – 150 mg/m2 d1 e d2
4 ciclos de Carboplatina, Vincristina
e Etoposide
IRSS IImargem de secção do
coto do nervo óptico
positiva
4 ciclos de Cisplatina, Vincristina,
Ciclofosfamida e Etoposide Radioterapia –
4.600 cGy
Alteração sinal suspeita de invasão microscópica do nervo óptico na
ressonância magnética
2 ciclos de Carboplatina, Vincristina e Etoposide
Enucleação
Cisplatina – 105 mg/m2 d1
Vincristina – 1,5 mg/m2 d1
Ciclofosfamida – 1950 mg/m2 d2 e d3
Mesna – 1950 mg/m2 d2 e d3
Etoposide – 150 mg/m2 d2 e d3
Filgrastim – a partir do d4 ate N > 1.000
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Retinoblastoma extra-ocular
IRSS IV-b 4 ciclos de Cisplatina, Vincristina,
Ciclofosfamida e EtoposideEnucleaçãopós 2 ciclos QT
Radioterapia
TCTH
Se disseminação liquórica
Tratamento Paliativo
Cisplatina – 105 mg/m2 d1
Vincristina – 1,5 mg/m2 d1
Ciclofosfamida – 1950 mg/m2 d2 e d3
Mesna – 1950 mg/m2 d2 e d3
Etoposide – 150 mg/m2 d2 e d3
Filgrastim – a partir do d4 ate N > 1.000
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Retinoblastoma extra-ocular
Cisplatina – 105 mg/m2 d1
Vincristina – 1,5 mg/m2 d1
Ciclofosfamida – 1950 mg/m2 d2 e d3
Mesna – 1950 mg/m2 d2 e d3
Etoposide – 150 mg/m2 d2 e d3
Filgrastim – a partir do d4 ate N > 1.000
Trilateral 4 ciclos de Cisplatina, Vincristina,
Ciclofosfamida e EtoposideRadioterapia
TCTHEnucleação
se necessária
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Children’s Oncology GroupARET-0321
CDDPVCRCTXVP16
CDDPVCRCTXVP16
CDDPVCRCTXVP16
CDDPVCRCTXVP16
RTX4500 cGy
Estadio 2 & 3
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CDDPVCRCTXVP16
CDDPVCRCTXVP16
CDDPVCRCTXVP16
CDDPVCRCTXVP16
TMO
RTXbaseada na
resposta
Estadio 4
Children’s Oncology GroupARET-0321
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Quimioterapia de Indução
DROGA VIA DOSE DIA
Idade < 36 meses Idade 36 meses
VINCRISTINA EV push 0.05 mg/kg/d 1.5 mg/m2/d Dias 0, 7, 14
CISPLATINA EV 6 horas 3.5 mg/kg/d 105 mg/m2/d Dia 0
CICLOFOSFAMIDA EV 1 hora 65 mg/kg/d 1950 mg/m2/d Dias 1 & 2
MESNA* EV 24 horas 40 mg/kg/d 1200 mg/m2/d Dias 1 & 2
ETOPOSIDE EV 1 hora 4 mg/kg/d 120 mg/m2/d Dias 1 & 2
FILGRASTIMA SC 5 mcg/kg/d Dias 3+
Ciclos 1 a 4
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DROGA VIA DOSE DIA
Idade < 36 meses Idade 36 meses
CARBOPLATINA EV 4 horas AUC = 7/d* (max 16.7 mg/kg)
AUC = 7/d* (max 500 mg/m2)
Dia -8 a -6
TIOTEPA EV 3 horas 10 mg/kg/d 300 mg/m2/d Dias -5 a -3
ETOPOSIDE EV 3 horas 8.3 mg/kg/d 250 mg/m2/d Dias -5 a -3
Infusão Cél. Tronco EV 2,5 x 106 CD34+/kg Dia 0
FILGRASTIMA SC 5 mcg/kg/d Dias 1+
Esquema de Condicionamento
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Passado ?
Retinoblastoma
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Campinas, SP
Ribeirão Preto, SP
São Paulo, SP
Rio de Janeiro, RJ
Grupo Brasileiro
Retinoblastoma
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x
?
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Obrigada