Câncer de ovário : doença avançada · Year Jemal et al. CA Cancer J Clin 2009 20 15 10 5 0...
Transcript of Câncer de ovário : doença avançada · Year Jemal et al. CA Cancer J Clin 2009 20 15 10 5 0...
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Câncer de ovário : doença
avançada
Prof. Angélica Nogueira-Rodrigues, PhD
Oncologista ANVISA e UFMG
Presidente EVA, Grupo Brasileiro de Tumores Ginecológicos
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Potenciais conflitos de interessesResolução CFM nº 1.595/2000
• Consultoria– ANVISA (Membro permanente CATEME, CATEBIO e Consultoria Ad hoc)
– Eurofarma
– Roche
• Financiamento de Pesquisas– CNPq, INCA/MS, FAPEMIG
• Palestras e atividades educacionais e Treinamentos– Roche, Eurofarma
• Ações em empresas– Nada a declarar
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Carcinoma epitelial de ovário
• 75% FIGO III e IV
• Altas taxas de
recidiva:
Jemal A, 2011
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Cervix Endometrial Ovarian Vulvar Vagina
Mean Age 52.4 62.9 54.9 66.4 60.9
White vs non White 38.7 vs 61.3% 58 vs 42% 53.4 vs 46.6% 52,6 vs 47.4% 50.2 vs 49.8%
Less than 8 years of
study
97.11 x 2.89% 91.57 x 8.43% 89.24 x 10.76% 97.39 x 2.61% 94.29 x 5.71%
Marital status
(married* x non
married#)
47.77 x 52.22% 47.87 x 52.12% 49.50 x 50,49% 38,26 x 61.73% 43.56 x 56,43%
Most common
Histology
SCC (82.1%); Adeno
12,9% AS 1,1%
Type I 84.8%
CCS 4,1% SPC 2,1 %
CCC 1,6 %
SC 50.3%, MC 22,5%
EC 11,9% CCC 4,5%
SCC 86.8% SCC 73.7%; Adeno
18.3%
Stage I 20,24 vs
II-IV 79.76%
I 51,49 vs
II-IV 48.50%
I-II 37.43 vs
III-IV 62.56%
I-II 44.09% vs III-IV
55,90%
I 20.88% vs II-IV
79.11%
Time to first
treatment >30 days
78,4% 77.5% 45,3% 74,5 74.8%
Paulino e Nogueira-Rodrigues,
2017
Carcinoma epitelial de ovário
Brasil
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Tratamento
Cirurgião
experiente
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Mort
alit
y p
er
100,0
00 w
om
en
1975 1985 1995 2005
Year Jemal et al. CA Cancer J Clin 2009
20
15
10
5
0
AlquilantesPlatina Platina/taxane 1a linha
Platinum-based
therapy
Paclitaxel, gemcitabine,
doxorubicin, topotecan
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Potencialização da ação
citotóxica
• Terceiro quimioterápico 1
• Quimioterapia de manutenção 2
• Aumento de dose 3
Bookman, 2006
Mei L, 2010
Levin, 1993
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Katsumata, 2014
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Modulação terapêutica
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Terapia de primeira linha
SLP mediana com quimioterapiaM
ES
ES
Cisplatina Taxane IP Dose Densa
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Kurman,2008
“CEO”
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Focos atuais de desenvolvimento
terapêutico
Kurman,2008
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EGFR
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Cirurgia Quimioterapia
IA -IIIC
Erlotinibe
Vergote, 2012
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Angiogênese
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Angiogênese no ovário
Órgão saudável Câncer Prova
terapêutica
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Adap BioOncology, 2012
1 Anticorpo
anti-VEGF
(bevacizumabe)
2 Receptores
solúveis
VEGF
(aflibercepte)
3 Anti-VEGFR
(ramucirumabe)
4 Inibidores tirosino quinase
(vatalanibe, sunitinibe,
vandetanibe)
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Burger et al.
GOG-0218
Placebo q3w
Placebo q3wBev 15mg/kg
Bevacizumabe15mg/kg q3w
●Estágio III ótimo
(macroscópico)
●Estágio III subótimo
●Estágio IV
N=1.873
15 meses
Paclitaxel 175mg/m2
Carboplatina AUC6
Carboplatin AUC6
Paclitaxel 175mg/m2
Carboplatin AUC6
Paclitaxel 175mg/m2
1:1:1
R
A
N
D
O
M
I
Z
A
I
II
III
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GOG 218: sobrevida livre de
progressão
0 6 12 18 24 30 36 42 48
SLP
1.0
0.8
0.6
0.4
0.2
0
Tempo (meses)
CP + Bev15 Pl (Arm II)
CP + Pl Pl (Arm I)
CP + Bev15 Bev15 (Arm III)
I
CP + Pl
Pl
(n=625)
SLP mediana meses 10.6
HR
(95% CI)
p value one-sided (log rank)
II
CP + Bev15
Pl
(n=625)
11.6
0.89
(0.78–1.02)
0.0437*
III
CP + Bev15
Bev15
(n=623)
14.7
0.70
(0.61–0.81)
<0.0001*
Burger et al.
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Ferriss 2014
Ascite: biomarcador preditivo
Placebo q3w
Bevacizumabe15mg/kg q3w
Ascite + (>50Ml)
versus
Ascite -
15 meses
Paclitaxel 175mg/m2
Carboplatina AUC6
Carboplatin AUC6
Paclitaxel 175mg/m2
1:1
I: 581
III: 570
• Presente em 79% dos pacientes GOG 218
• Preditor independente de pior SG
• Preditor de benefício em SG com bevacizumabe (HR 0,82; IC 0,7-
0,96; p=0,01)
• Dado com limitações
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ICON 7
Perren, et al.
Paclitaxel 175 mg/m2
Carboplatina AUC 5 or 6
Carboplatina AUC 5 or 6
Paclitaxel 175 mg/m2
18 ciclos (12 meses)
R
Bevacizumabe 7.5 mg/kg q3w
1:1
• FIGO estágio I–IIA alto
risco
ou
• FIGO estágio IIB–IV
n=1528*
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ICON 7: SLP
CP
CP +
Bev7.5 Bev7.5
Eventos, n (%) 464 (61) 470 (62)
Mediana, meses 17.4 19.8
Log-rank test p=0.04
HR (95% CI) 0.87 (0.77–0.99)
Time (months)
17.4 19.8
764
764
693
716
474
599
350
430
221
229
114
107
39
27
CP
CP + Bev7.5
Bev7.5
0 3 6 9 12 15 18 21 24 27 30 33 36
1.00
0.75
0.50
0.25
0
Perren et al.
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Sobrevida global por estratos de
risco
Control, non-high risk
Research, non-high risk
Control, high risk
Research, high risk
1.00
0.75
0.50
0.25
0
Pro
po
rtio
n a
live
Time (months)
0 6 12 18 24 30 36 42 48 54 60
HR 1.14
(0.93–1.40)
37% events
HR 0.78
(0.63–0.97)
66% events
Beva exposure
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QT citotóxicaQT IPInib. angiogênese
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GOG-0262
Paclitaxel q3w (175mg/m2)
Carboplatin AUC 6
Carboplatin AUC 6
Paclitaxel weekly (80mg/m2)
Suboptimally debulked
(>1cm) FIGO stage II–IV
EOC, PP or FTC
n=625
Bevacizumab 15mg/kg q3w
CP for 6 cycles
Bevacizumab 15mg/kg q3w
PD
PD
Randomisation
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GOG-0262: SLP estratificada por uso de
bevacizumabe
Bev
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GOG-252
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Conclusões Ovário Primeira linha
• QT IP aumenta SG pós ressecção ótima e após qt neoadjuvante
• QT dose densa aumenta SG DR> 1cm
• Bevacizumabe combinado à qt e em manutenção aumenta SLP e
possivelmente SG em pacientes de alto risco
• Ascite é um possível biomarcador preditivo de resposta
• Pazopanibe e nindetanibe aumentam SLP
• QT dose densa associado a bevacizumabe é seguro, mas sem
benefício
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Perspectivas
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Análise Molecular no subgrupo de cancer de ovário seroso de alto
grau como preditor de resposta a Bevacizumab.
J Clin Oncol 32:5s, 2014 (suppl; abstr 5502)
25% 31% 44%
Univariada: HR = 0.47 [0.32-0.71], p < 0.001
Multivariada HR = 0.52 [0.33-0.81], p = 0.004
PFS
Univariada: HR = 0.45, [0.26-0.79], p =0.005
Multivariada HR = 0.53 [0.29-0.96], p = 0.04
OS
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Bevacizumabe 15mg/kg 21/21 dias, 30m
AGO-OVAR 17 (BOOST)
Paclitaxel 175mg/m2
Carboplatina
AUC5
Carboplatina AUC5
CP x 6 ciclos
Paclitaxel 175mg/m2
Bevacizumabe 15mg/kg
21/21d,15m
FIGO IIb–IV
(micro- ou macro)
EOC, PP or FTC
(n=796)
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TCGA, 2011
• Inconstância genômica inter-pacientes
Ovário molecular 2018
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