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Tratamiento de quimioterapia en primera línea de cáncer ovario avanzado
“Antiangiogénico en cáncer de ovario avanzado. ¿Cuándo recomendar?. Estado actual”
Valeria Caceres, M.D., Ph.D.
Jefa del Departamento de Oncología Clínica
Directora de la Carrera Universitaria de Especialistas en Oncología
Instituto Angel H Roffo
Universidad de Buenos Aires
Abril de 2018
Abordaje de la paciente con cáncerde ovario avanzado
1a línea de tratamiento
Cáncer de ovario según estadío: 2017
*E?: no se indica estadio en la planilla de recolección de datos
4%
16%
5%
58%
17%
E ? (4)
E I (16)
E II (5)
E III (59)
E IV (17)
Edad mediana: 58
N: 101
Cáncer de ovario avanzado : evolución
Tratamiento primario
Estadío III, IV
1°Remisión clínica
Recaída (80%)
Segunda remisión clínica
Recaída (100%)
Cirugía
QMT 1 Línea
Candidata a Platino No candidate a Platino
QMT NA
CDI
Factores pronósticos
El estadío IIIc es un subgrupo heterogéneo
Omental cake Siembra miliar Ascitis
voluminosaGanglios
paraaórticos
IIIC: el cáncer se ha diseminado visiblemente más allá de la pelvis
hasta el abdomen y tiene más de 2 cm, con o sin diseminación a los
ganglios linfáticos retroperitoneales
ENFERMEDAD RESIDUAL
OS
(%
)
100
40
0
60
80
20
Time (months)
0 12 24 36 48 60 72 84 96 108 120 132 144
>10mm (n=1,105)
1–10 mm (n=975)
0 mm (n=1,046)
Pacientes con FIGO III/IV y enfermedad residual necesitan
mejores tratamientos
Pacientes con enfermedad residual tienen pobre OS1
Overall survival by debulking status1–10 mm vs 0 mm:
HR (95% CI)
2.70 (2.37–3.07)
>10 mm vs 1–10 mm:
HR (95% CI)
1.34 (1.24–1.49)
p<0.0001
Data combined from 3 randomised controlled trials performed by AGO-OVAR together with GINECO,
n=3,388.Patients enrolled had FIGO stage IIb–IV epithelial ovarian cancer.1. Du Bois, et al. Cancer 2009
VOLUMEN TUMORAL INICIAL
Volumen tumoral como factor pronóstico
• GOG demonstrated that stage III with large-volume
ovarian cancer before undergoing optimal cytoreduction
had a worse prognosis [1].
• SCOTROC showed that a clinically significant PFS
benefit with optimal surgery in stage IIIC to IV disease
was limited to patients with less-advanced disease [2].
• Eisenkop et al. observed that the need to remove a large
number of peritoneal implants correlates with biological
aggressiveness and diminished survival, but not
significantly enough to preclude long-term survival [3,4].
1. Hoskins WJ. The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic
Oncology Group study. Gynecol Oncol. 1992; 47:159–66. [PubMed: 1468693]
2. Crawford SC, Vasey PA, Paul J, Hay A, Davis JA, Kaye SB. Does aggressive surgery only benefit patients with less advanced ovarian cancer? Results from an
international comparison within the SCOTROC-1 Trial. J Clin Oncol. 2005; 23:8802–11. [PubMed: 16314640]
3. Eisenkop SM, Spirtos NM, Friedman RL, Lin WC, Pisani AL, Perticucci S. Relative influences of tumor volume before surgery and the cytoreductive outcome on
survival for patients with advanced ovarian cancer: a prospective study. Gynecol Oncol. 2003; 90:390–6. [PubMed: 12893206]
4. Eisenkop SM, Spirtos NM, Friedman RL, Lin WC, Pisani AL, Perticucci S. Relative influences of tumor volume before surgery and the cytoreductive outcome on
survival for patients with advanced ovarian cancer: a prospective study. Gynecol Oncol. 2003; 90:390–6. [PubMed: 12893206]
Upper abdominal disease cephalad to the
greater omentum (UAD) • UAD was defined as metastatic implants involving the diaphragm,
liver, porta hepatis, spleen, pancreas, stomach, celiac axis, and lesser
sac.
• The presence and volume of UAD is a marker for the general intra-
abdominal tumor burden and carcinomatosis.
• UAD is associated with adverse prognostic and tumor-volume factors
such as large-volume ascites and highly elevated serum CA-125
levels,
• 526 patients with FIGO stage IIIC ovarian cancer undergoing primary
cytoreductive surgery followed by intravenous or intraperitoneal
platinum-based chemotherapy from January 1, 1989 to December 31,
2006.
• The presence and size of UAD at the beginning of exploratory surgery
was collected
Zivanovik et al: Gynecol Oncol. 2010 March ; 116(3): 351–357.
doi:10.1016/j.ygyno.2009.11.022.
Población se dividió en tres grupos• First group: patients with no visible or palpable UAD on
exploration;
• Second group: patients with minimal UAD (1 cm or less);
• Third group: patients with bulky UAD (larger than 1 cm)
Optimal cytoreduction: 104/125 (83%), 106/158 (67%), and 104/243 (42%)
Zivanovik et al: Gynecol Oncol. 2010 March ; 116(3): 351–357. doi:10.1016/j.ygyno.2009.11.022.
PFS por grupo
First group: patients with no visible or
palpable UAD on exploration;
Second group: patients with minimal
UAD (1 cm or less)
PFS por grupo
PFS por grupo
Third group: patients with bulky UAD (larger than 1 cm)
Pronóstico en pacientes sin enfermedad residual
Hamilton et al. Gynecol Oncol 2011
Regimen I (control)
Paclitaxel 175 mg/m2 IV (3 h)
d 1
Carboplatin AUC 6 IV
d 1
Regimen II (triplet A)
Paclitaxel 135 mg/m2 IV (3 h)
d 1
Carboplatin AUC 5 IV
d 1
Gemcitabine 800 mg/m2/d IV
d 1, 8Regimen III (triplet B)
Paclitaxel 135 mg/m2 IV (3 h)
d 1
Carboplatin AUC 5 IV
d 1
Doxil 30 mg/m2 IV d 1
Every other cycle
Regimen IV (sequential module A)
Carboplatin AUC 5 IVd 3
Topotecan 1.25 mg/m2/d IV
d 1-3
Regimen V (sequential module A)
Carboplatin AUC 6 IV
d 8
Gemcitabine 1000 mg/m2/d IV
d 1, 8
Regimen IV (sequential module B)
Paclitaxel 175 mg/m2 IV (3 h)
d 1
Carboplatin AUC 6 IV
d 1
Regimen V (sequential module B)
Paclitaxel 175 mg/m2 IV (3 h)
d 1
Carboplatin AUC 6 IV
d 1
Randomization
• All patients
• Equal proportions
on each regimen
• Primary end points:
PFS, OS, RR
GOG 182-ICON5: Estadíos III/IV
Regimens I, II, and III: 8 cycles, 21-d cycle
interval
Regimens IV and V: 4 cycles, 21-d cycle
interval
Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002.
GOG = Gynecologic Oncology Group; ICON = International
Collaborative Ovarian Neoplasm Group; OS = overall survival;
PFS = progression-free survival; RR = response rate
GOG0182-ICON5: PFS y OS
Median PFS and HR (95% CI)
16.1 1.00016.4 0.990 (0.884-1.107)16.4 0.998 (0.891-1.117)15.3 1.094 (0.979-1.224)15.4 1.052 (0.940-1.176)
Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002.
C = carboplatin
D = pegylated liposomal doxorubicin
G = gemcitabine
P = paclitaxel; PFS = progression-free survival
T = topotecan
Median OS and HR (95% CI)
40.0 1.00040.4 0.978 (0.838-1.141)42.8 0.972 (0.832-1.136)39.1 1.068 (0.918-1.244)40.2 1.035 (0.888-1.206)
Carga de enfermedad (DS) y Score de Complejidad
quirúrgica (CS): GOG 182
• Carga de enfermedad (DS)
– DS Bajo: pelvis y retroperitoneo
– DS Moderado: Enfermedad abdominal adicional sin abdomen
alto
– DS Alto: enfermedad abdominal alta con compromiso del
diafragma, bazo, hígado ó páncreas
• Score de Complejidad quirúrgica (CS)
Procedimientos individuales que componen un score que se suma
en cada paciente
– CS Bajo: Score 1 a 3
– CS Moderado : Score 4-7
– CS Alto: score >8
Horowitz NS, JCO 2014,56,3106
DS: Impacto en PFS y OS: datos del GOG0182
Un DS bajo se asocia a PFS y OS mas prolongadas
Enfermedad residual por DS: PFS y OS: Datos del
GOG 0182
• R0 se asocia a mejor evolución
• Sin embargo RO, fue significativo solo en pacientes con
DS bajo
• Las pacientes RO DS alto se comportan como las de DS
Bajo con residuo
2004 GCIG quimioterapia standard de 1 línea
La rama standard de tratamiento debe contener un
taxano y una sal de platino por 6 ciclos
El regimen recomendado es paclitaxel (175 mg/m2) y
carboplatino (AUC 5-6) cada 3 semanas.
La PFS media es de 15.4-16.4 meses
La OS a 5 años de 30-35%
Es aceptable adiciones ó variaciones en la dosis, esquema o ruta
de administración y deben ser avaladas al menos por un estudio
clínico que demuestre superioridad o no inferioridad a
taxano/platino
3rd Ovarian Cancer Consensus Conference
September 3–5, 2004
Baden-Baden, Black Forest, Germany
Bookman, M. A. Et all. J Clin Oncol; 27:1419-1425 2009
Cáncer de ovario avanzado QT 1ª línea:
Intentos “fallidos” de mejorar resultados
Carboplatino AUC 5-7.5 + paclitaxel 175 mg/m2
Tripletes: 6 GCIG triales, 4 drogas y…≈10,000 pacientes
Dobletes secuenciales
Sustitución de paclitaxel: SCOTROC (docetaxel); MITO-2
(PLD): igual RR, PFS y OS (diseño de superioridad)
Consolidación/ Mantenimiento: SWOG 9701
Cáncer de ovario avanzado QT 1ª línea:
Intentos “exitosos” de mejorar resultados:
Administración intraperitoneal: GOG-104,114, 172, GOG 252
HIPEC
Paclitaxel dosis densas: NCT00226915
Nuevas terapias: antiangiogénicos
Alberts, N Engl J Med 1996 Dec 26 335(26)1950-5
Amstrong,N Engl J Med 2006 Jan 5 354(1)34-43
MarkmanJ Clin Oncol 2001 Feb 15 19(4)1001-7
Katsumata Lancet 2009 Oct 17 374(9698)1331-8
Cáncer de ovario avanzado QT 1ª línea:
Intentos “exitosos” de mejorar resultados:
Administración intraperitoneal
Alberts, N Engl J Med 1996 Dec 26 335(26)1950-5 Amstrong,N Engl J Med 2006 Jan 5 354(1)34-43
MarkmanJ Clin Oncol 2001 Feb 15 19(4)1001-7 Katsumata Lancet 2009 Oct 17 374(9698)1331-8
Datos maduros del GOG 172
110 meses
Limitaciones y
complicaciones del
GOG-172
QoL por FACT-O empeora al
final del 3 y 6 ciclo
8% nunca empezaron
34% recibió solo 1 ó 2 ciclos
Solo un 42% de las pacientes
completaron los 6 ciclos
planeados
NO factible en la mayoría de los pacientes
A PHASE III CLINICAL TRIAL OF BEVACIZUMAB
WITH IV VERSUS IP CHEMOTHERAPY IN OVARIAN,
FALLOPIAN TUBE AND PRIMARY PERITONEAL
CARCINOMA NCI-SUPPLIED AGENT(S):
BEVACIZUMAB (NSC #704865, IND #7921)
NCT01167712 a GOG/NRG Trial (GOG 252)
Joan L. Walker; Mark F Brady; Paul A Di Silvestro; Keiichi
Fujiwara; David Alberts; Wenxin Zheng; Krishnansu Tewari;
David E Cohn; Matthew Powell; Linda van Le; Stephen
Rubin; Susan A Davidson; Heidi J Gray; Steven Waggoner;
Tashanna Myers; Carol Aghajanian; Angeles Alvarez Secord;
Robert S Mannel
GOG 252: IP chemo and dose dense Paclitaxel
showed improved OS, both have toxicities; which is
best?
• 1560 patients
• Stage III-84%
• Stage II-10%
• Grade 3 Serous –72%
Across Study Comparisons for PFS
Paclitaxel semanal en cáncer de ovario
Estudio JaponésJapanese Gynecologic Oncology Group Trial
FIRST LINE
Stage II – IV
OVARIAN CANCER
(including primary
peritoneal fallopian
tube)
R
A
N
D
O
M
I
Z
E
Paclitaxel 180 mg/m2 day 1
Carboplatin AUC 6 day 1
Paclitaxel 80 mg/m2 days
1,8,15 Carboplatin AUC 6
day 1
q 3w
6 – 9 cycles
q 3w
6 – 9 cycles
Primary endpoint: PFS
Total accrual: 637 patients
Katsumata N, et al. Lancet. 2009;374(9698):1331-1338.
Katsumata N. et al .Lancet Oncol 2013; 14: 1020–26
Paclitaxel semanal en cáncer de ovarioEstudio Japonés
Lancet Oncol 2013; 14: 1020–26
Median PFS28.2 months vs 17.5 months
(HR 0.76, 95% CI 0.62–0.91; p=0.0037).
Median OS100.5 vs 62.2 months
(HR 0.79, 95% CI 0.63–0.99; p=0.039).
Estudios confirmatorios: GOG 262, MITO-7, ICON-8
• 62% (dd) vs 73% recibieron > 6 ciclos
• 36% (dd) vs 22% discontinuaron tto debido a AEs
R
an
do
m
Strata:
•Center
•PS (0, 1, 2)
•Residual disease after surgery
(absent, 1 cm, 1 cm, no surgery)
Control arm
Carboplatin AUC 6, d1 q21
Paclitaxel 175 mg/m2, d1 q21
Treatment repeated for 6 cycles
Experimental arm
1:1
MITO 7: diseño del estudio
Carboplatin AUC 2, d1, 8, 15 q21
Paclitaxel 60 mg/m2, d1, 8, 15 q21
Treatment repeated for 6 cycles
ClinicalTrials.gov NCT00660842
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18Weeks
Presented by: S.PignataPignata et al. Lancet Oncol. 2014 Apr;15(4):396-405
0 6 12 18 24 30 36 42 48
Months
0.0
0.2
0.4
0.6
0.8
1.0
Pro
babili
ty o
f pro
gre
ssio
n-f
ree s
urv
ival
Patients Events
Median PFS
Months (95% CI)
Every 3-week 403 214 16.5 (14.6 – 20.0)
Weekly 405 196 18.8 (17.1 – 22.0)
Log-rank test p = 0.18
Unadjusted HR: 0.88 (0.72 – 1.06)
Analysis: March 2013, median follow-up 19.9 months
PFS
Patients at risk
Every 3-week 403 354 217 118 72 38 14 1 -
Weekly 405 346 231 124 71 36 20 9 -
Presented by: S.PignataPignata et al. Lancet Oncol. 2014 Apr;15(4):396-405
0 6 12 18 24 30 36 42 48
Months
0.0
0.2
0.4
0.6
0.8
1.0
Pro
ba
bili
ty o
f su
rviv
al
Patients Events
Median OS
Months (95% CI)
Every 3-week 403 76 47.9 (47.9 – n.a.)
Weekly 405 89 n.a. (36.3 – n.a.)
Log-rank test p = 0.24
Unadjusted HR: 1.20 (0.88 – 1.63)
OS
Patients at risk
Every 3-week 403 380 303 193 120 75 31 5 2
Weekly 405 372 294 190 123 68 32 10 -
Presented by: S.Pignata
Analysis: March 2013, median follow-up 19.9 months
Pignata et al. Lancet Oncol. 2014 Apr;15(4):396-405
MITO 7
esmo.org
ICON8: A GCIG PHASE III RANDOMISED TRIAL EVALUATING WEEKLY DOSE-DENSE CHEMOTHERAPY INTEGRATION IN FIRST-LINE EPITHELIAL OVARIAN/FALLOPIAN TUBE/PRIMARY PERITONEAL CARCINOMA (EOC) TREATMENT: RESULTS OF PRIMARY PROGRESSION FREE SURVIVAL (PFS) ANALYSISA. Clamp1, I. McNeish2, A. Dean3, D. Gallardo4, J.W. Kim5, D.M. O’Donnell6, J. Hook7, C. Coyle8, S. Blagden9, J. Brenton10, R. Naik11, T. Perren7, S. Sundar12, A. Cook13, E. James13, A.M. Swart14, S. Stenning13, R. Kaplan13, J. Ledermann15
1The Christie NHS Foundation Trust, Manchester, UK; 2Institute of Cancer Sciences, University of Glasgow, UK; 3Oncology, St. John of God Hospital, Subiaco, Australia; 4Clinical Oncology, Instituto Nacional de Cancerologia, Mexico; 5Obstetrics and Gynaecology, Seoul National University Hospital, Seoul, Korea; 6Cancer Trials Ireland, Dublin, Ireland; 7St. James’s University Hospital, Leeds, UK; 8Imperial College London, Charing Cross Hospital, London, UK; 9Churchill Hospital, University of Oxford, Oxford, UK; 10Li Ka Shing Centre, Cancer Research UK, Cambridge Research Institute, Addenbrookes Hospital, Cambridge, UK; 11Gynaecology Oncology Centre, Queen Elizabeth Hospital, Gateshead, UK; 12Gynaecology Cancer Centre, University of Birmingham, Birmingham, UK; 13MRC Clinical Trials Unit, Institute of Methodology, UCL, London, UK; 14Norwich Medical School, University of East Anglia, Norwich, UK; 15Cancer Research UK & UCL Cancer Trials Centre, UCL, London, UK
8
Arm 3 Carboplatin AUC 2 q1w
Paclitaxel 80mg/m2 q1w
Arm 2 Carboplatin AUC 5 q3w
Paclitaxel 80mg/m2 q1w
Arm 1 Carboplatin AUC 5 q3w
Paclitaxel 175mg/m2 q3w
Diagnosis of Stage IC-IV
EOC/PPC/FTC
After immediate primary surgery or
planned to receive NACT plus
delayed primary surgery
Stratification factors:
GCIG group
Disease stage
Timing and outcome of surgery
Randomise
1:1:1
ICON8 TRIAL SCHEMA
• Six cycles chemotherapy mandated
Delayed Primary Surgery cohort
• Cytoreductive surgery strongly advised after 3 cycles of chemotherapy
• Cycle 3 day 15 treatment omitted in arms 2 and 3
16
ICON8 PROGRESSION FREE SURVIVAL (PFS)Arm 1 Arm 2 Arm 3
StandardWeekly
paclitaxel
Weekly carbo-
paclitaxel
Total Patients N=522 N=523 N=521
Progressions 330 (63%) 335 (64%) 338 (65%)
Median PFS 17.9 months 20.6 months 21.1 months
Log rank (vs Arm1) p=0.45 p=0.56
HR vs Arm 1
(97.5% CI)
0.92
(0.77, 1.09)
0.94
(0.79, 1.12)
Restricted means 24.4 months 24.9 months 25.3 months
17
ICON8 PFS (BY IPS & DPS)
Median PFS
IPS
Standard 49.3 months
Weekly paclitaxel 43.2 months
Weekly carbo-paclitaxel 43.7 months
DPS
Standard 13.8 months
Weekly paclitaxel 14.6 months
Weekly carbo-paclitaxel 15.4 months
19
ICON8 OVERALL SURVIVAL
Data immature –602 events per comparison required (58% of required events included here)
Arm 1 Arm 2 Arm 3
StandardWeekly
paclitaxel
Weekly carbo-
paclitaxel
Total Patients N=522 N=523 N=521
No. of deaths 183 (35%) 167 (32%) 166 (32%)
Log rank
(vs Arm 1 only)p=0.21 p=0.3
Median OS 46.5 months 48.1 months 54 months
2 year survival
(95% CI)
80%
(76%, 83%)
82%
(79%, 86%)
78%
(74%, 81%)
Antiangiogénicos en primera línea
Bevacizumab Pequeñas moléculas
Avanzado,
estadío III/IV
Inicial y
avanzado
Nindetanib
Inicial y avanzado
Pazopanib,
Solo
mantenimiento
Cuatro estudios positivos fase III con antiangiogénicos en 1 ° línea
de cáncer de ovario
PFS
HR=0.7171
PFS
HR=0.812
PFS
HR=0.844
PFS
HR=0.77 3
1. Burger, et al. NEJM 2011; 2. Perren, et al. NEJM 2011
3. Dubois ASCO 2013 ; 4. 2012
0.68
Alto riesgo Alto y Bajo riesgo Bajo riesgo Bajo riesgo
AGO-OVAR16 LUME
AGO-OVAR12
53
Front-line:
Epithelial OV, PP
or FT cancer
• Stage III optimal
(macroscopic)
• Stage III
suboptimal
• Stage IV
n=1800 (planned)
Stratification variables:
• GOG performance status
(PS)
• Stage/debulking status
R
A
N
D
O
M
I
Z
E
1:1:1
15 months
Paclitaxel (P) 175 mg/m2
Carboplatin (C) AUC 6
Placebo
I
Arm
Cytotoxic
(6 cycles)
Maintenance
(16 cycles)
(CP)
Carboplatin (C) AUC 6
Paclitaxel (P) 175 mg/m2
PlaceboBEV 15 mg/kg
II(CP + BEV)
BEV 15 mg/kg
Carboplatin (C) AUC 6
Paclitaxel (P) 175 mg/m2III
(CP + BEV
BEV)
Phase III Double Blind Trial of Bevacizumab in the Primary Treatment of Advanced
Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer:
A Gynecologic Oncology Group (GOG) StudyGOG-218
Burger et al. ASCO 2010
Following maximal debulking surgery: stage III
optimal (macroscopic residual disease ≤1cm) or
suboptimal (>1cm), or stage IV
>2/3 de las pacientes
de alto riesgo
54
Characteristic, n (%)
Arm I
CP
(n=625)
Arm II
CP + BEV
(n=625)
Arm III
CP + BEV
BEV
(n=623)
Stage/residual size
III optimal (macroscopic) 218 (35) 205 (33) 216 (35)
III suboptimal 254 (41) 256 (41) 242 (39)
IV 153 (25) 164 (26) 165 (27)
Histology
Serous 543 (87) 523 (84) 525 (84)
Endometrioid 20 (3) 15 (2) 25 (4)
Clear cell 11 (2) 23 (4) 18 (3)
Mucinous 8 (1) 5 (<1) 8 (1)
Tumor grade
3a
412 (66) 435 (70) 430 (69)
2 94 (15) 77 (12) 92 (15)
1 33 (5) 28 (4) 16 (3)
Not specified/pending 86 (14) 85 (14) 85 (14)
GOG-218Características clínicas
Burger et al. ASCO 2010
55
Adverse event (grade when limited), n
(%)
Arm I
CP
(n=601)
Arm II
CP + BEV
(n=607)
Arm III
CP + BEV
BEV
(n=608)
GI eventsa (grade ≥2) 7 (1.2) 17 (2.8) 16 (2.6)
Hypertension (grade ≥2) 43 (7.2)b 100 (16.5)b 139 (22.9)b
Proteinuria (grade ≥3) 4 (0.7) 4 (0.7) 10 (1.6)
Pain (grade ≥2) 250 (41.7) 252 (41.5) 286 (47.1)
Neutropenia (grade ≥4) 347 (57.7) 384 (63.3) 385 (63.3)
Febrile neutropenia 21 (3.5) 30 (4.9) 26 (4.3)
Venous thromboembolic event 35 (5.8) 32 (5.3) 41 (6.7)
Arterial thromboembolic event 5 (0.8) 4 (0.7) 4 (0.7)
CNS bleeding 0 0 2 (0.3)
Non-CNS bleeding (grade ≥3) 5 (0.8) 8 (1.3) 13 (2.1)
RPLS 0 1 (0.2) 1 (0.2)
RPLS = reversible posterior leukoencephalopathy syndromeaPerforation/fistula/necrosis/leak
bp<0.05
GOG-218Toxicidad
Burger et al. ASCO 2010
AE, No. of
patientsGrade
Arm ICP + PLA →
PLA(n=587)
Arm IICP + BEV →
PLA(n=587)
Arm IIICP + BEV →
BEV(n=585)
Total
Total 10 (1.7%) 20 (3.4%) 20 (3.4%) 50 (2.8%)
2 1 1 1 3
Fistula 3 3 2 3 8
4 0 1 0 1
GI leak 3 0 0 1 1
4 0 0 2 2
Necrosis 3 1 0 0 1
2 0 1 0 1
Perforation 3 2 5 5 12
4 0 2 0 2
5 0 3 2 5
Bleeding 2 2 3 3 8
3 1 2 3 6
0.7%
1.1%
0.8%
GOG-218Toxicidad GI G≥2
Burger, JCO 2014
1.2%1.8%0.3%
0
1
2
3
4
5
6
7
8
2 3 4 5 6 7+
Arm I CP + PLA → PLA
Arm II CP + BEV → PLA
Arm III CP + BEV → BEV
No. of patients with
a grade ≥2 GI AE
Cycle number
GOG-218Momento del diagnóstico de la toxicidad GI
Burger, SGO Marzo 2011
Model covariateEstimated odds of
grade ≥2 GI AE (95% CI)
BEV treatment 2.15 (1.05–4.40)
Treatment for IBD 13.4 (3.44–52.3)
Large bowel resection at primary surgery 2.05 (1.09–3.88)
Small bowel resection at primary surgery 1.95 (0.89–4.25)
GOG-218Modelo logístico de la asociación entre factores de riesgo y
toxicidad GI
Burger, JCO 2014
En un modelo de regresión
logística no hubo evidencia de
que bevacizumab exacerbara el
riesgo de un EA GI cuando estos
factores estuvieran presentes
•a p-value boundary = 0.0116
Pro
po
rtio
n s
urv
ivin
g p
rog
res
sio
n f
ree
0
0.2
0.4
0.6
0.8
1.0
Months since randomisation
0 12 24 36
I
CP
(n=625)
III
CP + BEV → BEV
(n=623)
No. of patients with event, n (%) 339 (54.2) 255 (40.9)
Median PFS, months 12.0 18.0
Stratified analysis HR (95% CI) –0.645
(0.551–0.756)
p value one-sided (log rank) – <0.0001a
Censored for CA-125, % 20 29
CP (Arm I)
+ BEV → BEV maintenance (Arm III)
0.1
0.3
0.5
0.7
0.9
Median follow-up: 17.4 months
GOG-218SLP censurando progresión bioquímica (CA 125)
Burger et al. ASCO 2010
>20%
Al comienzo del período de platino
sensibilidad hay más de un 20 % de
pacientes con bevacizumab que
pudieron adquirir esta condición
GOG 218: PFI
Distribución de la enfermedad Platino Sensible a la
recaída
PC + PL PC + BV
Intervalo Mediano libre de quimioterapia 7.6 14.3
PFS a los 12 meses 9% 30%
Recaída platino sensible 26% 42%
• Post last dose of carboplatin on study
• Reference Randall et al, submited to SGO 2013 Aghajanian et al. ESMO 2012
Una mayor proporción de pacientes en la rama de BV
están libres de progresión a 6 y 12 meses
Esto implica un incremento de 2 a 3 veces del porcentaje de pacientes en
la rama de bevacizumab que se beneficiaron de un período extendido sin
quimioterapia
GOG-0218: uso de terapias subsiguientes
CP + Pla(n=625)
CP + Bev → Pla
(n=625)
CP + Bev → Bev
(n=623)
Use of any non-protocol therapy 78% 79% 73%
Chemotherapy 74% 74% 70%
Use antiangiogenic treatments 39% 30% 17%
Bevacizumab 28% 28% 15%
Roche data on file
Year 1 Years 2–3 Years 4–5
CT Baseline; after cycles 3 & 6; at 9 & 12
months
Every 6
months
As indicated
CA-125/clinical
assessment
Every chemotherapy cycle; every 6
weeks during maintenance phase
Every 3
months
Every 6
months
Stratification variables:
• Stage & extent of debulking:I–III debulked ≤1cm vs stage I–III debulked >1 cm vs stage IV and inoperable stage III
• Timing of intended treatment start≤4 vs >4 weeks after surgery
• GCIG group (*also choice of AUC
dose 5 [AGO, NSGO, GINECO] or 6)
SchemaAcademic-led, industry-supported trial to investigate use of bevacizumab and to
support licensing. study population included only patients who had undergone
surgery with the aim of maximal debulking
Paclitaxel 175 mg/m2
Carboplatin AUC6
Carboplatin AUC6
Paclitaxel 175 mg/m2
18 cycles
R
n=1528*
Bevacizumab 7.5 mg/kg q3w
65
1:1
*Dec 2006 to Feb 2009
ICON-7Esquema de tratamiento
OC, PP, FTC
(n=1,528)
FIGO stageI–IIA if high risk: grade 3 or
clear cell histology
IIB–IV: all grades and
histological subtypes patients
debulked ≤1 cm or >1 cm
ECOG PS 0–2
>2/3 de los pacientes es
de bajo riesgo
Characteristic, n (%)Control (n=764)
Research (n=764)
FIGO stage, n (%)
I/IIA
IIB–IIIB
IIIC/IV
75 (10)
160 (21)
529 (69)
67 (9)
155 (20)
542 (71)
Debulking surgery/residuum
Optimal surgery (≤1 cm)
Suboptimal surgery (>1 cm)
No surgery
552 (74)
195 (26)
17 (2)
559 (74)
192 (26)
13 (2)
FIGO stage and residuum*
Stage I–III (≤1 cm)
Stage I–III (>1 cm)
Stage III (inoperable)/IV
508 (66)
150 (20)
106 (14)
518 (68)
140 (18)
106 (14)
Intent to start chemotherapy*
≤4 weeks from surgery
>4 weeks from surgery
328 (43)
436 (57)
326 (43)
438 (57)
66
ICON-7Características de las pacientes
2.10.1 0.4
0.90.4 0.3
1.7 1.3 0.4 0
15.1
2.0 2.0
18.3
0.5 1.30.8
1.3 1.2
4.32.7
0.3 0
16.5
2.6 3.5
0
5
10
15
20
25
30
35
40
45Control (n=753)
Research (n=745)
ATE = arterial thromboembolism; CHF = congestive heart failure; RPLS = reversible posterior leucoencephalopathy syndrome; VTE = venous thromboembolism
Patients
(%
)
67
Perren et al. ESMO 2010
ICON-7Toxicidad ≥ grado 3
Number at riskControl 764 715 676 529 419 247 175 91 65 26 16Research 764 733 696 617 546 330 232 100 62 19 11
1.00
0.75
0.50
0.25
0
Pro
po
rtio
n a
live
with
ou
t p
rog
ressio
n
Time (months)
0 3 6 9 12 15 18 21 24 27 30
Control Research
Events, n (%) 392 (51) 367 (48)
Median, months
16.0 18.3
Log-rank test p=0.0010
HR (95% CI) 0.79 (0.68–0.91)
16.0 18.3
ControlResearch
Regulatory analysis
68
Perren et al. ESMO 2010
ICON-7Sobrevida libre de progresión
ICON7: PFS de acuerdo a residuo
Subgroup HR (95% CI)
PFS High risk (N=502) 0.71 (0.58–0.86)
Stage IIIb–IV (N=1160) 0.81 (0.70–0.92)
Stage IIIb–IV no residual disease
(N=411)0.77 (0.59–0.99)
Stage IIIb–IV residual disease
(N=749)0.81 (0.69–0.95)
Bev better Reference better
HR (95% CI)
210.5
Exploratory outcome analyses according to stage and residual disease
in the ICON7 trial of front-line carboplatin/paclitaxel (CP) ±
bevacizumab (BEV) for ovarian cancer (OC) Gonzalez Martin et al.
ASCO 2015 (abstract 5548)
Preguntas después del GOG 218 y ICON7 :
Duración de tratamiento óptima?
TC
TC + Bev Bev
Pro
po
rtio
n a
live
wit
ho
ut
pro
gre
ss
ion
1.0
0.8
0.6
0.4
0.2
0
Time (months)
0 6 12 18 24 30 36 42 48
Maximo beneficio al final de la terapia con BEV
Mediana no reflejaría el máximo
beneficio de Bevacizumab
Paclitaxel 175 mg/m²
Carboplatin AUC5 q21 days
Bevacizumab 15 mg/kg q21 days15 Months
= 22 Courses
Paclitaxel 175 mg/m²
Carboplatin AUC5 q21 days
Bevacizumab 15 mg/kg q21 days
30 Months
= 44 Courses
AGO-OVAR 17Design
R
N = 900
1:1
Strata
Residual tumor (yes vs no)
FIGO Stage (IIB-III vs IV)
Group
National Institutes of Health. Available at: http://clinicaltrials.gov/show/NCT01462890.
Bevacizumab en 1ª línea de cáncer de ovario
Conclusiones
La tolerabilidad es buena en la mayoría de las pacientes, siendo la
toxicidad grave excepcional
La incidencia de perforaciones GI es < 2% (inferior a la MCRC)
Aumenta la SLP en dos ensayos fase III, independientemente del
residuo
Aumenta la OS en subgrupo de alto riesgo del ICON7 y en el
Estadío IV del GOG-0218
Y bevacizumab en
neoadyuvancia?
Ninety-five patients randomised (2:1) to receive four cycles of
neoadjuvant CP x 3 concomitant cycles of bevacizumab 15
mg/kg (BCP) followed by IDS.
Primary objective: evaluate the CRR at IDS in the BCP group
(reference CRR rate defined as 45% CRR).
A stopping rule based on bevacizumab- related adverse
events (AEs) of special interest was implemented.
Results:• In the BCP group (N 58), IDS was performed in 40 (69%)
patients. The CRR of this group was 58.6% (34 patients),
statistically over predefined 45%.
• The CRR in the CP group was 51.4%: 22 (60%) patients
underwent IDS.
• Grade 3 adverse events occurred in 62% of the BCP-treated
patients and 63% of the CP-treated patients: mainly blood and
lymphatic, gastrointestinal and vascular disorders, without
more toxicity with BCP.
• Postoperative complications (mainly wound, infectious and
gastrointestinal complications) occurred in 28% and 36% of the
patients, respectively.
• The pre-specified safety stopping rule was not reached.
Conclusion:
• The primary objective was met as the CRR
with BCP was significantly higher than the
reference rate.
• Bevacizumab may be safely added to a
preoperative program in patients deemed
non-optimally resectable, whatever the final
surgical decision.
• Bevacizumab’s role in this setting should be
further investigated.
Presented by: Andreas du Bois on behalf of the AGO led Intergroup consortium
AGO-OVAR 16
• Phase III randomized, placebo-controlled, double-blind, multicentre
• N= 940 patients randomized (1:1) from June 2009 to August 2010
• Pazopanib administered at 800 mg daily for up to 24 months*
– FIGO stage II–IV disease
ICFBaseline
first dose
Treatment
completion
Disease
assessments
completion
Study
completion
Survival
follow-up
(post-PD)
First-line
surgery and
chemotherapy
(allowed: dose-
dense, IP,
neoadjuvant)
Placebo
24 months
Pazopanib
24 months
Treatment
periodR
A
N
D
O
M
I
Z
E
Observation
(to PD)
Screening
baseline
Post-treatment
period
Follow-up
period
Study Design
If not PD
+ Tu < 2cm
Median 7 months from diagnosis to randomization
*Original design was for 12 months and later amended to 24 months
Presented by: Andreas du Bois on behalf of the AGO led Intergroup consortium
AGO-OVAR 161st endpoint: Progression-free Survival (RECIST)
[months]
Δ= 5.6 monthsMedian time from
Diagnosis: 7 months
472 332 234 171 91 19
468 318 208 164 88 20 1
Patients
at risk
0
0,5
1
0 6 12 18 24 30 36
HR = 0.766 [95% CI: 0.643-0.911]
Stratified Log-rank test : P = 0.0021
Pazopanib: 472 pts. / 237 events
median 17.9 [15.9 - 21.8] mos
Placebo: 468 pts. / 273 events
median 12.3 [11.8 - 17.7] mos
Presented by: Andreas du Bois on behalf of the AGO led Intergroup consortium
AGO-OVAR 16
0
0,5
1
0 6 12 18 24 30 36 42
Pazopanib: 472 pts. / 95 events - median not reached
Placebo: 468 pts. / 94 events - median not reached
Overall Survival: first analysis
472 428 397 362 273 53
468 441 412 388 274 65 3
Patients
at risk
P r
o b
a b
i l i t
y
[months]
First Interim analysis for OS:
551 events needed for final OS analysis
so far, 190 events (20% of population)
median observation: 24.3 months
HR= 0.994 [95% CI: 0.747; 1.321]; median not reached
Phase III Trial of Nintedanib (LUME-Ovar1/AGO-OVAR12): Design
www.clinicaltrials.gov/ct2/show/NCT01015118?term=NCT01015118&rank=1
Front-line,
FIGO stage IIB‒IV,
ECOG 0‒2
n=1,374
Paclitaxel q3w
Carboplatin q3w
Nintedanib (200mg BID)
Paclitaxel q3w
Carboplatin q3w
Placebo
Dis
ea
se
pro
gre
ssio
n o
r a
ma
xim
um
of
12
0 w
ee
ks
Multicenter, randomised, double-blind, Phase III trial to investigate the efficacy
and safety of BIBF 1120 in combination with standard treatment of carboplatin
and paclitaxel compared to placebo plus carboplatin and paclitaxel patients
with advanced ovarian cancer
Nindetanib/ Placebo :
- no intake on days of chemotherapy
- dose: 200 mg po bid (combi + mono)
- dose adaptation in case of undue toxicity
- max. duration of 120 weeks in non-
progressing pts
Primary Endpoint: Progression-Free SurvivalRECIST 1.1 and CA-125 in conjunction with Clinical MBO Criteria
0
0,5
1
0 6 12 18 24 30 36 42
Time from randomization (months)
455 381 257 168 76 3 0 0
911 761 542 352 160 17 1 0
TC +Nintedanib
(n=911)
TC +Placebo(n=455)
Events, n (%) 486 (53.3) 266 (58.5)
Median, months 17.3 16.6
HR* (95% CI) 0.84 (0.72, 0.98)
p value 0.0239
All patients (N=1366) – Cut-off date: 29 April 2013
*Stratified for macroscopic residual postoperative tumour, FIGO stage and carboplatin dose
Median + 0.7 months
A. Du Bois, ESGO 2013
Exploratory Subgroup Analysis
“ICON 7 defined low-risk patients subgroup”
(FIGO II or FIGO III and ≤ 1cm residual postoperative tumor)
Patients at risk
Es
tim
ate
d p
erc
en
tag
e a
live
an
d p
rog
res
sio
n-f
ree
Time from randomization (months)
Placebo 283 248 186 123 52 2 0
Nintedanib 556 478 380 270 124 9 0
TC +Nintedanib
(n=556)
TC +Placebo(n=283)
Events, n (%) 234(42.1) 149(52.7)
Median, months 27.1 20.8
HR (95% CI) 0.74 (0.61, 0.91)
0
0,5
1
0 6 12 18 24 30 36 42
median PFS difference: + 6.3 months (similar to OVAR 16)
A. Du Bois, ESGO 2013
Línea de investigación discontinuada por el
sponsor
Pacientes recaídas candidatas a
platino
CG +
PL
CG for 6 (up to 10) cyclesStratification variables:
• Platinum-free interval
(6–12 vs >12 months)
• Cytoreductive surgery for
recurrent disease (yes vs no)
Platinum-sensitive
recurrent OCa
•Measurable disease
•ECOG 0/1
•No prior chemo for
recurrent OC
•No prior BV
(n=484)
BV = bevacizumab; PL = placeboaEpithelial ovarian, primary peritoneal, or fallopian tube cancer
Gemcitabine 1000 mg/m2, d1 & 8
q3w
Carboplatin AUC 4
PL q3w until progression
Carboplatin AUC 4
BV 15 mg/kg q3w until progression
Gemcitabine 1000 mg/m2, d1 & 8q3wCG +
BV
Aghajanian et al. ASCO 2011
Estudio OCEANSEsquema del estudio
Published Ahead of Print on April 23, 2012 as
10.1200/JCO.2012.42.0505
CG + PL
(n=242)
CG + BV
(n=242)
Events, n (%) 148 (61) 119 (49)
Median PFS, months
(95% CI)8.6
(8.3–10.2)
12.3
(10.7–14.6)
Stratified analysis HR
(95% CI)
Log-rank p-value
0.451
(0.351–0.580)
<0.0001
1.0
0.8
0.6
0.4
0.2
0
Pro
po
rtio
n p
rog
ressio
n f
ree
0 6 12 18 24 30
242 168 31 8 3 0CG + PL242 195 73 22 7 0CG + BV
MonthsNo. at risk
Aghajanian et al. ASCO 2011
Estudio OCEANSSLP (Comité revisor independiente)
Median PFS
(months)
Baseline risk factorNo. of
patientsCG + PL
(n=242)
CG + BV
(n=242) HR (95% CI)
CG + BV
better
CG + PL
better
All patients 484 8.4 12.4 0.49 (0.40–0.61)
Platinum-free interval,
months6–12 202 8.0 11.9 0.41 (0.29–0.58)
>12 282 9.7 12.4 0.55 (0.41–0.73)
Cytoreductive surgery
for recurrent diseaseYes 54 7.5 16.7 0.50 (0.24–1.01)
No 430 8.4 12.3 0.49 (0.39–0.62)
Age, years <65 306 8.5 12.5 0.47 (0.36–0.62)
≥65 178 8.4 12.3 0.50 (0.34–0.72)
Baseline ECOG PS 0 367 8.6 12.5 0.47 (0.36–0.60)
1 116 8.3 10.6 0.61 (0.39–0.95)
HR0.2 0.5 1 2 5
Aghajanian et al. ASCO 2011
Estudio OCEANSAnálisis por subgrupos
OCEANS: Third Interim OS Analysisa
GC + PL
(n=242)
GC + BV
(n=242)
Events, n (%) 142 (58.7) 144 (59.5)
Median OS, months
(95% CI)
33.7
(29.3‒38.7)
33.4
(30.3‒35.8)
HR (95% CI)
Log-rank P value
0.960 (0.760–1.214)
p=0.7360
1.0
0.8
0.6
0.4
0.2
0.0
0 6 12 18 24 30 36 42 48 54 60
242 235 221 190 159 117 77 44 23 7 0
242 239 226 201 171 127 78 48 27 7 0
Number at risk:
GC + PL
GC + BV
aData cutoff date: March 30, 2012. Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths
(59.1% of patients)
Pro
po
rtio
n s
urv
ivin
g
Months
ClinicalTrials.gov. NCT00565851.
PI: Coleman
Yes No
Surgery No surgery CarboplatinPaclitaxel
CarboplatinPaclitaxel
Bevacizumab
Bevacizumab
To chemotherapy randomization
Randomize
Surgical candidate?
Recurrent ovarian, PPT, and FT cancerTFI ≥ 6 mos
Randomize
GOG-213
Preguntas sin respuesta
• Reutilización de bevacizumab luego del
la progresión
• La mejor quimioterapia para combinar
con bevacizumab
En BCRA mutadas candidatas a
platino…..
Pacientes recaídas no
candidatas a platino
PD = progressive disease
aEpithelial ovarian, primary peritoneal, or fallopian tube cancer; bOr 10 mg/kg q2w;c15 mg/kg q3w, permitted on clear evidence of progression
AURELIA diseño del estudio
Stratification factors:
• Chemotherapy selected
• Prior anti-angiogenic therapy
• Treatment-free interval
(<3 vs 3‒6 months from previous
platinum to subsequent PD)
Platinum-resistant OCa
• ≤2 prior anticancer
regimens
• No history of bowel
obstruction/abdominal
fistula, or clinical/
radiological evidence of
rectosigmoid involvement
Treat to
PD/toxicity
Treat to
PD/toxicity
Investigator’s
choice
(without BEV)
Optional BEV
monotherapyc
BEV 15 mg/kg q3wb
+ chemotherapy
Chemotherapy
R
1:1
Chemotherapy options (investigator’s choice):
• Paclitaxel 80 mg/m2 days 1, 8, 15, & 22 q4w
• Topotecan 4 mg/m2 days 1, 8, & 15 q4w
(or 1.25 mg/m2, days 1–5 q3w)
• PLD 40 mg/m2 day 1 q4w
Características de la población
• PFI = platinum-free interval
• aStratification factor. bFrom last platinum to subsequent PD
Characteristic
CT (n=182)
n (%)
BEV + CT (n=179)
n (%)
Median age, years 61 62
(range) (25‒84) (25‒80)
Origin of cancer: Ovary 157 (86) 167 (93)
Serous/adenocarcinoma at diagnosis
152 (84) 156 (87)
Histologic grade at diagnosis
1 9 (5) 10 (6)
2/3 153 (84) 147 (82)
Prior anti-angiogenic therapya 14 (8) 12 (7)
Two prior chemotherapy regimens 78 (43) 72 (40)
PFI <3 monthsa,b 46 (25) 50 (28)
ECOG PS
0 99 (54) 107 (60)
1/2 80 (44) 70 (39)
Measurable disease 144 (79) 143 (80)
Ascites 54 (30) 59 (34)
Median duration of follow-up: 13.9 months (CT arm) vs 13.0
months (BEV + CT arm)
Sobrevida libre de progresión
CT
(n=182)
BEV + CT
(n=179)
Events, n (%) 166 (91%) 135 (75%)
Median PFS, months (95%
CI)3.4
(2.2‒3.7)
6.7
(5.7‒7.9)
HR (unadjusted)
(95% CI)
Log-rank p-value
(2-sided, unadjusted)
0.48 (0.38‒0.60)
<0.001
1.0
0.8
0.6
0.4
0.2
0
Estim
ate
d p
rob
ab
ility
0 6 12 18 24 30
Time (months)
182 37 8 1 0
179 88 18 1 0
CT
BEV + CT
No. at risk:
93
140
20
49
1
4
0
1
3.4 6.7
Análisis de subgrupo de PFS
aUnadjusted. bMissing n=8
Subgroup
No. of
patients
Median PFS, months
HRa
BEV + CT
better
CT
better CT BEV + CT
All patients 361 3.4 6.7 0.48
Age, years <65
≥65
228
133
3.4
3.5
6.0
7.8
0.49
0.47
PFI, monthsb <3
3‒6
96
257
2.1
3.6
5.4
7.8
0.53
0.46
Measurable
disease, cm
No (<1)
Yes (1‒<5)
Yes (≥5)
74
126
161
3.7
3.3
3.3
7.5
7.5
6.0
0.46
0.50
0.47
Ascites Yes
No
113
248
2.5
3.5
5.6
7.6
0.40
0.48
Chemotherapy Paclitaxel
PLD
Topotecan
115
126
120
3.9
3.5
2.1
10.4
5.4
5.8
0.46
0.57
0.32
0.2 0.3 0.5 1 2 3 4 5
aTwo-sided chi-square test with Schouten correction
Tasa de Respuesta
12,6 11,8 11,6
30,927,3
31,8
0
5
10
15
20
25
30
35
40
45
50
Responders(RECIST and/or CA-125)
(n=350)
RECIST responders(n=287)
CA-125 responders(n=297)
CT BEV + CT
p=0.001ap<0.001a p<0.001a
Patients
(%
)
Data cut-off: 25 January 2013. Median duration of follow-up: 27.4 months in both armsITT = intent to treata2-sided log-rank, unadjusted
OS: ITT population
CT
BEV + CT
No. at risk:
CT
(N=182)
BEV + CT
(N=179)
Events, n (%) 136 (75) 128 (72)
Median OS,
months (95% CI)
13.3
(11.9‒16.4)
16.6
(13.7‒19.0)
HR (unadjusted)
(95% CI)
0.85
(0.66‒1.08)
p=0.174a
182 130 98 63 29 12 1 0
179 148 106 75 39 13 1 0
0 6 12 18 24 30 36 42
Time (months)
100
75
50
25
0
Overa
ll surv
ival (%
)
• Study not powered to detect a statistically
significant difference in OS
• No systematic capture of post-progression therapy
in either arm (except for BEV in the control arm)
Paclitaxel cohort: OSO
vera
ll surv
ival (%
)
75
50
25
00 6 12 18 24 30 36 42
100
CT
BEV + CT
No. at risk:
55 40 32 22 13 3 0
60 52 43 34 19 4 1
Time (months)
CT
(N=55)
BEV + CT
(N=60)
Events, n (%) 41 (75) 36 (60)
Median OS,
months (95% CI)
13.2
(8.2‒19.7)
22.4
(16.7‒26.7)
HR (unadjusted)
(95% CI)
0.65
(0.42‒1.02)
Updated safety results
RPLS = reversible posterior leucoencephalopathy syndrome; CHF = congestive heart failure
Grade ≥3 adverse events of special
interest, n (%)
CT
(N=181)
BEV + CT
(N=179)
Hypertension 2 (1.1) 14 (7.8)
Grade ≥2 10 (5.5) 36 (20.1)
Proteinuria 0 4 (2.2)
Grade ≥2 1 (0.6) 23 (12.8)
GI perforation 1 (0.6) 2 (1.1)
Grade ≥2 1 (0.6) 3 (1.7)
Fistula/abscess 0 2 (1.1)
Grade ≥2 0 4 (2.2)
Wound-healing complication 0 2 (1.1)
Bleeding 2 (1.1) 2 (1.1)
Thromboembolic event
Arterial
Venous
1 (0.6)
7 (3.9)
3 (1.7)
6 (3.4)
RPLS 0 1 (0.6)
CHF 1 (0.6) 1 (0.6)
QOL: aumento del 15% en los síntomas abdominales
EORTC QLQ-OV28
Martin R. Stockler et al. Published Ahead of Print on March 31, 2014
Cuales son las mejores opciones en
platino resistencia
Terapia de sostén
Monoquimioterapia con un agente no platino
La mejor opción es si se cuenta con acceso a
bevacizumab , es la combinación de agente único no
platino y terapia antiangiogénica (AURELIA)
Prometedores resultados de trebananib en pacientes
refractarias y pretratadas con antiangiogénicos aunque
con mayor toxicidad
Platinum sensible
Bevacizumab + quimioterapia Quimioterapia+bevacizumab
SI No
Evidencia clínica de estudios fase III del uso de Bevacizumab en pacientes con
cáncer de ovario estadío III y IV e incorporación de nuevas moléculas
Recurrencia
Ciirugía del intervalo
Estadío IIIb/IV
Quimioterapia Neoadyuvante
SI
CIRUGÍA INICIAL EIIIB IIC IV
Bevacizumab + quimioterapia
basada en platino
Tratar con
quimioterapia
Cirugía primaria
AURELIA
BCRA testing
M+ WT Olaparib + QMT
GOG 213
CIRUGÍA INICIAL EI, EII, EIIa
Reflexiones finales... A todas las pacientes con cancer de ovario se les debería ofrecer el testeo genético
La alta carga tumoral inicial es un factor de mal pronóstico
Las pacientes con cáncer de ovario avanzado, particularmente con enfermedad
residual postquirúrgica necesitan un mejor tratamiento
La inhibición del VEGF es un blanco terapéutico racional
El tratamiento de primera línea con bevacizumab y carboplatino/paclitaxel por 6
ciclos y luego la terapia como agente único hasta 15 meses ( 21 CICLOS) o toxicidad
inaceptable a 15 mg/kg cada 3 semanas, produce mejorías estadísticamente
significativas en el PFS en pacientes con estadíos FIGO III B, III C y IV
Las mujeres con enfermedad residual postcx obtienen un beneficio particularmente
significativo con la adición de bevacizumab (OS)
Las pacientes con recaída platino sensible y platino refractaria se benefician del
tratamiento con quimioterapia en combinación con bevacizumab
Las pacientes con recaída platino sensible y mutación de BRCA se benefician con un
doblete con platino y mantenimiento con olaparib
Muchas gracias!!!!!
[email protected]@institutoroffo.uba.ar