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!!!!!

valeriacaceres@yahoo.comvcaceres@institutoroffo.uba.ar