09 state of the art of the management of advanced and recurrent ovarian cancer
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Transcript of 09 state of the art of the management of advanced and recurrent ovarian cancer
Fernando Cotait Maluf
Chairof Medical OncologyDepartment
São José Hospital
São Paulo São Paulo Brazil
•Advancedstagesatdiagnosis (~75%)
•Highlychemotherapy-sensitive
• Complete clinicalresponse to platinum-based CT: 70-85%
•Stage III: 20-25% of complete remissionat 5y
• 81 studies
• 6885 patients
•StageIIIandIV
•Cytoreductivesurgeryfollowedbyplatinum-based CT
Bristowet al. J ClinOncol, 2002
• CT platinum-basedversus CT NON platinum-based1,2
• HR death: 0.88 [0.79 – 0.98]
OvarianCancerMeta-Analysis Project (GynecolOncol, 2002) 1
AdvancedOvarianCancerTrialistsGroup (2002) 2
OvarianCancerMeta-Analysis Project (J ClinOncol, 1991) 3
•CT anthracyline-basedversus CT NON anthracyline-based3
•Absolutesurvivalbenefit: 5% ( p = 0.02)
•CisplatinversusCarboplatin1,2
• HR death: 1.02 [0.93 – 1.12]
•Platinum-dosenotassociatedwithsurvivalbenefit3
•MONOCT platinum-basedversus POLICT platinum-based1,2
• HR death: 0.91 [0.75 – 1.05]
OvarianCancerMeta-Analysis Project (GynecolOncol, 2002) 1
AdvancedOvarianCancerTrialistsGroup (2002) 2
ICON 3: CarboplatinvsCarboplatin + Paclitaxel
GOG 111 andOV 10(Intergroup)
McGuireetal, N Eng J Med, 1996;
n=386,suboptimalcytoreduction III/IV
SLPSG
PT 18m 38m
PC 13m 24m
Piccartetal, J Nat CancerInst, 2000;
n=668, debulkingsurgery, II-IV
SLPSG
PT 17m 35m
PC 12m 25m
Standard arm IV
D1 D2
IV IV
D1 Paclitaxel IV 135mg/m2/24hs
D2 CisplatinIV 75mg/m2
D1 D2 D8
IVIP IP
Experimental arm IV/IP D1 Paclitaxel EV 135mg/m2/24hs
D2 CisplatinIP100mg/m2
D8 PaclitaxelIP60mg/m2
GOG 172
Armostrong e al, NEJM, 2006;
N=429, optimaldebulkingsurgery, stage III
SLPSG
PT IV 19m 50m
PT IV/IP 24m 65m
Only 42% ofptscompletedtreat. IV/IP arm
GOG randomized studies: IV vs IP
PFS (m) %Advantage OS (m) %Advantage
IV IP IV IP
Alberts -- -- 41 49
Markman 22 28 27 52 63
Armstrong 19 24 20 50 65 25
* Statisticallysignificant : p < 0.05
AdvancedOvaria
nCancer
(n = 637)
RANDOMIZATION
CarboplatinAUC 6 + Paclitaxel
180mg/m2
q 21 days x 6 cycles
Katsumata N, Lancet: 374, 2009
CarboplatinAUC 6 + Paclitaxel
80mg/m2 d1,8,15
q 21 days x 6 cycles
Katsumata N, Lancet: 374, 2009
Progression-freeSurvival Overall Survival
AdvancedOv
arianCancer
(III/IV)
(n = 718)
RANDOMIZATION
PrimaryCitoreduc
tion
Vergote I, NEJM: 363 2010
Platinun-CT
x 3 cycles
IntervalCytored
uction
Platinun-CT
x 3 cycles
Platinun-CT
x 6 cycles
Vergote I, NEJM: 363 2010
OverallSurvival Overall Survivalvs Residual Disease
Vergote I, NEJM: 363 2010
Citoreduction CT CT Citoreduction
Complete resection
20.4% 50.0%
Vergote I, NEJM: 363 2010
Citoreduction CT
CT Citoreductio
n
Pos-op Death 2.5% 0.7%
Hemorraghe G III/IV 7.1% 4.1%Infection 8.1% 1.7%
DVT/PE 2.5% 0%
GOG-0218: Scheme
Stratification
• PS
• Stage/Citoreduction BEV 15 mg/kg
15 months
Paclitaxel (P) 175 mg/m2
Carboplatin(C) AUC 6
Carboplatin(C) AUC 6
Paclitaxel (P) 175 mg/m2
Carboplatin(C) AUC 6
Paclitaxel (P) 175 mg/m2
Placebo
PlaceboBEV 15 mg/kg
First-line : Epithelial
OV, PP or F
• Stage III optimal
• Stage III suboptimal
• Stage IV
n=1800 (planned)
R
A
N
D
O
M
I
Z
E
I
II
III
Arm
1:1:1
GOG-218: Progression-Free SurvivalArm I
CP
(n=625)
Arm II
CP + BEV
(n=625)
Patients with event, n (%)423
(67.7)
418
(66.9)
Median PFS, months 10.3 11.2
Stratified analysis HR
(95% CI)
0.908
(0.759–1.040)
One-sided p-value (log rank) 0.080a
+ BEV (Arm II)CP (Arm I)
+ BEV → BEV maintenance (Arm III)Pro
po
rtio
n s
urv
ivin
g p
rog
ress
ion
fre
e
Months since randomization
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 12 24 36
Arm III
CP + BEV BEV
(n=623)
360
(57.8)
14.1
0.717
(0.625–0.824)
<0.0001a
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)
GOG-218: Select Adverse EventsOnset between cycle 2 and 30 days after date of last treatment
RPLS = reversible posterior leukoencephalopathy syndromeaPerforation/fistula/necrosis/leak
bp<0.05
ICON 7: Scheme
• Open-label study
• Endpoints
– primary: PFS
– secondary: RR, OS, safety, QoL, cost effectiveness, translational
• Stratification
– FIGO stage/surgery; time since surgery; GCIG group
Paclitaxel 175mg/m2 q3w
CarboplatinAUC6* q3w
Bevacizumab 7.5mg/kg q3w
Paclitaxel 175mg/m2 q3w
CarboplatinAUC6* q3w
18 cycles
Stage I or IIa (grade
3 or clear cell) or
stage IIb–IV EOC,
PP, FTC
(n=1,520)
ICON 7: Progression-Free Survival
Control Experimental
Events, n (%) 130 (17) 111 (15)
Log-rank p=0.098
Hazard ratio (95% CI) 0.81 (0.63–1.04)
Sobrevida 1-ano, % 93 95
1.00
0.75
0.50
0.25
0
Pro
port
ion s
urv
ivin
g
Time (months)
0 3 6 9 12 15 18 21 24 27 30
ICON 7: Select Adverse Events
6.2
2.5 2.1 1.3 0.4
11.6
4.1
1.50.4 0
29.1
2.0
9.2
25.9
4.4 5.0
1.7 1.3
39.6
6.7
3.6
0.4 0
28.3
2.8
12.5
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
(%
)
GOG 218 and ICON 7: Comparison of TrialsTrial GOG-0218 ICON7
Number of patients 1,800 1,520
Setting/design •Double-blinded, placebo-controlled
•First-line setting
•3-arm study:
Arm I: CT + placebo
Arm II: CT + Bevacizumab (5 cycles)
Arm III: CT + Bevacizumab (extended)
•Bevacizumab continued for 16 months
•Bevacizumab dose: 5mg/kg/week
•Rigid AUC for carboplatin
• Open-label
•First-line setting
• 2-arm study:
Arm A: carboplatin/paclitaxel (CT)
Arm B: CT + Bevacizumab
•Bevacizumab continued for 12 months
•Bevacizumab dose: 2.5mg/kg/week
•Flexibility in AUC for carboplatin
Patient population Post-cytoreductive surgery
Sub-optimally debulked stage III/IV
Macroscopic optimally debulked stage III
Post-cytoreductive surgery
I or IIa (grade 3 or clear-cell histology)
IIb–IV (all grades and histological types)
Target disease Epithelial ovarian, fallopian tube or primary
peritoneal cancer
Epithelial ovarian, fallopian tube or primary
peritoneal cancer
Stratification • PS (0–1 vs 2)
• Stage (III vs IV)
• FIGO stage
• ≤ vs>4 weeks after surgery
• GCIG group
Primary endpoint • Investigator-assessed PFS data
• Exploratory: IRC-assessed PFS data
• Investigator-assessed PFS data
P
R
I
M
A
R
Y
T
R
E
A
T
M
E
N
T
0 3 6 12 18 24
Refractory
Resistent
Sensitive
Highlysensitive
Months
70
60
50
40
30
20
10
0
12
33
59
< 6 months
12-18 months
> 18 months
Overall ResponseRate (%)
Intervalfrom prior platinumtreatment (months)
Platinum-
Sensitive
Platinum-
ResistantorRefrac
tory
Platinum-
basedTherapy
Platinum-sensitiveovariancancer
ΔT >6 m
RANDOMIZATION
CarboplatinAUC 5 a 6 EV
OR
Cisplatin75mg/m2 EV
q 21 days
CarboplatinAUC 5 EVOR
Cisplatin50mg/m2 EV+
Paclitaxel 175mg/m2 EVQ 21 days
Parmar MK, Lancet: 361, 2003
ICON-4/AGO-OVAR-2.2 Trial
Parmar MK, Lancet: 361, 2003
Overall Survival
ICON-4/AGO-OVAR-2.2 Trial
Pujades E etal, J ClinOncol, 2010
Inclusion Criteria:
• Platinum-sensitive (> 6 m)
• 1 or 2 prior platinum-based CT
• Measurable disease (image or CA125)
RANDOMIZATION
CarboplatinAUC 5 EV + Paclitaxel 175
mg/m2 IV 3
q21dx6 cycles
CarboplatinAUC 5 EV + DoxoLipossomal
30 mg/m2 IV 1 h
q 28 days x6 cycles*
*or until PD in patients with stable disease or response
CALYPSO: Scheme
Pujades E etal, J ClinOncol, 2010
CALYPSO: Progression-Free Survival
•Endpoints
– primary: PFS
– secondary: ORR, OS, response duration, safety
– exploratory: IRC, CA125 response, ascites
•Stratification: time to recurrence, cytoreductive surgery
Gemcitabine 1000mg/m2
days 1 and 8 q3w
CarboplatinAUC4 q3w
Gemcitabine 1000mg/m2
days 1 and 8 q3w
CarboplatinAUC4 q3w
Bevacizumab 15mg/kg
Placebo
EOC = epithelial ovarian; PP = primary peritoneal; FTC = fallopian tube carcinoma
PD
PD
Bev.
15mg/kg
Pretreated
platinum-sensitive,
EOC, PP or FTC
(n=480)
Placebo
OCEANS: Scheme
OCEANS: Patients Characteristics
CharacteristicCG + PL
(n=242)
CG + BV
(n=242)
Median age, years
(range)
61
(28−86)
60
(38–87)
Age ≥65 years, % 38 35
Race, %
White
Other
92
8
90
10
ECOG PS 0, % 76 75
Histologic subtype, %
Serous
Mucinous/clear cell
Other
84
3
14
78
5
17
Platinum-free interval, %
6–12 months
>12 months
42
58
41
59
Cytoreductive surgery for recurrent disease, % 10 12
OCEANS: Progression-free SurvivalCG + 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
ress
ion
fre
e
0 6 12 18 24 30
242 168 31 8 3 0CG + PL242 195 73 22 7 0CG + BV
MonthsNo. at risk
OCEANS: Progression-free Survival vs Subgroups
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
OCEANS: Response Rate
Duration of response CG + PL
(n=139)
CG + BV
(n=190)
Median, months 7.4 10.4
HR (95% CI) 0.534
(0.408–0.698)
p<0.0001a
100
80
60
40
20
0
%
78.5
57.4 PR = 61
PR = 48
CR = 17CR = 9
Difference: 21.1%
p<0.0001
aCompared for descriptive purposes only
CG + PL
(n=242)
CG + BV
(n=242)
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
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
Platinum-
Sensitive
Platinum-
ResistantorRefrac
tory
Retrospectiveanalysis: 111 pts
Recurrence< 3m orØ Response
Median OS 6
months
SV <4months 32%
SV <12months 73%Markmanet al. GynecolOncol, 2004
LiposomalDoxorrubicin
Gemcitabine
Paclitaxel (weekly)
Docetaxel
Topotecan
Etoposide (oral)
Vinorelbine
Ifosfamide
AURELIA/MO22224: Scheme
Physician’s choice:
Bevacizumab
15mg/kg q3w or
SOC
•Endpoints
– primary: PFS
– secondary endpoints: ORR (RECIST and/or CA125), biological progression-free interval, OS, QoL, safety
•FPI: October 2009 (recruitment: 24 months)EOC = epithelial ovarian; PP = primary peritoneal; FTC = fallopian tube carcinoma; PLD = pegylated liposomal doxorubicin;
SOC = standard of care
Bevacizumab 10mg/kg q2w or
15mg/kg q3w+
chemotherapy (physician’s
choice, as in control arm)
SOC
Progression
Progression
Chemotherapy alone
(physician’s choice):
paclitaxel 80mg/m2qw or
topotecan4mg/m2 days 1, 8 and 15
q4w or 1.25mg/kg days 1–5 q3wor
PLD 40mg/m2 q4w
EOC, PP or FTC
that relapsed
within <6 months
after platinum-
based
chemotherapy
(n=300)
PARP inhibitors
Randomized Phase II trial: (Ledermann et al, ASCO , 2011)
N = 265
CTOlaparibvs Placebo
PFS: 8.4 vs 4.8 months (p< 0.00001)
Phase II trial: (Penson et al, ASCO , 2011)
N = 41
Carboplatin + Gemcitabine + Iniparib
OR: 70%
Convidados
Internacionais