Fernando Cotait Maluf
Director of Medical Oncology Department
São José Hospital
São Paulo São Paulo Brazil
[email protected]
A Transformação..............
Primeiro fase (fase I)
Segunda fase (fase II)
• Advanced stages at diagnosis (~75%)
• Highly chemotherapy-sensitive
• Complete clinical response to platinum-based CT: 70-85%
• Stage III: 20-25% of complete remission at 5y
• 81 studies
• 6885 patients
• Stage III and IV
• Cytoreductive surgery followed by platinum-based CT
Bristow et al. J Clin Oncol, 2002
• CT platinum-based versus CT NON platinum-based 1,2
• HR death: 0.88 [0.79 – 0.98]
• CT anthracyline-based versus CT NON anthracyline-based 3
• Absolute survival benefit: 5% ( p = 0.02)
• Cisplatin versus Carboplatin 1,2
• HR death: 1.02 [0.93 – 1.12]
• Platinum-dose not associated with survival benefit 3
Ovarian Cancer Meta-Analysis Project (Gynecol Oncol, 2002) 1
Advanced Ovarian Cancer Trialists Group (2002) 2
Ovarian Cancer Meta-Analysis Project (J Clin Oncol, 1991) 3
• MONOCT platinum-based versus POLICT platinum-based 1,2
• HR death: 0.91 [0.75 – 1.05]
Ovarian Cancer Meta-Analysis Project (Gynecol Oncol, 2002) 1
Advanced Ovarian Cancer Trialists Group (2002) 2
ICON 3: Carboplatin vs Carboplatin + Paclitaxel
GOG 111 and OV 10(Intergroup)
McGuire et al, N Eng J Med, 1996;
n=386, suboptimal cytoreduction III/IV
SLP
SG
PT
18m
38m
PC
13m
24m
Piccart et al, J Nat Cancer Inst, 2000;
n=668, debulking surgery, II-IV
SLP
SG
PT
17m
35m
PC
12m
25m
Advanced
Ovarian Cancer
(n = 637)
R
A
N
D
O
M
I
Z
A
T
I
O
N
Carboplatin AUC 6 + Paclitaxel
180mg/m2
q 21 days x 6 cycles
Carboplatin AUC 6 + Paclitaxel
80mg/m2 d1,8,15
q 21 days x 6 cycles
Katsumata N, Lancet: 374, 2009
Progression-free Survival
Overall Survival
Katsumata N, Lancet: 374, 2009
GOG 172
Standard arm IV
D1 Paclitaxel IV 135mg/m2/24hs
D1
IV
D2
IV
D2 Cisplatin IV 75mg/m2
Experimental arm IV/IP
D1 Paclitaxel EV 135mg/m2/24hs
D2 Cisplatin IP 100mg/m2
D1
D2
D8
IV
IP
IP
D8 Paclitaxel IP 60mg/m2
Armostrong e al, NEJM, 2006;
N=429, optimal debulking surgery, stage III
SLP
SG
PT IV
19m
50m
PT IV/IP
24m
65m
Only 42% of pts completed treat. IV/IP arm
GOG randomized studies: IV vs IP
PFS (m) % Advantage
IV
Alberts
--
IP
--
OS (m)
IV
IP
41
49
Markman
22
28
27
52
63
Armstrong
19
24
20
50
65
* Statistically significant : p < 0.05
% Advantage
25
GOG-0218: Scheme
Arm
Carboplatin (C) AUC 6
Paclitaxel (P) 175 mg/m2
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
Stratification
• PS
• Stage/Citoreduction
I
Placebo
Carboplatin (C) AUC 6
1:1:1
Paclitaxel (P) 175
BEV 15 mg/kg
mg/m2
II
Placebo
Carboplatin (C) AUC 6
Paclitaxel (P) 175
mg/m2
III
BEV 15 mg/kg
15 months
GOG-218: Progression-Free Survival
Proportion surviving progression free
1.0
0.9
Patients with event, n (%)
0.8
Arm I
CP
(n=625)
Arm II
CP + BEV
(n=625)
Arm III
CP + BEV  BEV
(n=623)
423
(67.7)
418
(66.9)
360
(57.8)
10.3
11.2
14.1
Median PFS, months
0.7
Stratified analysis HR
(95% CI)
0.6
One-sided p-value (log rank)
0.717
0.908
(0.759–1.040) (0.625–0.824)
<0.0001a
0.080a
0.5
0.4
0.3
0.2
CP (Arm I)
+ BEV (Arm II)
0.1
+ BEV → BEV maintenance (Arm III)
0
0
12
24
Months since randomization
36
ICON 7: Scheme
CarboplatinAUC6* q3w
Stage I or IIa (grade
3 or clear cell) or
stage IIb–IV EOC,
PP, FTC
(n=1,520)
Paclitaxel 175mg/m2 q3w
CarboplatinAUC6* q3w
Paclitaxel 175mg/m2 q3w
Bevacizumab 7.5mg/kg q3w
•
•
Open-label study
Endpoints
– primary: PFS
– secondary: RR, OS, safety, QoL, cost effectiveness, translational
•
Stratification
– FIGO stage/surgery; time since surgery; GCIG group
18 cycles
ICON 7: Progression-Free Survival
Proportion surviving
1.00
0.75
0.50
Events, n (%)
Control
Experimental
130 (17)
111 (15)
Log-rank
p=0.098
Hazard ratio (95% CI)
0.25
0.81 (0.63–1.04)
Sobrevida 1-ano, %
0
0
3
6
93
9
12
15
18
Time (months)
95
21
24
27
30
P
R
I
M
A
R
Y
T
R
E
A
T
M
E
N
T
0
3
6
12
Refractory
18
24
Months
Resistent
Sensitive
Highly sensitive
< 6 months
12-18 months
70
60
Overall Response 50
Rate (%)
40
30
20
10
0
59
> 18 months
33
12
Interval from prior platinum treatment (months)
PlatinumSensitive
Platinum-based
Therapy
PlatinumResistant or
Refractory
ICON-4/AGO-OVAR-2.2 Trial
Platinum-sensitive
ovarian cancer
ΔT > 6 m
R
A
N
D
O
M
I
Z
A
T
I
O
N
Carboplatin AUC 5 a 6 EV
OR
Cisplatin 75mg/m2 EV
q 21 days
Carboplatin AUC 5 EV
OR
Cisplatin 50mg/m2 EV
+
Paclitaxel 175mg/m2 EV
Q 21 days
Parmar MK, Lancet: 361, 2003
ICON-4/AGO-OVAR-2.2 Trial
Progression-free Survival
Parmar MK, Lancet: 361, 2003
ICON-4/AGO-OVAR-2.2 Trial
Overall Survival
Parmar MK, Lancet: 361, 2003
End-point
HR PoliCT/MonoCT
p
RR
1,32 (1,08 - 1,62)
0,05
2-year TTP
0,67 (0,52 - 0,86)
0,02
2-year OS
0,77 (0,64 - 0,91)
0,04
Orlando M, J Clin Oncol 25:18s 2007 (abstr 5524)
CALYPSO: Scheme
Inclusion Criteria:
• Platinum-sensitive (> 6
m)
• 1 or 2 prior platinumbased CT
• Measurable disease
(image or CA125)
R
A
N
D
O
M
I
Z
A
T
I
O
N
Carboplatin AUC 5 EV + Paclitaxel 175
mg/m2 IV 3
q 21 d x 6 cycles
Carboplatin AUC 5 EV + Doxo
Lipossomal 30 mg/m2 IV 1 h
q 28 days x 6 cycles*
*or until PD in patients with stable disease or response
Pujades E et al, J Clin Oncol, 2010
Hematologic Toxicity
Doxo Lipossomal
+ Carboplatin
(n = 102)
Paclitaxel +
Carboplatin
(n = 98)
Neutropenia, grade 3/4
37%
48%
Febrile Neutropenia
3%
2%
Anemia, grade 3/4
9%
5%
19%
5%
Thrombocitopenia, grade 3/4
Pujades E et al, J Clin Oncol, 2010
Neuropathy
Pujades E et al, J Clin Oncol, 2010
CALYPSO: Progression-Free Survival
Pujades E et al, J Clin Oncol, 2010
OCEANS: Scheme
CarboplatinAUC4 q3w
Pretreated
platinum-sensitive,
EOC, PP or FTC
(n=480)
Gemcitabine 1000mg/m2
days 1 and 8 q3w
Placebo
PD
Bev.
15mg/kg
PD
CarboplatinAUC4 q3w
Gemcitabine 1000mg/m2
days 1 and 8 q3w
Bevacizumab 15mg/kg
•Endpoints
– primary: PFS
– secondary: ORR, OS, response duration, safety
– exploratory: IRC, CA125 response, ascites
•Stratification: time to recurrence, cytoreductive surgery
EOC = epithelial ovarian; PP = primary peritoneal; FTC = fallopian tube carcinoma
Placebo
OCEANS: Patients Characteristics
Characteristic
CG + PL CG + BV
(n=242) (n=242)
Median age, years
(range)
Age ≥65 years, %
61
(28−86)
38
60
(38–87)
35
92
8
76
90
10
75
84
3
14
78
5
17
42
58
10
41
59
12
Race, %
White
Other
ECOG PS 0, %
Histologic subtype, %
Serous
Mucinous/clear cell
Other
Platinum-free interval, %
6–12 months
>12 months
Cytoreductive surgery for recurrent disease, %
OCEANS: Progression-free Survival
Events, n (%)
Proportion progression free
1.0
Median PFS,
months (95% CI)
0.8
Stratified analysis
HR (95% CI)
Log-rank p-value
0.6
CG + PL
(n=242)
CG + BV
(n=242)
148 (61)
119 (49)
8.6
(8.3–10.2)
12.3
(10.7–14.6)
0.451
(0.351–0.580)
<0.0001
0.4
0.2
0
0
No. at risk
CG + PL
CG + BV
6
12
18
24
30
8
22
3
7
0
0
Months
242
242
168
195
31
73
OCEANS: Progression-free Survival vs Subgroups
Median PFS
(months)
No. of CG + PL CG + BV
patients (n=242) (n=242)
Baseline risk factor
All patients
HR (95% CI)
484
8.4
12.4
0.49 (0.40–0.61)
Platinum-free interval,
months
6–12
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 disease
Yes
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)
0
367
8.6
12.5
0.47 (0.36–0.60)
1
116
8.3
10.6
0.61 (0.39–0.95)
Baseline ECOG PS
CG + BV CG + PL
better
better
0.2
0.5
1
HR
2
5
OCEANS: Response Rate
%
Difference: 21.1%
p<0.0001
100
78.5
80
60
57.4
40
PR = 48
PR = 61
Duration of response
Median, months
HR (95% CI)
20
0
CG + PL
(n=139)
CG + BV
(n=190)
7.4
10.4
0.534
(0.408–0.698)
p<0.0001a
CR = 9
CG + PL
(n=242)
CR = 17
CG + BV
(n=242)
aCompared
for descriptive purposes only
Median PFS
(months)
No. of CG + PL CG + BV
patients (n=242) (n=242)
Baseline risk factor
All patients
HR (95% CI)
484
8.4
12.4
0.49 (0.40–0.61)
Platinum-free interval,
months
6–12
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 disease
Yes
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)
0
367
8.6
12.5
0.47 (0.36–0.60)
1
116
8.3
10.6
0.61 (0.39–0.95)
Baseline ECOG PS
CG + BV CG + PL
better
better
0.2
0.5
1
HR
2
5
CG + PL
(n=233)
CG + BV
(n=247)
Any AE
100
100
Serious AE
25
35
Grade 3–5 AE
82
90
Grade 3–5 AE of special interest
62
74
Grade 5 AE
<1a
<1b
Patients, %
aAcute
myocardial infarction in one patient
hemorrhage in one patient
bIntracranial
Patients, %
ATE, all grades
CG + PL
(n=233)
1
CG + BV
(n=247)
3
VTE, grade ≥3
3
4
CNS bleeding, all grades
<1
1
Non-CNS bleeding, grades ≥3
1
6
CHF, grades ≥3
1
1
Neutropenia, grade ≥3
56
58
Febrile neutropenia, grade ≥3
2
2
Hypertension, grade ≥3
<1
17
Fistula/abscess, all grades
<1
2
GI perforation, all grades
0
0
Proteinuria, grade ≥3
1
9
RPLS, all grade
0
1
Wound-healing complication, grades ≥3
0
1
a
ATE = arterial thromboembolic event; CHF = congestive heart failure; GI = gastrointestinal;
RPLS = reversible posterior leukoencephalopathy syndrome; VTE = venous thromboembolic event
aTwo GI perforations occurred 69 days after last BV dose
PlatinumSensitive
Median OS 6
months
PlatinumResistant or
Refractory
Retrospective analysis: 111 pts
Recurrence < 3m or Ø Response
SV < 4months 32%
SV < 12months 73%
Markman et al. Gynecol Oncol, 2004
PlatinumSensitive
PlatinumResistant or
Refractory
Poli-CT vs
Mono-CT
MONO-CT

Better toxicity
profile
POLI-CT



No improvement
in Overall
Survival
Worse toxicity profile
Higher response rates
Questionable Higher TTP








Liposomal Doxorrubicin
Gemcitabine
Paclitaxel (weekly)
Docetaxel
Topotecan
Etoposide (oral)
Vinorelbine
Ifosfamide
*Multicentre Italian Trials in Ovarian cancer
Recurrent Ovarian Cancer
TTP  12 m
R
a
n
d
o
m
i
z
a
ti
o
n
Gemcitabine 1000mg/m2 IV
D1,8,15 q4w
Doxo Lipossomal 40 mg/m2 IV
D1 q4w
Caelyx 40mg/m2 EV cada 28 dias
 Primary end-point: TTP
 Secondary end-points: OS, RR, QOL
Ferrandina et al. J Clin Oncol, 2008
Ferrandina et al. J Clin Oncol, 2008
Response Rates
Ferrandina et al. J Clin Oncol, 2008
Time to Progression
Ferrandina et al. J Clin Oncol, 2008
Quality of Life
Ferrandina et al. J Clin Oncol, 2008
Recurrent Ovarian Cancer
TTP  6 m
 Primary end-point
R
a
n
d
o
m
i
z
a
t
i
o
n
Gemcitabine 1000mg/m2 EV
D1,8 q 3 w
Doxo Lipossomal 50 mg/m2 EV
D1 q 4 w
 Secondary end-point: OS, RR, QOL
Mutch et al. J Clin Oncol, 2007
Progression-free Survival
Mutch et al. J Clin Oncol, 2007
Overall Survival
Mutch et al. J Clin Oncol, 2007
AURELIA/MO22224: Scheme
EOC, PP or FTC
that relapsed
within <6 months
after platinumbased
chemotherapy
(n=300)
Progression
Chemotherapy alone
(physician’s choice):
paclitaxel 80mg/m2 qw or
topotecan 4mg/m2 days 1, 8 and 15
q4w or 1.25mg/kg days 1–5 q3w or
PLD 40mg/m2 q4w
Physician’s choice:
Bevacizumab
15mg/kg q3w or
SOC
Bevacizumab 10mg/kg q2w or
15mg/kg q3w +
chemotherapy (physician’s
choice, as in control arm)
SOC
•Endpoints
– primary: PFS
Progression
– 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
Primary objective: To compare PFS with chemotherapy (CT) alone vs
BEV + CT according to RECIST v1.0
Secondary objectives: To compare

Objective response rate (ORR) according to RECIST v1.0 and/or
GCIG CA-125 criteria

Overall survival

Quality of life

Safety and tolerability
Statistical assumptions

HR of 0.7 (median PFS 4.0 → 5.7 months with BEV)

80% power for 2-sided log-rank test at α=0.05
Primary analysis: PFS events in 301 of 361 patients

Data cut-off: November 14, 2011
Characteristic
Median age, years
(range)
Origin of cancer: Ovary
Serous/adenocarcinoma at diagnosis
Histologic grade at diagnosis
1
2/3
Prior anti-angiogenic therapya
Two prior chemotherapy regimens
PFI <3 monthsa,b
ECOG PS
0
1/2
Measurable disease
Ascites
PFI = platinum-free interval
aStratification
factor. bFrom last platinum to subsequent PD
CT (n=182)
n (%)
61
(25‒84)
157 (86)
152 (84)
BEV + CT (n=179)
n (%)
62
(25‒80)
167 (93)
156 (87)
9 (5)
153 (84)
14 (8)
78 (43)
46 (25)
10 (6)
147 (82)
12 (7)
72 (40)
50 (28)
99 (54)
80 (44)
144 (79)
54 (30)
107 (60)
70 (39)
143 (80)
59 (34)
1.0
Estimated probability
Events, n (%)
Median PFS, months
(95% CI)
HR (unadjusted)
(95% CI)
Log-rank p-value
(2-sided, unadjusted)
0.8
0.6
0.4
BEV + CT
(n=179)
166 (91%)
3.4
(2.2‒3.7)
135 (75%)
6.7
(5.7‒7.9)
0.48
(0.38‒0.60)
<0.001
0.2
3.4
0
0
No. at risk:
CT
BEV + CT
CT
(n=182)
182
179
6.7
6
93
140
37
88
12
20
49
8
18
18
Time (months)
1
4
Median duration of follow-up: 13.9 months (CT arm) vs 13.0 months (BEV + CT arm)
1
1
24
0
1
0
0
30
No. of
patients
CT
BEV + CT
HRa
361
3.4
6.7
0.48
<65
228
3.4
6.0
0.49
≥65
133
3.5
7.8
0.47
<3
96
2.1
5.4
0.53
3‒6
257
3.6
7.8
0.46
No (<1)
74
3.7
7.5
0.46
Yes (1‒<5)
126
3.3
7.5
0.50
Yes (≥5)
161
3.3
6.0
0.47
Yes
113
2.5
5.6
0.40
No
248
3.5
7.6
0.48
115
3.9
10.4
0.46
PLD
126
3.5
5.4
0.57
Topotecan
120
2.1
5.8
0.32
Subgroup
All patients
Age, years
PFI, monthsb
Measurable
disease, cm
Ascites
Median PFS, months
Chemotherapy Paclitaxel
BEV + CT
better
0.2 0.3 0.5
aUnadjusted. bMissing
n=8
CT
better
1
2
3 4 5
Patients (%)
50
45
40
35
30
25
20
15
10
5
0
CT
p<0.001a
30.9
12.6
Responders
(RECIST
and/or CA-125) (n=350)
aTwo-sided
chi-square test with Schouten correction
p=0.001a
BEV + CT
p<0.001a
31.8
27.3
11.8
RECIST responders
(n=287)
11.6
CA-125 responders
(n=297)
Grade ≥3 adverse events of special
interest, n (%)
Hypertension
Grade ≥2
Proteinuria
Grade ≥2
GI perforation
Grade ≥2
Fistula/abscess
Grade ≥2
Bleeding
Thromboembolic event
Arterial
Venous
Wound-healing complication
RPLS
CHF
Cardiac disorders (excluding CHF)
CT
(n=181)
BEV + CT
(n=179)
2 (1.1)
12 (6.6)
0
1 (0.6)
0
0
0
0
2 (1.1)
8 (4.4)
0
8 (4.4)
0
0
1 (0.6)
0
13 (7.3)
36 (20.1)
3 (1.7)
19 (10.6)
3 (1.7)
4 (2.2)
2 (1.1)
4 (2.2)
2 (1.1)
9 (5.0)
4 (2.2)
5 (2.8)
0
1 (0.6)
1 (0.6)
0
RPLS = reversible posterior leukoencephalopathy syndrome; CHF = congestive heart failure
18
≈
CT (n=181)
BEV + CT (n=179)
16
Patients (%)
14
12
10
8
6
≈
4
2
0
HFS = hand-foot syndrome
aPreferred
terms. bIncludes abdominal pain upper
≈ ≈
100
90
CT (CT arm) (n=181)
80
Patients (%)
70
CT (BEV + CT arm) (n=179)
60
50
40
30
20
10
0
1
2
3
4
5
1 cycle = 4 weeks except for q3w (day 1–5) topotecan
6
7
8 9 10 11 12 13 14 15 16 17 18
Cycle number
Grade ≥2 hand-foot syndrome by cycle
(PLD cohort)
100
90
Patients (%)
80
CT
BEV + CT
70
60
50
40
30
20
10
0
No. at risk
CT
BEV + CT
aIncidence
1
2
3
4
Cycle number
5
6
7
63
62
59
61
36
48
31
41
23
30
18
23
9
10
is based on the No. at risk receiving PLD in the respective cycle
Vertical bars represent 95% Pearson‒Clopper confidence intervals
Cycles with <10 patients in each arm not shown
Grade ≥2 peripheral sensory neuropathy by cycle
(paclitaxel cohort)
100
90
CT
Patients (%)
80
BEV + CT
70
60
50
40
30
20
10
0
No. at risk
CT
BEV + CT
aIncidence
1
2
3
4
55
60
54
58
43
53
35
47
5
6
Cycle number
24
41
is based on the No. at risk receiving paclitaxel in the respective cycle
Vertical bars represent 95% Pearson‒Clopper confidence intervals
Cycles with <10 patients in each arm not shown
19
34
7
8
9
8
20
6
16
2
11

The primary objective was met



Significant improvement in ORR


30.9% vs 12.6%, respectively (p=0.001) by RECIST and/or
CA-125
BEV safety profile consistent with previous experience


PFS HR 0.48 (p<0.001) in favor of BEV combination therapy vs
single-agent CT
Median PFS: 6.7 vs 3.4 months, respectively
Patients at high risk of GI perforation were excluded from
the study
Overall survival data expected in 2013
 PARP inhibitors
 Randomized Phase II trial: (Ledermann et al, NEJM, 2012)
 N = 265
 CT 
Olaparib vs 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%
* Time intervalo between two cytorecuctive surgeries: 36 months
* F/U after salvage surgery: 19 months
50% !
Berek et al. Ann Oncol, 1999
Berek et al. Ann Oncol, 1999
Berek et al. Ann Oncol, 1999
Berek et al. Ann Oncol, 1999
Berek et al. Ann Oncol, 1999
Secondary cytoreduction in recurrent
ovarian cancer:
need for a randomized trial
Patients
• Platinum sensitive
ovarian cancer
• First recurrence
R
A
N
D
O
M
I
Z
E
D
1:1
Efficacy end points
Chemotherapy
Primary:
• OS
Secondary Cytoreduction 
Chemotherapy
Secondary:
• Progressin-free surviv
• Quality of life
• Treatment morbidity
Platinum sensitive
Platinum
resistant/refractory
Platinum sensitive
Carboplatin-Gemcitabine-BEV
or
Carboplatin + Liposomal Doxo
Platinum
resistant/refractory
Platinum sensitive
Salvage Surgery
Carboplatin-Gemcitabine-BEV
or
Carboplatin + Liposomal Doxo
Platinum
resistant/refractory
Platinum sensitive
Salvage Surgery
Carboplatin-Gemcitabine-BEV
or
Carboplatin + Liposomal Doxo
Platinum resistant/refractory
Platinum
resistant/refractory
Platinum sensitive
Platinum
resistant/refractory
Salvage Surgery
Carboplatin-Gemcitabine-BEV
or
Carboplatin + Liposomal Doxo
Platinum resistant/refractory
CT + BEV
(PLD/paclitaxel/topotecan)
Platinum sensitive
Platinum
resistant/refractory
Salvage Surgery
Carboplatin-Gemcitabine-BEV
or
Carboplatin + Liposomal Doxo
Platinum resistant/refractory
CT + BEV
(PLD/paclitaxel/topotecan)
Gemcitabine
Paclitaxel
Topotecan
Etoposide
Ifosfamide
Hormonal therapy
[email protected]