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State of the art of the management of advanced
and recurrent ovarian cancer
Fernando Cotait Maluf Director of Medical Oncology Department
São José HospitalSão Paulo São Paulo Brazil
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
Introduction
Surgery
• 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]
Lessons from Chemotherapy-1990’
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
• 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
• MONOCT platinum-based versus POLICT platinum-based 1,2
• HR death: 0.91 [0.75 – 1.05]
Lessons from Chemotherapy-1990’
Ovarian Cancer Meta-Analysis Project (Gynecol Oncol, 2002) 1
Advanced Ovarian Cancer Trialists Group (2002) 2
ICON 3: Carboplatin vs Carboplatin + Paclitaxel
Lessons from Chemotherapy-2000’
GOG 111 and OV 10(Intergroup)
McGuire et al, N Eng J Med, 1996;n=386, suboptimal cytoreduction III/IV SLP SGPT 18m 38mPC 13m 24m
Piccart et al, J Nat Cancer Inst, 2000;n=668, debulking surgery, II-IV SLP SGPT 17m 35mPC 12m 25m
Evolvement of Traditional Chemotherapy
Dose-dense IV chemotherapy
Advanced Ovarian Cancer
(n = 637)
RANDOMIZATION
Carboplatin AUC 6 + Paclitaxel 180mg/m2
q 21 days x 6 cycles
Katsumata N, Lancet: 374, 2009
Carboplatin AUC 6 + Paclitaxel 80mg/m2
d1,8,15
q 21 days x 6 cycles
Evolvement of Traditional Chemotherapy
Dose-dense IV chemotherapy
Katsumata N, Lancet: 374, 2009
Progression-free Survival Overall Survival
Evolvement of Traditional Chemotherapy
IP administration
Standard arm IV
D1 D2 IV IV
D1 Paclitaxel IV 135mg/m2/24hs
D2 Cisplatin IV 75mg/m2
D1 D2 D8
IV IP IP
Experimental arm IV/IP D1 Paclitaxel EV 135mg/m2/24hsD2 Cisplatin IP 100mg/m2
D8 Paclitaxel IP 60mg/m2
GOG 172
Armostrong e al, NEJM, 2006;N=429, optimal debulking surgery, stage III SLP SGPT IV 19m 50mPT IV/IP 24m 65m
Only 42% of pts completed treat. IV/IP arm
Evolvement of Traditional Chemotherapy
IP administration
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
* Statistically significant : p < 0.05
New targets and new agents
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)
RANDOMIZ E
I
II
III
Arm
1:1:1
New targets and new agents
GOG-218: Progression-Free SurvivalArm I
CP (n=625)
Arm IICP + 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 IIICP + BEV BEV
(n=623)
360 (57.8)
14.1
0.717 (0.625–0.824)
<0.0001a
New targets and new agents
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) orstage IIb–IV EOC,
PP, FTC(n=1,520)
New targets and new agents
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
Management of Recurrent Ovarian Cancer: Importance of Platinum-
intervalPRIMARY TREATMENT
0 3 6 12 18 24
Refractory
Resistent
Sensitive
Highly sensitive
Months
Management of Recurrent Ovarian Cancer: Importance of Platinum-interval
70
60
50
40
30
20
10
0
12
33
59
< 6 months
12-18 months
> 18 months
Overall Response Rate (%)
Interval from prior platinum treatment (months)
Management of Recurrent Disease
Platinum-Sensitive
Platinum-Resistant or Refractory
Platinum-based Therapy
Platinum-sensitive ovarian cancer
ΔT > 6 m
RANDOMIZATION
Carboplatin AUC 5 a 6 EV OR
Cisplatin 75mg/m2 EVq 21 days
Carboplatin AUC 5 EV OR
Cisplatin 50mg/m2 EV +
Paclitaxel 175mg/m2 EVQ 21 days
Parmar MK, Lancet: 361, 2003
ICON-4/AGO-OVAR-2.2 Trial
Recurrent Sensitive Ovarian Cancer:
MonoCT vs PoliCT platinum-based
Recurrent Sensitive Ovarian Cancer:
MonoCT vs PoliCT platinum-based
Parmar MK, Lancet: 361, 2003
Progression-free Survival
ICON-4/AGO-OVAR-2.2 Trial
Recurrent Sensitive Ovarian Cancer:
MonoCT vs PoliCT platinum-based
Parmar MK, Lancet: 361, 2003
Overall Survival
ICON-4/AGO-OVAR-2.2 Trial
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)
Recurrent Sensitive Ovarian Cancer:
MonoCT vs PoliCT platinum-based
Pujades E et al, J Clin Oncol, 2010
Inclusion Criteria:
• Platinum-sensitive (> 6 m)
• 1 or 2 prior platinum-based CT
• Measurable disease (image or CA125)
RANDOMIZATION
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
CALYPSO: Scheme
Recurrent Sensitive Ovarian Cancer:
Optimal platinum-based combination
Pujades E et al, J Clin Oncol, 2010
Hematologic Toxicity
Recurrent Sensitive Ovarian Cancer:
Optimal platinum-based combination
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%
Thrombocitopenia, grade 3/4 19% 5%
Pujades E et al, J Clin Oncol, 2010
Neuropathy
Recurrent Sensitive Ovarian Cancer:
Optimal platinum-based combination
Recurrent Sensitive Ovarian Cancer:
Optimal platinum-based combination
Pujades E et al, J Clin Oncol, 2010
CALYPSO: Progression-Free Survival
Recurrent Sensitive Ovarian Cancer: platinum-based combo with optimal
target agents
•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
Recurrent Sensitive Ovarian Cancer: platinum-based combo with optimal
target agents
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
928
9010
ECOG PS 0, % 76 75Histologic subtype, % Serous Mucinous/clear cell Other
843 14
785
17
Platinum-free interval, % 6–12 months >12 months
4258
4159
Cytoreductive surgery for recurrent disease, % 10 12
Recurrent Sensitive Ovarian Cancer: platinum-based combo with optimal
target agents
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
port
ion
pro
gre
ssio
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
Recurrent Sensitive Ovarian Cancer: platinum-based combo with optimal
target agentsOCEANS: 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 12.40.49 (0.40–
0.61)Platinum-free interval, months
6–12 202 8.0 11.90.41 (0.29–
0.58)
>12 282 9.7 12.40.55 (0.41–
0.73)Cytoreductive surgery for recurrent disease
Yes 54 7.5 16.70.50 (0.24–
1.01)
No 430 8.4 12.30.49 (0.39–
0.62)Age, years <65 306 8.5 12.5
0.47 (0.36–0.62)
≥65 178 8.4 12.30.50 (0.34–
0.72)Baseline ECOG PS 0 367 8.6 12.5
0.47 (0.36–0.60)
1 116 8.3 10.60.61 (0.39–
0.95) HR0.2 0.5 1 2 5
Recurrent Sensitive Ovarian Cancer: platinum-based combo with optimal
target agents
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 12.40.49 (0.40–
0.61)Platinum-free interval, months
6–12 202 8.0 11.90.41 (0.29–
0.58)
>12 282 9.7 12.40.55 (0.41–
0.73)Cytoreductive surgery for recurrent disease
Yes 54 7.5 16.70.50 (0.24–
1.01)
No 430 8.4 12.30.49 (0.39–
0.62)Age, years <65 306 8.5 12.5
0.47 (0.36–0.62)
≥65 178 8.4 12.30.50 (0.34–
0.72)Baseline ECOG PS 0 367 8.6 12.5
0.47 (0.36–0.60)
1 116 8.3 10.60.61 (0.39–
0.95)
OCEANS: PFS subgroup analyses
HR0.2 0.5 1 2 5
Recurrent Sensitive Ovarian Cancer: platinum-based combo with optimal
target agents
OCEANS: Overview of AEs
Patients, %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
aAcute myocardial infarction in one patientbIntracranial hemorrhage in one patient
Recurrent Sensitive Ovarian Cancer: platinum-based combo with optimal
target agents
OCEANS: AEs of special interest
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
Patients, %
CG + PL(n=233)
CG + BV(n=247)
ATE, all grades 1 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 0a
Proteinuria, grade ≥3 1 9
RPLS, all grade 0 1
Wound-healing complication, grades ≥3 0 1
Recurrent Sensitive Ovarian Cancer: platinum-based combo with optimal
target agents
Management of Recurrent Disease
Platinum-Sensitive
Platinum-Resistant or Refractory
Retrospective analysis: 111 pts
Recurrence < 3m or Ø Response
Median OS 6 months
SV < 4months 32%SV < 12months 73% Markman et al. Gynecol Oncol, 2004
Management of Recurrent Disease
Platinum-Sensitive
Platinum-Resistant or Refractory
Poli-CT vs Mono-CT
Management of Recurrent Disease
MONO-CT POLI-CT
Better toxicity profile
Worse toxicity profile
Higher response rates
Questionable Higher TTP
No improvement
in Overall Survival
Classic Chemotherapy Agents for Recurrent Resistant Ovarian
Cancer
Liposomal Doxorrubicin Gemcitabine Paclitaxel (weekly) Docetaxel Topotecan Etoposide (oral) Vinorelbine Ifosfamide
Doxo Lipossomal vs Gemcitabina (MITO)*
*Multicentre Italian Trials in Ovarian cancer
Recurrent Ovarian Cancer
TTP 12 m
Randomi z ation
Gemcitabine 1000mg/m2 IV
D1,8,15 q4w
Caelyx 40mg/m2 EV cada 28 dias
Doxo Lipossomal 40 mg/m2 IV D1 q4w
Primary end-point: TTP
Secondary end-points: OS, RR, QOL Ferrandina et al. J Clin Oncol, 2008
Doxo Lipossomal vs Gemcitabina (MITO)*
Ferrandina et al. J Clin Oncol, 2008
Doxo Lipossomal vs Gemcitabina (MITO)*
Response Rates
Ferrandina et al. J Clin Oncol, 2008
Doxo Lipossomal vs Gemcitabina (MITO)*
Time to Progression
Ferrandina et al. J Clin Oncol, 2008
Doxo Lipossomal vs Gemcitabina (MITO)*
Quality of Life
Ferrandina et al. J Clin Oncol, 2008
Doxo Lipossomal vs Gemcitabina
Randomi z at
ion
Gemcitabine 1000mg/m2
EV D1,8 q 3 w
Doxo Lipossomal 50 mg/m2 EV D1 q 4 w
Primary end-point
Secondary end-point: OS, RR, QOL Mutch et al. J Clin Oncol, 2007
Recurrent Ovarian Cancer
TTP 6 m
Doxo Lipossomal vs Gemcitabina
Progression-free Survival
Mutch et al. J Clin Oncol, 2007
Doxo Lipossomal vs Gemcitabina
Overall Survival
Mutch et al. J Clin Oncol, 2007
Management of Recurrent Resistant Ovarian Cancer: evolvement of the role of
target agents
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/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
EOC, PP or FTC that relapsed
within <6 months after platinum-
based chemotherapy
(n=300)
Statistical design
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
Baseline characteristics
PFI = platinum-free intervalaStratification factor. bFrom last platinum to subsequent PD
CharacteristicCT (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)
Progression-free survival
Median duration of follow-up: 13.9 months (CT arm) vs 13.0 months (BEV + CT arm)
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
Est
imat
ed p
roba
bilit
y
0 6 12 18 24 30Time (months)
182 37 8 1 0179 88 18 1 0
CTBEV + CT
No. at risk: 93140
2049
14
01
3.4 6.7
Subgroup analysis of PFS
aUnadjusted. bMissing n=8
SubgroupNo. of
patients
Median PFS, months
HRa
BEV + CT
betterCT
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
0.320.2 0.3 0.5 1 2 3 4 5
aTwo-sided chi-square test with Schouten correction
Summary of best overall response rates
Responders (RECIST and/or CA-
125) (n=350)
RECIST responders (n=287)
CA-125 responders (n=297)
0
5
10
15
20
25
30
35
40
45
50
12.6 11.8 11.6
30.927.3
31.8
CT BEV + CT
p=0.001ap<0.001a p<0.001a
Pat
ient
s (%
)
RPLS = reversible posterior leukoencephalopathy syndrome; CHF = congestive heart failure
Adverse events of special interest
Grade ≥3 adverse events of special interest, n (%)
CT (n=181)
BEV + CT(n=179)
Hypertension 2 (1.1) 13 (7.3) Grade ≥2 12 (6.6) 36 (20.1)Proteinuria 0 3 (1.7) Grade ≥2 1 (0.6) 19 (10.6)GI perforation 0 3 (1.7) Grade ≥2 0 4 (2.2)Fistula/abscess 0 2 (1.1) Grade ≥2 0 4 (2.2)Bleeding 2 (1.1) 2 (1.1)Thromboembolic event Arterial Venous
8 (4.4)0
8 (4.4)
9 (5.0)4 (2.2)5 (2.8)
Wound-healing complication 0 0RPLS 0 1 (0.6)CHF 1 (0.6) 1 (0.6)Cardiac disorders (excluding CHF) 0 0
HFS = hand-foot syndromeaPreferred terms. bIncludes abdominal pain upper
Additional grade ≥3 adverse eventsa in ≥2% of patients in
either arm
Neutro
penia
Fatig
ue
Leuk
open
ia
Vomiting HFS
Dyspn
ea
Diarrhe
a
Anem
ia
Thro
mbo
cyto
p...
0
2
4
6
8
10
12
14
16
18
CT (n=181)
Pat
ient
s (%
)
Periph
eral
sens
ory
neur
opat
hy
Abdom
inal p
ainb
≈≈
≈
≈
1 cycle = 4 weeks except for q3w (day 1–5) topotecan
Higher chemotherapy exposure in the BEV + CT arm than in the CT
arm
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 180
10
20
30
40
50
60
70
80
90
100
CT (CT arm) (n=181)
CT (BEV + CT arm) (n=179)
Pat
ient
s (%
)
Cycle number
1 2 3 4 5 6 70
10
20
30
40
50
60
70
80
90
100
CT BEV + CT
aIncidence is based on the No. at risk receiving PLD in the respective cycleVertical bars represent 95% Pearson‒Clopper confidence intervalsCycles with <10 patients in each arm not shown
Similar time course of cumulative hand-foot syndrome in the two
armsa
Pat
ient
s (%
)
Cycle numberNo. at riskCT 63 59 36 31 23 18 9BEV + CT 62 61 48 41 30 23 10
Grade ≥2 hand-foot syndrome by cycle (PLD cohort)
aIncidence is based on the No. at risk receiving paclitaxel in the respective cycleVertical bars represent 95% Pearson‒Clopper confidence intervalsCycles with <10 patients in each arm not shown
Similar time course of cumulative neuropathy in the two armsa
Pat
ient
s (%
)
Grade ≥2 peripheral sensory neuropathy by cycle(paclitaxel cohort)
Cycle numberNo. at riskCT 55 54 43 35 24 19 8 6 2BEV + CT 60 58 53 47 41 34 20 16 11
1 2 3 4 5 6 7 8 90
10
20
30
40
50
60
70
80
90
100
CT BEV + CT
Summary
The primary objective was met 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
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 Patients at high risk of GI perforation were excluded from
the study
Overall survival data expected in 2013
Management of Recurrent Resistant Ovarian Cancer: evolvement of the role of target agents
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%
Management of Recurrent Resistant Ovarian Cancer: evolvement of the role of target agents
Recurrent Ovarian Cancer:
The role of Salvage Surgery
* F/U after salvage surgery: 19 months
* Time intervalo between two cytorecuctive surgeries: 36 months
Berek et al. Ann Oncol, 1999
50% !
Recurrent Ovarian Cancer:
The role of Salvage Surgery
Berek et al. Ann Oncol, 1999
Recurrent Ovarian Cancer:
The role of Salvage Surgery
Berek et al. Ann Oncol, 1999
Recurrent Ovarian Cancer:
The role of Salvage Surgery
Berek et al. Ann Oncol, 1999
Recurrent Ovarian Cancer:
The role of Salvage Surgery
Berek et al. Ann Oncol, 1999
Recurrent Ovarian Cancer:
The role of Salvage Surgery
Secondary cytoreduction in recurrent ovarian cancer:
need for a randomized trial
Chemotherapy
Secondary Cytoreduction Chemotherapy
RANDOMIZED
1:1
Patients
• Platinum sensitive ovarian cancer
• First recurrence
Efficacy end points
Primary:
• OS
Secondary:• Progressin-free
survival• Quality of life• Treatment morbidity
Platinum sensitive
Platinum resistant/refracto
ry
Recurrent Ovarian Cancer
Platinum sensitive
Platinum resistant/refracto
ry
Carboplatin-Gemcitabine-BEVor
Carboplatin + Liposomal Doxo
Recurrent Ovarian Cancer
Platinum sensitive
Platinum resistant/refracto
ry
Carboplatin-Gemcitabine-BEVor
Carboplatin + Liposomal Doxo
Salvage Surgery
Recurrent Ovarian Cancer
Platinum sensitive
Platinum resistant/refracto
ry
Carboplatin-Gemcitabine-BEVor
Carboplatin + Liposomal Doxo
Platinum resistant/refractory
Salvage Surgery
Recurrent Ovarian Cancer
Platinum sensitive
Platinum resistant/refracto
ry
Carboplatin-Gemcitabine-BEVor
Carboplatin + Liposomal Doxo
CT + BEV(PLD/paclitaxel/
topotecan)
Salvage Surgery
Recurrent Ovarian Cancer
Platinum resistant/refractory
Platinum sensitive
Platinum resistant/refracto
ry
Carboplatin-Gemcitabine-BEVor
Carboplatin + Liposomal Doxo
CT + BEV(PLD/paclitaxel/
topotecan)
Salvage Surgery
GemcitabinePaclitaxel TopotecanEtoposideIfosfamideHormonal therapy
Recurrent Ovarian Cancer
Platinum resistant/refractory
Thank You