State of the art of the management of advanced
and recurrent ovarian cancer
Fernando Cotait Maluf
Chair of Medical Oncology Department
São José HospitalSão Paulo São Paulo Brazil
• 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
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
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
Optimal sequence of Surgery and Chemotherapy
Advanced Ovarian Cancer
(III/IV)
(n = 718)
RANDOMIZATION
Primary Citoreduction
Vergote I, NEJM: 363 2010
Platinun-CT
x 3 cycles
Interval Cytoreductio
n
Platinun-CT
x 3 cycles
Platinun-CT
x 6 cycles
Optimal sequence of Surgery and Chemotherapy
Vergote I, NEJM: 363 2010
Overall Survival Overall Survival vs Residual
Disease
Optimal sequence of Surgery and Chemotherapy
Vergote I, NEJM: 363 2010
Citoreduction CT
CT Citoreduction
Complete resection
20.4% 50.0%
Ressecability: Sequential Treatment
Optimal sequence of Surgery and Chemotherapy
Vergote I, NEJM: 363 2010
Safety at the time of Resection: Sequential Treatment
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%
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
Adverse event (grade when limited), n (%)
Arm ICP
(n=601)
Arm IICP + BEV(n=607)
Arm IIICP + 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 neutropenia21
(3.5)30
(4.9)26
(4.3)
Venous thromboembolic event35
(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
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
New targets and new agents
ICON 7: Select Adverse Events
6.2
2.5 2.1 1.3 0.4
11.6
4.11.5 0.4 0
29.1
2.0
9.2
25.9
4.4 5.0
1.7 1.3
39.6
6.73.6
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
Pati
ents
(%
)
New targets and new agents
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
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
Overall Survival
ICON-4/AGO-OVAR-2.2 Trial
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
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
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
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
Classic Chemotherapy Agents for Recurrent Resistant Ovarian
Cancer
Liposomal Doxorrubicin Gemcitabine Paclitaxel (weekly) Docetaxel Topotecan Etoposide (oral) Vinorelbine Ifosfamide
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)
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 (%
)
Management of Recurrent Resistant Ovarian Cancer: evolvement of the role of
target agents
PARP inhibitors
Randomized Phase II trial: (Ledermann et al, ASCO , 2011)
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%
Convidados Internacionais
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