07 state of the art of the management of advanced and recurrent ovarian cancer

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]


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 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


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


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


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



Overall Survival Overall Survival vs Residual

Disease



Citoreduction CT

CT Citoreduction

Complete resection

20.4% 50.0%

Ressecability: Sequential Treatment



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





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


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


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


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)


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

4.11.5 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

(%

)


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


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


Optimal platinum-based combination


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


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


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


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


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

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

Thank You

07 state of the art of the management of advanced and recurrent ovarian cancer

Health & Medicine

Transcript of 07 state of the art of the management of advanced and recurrent ovarian cancer