Transcript Slide 1

Ovarian Cancer:
A new look at an old veteran
Sana Al-Sukhun, MD, MSc.
Assistant Professor, Medical Oncology/ Hematology
University of Jordan
Best of ASCO
July 11th 2009
Ovarian Cancer
 First line treatment:
Standard Tx : Carboplatin / paclitaxel.
 Relapsed setting:
• Choice of relapsed disease treatment is dependent on
interval since prior platinum-based therapy
• Relapse within 6 months: platinum-resistant disease
• Relapse over 6 months: platinum-sensitive disease
• Carboplatin-paclitaxel is standard in platinum-sensitive
disease
Ozols RF et al, J Clin Oncol 2003, 21: 3194-3200
Is carboplatin / liposomal
doxorubicin a replacement
doublet for carboplatin /
paclitaxel?
Introduction
• Single-agent pegylated liposomal doxorubicin
(PLD) is a standard option for platinum resistant
relapsed ovarian cancer 1.
• Combination of carboplatin and PLD is highly
active as second-line chemotherapy in patients with
advanced ovarian cancer in late relapse 2-3
•
•
1Gordon
•
3Ferrero
AN et al, J Clin Oncol 2001, 19: 3312-3322
2Ferrero JM et al, Proc Am Soc Clin Oncol 2002
JM et al, Ann Oncol 2007, 18: 263-268
Carboplatin plus Paclitaxel versus
Carboplatin plus Stealth Liposomal Doxorubicin
in patients with advanced ovarian cancer:
activity and safety results of the
MITO-2 randomized multicenter trial
S. Pignata1, G. Scambia2, A. Savarese3, R. Sorio4, E. Breda5,
G. Ferrandina2, V. Gebbia6, P. Musso7, C. Gallo8, F. Perrone9
1Istituto
Nazionale Tumori, Napoli; 2Università Cattolica del Sacro Cuore, Roma; 3Istituto Regina Elena, Roma;
4CRO, Aviano; 5Ospedale Fatebenefratelli, Isola Tiberina, Roma;
6Casa di Cura La Maddalena, Università di Palermo; 7Ospedale Oncologico M.Ascoli A.R.N.A.S., Palermo;
8Seconda Università di Napoli; 9Istituto Nazionale Tumori di Napoli,Italy.
Study design
R
a
n
d
o
m
Control arm
Carboplatin AUC 5, day 1
Paclitaxel 175 mg/m2, day 1
1:1
Treatment repeated every 21 days, for 6 cycles
Experimental arm
Carboplatin AUC 5, day 1
PLD 30 mg/m2, day 1
Strata:
Treatment
•Center
•PS (0-1, 2)
•Stage (IC, II, III, IV)
•Residual disease after surgery
(absent, 1 cm, 1 cm, no surgery)
repeated every 21 days, for 6 cycles
Study design
R
a
n
d
o
m
Control arm
1:1
Carboplatin AUC 5, day 1
Paclitaxel 175 mg/m2, day 1
Experimental arm
Carboplatin AUC 5, day 1
PLD 30 mg/m2, day 1
Is carboplatin plus PLD more effective than carboplatin plus
paclitaxel as first-line treatment of patients with advanced ovarian
cancer?
Objective : To demonstrate improvement in PFS from 18 to 22.5
months ( HR 0.8, 80% power).
Study population
Inclusion criteria
•
•
•
•
•
Cyto/histological diagnosis of ovarian cancer
FIGO Stage IC – II – III – IV
Age  75
ECOG Performance Status 0-2
No previous chemotherapy
Main exclusion criteria
• ANC  2000/L, platelets  100000/L
• Creatinine  1.25 x UNL, SGOT and SGPT  1.25 x UNL
• Life expectancy of less than 3 months
Study endpoints
Primary endpoint
• Progression-free survival (PFS)
Secondary endpoints
• Overall survival (OS)
• Objective response rate (RECIST)
• Toxicity (NCI – CTC v2.0)
• Quality of Life (EORTC QLQ C30)
Baseline characteristics
Carbo + Paclitaxel
(n = 410)
Age median (range)
57 (21-77)
ECOG Performance Status
0-1
398 (97%)
2
12 (3%)
FIGO Stage
IC
38 (9%)
II
40 (10%)
III
243 (59%)
IV
89 (22%)
Residual disease after surgery
Absent
152 (37%)
 1 cm
68 (17%)
 1 cm
117 (28%)
No surgery
73 (18%)
Carbo + PLD
(n=410)
57 (25-77)
397 (97%)
13 (3%)
38
37
247
88
(9%)
(9%)
(60%)
(22%)
150
69
114
67
(37%)
(19%)
(28%)
(16%)
Treatment compliance: delays
350
Carboplatin + Paclitaxel
Carboplatin + PLD
300
Number 250
of
200
patients
Delays due to non hematologic toxicity
Delays due to hematologic toxicity
150
100
50
0
Cycle 2
2 CP
Cycle 3
Cycle 4
3 4 CP
CLD
x
Cycle 5
Cycle 6
5 6 CP
CLD
Completed 6 cycles : 82% Carboplatinum / PLD
Vs 88% receiving Carboplatinum / Paclitaxel
x
P= 0.39
Toxicity (2)
Any grade
Allergy
Heart
Fatigue
Constipation
Nausea
Vomiting
Diarrhoea
Hair loss
Skin toxicity
Stomatitis
Neurotoxicity
C+P
6%
2%
44%
32%
47%
29%
13%
63%
6%
9%
47%
C+PLD
5%
4%
43%
32%
51%
30%
6%
14%
20%
20%
15%
Severe (G3)
p*
0.60
0.26
0.86
0.99
0.21
0.83
0.001
0.001
0.001
0.001
0.001
C+P
2%
0.3%
3%
1%
2%
2%
1%
C+PLD
2%
2%
3%
1%
2%
3%
-
p*
0.86
0.06
0.94
0.73
0.95
0.42
0.25
0.3%
3%
2%
0.5%
0.2%
0.01
0.62
0.004
C+P: carboplatin + paclitaxel, 399 patients; C+PLD: carboplatin + PLD, 386 patients
*Chi square or Fisher exact test as appropriate
Objective response – RECIST
Women with target lesions
Carbo
+ Paclitaxel
(n=156)
Carbo
+ PLD
(n=134)
p (2)*
92 (59%)
76 (57%)
0.70
Complete response
24 (15%)
22 (16%)
Partial response
68 (44%)
54 (40%)
64 (41%)
58 (43%)
45 (29%)
41 (31%)
Progressive disease
9 (6%)
7 (5%)
Not evaluated
10 (6%)
10 (7%)
Objective response
No response
Stable disease
*Objective response vs no response
Activity
Women not eligible for RECIST
Carbo
+ Paclitaxel
Carbo
+ PLD
p (2)
Complete response (CR)
27 / 83 (33%)
29 / 99 (29%)
0.64*
No CR / No PD
46 / 83 (55%)
48 / 99 (48%)
2 / 83 (2%)
4 / 99 (4%)
8 / 83 (10%)
18 / 99 (18%)
73 / 88 (83%)
69 / 80 (86%)
Non-target lesions only
Progressive disease
Not evaluated
Elevated Ca125 only
Ca125 normalized
*
**
Complete response vs not
Ca125 normalized vs not
0.56**
Primary endpoint
• Number of events required for final
analysis (632) has not been reached yet
• As of May 4, 2009, with a median follow-up
of 35 months, 531 progressions have been
recorded
• Only overall curves are shown
0.8
Events
820
531
1-yr
PFS
2-yr
PFS
17.7
(95%CI
16.3-19.9)
65.0%
41.9%
48
60
72
69
21
-
0.2
0.4
0.6
Patients
Median PFS
(months)
0.0
Probability of progression-free survival
1.0
Progression-free survival*
Patients at risk
0
12
24
36
Months
820
531
258
134
*May 2009
What have we learned?
 Three weekly Carboplatinum / PLD is associated with:
• More delays- mainly due to hematological toxicity.
• More skin toxicity and stomatitis.
• Less hair loss and neurotoxicity.
 RECIST response and complete remission – similar.
 PFS ?
What is the standard for platinum
sensitive relapse?
ICON 4 / OVAR 2.2
Platinum VS platinum / paclitaxel.
OVAR 2.5
Carboplatin VS carboplatin / gemcitabine.
CALYPSO trial
Carboplatin & Pegylated Liposomal Doxorubicin (PLD)
versus Carboplatin & Paclitaxel
in Relapsed, Platinum-sensitive
Ovarian Cancer
Eric Pujade-Lauraine
on behalf of all GCIG collaborators
CALYPSO Study Schema
International, Intergroup, Open-label, Randomized Phase III Study
Ovarian cancer in late
relapse (> 6 months) after
1st- or 2nd-line platinumbased therapy (previous
taxane required)
Stratification:
• Therapy-free interval
(6-12 mo vs > 12 mo)
R
A
N
D
O
M
I
Z
E
• Measurable disease
Treatment
continues longer
(yes
vs no)
• Center
if
SD or Responsive.
Experimental arm: CD
PLD 30 mg/m2 IV d 1
Carboplatin AUC 5 d 1
Q 28 days x 6 courses*
Control arm: CP
Paclitaxel 175 mg/m2 IV d 1
Carboplatin AUC 5 d 1
Q 21 days x 6 courses*
*or progression in patients with SD or PR
CALYPSO Study Schema
NON-INFERIORITY study design
International, Intergroup, Open-label, Randomized Phase III Study
Ovarian cancer in late
relapse (> 6 months) after
1st- or 2nd-line platinumbased therapy (previous
taxane required)
- Primary endpoint:
PFS.
- Secondary endpoints:
QOL
OS
R
A
N
D
O
M
I
Z
E
Experimental arm: CD
PLD 30 mg/m2 IV d 1
Carboplatin AUC 5 d 1
Q 28 days x 6 courses*
Control arm: CP
Paclitaxel 175 mg/m2 IV d 1
Carboplatin AUC 5 d 1
Q 21 days x 6 courses*
*or progression in patients with SD or PR
Baseline Characteristics (1)
Characteristic
Age, median
CD (n=466)
CP (n=508)
Number of patients (%)
60.5
61.0
ECOG performance status*
0
1
2
286 (61)
159 (34)
13 (3)
317 (62)
164 (32)
15 (3)
Primary site of disease
Ovarian
415 (89)
451 (89)
334 (72)
366 (72)
Initial FIGO stage*
I/II
III/IV
52 (11)
401 (86)
59 (12)
427 (84)
Number of previous lines
One
Two
408 (88)
58 (12)
Papillary/Serous histology
* Missing values to attain 100%.
421 (83)
87 (17)
Baseline Characteristics (2)
Characteristic
CD (n=466)
CP (n=508)
Number of patients (%)
Prior taxane
462 (99)
500 (99)
Interval since prior therapy, median
6-12 months
> 12 months
162 (35)
304 (65)
182 (36)
326 (64)
Measurable disease
Yes
No
281(60)
185 (39)
321 (63)
188 (37)
Tumour size
< 5 cm
> 5 cm
377(81)
89(19)
419 (82)
90 (18)
217(47)
249 (53)
245(48)
264(52)
Number of sites
1
>1
Treatment Feasibility
CD (n=465)**
CP (n=501)**
21
16
Carbo: 99
PLD: 99
Carbo: 99
Paclitaxel: 98
Patients with ≥ 6 cycles, n (%)*
395 (85)
392 (78)
Patients with ≥ 9 cycles, n (%)
36 (8)
36 (7)
Treatment discontinuation
70 (15)
110 (22)
Toxicity - related treatment
discontinuation*
27 (6)
73 (15)
Hypersensitivity reactions*
(5)
(19)
Hypersensitivity - related
discontinuation*
(1)
(4)
Total treatment duration, median wk*
Relative dose intensity %
*
P< 0.001; ** Patients receiving at least one cycle
Progression-Free Survival (ITT)
CD
CP
Median PFS, mo
11.3
9.4
HR (95% CI)
0.82 (0.72, 0.94)
Log-rank p-value (superiority)
0.005
P-value (non-inferiority)
<0.001
Combination chemotherapy for
platinum sensitive disease
What have we learned?
 Four weekly Carboplatinum / PLD is associated with:
• Less hematologic toxicity.
• More skin toxicity and stomatitis.
• Less hair loss and neurotoxicity.
 The combination of PLD-carboplatin was not inferior in
term of PFS to paclitaxel-carboplatin, BUT the question of
superiority remains open.
18% reduction in risk of recurrence (HR 0.82; P=0.005).
 Overall survival data & QOL pending.
What have
What’s
the we
implication?
learned?
 Carboplatinum / PLD is associated with different toxicity profile from
carboplatin/ paclitaxel.
•
•
•
Discuss options with patient !
More delays- mailnly due to hematologic toxicity.
More skin toxicity and stomatitis.
Less hair loss and neurotoxicity.
 First line setting … may be equivalent.
RECIST response and complete remission – similar.
PFS ?
How does this compare
Paclitaxel?
 Relapsed setting …. Definitely not inferior.
to weekly
Isonishi et al, ASCO 2008
Sana Al Sukhun, MD, MSc.