Download Gynecologic Cancers

Gynecologic Cancer Treatment
Stanford University
Cancer Center
ASCO 2006 Update:
Gynecologic Cancers
Amreen Husain, M.D.
Assistant Professor
Division of Gynecologic Oncology
Stanford University School of Medicine
Gynecologic Cancer Treatment
Stanford University
Cancer Center
Overview
• Ovarian cancer
• Benefit of adding a third drug?
• Intraperitoneal vs. intravenous?
• Benefit of Prolonged “maintenance” therapy
• Use of Bevacizumab in ovarian cancer
• Endometrial cancer
• Adjuvant therapy – radiation vs. chemotherapy?
• laparoscopy vs. laparotomy?
Gynecologic Cancer Treatment
Stanford University
Cancer Center
Ovarian Cancer
Benefit of adding a third cytotoxic agent?
Gynecologic Cancer Treatment
Stanford University
Cancer Center
GOG0182-ICON5:
Phase III Randomized Trial of Paclitaxel and Carboplatin vs
Combinations with Gemcitabine, PEG-Lipososomal
Doxorubicin, or Topotecan in Patients with Advanced-Stage
Epithelial Ovarian or Primary Peritoneal Carcinoma
GOG, MRC, SWOG, ANZGOG,
M Negri, and NCI-CTSU
Bookman, ASCO 2006
Gynecologic Cancer Treatment
Stanford University
Cancer Center
RANDOMIZE
GOG0182-ICON5: Schema
I
Carboplatin AUC 6 (d1)
Paclitaxel 175 mg/m2 (d1)
x8
II
Carboplatin AUC 5 (d1)
Paclitaxel 175 mg/m2 (d1)
Gemcitabine 800 mg/m2 (d1,8)
x8
III
Carboplatin AUC 5 (d1)
Paclitaxel 175 mg/m2 (d1)
Doxil 30 mg/m2 (d1, every other cycle)
x8
IV
Carboplatin AUC 5 (d3)
Topotecan 1.25 mg/m2 (d1-3)
V
Carboplatin AUC 6 (d8)
Gemcitabine 1 g/m2 (d1,8)
x4
Carboplatin AUC 6 (d1)
Paclitaxel 175 mg/m2 (d1)
x4
x4
Bookman, ASCO 2006
Gynecologic Cancer Treatment
Stanford University
Cancer Center
GOG0182-ICON5: Characteristics
ARM:
Age (Median)
FIGO Stg IV
1º Peritoneal
C+P
(n = 864)
C+P+G
(n = 864)
C+P+D
(n = 862)
CTCP
(n = 861)
CGCP
(n = 861)
57.7 y
59.1 y
59.5 y
58.5 y
59.3 y
16.2%
13.3%
100%
Other / Pending 75%
Mucinous
Clear Cell
50%
Endometrioid
Papillary Serous 25%
0%
13.3%
13.0%
13.8%
14.5%
13.7%
12.7%
16.3%
12.8%
Gynecologic Cancer Treatment
Stanford University
Cancer Center
GOG0182-ICON5: Stratification
ARM:
C+P
(n = 864)
C+P+G
(n = 864)
C+P+D
(n = 862)
CTCP
(n = 861)
CGCP
(n = 861)
21.6%
7.7%
22.6%
8.2%
22.7%
7.7%
23.3%
7.1%
24.2%
7.8%
100%
Microscopic
75%
<=1 cm Optimal 50%
> 1 cm Subopt
25%
0%
Measurable
Interval Surgery
Bookman, ASCO 2006
Gynecologic Cancer Treatment
Stanford University
Cancer Center
GOG0182-ICON5: Heme Toxicity
80%
Control
Gem Triplet
PLD Triplet
Topo Doublet
Gem Doublet
70%
60%
50%
40%
30%
20%
10%
0%
ANC*
(Grade:4+)
Plts*
(Grade:3+)
* p < 0.001 global test of null hypothesis
Hgb*
(Grade:3+)
Fever/Inf*
(Grade:3+)
Bookman, ASCO 2006
Gynecologic Cancer Treatment
Stanford University
Cancer Center
GOG0182-ICON5: Non-Heme Toxicity
30%
Control
Gem Triplet
PLD Triplet
Topo Doublet
Gem Doublet
25%
20%
15%
10%
5%
0%
Neuropathy*
(Grade:2+)
Pulmonary
(Grade:2+)
* p < 0.001 global test of null hypothesis
Hepatic*
(Grade:2+)
Bookman, ASCO 2006
Gynecologic Cancer Treatment
Stanford University
Cancer Center
GOG0182-ICON5: Overall Survival
Bookman, ASCO 2006
Gynecologic Cancer Treatment
Stanford University
Cancer Center
GOG0182-ICON5: Progression-Free Survival
Median PFS and HR (95% CI)
16.1
16.4
16.4
15.3
15.4
1.000
0.990
0.998
1.094
1.052
(0.884-1.107)
(0.891-1.117)
(0.979-1.224)
(0.940-1.176)
Bookman, ASCO 2006
Gynecologic Cancer Treatment
Stanford University
Cancer Center
GOG0182-ICON5: Overall Survival
Median OS and HR (95% CI)
40.0
40.4
42.8
39.1
40.2
1.000
0.978
0.972
1.068
1.035
(0.838-1.141)
(0.832-1.136)
(0.918-1.244)
(0.888-1.206)
Bookman, ASCO 2006
Gynecologic Cancer Treatment
Stanford University
Cancer Center
GOG0182-ICON5: Conclusions
• The addition of a third cytotoxic agent was associated with
increased, but manageable, hematologic toxicity
• A third cytotoxic agent was not associated with improved clinical
outcomes, including progression-free and overall survival
• After more than 25 years, carboplatin remains the dominant agent
for treatment of advanced ovarian cancer, with an impact on
evaluation of new agents and potential non-platinum alternatives
Bookman, ASCO 2006
Gynecologic Cancer Treatment
Stanford University
Cancer Center
Ovarian Cancer
Intraperitoneal vs. Intravenous chemotherapy?
Gynecologic Cancer Treatment
Stanford University
Cancer Center
Intraperitoneal chemotherapy
GOG 172
• N = 416, Stage III, Optimal (<1cm)
• Randomized trial
• Group 1
Paclitaxel 135 mg/m2/24h
Cisplatin 75 mg/m2
q 21 days x 6
• Group 2
Paclitaxel 135 mg/m2/24h
Cisplatin 100 mg/m2 IP D2
Paclitaxel 60 mg/m2 IP D8
q 21 days x 6
• Quality of life:
• Greater short term decline
• No difference after 12 months
PFS
OS
IV
18.3 Months
IP
24 Months
IV
49.7 Months
IP
65.6 Months
Armstrong et al, NEJM 2006
Gynecologic Cancer Treatment
Stanford University
Cancer Center
Figure 2
By Treatment Group
1.0
Proportion Surviving
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
l
IV
IP
0.0
0
12
24
36
Months on Study
48
60
Gynecologic Cancer Treatment
Stanford University
Cancer Center
Patient-Reported FACT-O Scores
140
130
120
110
100
90
80
70
Pre-Randomization
Pre-4th Cycle
3~6 Weeks Post 6th 12 Months Post 6th
Cycle
Cycle
IV
IP
Wensel ASCO 2006
Gynecologic Cancer Treatment
Stanford University
Cancer Center
Baseline Quality of Life and Tolerance for Intraperitoneal Chemotherapy for
Advanced Epithelial Ovarian Cancer: A GOG Study
• To determine if patient-reported baseline QOL scores are associated
with number of IP cycles completed in the GOG 172
• Results –
higher FACT-O scores significantly more likely
• to complete more IP cycles (OR: 1.27 for every 10 points; 95%
CI: 1.11 ~ 1.46; p<0.001),
• to tolerate 6 cycles of IP therapy (OR: 1.31 for every 10 points;
95% CI: 1.11 ~ 1.56; p=0.002)
• Conclusions –
– Baseline QOL associated with tolerance to IP chemotherapy and
may be useful in identifying those at risk for serious toxicities
Wensel ASCO 2006
Gynecologic Cancer Treatment
Stanford University
Cancer Center
Wensel ASCO 2006
Gynecologic Cancer Treatment
Stanford University
Cancer Center
• Question of abstracts 5004
(Markman et al.)
Will 12 months of paclitaxel prolong
survival in patients with clinical complete
remission after primary treatment?
Gynecologic Cancer Treatment
Stanford University
Cancer Center
Progression-Free Survival
100%
80%
At Risk
Paclitaxel 12 courses 150
Paclitaxel 3 courses 146
60%
Median
Failed in Months
102
22
115
14
P=0.01
40%
20%
0%
0
24
48
Months After Registration
72
96
Gynecologic Cancer Treatment
Stanford University
Cancer Center
Overall Survival
100%
80%
P=0.27
60%
40%
20%
Paclitaxel 12 courses
Paclitaxel 3 courses
At Risk
150
146
Median
Deaths in Months
66
53
80
46
0%
0
24
48
Months After Registration
72
96
Gynecologic Cancer Treatment
Stanford University
Cancer Center
Increased PFS but:
• More time on first line treatment and toxicity
• Equal treatment free interval= equal symptoms and
toxicity-free survival
• Potential for decreased tolerance to subsequent
treatment (g 2-3 neuropathy)
• No increased in survival
Gynecologic Cancer Treatment
Stanford University
Cancer Center
Abstract 5004: Clinical implication
PFS=22 mos
1
treatment
12
Treatment and
PFS = 10 mos
PFS=14 mos
1
3
Treatment and
PFS = 11 mos
14
22
Gynecologic Cancer Treatment
Stanford University
Cancer Center
Recurrent ovarian - Bevacizumab – multicenter phase II
• 44 patients
• recurrent /
persistent
ovarian or
primary
peritoneal ca
• Progression
within <6 mos
• No more than
3 prior
therapies
P
h
a
s
e
II
Bevacizumab
15 mg/kg IV q 3 wks
• Response:
Overall = 15.9%
– CR = 0
– PR = 7
– SD = 11
• Median Duration: 4.2 mos
• Toxicity (Grade 3):
– 5 htn, 3 MI, 1 CVA, 1
pulm htn, 1 bldg, 5 GI
perforation
Cannistra, et al, ASCO 2006
Gynecologic Cancer Treatment
Stanford University
Cancer Center
Comparison with other trials
Current Study
(N = 44)
GOG 170-D*
(N = 63)
NCI 5789**
(N = 29)
Study Treatment
Single agent
BV 15 mg/kg
q 3 wk
Single agent
BV 15 mg/kg q
3 wk
BV 10 mg/kg q 2
wks + low dose oral
cytoxan
Prior Treatment
Setting
Platinum refractory
resistant,
up to 3 regimens
42% DDP
sensitive
up to 2 prior
regimens
42% DDP sensitive
up to 2 prior
regimens
16%
27.4%
18%
39%
28%
57%
Efficacy Results
ORR
6-mo PFS
Gynecologic Cancer Treatment
Stanford University
Cancer Center
GI Perforations
• Five GI perforations observed in this trial
– Four occurred within 9 weeks of initiating therapy
– Perforation confirmed surgically in 4 cases; 5th developed
large pelvic abscess
– One fatality out of 5 GIP cases despite surgical intervention
• IND Action letter (NIH) - Oct 4, 2005
– Alerted investigators of risk of GI perforations
– CTEP database: 144 pts with 1 perforation and 3 fistulas (2.8%)
– Total 4+5/144+44= 4.8% risk of perforation
Gynecologic Cancer Treatment
Stanford University
Cancer Center
Bevacizumab: Clinical implications
• Activity confirmed in relapsed ovarian cancer
• Should be avoided in heavily pretreated patients with:
– Extensive bowel involvement
– Bowel obstruction
– Bowel wall thickening
Gynecologic Cancer Treatment
Stanford University
Cancer Center
Endometrial cancer
– Adjuvant therapy – radiation vs. chemotherapy?
– laparoscopy vs. open surgery?
Gynecologic Cancer Treatment
Stanford University
Cancer Center
GOG 150 - Uterine Carcinosarcoma
• 206 eligible with
•
•
•
•
•
carcinosarcoma of
uterus
Stage I-IV
TAH/BSO
Debulking to <1cm
washings, PA node
sampling and
omental biopsy
optional
1993-2005
R
A
N
D
O
M
I
Z
E
Abdomino (3000 cGy)
PelvicRadiation (4980 cGy)
Vs.
Cisplatin 20 mg/m2/d x 4 d
Ifosfamide 1.5 g/m2 x 4 d
• Endpoints –
• PFS and OS
• Toxicity
Mesna 120 mg/m2 IV bolus over 15
minutes then 1.5 g/m2/d IV infusion
over 24 hrs.
Repeated q 3 weeks x 3
cycles
Stage I (31%), II (13%), III (45%), IV (11%)
Wolfson, ASCO 2006
Gynecologic Cancer Treatment
Stanford University
Cancer Center
By Randomized Treatment
• CIM improves PFS
and OS compared
whole abdomino
pelvic irradiation
1.0
Estimate 5 year survival WAI - 34%
CIM - 47%
0.9
Proportion Surviving
0.8
0.7
• With increased
vaginal, decreased
distant recurrence
0.6
0.5
0.4
• More acute anemia
& neuropathy, less
chronic GI toxicity
0.3
0.2
Treatment Group
Whole AbdmRT
Cispt+Ifos
0.1
0.0
0
12
24
Alive
39
48
36
Died Total
66 105
53 101
48
60
Months on Study
72
84
96
Gynecologic Cancer Treatment
Stanford University
Cancer Center
GOG 150 - Conclusions
• Adjuvant chemotherapy is more effective with less long term toxicity
than radiotherapy in reducing recurrence and prolonging the survival
of patient with optimally debulked uterine CS
• Future therapeutic trials for this patient population should consider at
least adjunctive vaginal brachytherapy and 3 cycles of CIM as a
“control arm”
Wolfson, ASCO 2006
Gynecologic Cancer Treatment
Stanford University
Cancer Center
Early endometrial ca – laparoscopy GOG LAP2
•2616 patients
R
A
•Clinical stage I/IIA
N
•2:1 randomization D
•Lymph node from O
M
R & L pelvic/PA
I
•1996-2005
Z
E
Laparoscopy
(n=1696)
Laparotomy
(n=920)
Results –
• 23% conversion rate for poor
exposure, bleeding
• Length of stay shorter with
laparoscopy, 2 vs 4 days
• OR time longer with
laparoscopy, 3.3h vs. 2.2h
• Fewer G2 or higher morbidity
• Acceptable alternative
Walker, SGO 2006
Gynecologic Cancer Treatment
Stanford University
Cancer Center
Early endometrial ca – laparoscopy GOG LAP2 - QOL
R
A
•Clinical stage I/IIA
N
•FACT-G – physical,
D
emotional, social well O
being before, 1,3,6
M
wks and 6 mos after
I
surgery
Z
E
•782 patients
Laparoscopy
(n=524)
Laparotomy
(n=258)
Kornblith et al, SGO 2006
Results –
•QOL significantly higher with
laparoscopy at 1 wk, 3 wks, and 6
wks after adjusting for baseline
scores
• No difference at 6 months
• OR time longer with
laparoscopy, 3.3h vs. 2.2h
• no difference in acute perioperative morbidity or wound
complications
Gynecologic Cancer Treatment
Stanford University
Cancer Center
Predicted Probability of Successful Laparoscopy by BMI - Updated
1.0
0.9
% SUCCESSFUL
LAPAROSCOPY
Predicted Probability of Success
0.8
0.7
0.6
0.5
0.4
74% success
0.3
0.2
0.1
0.0
0
5
10
15
20
25
30
BMI
BMI
35
40
45
50
55
60
Gynecologic Cancer Treatment
Stanford University
Cancer Center
Number of Nodes
Median Number of Nodes at Each Site
12
10
Open Arm
8
Scope Arm
6
Successful Scope
4
Convert to Open
2
0
Left PA
Right PA
Left Pelvic
Lymph Node Location
Right
Pelvic
Gynecologic Cancer Treatment
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Pelvic Cytology: Randomization Arm
7.00%
Percent
6.00%
5.00%
4.00%
open
3.00%
scope
2.00%
1.00%
0.00%
positive
susp
Cytology Result
missing
p= 0.010
Gynecologic Cancer Treatment
Stanford University
Cancer Center
• Laparoscopy is an acceptable alternative to laparotomy for
uterine cancer treatment and staging.
– Surgeons were encouraged to convert to laparotomy when they
encountered metastatic disease.
– Conversion to laparotomy is advised when incomplete staging
results would yield inadequate information for treatment planning.
– Previously reported QOL improvement and decreased hospital stay,
fewer grade > 2 complications makes laparascopic staging
desirable from a patient perspective.
– Survival results are pending.
Gynecologic Cancer Treatment
Stanford University
Cancer Center
Review
• Ovarian cancer
– 3rd agent does not improve outcome
– Intraperitoneal therapy for selected patients
– Prolonged therapy does not improve outcome.
• Endometrial cancer
– Laparoscopy is an alternative for selected patients
– Adjuvant therapy –chemotherapy better than radiation
Gynecologic Cancer Treatment
Stanford University
Cancer Center