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Mello-Abrams Lectureship
Surgical Advances in Ovarian Cancer
Richard R. Barakat, M.D.
Chief Gynecology Service, Department of Surgery
Ronald O. Perelman Chair in Gynecologic Surgery
Memorial Sloan-Kettering Cancer Center
New York, New York
Treatment of Ovarian Cancer
Role of Surgery
• Establish diagnosis
• Comprehensive staging for early
disease
• Primary cytoreduction (debulking)
removal of as much gross tumor as
possible
Benefits of Cytoreductive Surgery for
Advanced Ovarian Carcinoma
• Removal of large bulky tumors with poor
blood supply
• Improved sensitivity of residual masses to
postoperative chemotherapy
• Greater likelihood of tumor eradication before
chemoresistance develops
• Improved PFS and OS
Residual Disease
• The maximum diameter of the largest
tumor mass remaining after
cytoreductive surgery
• By convention, measured in cm
• Optimal versus suboptimal
cytoreduction or debulking refers to the
amount of residual disease in relation to
a certain cutoff point (GOG < 1.0cm)
Surgical Resection of Tumor Bulk in the Primary
Treatment of Ovarian Carcinoma
Grifiths CT, NCI Monograph 42:1010, 1975
Meta-Analysis of Cytoreduction for Epithelial
Ovarian Cancer
Percent Maximum Cytoreductive Surgery
- With each 10% increase in maximal cytoreduction,
there is a 5.5% to 6.0% increase in median survival
Expert / Less-Experienced Center Comparison
- Cohorts with < 25% maximal cytoreduction:
weighted median survival, 22.7 months
- Cohorts with > 75% maximal cytoreduction:
weighted median survival, 33.9 months; an increase of
50%
Bristow et al. J Clin Oncol 2002
Meta-Analysis (N = 6,885)
Weighted Median Survival (months)
40
%MaxCyto
38
36
34
32
30
28
26
24
22
20
0
10 20 30 40 50 60 70 80 90 100
Percent Maximum Cytoreductive Surgery
Bristow et al. J Clin Oncol 2002
Procedures to Achieve Optimal
Cytoreduction in Advanced Ovarian
Carcinoma
• Standard: TAH/BSO plus
–
–
–
–
Extensive lymph node dissection
Rectosigmoid resection
Resection of ureteral/bladder segment
Extensive bowel resection
• Advanced:
– Resection of liver, omentum, diaphragm,
spleen, porta hepatis, gallbladder (upper
abdomen)
Omental Cake
Splenectomy
Diaphragm Stripping
Optimal Cytoreduction Rates in Advanced Ovarian
Carcinoma with Standard Surgical Techniques
Author
Year
Smith
1979
792
24%
Wharton
1984
395
39%
Neijt
1993
265
46%
Makar
1995
455
27%
Chi
2001
282
25%
2189
30%
Total
No. Pts
Optimally
Cytoreduced
Role of Extensive Cytoreductive Procedures
Survey mailed to SGO membership with 61% response:
• Reason for suboptimal debulking:
Unresectable upper abd metastases 85%
• Disease sites precluding optimal cytoreduction:
• Disease involving base of mesentery 83%
• Portal triad disease
77%
• Bulky diaphragmatic metastases
76%
Eisenkop. Gynecol Oncol 2001; 82: 489
Improved Optimal Cytoreduction Rates for Stage IIIC
and IV Epithelial Ovarian, Fallopian Tube, and Primary
Peritoneal Cancer:
A Change in Surgical Approach
• Group 1: primary surgery 11/98 – 5/00
– extensive procedures not routinely used
• Group 2: primary surgery 1/01 – 5/02
– extensive procedures used as needed
• Extensive Upper Abdominal Procedures:
– diaphragm stripping/resection, splenectomy, distal
pancreatectomy, liver resection, resection of tumor
from porta hepatis, cholecystectomy
Chi DS et al. Gynecol Oncol 2004
Improved Optimal Cytoreduction Rates:
A Change in Surgical Approach
Variable
Group 1
(n=70)
Group 2
(n=70)
P-value
Median Age
60 yrs
60 yrs
NS
Stage IIIC
61 (87%)
59 (84%)
NS
Serous Histology
51 (73%)
56 (80%)
NS
Primary Ovary
56 (80%)
63 (90%)
NS
CA-125 > 500
39 (68%)
35 (57%)
NS
Chi DS et al. Gynecol Oncol 2004
Improved Optimal Cytoreduction Rates:
A Change in Surgical Approach
Variable
Group 1
(n=70)
Group 2
(n=70)
P-value
Extensive Procedure(s)
2 (3%)
19 (27%)
< 0.001
Optimal Cytoreduction
35 (50%)
53 (76%)
< 0.01
Average Operative Time
174 min
264 min
< 0.001
Average EBL
460 ml
880 ml
< 0.001
Complication Rates
3 (4.3%)
4 (5.7%)
NS
Length of Stay
8 days
9 days
NS
Chi DS et al. Gynecol Oncol 2004
Optimal Cytoreduction Rates for
Advanced Ovarian Cancer at MSKCC
Extensive Upper Abdominal Surgery to
Achieve Optimal Cytoreduction Improves
Survival in Advanced Ovarian Cancer
• Analysis of 262 patients with stage IIIC-IV ovarian
carcinoma who underwent primary surgery between
1998-2003
• Divided into 3 groups:
– Optimal residual (< 1 cm) with extensive upper
abdominal surgery
– Optimal residual (< 1 cm) without need for
extensive upper abdominal surgery
– Suboptimal residual (> 1 cm)
Eisenhauer EL et al. SGO 2006
Extensive Upper Abdominal Surgery to Achieve
Optimal Cytoreduction Improves Survival in
Advanced Ovarian Cancer
Group 1
(n=57)
Group 2
(n=122)
Group 3
(n=83)
Extensive Procedure(s)
57 (100%)
0 (0%)
0 (0%)
Optimal Cytoreduction
57 (100%)
122 (100%)
0 (0%)
Complete Clinical Response
47 (82%)
95 (78%)
47 (57%)
24 mos
23 mos
11 mos
> 68 mos
> 86 mos
38 mos
Variable
Progression-Free Survival
Median Overall Survival
Eisenhauer EL et al. Gynecol oncol 103, 2006
Overall Survival, Stage IIIC-IV Ovarian Cancer 1998-2003
1.0
Log-rank p<0.0001
Proportion. Surviving
0.8
0.6
0.4
0.2
Events Censored Total
Group 1 - optimal, extensive
13
44
57
Group 2 - optimal, standard
41
81
122
Group 3 - suboptimal
54
29
83
0.0
0
12
24
36
48
Time in Months
60
72
84
Improved Optimal Cytoreduction Rates
A Change in Surgical Approach
Conclusions
• The use of extensive upper abdominal procedures
significantly increased the rate of primary optimal
cytoreduction from 50% to 76%
• Operative time and EBL were also increased
• Rate of major complications and length of
hospitalization remained the same
• Performing extensive upper abdominal procedures
to achieve optimal cytoreduction significantly
improved the survival of patients who would have
otherwise been suboptimally cytoreduced
Is Less Than 1 cm Residual the Best
Cutoff Point for “Optimal” Cytoreduction?
• “As data accumulate, it is becoming increasingly
clear that even among optimally resected patients,
extended survival rates are associated with debulking
of all visible disease.”
• Median progression-free survival:
– No gross residual: 22 mos
– Gross 0.1-1.0 cm: 12 mos
– Gross > 1.0 cm: 6 mos
Bristow and Montz. Gynecol Onocol 2001
What is the Optimal Goal of Cytoreduction
in Patients with Bulky Stage IIIC Ovarian Carcinoma?
• Review of 426 consecutive patients (1989-2002)
• No pts were stage IIIC based solely on lymph node
metastasis
• 16 factors analyzed for prognostic significance
• Multivariate analysis:
– Age
– Ascites
– Residual disease
Chi et al, Gynecol Oncol. 2006 Nov;103(2):559-64
Survival Function for Residual Disease
Residual Disease
1.0
no visable
residual
<0.5cm
0.5 - <1 cm
0.8
1 - 2 cm
Cum Survival
> 2cm
0.6
0.4
0.2
0.0
0.00
20.00
40.00
60.00
80.00
100.00
months to deceased or last followup
120.00
Median Survival by Residual Disease
Residual Disease
No. Patients
Median Survival
No gross
57
81 mos
Gross < 0.5 cm
51
56 mos
Gross 0.5 – 1.0 cm
92
47 mos
Gross 1 – 2 cm
53
31 mos
Gross > 2 cm
172
34 mos
Chi DS et al. SGO 2005
What is the Optimal Goal of Cytoreduction in
Patients with Bulky Stage IIIC Ovarian Carcinoma?
Conclusions
• Cytoreduction to > 1 cm residual has no
benefit on overall survival
• There is a survival benefit associated with
cytoreduction to < 1 cm residual
• Within the gross residual but < 1 cm category,
the closer to no gross residual, the longer the
median survival
GOG #172
Armstrong et.al. N Engl J Med. 2006 Jan 5;354(1):34-43
BRCA Analysis
DNA Banking
Ovarian cancer
Optimal (<1cm)
Stage III
Stratify:
Gross residual
Planned 2nd look
R
A
N
D
O
M
I
Z
E
Second look
Laparotomy
(if chosen)
Paclitaxel 135 mg/m2/24h
Cisplatin 75 mg/m2
q 21 days x 6
Paclitaxel 135 mg/m2/24h
Cisplatin 100 mg/m2 IP D2
Paclitaxel 60 mg/m2 IP D8
q 21 days x 6
GOG #172: Survival
Regimen 1
Intravenous
Regimen 2
Intraperitoneal
Progression-free
18.3 mos
23.8 mos
Overall Survival
49.5 mos
66.9 mos
Surgery in Primary Advanced
Ovarian Cancer
Current Debate:
Surgery or chemotherapy?
Which one first?
Vergote et al. N Engl J Med. 2010 Sep 2;363(10):943-53
MSKCC Contemporaneous Experience to
EORTC/NCIC Trial of
PDS vs NACT + IDS (9/98-12/06)
All Patients
Seen During
Study Period
342
All “Eligible”
Patients
316
Neoadjuvant
Chemotherapy
31 (10%)
Extraabdominal
Disease
18 (6%)
Extensive
abdominal
Disease
11 (3.5%)
Poor KPS
and/or refused
Surgery
26
Primary
Surgery
285 (90%)
Advanced Age
(> 85 yo)
2 (0.5%)
Optimal
Cytoreduction
203 (71%)
Suboptimal
Cytoreduction
82 (29%)
Chi DS et al. SGO 2010
MSKCC Contemporaneous Experience
to EORTC/NCIC Trial of
PDS vs NACT + IDS
• Identical inclusion criteria for all patients
undergoing primary surgery at MSKCC during
same time period (9/98-12/06)
• Excluded patients with borderline, germ cell,
stromal, and advanced carcinoma based
solely on microscopic nodal metastasis
• All pts “eligible” for EORTC trial: 316
Chi DS et al. SGO 2010
Progression-Free Survival
Both Arms of EORTC Neoadjuvant
Trial vs MSKCC
MSKCC
(optimals + suboptimals)
Both EORTC arms
Median PFS 12 months
Overall Survival Both Arms of EORTC
Neoadjuvant Trial vs MSKCC
MSKCC
(optimals + suboptimals)
Both EORTC arms
Median OS 30 months
NEO-ADJUVANT CHEMOTHERAPY VS.
PRIMARY DEBULKING
Conclusions
• Patients who have primary optimal cytoreduction
have five-year survival rates of approximately
50% and even greater if a complete gross
resection can be attained
• With appropriate training, support, and
commitment primary optimal cytoreduction rates
of over 70-75% can be achieved utilizing
extensive upper abdominal surgical techniques
• This translates into a median overall survival for
combined optimally and suboptimally
cytoreduced patients of ≥ 50 months
NEO-ADJUVANT CHEMOTHERAPY VS.
PRIMARY DEBULKING
Conclusions
• Patients treated with NACT are not candidates
for primary IP chemotherapy
• Progression-free and overall survival with a
NACT is equivalent to that seen for primary
suboptimal cytoreduction
• NACT appears inferior to the survival outcomes
attained at “expert” ovarian cancer surgical
centers
• Until confirmatory data exists, NACT should be
restricted to those most unlikely/unable to
undergo attempt at optimal debulking
Who benefits from NACT?
Identification of patient groups at highest risk from
traditional approach to ovarian cancer treatment:
• High tumor dissemination including stage IV
• Age >75 years
• Performance and/or nutritional status (ASA≥3,
preoperative albumin≤ 3.0 g/dL)
Combining these three factors together, identified a
subgroup of patients (6.6%) in whom the benefits
from aggressive debulking do not appear to outweigh
the risks.
Aletti et al. Gynecol Oncol. 2010 Oct 7.Epub ahead of print
Advances in Chemotherapy
JGOG: Phase III Trial IV paclitaxel and
carboplatin vs. dose dense (TC-T-T)
• JGOG: 637 patients randomized, Stage III diagnosis
• TC vs TC-T-T (80 mg/m2) weekly
• Primary endpoint PFS
– 0.8 power to detect 5 month difference
Treatment
N
Median
PFS
TC
319
17.2 mos
TC-T- T
312
28.0 mos
P value
HR
95% CI
0.0015
0.71
0.581-0.88
0.03
0.75
0.57-0.98
3 year OS
TC
319
65.1%
TC-T-T
312
72.1%
Katsumata et al. Lancet 374: 2009
Beyond Traditional Chemotherapy:
Targeting a Different Mechanism
Small localized tumor
Tumor increases in size and spreads
Angiogenesis
Blood vessel
Signaling
molecule
(VEGF)
Phase III: GOG 218
Carboplatin/Paclitaxel - cycles 1-6
Concurrent Placebo - cycles 2-6
Placebo - cycles 7-22
Stage III* or IV,
Ovarian, primary
peritoneal, or
fallopian tube cancer
• Activated: 9/26/05
• Closed: 6/29/09
• Accrual: 1873 pts
• Primary end point: PFS
Carboplatin/Paclitaxel – cycles 1-6
Concurrent Bevacizumab – cycles 2-6
Placebo – cycles 7-22
Carboplatin/Paclitaxel – cycles 1-6
Concurrent Bevacizumab – cycles 2-6
Bevacizumab – cycles 7-22
*optimal (gross ) or suboptimal
48
GOG-0218: Investigator-Assessed PFS
Proportion surviving progression free
1.0
0.9
Arm I
CP
(n=625)
Arm II
CP + BEV
(n=625)
Arm III
CP + BEV  BEV
(n=623)
423
(67.7)
418
(66.9)
360
(57.8)
10.3
11.2
14.1
0.908
(0.759–1.040)
0.717
(0.625–0.824)
0.080a
<0.0001a
Patients with event, n (%)
0.8
Median PFS, months
0.7
Stratified analysis HR
(95% CI)
0.6
One-sided p-value (log rank)
0.5
0.4
0.3
0.2
CP (Arm I)
+ BEV (Arm II)
0.1
+ BEV → BEV maintenance (Arm III)
0
0
12
24
Months since randomization
36
Burger et al. Plenary Session, ASCO 2010.
ap-value
boundary = 0.0116
GOG-0218: Overall Survival Analysis
1.0
At time of final PFS analysis
0.9
Proportion alive
0.8
0.7
0.6
0.5
0.4
Patients with
events, n (%)
0.3
Median, months
0.2
HRa
0.1
One-sided p-value
Arm I
CP
(n=625)
Arm II
CP + BEV
(n=625)
Arm III
CP + BEV  BEV
(n=623)
156
(25.0)
150
(24.0)
138
(22.2)
39.3
38.7
39.7
1.036
0.915
(0.827–1.297)
(0.727–1.152)
0.361
0.252
(95% CI)
0
24
No. at
risk
625/625/623
36
442/432/437
480
Months since randomization
173/162/171
12
46/39/40
Burger et al. Plenary Session, ASCO 2010.
aStratified
analysis
Phase III GOG 218: Many Questions
• Will there be an overall survival benefit?
• Could it be given with same benefit later in
disease course?
• How long should it be administered? Until PD?
For life?
• What will the phenotype of relapsed disease look
like? Is there rebound?
• What is the required dose? Is less equally
effective?
Phase III: GOG 0252
Ovarian, primary
peritoneal, or
fallopian tube
cancer
Optimal
R
A
N
D
O
M
I
Z
E
Paclitaxel 80 mg/m2/1h IV, Days 1, 8, 15, Cycles 1-6
Carboplatin AUC 6 IV, Day 1, Cycles 1-6
Bevacizumab 15 mg/kg IV, Cycles 2-22
Paclitaxel 80 mg/m2/1h IV, Days 1, 8, 15, Cycles 1-6
Carboplatin AUC 6 IP, Day 1, Cycles 1-6
Bevacizumab 15 mg/kg IV, Cycles 2-22
• Activated: July 27, 2009
• Accrual goal: 1100 pts
• Primary end point: PFS
Paclitaxel 135 mg/m2/3h IV, Day 1, Cycles 1-6
Cisplatin 75 mg/m2 IP, Day 2, Cycles 1-6
Paclitaxel 60 mg/m2 IP, Day 8, Cycles 1-6
Bevacizumab 15 mg/kg IV, Cycles 2-22
Phase III: GOG 0262
Ovarian, primary
peritoneal, or
fallopian tube
cancer
suboptimal
R
A
N
D
O
M
I
Z
E
Paclitaxel 80 mg/m2/1h IV, Days 1, 8, 15, Cycles 1-6
Carboplatin AUC 6 IV, Day 1, Cycles 1-6
Optional:
Bevacizumab 15 mg/kg IV q 21 until POD
• Activated: 9/2010
• Accrual goal: 625 patients
• Primary end point: PFS
Paclitaxel 175 mg/m2/3h IV q 21 days
Carboplatin AUC 6 IV, Day 1, Cycles 1-6
Optional:
Bevacizumab 15 mg/kg IV q 21 until POD
OCEANS Trial:
Randomized Phase II(III) Study
Recurrent
Ovarian Cancer
> 6 months DFS
gemcitabine +
carboplatin
+ bevacizumab
gemcitabine +
carboplatin
+ placebo
Patients: 484
Endpoint: > G 1 perforation, PFS
Carol Aghajanian, MD, USA Study Chair, ASCO 2011
Proportion progression free
OCEANS: PFS
1.0
Events, n (%)
0.8
Median PFS,
months (95% CI)
0.6
Stratified analysis
HR (95% CI)
Log-rank p-value
CG + PL
(n=242)
CG + BV
(n=242)
187
(77)
151
(62)
8.4
(8.3–9.7)
12.4
(11.4–12.7)
0.484
(0.388–0.605)
<0.0001
0.4
0.2
0
0
No. at risk
CG + PL
242
CG + BV 242
6
12
18
24
30
11
33
3
11
0
0
Months
177
203
45
92
Carol Aghajanian, MD, USA Study Chair, ASCO 2011
OCEANS: Interim OS
Proportion alive
1.0
0.8
0.6
Events, n (%)
0.4
Median OS,
months (95% CI)
0.2
Stratified analysis
HR (95% CI)
Log-rank p-value
CG + PL
(n=242)
CG + BV
(n=242)
78 (32)
63 (26)
29.9
(26.4–NE)
35.5
(30.0–NE)
0.751
(0.537–1.052)
0.094a
0
0
No. at risk:
CG + PL
242
CG + BV 242
6
12
18
Months
24
30
36
42
235
238
195
200
131
146
77
82
26
42
8
8
0
0
NE = not estimated
ap-value does not cross pre-specified boundary
Carol Aghajanian, MD, USA Study Chair, ASCO 2011
Advanced Ovarian Cancer
Median Survival: 1975 - 2010
80
months
60
40
20
0
1975
Alkeran
1983
1986
multi-drug
1996
1998
cisplatin
2003
paclitaxel
2009
IP therapy
Thank You
2011
1884