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Resection Criteria: Advance Ovarian Cancer
Robert L. Coleman, M.D.
Professor & Vice Chair, Clinical Research
Department of Gynecologic Oncology
M.D. Anderson Cancer Center
What is Really Being Asked?
• What are the surgical goals?
• What is the evidence that achieving these
goals will translate into better outcomes for
patients?
• Can aggressive surgery overcome innate
biology?
• Can we predict in whom heroic surgical
effort should be undertaken?
• Options? See the coming debate…
Surgical Management of
Primary Ovarian Cancer
• Theoretical:
– Reduced the volume of
hypoxic, poorly perfused
cells
– Host immunocompetence
is improved with lower
tumor burden
– Recruitment of residual
cells into G1 potentiating
the effects of cytotoxic
therapy
– Removal of chemoresistant
clones
• Practical:
– “Biology vs Brawn”
The Case to Operate
Griffiths, Natl Cancer Inst Monogr 42:101, 1975
Survival By
Cytoreduction Outcome
Griffiths, Natl Cancer Inst Monogr 42:101, 1975
Primary Cytoreduction
 Meta-analysis: 53 studies
(1989-98)
– 81 cohorts (Stage III/IV)
– N = 6885 patients
 Results
– Expert centers have high
optimal rates
– Optimal vs. not: 11 mos
(50% increase)
– Each 10%  in
cytoreduction = 5.5%  in
survival
– Platinum intensity = NS
42
100
40
90
38
80
36
70
34
60
32
50
30
40
28
30
26
24
20
22
10
20
0
0
10
20
30
40
50
60
70
80
90
100
Bristow, J Clin Oncol 20:1248, 2002
Aggressive Cytoreduction:
What’s Optimal?
• N = 408, Stage IIIC patients
• “Ranked” (Likert 0-3)
– RUQ, LUQ, Pelvis
– Retroperitoneum, Central
Abdomen
No Residual
Residual: 1-10 mm
Residual > 10 mm
Eisenkop Gynecol Oncol 90:390, 2003
Survival Data based on Primary
Surgical Intent
“Optimal”
“Suboptimal”
Chi Gynecol Oncol (2006) 103:559-64
The Impact of Residual Tumor:
What Is Optimal Debulking?
% Progression-free Survival
100%
75%
HR
50%
0 mm
25%
(95%CI)
1-10 mm vs. 0 mm:
2.52 (2.26;2.81)
>10 mm vs. 1-10 mm:
1.36 (1.24;1.50)
log-rank: p < 0.0001
1-10 mm
> 10 mm
0%
0
12
24
36
48
60
72
84
96
108
120
132
144
Generated from 3 prospective
Phase III trials (OVAR 3,5, & 7)
N = 3126 pts
100%
% Overall Survival
75%
HR
0 mm
50%
25%
1-10 mm
24
36
48
60
72
84
96
108
120
132
2.70 (2.37; 3.07)
>10 mm vs. 1-10 mm:
1.34 (1.21; 1.49)
DuBois, Cancer (2009)115:1234
0%
12
1-10 mm vs. 0 mm:
log-rank: p < 0.0001
> 10 mm
0
(95%CI)
144
Can Surgery Overcome Biology?
Presented with “Optimal Disease (≤ 1cm)
Was debulked to “Optimal Disease (≤ 1 cm)
Hoskins, Gynecol Oncol 1992; 47:159
Advanced stage ovarian cancer –
Does complex surgery improve
survival?
An analysis of GOG 182
Bunja Rungruang, MD
Magee-Womens Hospital
of UPMC
Primary Therapy: GOG-0182
FIGO III-IV
All residuum
EOC or PPC
International
Paclitaxel 175 mg/m2 3-hour
Carboplatin AUC 6 mg/ml.min
All regimens = 8 cycles
Interval cytoreduction allowed
NO Second Look surgery
Paclitaxel 175 mg/m2 3 -hour
Carboplatin AUC 5 mg/ml.min
Gemcitabine 800 mg/m2 day 1,8
End Points: PFI, Survival, Response
N = 4312 (4135 evaluable)
Paclitaxel 175
3-hour
ALTERNATE
Carboplatin AUC 5 mg/ml.min
Paclitaxel 175 mg/m2 3 -hour
Carboplatin AUC 5 mg/ml.min
PLD 30 mg/m2
Topotecan 1.5 mg/m2 Day 1-3
Carboplatin AUC 5 mg/ml.min
Paclitaxel 175 mg/m2 3-hour
Carboplatin AUC 6 mg/ml.min
mg/m2
Gemcitabine 1000 mg/m2 day 1,8
Carboplatin AUC 6 mg/ml.min
THEN
THEN
Paclitaxel 175 mg/m2 3-hour
Carboplatin AUC 6 mg/ml.min
GOG 182-ICON5: Endpoints
PFS
OS
Bookman, J Clin Oncol (2009), 27:1419-25
Microscopic residual has better OS
Overall Survival Rate
Microscopic n=860 (median 77 mo)
Macroscopic n=1 795 (median 41 mo)
Microscopic
Macroscopic (<1cm)
Logrank p<0.0001
Time at risk (months)
Disease Burden Score (DS)
Group
Pelvic and
retroperitoneal
Abdominal
DS-low
X
DS-moderate
(DS-mod)
X
X
DS-high
X
X
Upper
abdominal
X
Surgical Complexity Score
(CS)
Procedure
Points
TH-BSO
1
Omentectomy
1
Pelvic lymphadenectomy
1
Paraaortic lymphadenectomy
1
Pelvic peritoneum stripping
1
Abdominal peritoneum stripping
1
Small bowel resection(s)
1
Large bowel resection
2
Diaphragm stripping/resection
2
Splenectomy
2
Liver resection(s)
2
Rectosigmoidectomy with anastomosis
3
Group
Surgical
Complexity
Score
CS-low
1-3
CS-moderate
(CS-mod)
4-7
CS-high
>8
Aletti, et al. Am J Obstet Gynecol 2007.
Biology of Disease vs. Effort
Analysis of GOG 182
Micro+CS-highn=81 (46.1 mos)
DS-mod group n=846 (med: 71 mos)
<1cm+CS-low n=226 (39.4 mos)
DS-high group n=1636 (med:40 mos)
<1cm+CS-mod n=925 (39.3
Overall Survival Rate
DS-low group n=173 (med: 86 mos)
mos)
<1cm+CS-high n=286(40.4 mos)
DS-low
<1cm + DS-high + CS-mod
<1cm + DS-high + CS-high
Logrank
p<0.0001
All with
R0 disease
Time at risk (months)
All Optimal (R0 or R<1cm)
Logrank p=0.1830
Time at risk (months)
All DS-High (12% with R0)
Rungruang, SGO 2012
Paradigm shift for high disease burden
• Extensive disease
Primary complete resection
microscopically
debulked in only 12%
• Surgical gains are
achieved though
Neoadjuvant chemotherapy
cytoreduction to
with interval complete resection
microscopic residual
• Efforts to better define
candidates for complete
Primary surgery with gross
residual disease
resection
Central Question…
“One of the important questions is how to
select patients for primary debulking or
interval debulking with the aim of leaving
no residual tumor at the time of surgery.”
Vergote I. Gynecol Oncol 2010; 119: 1.
Selection of Surgical Candidates
• Easy to assess:
– Medically unfit/unstable
• High intraoperative surgical risk (cardiovascular, pulmonary, etc)
• High postoperative healing risk (uncontrolled DM, steroid
dependency, etc)
• Harder to assess:
– Heavy disease burden not amenable to resection
• Hepatic, portal, extra-abdominal disease
– Heavy disease burden not amenable to optimal resection
• Upper abdomen, diaphragm, pleural
Predicting Suboptimal Resection
● CA125
- >500 U/ml common threshold
- False positive in 22% to 31% of cases
● Imaging (CT/MRI)
- Multiple criteria proposed
- False positive in 12% to 33% of cases
● Diagnostic surgery
- laparoscopy to assess resectability
Predicting Suboptimal Resection
Problem: External Validity
Axtell, J Clin Oncol 2007
Cytoreduction and Biology
• RNA 44 patients (19
optimal, 25 suboptimal)
• Affymetrix chip (22,283)
– Top 120 genes used in
model
– MAP2K4 & MAP3K7
(metastases suppressing
genes)
• Predictive accuracy:
72.7%
– CA-125 > 500: 75%
accuracy (Berek, Gyn Onc,
2000)
Berchuck, Am J Obstet Gynecol 190:910, 2004
Cause Célèbre
Management Options
Presumed
Advanced
Ovarian Cancer
I. Primary
Cytoreduction
(Extensive if
Needed)
II. Limited Primary
Cytoreduction
Interval
Cytoreduction
III. Neoadjuvant
Chemotherapy
Followed by
Cytoreduction
Neoadjuvant Chemotherapy in
Ovarian Cancer
9/21/10
1/20/11
NACT: Interpretation
• Powerful effect of selection bias
– Sicker patients get NACT
– Responding patients get surgery
– Surgical effort different in primary vs NACT patients
within and between individual centers
• No standards on appropriate therapy before
surgical consideration
Primary Approach:
What’s Best?
N Engl J Med (2010) 363:943
Thank You!