Ovarian cancer

1. Recent Advances in the Surgical
Management of Ovarian Cancer
Neil S. Horowitz, M.D.
Neil S. Horowitz, M.D.
Assistant Professor, Harvard Medical School
Assistant Professor, Harvard Medical School
Division of Gynecologic Oncology Brigham and Women
Division of Gynecologic Oncology Brigham and Women’
’s/Dana Farber
s/Dana Farber

2. Ovarian Cancer
Ovarian Cancer
Cervix
Cervix
Annual deaths
Annual deaths
in the United States: 2009
in the United States: 2009
Vulva
Vulva
Uterine
Uterine
Ovary
Ovary
14,600
14,600
Vagina +
Vagina +
other
other
Jemal A
Jemal A –
– CA Cancer J Clin 2009
CA Cancer J Clin 2009

3. Debulking Surgery for Ovarian Cancer
Debulking Surgery for Ovarian Cancer
ν
ν First recognized by Joe
First recognized by Joe
V.
V. Meigs
Meigs –
– 1934
1934
“
“Tumors of the Female
Tumors of the Female
Pelvic Organs
Pelvic Organs
ν
ν Confirmed by Griffiths
Confirmed by Griffiths
in 1975
in 1975

4. Theoretic Benefits of Cytoreduction
Theoretic Benefits of Cytoreduction
ν
ν Physiologic
Physiologic
–
– Improved bowel function and metabolism
Improved bowel function and metabolism
–
– Decrease nausea and vomiting
Decrease nausea and vomiting
ν
ν Removal of large, poorly vascularized tumor
Removal of large, poorly vascularized tumor
–
– Improved chemo delivery
Improved chemo delivery
–
– Increased fraction of G
Increased fraction of G0
0 cells migrate to high growth
cells migrate to high growth
fraction
fraction
ν
ν Decrease chance of acquired drug resistance
Decrease chance of acquired drug resistance
ν
ν Smaller tumor mass less immunosuppressive
Smaller tumor mass less immunosuppressive

5. Cytoreduction Techniques
Cytoreduction Techniques
ν
ν TAH/BSO
TAH/BSO
ν
ν Sigmoid resection
Sigmoid resection
ν
ν Pelvic and PA LND
Pelvic and PA LND
ν
ν Peritoneal stripping
Peritoneal stripping
ν
ν Bowel resection
Bowel resection
ν
ν Splenectomy
Splenectomy
ν
ν Omentectomy
Omentectomy
ν
ν Resection of
Resection of…
….
.
–
– Ureter/Bladder
Ureter/Bladder
–
– Recto
Recto-
-sigmoid
sigmoid
–
– Multiple bowel loops
Multiple bowel loops
–
– Diaphragm
Diaphragm
–
– Liver, Kidney, Spleen
Liver, Kidney, Spleen
ν
ν Radical oophorectomy
Radical oophorectomy
ν
ν Diaphragm stripping
Diaphragm stripping
Simple Radical

6. Primary debulking surgery (PDS)
Primary debulking surgery (PDS)

7. Effect of Residual Disease on Survival
Effect of Residual Disease on Survival
Gynecologic Oncology
Gynecologic Oncology
Group definition:
Group definition: <
< 1 cm
1 cm
residual disease
residual disease
Fader, AN. JCO 2007;25(20):2873
Fader, AN. JCO 2007;25(20):2873-
-83
83

8. ‘
‘Success
Success’
’ rates of debulking
rates of debulking

9. Meta
Meta-
-analysis of retrospective studies
analysis of retrospective studies
ν
ν Meta
Meta-
-analysis (1989
analysis (1989-
-98)
98)
–
– 81 cohorts (Stage III/IV)
81 cohorts (Stage III/IV)
–
– N = 6,885 patients
N = 6,885 patients
ν
ν Results
Results
–
– Each 10%
Each 10% Ï
Ï in primary cytoreduction =
in primary cytoreduction =
2 month
2 month Ï
Ï in survival time (P = 0.03)
in survival time (P = 0.03)
»
» < 25% optimal ,median survival = 23 mo
< 25% optimal ,median survival = 23 mo
»
» > 75% optimal, median survival = 34 mo
> 75% optimal, median survival = 34 mo
–
– CONC
CONC:
: Stage III/IV ovarian cancers
Stage III/IV ovarian cancers
should be referred to centers with high
should be referred to centers with high
rates of optimal PDS
rates of optimal PDS
20
22
24
26
28
30
32
34
36
38
40
0 10 20 30 40 50 60 70 80 90 100
% Cytoreduction
% Cytoreduction
Median
Survival
(Months)
Median
Survival
(Months)
Bristow R
Bristow R –
– JCO 2002
JCO 2002

10. ULTRARADICAL SURGERY
ULTRARADICAL SURGERY
Memorial Sloan
Memorial Sloan-
-Kettering Experience
Kettering Experience
ν
ν 140 stage IIIC/IV pts
140 stage IIIC/IV pts
ν
ν Switched to more comprehensive debulking of
Switched to more comprehensive debulking of
upper abd disease:
upper abd disease:
»
» Diaphragm resection
Diaphragm resection
»
» Splenectomy
Splenectomy
»
» Distal pancreatectomy
Distal pancreatectomy
»
» Liver resection
Liver resection
»
» Porta hepatis tumor
Porta hepatis tumor
»
» Opt PDS
Opt PDS
ν
ν Optimal PDS
Optimal PDS ≤
≤1
1-
-cm residual disease increased
cm residual disease increased
from 50 to 76%
from 50 to 76%
ν
ν Longer OR time, more EBL
Longer OR time, more EBL
ν
ν No difference in rate of major complications or
No difference in rate of major complications or
length of hosp stay
length of hosp stay
Chi DS
Chi DS -
- Gynecol Oncol 2004
Gynecol Oncol 2004

12. Change surgical paradigm
ν
ν MSKCC
MSKCC –
– stage IIIC/IV ovarian cancers
stage IIIC/IV ovarian cancers
ν
ν Grp 1: 168 pts (1996
Grp 1: 168 pts (1996-
-1999) v Grp 2: 210 pts (2001
1999) v Grp 2: 210 pts (2001-
-2004)
2004)
ν
ν Extensive upper abdominal procedures in Grp 2
Extensive upper abdominal procedures in Grp 2 only
only
ν
ν Optimal PDS <1
Optimal PDS <1-
-cm residual: 46 to 80%
cm residual: 46 to 80%

13. Change surgical paradigm
5
5-
-yr OS: 35 to 47%
yr OS: 35 to 47% Chi DS
Chi DS –
– Gynecol Oncol 2009
Gynecol Oncol 2009
Median OS 43 vs 54 mo

14. Winter WE et al, JCO 2008 Bookman M, JCO 2009
What is “optimal”?
29 v16 v 13 mo
68 v 40 v 33mo
64 v 30 v 19 mo

15. Biology or Surgery?

16. Can CA125 Predict Debulking
Chi DS, Gyncologic Oncology 2009
N = 277 pts
33% required radical upper
abdominal procedures
40% preop CA125 < 500 U/mL

17. CT Scan Prediction of Cytoreduction
Bristow RE, Cancer 2000
N = 41 pts

18. CT Scan Prediction of Cytoreduction
Bristow RE, Cancer 2000
85% of pts ultimately having optimal
debulking were identified correctly at PI > 4
PI < 4, 100% had optimal debulk (NPV)

19. CT Scan Prediction of
Cytoreduction
Axtell AE, JCO 2007

20. CT Scan Prediction of
Cytoreduction
Axtell AE, JCO 2007

21. Can Laparoscopy Predict?
Fagotti, AJOG 2008

22. Can Laparoscopy Predict?
Fagotti, AJOG 2008

23. Predicting Optimal vs Suboptimal Debulking
ν RNA from 44 serous ovarian cancers
(19 opt, 22 subopt)
ν Affymetrix microarray of 22,000
genes
ν 32 genes distinguished optimal vs
suboptimal with 73% accuracy
– Retinoic acid receptor beta, P2X6
– MAP2K4
ν Favorable survival associated with
debulking due to biology
Berchuck A, AJOG 2004

24. Role of
Role of Lymphadenctomy
Lymphadenctomy?
?
Exploratory analysis of 3 AGO trials
1,924 patients
No gross residual 84 mo 103 mo (p=0.01)
Residual 1- 10 mm 35 mo 39 mo (p=0.06)
No LAD LAD
du Bois A, JCO 2010

25. Fertility Sparing Surgery for Stage I
Fertility Sparing Surgery for Stage I
Ovarian Cancer
Ovarian Cancer
Satoh T, JCO 2010
„ 211 patients (126 =IA, 85=IC)
„ 41% optimally staged; 60% adjuvant
platinum chemo
„ 8.5%(18 pts) recurrence rate – 5 in
contralat ovary, 8 alive and NED
„ 54% (45/84 pts) G0 achieved 65
pregnancies, 56 healthy babies
Group I: Stage IA, good histology; Group
2: stage IA CC or IC favorable histology
Group 3: Stage IA/IC, grade 3, IC CC

26. Secondary Cytoreduction
Secondary Cytoreduction
ν
ν Surgical cytoreduction of tumor volume correlates with
Surgical cytoreduction of tumor volume correlates with
prolongation of patient survival
prolongation of patient survival
ν
ν The role of secondary surgery in the standard
The role of secondary surgery in the standard
management of disease recurrence remains poorly
management of disease recurrence remains poorly
defined
defined
ν
ν Patients who develop recurrent disease may be eligible
Patients who develop recurrent disease may be eligible
for secondary cytoreduction if
for secondary cytoreduction if
–
– Response to first
Response to first-
-line therapy
line therapy
–
– Limited number of recurrent disease sites
Limited number of recurrent disease sites
–
– Good PS
Good PS
Fader, AN. JCO 2007;25(20):2873
Fader, AN. JCO 2007;25(20):2873-
-83
83

27. Secondary Cytoreduction Impact on Survival
Secondary Cytoreduction Impact on Survival
Fader, AN. JCO 2007;25(20):2873
Fader, AN. JCO 2007;25(20):2873-
-83
83

28. DESKTOP
DESKTOP-
-OVAR I
OVAR I
No Residuals
Median OS 45.2 mos
Survival
Probability
0 12 24 36 48
Months
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.9
0.8
1
Residuals > 10 mm
Median OS 19.7 mos
Residuals 1-10 mm
Median OS 19.6 mos
Harter P, et.al. Ann Surg Oncol.2006;13(12):1702-1701.

29. Secondary Debulking Candidate
Secondary Debulking Candidate
Selection
Selection
ν
ν Optimal patient meets
Optimal patient meets >
> 3 of the following criteria
3 of the following criteria
–
– DFI > 12 months
DFI > 12 months
–
– No liver metastasis
No liver metastasis
–
– Solitary tumor
Solitary tumor
–
– Tumor size < 6 cm
Tumor size < 6 cm
–
– Good performance status
Good performance status
Chi DS, et al. Cancer. 2006;106:1933-1939; Onda T, et al. Br J Cancer. 2005;92(6):1026-1032.
DFI
DFI Single Site Only
Single Site Only Multiple Sites; No
Multiple Sites; No
Carcinomatosis
Carcinomatosis
Carcinomatosis
Carcinomatosis
6
6-
-12 Months
12 Months Yes
Yes Yes / No
Yes / No No
No
12
12-
-30 Months
30 Months Yes
Yes Yes
Yes Yes / No
Yes / No
> 30 Months
> 30 Months Yes
Yes Yes
Yes Yes
Yes

30. Phase III GOG 213
Phase III GOG 213
Surgery
Recurrent Ovarian, PPT, or FT
Cancer; TFI > 6 months
Recurrent Ovarian, PPT, or FT
Cancer; TFI > 6 months
Surgical Candidate?
No
Yes
Randomize
Randomize
Randomize
Randomize
No Surgery
Bevacizumab
Carboplatin /
Paclitaxel
Carboplatin /
Paclitaxel /
Bevacizumab
Chemotherapy
Randomization
Chemotherapy
Randomization
Available at http://www.cancer.gov/clinicaltrials/GOG-0213.

31. DESKTOP
DESKTOP-
-OVAR III
OVAR III
Recurrent Ovarian, FT or PPT, TFI > 6 mo from
1st platinum-based chemotherapy, prior
complete debulking, PS 0, and absence of
ascites > 500 mL
Recurrent Ovarian, FT or PPT, TFI > 6 mo from
1st platinum-based chemotherapy, prior
complete debulking, PS 0, and absence of
ascites > 500 mL
Platinum-Based Combination
Chemotherapy
No Surgery
Secondary Cytoreductive Surgery
Randomize
Available at: http://www.ago-ovar.de/global/dbbin/141207_175503_11_-_desktop_ii-short.pdf.

32. IGCS Bangkok/Oct 2008
ASCO/April 2009

33. Randomisation
Ovarian, tubal or peritonal cancer
FIGO stage IIIc-IV (n = 718)
Primary Debulking Surgery Neoadjuvant chemotherapy
3 x Platinum based CT
Interval debulking
(not obligatory)
Interval debulking if no PD
3 x Platinum based CT
> 3 x Platinum based CT > 3 x Platinum based CT
Primary Endpoint: Overall survival
Secondary endpoints: Progression Free Survival, Quality of Life, Complications

34. Randomised EORTC-GCG/NCIC-CTG trial on
NACT + IDS versus PDS
Study conduct
ν September 1998 and December 2006
ν 718 patients randomised in 60 institutions (median
accrual/institution 5; range: 1 – 125 patients).
ν 498 events were needed to perform the final analysis,
and were reached in August 2008
ν Median follow-up was 4.8 years.

35. Randomised EORTC-GCG/NCIC-CTG trial on
NACT + IDS versus PDS
Surgical findings and results
Surgical findings and results
PDS
(n = 329)
NACT -> IDS
(n = 339)*
Mets before > 2 cm 95% 68%
Mets before > 10 cm 62% 27%
No residual after surgery 21%
21% 53%
53%
≤ 1 cm after surgery 46%
46% 82%
82%
* % calculated on the 306 patients who underwent IDS.

36. NACT + IDS versus PDS: ITT
(years)
0 2 4 6 8 10
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment
259 361 183 68 16 2
251 357 191 56 11 1
Upfront debulking s
Neoadjuvant chemo
Overall survival

37. Overall Survival of IP vs IV Chemotherapy as per
GOG 172 Compared to NACT
0 2 4 6
0
10
20
30
40
50
60
70
80
90
00

38. Conclusions
1 - Optimal debulking surgery is the strongest independent
prognostic factor for overall survival - should remain the
goal of every surgical effort – but the timing does not seem
to play a role.
2 – Neoadjuvant chemo with interval debulking may be
considered preferred treatment due to the lower morbidity
and similar survival

39. Conclusions
Conclusions
„ Optimal cytoreduction (defined as microscopic) is associated with
improved survival
„ The ability to achieve optimal cytoreduction is likely a factor of
tumor biology and surgeon aggressiveness.
„ No reliable way to predict pre-operatively the ability to achieve
optimal cytoreduction
„ NACT is an acceptable treatment in certain populations.
„ Secondary cytoreduction, in the appropriate patient population,
maybe associated with improved survival.