This document discusses surgical options for recurrent ovarian cancer. It begins by outlining the goals of primary surgery for ovarian cancer, including establishing a tissue diagnosis, staging the disease, and debulking tumors. It then discusses cytoreductive surgery for advanced stage disease, noting that surgery is both diagnostic and therapeutic by removing large tumor masses. Secondary and tertiary debulking surgeries can provide a survival advantage for selected patients. New options like heated intraperitoneal chemotherapy are shown to augment surgical outcomes for recurrent ovarian cancer.

1. Recurrent Ovarian Cancer:Recurrent Ovarian Cancer:
Surgical OptionsSurgical Options
Ginger J. Gardner, MDGinger J. Gardner, MD
Associate Attending SurgeonAssociate Attending Surgeon
Director, International Fellowship ProgramDirector, International Fellowship Program
in Gynecologic Oncologyin Gynecologic Oncology
Memorial Sloan-Kettering Cancer CenterMemorial Sloan-Kettering Cancer Center
Division of Gynecology, Department of SurgeryDivision of Gynecology, Department of Surgery

2. Ovarian Cancer Treatment
Surgery and Chemotherapy work…

3. Goals of Primary Surgery
for Ovarian Cancer
1. Establish Tissue Diagnosis
2. Identify Histologic Subtype
3. Stage of Disease
4. Tumor Debulking
5. Relieve Symptoms
6. Place Intraperitoneal Port (in some cases)

4. Goals of Primary Surgery
for Ovarian Cancer
1. Establish Tissue Diagnosis
2. Identify Histologic Subtype
3. Stage of Disease
** Tumor Debulking
** Relieve Symptoms
6. Place Intraperitoneal Port (in some cases)

5. Ovarian Cancer
Prognostic FactorsPrognostic Factors
AgeAge
StageStage
GradeGrade
HistologyHistology
AscitesAscites
ChemosensitivityChemosensitivity
Volume of Residual DiseaseVolume of Residual Disease

6. Cytoreductive Surgery for
Advanced Stage Disease
Surgery is Diagnostic AND Therapeutic
– Excision of large tumor mass of poorly perfused,
anoxic cells which would otherwise be exposed to
sublethal concentration of drug
– Increase proliferating fraction of cells post-op
– Removal of 80-90% tumor burden favorable to
"fractional cell kill hypothesis"
– Provides opportunity for IP treatment

7. Overall Survival by Residual Disease
Hoskins WJ et al. Gynecol Oncol 1992; 47: 159Hoskins WJ et al. Gynecol Oncol 1992; 47: 159

8. 20
22
24
26
28
30
32
34
36
38
40
0 10 20 30 40 50 60 70 80 90 100
% Cytoreduction
MedianSurvival(Months)
Significant survival advantage
for optimally debulking
Procedures may include:
-En bloc resection of uterus
ovaries and pelvic tumor
-Omentectomy
-Lymphadenectomy
-Bowel resection
-Diaphragm resection
-Splenectomy, Appendectomy
Cytoreductive Surgery for
Advanced Stage Disease
Bristow, RE, JCO, 20:1248, 2002

9. Secondary Debulking
and Overall Survival
Time
ProportionSurviving
Chi DS et al, Cancer, 2006

10. Tertiary Debulking
Shih, K J Gyn Onc 2010, 117:330-335

12. Who Will Benefit
from Secondary Debulking?
Chi, DS, Cancer, 2006

13. Is Restarting the Clock
with Secondary Surgery Enough?
Can we do Better??

14. • Phase III evidence in favor of postoperative IP
therapy
• Combination of hyperthermia (heat) and some
chemotherapy agents increases drug effectiveness
• Increased peritoneal tumor penetration
• Intraoperative chemoperfusion: no adhesion barriers
• Controlled application under anesthesia
Hyperthermic Intraperitonel
Chemotherapy (HIPEC)
…The Chemo Wash

15. platinum-sensitive recurrent EOC
platinum-free interval >6months
ECOG 0/1
no prior chemotherapy for recurrent EOC
secondary cytoreductive surgery
HIPEC (cisplatin 60 mg/m2
) HIPEC (cisplatin 80 mg/m2
) HIPEC (cisplatin 100 mg/m2
)
6 cycles postoperative platinum based IV combination chemotherapy*
-temporary abdominal closure
-closed- abdomen technique
-in 3 L of saline solution
-90 minutes at 42°C
-after HIPEC:
irrigation (3 L saline solution)
EOC= epithelial ovarian cancer
* the use of bevacizumab is allowed; OCEANS study, Aghajanian JCO 2012
HIPEC Protocol

16. Mean cisplatin concentrations during HIPEC in the peritoneal cavity and plasma at 100
mg/m² compared to same dose IV administration*
* Model with 80 mg/m² IV cisplatin administered in 30 minutes; Urien et al. 2004
0
5000
10000
15000
20000
25000
30000
35000
0 0.5 1 1.5 2
Platinumconcentration[µg/L]
Time [h]
platinum concentration during HIPEC
IP
Plasma after IP
Plasma after iv
HIPEC Pharmacokinectics

17. Patient No. Postoperative IV chemotherapy No. of cycles
1 Carboplatin AUC 5/ Gemcitabine 1000 mg/m2
(days 1 and 8) 6
2 Carboplatin AUC 4/ Gemcitabine 1000 mg/m2
(days 1 and 8)
Bevacizumab 15 mg/kg q 21 days
6
3 Carboplatin AUC 5/ Gemcitabine 1000 mg/m2
(days 1 and 8) 6
4 Carboplatin AUC 5/ Gemcitabine 1000 mg/m2
(days 1 and 8) 6
5 Carboplatin AUC 5/ Gemcitabine 1000 mg/m2
(days 1 and 8) 6
6 Carboplatin AUC 5/ Gemcitabine 1000 mg/m2
(days 1 and 8) 6
7 Carboplatin AUC 5/ Gemcitabine 1000 mg/m2
(days 1 and 8) 6
8 Carboplatin AUC 5/ Gemcitabine 1000 mg/m2
(days 1 and 8) 6
9 Carboplatin AUC 5/ Gemcitabine 1000 mg/m2
(days 1 and 8) 6
10 Carboplatin AUC 5/ Gemcitabine 1000 mg/m2
(days 1 and 8) 6
11 Carboplatin AUC 4/ Gemcitabine 1000 mg/m2
(days 1 and 8)
Bevacizumab 15 mg/kg q 21 days
ongoing
12 Carboplatin AUC 5/ Gemcitabine 1000 mg/m2
(days 1 and 8) ongoing
HIPEC Post-Operative Treatment

18. • Secondary cytoreduction and HIPEC with cisplatin at 100 mg/m 2
is
feasible in patients with platinum sensitive recurrent ovarian cancer
• Favorable pharmacokinetic properties of HIPEC with cisplatin are
confirmed at all dose levels, especially at 100 mg/m2
• Ability to administer 6 cycles of standard IV platinum-based
chemotherapy after HIPEC does not seem to be compromised
• Further randomized trials need to determine the efficacy of HIPEC with
cisplatin in comparison to IV chemotherapy alone
• Cytoreductive surgery + HIPEC and postoeprative chemotherapy are not
competitive but can be complementary elements of multimodality treatment
HIPEC Interim Conclusions

19. • Phase I studies with new drugs and drug combinations adminstered as HIPEC
• Quality of life assessment
• Cost-effectiveness
• Integration of HIPEC-studies into the primary setting
• Opportunity for multidisciplinary research collaborations (medical
oncology, anesthesia, colorectal surgery, pharmacology, biostatistics,
drug development, nursing)
HIPEC Future Directions

20. How Can We
Prevent Ovarian Cancer?

21. Risk factorRisk factor Relative RiskRelative Risk
Older ageOlder age 33
North American/EuropeanNorth American/European 2-52-5
High socioeconomic statusHigh socioeconomic status 1.5-21.5-2
White raceWhite race 1.51.5
NulligravidityNulligravidity 2-32-3
InfertilityInfertility 2-52-5
Early menarcheEarly menarche 1.51.5
Late menopauseLate menopause 1.5-21.5-2
History of hysterectomyHistory of hysterectomy 0.5-0.70.5-0.7
History of OCP useHistory of OCP use 0.3-0.50.3-0.5
Family history OVCAFamily history OVCA 3-43-4
Risk Factors for Ovarian Cancer

22. Risk factorRisk factor Relative RiskRelative Risk
Older ageOlder age 33
North American/EuropeanNorth American/European 2-52-5
High socioeconomic statusHigh socioeconomic status 1.5-21.5-2
White raceWhite race 1.51.5
NulligravidityNulligravidity 2-32-3
InfertilityInfertility 2-52-5
Early menarcheEarly menarche 1.51.5
Late menopauseLate menopause 1.5-21.5-2
History of hysterectomyHistory of hysterectomy 0.5-0.70.5-0.7
History of OCP useHistory of OCP use 0.3-0.50.3-0.5
Family history OVCAFamily history OVCA 3-43-4
Risk Factors for Ovarian Cancer

23. Op-Ed Contributor
My Medical Choice
By ANGELINA JOLIE
Published: May 14, 2013
MY MOTHER fought cancer for almost a decade
and died at 56. She held out long enough to
meet the first of her grandchildren and to hold
them in her arms. But my other children will
never have the chance to know her and
experience how loving and gracious she was.
We often speak of “Mommy’s mommy,” and I
find myself trying to explain the illness that took
her away from us. They have asked if the same
could happen to me. I have always told them not
to worry, but the truth is I carry a “faulty” gene,
BRCA1, which sharply increases my risk of
developing breast cancer and ovarian cancer.

24. Hereditary Risk of Ovarian Cancer
Hereditary
(~10-15%)
Sporadic
BRCA1 (~70-75%)
Other single
genes (<5%) BRCA2 (~20%)HNPCC
(~2%)

25. BRCA Mutation Carriers
• Lifetime risk of ovarian cancer
– BRCA1 ~36-46%
– BRCA2 ~10-27%
• BRCA-associated Ovarian Cancer
– Young age, high grade serous histology,
advanced stage
– 16-21% of high grade serous EOC will
have a BRCA1 or BRCA2 mutation
• BRCA-associated Breast Cancer
King, et al. Science, 2003.
Risch, et al., Am
J Hum Genet, 2001
Rubin, et al., Am J Obstet Gynecol, 1998
Pal, et al., Cancer, 2005

26. Risk-Reduction Strategies
– Breast
• Intensive Surveillance (Mammogram, U/S, MRI)
• Chemoprevention (Tamoxifen, Raloxifene,
Aromatase Inhibitors)
• Risk-Reducing Surgery (Mastectomy,
Oophorectomy)
– Ovary
• Surveillance (Transvaginal U/S, CA125)
• Chemoprevention (Oral Contraceptives)
• Risk-Reducing Surgery (Tubal Ligation,
Oophorectomy)

27. Semi-Annual (twice/yr):
• Pelvic Exam
• Pelvic Ultrasound
• CA125
**Reinforce limitations of screening
**Perform until prophylactic salpingo-
oophorectomy is completed
Ovarian Screening in BRCA Patients

28. MSKCC Experience 1995-2001
– 62 BRCA Mutation Carriers Undergoing Surveillance
• Mean F/U: 17 months
• Twice yearly TV ultrasound and CA125
– 22/62 (35%) had at least 1 Abnormal U/S or CA125
– 10 with persistent abnormalities that underwent surgery
– 5 Ovarian or Fallopian Tube Cancers (4 Stage I or II)
– 5 Benign Findings
– 2 patients with normal screening were found to cancer at
RRSO
– 71% Sensitivity 91% Specificity
Scheuer L, Kauff N, et al. JCO 2002
Ovarian Screening in BRCA Patients

29. Gilda Radner OCDP Experience 1991-2000
– 213 Jewish women with a first or second degree relative with
ovarian or early onset breast cancer (33 with BRCA
mutations)
• Mean F/U: 60 months
• Annual TV ultrasound and CA125
– 8 ovarian, fallopian tube or primary peritoneal ca (7 in BRCA
carriers)
• 4 screen detected (1 – Ic; 3 – IIIc)
• 4 Interval cancers (1-IIc; 3 – IIIc)
Liede A, et al. JCO 2002
Ovarian Screening in BRCA Patients

30. Ovarian Screening in BRCA Patients
Annual TV ultrasound and CA125
Woodward et al. BJOG 2007
– 179 women (31 BRCA +) at high risk of ovarian cancer
– 29 months f/u
– 3 of 4 ovarian cancers were interval (1 – stage IIc; 2 – stage IIIc)
– 30 women with abnormal findings under went surgery
• 2 cancers detected (1 – stage IIIc ovarian; 1 – endometrial
carcinoma)
Hermsen et al. Br J Cancer 2007
– 888 BRCA mutation carriers (20 months mean f/u)
– 5 of 10 incident cancers were interval
– 80% of both screen detected and interval cancers were Stage
III/IV

31. Ovarian Screening in BRCA Patients
Conclusions
• Equivocal evidence that screening detects
ovarian cancer at an early stage.
• No evidence that screening results in a
survival benefit in women at inherited risk.
• Until further data is available, ovarian cancer
screening should only be thought of as a
bridge until a women with a BRCA mutation
is ready to undergo a RRSO.

32. Risk-Reducing Salpingo-Oophorectomy
(RRSO)
The most effective risk-reducing strategy
for women with BRCA 1/2 mutations
Kauff & Barakat, J Clin Oncol, 2007

33. Spread of STIC from the fimbria to the ovarian surface.
Site of Origin: Fallopian Tube
Kurman et al. Hum Path 42: 918-31, 2011

34. Site of Origin: Fallopian Tube
Kurman et al. Hum Path 42: 918-31, 2011
Implications for Screening: Molecular Signature of Fallopian
Tube/ Uterine Washings
Levine et al. MSKCC/PPG

35. Conclusions
• OCP use reduces risk of Ovarian Cancer
• Consider Genetics Evaluation for BRCA
mutation among all ovarian cancer
patients, and those with family history
• Secondary surgical debulking is available
for selected patients with recurrent ovarian
cancer

36. Conclusions
• Heated intraperitoneal chemotherapy
protocols are now available to augment
the surgical outcome for recurrent
disease.
• Surgery may be appropriate in selected
cases of recurrent disease for symptom
control.

37. Ginger J. Gardner, MD
Gynecologic Cancer Surgeon
Memorial Sloan-Kettering Cancer Center