SURGICAL MANAGEMENT OF
PRIMARY EPITHELIAL OVARIAN
CANCER
Robert P Edwards M.D
Professor of Obstetrics, Gynecology, Reproductive Sciences, and Immunology
University of Pittsburgh School of Medicine
UPMC Cancer Centers
Magee-Womens Hospital

Ovarian Cancer
American Cancer Society Estimates, 2001
200,000
180,000
160,000
140,000
120,000
100,000
80,000
60,000
40,000
20,000
0
Breast Lung and
Bronchus
Colon and
Rectum
Uterine
Corpus
Non-
Hodgkin ’ s
Lymphoma
Ovarian Melanoma of the
Skin
Greenlee RT, et al. CA Cancer J Clin.
2001;51:15-36.
Estimated New Cancer
Cases in US Women
Estimated Cancer
Deaths in US Women

2010 Gynecologic Cancer US Statistics
Ovary
Uterine
Cervix
Vulva
Vagina
New Cases
21,880
43,470
12,200
3,900
2,300
Deaths
13,850
7,950
4,210
920
780

Ovarian Cancer: Staging

HISTOLOGY AND CARCINOGENESIS
• MUELLERIAN METAPLASIA/DYSPLASIA
AND INFLAMMATION
– PAPILLARY SEROUS – TUBAL DYSPLASIA
– ENDOMETRIOD AND CLEAR CELL –
ENDOMETRIOSIS
– MUCINOUS – PERITONEAL MUCINOUS
METAPLASIA
– BRENNER TUMORS - UROEPITHELIA

How Much Breast and Ovarian Cancer is Hereditary
Breast Cancer
15% - 20%
5% - 10%
Sporadic
Family Cluster
Hereditary
Ovarian Cancer
5% - 10%
ASCO 1998

BRCA 1-Associated Cancers: Lifetime Risk
Breast cancer 50%-85% (often early age at onset)
Second primary breast cancer 40%-60%
Ovarian cancer 15%-45%
Possible increased risk of other cancers (eg, prostrate, colon)
ASCO 1998

BRCA2-Associated Cancers: Lifetime Risk
Breast cancer
(50%-85%)
Ovarian cancer
(10%-20%)
Male breast cancer
(6%)
Increased risk of prostate, laryngeal, and pancreatic cancers (magnitude unknown)
ASCO 1998

Relative Survival:
Ovarian & Breast Cancers
Five-Year Relative Survival Rates by
Stage at Diagnosis
Stage Ovary Breast
Local
Regional
93%
55%
97%
76%
Distant
All Stages
25%
50%
21%
84%

Ovarian Cancer:
Stage Distribution and Survival
Stage Percent Survival
I 24 95%
II 6 65%
III 55 15-30%
IV
Overall
15 0-20%
50%
American Cancer Society 2000

Ovarian Cancer:
Scope of the Problem In the US
• 22,220 new cases estimated for 2005
– 3% of cancer in women
– 2nd gynecologic cancer
• 16,210 deaths estimated for 2005
– Leading cause of death of gynecologic cancers
• 70% to 75% Stage III or IV at diagnosis
• Five-year survival: 44% overall
– Advanced stage: 29%
• Most will develop recurrent disease
American Cancer Society (www.cancer.org), 2005.

Ovarian Cancer Therapy
• Proven factors that determine outcome
– Surgical staging with optimal surgical effort
– Chemotherapy with a platinum agent combination with consideration for peritoneal delivery
– Monitoring of progress with frequent examination to determine therapy effectiveness

Ovarian Cancer Symptoms
• Abdominal/pelvic pain
• Vaginal bleeding
• Bloating
• Abdominal distension
• Irregular menses
• Change in bowel habits

First-Line Therapy –
Treatment Considerations

First-Line Therapy –
Standard Treatment Options
Surgery with maximum cytoreduction effort
Platinum + Taxane Chemotherapy
(Carboplatin + Paclitaxel)

Surgical Resection of Tumor Bulk in the Primary Treatment of Ovarian Carcinoma
C. Thomas Griffiths
●
●
First to evaluate effect of debulking in stage II-III ovarian cancer patients
Histologic grade also important prognostic factor
Table 2 – Survival, by diameter of largest residual mass
Size (cm)
0
Number of Patients MST (mo)
29 39
0-0.5
28 29
0.6-1.5
>1.5
16
29
18
11
NCI Monograph, 1975

Ovarian Cancer: Surgical Treatment is more than a hysterectomy
• Significant survival advantage for women optimally cytoreduced
• Procedures may include:
– En bloc resection of uterus, ovaries and pelvic tumor
– Omentectomy
– Selective lymphadenectomy
– Bowel resection
– Removal of diaphragmatic and peritoneal implants
– Splenectomy, appendectomy
24
22
20
30
28
26
40
38
36
34
32
0 10 20 30 40 50 60 70 80 90 100
% Cytoreduction
Bristow, J., Clin. Oncol.
20: 1248, 2002

●
Confirmed the prognostic significance of residual disease in patients with advanced ovarian cancer from GOG protocols 52 and 97
AJOG, 1994

●
●
81 cohorts of stage III/IV ovarian cancer patients evaluated using linear regresssion models
Each 10% increase in cytoreduction associated with 5.5% increase in median survival
●
Platinum dose intensity not significant
JCO, 2002
JCO, 2002

Evaluating the Role of Neoadjuvant
Chemotherapy in Advanced Ovarian Cancer
EORTC 55971
• From 1998-2006, 718 randomized between PDS vs. neoadjuvant chemo with IDS after 3 cycles
• Only 46% optimal in PDS arm
• Not all patients treated with taxane
• Morbidity and mortality higher in the PDS arm

Extensive Upper Abdominal Surgery in
Advanced Stage Ovarian Cancer
 229 EUAS procedures in 141 patients – diaphragm stripping/resection, splenectomy, partial hepatectomy, distal pancreatectomy
 Residual disease
 None – 30%
 < 1 cm – 60%
 > 1 cm – 10%
 Mortality 1.4%, grade 3-5 morbidity – 22%
 Median survival 57 mos.
Chi, Gyn Onc 2010

Ovarian Cancer:
Survival by Residual Disease
Hoskins et al ‘ 94

Theory of Peritoneal Therapy
• Ovarian Cancer predominantly intraperitoneal disease
• Dissemination is by exfoliation or “ snow globe ” phenomena
• Peritoneal infusion may increase cell kill with less systemic exposures

Peritoneal Therapy
Regional Perfusion
High Drug Concentration
Locoregional
Systemic Compartment
Low Drug Concentration
Dedrick 1977

Intraperitoneal Chemotherapy offers
Survival Advantage in Optimally Debulked
Stage III Epithelial Ovarian Carcinoma
• GOG 172: PFS RR 0.73
• GOG 114: PFS RR 0.78 Surv RR 0.81
• GOG 104: Survival HR 0.76

Bevacizumab
• Phase II studies
– GOG 170 - 2 CR 11 PR /62 patients (21%) PFS
4.7 months
– Increased risk of bowel perforations
• Phase III trial
– GOG 218 presented in abstract form
– Improved time to recurrence with maintenance

NEW THERAPIES
• MOLECULAR PROFILING
• MOLECULAR TARGET SCREENS
• PERSONALIZED APPROACHES
• REDUCE NUMBER OF CYCLES OF
INEFFECTIVE TREATMENTS

Distinctive molecular alterations in subtypes
PTEN b
-catenin
ARID1a
PPP2R1a
KRAS
Her-2 amp mucinous high-grade serous p53/Rb pathway
BRCA
Chromosomal instability
PIK3CA
ZNF217
ARID1a PPP2R1a
Others… clear cell
KRAS
BRAF
ERBB2 endometrioid
Annual Review Pathol 2009, 4:287
Cancer Res 2009, 69:4036
J Natl Can Inst 2003, 95:484
Am J Pathol 2009, 174:1597
Int J Gyn Cancer 2008, 18:487
Am J Surg Pathol 2005, 29:218
Future Oncol 2009, 5: 1641
Wiegand NEJM 20101
Jones science express 2010
McChonechy and Angelsio in press
Slide framework courtest of IM Shih