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SURGICAL MANAGEMENT OF PRIMARY EPITHELIAL OVARIAN
CANCER
Robert P Edwards M.DProfessor of Obstetrics, Gynecology, Reproductive Sciences,
and ImmunologyUniversity of Pittsburgh School of Medicine
UPMC Cancer CentersMagee-Womens Hospital
Ovarian Cancer American Cancer Society Estimates, 2001
0
20,000
40,000
60,000
80,000
100,000
120,000
140,000
160,000
180,000
200,000
Breast UterineCorpus
Lungand
Bronchus
Colonand
Rectum
Non-Hodgkin’sLymphoma
Estimated New Cancer Cases in US Women
Estimated Cancer Deaths in US Women
OvarianOvarian Melanomaof theSkin
Greenlee RT, et al. CA Cancer J Clin. 2001;51:15-36.
2010 Gynecologic Cancer US Statistics
New Cases Deaths
Ovary 21,880 13,850
Uterine 43,470 7,950
Cervix 12,200 4,210
Vulva 3,900 920
Vagina 2,300 780
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 Ovarian Cancer
15% - 20%
5% - 10% 5% - 10%
ASCO 1998
Sporadic
Family Cluster
Hereditary
BRCA 1-Associated Cancers: Lifetime Risk
ASCO 1998
Possible increased risk of other cancers (eg, prostrate, Possible increased risk of other cancers (eg, prostrate,
colon)colon)
Breast cancer 50%-85% (often early age at onset)Breast cancer 50%-85% (often early age at onset)
Second primary breast cancer 40%-60% Second primary breast cancer 40%-60%
Ovarian cancer 15%-45% Ovarian cancer 15%-45%
BRCA2-Associated Cancers: Lifetime Risk
Increased risk of prostate, laryngeal, and pancreatic Increased risk of prostate, laryngeal, and pancreatic
cancers (magnitude unknown)cancers (magnitude unknown)
Breast cancerBreast cancer
(50%-85%)(50%-85%)
Ovarian cancerOvarian cancer
(10%-20%)(10%-20%)
Male breast cancerMale breast cancer
(6%)(6%)
ASCO 1998
Relative Survival: Ovarian & Breast Cancers
Five-Year Relative Survival Rates by Stage at Diagnosis
Stage Ovary Breast
Local 93% 97%
Regional 55% 76%
Distant 25% 21%
All Stages 50% 84%
Ovarian Cancer: Stage Distribution and Survival
American Cancer Society 2000
Stage Percent Survival
I 24 95%
II 6 65%
III 55 15-30%
IV 15 0-20%
Overall 50%
American Cancer Society (www.cancer.org), 2005.
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
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
Platinum + Taxane ChemotherapyPlatinum + Taxane Chemotherapy(Carboplatin + Paclitaxel)(Carboplatin + Paclitaxel)
Surgery with maximum Surgery with maximum cytoreduction effortcytoreduction effort
What has been the standard of care for the treatment of
advanced stage ovarian cancer?
NCI Monograph, 1975
● First to evaluate effect of debulking in stage First to evaluate effect of debulking in stage
II-III ovarian cancer patientsII-III ovarian cancer patients
● Histologic grade also important prognostic Histologic grade also important prognostic
factorfactor
Surgical Resection of Tumor Bulk in the Primary Treatment of Ovarian Carcinoma
C. Thomas Griffiths
Table 2 – Survival, by diameter of largest residual mass
Size (cm)Number
of Patients MST (mo)
0 29 39
0-0.5 28 29
0.6-1.5 16 18
>1.5 29 11
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
% CytoreductionM
edia
n S
urv
ival
(M
on
ths)
Bristow, J., Clin. Oncol. 20: 1248, 2002
AJOG, 1994
● Confirmed the prognostic significance of Confirmed the prognostic significance of
residual disease in patients with advanced residual disease in patients with advanced
ovarian cancer from GOG protocols 52 and ovarian cancer from GOG protocols 52 and
9797
JCO, 2002
● 81 cohorts of stage III/IV ovarian cancer patients evaluated 81 cohorts of stage III/IV ovarian cancer patients evaluated
using linear regresssion modelsusing linear regresssion models
● Each 10% increase in cytoreduction associated with 5.5% Each 10% increase in cytoreduction associated with 5.5%
increase in median survivalincrease in median survival
● Platinum dose intensity not significant Platinum dose intensity not significant
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
What new standards have evolved over the past decade for the treatment
of advanced stage ovarian cancer?
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
Systemic Compartment
Low Drug Concentration
Locoregional
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
high-grade serous
PTEN
-catenin
ARID1a
PPP2R1a
KRAS
BRAF
ERBB2
PIK3CA
ZNF217
ARID1aPPP2R1a
Others…
KRAS
Her-2 amp
low-grade
endometrioid
clear cell
mucinousp53/Rb pathway
BRCA
Chromosomal
instability
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