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