SURGICAL MANAGEMENT OF PRIMARY EPITHELIAL OVARIAN CANCER

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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

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Ovarian Cancer American Cancer Society
Estimates, 2001
200,000
180,000
160,000
140,000
120,000
Estimated New Cancer Cases in US Women
100,000
80,000
Estimated Cancer Deaths in US Women
60,000
40,000
20,000
0
Breast
Uterine Corpus
Lung and Bronchus
Colon and Rectum
Non- Hodgkins Lymphoma
Ovarian
Melanoma of the Skin
Greenlee RT, et al. CA Cancer J Clin.
20015115-36.
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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
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Ovarian Cancer Staging
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HISTOLOGY AND CARCINOGENESIS

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

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How Much Breast and Ovarian Cancer is Hereditary
15 - 20
5 - 10
5 - 10
Breast Cancer
Ovarian Cancer
Sporadic
Family Cluster
Hereditary
ASCO 1998
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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
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BRCA2-Associated Cancers Lifetime Risk
Breast cancer (50-85)
Male breast cancer (6)
Ovarian cancer (10-20)
Increased risk of prostate, laryngeal, and
pancreatic cancers (magnitude unknown)
ASCO 1998
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Relative Survival Ovarian Breast Cancers
Five-Year Relative Survival Rates by Stage at Diagnosis Five-Year Relative Survival Rates by Stage at Diagnosis 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
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Ovarian Cancer Stage Distribution and Survival
Stage Percent Survival
I 24 95
II 6 65
III 55 15-30
IV 15 0-20
Overall 50

• American Cancer Society 2000

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Ovarian CancerScope 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.
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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

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Ovarian Cancer Symptoms

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

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First-Line Therapy Treatment Considerations
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First-Line Therapy Standard Treatment Options
Surgery with maximum cytoreduction effort
Platinum Taxane Chemotherapy(Carboplatin
Paclitaxel)
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What has been the standard of care for the
treatment of advanced stage ovarian cancer?
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Surgical Resection of Tumor Bulk in the Primary
Treatment of Ovarian Carcinoma C. Thomas Griffiths
Table 2 Survival, by diameter of largest residual mass Table 2 Survival, by diameter of largest residual mass 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
gt1.5 29 11

• First to evaluate effect of debulking in stage
  II-III ovarian cancer patients
• Histologic grade also important prognostic factor

NCI Monograph, 1975
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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

Median Survival (Months)
Cytoreduction
Bristow, J., Clin. Oncol. 20 1248, 2002
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• Confirmed the prognostic significance of residual
  disease in patients with advanced ovarian cancer
  from GOG protocols 52 and 97

AJOG, 1994
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• 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
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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

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What new standards have evolved over the past
decade for the treatment of advanced stage
ovarian cancer?
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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
• lt 1 cm 60
• gt 1 cm 10
• Mortality 1.4, grade 3-5 morbidity 22
• Median survival 57 mos.

Chi, Gyn Onc 2010
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Ovarian Cancer Survival by Residual Disease

• Hoskins et al 94

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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

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

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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

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NEW THERAPIES

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

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Distinctive molecular alterations in subtypes
KRAS Her-2 amp
PTEN b-catenin ARID1a PPP2R1a
p53/Rb pathway BRCA Chromosomal instability
mucinous
endometrioid
PIK3CA ZNF217 ARID1aPPP2R1a Others
clear cell
high-grade serous
low-grade
Ovarian epithelial carcinoma
KRAS BRAF ERBB2
Annual Review Pathol 2009, 4287 Cancer Res 2009,
694036 J Natl Can Inst 2003, 95484 Am J Pathol
2009, 1741597 Int J Gyn Cancer 2008, 18487 Am
J Surg Pathol 2005, 29218 Future Oncol 2009, 5
1641 Wiegand NEJM 20101 Jones science express
2010 McChonechy and Angelsio in press Slide
framework courtest of IM Shih