Transcript Hyderabad.Primary.Ovary.talk1.edwards.12

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
Estimated New Cancer
Cases in US Women
Estimated Cancer
Deaths in US Women
Breast
Lung
Colon
and
and
Bronchus Rectum
Greenlee RT, et al. CA Cancer J Clin. 2001;51:15-36.
Uterine
NonOvarian Melanoma
Corpus Hodgkin’s
of the
Lymphoma
Skin
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
15% - 20%
5% - 10%
5% - 10%
Breast Cancer
Ovarian Cancer
Sporadic
Family Cluster
Hereditary
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%)
Male breast cancer
(6%)
Ovarian cancer
(10%-20%)
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
93%
97%
Regional
55%
76%
Distant
25%
21%
All Stages
50%
84%
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
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)
What has been the standard of
care for the treatment of
advanced stage ovarian cancer?
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)
Number
of Patients
MST (mo)
0
29
39
0-0.5
28
29
0.6-1.5
16
18
>1.5
29
11
NCI Monograph, 1975
• 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)
Ovarian Cancer: Surgical Treatment
is more than a hysterectomy
40
38
36
34
32
30
28
26
24
22
20
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
46% optimal in PDS arm
• Only
all patients treated with taxane
• Not
and mortality higher in the PDS
• Morbidity
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
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
KRAS
Her-2 amp
PTEN
b-catenin
ARID1a
PPP2R1a
p53/Rb pathway
BRCA
Chromosomal
instability
mucinous
endometrioid
PIK3CA
ZNF217
ARID1aPPP2R1a
Others…
clear cell
KRAS
BRAF
ERBB2
high-grade serous
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