Update on Ovarian and Endometrial
Cancers
Steven W Remmenga, MD
McClure L Smith Professor of Gynecologic Oncology
Director, Division of Gynecologic Oncology
University of Nebraska Medical Center
7/12/2016
1
Conflict of Interest

I have no conflict of interest
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2
Objectives

To review risk factors, signs & symptoms

To understand steps in the diagnostic
evaluation

To consider the role of disease specific
treatment
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3
2007 Estimated US Cancer Deaths*
Lung & bronchus
Prostate
9%
Colon & rectum
9%
Pancreas
6%
Leukemia
4%
Liver & intrahepatic
bile duct
4%
Esophagus
4%
Urinary bladder
3%
Non-Hodgkin
3%
Kidney
3%
All other sites
Men
289,550
31%
lymphoma
24%
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ONS=Other nervous system.
Source: American Cancer Society, 2007.
Women
270,100
26%
Lung & bronchus
15%
Breast
10%
Colon & rectum

6% Pancreas

6% Ovary

4% Leukemia

3% Non-Hodgkin
lymphoma

3% Uterine corpus

2% Brain/ONS

2% Liver & intrahepatic
bile duct
23%
All other sites
4
Cancer Death Rates*, for Women, US,1930-2003
100
Rate Per 100,000
80
60
Lung & bronchus
40
Uterus
Breast
Colon & rectum
Stomach
20
Ovary
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*Age-adjusted to the 2000 US standard population.
Source: US Mortality Public Use Data Tapes 1960-2003, US Mortality Volumes 1930-1959,
National Center for Health Statistics, Centers for Disease Control and Prevention, 2006.
2000
1995
1990
1985
1980
1975
1970
1965
1960
1955
1950
1945
1940
1935
Pancreas
1930
0
5
Lifetime Probability of Developing Cancer, by Site, Women, US,
2001-2003*
Site
‡ Includes
Risk
All sites†
Breast
1 in 3
1 in 8
Lung & bronchus
1 in 16
Colon & rectum
1 in 19
Uterine corpus
1 in 40
Non-Hodgkin lymphoma
1 in 55
Ovary
1 in 69
Melanoma
1 in 73
Pancreas
1 in 79
Urinary bladder‡
1 in 87
Uterine cervix
1 in 138
invasive and in situ cancer cases
* For those free of cancer at beginning of age interval. Based on cancer cases diagnosed during 2001 to 2003.
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6
Source: DevCan: Probability of Developing or Dying of Cancer Software, Version 6.1.1 Statistical Research and Applications
Branch, NCI, 2006. http://srab.cancer.gov/devcan
Ovarian Cancer: Histologic
Distribution
8%
25%
Epithelial
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65%
Germ Cell
Sex Cord Stroma
7
Epithelial Ovarian Carcinoma




1 in 70 risk / 1 in 100 die of disease
Leading cause of death from gyn cancer
Majority present as stage III/IV
Five-year survival (surgery + chemotherapy)
– recent past
– current estimates
< 21%
~ 40%
The best hope for improved survival lies in
prevention, early detection and more effective
treatment
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Ovarian Cancer Symptoms
abdominal pain, distention
 change in weight
 early satiety
 urinary urgency, frequency
 change in bowel habits
 fatigue, dyspnea

“asymptomatic”……. ~ 95% of women do report symptoms, often
vague & non-gynecologic
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Adnexal Mass
MALIGNANT
BENIGN
–
–
–
–
–
–
–
–
unilateral
mobile
cystic
< 6.0 cm
slow growth
reproductive age
normal blood flow
isolated finding
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–
–
–
–
–
–
–
bilateral
fixed
complex or solid
> 6.0 cm
rapid growth
postmenopausal
abdominal mass,
ascites, pleural
effusion, adenopathy
10
ADNEXAL MASS
septations
papillary
projection
s
thick wall
complexity
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Fleischer A et al. Ultrasound Imaging
in Obstetrics & Gynecology.
Ovarian Cancer - Ultrasound Screening
Studies

Screening of 14,469 women
(University of Kentucky)
– 180 surgeries / 17 with ovarian CA
– ~ 11 surgical procedures per dx

Screening of 51,500 women
(Hirosaki University, Japan)
– 324 surgeries / 22 with ovarian CA
– ~ 15 surgical procedures per dx

Survival benefit unproven
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DePriest
PD, DeSimone CP. J Clin Oncol 2003;15(21):194-9.
Fleischer A et al. Ultrasound Imaging in Obstetrics & Gynecology.
12
CA-125





Elevated (>35 U/ml) in ~80% of cases
Elevated in ~ 50% of stage I cases
Low specificity & sensitivity
Has poor specificity, especially in premenopausal
women as elevated due to many causes including
infections, early pregnancy, endometriosis,
fibroids, other cancers, even surgery incisions
Most useful in clinical follow-up
– rising levels ~ recurrent disease
– precedes clinical & radiologic detection
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Proteomics




Recently developed technology
Measures multiple proteins, fragments of
proteins from a small sample
Ionizes the sample with a LASER in vacuum
chamber and performs mass spectrometry
Computer program using Artificial
Intelligence analyzes the patterns
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Proteomics


Computer “learns” to recognize patterns
that are seen in cancer and non-cancer
samples
Applies that “learning” curve to new
samples to differentiate between cancer
and non-cancer
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Proteomics

Petricoin et al from National Cancer
Institute published initial paper 2002
– 116 samples evaluated
50 of 50 known cancers found
 64 of 66 non cancers diagnose

Petricoin et al, Lancet 359(9306)
572-577 (2002)
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Proteomics

Can be automated using robotics allowing:
– Better quality control
– Low cost of $10-15 dollars per sample
– Patient cost estimated to $100-200 or higher
– Rapid turn around
– Large volume testing
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Proteomics

Results showed
– 100% Sensitivity
– 94% Positive Predictive Value
– Correctly identified early stage tumors
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Proteomics

Best Case Positive Predictive Value
– Ultrasound 40%
– CA-125
16%
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Proteomics



For a relative rare disease, must have very
high Positive Predictive Value to be
screening test
Ovarian cancer screening needs 99.6% to
be appropriate screening test
A 99% Positive Predictive value means 1000
FALSE diagnosis for every 15 TRUE cancers
found in the US population
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Proteomics…So What is the
Issue?



Three independent Biostatistical Analysis
unable to verify using standard statistics
Difficulty with Researchers Reproducing
their Data
No one is able to identify what exactly is
being measured as the materials measured
are fragments of proteins and other
substances
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Proteomics…So What is the
Issue?

Very small data set used for “learning”
curve
– There are 35 different cell types of Ovarian
Cancer and only a few cell types developed
– NO large scale trial has been performed to
verify the data
– FDA Required Testing has not been performed
and a “backdoor” approach to bypass FDA
regulations
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Ovarian Cancer - Goals of Initial
Surgery
 diagnosis
 staging
 cytoreduction
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Management of Ovarian Cancer:
Surgery
Omentum
Full abdominal
exploration and
sampling mandatory
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Total hysterectomy, bilateral
salpingo-oophorectomy
and omentectomy in all cases
25
DeVita et al. Cancer: Principles & Practice of Oncology.1993
Ovarian Cancer – Stages I
and II
Stage I
Stage II
Stage IIa
Stage Ib
Stage Ia
Stage IIb
or
with positive
ascites
Stage Ic
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Stage IIc
26
Beecham Sevigne, Mémento de Stadification des Principales Tumeurs Solides
Ovarian Cancer – Stages III and IV
Stage III
Stage IV
Supraclavicular
lymph nodes
Subcapsular
hepatic metastases
Positive pleural
cytology
Histologically
proven metastases
of the abdominal
peritoneal surfaces
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Parenchymous
hepatic metastases
27
Beecham Sevigne, Mémento de Stadification des Principales Tumeurs Solides
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Sainz de la Cuesta R et al. 1994: NEAGO Abstract.
30
Primary Cytoreduction

Meta-analysis:
53 studies (1989-98)
81 cohorts (Stage III/IV)
–
N = 6885 patients
Results
–
Expert centers have higher optimal
rates
–
Each 10%  in cytoreduction = 5.5%
 in survival
–
Platinum intensity = NS
38
Median Survival (Months)

–
40
36
34
32
30
28
26
24
22
20
0
10 20 30 40 50 60 70 80 90 100
% Cytoreduction
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Bristow, J Clin Oncol 20:1248, 2002
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The Role of the Generalist
Obstetrician-Gynecologist in the
Early Detection of Ovarian Cancer

Consider referral or consultation with Gynecologic
Oncologist if:
–
Postmenopausal and one of the following: increased CA-125,
ascites, nodular or fixed mass, metastasis, or family history of
breast or ovarian cancer
– Premenopausal and one of the following: very elevated CA-125
(>200), ascites, metastasis, or family history of breast or ovarian
cancer
ACOG Committee Opinion #280, December 2002
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Berman ML et al. Obstet Gynecol. 2005 Jan;105(1):35-41.
33
Ovarian Carcinoma: En-bloc Resection
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Morrow, CP and Curtin, JP: Gynecologic Cancer Surgery,
Churchill Livingstone, 1996
34
Rectosigmoid Anastomosis
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Morrow, CP and Curtin, JP: Gynecologic Cancer Surgery, Churchill Livingstone, 1996
35
Ovarian Cancer - Rectosigmoid Resection
# of pts
Obermair et. al.
Gynecol Oncol 2001, 83(1):115-20
65
leak(%) fistula(%) sepsis(%)
3.1
1.5
13.8
“An en bloc resection as part of primary cytoreductive surgery for
ovarian cancer is effective….. with acceptably low morbidity.”
Tamussino et. al.
14.4 Gynecol Oncol 2001, 80(1):79-84
82
3.7
1.1
“GI surgery is often indicated during operations for ovarian
cancer…..but colostomy is not frequently required”
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Ovarian Cancer: Survival by Residual
Disease
GOG Protocols 52 and 97
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Hoskins WJ, McGuire WP, Brady F, et al,
Am J Obstet Gynecol 170:974;1994.
37
Survival of Ovarian Cancer
Patients Following Chemotherapy
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McGuire WP et al. N Engl J Med. 1996
Management of Refractory or
Relapsed Ovarian Cancer



~ 50% of patients will ultimately relapse
despite initial complete remission
Once relapsed or initially refractory,
currently available therapy is rarely curative
Patients who relapse within 6 months are
less likely to respond to platinum-based
therapy
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Effect of Platinum-Free Interval on Response
Rate
80%
57%
60%
40%
40%
27%
20%
17%
59%
60%
27%
33%
20%
0%
0%
< 12
12 - 24
>24
5 - 12
13 - 24
>24
Months
Gore et al., Gyn Onc, 1990
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Markman et al., JCO, 1991
40
Treatment Timeline and Extending the PFI
-------------------- Platinum-Free Interval --------------------
1st line
platinumbased
chemotherapy
0
months
6
months
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remission
12
months
R
E
L
A
P
S
E
18
months
2nd Line
chemotherapy
24
months
remission
30
months
R
E
L
A
P
S
E
platinum
re-induction
36
months
41
Ovarian Cancer:
Phases of Management
Progression
Secondary
Surgery
Evaluation
? SLL
Diagnosis
Symptoms
Chemotherapy #1
Death
Consolidation
Surgical Management
Chemo #2
Chemo #3+
Supportive Care
Curative intent
Palliative intent
Surveillance
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Important Adjuvant Therapy
Questions in Advanced-Stage
Ovarian Cancer

Are there alternatives to paclitaxel/platinum-based
regimens for primary therapy? (i.e., other taxanes,
other agents, monotherapy, alternative schedules)

What is role of intraperitoneal therapy?

What is role of consolidation therapies?
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Optimally Debulked AdvancedStage Ovarian Cancer
GOG 1041 – Improved outcome in CP treated patients when
cisplatin administered IP
(RR 0.76)
GOG 1142 – Improved outcome in TP treated patients when
cisplatin administered IP
(RR 0.78)
GOG 1723 – Improved outcome in TP treated patients when
paclitaxel and cisplatin administered IP (RR 0.73)
1.
2.
3.
David S. Alberts, et al, N Engl J Med 1996;335:1950-5
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Maurie
Markman, et al, J Clin Oncol 2001;19:1001-1007
ASCO 2002 Abstract # 803
44
GOG Protocol 172
Optimal epithelial
ovarian carcinoma
(<1cm) stage III
or
Primary peritoneal
cancer
•Stratify by presence
of gross residual
disease and planned
second-look
laparotomy
D7/12/2016
Armstrong PI
R
a
n
d
o
m
i
z
e
-Paclitaxel: 135 mg/m2 IV over
24 hrs day 1, q21, days x 6
-Cisplatin: 75 mg/m2 IV day 2,
q21 days x 6
-Paclitaxel: 135 mg/m2 IV over
24 hrs day 1, q 21, days x 6
-Cisplatin: 100 mg/m2 IP day 2,
q 21 days x 6
-Paclitaxel: 60 mg/m2 IP day 8,
q21 days x 6
45
Proportion Surviving
GOG Protocol 172
Survival
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
By Treatment Group
Rx Group
___ IV
___ IP
0
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6
Alive Dead Total
93
117
210
117
88
205
12
18
24
30
36
Months on Study
42
48
54
60
46
GOG Protocol 172 Toxicity
G4
G3/4
G3/4
G3/4
G3/4
G3/4
G3/4
G3/4
G3/4
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WBC
Platelet
GI
Renal
Neuropathy 9%
Fatigue
Infection
5%
Metabolic
7%
Pain
IV
14%
4%
24%
1%
19%
5%
16%
27%
1%
IP
31%
12%
46%
6%
17%
11%
47
Future Chemotherapy
Strategies

Targeted Chemotherapy
– Bevacizumab targets VEGF
– Multiple trials showing efficacy
– GOG 218 Phase III trial ongoing combined with
Carboplatin and Taxol as primary treatment
– Toxicities include spontaneous bowel
perforations
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Future Strategies

Consolidation Therapy
– GOG 212
– GOG 218
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OVARIAN CARCINOMA
Family History
No history
One relative
lst degree
2nd degree
Two relatives
1 lst degree
> 1 2nd degree
Hereditary Syndrome
> 2 lst degree
Lifetime Probability
in 35 y/o (%)
1.6
5.0
7.6
50.0
Kerlikowske K, et al. Obstet Gynecol 1992; 80:703
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OVARIAN CANCER: SURVEILLANCE
AND TREATMENT
SUMMARY
Ovarian Cancer




no effective screening / vague symptoms
surgical cytoreduction / intact GI function are key
~ all patients benefit from chemotherapy
further improvement needed / clinical trials are
vital
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Uterine Cancer




Most common Gynecologic Malignancy in
US
39080 new cases are projected in 2007 by
American Cancer Society
7400 deaths projected 2007
Lifetime risk 1:40
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Uterine Cancer


Adenocarcinoma (glandular) is most common
type
Sarcoma is rare approximately 5%
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Symptoms

Abnormal Bleeding
– Any postmenopausal
– History of irregular premenopausal bleeding
– Heavy, irregular bleeding perimenopausal
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Adenocarcinoma


Type I
–
–
–
–
–
Estrogen Related
Younger and heavier patients
Low grade
Perimenopausal
Exogenous estrogen
–
–
–
–
Aggressive
Unrelated to estrogen stimulation
Occurs in older & thinner women
Potential genetic basis
Type II


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Lynch syndrome
Familial trend
59
Risk Factors
Characteristic
Obesity
>30 LBS
>50 LBS
Nulliparous
Late Menopause
Unopposed Estrogen
Atypical Hyperplasia
Diabetes
Hypertension
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Relative Risk [X]
3
10
2
4
9.5
29
2.8
1.5
60
Screening





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Patient – Primary
Cytology – Not satisfactory
Histology - Secondary
Hysteroscopy – Not satisfactory
Sonography – Cost-effective issue
61
Indications for Biopsy





Postmenopausal bleeding
Postmenopausal women with endometrial
cells on Pap
Perimenopausal intermenstrual bleeding
Abnormal bleeding with history of
anovulation
Thickened endometrial stripe via
sonography
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Endometrial Cancer - Transvaginal
Ultrasound
N=250
Endometrial Stripe Thickness
Diagnosis
Atrophy
<5mm 6-10mm
93%
11>15mm
15mm
7%
Hyperplasia
58%
42%
Polyp
53%
47%
Cancer
18%
41%
Grigoriou:
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Maturitus 23:9-14,1996
41%
63
Staging




Surgical Staged tumor
Stage 1 Confined to Uterus
Stage 2 Extension to Cervix
Stage 3 Extension to Serosa, Adnexa,
Positive Cytology, Positive Pelvic or
Paraaortic Lymph nodes, Vagina
Stage 4 Distant disease, bowel or bladder

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Prognostic Factors




Age
Stage
Grade
Histologic Type
– Serous
– Clear Cell
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Endometrial Cancer - Nodal
Involvement
Situation
G1, no myometrial invasion, no
extrauterine disease.
G2 or G3, inner 1/3 invasion,
no extrauterine disease
G3, outer muscle, and/or
extrauterine disease
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% Positive Nodes
<1%
5-9% Pelvic
4% Aortic
20-60% Pelvic
10-30% Aortic
66
Endometrial Cancer: Surgical
Approach

Complete Surgical Staging*
– All tumors in Surgical Candidates
– TAH/BSO or TLH/BSO
– Pelvic Cytology Washings
– Pelvic and Peri-Aortic Lymphnode Dissection
– Omentectomy, Peritoneal Biopsies and possible
debulking for Serous and Clear subtypes
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Laparoscopic Hysterectomy
and Lymphnode Dissections


Multiple studies showing excellent results
GOG Lap 2 Protocol
– Selected patients with presumed Stage I or IIA
– 23% conversion most associated with BMI >32
– Data still maturing but appears to be
comparable in all regards
Walker et al: SGO Plenary Presentation 3/24/06
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Endometrial Cancer
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Endometrial Cancer:
Adjuvant Therapy
Brachytherapy
 External beam radiotherapy
 Hormonal therapy
 Cytotoxic chemotherapy
 Combination therapy

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Determinants of Adjuvant
Therapy
Stage
 Histologic subtype
 Staging completeness
 Tumor biology
 Medical conditions

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Chemotherapy Response
Rates
Single Agent
11-37%
CAP
45-56%
AP
33-81%
CA
31-46%
TAX/CARBO
63%
TEP
73%
AP-VP-16
75%
GOG Symposium July, 1999, Goff
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Endometrial Cancer: FollowUp




Pelvic examination
Pap smears
CA125 high-risk
Chest X-ray high-risk
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Endometrial Cancer: Stage Distribution
and Survival
Stage
Percent
Survival
I
73
87%
II
11
72%
III
13
51%
IV
3
9%
Overall
73%
FIGO Annual Report - 1998
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Endometrial Cancer:
Recurrence
80% of recurrences happen first 3 years
 Most will be symptomatic
 Rare to cure distant recurrences
 50% vaginal recurrences cured

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Recurrent Endometrial
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Endometrial Cancer: Site of
Recurrence
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Site
%
Distant
65
Pelvic and distant
15
Pelvis only
15
Vagina
6
78
Endometrial Cancer:
ERT/HRT
3 published studies
 GOG study closed due to poor accrual
after WHI
 No evidence that ERT/HRT adversely
influences the disease-free survival of
women treated for selected endometrial
cancer patients with low risk disease

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Prevention




Weight control
Low dietary fat intake
Use of Oral Contraceptives
No Unopposed estrogen exposure
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Sarcoma



Rare tumors approximately 5% of tumors
Aggressive in Nature
3 major types
– Mixed MullerianTumors
– Leiomyosarcoma
– Endometrial Stromal Sarcoma
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Symptoms



Rapidly enlarging uterus in postmenopausal
woman
Abnormal uterine bleeding
Large mass extending through the cervix
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Sarcoma
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Sarcoma
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Sarcoma
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Sarcoma
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Treatment


Primarily Surgical with staging
Adjuvant Therapy
– Radiation shown to control local recurrence
rates but not survival
– Chemotherapy
Few effective agents
 IFX, Adriamycin, Progestins

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Questions?
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