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Management of
Epithelial Ovarian Cancer
Mohamed Abdulla (M.D.)
Department of Clinical Oncology
Kasr El-Aini School of Medicine
Cairo University
Egyptian Cancer Society
Meeting, Demiat Cancer Center
– June, 2009
Magnitude of The Clinical Problem:
Magnitude of The Clinical Problem:
Steep Survival Gradient of Ovarian Cancer and
Stage at Diagnosis
Stage
Description
I
II
III
IV
Confined to
ovaries
Confined to
pelvis
Confined to
abdomen/lymph
nodes
Distant
metastases
20%
5%
58%
17%
73%
45%
21%
< 5%
Incidence
Survival
80
70
60
50
40
30
20
10
0
I
II
III
IV
Jelic S, et al. 2002 Congress of the European Society for Medical Oncology.
Mocharnuk R. Available at: http://www.medscape.com/viewarticle/444134.
Magnitude of The Clinical Problem:
FDA-Approved Drugs in Ovarian Cancer
1978
• 1978
Cisplatin
• 1989
Carboplatin
• 1990
Altretamine
• 1992
Paclitaxel
• 1996
Topotecan
• 1999
Liposomal doxorubicin
(accelerated)
2008
• 2005
Liposomal doxorubicin (full)
• 2006
Gemcitabine
Magnitude of The Clinical Problem:
• Stage I/II
– Essentially all patients will achieve a clinical CR after surgery
and chemotherapy
– 20% to 25% will relapse
• Optimal stage III
– > 90% will achieve a clinical CR
– 75% will recur
• Suboptimal stage III/IV
– 50% will achieve a clinical CR
– > 90% will recur
Magnitude of The Clinical Problem:
Ovarian Carcinoma--Symptoms







Abdominal bloating, increased girth, pressure
Abdominal / pelvic pain
Fatigue
GI (nausea, gas, constipation, diarrhea)
Urinary frequency/ incontinence
Weight loss/ gain
Shortness of breath
Vague and often non-gynecologic-- NOT Silent
Magnitude of The Clinical Problem:
Ovarian Carcinoma--Signs





Palpable pelvic mass
Abdominal mass
Abdominal distension
Decreased breath sounds due to effusions
Adenopathy -- groin, supraclavicular
Spreads by local growth, bloodstream and lymphatic routes
Ovarian Cancer Risk Factors
• 50 years of age or older
• Familial factors
– Family history of breast,
ovarian, or colon cancer
– Personal history of breast
or colon cancer
– BRCA (breast cancer)
gene mutation
– Hereditary nonpolyposis
colon cancer (HNPCC)
• Other potential risk factors
– Early menarche (younger
than 12 years of age)
– Late menopause (older
than 52 years of age)
– Hormone replacement
therapy or fertility drugs
– First pregnancy at older
than 30 years of age
– Infertility
How Much Cancer Is Hereditary?
~5% to 10% of
breast, colon,
endometrial, and
ovarian
cancers are
hereditary
90%
90%
not
not hereditary
hereditary
Lifetime Risk of Cancers Associated With Specific
Genes
Cancer, %
BRCA1
BRCA2
MMR*
Breast
35-60
30-55
0
Ovarian
30-40
15-25
6-20
0
0
40-60
Endometrial
*MMR (mismatch repair) = HNPCC.
Chen S, et al. J Clin Oncol. 2007:25:1329-1333.
Aarnio M, et al. Int J Cancer. 1999:81:214-218.
Ovarian Cancer: Ovulation
>5
Duration
of Oral
Contraceptive 2-3
Use (Yrs)
0
Duration 12-23
of BreastFeeding
1-5
(Mos)
>6
Number
of Term
Pregnancies
4
2
0
0.0
0.5
1.0
Relative Risk of Ovarian Cancer
Whittemore AS, et al. Am J Epidemiol. 1992;136:1212-1220.
Limiting HRT May Reduce Ovarian Cancer
Risk:
Estrogen Use
No. of
Deaths
No. of
Person-Years
Rate Ratio
(95% CI)*
Rate Ratio
(95% CI)†
Never
689
2,185,876
1.00 (referent)
1.00 (referent)
Ever
255
625,984
1.21 (1.05-1.41)
1.23 (1.06-1.43)
• Current (baseline)
62
151,880
1.45 (1.11-1.88)
1.51 (1.16-1.96)
• Former
193
474,103
1.15 (0.98-1.36)
1.16 (0.99-1.37)
• < 10
31
110,379
1.07 (0.74-1.54)
1.14 (0.79-1.65)
• ≥ 10
31
41,396
2.13 (1.48-3.06)
2.20 (1.53-3.17)
• < 10
158
416,823
1.09 (0.92-1.30)
1.10 (0.92-1.31)
• ≥ 10
35
57,281
1.55 (1.10-2.18)
1.59 (1.13-2.25)
Frequency
Current users, yrs
Former users, yrs
*Rate ratio estimates adjusted for age and race.
†Models adjusted for age at baseline, race, duration of oral contraceptive use, number of live births, age at
menopause, body mass index, age at menarche, and tubal ligation.
Rodriguez C, et al. JAMA. 2001;285:1460-1465.
Ovarian Screening Methods for
Average-Risk Women
CA-125: poor sensitivity in
early stage disease
Pelvic exam
Transvaginal ultrasound: poor
sensitivity in early-stage
disease, cannot reliably
distinguish benign from
malignant changes
Ovarian Screening Methods for
Average-Risk Women (cont’d)
• Insufficient evidence to recommend populationbased screening
• Low prevalence of ovarian cancer in general
population
• Not cost-effective
• Difficult to screen premenopausal women
• Appropriate screening is undefined
Prevention of Ovarian Cancer
• Chemoprevention
– Oral contraceptive pills
– Limit clomifene citrate
– Limit hormone replacement therapy
• Surgical prevention
– Oophorectomy: 80% risk reduction in high-risk
women[1]
– Bilateral tubal ligation: 72% risk reduction when used
with oral contraception[2]
1. Finch A, et al. JAMA. 2006;296:185-192.
2. Narod SA, et al. Lancet. 2001;357:1467-1470.
Prophylactic Oophorectomy: Counseling
about Risks/Benefits
• Medical benefits
• Medical risks
– Prevention of ovarian
– Loss of endogenous
cancer (unknown risk of
estrogen (effect on heart,
peritoneal cancer)
bones, sexual function)
– Decreases risk of recurrent • Effect of hormone
breast cancer
replacement therapy on breast
cancer risk
• Emotional benefits
• Emotional risks
– Issues around castration
– Relief from fear of
developing ovarian cancer
At What Age Should a Patient Undergo
Surgery?
• Limited data available
– Decision often relies on pedigree information
• National Institutes of Health consensus panel
recommendation: 35 years of age or older or
after childbearing is complete[1]
1. JAMA. 1995;273:491-497
Epithelial Ovarian Cancer
Standards of Care
Goals of Therapy:
•
•
•
•
Manage symptomatic patients.
Better durability of response.
Survival improvement.
Maintain Quality of Life.
GOG 111: Standard of Care
• Study design
Patients with suboptimally
debulked, stage III/IV
epithelial ovarian cancer
within 6 weeks of
surgery
(N = 386)
McGuire W, et al. N Engl J Med. 1996;334:1-6.
Cisplatin 135 mg2 IV over 24 hours +
Paclitaxel 75 mg/m2 x 6 cycles
(n = 184)
Cisplatin 75 mg/m2 x 6 cycles +
Cyclophosphamide 750 mg/m2 IV
(n = 202)
GOG 111: PFS and OS
PFS (P < .001)
OS (P < .001)
1.0
Proportion Surviving Progression
Free
1.0
0.9
0.8
0.8
Proportion Surviving
0.9
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
0
6
12
18
24
30
36
42
48
0
6
Months After Entry Into Study
Treatment
No.
No. With Total
Progression Treatment
Free
Failure
12
18
24
30
36
42
Months After Entry Into Study
Median
PFS, mos
Treatment
No. Alive
No. Dead Total
Median
Survival, mos
Cisplatin +
cyclophosphamide
28
174
202
13
Cisplatin +
cyclophosphamide
65
137
202
24
Cisplatin + paclitaxel
45
139
184
18
Cisplatin + paclitaxel
86
98
184
38
McGuire W, et al. N Engl J Med. 1996;334:1-6.
48
NCCN Guidelines: v2.2009
•
1.
2.
•
Stage IA & IB:
Grade 1 & 2: Observe.
Grade 3: 3-6 Courses Paclitaxel/Carboplatin.
Stage IC: 3-6 Courses Paclitaxel/Carboplatin.
• Stages II, III & IV:
1. Stage II: Intraperitoneal Chemotherapy vs Systemic 6-8
Courses of Paclitaxel/Carboplatin.
2. Stage III (< 1 cm Residual): Intraperitoneal Chemotherapy
vs Systemic 6-8 Courses of Paclitaxel/Carboplatin.
3. Stages III (> 1 cm Residual) & IV: Systemic 6-8 Courses
of Paclitaxel/Carboplatin.
4. Completion of Surgery.
New Agents for the Clinical Management of
Ovarian Cancer
1.
Bevacizumab
Death
Secondary
Surgery
Diagnosis
Symptoms
Chemotherapy #1
Maintenance
Chemo #2
Progression
Staging
1.
2.
3.
Paclitaxel poliglumex
Oregovomab
Abagovomab
1.
2.
3.
4.
5.
Canfosfamide
Patupilone
Phenoxodiol
Karenitecin
Trabectedin
Chemo #3+
GOG 218: Potential New Standard
of Care
Paclitaxel +
Carboplatin + Placebo*
Patients with stage III/IV ovarian or
primary peritoneal cancer and
GOG PS 0-2 entered 1-12 weeks
after initial surgery
(N = 2000)
Placebo† x 15 months
Paclitaxel +
Carboplatin + Bevacizumab*
Placebo† x 15 months
Paclitaxel +
Carboplatin + Bevacizumab*
Bevacizumab† x 15 months
*Beginning in course 2 of chemotherapy.
†Beginning in course 7 of chemotherapy.
•
•
Primary endpoint: PFS measured by RECIST
Secondary endpoints: OS, safety, QoL, translational objectives, response
ClinicalTrials.gov. NCT00262847.
GC vs TC Induction Regimens Followed by T
Consolidation: Study Design
Histologic diagnosis and prior resection of
stage IC-IV epithelial ovarian, primary peritoneal,
or fallopian tube carcinoma
Induction GC
Gemcitabine 1000 mg/m2 Days 1, 8
+ Carboplatin AUC 5 Day 1
x 6 cycles every 21 days
Induction TC
Paclitaxel 175 mg/m2 Day 1
+ Carboplatin AUC 6 Day 1
x 6 cycles q 21 days
Clinical CR
Anything other than CR
(PR, SD, PD)
Anything other than CR
(PR, SD, PD)
Elective
T Consolidation Therapy
Paclitaxel 135 mg/m2
every 28 days for 12 cycles
Single-agent crossover
Paclitaxel 175 mg/m2 Day 1
Single-agent crossover
Gemcitabine 1000 mg/m2 Days 1, 8
Gordon A, et al. ASCO 2008. Abstract 5536.
Conventional vs Dose-Dense TC (NOVEL):
Study Design
Ovarian epithelial, primary peritoneal, or
fallopian tube cancer with
FIGO stage II-IV
Stratified by
residual disease ≤ 1 cm vs > 1 cm;
FIGO stage II vs III vs IV;
histology: clear cell/mucinous vs serous/others
Conventional TC (c-TC)
Paclitaxel 180 mg/m2 Day 1 +
Carboplatin AUC 6.0 Day 1
every 21 days for 6-9 cycles
Dose-dense weekly TC (dd-TC)
Paclitaxel 80 mg/m2 Days 1, 8, 15 +
Carboplatin AUC 6.0 Day 1
every 21 days for 6-9 cycles
Isonishi S, et al. ASCO 2008. Abstract 5506.
Conventional vs Dose-Dense TC (NOVEL): PFS
Proportion Surviving
Progression Free
1.0
0.9
dd-TC
0.8
c-TC
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
6
12
18
24
30
36
42
48
54
Mos From Randomization
Treatment
n
Event
Median PFS, mos
c-TC
319
200
17.2
dd-TC
312
160
28.0
P Value
HR
95 %CI
.0015
0.714
0.581-0.879
Isonishi S, et al. ASCO 2008. Abstract 5506.
Intra-Peritoneal Chemotherapy:
•
•
1.
2.
3.
Toxicity profile.
GOG III :
Systemic Paclitaxel/Cisplatin.
Intraperitoneal Paclitaxel.
Intraperitoneal Cisplatin.
ClinicalTrials.gov/ct2/show/NCT00003322. August 2008
Patterns of Recurrence
• Serologic relapse
– Rising CA-125 only evidence of disease
•
•
•
•
Localized recurrence
Disseminated intraperitoneal disease
Extraperitoneal metastases
Recurrences can be symptomatic or asymptomatic
Management of a Rising CA-125 in a
Patient Who Is Clinically Disease Free
• Rising CA-125 is highly predictive of a clinical
relapse
– Median time of 4-6 months before symptoms develop
and/or a clinical recurrence (physical exam or imaging
studies) is documented[1,2]
• Patient/physician preference about instituting
chemotherapy is similar (~ 50%)
– No evidence that delaying chemotherapy until clinical
relapse is detrimental
• Randomized trial in progress in Europe
1. Niloff JM, et al. Am J Obstet Gynecol. 1986;155:56-60. 2.
Vergote IB, et al. Tumour Biol. 1992;13:168-174.
Role of Secondary Cytoreduction
• No RCT establishing clinical benefit
– Gynecologic Oncology Group trial in progress[1]
• Easier to define patients who should not undergo
secondary cytoreduction
– Short disease-free interval
– Intraperitoneal carcinomatosis precludes complete
resection
– Ascites
– Drug-resistant disease
1. ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov/ct2/show/
NCT00002568?term=GOG+cytoreduction&rank=1. Accessed February 4, 2008.
Platinum-Sensitive Recurrent Ovarian
Cancer:
• Carboplatin is key drug
• Carboplatin combinations are superior to singleagent carboplatin
• Choice of carboplatin/gemcitabine vs
carboplatin/paclitaxel based on toxicity
considerations
• Results of carboplatin/PLD vs
carboplatin/paclitaxel will be available soon
Strategies to Improve Outcomes in
Platinum-Resistant Disease
• No evidence that combinations of cytotoxic agents
superior to single agents
– RCT of canfosfamide + carboplatin vs PLD: negative
– PLD + trabectedin vs PLD in progress
• No RCTs of in vitro sensitivity/resistance assays
have shown improvement
• Biologic agents
– Bevacizumab
• ? single agent or in combination with chemotherapy
How Long to Treat Patients With
Recurrent Disease?
• No RCTs in recurrent disease directly address this
issue
• In previously untreated patients, RCTs have failed to
show any benefit for either continuing with the same
chemotherapy or switching to a non–cross-resistant
regimen
– In recurrent disease, the same could be expected
• Currently, this is a personal choice issue with
patient/physician
– Toxicity is key
– Some patients will choose more therapy as long as there is
evidence they are not in a remission—“psychochemotherapy”
– Benefit of “drug holidays”