1. 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

2. Magnitude of The Clinical Problem:

3. Magnitude of The Clinical Problem:
Steep Survival Gradient of Ovarian Cancer and Stage at Diagnosis
Stage I II
III IV
Description
Confined to ovaries
Confined to pelvis
Confined to abdomen/lymph nodes
Distant metastases
Incidence
20% 5%
58%
17%
Survival
73%
45%
21%
< 5% 10 20 30 40 50 60 70 80 I II
III IV
Jelic S, et al Congress of the European Society for Medical Oncology. Mocharnuk R. Available at:

4. 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)
2005 Liposomal doxorubicin (full)
2006 Gemcitabine
2008

5. 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

6. 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

7. 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

8. 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

9. endometrial, and ovarian cancers are hereditary
How Much Cancer Is Hereditary?
~5% to 10% of
breast, colon,
endometrial, and ovarian
cancers are hereditary
90%
not hereditary
90%
not hereditary

10. Lifetime Risk of Cancers Associated With Specific Genes
BRCA1
BRCA2
MMR*
Breast
35-60
30-55
Ovarian
30-40
15-25
6-20
Endometrial
40-60
*MMR (mismatch repair) = HNPCC.
Chen S, et al. J Clin Oncol. 2007:25: Aarnio M, et al. Int J Cancer. 1999:81:

11. Relative Risk of Ovarian Cancer
Ovarian Cancer: Ovulation
> 5
Duration
of Oral
Contraceptive
Use (Yrs)
2-3
Duration
of Breast-
Feeding
(Mos)
12-23
1-5
> 6
Number
of Term
Pregnancies 4 2
0.0
0.5
1.0
Relative Risk of Ovarian Cancer
Whittemore AS, et al. Am J Epidemiol. 1992;136:

12. 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)
Ever
255
625,984
1.21 ( )
1.23 ( )
Frequency
Current (baseline) 62
151,880
1.45 ( )
1.51 ( )
Former
193
474,103
1.15 ( )
1.16 ( )
Current users, yrs
< 10 31
110,379
1.07 ( )
1.14 ( )
≥ 10
41,396
2.13 ( )
2.20 ( )
Former users, yrs
158
416,823
1.09 ( )
1.10 ( ) 35
57,281
1.55 ( )
1.59 ( )
*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:

13. Ovarian Screening Methods for Average-Risk Women
CA-125: poor sensitivity in early stage disease
Transvaginal ultrasound: poor sensitivity in early-stage disease, cannot reliably distinguish benign from malignant changes
Pelvic exam

14. Ovarian Screening Methods for Average-Risk Women (cont’d)
Insufficient evidence to recommend population-based screening
Low prevalence of ovarian cancer in general population
Not cost-effective
Difficult to screen premenopausal women
Appropriate screening is undefined

15. 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: Narod SA, et al. Lancet. 2001;357:

16. Prophylactic Oophorectomy: Counseling about Risks/Benefits
Medical benefits
Prevention of ovarian cancer (unknown risk of peritoneal cancer)
Decreases risk of recurrent breast cancer
Emotional benefits
Relief from fear of developing ovarian cancer
Medical risks
Loss of endogenous estrogen (effect on heart, bones, sexual function)
Effect of hormone replacement therapy on breast cancer risk
Emotional risks
Issues around castration

17. 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:

18. Epithelial Ovarian Cancer Standards of Care

19. Goals of Therapy: Manage symptomatic patients.
Better durability of response.
Survival improvement.
Maintain Quality of Life.

20. GOG 111: Standard of Care Study design
Cisplatin 135 mg2 IV over 24 hours +
Paclitaxel 75 mg/m2 x 6 cycles
(n = 184)
Patients with suboptimally
debulked, stage III/IV
epithelial ovarian cancer
within 6 weeks of surgery
(N = 386)
Cisplatin 75 mg/m2 x 6 cycles +
Cyclophosphamide 750 mg/m2 IV
(n = 202)
McGuire W, et al. N Engl J Med. 1996;334:1-6.

21. GOG 111: PFS and OS PFS (P < .001) OS (P < .001) 1.0 1.0 0.9 0.9
0.8
0.8
0.7
0.7
0.6
0.6
Proportion Surviving Progression Free
0.5
Proportion Surviving
0.5
0.4
0.4
0.3
0.3
0.2
0.2
0.1
0.1 6 12 18 24 30 36 42 48 6 12 18 24 30 36 42 48
Months After Entry Into Study
Months After Entry Into Study
Treatment
No. Progression Free
No. With Treatment Failure
Total
Median PFS, mos
Cisplatin + cyclophosphamide 28
174
202 13
Cisplatin + paclitaxel 45
139
184 18
Treatment
No. Alive
No. Dead
Total
Median Survival, mos
Cisplatin + cyclophosphamide 65
137
202 24
Cisplatin + paclitaxel 86 98
184 38
McGuire W, et al. N Engl J Med. 1996;334:1-6.

22. NCCN Guidelines: v2.2009 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:
Stage II: Intraperitoneal Chemotherapy vs Systemic 6-8 Courses of Paclitaxel/Carboplatin.
Stage III (< 1 cm Residual): Intraperitoneal Chemotherapy vs Systemic 6-8 Courses of Paclitaxel/Carboplatin.
Stages III (> 1 cm Residual) & IV: Systemic 6-8 Courses of Paclitaxel/Carboplatin.
Completion of Surgery.

23. New Agents for the Clinical Management of Ovarian Cancer
Bevacizumab
Death
Diagnosis
Secondary
Surgery
Symptoms
Chemotherapy #1
Maintenance
Chemo #2
Chemo #3+
Progression
Staging
Paclitaxel poliglumex
Oregovomab
Abagovomab
Canfosfamide
Patupilone
Phenoxodiol
Karenitecin
Trabectedin

24. GOG 218: Potential New Standard of Care
Paclitaxel +
Carboplatin + Placebo*
Placebo† x 15 months
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*
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. NCT

25. 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 Abstract 5536.

26. Conventional TC (c-TC) Dose-dense weekly TC (dd-TC)
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 Abstract 5506.

27. Proportion Surviving Progression Free Mos From Randomization
Conventional vs Dose-Dense TC (NOVEL): PFS
1.0
0.9
dd-TC
0.8
c-TC
0.7
0.6
Proportion Surviving Progression Free
0.5
0.4
0.3
0.2
0.1
0.0 6 12 18 24 30 36 42 48 54
Mos From Randomization
Treatment n
Event
Median PFS, mos
P Value HR
95 %CI
c-TC
319
200
17.2
dd-TC
312
160
28.0
.0015
0.714
Isonishi S, et al. ASCO Abstract 5506.

28. Intra-Peritoneal Chemotherapy:
Toxicity profile.
GOG III :
Systemic Paclitaxel/Cisplatin.
Intraperitoneal Paclitaxel.
Intraperitoneal Cisplatin.
ClinicalTrials.gov/ct2/show/NCT August 2008

29. 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

30. 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: Vergote IB, et al. Tumour Biol. 1992;13:

31. 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: NCT ?term=GOG+cytoreduction&rank=1. Accessed February 4, 2008.

32. Platinum-Sensitive Recurrent Ovarian Cancer:
Carboplatin is key drug
Carboplatin combinations are superior to single-agent carboplatin
Choice of carboplatin/gemcitabine vs carboplatin/paclitaxel based on toxicity considerations
Results of carboplatin/PLD vs carboplatin/paclitaxel will be available soon

33. 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

34. 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”