1. Treatment of Refractory Ovarian Cancer

2. OVARIAN CANCER Worldwide incidence*
10.0
11.5
6.4
9.6
5.4
2.8
5.3
7.6
11.2
Eastern
Europe
Japan
Australia
New Zealand
South Central Asia
Northern
Africa
Southern
Central
America
Western
North
1. Ovarian Cancer: Worldwide Incidence
The incidence of ovarian cancer is highest in industrialized countries and regions, with incidence rates exceeding 8 per 100,000 in these areas. Northern, Eastern, and Western Europe, and North America have the highest incidence rates of ovarian cancer of all world regions.
*Incidence per 100,000 population.
Parkin DM, et al. CA Cancer J Clin. 1999;49:61.

3. OVARIAN CANCER Risk factors
Increasing age
Nulliparous history
Non-use of oral contraceptives
Personal history of breast cancer
Family history
Genetic cancer syndrome
BRCA 1/BRCA 2
Hereditary non-polyposis colon cancer
3. Ovarian Cancer: Risk Factors
Several risk factors have been identified for ovarian cancer, including increasing age, a nulliparous history, non-use of oral contraceptives and a personal history of breast cancer. A family history of ovarian cancer is the most important risk factor for developing the disease. Mutations in BRCA 1 and BRCA 2 and mutations that lead to hereditary nonpolyposis colon cancer have been implicated in familial ovarian cancer.
American Cancer Society. Cancer Facts & Figures—1999;13.
Lynch HT et al. Semin Oncol. 1998;25:

4. OVARIAN CANCER Early detection
Early detection is rare due to:
Lack of accurate screening methods
Late appearance of signs and symptoms
Insidious, nonspecific symptoms
4. Ovarian Cancer: Early Detection
Early detection of ovarian cancer remains a clinical challenge because symptoms of the disease are vague and nonspecific, and may not appear until the cancer has advanced. Currently, an annual pelvic examination is recommended as it may lead to detection of a tumor; however the exam has not been shown to decrease mortality. Pap tests rarely reveal early-stage disease and, although transvaginal ultrasound (TVUS) with CA 125 evaluation may be useful in diagnosis, this approach is currently not recommended for routine screening.
American Cancer Society. Cancer Facts & Figures—1999;13.
NCI. A 16-year randomized screening study for prostate, lung, colorectal, and ovarian cancer—PLCO trial.
Rosenthal A, Jacobs I. Semin Oncol. 1998;25:
Stern JL. Everyone’s Guide to Cancer Therapy. 1997;602.

5. OVARIAN CANCER Screening
Currently available techniques
Pelvic exam
Transvaginal ultrasound
Serum CA 125
None sufficiently accurate for general screening
Routine screening not recommended
Evaluation of a panel of more sensitive tumor markers (eg, CA 125, M-CSF, OVX-1) may improve detection of early-stage disease
NCI PLCO trial evaluating TVUS + CA 125
6. Ovarian Cancer: Screening
Screening for ovarian cancer has been generally unsuccessful, in large part because the currently available techniques, ovarian palpation, transvaginal ultrasound, and serum CA 125, are not sufficiently accurate. Therefore, routine screening with these techniques is not recommended. A panel of more sensitive tumor markers, such as CA 125 plus macrophage colony-stimulating factor (M-CSF) and OVX-1, has been shown to be extremely sensitive and moderately specific in preliminary studies. In addition, a large study is evaluating the effectiveness of transvaginal ultrasound plus CA 125 screening in reducing mortality from ovarian cancer. These evaluations may lead to improved screening of ovarian cancer in the future.
Ozols RF, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1509.
NCI. A 16-year randomized screening study for prostate, lung, colorectal, and ovarian cancer—PLCO trial.

6. OVARIAN CANCER Pathogenesis
Common epithelial tumors account for
60% of ovarian neoplasms
80%-90% of ovarian malignancies
Most common form of tumor spread: exfoliation of malignant cells through the epithelial surface of ovarian capsule
Malignant cells circulate in peritoneal fluid and through lymphatics
Late presentation with metastatic disease outside the peritoneum
7. Ovarian Cancer: Pathogenesis
The majority of ovarian cancers are common epithelial tumors, which account for 60% of all ovarian neoplasms and up to 90% of all ovarian malignancies. The most common route of epithelial tumor spread is the exfoliation of malignant cells through the surface of the ovarian capsule. Additionally, malignant cells can circulate within the peritoneal fluid and through regional lymphatics. Approximately 2 to 3 percent of patients present with involvement of vital organ parenchyma, such as lung and liver.
Ozols RF, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;
Berek JS, Hacker NF. Cancer Treatment. 4th ed. 1995;

7. OVARIAN CANCER Prognostic factors
FIGO Stage
Patient’s age
Postsurgical volume of residual disease
Postsurgical CA 125
Histologic subtype
Histologic grade
14. Ovarian Cancer: Prognostic Factors
Several prognostic factors are useful in managing patients with ovarian cancer. The most important of these is the FIGO stage. The patient’s age and volume of residual disease following surgery are additional considerations in determining a prognosis. Other factors, such as histologic subtype and grade, and postsurgical CA 125 may be of some use.
Ozols RF, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1510.

8. OVARIAN CANCER Survival by stage
FIGO Stage 5-Year Survival
I > 90%
II  80%
III 15% to 20%
IV < 5%
15. Ovarian Cancer: Survival by Stage
The prognostic importance of staging in ovarian cancer is demonstrated in this slide. Five-year survival is dramatically different in early-stage disease compared with late-stage disease. In Stage I and II disease, five-year survival rates of greater than 90% and approximately 80%, respectively, have been reported. Five-year survival in Stage III depends in large part on the volume of disease present in the upper abdomen, with average rates of 15% to 20%, which may extend to approximately 35% in patients with no residual nodules of more than 1 cm in diameter postoperatively. Less than 5% of patients diagnosed with Stage IV ovarian cancer survive five years.
Ozols RF, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;

9. Current Management for Epithelial Ovarian Cancer
Surgical staging and cytoreduction at diagnosis
Postoperative chemotherapy for high-risk limited stage and all advanced stage patients
Chemotherapy
IV paclitaxel (175 mg/m2 over 3 hrs) plus IV carboplatin (AUC ) for 6 cycles
Vast majority of patients with advanced stage ovarian cancer will relapse
1. National Cancer Institute. NCI Clinical Announcement. January 2006.

10. Treatment Considerations in Recurrent Ovarian Cancer
Definitions
Refractory disease: no response or incomplete response to platinum-based therapy
Relapsed disease: progression after clinical complete response
Platinum sensitive:  12 month platinum-free interval
Partially Platinum sensitive: 6-12 month platinum-free interval
Platinum resistant:  6 month platinum-free interval

11. Treatment Modalities for Recurrent Ovarian Cancer
Chemotherapy
Primary modality
Surgery
Late relapse with potential for complete resection
Bowel obstruction
Radiation
Palliation for drug-resistant, symptomatic, isolated lesions

12. Chemotherapy Principles in Recurrent Ovarian Cancer
Combinations are superior to single-agent platinum in platinum-sensitive patients
Multiple agents have clinical activity
Activity superior in platinum-sensitive patients
No established role for combinations in platinum-resistant disease
Management considerations
Length of treatment and “drug holidays”
Choice of combination in platinum-sensitive patients
Choice of drug in platinum-resistant patients
Maintenance chemotherapy

13. Active Agents in Recurrent Ovarian Cancer
Carboplatin
Taxanes
Paclitaxel
Docetaxel
Topotecan
Liposomal doxorubicin
Gemcitabine
Less commonly used
Oral etoposide
Altretamine
Tamoxifen
Vinorelbine

14. Platinum-sensitive ovarian cancer

15. Chemotherapy for Platinum-Sensitive Recurrent Ovarian Cancer
“Old standard”
Single-agent carboplatin
“New standard”
Paclitaxel plus carboplatin
Gemcitabine plus carboplatin
Other combinations under evaluation
Liposomal doxorubicin plus carboplatin
Biologic agents plus chemotherapy

16. Methods: Patients and methods:
GINECO: phase II Carboplatin (PA) and PLD (CA; PACA regimen) in patients with AOC in late (>6 ms) relapse (AOCLR): trial ASCO Abstract No: 5022 J.-M. Ferrero et al. Published in Annals of Oncology, November 15, 2006
Methods:
105 pts received a q4w schedule of CA (30 mg/m², d1) followed by PA (AUC 5 mg.ml-1.mn, d1) median 6 cycles
Patients and methods:
The median age was 61 years (23-79), 47% had PS % had serous histology; 54% had MD; and 86% had CA-125 levels >40 IU/ml.

17. Results: Conclusions:
GINECO: phase II Carboplatin (PA) and PLD (CA; PACA regimen) in patients with AOC in late (>6 ms) relapse (AOCLR): trial ASCO Abstract No: 5022 J.-M. Ferrero et al. Published in Annals of Oncology, November 15, 2006
Results:
The ORR is 63% (65/105 pts) including 38% with CR
Median PFS is 9 months. Median OS 31.1-month
NCI G 3-4 neutropenia (23% of cycles), anemia (4%) and thrombocytopenia (8%).
G 2-3 nausea/vomiting (32%), G 2 PPE (11%), and G 2-3 mucositis (12%).
Conclusions:
PLD plus Carboplatin is highly effective, prolongs OS, and is well tolerated in women with AOC in late relapse previously treated with both platinum and taxanes.

18. Platinum-refractory ovarian cancer

19. Management of Platinum-Resistant Recurrent Ovarian Cancer
Remissions are achievable in about 20% of patients using the most active single agents:
tubulin interacting agents (taxans, vinorelbine)
Liposomal doxorubicin
topoisomerase-II-inhibitors (anthracyclines, etoposid)
Topotecan
Gemcitabine
Which is better?
Few randomized trials have been performed
Topotecan vs paclitaxel
Liposomal doxorubicin vs topotecan
Gemcitabine vs liposomal doxorubicin
Until today, no combination regimen has shown superior results compared with an active single agent in comparative trials

20. 30-49 Study Design R A N D O M I Z T CAELYX® (PLD) 50 mg/m2 q 4 wks
Enrollment
recurrent epithelial ovarian cancer
474 patients
104 US and international sites
Endpoints
Primary
time to progression
Secondary
overall survival
response rate
toxicity R A N D O M I Z T
CAELYX® (PLD) 50 mg/m2 q 4 wks
Study Design
Randomized, multicenter, open-label, comparative study.
Eligible patients were randomized in a 1:1 fashion to receive CAELYX™/Doxil® (PLD) 50 mg/m2 every 4 weeks or topotecan 1.5 mg/m2/d, 5 days every 3 weeks.
Patients were prospectively stratified based on platinum sensitivity and presence or absence of bulky disease.
Platinum-sensitive patients had a progression-free survival of >6 months after first-line, platinum-based chemotherapy.
Patients were considered platinum-refractory if they progressed during initial platinum-based chemotherapy, demonstrated stable disease, or relapsed within 6 months after completing platinum-based chemotherapy.
Bulky disease was defined as the presence of a tumor mass larger than 5 cm.
Inclusion Criteria
Women ³18 years of age.
Measurable, or measurable and assessable disease that recurred or failed first-line treatment with platinum-based therapy.
Adequate bone marrow, renal, liver, and cardiac function.
Karnofsky performance status ³60%.
Efficacy Assessments
Primary: To compare time to progression after treatment with either PLD or topotecan in patients with epithelial ovarian cancer that recurred, or did not respond to first-line, platinum-based therapy.
Secondary: Overall survival, response rate, toxicity.
Gordon AN, et al. J Clin Oncol. 2001;19:
PLD = pegylated liposomal doxorubicin hydrochloride.
Topotecan 1.5 mg/m2/day for 5 consecutive days, q 3 wks
Gordon AN, et al. J Clin Oncol. 2001;19:

21. PLD vs Topotecan in Recurrent/Refractory Ovarian Cancer
100
Median Survival
Pegylated liposomal doxorubicin: 62.7 wks
Topotecan: 59.7 wks
Hazard ratio: 1.23 (95% CI: ); P = .038 90 80 70 60
Overall Survival (%) 50
Pegylated liposomal
Doxorubicin (n = 240) 40 30 20 10
Topotecan (n = 241) 20 40 60 80
100
120
140
160
180
200
220
240
260
Weeks Since Randomization
Gordon AN, et al. Gynecol Oncol. 2004;95:1-8.

22. PLD vs Topotecan: Patients With Platinum-Refractory Disease
100 90
No significant difference in survival
HR: (95% CI: ); P = .618 80 70 60
Overall Survival (%) 50
Pegylated liposomal
doxorubicin (n = 130) 40 30 20
Topotecan (n = 125) 10 20 40 60 80
100
120
140
160
180
200
220
240
260
Weeks Since First Dose
Gordon AN, et al. Gynecol Oncol. 2004;95:1-8.

23. PLD vs Topotecan: Patients With Platinum-Sensitive Disease
100 90
Median Survival
Pegylated liposomal doxorubicin: wks
Topotecan: 70.1 wks
HR: (95% CI: ); P = .017 80 70 60
Overall Survival (%) 50
Pegylated liposomal
doxorubicin (n = 109) 40 30 20
Topotecan (n = 110) 10 20 40 60 80
100
120
140
160
180
200
220
240
260
Weeks Since First Dose
Gordon AN, et al. Gynecol Oncol. 2004;95:1-8.

24. Related Adverse Events: All Grades
PEG Liposomal doxorubicin %
Topotecan %
p value
Neutropenia 35 81
0.001
Anaemia 72
Thrombocytopenia 13 65
Leukopenia 36 64
Alopecia 16 49
PPE
Stomatitis 40 15
PPE, palmar-plantar erythema.

25. Related Adverse Events: Grades 3/4
PLD %
Topotecan %
p value
Neutropenia 12 77
0.001
Anaemia 5 28
Thrombocytopenia 1 34
Leukopenia 10 50
Alopecia 6
0.007
PPE 23
Stomatitis 8

26. Growth Factor Support/ Blood Transfusions
PEG Liposomal doxorubicin %
Topotecan %
p value
G-CSF or GM-CSF 5 29
0.001
Erythropoietin 6 23
Blood transfusions 16 59

27. PLD vs Topotecan In conclusion:
This long-term follow up analysis demonstrates that treatment with pegylated liposomal doxorubicin significantly prolongs survival compared with Topotecan in patients with recurrent or refractory epithelial ovarian cancer.
The results of this analyses, as well as the ease of administration and adverse event profile, suggest that PLD is the treatment of choice among non-platinum agents for patients with relapsed ovarian cancer, especially those with platinum-sensitive disease.
Gordon AN, et al. Gynecologic Oncology 95 (2004) 1-8.

28. Thank you!