Treatment of Refractory Ovarian Cancer

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.

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;25:265-280.

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. http://Cancernet.nci.nih.gov/ Rosenthal A, Jacobs I. Semin Oncol. 1998;25:315-325. Stern JL. Everyone’s Guide to Cancer Therapy. 1997;602.

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. http://Cancernet.nci.nih.gov/

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;1503-1504. Berek JS, Hacker NF. Cancer Treatment. 4th ed. 1995;628-661.

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.

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;1510-1511.

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 6.0-7.5) for 6 cycles Vast majority of patients with advanced stage ovarian cancer will relapse 1. National Cancer Institute. NCI Clinical Announcement. January 2006.

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

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

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

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

Platinum-sensitive ovarian cancer

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

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. 2004 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 1-2 66% had serous histology; 54% had MD; and 86% had CA-125 levels >40 IU/ml.

Results: Conclusions: GINECO: phase II Carboplatin (PA) and PLD (CA; PACA regimen) in patients with AOC in late (>6 ms) relapse (AOCLR): trial. 2004 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.

Platinum-refractory ovarian cancer

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

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;19:3312-3322. 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;19:3312-3322.

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: 1.01-1.50); 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.

PLD vs Topotecan: Patients With Platinum-Refractory Disease 100 90 No significant difference in survival HR: 1.069 (95% CI: .823-1.387); 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.

PLD vs Topotecan: Patients With Platinum-Sensitive Disease 100 90 Median Survival Pegylated liposomal doxorubicin: 107.9 wks Topotecan: 70.1 wks HR: 1.432 (95% CI: 1.066-1.923); 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.

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.

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

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

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.

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