Relapsed/Refractory Ovarian Cancer: Decision Points in Diagnosis and New Treatment Strategies Friday, March 24, 2006 Palm Springs Convention Center Primrose Ballroom C/D Palm Springs, California
Current Issues in the Management of Recurrent Ovarian Cancer Robert F. Ozols, MD, PhD Senior Vice President, Medical Science Fox Chase Cancer Center Philadelphia, Pennsylvania
clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer 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/m 2 over 3 hrs) plus IV carboplatin (AUC ) for 6 cycles –Intraperitoneal (IP) chemotherapy for optimal stage III “should be considered” 1 Vast majority of patients with advanced stage ovarian cancer will relapse 1. National Cancer Institute. NCI Clinical Announcement. January 2006.
clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Potential for Relapse: Disease Stage and Diagnosis Disease StagePatients at Diagnosis, % Patients Who Will Relapse, % Low-risk early stage disease (Stage IA and IB, grade 1 and 2) 5< 5 High-risk early stage disease (Stage I, grade 3) 20 Stage II1030 Stage III, optimally debulked (< 1 cm residual) Stage III, suboptimally debulked (> 1 cm residual) Stage IV580-90
clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Survival From Time of Recurrence Months From Progression Proportion Surviving, % Ozols RF, et al. J Clin Oncol. 2003;21: Treatment GroupAliveDeadTotal Cisplatin/paclitaxel Carboplatin/paclitaxel
clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Patterns of Recurrence After Achieving a Complete Response Median progression-free survival –18 months (suboptimal or stage IV) and months (optimal stage III) Serologic relapse –CA-125 in asymptomatic patients with normal physical exam and CT Clinical relapse –Symptomatic with measurable disease –Asymptomatic with measurable disease –Symptomatic without measurable disease
clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer 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: 6 month platinum-free interval –Platinum resistant: 6 month platinum-free interval
clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Effect of PFI on Response Rate Markman M, et al. J Clin Oncol. 1991;9: Months Response Rate (%) 27% 33% 59% > 24
clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Treatment Considerations in Recurrent Ovarian Cancer Goals of therapy –Palliate symptoms –Prevent symptom development –Maintain quality of life –Increase progression-free survival –Prolong overall survival
clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Selection of Therapy in Recurrent Ovarian Cancer Platinum sensitivity or resistance Length of disease-free interval Disease volume Sites of disease Serologic relapse Symptomatic vs asymptomatic disease Residual toxicity from prior chemotherapy –Neuropathy –Myelosuppression –Allergic reactions Patient preference –Schedule of administration –Importance of alopecia –Anticipated toxicity
clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer 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
clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Management of Rising CA-125 in an Asymptomatic Patient Highly predictive of clinical recurrence within median of 4-6 months 1,2 No evidence immediate chemotherapy superior to delayed chemotherapy at time of clinical progression –European randomized trial in progress –Gynecologic Oncology Group (GOG) randomizes patients to biologic agents 1. Niloff JM, et al. Am J Obstet Gynecol. 1986;155: Vergote IB, et al. Tumour Biol. 1992;13:
clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Chemotherapy Principles in Recurrent Ovarian Cancer Multiple agents have clinical activity –Activity superior in platinum-sensitive patients Combinations are superior to single-agent platinum 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
clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Active Agents in Recurrent Ovarian Cancer Carboplatin Taxanes (q 3 wks vs q wk) –Paclitaxel –Docetaxel Topotecan Liposomal doxorubicin Gemcitabine Less commonly used Oral etoposide Altretamine Tamoxifen Vinorelbine
clinicaloptions.com/oncology Relapsed/Refractory 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
clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer ICON 4/AGO-OVAR 2.2 2 parallel randomized multicenter trials Parmar MK, et al. Lancet. 2003;361: Paclitaxel plus Platinum-based chemotherapy (n = 392) Platinum-based chemotherapy (n = 410) Patients with platinum- sensitive recurrent ovarian cancer (N = 802)
clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Parmar MK, et al. Lancet. 2003;361: Paclitaxel plus platinum Conventional treatment Hazard ratio: 0.76; P = Time From Randomization (yrs) Progression-Free Survival (%) Patients at risk Paclitaxel plus platinum Conventional treatment Paclitaxel/Platinum vs Conventional Platinum-Based Chemotherapy: PFS
clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Paclitaxel/Platinum vs Conventional Platinum-Based Chemotherapy: OS Parmar MK, et al. Lancet. 2003;361: Paclitaxel plus platinum Conventional treatment Hazard ratio: 0.82; P =.0023 Proportion Surviving (%) Patients at risk Paclitaxel plus platinum Conventional treatment Time From Randomization (yrs)
clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Gemcitabine/Carboplatin vs Carboplatin Randomized phase III trial AGO OVAR, NCIC CTG, EORTC GCG Pfisterer J, et al. ASCO Abstract Gemcitabine (1000 mg/m 2 ) Days 1 and 8 Carboplatin (AUC = 4) day 1 (n = 178) Carboplatin (AUC = 5) Day 1 (n = 178) Patients with platinum-sensitive recurrent ovarian cancer ≥ 6 months out from initial platinum therapy (N = 356)
clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Study Endpoints: OVAR 2.5 and ICON 4 ParameterGemcitabine/Carboplatin vs Carboplatin (OVAR 2.5) 1 Paclitaxel/Platinum vs Platinum (ICON 4) 2 ORR, %47.2 vs vs 54 CR, %14.6 vs 6.2Not reported PFS, mos8.6 vs vs 9 HR OS, mosNA*29 vs 24 HRNA Pfisterer J, et al. ASCO Abstract Parmar MK, et al. Lancet. 2003;361: *Study not powered for overall survival.
clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Management of Platinum-Resistant Recurrent Ovarian Cancer Weekly paclitaxel Liposomal doxorubicin Topotecan Gemcitabine Which is better? Few randomized trials have been performed –Topotecan vs paclitaxel –Liposomal doxorubicin vs topotecan –Gemcitabine vs liposomal doxorubicin
clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer PLD vs Topotecan in Recurrent/Refractory Ovarian Cancer Gordon AN, et al. Gynecol Oncol. 2004;95: Weeks Since Randomization Pegylated liposomal Doxorubicin (n = 240) Topotecan (n = 241) Overall Survival (%) Median Survival Pegylated liposomal doxorubicin: 62.7 wks Topotecan: 59.7 wks Hazard ratio: 1.23 (95% CI: ); P =.038
clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer PLD vs Topotecan: Patients With Platinum-Refractory Disease Weeks Since First Dose Overall Survival (%) Pegylated liposomal doxorubicin (n = 130) Topotecan (n = 125) No significant difference in survival HR: (95% CI: ); P = Gordon AN, et al. Gynecol Oncol. 2004;95:1-8.
clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer PLD vs Topotecan: Patients With Platinum-Sensitive Disease Weeks Since First Dose Overall Survival (%) Pegylated liposomal doxorubicin (n = 109) Topotecan (n = 110) Median Survival Pegylated liposomal doxorubicin: wks Topotecan: 70.1 wks HR: (95% CI: ); P =.017 Gordon AN, et al. Gynecol Oncol. 2004;95:1-8.
clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Management of Recurrent Ovarian Cancer Recurrent ovarian cancer a major clinical problem Multiple therapeutic options –Surgery, radiation, chemotherapy –Combination chemotherapy superior in platinum-sensitive patients New treatments needed to improve poor outcomes with current therapy