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Topotecan in Ovarian Cancer

Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111

1. Standard Therapy for Advanced Untreated Ovarian Cancer:
   1. Cisplatin (75 mg/m²) plus paclitaxel (135 mg/m² - 24h): OR
      
   2. Carboplatin (AUC = 7.5) plus paclitaxel (175 mg/m² - 3h)
      
   
   
2. Results of Initial Treatment:
   1. 70%-80% will be in clinical complete remission following cytoreductive surgery and chemotherapy with paclitaxel plus a platinum compound
      
   2. Most patients will recur; overall survival is 30%-35%
      
   
   
3. Management of Recurrent Ovarian Cancer:
   1. Treatment decision based on clinical drug response
      1. Drug sensitive: responded to therapy with DFI>6 months
         
      2. Drug resistant: responded to therapy with DFI<6 months
         
      3. Drug refractory: no response
         
      
      
   2. Treatment options for drug-sensitive patients
      1. Retreatment with agents used in initial therapy
         
      2. Single agents
         
      3. Combinations if DFI>18 months
         
      4. Use of non-cross-resistant agents
         
      
      
   3. Treatment for recurrent ovarian cancer: drug resistant
      1. Drugs used as part of initial therapy not useful
         
      2. Non-cross-resistant drugs:

         Topotecan
         

         Oral Etoposide
         

         Gemcitabine
         

         Navelbine
         

         Encapsulated Doxorubicin (Doxil)
         

         Hexamethylmelamine
         

         Ifosfamide
         

         
         
      
      
   4. Topotecan
      1. Topoisomerase I inhibitor
         
      2. Phase I Trials

         DLT - hematologic
         

         Non-hematologic toxicity generally mild: alopecia, N/V, fatigue
         

         Hematologic: predictable, manageable, non-cumulative and primarily neutropenia
         

         
         
      3. Schedule: 1.5 mg/m² qd x 5 every 3 weeks
         
      4. Results of topotecan in ovarian cancer
         1. Response rate depends on prior response to initial chemotherapy:

            Platinum sensitive: 26%
            

            Platinum resistant: 18%
            

            Platinum refractory: 6%
            

            
            
         2. Randomized comparison with paclitaxel in recurrent ovarian cancer:

            Response: 23% versus 14%
            

            Response duration: 32 weeks versus 20 weeks
            

            TTP: 23 weeks versus 14 weeks
            

            
            
         3. More hematologic toxicity than paclitaxel
            
         
         
      5. Future directions with topotecan
         1. Different schedules
            
         2. Combinations with other agents
            
         3. As part of initial therapy
            
         
         
      
      
   5. Oral Etoposide
      1. GOG trial in 70 Patients
         Response:

         Platinum resistant: 27%
         Platinum sensitive: 34%
         

         
         
      
      
   6. Gemcitabine
      1. 19% response rate in platinum-resistant tumors
         
      2. In vitro synergy with cisplatin
         
      
      
   7. Other new active agents include Doxil and Navelbine
      
   8. Selection of second-line therapy
      1. No objective criteria have established any non-cross-resistant agent as "drug of choice"
         
      2. Criteria for selection: patient preference, toxicity profile, oral versus i.v.
         
      3. Recommendation: Select drug and evaluate after two courses of treatment
         
      
      
   
   

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