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Topotecan in Ovarian Cancer: Schedule and Doses, Activity and Toxicity

Topotecan in Ovarian Cancer: Schedule and Doses, Activity and Toxicity. T amar Safra 1 , M.D., Moshe Inbar 1 , M.D., Talia Levy 2 , M.D. 1 Tel-Aviv Medical Center, Dept. of Oncology, Tel-Aviv, 2 Wolfson Medical Center , Dept. of Gynecology, Holon, ISRAEL.

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Topotecan in Ovarian Cancer: Schedule and Doses, Activity and Toxicity

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  1. Topotecan in Ovarian Cancer: Schedule and Doses, Activity and Toxicity Tamar Safra1, M.D., Moshe Inbar1, M.D., Talia Levy2, M.D.1Tel-Aviv Medical Center, Dept. of Oncology, Tel-Aviv, 2 Wolfson Medical Center , Dept. of Gynecology, Holon, ISRAEL

  2. Topotecan in Ovarian Cancer Treatment • Topotecan mechanism of action • Studies using different doses and schedules • Characteristics of the different schedules

  3. Ovarian Cancer • Treatment of recurrent epithelial ovarian cancer (EOC) is mainly palliative • Topotecan was FDA approved for recurrent EOC • Survival as well as quality of life (QoL) are very important • Improved efficacy and reduced toxicity are important tasks

  4. Topotecan Mechanism of Action • Topotecan is a semisynthetic water-soluble topoisomerase –I inhibitor • It stabilizes the covalent DNA-enzyme complex - blocking DNA repair • It binds to the cleavable complexes - prevents religation, leading to permanent strand breaks followed by cell death • Topotecan is an S-phase‑specific compound

  5. Topotecan • Activity and toxicity are schedule dependent • Investigated methods • Daily administration - 5-days q 3 weeks • Low‑dose continuous infusion (CI) • Weekly schedules

  6. Topotecan Daily

  7. Topotecan Versus Paclitaxel in the treatment of recurrent Ovarian Cancer FDA‑APPROVAL Ten Bokkel Huinink. J Clin Oncol 1997;15:2183-93

  8. Study Design Multicenter, prospective, randomized phase-III study Topotecan 1.5 mg/m2/d D1-5 Q21d 30-minute infusion Stratification by age, ascites and previous response to platinum-based therapy Paclitaxel 175 mg/m2 D1 Q21d over 3 hours Ten Bokkel Huinink. J Clin Oncol 1997;15:2183-93

  9. 1.0 topotecan(n=112) 0.8 Paclitaxel (n=114) 0.6 P =.072 Proportion 0.4 0.2 0.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 Time (weeks) Time to Progression Median TTP 19.8w 14.7w Ten Bokkel Huinink. Ann Onc. 2004;15:100-3

  10. Hematological Side Effects Ten Bokkel Huinink. J Clin Oncol 1997;15:2183-93

  11. Conclusions • Topotecan is as effective as paclitaxel in the treatment of recurrent ovarian cancer • Topotecan toxicity : significant noncumulative hematologic with moderate non-hematologic toxicity • At least four courses of therapy are recommended - as median time to response is 8 to 12 weeks • Paclitaxel moved to primary therapy and topotecan to recurrent EOC Ten Bokkel Huinink. J Clin Oncol 1997;15:2183-93

  12. Topotecan Continuous Infusion (CI)

  13. Continuous Infusion Phase-II 0.4 mg/m2/24h, D1-21 Q28d N=24 Response • RR - 35% (95% CI, 15% to 54%) • TTP - 26 weeks Toxicity • 31% grade III-IV neutropenia • 52% anemia requiring transfusion • 4% grade IV thrombocytopenia Hochster H. J Clin Oncol. 1999;17:2553-61

  14. 14-Day CI • 0.4 mg/m2/24h, D1-14 Q28d • Responses seen in heavily pretreated patients • Investigated also with combinations: oxaliplatin, Doxil Hochster et al at NYU

  15. Future Issues with CI • The inconvenience of pump - might be replaced with the oral topotecan • 14 day CI • More understanding about activity and toxicity in relation to length of exposure

  16. Topotecan Weekly

  17. Weekly 1.75 mg/m2/24h of Topotecan A randomized phase II study 1.5 mg/m2/d D1-5 Q21d 1.75 mg/m2/24h 4/6 weeks RR - 3.1% 52% - Grade III-IV granulocytopenia RR - 22.6% 94% -Grade III-IV granulocytopenia Hoskins P. J Clin Oncol. 1998;16:2233-7

  18. A Dose-Escalating Study of Bolus Topotecan • 1.5 mg/m2 weekly with escalation of 0.5 mg/m2 • Results • 2 mg/m2 - minimal dose for anti-tumor activity • MTD - 4 mg/m2 without G-CSF support • MTD - 6 mg/m2 with G-CSF support Homesley HD. Gynecol Oncol. 2001;83:394-9

  19. Weekly Topotecan in Patients with Recurrent or Persistent Epithelial Ovarian Cancer Phase-II Study Safra T, Inbar M, Levy T et al

  20. Objectives To investigate the safety and efficacy of weekly topotecan in relapsed and persistant EOC Safra T, Inbar M, Levy T et al

  21. Treatment Regimen 4 mg/m² topotecan D1,8,15 Q28d IV 30-min bolus Safra T, Inbar M, Levy T et al

  22. Eligibility Criteria • Recurrent or persistant EOC and primary • peritoneal carcinoma • Previous exposure to at least one line of • platinum based chemotherapy • Measurable or assessable disease (CA-125>75) • Performance status - ECOG <2 • Life expectancy >3m Safra T, Inbar M, Levy T et al

  23. Patients Characteristics • N=45 • Age – median 64y (range 42-87) • Stage – Ic-IIc in 4 (9%) patients III-IV in 41 (91%) patients • Platinum status – Sensitive 56% Resistant 44% • Previous chemotherapy – median 1(range 1-5) Safra T, Inbar M, Levy Taet al

  24. RESULTS Safra T, Inbar M, Levy T et al

  25. Time to Progression Median TTP 4.43m (95%CI, 3.64-5.23) Safra T, Inbar M, Levy T et al

  26. P= 0.290 TTP in Platinum Sensitive and Resistant Median TTP Sens 4.26 m (95%CI, 3.25-5.28) Resis 4.90 m (95%CI, 2.13-7.67) Safra T, Inbar M, Levy T et al

  27. P= 0.164 TTP with one or more previous Chemotherapy * 1st line mTTP – 6.00m (95%CI, 3.90-8.09) Several lines mTTP – 3.00m (95%CI, 0.00-6.05) Safra T, Inbar M, Levy T et al

  28. Overall Survival 1Y OS - 76% 2Y OS - 50% OS – median 11.6+ m (0.57-31) Safra T, Inbar M, Levy T et al

  29. Toxicity Safra T, Inbar M, Levy T et al

  30. Conclusions • Weekly topotecan is efficacious in relapsed and persistent EOC • Weekly topotecan is very feasible • Low rate of grade III-IV hematological toxicity • Mild non-hematological toxicity with no alopecia Safra T, Inbar M, Levy T et al

  31. Schedule Characteristics

  32. Schedules Characteristics (2) Hochster H. J Clin Oncol. 1999;17:2553-61 (1) Ten Bokkel Huinink. Ann Onc. 2004;15:100-3

  33. Summary • Weekly administrationand continuous infusion are effective in recurrent EOC • Our weekly administration has significantly better toxicity profile • Weekly topotecsan is by far more convenient and QoLis greatlyimproved

  34. Tel-Aviv Medical Center, Tel-Aviv, ISRAEL

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