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Gemcitabine in Ovarian Cancer

Gemcitabine in Ovarian Cancer. Phase III Gemcitabine in First-Line Therapy. Control Paclitaxel 175 mg/m 2 d1 x 8 cycles (q 21 days) Carboplatin AUC 6 d 1. R A N D O M I Z E. Gemcitabine t riplet Paclitaxel 175 mg/m 2 d1 x 8 cycles (q 21 days) Carboplatin AUC 5 d 1

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Gemcitabine in Ovarian Cancer

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  1. Gemcitabine in Ovarian Cancer

  2. Phase III Gemcitabine in First-Line Therapy

  3. ControlPaclitaxel 175 mg/m2d1 x 8 cycles (q 21 days) Carboplatin AUC 6 d1 R A N D O M I Z E Gemcitabine triplet Paclitaxel 175 mg/m2 d1 x 8 cycles (q 21 days) Carboplatin AUC 5 d1 Gemcitabine 800 mg/m2 d1,8 Doxorubicin triplet Paclitaxel 175 mg/m2 d1 x 8 cycles (q 21 days) Carboplatin AUC 5d1 Doxorubicin 30 mg/m2 d1 Topotecan doublet Carboplatin AUC 5 d3 Topotecan 1.25 mg/m2 d1-3x 4 cycles (q 21 days) Topotecan doublet Paclitaxel 175 mg/m2 d1 Carboplatin AUC 6 d1x 4 cycles (q 21 days) Gemcitabine doublet Carboplatin AUC 6d8Gemcitabine 1000 mg/m2 d1,8x 4 cycles (q 21 days) Gemcitabine doublet Paclitaxel 175 mg/m2 d1 Carboplatin AUC 6 d1x 4 cycles(q 21 days) GOG0182-ICON5: Cb/P vs Combinations with Gemcitabine, Doxorubicin, or Topotecan vs Triplets vs Sequential Doublets Primary endpoints: Progression-free survival Overall survival Response rate Bookman et al. J Clin Oncol 2006;24(18S):5002.

  4. GOG0182-ICON5: Preliminary Conclusions • Addition of 3rd cytotoxic agent: hematological toxicity, manageable, “related to regimen intensity” • Does not improve PFS • Median PFS: approximately 16 months • OS results to be reported shortly

  5. AGO-OVAR 9 (AGO/GINECO/NSGO):Gem/Cb/P vs Cb/P q 21 days* • Carboplatin AUC 5 d1 + paclitaxel 175 mg/m2 d1 • Gemcitabine 800 mg/m2 d1,8 + carboplatin AUC 5 d1 + paclitaxel 175 mg/m2 d1 *Interim analysis N=1742 Sehouli et al. ESGO 2007; http://www.esgo.org/esgo15/program/ViewAbstract.asp.

  6. S302: Gem/Cb vs Cb/PProgression-Free Survival Single-agent crossover PR, SD, PD R A N D O M I Z E Gemcitabine/Carboplatin CR q 21 days for 6 cycles Elective consolidation Paclitaxel/Carboplatin Single-agent crossover PR, SD, PD Data on File, Lilly Research Laboratories (B9EFEB2006D).

  7. Recurrent Ovarian Cancer • Platin-sensitive:Late recurrence • Response to platin-containing therapy • Platin-free interval > 6 months • Questions: • Combination > single? • Main goal: PFS Disease Categories • Platin-resistant:Early recurrence/persistence • < partial response to platin = platin refractory • Recurrence within 6 months • Questions: • Advantage of chemotherapy? • If yes, which treatment? • Main goal: Symptoms, ↑ QoL Markman et al. JClinOncol 1992;10(4):513-14. mod. du Bois et al. 1997.

  8. 1,00 ~20% of patients have recurrence < 6 months after 1st-line Cb/P 0,75 ~25% of patients have recurrence 6-12 months after 1st-line Cb/P 0,50 Probability PFS ~ 30% of patients have recurrence 12+ months after 1st-line Cb/P 0,25 0,00 0 12 24 36 48 60 72 84 Distribution of Recurrences According to Recurrent-free Interval AGO-OVAR 3 trial: Carboplatin/Paclitaxel Months du Bois et al. J Natl Cancer Inst 2003;95(17):1320-30.

  9. Phase III Gemcitabine in Recurrent Ovarian Cancer

  10. Phase III Inter-group Study: Platin- Sensitive (PS) Recurrent Disease • Stratify according to: • Platinum-free interval (≥6-12 or >12 mos) • First-line therapy platinum (± paclitaxel) • Measurable disease vs evaluable disease RANDOMIZE Gemcitabine 1000 mg/m2 d1,8 + Carboplatin AUC 4 d1, q 21days Carboplatin AUC 5 d1, q 21 days Pfisterer et al. J Clin Oncol 2006;24(29):4699.

  11. Phase III Inter-group Study PS Recurrent Disease • Primary Objective • Progression-free Survival • Secondary Objectives • Overall Survival • Response Rate • Toxicity • Quality of Life Pfisterer et al. J Clin Oncol 2006;24(29):4699.

  12. Phase III Inter-group Study PS Recurrent Disease PS = Performance status; FIGO = International Federation of Oncology and Obstetrics Pfisterer et al. J Clin Oncol 2006;24(29):4699-707.

  13. Phase III Inter-group Study PS Recurrent Disease Pfisterer et al. J Clin Oncol 2006;24(29):4699.

  14. Phase III Inter-group Study PS Recurrent Disease *p <.001 Pfisterer et al. J Clin Oncol 2006;24(29):4699.

  15. Phase III Inter-group StudyPS Recurrent Disease *p = .0016†p = .0031 Pfisterer et al. J Clin Oncol 2006;24(29):4699.

  16. 1.0 Carboplatin median 5.8 months (5.2–7.1) 0.9 0.8 Gemcitabine plus carboplatin median 8.6 months (7.9–9.7) 0.7 0.6 Log-rank p-value = .0031 Probability of Progression-Free Survival 0.5 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 36 42 48 Months Phase III Inter-group Study: PS Recurrent Disease: Progression-Free Survival • Carboplatin 178 patients, 162 events; Gemcitabine plus carboplatin 178 patients, 163 events • Overall survival data immature, study not designed to detect difference Pfisterer et al. J Clin Oncol 2006;24(29):4699.

  17. Phase III PS Recurrent Disease: Overall Survival 1.0 Carboplatin median 17.3 months (15.2–19.3) 0.9 0.8 Gemcitabine plus carboplatin median 18.0 months (16.2–20.2) 0.7 0.6 Survival Probability 0.5 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 36 42 48 Months • Carboplatin 178 patients, 126 events; Gemcitabine plus carboplatin 178 patients, 127 events • Overall survival data immature, study not designed to detect difference Pfisterer et al. J Clin Oncol 2006;24(29):4699.

  18. Gemcitabine + Carboplatin vs Carboplatin: Summary of Sub-Group Analysis Pfisterer et al. Int J Gynecol Cancer 2005;15(Suppl 1):36-41.

  19. Phase III PS Recurrent Disease: Summary • Gemcitabine + carboplatin significantly improves PFS and RR without worsening quality of life for patients with PS recurrent ovary cancer1 • Gemcitabine + carboplatin offers significantly faster palliation of abdominal symptoms and significantly improved global quality of life to patients with PS ovarian cancer2 1Pfisterer et al. J Clin Oncol 2006;24(29):4699. 2Pfisterer et al. Int J Gynecol Cancer 2005;15(Suppl 1):36-41.

  20. Phase III Trial Gemcitabine vs PEG-Lipososomal Doxorubicin (PLD) in Platin-Resistant (PR) Ovarian Cancer Randomization Gem Treatment Arm Gem 1000mg/m2 d1,8 q 21 days up to 2 cycles after CR is attained, provided a minimum of 6 cycles is given. If SD or PR, no maximum # of Gem cycles PLD Treatment Arm PLD 50mg/m2 d1 q 28 days up to 2 cycles after CR is attained, provided a minimum of 6 cycles is givenor a cumulative dose of 500mg/m2 PD, unacceptable toxicity, or maximum cumulative dose of 500 mg/m2 PLD PD or unacceptable toxicity Gem Crossover ArmSame as initial treatment regimen PLD Crossover Arm Same as initial treatment regimen PD, unacceptable toxicity, or maximum cumulative dose of 500 mg/m2 PLD PD, unacceptable toxicity or study withdrawal Post-Study Follow-up Mutch et al. J Clin Oncol 2007;25(19):2811-18.

  21. Phase III Trial Gemcitabine vs PLDin PR Ovarian Cancer • Primary Objective • Progression-free survival (PFS) • Secondary Objectives • Response rate • Duration of response • Time to treatment failure • Overall Survival • Quality of life Mutch et al. J Clin Oncol 2007;25(19):2811-18

  22. Phase III Gemcitabine vs PLD in PR Ovarian Cancer: Patient Characteristics Mutch et al. J Clin Oncol 2007;25(19):2811-18

  23. Phase III Trial Gemcitabine vs PLD in PR Ovarian Cancer: Toxicity *Nat’l Cancer Institute Common Toxicity Criteria Mutch et al. J Clin Oncol 2007;25(19):2811-18.

  24. Phase III Trial Gemcitabine vs PLD inPR Ovarian Cancer: Initial Treatment Gemcitabine PLD 43.8% 5.1% 1.0% 31.3% 2.1% 6.3% 38.5% 54.5% *n = 60†n = 65 Mutch et al. J Clin Oncol 2007;25(19):2811-18.

  25. Phase III Trial Gemcitabine vs PLD in PR Ovarian Cancer: Progression Free Survival 1.0 Gemcitabine PLD 0.8 0.6 Probability of PFS 0.4 0.2 0.0 120 480 240 360 600 720 840 0 Days Mutch et al. J Clin Oncol 2007;25(19):2811-18.

  26. Phase III Trial Gemcitabine vs PLD in PR Ovarian Cancer: Overall Survival Mutch et al. J Clin Oncol 2007;25(19):2811-18.

  27. Phase III Trial Gemcitabine vs PLD in PR Ovarian Cancer: Cross-over Treatment *p = .052†n = 45 Mutch et al. J Clin Oncol 2007;25(19):2811-18.

  28. Phase III Trial Gemcitabine vs PLD in PR Ovarian Cancer: Conclusions • Comparable efficacy between gemcitabine and PLD • PFS, overall response rate, disease control rate • Toxicity patterns differed between arms but were manageable • Gem: ↑ constipation, uncomplicated neutropenia • PLD: ↑ mucositis, hand-foot-mouth syndrome • Median PFS and OS were not statistically different • Gemcitabine may be considered an acceptable treatment option for this patient population Mutch et al. J Clin Oncol 2007;25(19):2811-18.

  29. Gemcitabine in Ovarian Cancer: General Conclusions • Monotherapy- has modest activity in recurrent disease • Doublets and triplets are feasible • Addition of 3rd cytotoxic agent: hematological toxicity, manageable, “related to regimen intensity” • Gemcitabine + carboplatin significantly improves PFS and RR without worsening quality of life for patients with PS recurrent ovary cancer • Similar efficacy between gemcitabine and pegylated liposomal doxorubicin (PLD) in PR ovary cancer

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