Treatment of Recurrent Platinum-Refractory Ovarian Cancer Andreas du Bois Dept. Gynecology & Gynecologic Oncology Wiesbaden, Germany.

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Treatment of Recurrent Platinum-Refractory Ovarian Cancer Andreas du Bois Dept. Gynecology & Gynecologic Oncology Wiesbaden, Germany

AGO-OVAR Definitions of Platinum Sensitivity* * A. du Bois et al. 1997

Treatment modalities in Platinum-resistent Recurrent Ovarian Cancer: non-Pt mono-Tx non-Pt combination Tx combination Tx

© AdB & JP 2007 What is the Evidence – 9/2008 ? Randomised Studies in Recurrent OC: Studies Pts. mono- vs. mono chemotherapy mono: schedule/dose/application mono- vs. endocrine therapy endocrine vs. endocrine therapy combination vs. combination mono vs. combination* all: * Including 1 trial with multiple regimens according to testing; most other trials in pts. with platinum sensitive relapse

© AdB 2008 TCA Ovarian Cancer Trial A prospective randomised controlled trial of tumour chemosensitivity assay directed chemotherapy versus physician’s choice in patients with recurrent platinum-resistant ovarian cancer. Ian A Cree, on behalf of the TCA Ovarian Cancer Trial Group Methode: ATP-based Tumor Chemosensitivity Assay (ATP-TCA) Andreotti et al., Cancer Research 1995; 55:

© AdB 2008 Patients - tested drugs/combinations  cisplatin  gemcitabine  cisplatin + gemcitabine  doxorubicin (Doxil/Caelyx)  paclitaxel  mitoxantrone  mitoxantrone + paclitaxel  topotecan  treosulfan  treosulfan + gemcitabine  treosulfan + epirubicin  cisplatin (x2) + etoposide  etoposide Physicians choice: mainly single agent therapy

© AdB 2008 Results: Chemosensitivity-Assay without any Impact on Outcome Median PFS: HR: 0.80, 95%CI Physician’s choice: 93 days Assay-directed: 104 days = + 11 days (median) Median OS: HR: %CI Physician’s choice: 260 days Assay-directed: 261 days = + 1 day (median)

© AdB & JP 2007 mono vs. combination chemotherapy in refractory recurrent OC R Melphalan 8 mg/m² d1-4 q28 Melphalan 6 mg/m² d1-4 q28 Hexa-MM 120 mg/kg d1-14 q28 Pater JL 1987, Cancer Treat Rep 103 pts. 102 pts. results: OR 2% vs 3% (combi), PFS and OS n.a. R Paclitaxel 175 mg/m² 3h q28 Paclitaxel 150 mg/m² Epirubicin 120 mg/m² q28 Bolis G 1999, Gynecol Oncol 41 pts. 40 pts. results: OR 17% vs. 34% (combi), PFS n.a. 2-YSR 10% vs. 18% (n.s.)

© AdB & JP 2007 R Paclitaxel 175 mg/m² 3h q21 Paclitaxel 175 mg/m² Epirubicin 80 mg/m² q21 Buda A 2004, Br J Cancer 106 pts. ≤ 12 mos. 106 pts. results: OR 47% vs. 37% (combi), PFS 6 vs. 6 mos. OS 14 vs. 12 mos. (n.s.) R Topotecan 1.25 mg/m² d1-5 q21 Topotecan 1.0 mg/m² d1-5 Etoposid 50 mg po d 6-12 q21 Sehouli J 2008, JCO 178 pts. 177 pts. results: OR 36% (TE) vs. 32% (TG) vs. 28 % (Topo) mean PFS 15 vs. 13 vs. 13 months (n.s.) mean OS 23 vs. 18 vs. 24 months (n.s.) Topotecan mg/m² d1-5 Gemcitabine 800 mg/m² d mg/m² d8 q21 app. 20% refractory 41% > 12 Mon. 147 pts. mono vs. combination chemotherapy in refractory recurrent OC

© AdB & JP 2007 Trabectedin+PLD 4.0 mos PLD 3.7 mos PFS events: 163 HR: 0.95 ( ) P = by courtesy of BJ Monk et al ( mono vs. combination chemotherapy in refractory recurrent OC R Doxil/Caelyx (PLD) 50 mg/m² q28 Trabectedin 1.1 mg/m² q 21 + Doxil/Caelyx (PLD) 30 mg/m² q28 BJ Monk et all, ESMO pts. 113 pts. results: OR 12,2% vs 13,4% (combi; n.s.), PFS/OS n.s.

Treatment modalities in Platinum-resistent Recurrent Ovarian Cancer: non-Pt mono-Tx Today, no strong evidence combination Tx supporting combination Tx outside trials (eg.DOVE)

© AdB & JP 2007 What is the Evidence – 9/2008 ? Randomised Studies in Recurrent OC: Studies Pts. mono- vs. mono chemotherapy mono: schedule/dose/application mono- vs. endocrine therapy endocrine vs. endocrine therapy combination vs. combination mono vs. combination* all: * Including 1 trial with multiple regimens according to testing; most other trials in pts. with platinum sensitive relapse

© AdB & JP 2007 AGO-OVAR 2.3 (Stratum 1, Relapse within 6 mos. after Platinum-Paclitaxel) R Treosulfan 7 g/m² iv q21 Topotecan 1,5 mg/m² d1-5 q21 Meier W 2003, ASCO 65 pts. 63 pts. OR 19.3% (topo) vs 7.0% (p=.0524), OS n.s. (+3,9 mos. for topo), PFS significantly superior after topotecan (median +2 mos.) OS PFS

© AdB & JP 2007 R Paclitaxel 175 mg/m² 3h iv q21 Topotecan 1,5 mg/m² iv d1-5 q21 ten Bokkel Huinink 1997, J Clin Oncol 114 pts. 50% refractory, but „only“ to platinum 112 pts. results: OR 14% vs. 21% (Topotecan) median PFS 15 vs. 19 months (n.s.) median OS 53 vs. 63 months (n.s.) Cave: patients had no taxans during 1st-line … but today, most patients had platinum plus taxan-containing 1st-line therapy! Therefore, data support mainly Topotecan. mono vs. mono chemotherapy in recurrent (mostly) refractory OC - RCTs

© AdB & JP 2007 R Paclitaxel 175 mg/m² 3h iv q21 Caelyx 50 mg/m² iv q28 O’Byrne 2002, ASCO 107 pts. 62% refractory, but „only“ to platinum 106 pts. results: OR 23% vs 19% (Caelyx; n.s.) median PFS 4.4 vs. 4.8 months (n.s.) median OS 13 vs. 11 months (n.s.) Cave: patients had no taxans during 1st-line … but today, most patients had platinum plus taxan-containing 1st-line therapy! Therefore, data support mainly Caelyx. mono vs. mono chemotherapy in recurrent (mostly) refractory OC - RCTs

© AdB & JP 2007 R Topotecan 1,5 mg/m² iv d1-5 q21 Caelyx 50 mg/m² iv q28 Gordon 2001, J Clin Oncol 2004, Gynecol Oncol 235 pts. 55% Pt.-refractory, > 70% prior taxans 239 pts. Results platinum refractory subgroup:Caelyx (130)Topotecan (124) p-value PFS (weeks, median) 9,1 13, OS (weeks, median) G3/4 toxicity (all pts.;%) Neutropenia < Anemia 5 28 < Thrombocytopenia 1 34 < Leukopenia < Treatment-related sepsis 0 4 < Alopecia (all grades) Hand-Foot-Syndrom 23 0 < Stomatitis < mono vs. mono chemotherapy in recurrent (mostly) refractory OC - RCTs

© AdB & JP 2007 R Canfosfamid 1000 mg/m² iv d1 q21 Caelyx 50 mg/m² iv q28 or Topotecan 1.5mg/m² iv d1-5 q21 Vergote 2007, ASCO 232 pts. 3rd-line after platinum-taxan and caelyx or topotecan 2nd-line 229 pts. mono vs. mono chemotherapy in recurrent (mostly) refractory OC - RCTs Results: canfosfamide inferior compared to standard arm

© AdB & JP 2007 R Gemcitabine 1000 mg/m² d1+8 q21 Caelyx 50 mg/m² d1 q28 Mutch, JCO pts. 96 pts. Results: mono vs. mono chemotherapy in recurrent (mostly) refractory OC - RCTs 66 pts. 64 pts. Parameter CAELYX (n=96) Gemcitabine (n=99) ORR (pts w/ measurable disease) median PFS median OS 8% 3.1 mos mos. 6% 3.6 mos mos. Toxicity Neutropenia, grade 3/4 Constipation, grade 2-4 N/V, grade 2-4 HFS, grade 2/3 Mucositis, grade 2/3 18% 9% 12% 19%* 15%* 38%* 25%* 28%* -- 3% *Statistically significant.

© AdB & JP 2007 Results: OR 16% vs. 18% (Gem), OR duration 18 vs. 17 (Gem) weeks ; n.s. QoL advantage for caelyx in 2 of 4 time points (p < 0.05) R Gemcitabine 1000 mg/m² d1,8, 15 q28 Caelyx 40 mg/m² d1 q28 Mito-3 G Ferrandina et al JCO pts. 100% platinum-taxan, TFI < 12 mos. (57% < 6 mos.) 76 pts. mono vs. mono chemotherapy in recurrent (mostly) refractory OC - RCTs

Treatment modalities in Platinum-resistent Recurrent Ovarian Cancer: 1st choice: non-Pt mono-Tx Caelyx Caelyx Topotecan Topotecan Gemcitabine Today, no strong evidence combination Tx supporting combination Tx outside trials (eg.DOVE)