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1. Nordic Society of Gynecologic Oncology ( NSGO ) Denmark, Finland, Norway, Sweden

A randomized, phase III study gemcitabine-paclitaxel-carboplatin (TCG) versus paclitaxel-carboplatin (TC) as first-line treatment of ovarian cancer: survival of FIGO stage I-IIA patients.

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1. Nordic Society of Gynecologic Oncology ( NSGO ) Denmark, Finland, Norway, Sweden

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  1. A randomized, phase III study gemcitabine-paclitaxel-carboplatin (TCG) versus paclitaxel-carboplatin (TC) as first-line treatment of ovarian cancer: survival of FIGO stage I-IIA patients Jørn Herrstedt1, Jens Huober2, Franck Priou3, Hans-Helge Müller2, Mark Baekelandt1, Christian Kurzeder2, Jacobus Pfisterer2, Anne Stähle2, Isabelle Ray-Coquard3, Andreas du Bois2 (PI). 1. Nordic Society of Gynecologic Oncology (NSGO) Denmark, Finland, Norway, Sweden 2. Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Studiengruppe Ovarialkarzinom 3. Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO), France a GCIG Intergroup Study

  2. ? negative ADDING A THIRD CYTOSTATIC DRUG TO TCRESULT Triplet combination GemcitabineAGO-GINECO-NSGO GOG-ANZGOG-MRC Epirubicin1,2AGO-GINECO NSGO-EORTC-NCIC-GEICO Peg.-lip. Dox3GOG-ANZGOG-MRC Sequential doublet Gemcitabine3GOG-ANZGOG-MRC Topotecan3,4NCIC-EORTC-GEICO GOG-ANZGOG-MRC Sequential single Topotecan5AGO-GINECO negative negative negative negative negative 1. du Bois A et al. J Clin Oncol 2006;24:1127-35. 2. Kristensen GB et al. J Clin Oncol 2004;22 (suppl):A5003 3. Bookman MA et al. J Clin Oncol 2009;27:1419-1425. 4. Hoskins PJ et al. J Clin Oncol 2008;26(suppl):LBA5505 5. Pfisterer J et al. JNCI 2006;98;1036-45.

  3. STUDY DESIGN RANDOMISATION Gemcitabine 800 mg/m² d1+8 Paclitaxel 175 mg/m² d1 Carboplatin AUC 5 d1 q 21 x 6 Paclitaxel 175 mg/m² d1 Carboplatin AUC 5 d1 q 21 x 6

  4. STRATIFICATION • Center • Interval debulking surgery planned (yes/no) • FIGO Stage and Tumor Residuals • Stratum 1: FIGO IA/B G3 or IC – IIA • Stratum 2: FIGO IIB - IIIC + Tumor residual < 1 cm • Stratum 3: FIGO IV or Tumor residual > 1 cm

  5. ENDPOINTS 1st ENDPOINT Overall Survival in stratum 2+3 2nd ENDPOINTS PFS in stratum 2+3 PFS and OS in stratum 1 PFS and OS in all strata Response Rate Toxicity (NCI/CTC grade 3/4) EORTC QLQ-C 30 , QLQ-OV 28

  6. PATIENT CHARACTERISTICS

  7. RECRUITMENT AND COHORTS

  8. PATIENT CHARACTERISTICS (%)

  9. PATIENT CHARACTERISTICS (%)

  10. PATIENT CHARACTERISTICS (%)

  11. PATIENT CHARACTERISTICS (%)

  12. FEASIBILITY

  13. FEASIBILITY

  14. DOSE DEVIATIONS (%)

  15. DOSE DEVIATIONS (%)

  16. RESULTS STRATUM 1

  17. PROGRESSION-FREE SURVIVAL (RECIST & CA125) BY THERAPY: STRATUM 1 (FIGO I-IIA) TC89 pts. / 21 evts. median - mos. TCG 86 pts. / 17 evts. median - mos. P r o b a b i l i t y HR = 0.85 [95% CI: 0.45-1.61] p = 0.6199 89 87 82 79 75 67 62 57 46 29 17 5 1 0 0 86 79 76 75 72 67 58 51 46 33 15 4 2 0 0 Patients at risk [months]

  18. OVERALL SURVIVAL BY THERAPY STRATUM 1 (FIGO I-IIA) TC89 pts. / 5 evts. median - mos. TCG86 pts. / 10 evts. median - mos. P r o b a b i l i t y HR = 2.19 [95% CI: 0.75-6.41] p = 0.1419 Patients at risk 89 88 85 81 79 75 73 69 56 41 23 6 1 0 0 86 80 79 78 75 72 67 58 52 38 19 4 2 0 0 [months]

  19. RESULTSSTRATUM 2 +3

  20. PROGRESSION-FREE SURVIVAL (RECIST & CA125) BY THERAPY: STRATUM 2+3 (FIGO IIB-IV) TC793 pts. / 588 evts. median 16.0 [14.9-17.4] mos. TCG 774 pts. / 629 evts. median 14.7 [14.0-15.9] mos. HR = 1.17 [95% CI: 1.05-1.31] Logrank test:p = 0.0065 [months] Patients at risk 793 699 511 351 270 225 191 152 95 43 14 2 774 685 483 307 228 185 155 116 72 36 12 2

  21. OVERALL SURVIVAL BY THERAPY STRATUM 2+3 (FIGO IIB-IV) TC793 pts. / 401 evts. median 48.9 [43.1-51.2] mos. TCG 774 pts. / 404 evts. median 45.8 [40.0-49.5] mos. P r o b a b i l i t y HR = 1.03 [95% CI: 0.90-1.18] p = 0.6955 [months] Patients at risk 793 750 705 638 557 489 420 338 226 89 31 5 774 740 693 628 554 484 411 322 208 87 28 5

  22. TOXICITY ALL PATIENTS

  23. HEMATOLOGICAL TOXICITIES Grade 3/4 WORST OF ALL COURSES Toxicity (NTC/NTCG) TC TCG p-value Anemia (5168/5067)1.0 4.9 < .0001 Thrombocytopenia (5168/5068) 1.1 11.4 < .0001 Leukopenia (5168/5067) 9.3 28.3 < .0001 Neutropenia (4905/4882) 32.3 45.2 < .0001 Febrile Neutropenia (5115/5003) 0.4 1.2 < .0001 Inf. without Neutropenia (5122/5009) 0.7 0.9 0.2705 G-CSF 5.2 12.5 < .0001 EPO 5.6 12.3 < .0001 Antibiotics 3.2 5.3 < .0001 Blood Products 2.3 9.3 < .0001

  24. NON-HEMATOLOGICAL TOXICITIES Grade 3/4 WORST OF ALL COURSES Toxicity (NTC/NTCG) TC TCG p-value Fatigue (865/840)7.1 10.5.0125 Nausea (865/841) 3.2 4.3 .2579 Constipation (865/841) 4.5 6.5 .0672 Neuropathy-motor (865/840) 2.2 3.0 .3139 Neuropathy-sensory (865/840) 6.5 7.4 .4655 Athralgia (865/840) 4.7 4.1 .4871 Myalgia (865/840)4.7 3.6 .2281 Pain (865/842)6.1 6.1 .9475 Alopecia grade 2 (859/827) 93.8 92.9 .4330

  25. negative negative ADDING A THIRD CYTOSTATIC DRUG TO TCRESULT Triplet combination Gemcitabine3AGO-GINECO-NSGO GOG-ANZGOG-MRC Epirubicin1,2AGO-GINECO NSGO-EORTC-NCIC-GEICO Peg.-lip. Dox3GOG-ANZGOG-MRC Sequential doublet Gemcitabine3GOG-ANZGOG-MRC Topotecan3,4NCIC-EORTC-GEICO GOG-ANZGOG-MRC Sequential single Topotecan5AGO-GINECO negative negative negative negative negative 1. du Bois A et al. J Clin Oncol 2006;24:1127-35. 2. Kristensen GB et al. J Clin Oncol 2004;22(suppl)A5003. 3. Bookman MA et al. J Clin Oncol 2009;27:1419-1425. 4. Hoskins PJ et al. J Clin Oncol 2008;26(suppl)LBA5505. 5. Pfisterer J et al. JNCI 2006;98;1036-45.

  26. Acknowledgement: Patients, all centres, IDMSC, and… AGO-OVAR Coordinating Group A. Belau (Greifswald) A. Burges (München) U. Canzler (Dresden) A. du Bois - PI (Wiesbaden) M. Gropp (Düsseldorf) P. Harter (Wiesbaden) V. Heilmann (Ulm) F. Hilpert (Kiel) J. Huober (Tübingen) Ch. Jackisch (Marburg) R. Kimmig (Essen) S. Loibl (Frankfurt) H.-J. Lück (Hannover) W. Meier (Düsseldorf) J. Pfisterer (Kiel) B. Richter (Radebeul) B. Schmalfeldt (München) W. Schröder (Bremen) J. Sehouli (Berlin) A. Stähle (Karlsruhe) U. Wagner (Marburg) K. Wollschlaeger (Magdeburg) GINECO A.-C. Hardy-Besard (Saint-Brieuc) F. Joly (Caen) B. Weber (Nancy) E. Lévy (Paris) F. Priou (La-Roch-Sur-Yon) J.-P. Guastalla (Lyon) J. Plaza (Montbéliard) D. Berton-Rigaud (Nantes) S. Abadie-Lacourtoisie (Angers) C. Platini (Metz) F. Mefti (Saint-Cloud) K. Yakendji (Créteil) H. Bourgeois (Poitiers) L. Bastit (Rouen) P. Chinet-Charrot (Rouen) E. Pujade-Lauraine –PI (Paris) NSGO J. Herrstedt - PI (Herlev) G. Kristensen (Oslo) J. Kaern (Oslo) T. Skeie-Jensen (Oslo) E. Lorenz (Trondheim) K. Bertelsen (Odense) M. Mirza (Odense) J. Lindegaard (Aarhus) H. Havsteen (Aarhus) E. Aavall-Lundqvist (Stockholm) B. Tholander (Stockholm) M. Kalling (Lund) T. Høgberg (Linkøping) K. Boman (Umeaa) J. Mâenpââ (Tampere) S. Jelic (Beograd) Ljiljana Stamatovic(Beograd) I. Takac (Maribor) Supported by Eli Lilly and Company Statistics and Data management Study Office Monitoring AGO-OVAR H.-H. Müller G. Elser, C. Ackermann P. Schantl, S. Oxe, S. Bigus M. Hahmann, B. Aminossadati A. Igler, U. Weitzel F. Gottwald, S. Lang, H. Lüers K. Friccius, B. Saile, C. Renné, GINECO D. Paraiso, N. Le Fur C. Dumont-Puléo M. Bekhiti, S. Lahmar NSGO R. DePont Christensen G. Andersen C. Ramstad, L. Rosquist, H. Holst

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