1. Gemcitabine/Docetaxel association: Retrospective analysis of 133 soft tissue sarcomas J.-O. Bay, for the French Sarcoma Group

2. First line of chemotherapy   doxorubicine median OR = 26%  ifosphamide  ifosphamide median OR = 26%  MAID 47% OR with 10% CR (Elias, JCO 1989) Gemcitabine (Patel et al.)   inhibitor of ribonucleotide reductase and intercalating agent Docetaxel   stabilization of tubulin, phosphorylation of bcl-2 (apoptotic activity) Background Gemcitabine/docetaxel combination (Hensley et al.) synergistic effect with DNA synthesis arrest and induction of apoptosis Second line of chemotherapy   cisplatine, topotecan, paclitaxel, mitoxantrone, vinorelbine etc … 10 - 20% OR with no standard

3. Preliminary study for a phase II trial from the French Sarcoma Group evaluating gemcitabine/docetaxel in soft tissue sarcomas Analysis of the best response Objectives of this retrospective study Survival Toxicity evaluation

4. 133 patients (75 women / 58 men) treated from 10/2001 to 12/2004 Median age at diagnosis: 51.7 [18-82] 112 patients had already received doxorubicine and/or ifosphamide Initial surgery: 115 patients  R0 = 63 (55 %)  R1 = 30 (26 %)  R2 = 21 (19 %) Patient characteristics (1)

5. Histological subtypes Leiomyosarcoma:76(57.1 %) Undifferentiated :17(12.8 %) Synovialosarcoma:10(7.5 %) Liposarcoma: 6(4.5 %) Angiosarcoma: 5(3.8 %) Rhabdomyosarcoma: 5(3.8 %) Epithelioid sarcoma: 5(3.8 %) Fibrosarcoma: 5(3.8 %) Others: 4(3.0 %) Grading (missing information for 10 patients) Grade I:10 Grade II:43 Grade III:70 Patient characteristics (2)

6. Limbs 44 (34 %) Uterine corpus 32 (24 %) Bone 15 (11 %) Organs 23 (14 %) Retroperitoneal 19 (17 %) Initial localization Patient characteristics (3)

7. Neoadjuvant chemotherapy: 22 patients 115/133 with initial surgery (R0=63; R1=30; R2=22) 36 patients with metastatic surgery at the time of the initial surgery 92 patients with adjuvant chemotherapy before metastatic evolution 90 patients with a first line chemotherapy for metastatic or unresectable disease Number of anterior lines of chemotherapy None: 21patients(17 %) One:60patients(45 %) Two:35patients(26 %) Three:9patients(7 %) Four:2patients(1.5 %) Five:5patients(3.5 %) Patient characteristics (4)

8. Number of metastatic patients: 130 Metastatic localizations Lung: 117 Liver: 42 Bone: 25 Others: 23 Number of metastatic sites One: 72 patients (55 %) Two: 39 (30 %) Liver and lung : 23 Lung and bone : 7 More than three: 19 (15 %) Patient characteristics (5)

9. Patient characteristics (6) Performance Status (PS) before Gemcitabine-Docetaxel OMS 0 32 % OMS 1 48 % OMS 2 14 % OMS 3 6 % Correlation between PS and the number of anterior chemotherapy lines 125 patients available

10. Treatment J1J8J1 J8 21 or 28 days Gemcitabine 900 mg/m 2 over 1h and Docetaxel 100 mg/m 2 over 1h Gemcitabine 900 mg/m 2 over 1h Gemcitabine 900 mg/m 2 over 1h and Docetaxel 100 mg/m 2 over 1h

11. Number of courses: mean = 4,0 courses and median = 3 courses [1-11] 1 118.3 % | ************ 2 3022.6 % | ********************************* 3 2720.3 % | ***************************** 4 2015.0 % | ********************** 5 118.3 % | ************ 6 1410.5 % | *************** 7 75.3 % | ******* 8 75.3 % | ******* 9 43.0 % | **** 10 10.8 % | * 11 10.8 % | * Dose of docetaxel per course and per m² for 528 courses: Mean: 135.3Standard error: 24,3 Median: 141.2 Interquartile interval:[124 ; 179] Dose of gemcitabine per m² for 519 courses: Mean: 1455 Standard error: 445 Median: 1655 Interquartile interval:[1189 ; 1791] Results (1) : Treatments received

12. For 515 courses Results (2) : Toxicity Toxicitygrade OMS-069.90 %79.61 %53.79 %89.60 %95.76 %94.99 %75.10 % OMS-15.83 %6.99 %28.54 %7.90 %1.93 %3.47 % OMS-24.66 %5.05 %14.76 %1.54 %1.16 %0.77 %12.16 % OMS-310.29 %6.02 %2.52 %0.58 %1.16 %0.58 %9.07 % OMS-49.32 %2.33 %0.39 % 0.19 % Neutropenia Thrombopenia Anemia Nausea / vomiting Diarrhea Mucosis Alopecia

13. Grade-4 Grade-3 Grade-2 Grade-1 Grade-0 Results (3) : Toxicity Toxicity over 515 courses of gemcitabine-docetaxel

14. Stable 33 patients (29 %) Partial response 18 patients (15.8 %) Complete response 3 patients (2.6 %) Progression 60 patients (52.6 %) Best response observed Results (4) : Best response 114 patients evaluable for response

15. Results (5) : Univariate response analysis VariablesBest response - AgeNS (p = 0.83) - SexNS (p = 0.51 - Initial localizationNS (p = 0.78) - Mesastasis localizations (liver-bone-lung)NS (0.07/0.70/0.74) - Number of metastatic localizationsNS (p = 0.18) - Histological subtypes limite (p = 0.06) - GradeNS (p = 0.74) - Number of previous chemotherapy coursesNS (p = 0.25) - OMS Status (0 versus 1, 2 et 3)p = 0.023 - Mean dose of gemcitabine receivedNS (p = 0.40) - Mean dose of docetaxel receivedNS (p = 0.32) - Number of previous lines of chemotherapy receivedp < 10 -5 OR (CR + PR) rates Global18.4 % 21/114 en OR IC-95% [11.3 ; 25.5] Leiomyosarcoma24.2 % 16/66 en OR Other histological subtypes10.4 % 5/48 en OR Uterine localization18.5 % 5/27 en OR Other localization18.4 % 16/87 en OR Status OMS-030.6 % 11/36 en OR Status OMS-1, 2 et 312.5 % 9/72 en OR Objective response versus stable and progression CR or PR: mean of 6 courses [5.2-7] non responders: mean of 3.5 course [3.2-4] OMS-0: 11/36; OMS-1, 2 ou 3: 9/72 leiomyosarcoma

16. Results (6) : Multivariate analysis of the response OMS-0 versus OMS-1, 2 and 3 Only performance status at the time of gemcitabine/docetaxel treatment was significant, with RR = 3 [1.13-7.7] (p = 0.027) leiomyosarcomas versus other histological subtypes Tendency for leiomyosarcoma, with RR = 2.25 [0.74-6.87] (p = 0.09)

17. Available for 130/133 patients. 23 patients were still under gemcitabine-docetaxel treatment. Median survival of 12.1 months [1-28] Rate at6 months: 76 %, 12 months: 51%, 18 months: 30%, 2 years: 15 %. Results (7) : Overall survival Median of follow-up : 16.2 months [6-45] months

18. Results (8) : Overall survival CovariatesOverall survival - AgeNS - SexNS - Initial localizationNS - Metastasis localizationNS - Number of metastatic sitesNS - Histological subtypesp = 0.01 - GradeNS - Nb previous chemo. courses NS - OMS statusp < 10 -4 - Dose of gemcitabine receivedNS - Dose of docetaxel receivedp = 0.008 -Nb of previous lines of chemotherapyp < 10 -3 -Responsep = 0.016 Survival at 6 monthat 12 monthsat 18 monthsat 20 months Global 76 %51 %30 %15 % Leiomyosarcoma87 %56 %42 %21 % Other histology60 %45 % Uterine localization74 %50 %37 % Other localization76 %52 %28 %19 % OMS-0100 %84 %76 %51 % OMS-1, 2 et 365 %39 %13 %

19. Results (9) : Multivariate analysis of survival OMS-0 versus OMS-1, 2 and 3 Performance status at gemcitabine/docetaxel treatment was significant, with RR = 3.13 [1.51-6.49] (p = 0.0022) Quality of the response Patients in progression versus others: RR = 4.02 [2.16-7.51] (p = 0.000012) Histology Leiomyosarcomas: slightly better overall survival, with RR = 1.52 [0.86-2.69] (p = 0.15)

20. months Overall survival according to histology 1 : leiomyosarcoma 2 : other Leiomyosarcoma (range [1-28]): better prognosis than others [1-16] : (p = 0.01) with median of survival of 13.4 months and 9.1 months respectively Overall survival according to initial localization 1 : cutaneous 2 : soft tissue 3 : retroperitoneal 4 : bone 5 : organ Results (10) : Overall survival (p = 0.96)(p = 0.01)

21. months Overall survival according to PS 1 = OMS-0 2 = OMS-1, 2 and 3 Overall survival according to response 1 = complete response 2 = partial response 3 = stable 4 = progression Best response = prognosis factor (p = 0.00087) Results (11) : Overall survival 100 % 84 % 76 % 51 % 1 2 65 % 39 % 13 %

22. Gemcitabine/docetaxel : leiomyosarcoma Patel et al. (J Clin Oncol 2001) Hensley et al. (J Clin Oncol 2002) Hensley et al. (abstract 9010 – ASCO 2004) Look et al. (Gynecol Oncol 2004) Morgan et al. (abstract 9009 – ASCO 2004) ChemotherapyGemcitabine J1 – J8 Gemcitabine + Docetaxel Gemcitabine J1 – J8 – J15 Gemcitabine + vinorelbine Number of patients 3934524818 Leiomyosarcoma1029 uterin 4 others 4248 uterin9 uterin 9 others Response rate18% [7%-29] 4/10 = prog 53 % [35%-70%] 3 = CR; 15 = prog 35 % [22%-48%] 40 % versus 10 % 20.5 % 1 = CR; 8 = prog 2 = prog 1 stable

23. Conclusions Better reponse with leiomyosarcoma but without a clear statistical difference in comparison with other histologies The initial localization did not influence response or survival Performance status was an important prognosis factor Lower response rate for leimyosarcomas than that described in literature

24. Jérôme Fayette, Jean-Yves Blay, Centre Léon Bérard et CHU E. HerriotJérôme Fayette, Jean-Yves Blay, Centre Léon Bérard et CHU E. Herriot Serge Leyvraz, CHUV, LausanneSerge Leyvraz, CHUV, Lausanne Sophie Piperno-Neumann, Institut CurieSophie Piperno-Neumann, Institut Curie Christine Chevreau, Institut Claudius Regaud, ToulouseChristine Chevreau, Institut Claudius Regaud, Toulouse Axel Lecesne, Institut Gustave Roussy, VillejuifAxel Lecesne, Institut Gustave Roussy, Villejuif Nicolas Isambert, Centre Georges-François Leclerc, DijonNicolas Isambert, Centre Georges-François Leclerc, Dijon Etienne Brain, Centre René Huguenin, Saint-CloudEtienne Brain, Centre René Huguenin, Saint-Cloud Nicolas Penel, Centre Oscar Lambret, LilleNicolas Penel, Centre Oscar Lambret, Lille Frédéric Peyrade, Centre Antoine Lacassagne, NiceFrédéric Peyrade, Centre Antoine Lacassagne, Nice Pierre Kerbrat, Centre Eugène Marquis, RennesPierre Kerbrat, Centre Eugène Marquis, Rennes Cécile Guillemet, Centre Henri Becquerel, RouenCécile Guillemet, Centre Henri Becquerel, Rouen Acknowledgements