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Gemcitabine/Docetaxel association: R e trospective analysis of 133 soft tissue sarcomas

Gemcitabine/Docetaxel association: R e trospective analysis of 133 soft tissue sarcomas. J.-O. Bay, for the French Sarcoma Group. Background.  First line of chemotherapy  doxorubicine m e dian OR = 26%  ifosphamide m e dian OR = 26%

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Gemcitabine/Docetaxel association: R e trospective analysis of 133 soft tissue sarcomas

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

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

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

  4. Patient characteristics (1) 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 %)

  5. Patient characteristics (2)  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

  6. Patient characteristics (3)  Initial localization Bone15 (11 %) Limbs44 (34 %) Organs23 (14 %) Retroperitoneal19 (17 %) Uterine corpus 32 (24 %)

  7. Patient characteristics (4)  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 : 21 patients (17 %) • One : 60 patients (45 %) • Two : 35 patients (26 %) • Three : 9 patients (7 %) • Four : 2 patients (1.5 %) • Five : 5 patients (3.5 %)

  8. Patient characteristics (5)  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 %)

  9. Patient characteristics (6) 125 patients available Performance Status (PS) before Gemcitabine-Docetaxel OMS 36 % OMS 032 % Correlation between PS and the number of anterior chemotherapy lines OMS 214 % OMS 148 %

  10. Gemcitabine 900 mg/m2 over 1h Gemcitabine 900 mg/m2 over 1h Treatment Gemcitabine 900 mg/m2 over 1h and Docetaxel 100 mg/m2 over 1h Gemcitabine 900 mg/m2 over 1h and Docetaxel 100 mg/m2 over 1h J1 J8 J1 J8 21 or 28 days

  11. Results (1): Treatments received  Number of courses: mean = 4,0 courses and median = 3 courses [1-11] 1 11 8.3 % | ************ 2 30 22.6 % | ********************************* 3 27 20.3 % | ***************************** 4 20 15.0 % | ********************** 5 11 8.3 % | ************ 6 14 10.5 % | *************** 7 7 5.3 % | ******* 8 7 5.3 % | ******* 9 4 3.0 % | **** 10 1 0.8 % | * 11 1 0.8 % | * •  Dose of docetaxel per course and per m² for 528 courses: • Mean: 135.3 Standard 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]

  12. Results (2): Toxicity • For 515 courses Nausea / vomiting Toxicity grade Thrombopenia Anemia Diarrhea Mucosis Alopecia Neutropenia OMS-0 69.90 % 79.61 % 53.79 % 89.60 % 95.76 % 94.99 % 75.10 % OMS-1 5.83 % 6.99 % 28.54 % 7.90 % 1.93 % 3.47 % 3.47 % OMS-2 4.66 % 5.05 % 14.76 % 1.54 % 1.16 % 0.77 % 12.16 % OMS-3 10.29 % 6.02 % 2.52 % 0.58 % 1.16 % 0.58 % 9.07 % OMS-4 9.32 % 2.33 % 0.39 % 0.39 % 0.19 % 0.19 %

  13. 100% 90% Grade-4 80% Grade-3 70% 60% Grade-2 50% Grade-1 anemia alopecia diarrhea mucosis neutropenia thrombopenia nausea / vomiting Grade-0 Results (3): Toxicity Toxicity over 515 courses of gemcitabine-docetaxel

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

  15. Results (5): Univariate response analysis OR (CR + PR) rates Global 18.4 % 21/114 en OR IC-95% [11.3 ; 25.5] Leiomyosarcoma 24.2 % 16/66 en OR Other histological subtypes 10.4 % 5/48 en OR Uterine localization 18.5 % 5/27 en OR Other localization 18.4 % 16/87 en OR Status OMS-0 30.6 % 11/36 en OR Status OMS-1, 2 et 3 12.5 % 9/72 en OR Variables Best response - Age NS (p = 0.83) - Sex NS (p = 0.51 - Initial localization NS (p = 0.78) - Mesastasis localizations (liver-bone-lung) NS (0.07/0.70/0.74) - Number of metastatic localizations NS (p = 0.18) - Histological subtypes limite (p = 0.06) - Grade NS (p = 0.74) - Number of previous chemotherapy courses NS (p = 0.25) - OMS Status (0 versus 1, 2 et 3) p = 0.023 - Mean dose of gemcitabine received NS (p = 0.40) - Mean dose of docetaxel received NS (p = 0.32) - Number of previous lines of chemotherapy received p < 10-5 Objective response versus stable and progression leiomyosarcoma OMS-0: 11/36; OMS-1, 2 ou 3: 9/72 CR or PR: mean of 6 courses [5.2-7] non responders: mean of 3.5 course [3.2-4]

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

  18. Results (8): Overall survival Survival at 6 month at 12 months at 18 months at 20 months Global 76 % 51 % 30 % 15 % Leiomyosarcoma 87 % 56 % 42 % 21 % Other histology 60 % 45 % Uterine localization 74 % 50 % 37 % Other localization 76 % 52 % 28 % 19 % OMS-0 100 %84 % 76 % 51 % OMS-1, 2 et 3 65 %39 % 13 % • Covariates Overall • survival • - Age NS • - Sex NS • - Initial localization NS • - Metastasis localization NS • - Number of metastatic sites NS • - Histological subtypes p = 0.01 • - Grade NS • - Nb previous chemo. courses NS • - OMS status p < 10-4 • - Dose of gemcitabine received NS • - Dose of docetaxel received p = 0.008 • Nb of previous lines of chemotherapy p < 10-3 • -Response p = 0.016

  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 months Results (10): Overall survival (p = 0.96) (p = 0.01) Overall survival according to initial localization 1 : cutaneous 2 : soft tissue 3 : retroperitoneal 4 : bone 5 : organ 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

  21. months months Results (11): Overall survival 100 % 84 % 76 % 51 % 65 % 1 13 % 39 % 2 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)

  22. Gemcitabine/docetaxel : leiomyosarcoma

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

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