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MCO 2011 - Slide 31 - P. Casali - Spotlight session Sarcoma

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  • The results of our large European randomized trial are going to be published now, and they are even more disappointing, because not only did we fail to demonstrate any survival improvement for doxorubicin plus ifosfamide, but also we failed to show any difference in the response rate. Actually this trial, of which I was the study coordinator, suffers from some limitations. First of all the dose of doxorubicin was fifty milligrams per meter square, and it is possible that the fifty-seventy milligrams range is the most critical in the dose response curve for doxorubicin. In addition, large trials cannot select those patient populations that are more likely to benefit from some improvement in the response rate, as probably is achievable with combination regimens. So, in my opinion, these trials have demonstrated that, at full doses, combination regimens may allow higher response rates. Whenever the physician believes that a response rate may be useful to the patient, I think he is allowed to propose a combination regimen to his patient, even if a survival advantage for the average sarcoma patient has not been demonstrated by published studies.
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    • 1. Sarcoma Medical therapy Paolo G. Casali [email_address]
    • 2. Incidence STS 5 /100,000/year GIST 1.5 Osteosa 0.3 Ewing 0.2 Rhabdomyosa 0.1 benign tumors 300 Sex M > F Median age STS 60 y GIST 60 y Osteosa 15 y Ewing 15 y Rhabdomyosa 5 y
    • 3. STS OS EFT RMS
    • 4. STS OS EFT RMS
    • 5. Soft tissue sarcoma
    • 6. Adipocytic tumours Well deifferentiated / dedifferentiated liposarcoma Myxoid / round cell liposarcoma Pleomorphic liposarcoma … .. Fibroblastic / myofibroblastic tumours Fibromatosis (desmoid) Solitary fibrous tumour / haemangiopericytoma Low grade myofibroblastic tumour Infantile fibrosarcoma Adult fibrosarcoma Mixofibrosarcoma … .. So-called fibrohistiocytic tumours Pleomorphic MFH / Undifferentiated pleomorphic sarcoma … .. Smooth muscle tumours Leiomyosarcoma … .. Skeletal muscle tumours Embryonal rhabdomyosarcoma Alveolar rhabdomyosarcoma Pleomorphic rhabdomyosarcoma Vascular tumours Epithelioid haemangioendothelioma Angiosarcoma of soft tissue … .. Chondro-osseous tumours Mesenchymal chondrosarcoma Extraskeletal osteosarcoma Tumours of uncertain differentiation Synovial sarcoma Epithelioid sarcoma Alveolar soft part sarcoma Clear cell sarcoma of soft tissue Extraskeletal myxoid chondrosarcoma Extraskeletal Ewing tumour Desmoplastic small round cell tumour Extra-renal rhabdoid tumour Malignant mesenchymoma Neoplasms with perivascular epithelioid cell differentiation (PEComa) Intimal sarcoma
    • 7. …… .
    • 8. Head & neck 5% Superficial trunk 10% Retroperitoneum 15% Viscera 10% Limbs 60%
    • 9. Adjuvant chemotherapy L = limbs – T = trunk – HN = head & neck – R = retrop – U = uterus – V = viscera gruppo aa n. pz setting regime DFS OS EORTC 77-88 468 L T HN ADM CTX DTIC VCR +13% +7% SSG 81-86 181 L T HN ADM +6% +5% DFCI ECOG IGSC 78-83 168 L T HN R V ADM +13% +3% GOG 73-82 156 U ADM +12% +8% UCLA 81-84 119 L ADM +4% +4% IOR 81-86 77 L ADM +28% +21% NCI 77-81 67 L ADM CTX HDMTX +26% +6% Mayo 75-81 61 L T ADM ActD VCR DTIC -3% 0 Bergonié 81-88 59 L T HN R ADM CTX VCR DTIC +41% +34% MDA 73-76 47 L T ADM ActD CTX VCR -7% NCI 77-81 31 T HN ADM CTX HDMTX +28% +10% NCI 77-81 15 R ADM CTX HDMTX -53%
    • 10.  
    • 11. Localized disease Woll PJ, ASCO Ann meet 2007; #10008
    • 12. Frustaci S et al, J Clin Oncol 2001;19:1238
    • 13.  
    • 14. 0 epiADM+IFX x 3
    • 15.  
    • 16.  
    • 17.  
    • 18. LOCALIZED, HIGH-RISK SOFT TISSUE SARCOMAS (STS) OF THE EXTREMITIES AND TRUNK WALL IN ADULTS: THREE VS FIVE CYCLES OF FULL-DOSE ANTHRACYCLINE AND IFOSFAMIDE ADJUVANT CHEMOTHERAPY: A PHASE III RANDOMIZED TRIAL FROM THE ITALIAN SARCOMA GROUP AND SPANISH SARCOMA GROUP Alessandro Gronchi , Sergio Frustaci, Mario Mercuri, Javier Martin, Antonio Lopez-Pousa, Lidia Mariani, Paolo Verderio, Vittorio Quagliuolo, Paolo G. Casali and Piero Picci
    • 19.  
    • 20. Epirubicin 120 mg/m 2 ( ~ DOX 80 mg/m 2 ) + Ifosfamide 9,000 mg/m 2 q 21 days
    • 21. OS by study arm 70% 69% one-sided 95%: 0.941 (95% CI 0.664 - 1.334) 70% 69% N. at risk Arm A 164 154 138 106 77 43 Arm B 164 157 143 114 77 47
    • 22. RFS by study arm 61% 60% N. at risk Arm A 156 123 108 74 55 33 Arm B 158 126 108 77 47 31
    • 23. OS vs previous ISG trial
    • 24. Sarcomas: spread of disease local isolated extra pulmonary pulmonary
    • 25. Isolated pulmonary metastatic disease
    • 26.  
    • 27. Advanced disease R ADM 75 mg/sqm + IFX 7.5 g/sqm ADM 75 mg/sqm EORTC Soft Tissue & Bone Sarcoma Group
    • 28. ADM vs ADM+IFX in advanced STS
      • no. pts. Regimen OR OS
      • ECOG , 1993 90 ADM 80 mg/mq 20% =
      • 88 ADM 60 mg/mq 34% + (NS)
      • IFX 7500 mg/mq
      • 84 ADM 40 mg/mq 32% =
      • CDDP 60 mg/mq
      • MMC 8 mg/mq
      • SWOG/CALGB , 170 ADM 80 mg/mq 17% =
      • 1993 DTIC 1000 mg/mq
      • 170 ADM 60 mg/mq 32% =
      • IFX 60-7500 mg/mq
      • DTIC 1000 mg/mq
      p<.05
    • 29. ADM vs ADM+IFX in advanced STS no. pts. Regimen OR OS EORTC , 1991 244 ADM 75 mg/mq 24% = 233 ADM 50 mg/mq 27% = IFX 5000 mg/mq 135 ADM 50 mg/mq 27% = DTIC 750 mg/mq CTX 500 mg/mq VCR 1.5 mg/mq
    • 30. OR OS Duration of response 218 d (PR) 243 d (CR) Time to progression 240 d (SD) 288 d (PR) 317 d (CR)
    • 31. …… .
    • 32.  
    • 33. Endometrial stromal sarcoma: progestins, aromatase inhibitors ER PR
    • 34. Dermatofibrosarcoma: Imatinib COL1A1-PDGFB  PDGFB t(17;22)
    • 35. Desmoid tumors (aggressive fibromatosis)
    • 36.  
    • 37.  
    • 38. L LMS
    • 39.  
    • 40. Stacchiotti S et al, Ann Oncol 2010, 21:1130
    • 41.  
    • 42.  
    • 43. Stacchiotti S et al, Mol Cancer Ther 2010;9:1286
    • 44.  
    • 45. PEComas
      • Kidney
      • Liver
      • Gastrointestinal tract
      • Prostate
      • Retroperitoneum
      • Uterus
      • Soft tissue
      • Skin
      • …… .
    • 46.  
    • 47. Laplante et Sabatini, J Cell Science 2009
    • 48. SUCCEED study standard CT: best response R Ridaforolimus placebo in advanced STS
    • 49. Leiomyosarcoma: Dacarbazine 0 DTIC x 2
    • 50. Dedifferentiated liposa: HD-IFX 0 HD-ci-IFX x 5
    • 51. Sinovyal sa: HD-IFX 0 +3 mos
    • 52. Angiosarcoma: taxanes Fata F et al. Cancer 1999; 86: 2034
    • 53.  
    • 54. Angiosarcoma: Gemcitabine 0 +1 mos +4 mos
    • 55. Leiomyosarcoma: Gemcitabine
    • 56.  
    • 57.  
    • 58. A pooled analysis of the final results of the two randomized phase II studies comparing Gemcitabine (G) vs Gemcitabine + Docetaxel (G+D) in patients (pts) with metastatic/relapsed leiomyosarcoma (LMS) F.Duffaud , P. Pautier, B. Bui, M.L Hensley, A.Rey, N.Penel, D.Reinke, A. Le Cesne, J.Y Blay, R.G Maki ESMO Congress, 2010
    • 59. Pooled analysis – Progression-free survival
    • 60. Pooled analysis – Progression-free survival
    • 61. Trabectedin (ET-743)
    • 62. L -sarcoma liposarcoma leiomyosarcoma
    • 63. Dedifferentiated liposa 0 ET743 x 16 mos
    • 64. Uterine leiomyosarcoma 0 ET743 x 3
    • 65. Lipo sarcoma well diff  dediff myxoid  round cell pleomorphic
    • 66. well diff  dediff myxoid  round cell pleomorphic
    • 67. t(12;16)(q13;p11) FUS CHOP 12 16 FUS/CHOP q13 p11
    • 68.  
    • 69.  
    • 70. 0 + 1 c +4 c
    • 71.  
    • 72. Mol Cancer Therap 2009;8:449
    • 73. Synovial sa: Trabectedin
    • 74. T -STS simple cariotype with reciprocal translocations complex cariotype
    • 75. Synovial sa t(X;18)(p11;q11) SS18-SSX1 SS18-SSX2 SS18-SSX4 Myxoid liposa t(12;16)(q13;p11) FUS-CHOP t(12;22)(q13;q12) EWS-CHOP Esk. myx. chondrosa t(9;22)(q22;q12) EWS-NR4A3 t(9;17)(q22;q11) RBP56-NR4A3 t(9;15)(q22;q21) TCF12-NR4A3 Fibromyxoid sa t(7;16)(q33;p11) FUS-CREB3L2 t(11;16)(p11;p11) FUS-CREB3L1 Clear cell sa t(12;22)(q13;q12) EWS-ATF1 Dermatofibrosa t(17;22)(q22;q13) COL1A1-PDGFB EFT t(11;22)(q24;q12) EWS-FL1 t(21;22)(q22;q12) EWS-ERG t(7;22)(p22;q12) EWS-ETV1 t(17;22)(q12;q12) EWS-E1AF t(2;22)(q33;q12) EWS-FEV Desmopl. SRCT t(11;22)(p13;q12) EWS-WT1 Alv. rhabdomyosa t(2;13)(q35;q14) PAX3-FOXO1A t(1;13)(p36;q14) PAX7-FOXO1A Alv. soft part sa t(X;17)(p11;q25) TFE3-ASPL Angiomatoid f. histiocytoma t(12;16)(q13;p11) FUS-ATF1 Cong fibrosa t(12;15)(p13;q25) ETV6-NTRK3 Endometrial stromal sa t(7;17)(p15;q21) JAZF1-JJAZ1 Infl. myofibro. t. t(1;2)(q22;p23) TPM3-ALK t(2;19)(p23;p13) TPM4-ALK t(2;17)(p23;q23) CLTC-ALK t(2;2)(p23;q13) RANBP2-ALK
    • 76.
      • Leiomiyosarcoma : GEM, Trabectedin, DTIC (& Temozolomide), …..
      • Liposarcoma, dediff : Trabectedin, HD-IFX …..
      • Liposarcoma, myxoid : Trabectedin, …..
      • Angiosarcoma : taxanes, GEM, HD-IFX, …..
      • Synovial sa : HD-IFX, Trabectedin, …..
      • MPNST : HD-IFX, VP16 + …..
      • …… .
      Histology-driven chemotherapy
    • 77.
      • Dermatofibrosarcoma : Imatinib
      • Desmoids : hormones, Imatinib, Sorafenib, …..
      • Alveolar sa : Sunitinib, Cediranib
      • Solitary fibrous tumor : Sunitinib, …..
      • Angiosarcoma : Sorafenib
      • Inflammatory myofibroblastic tumor : Crizotinib
      • LAM and Pecomas : m-TOR inhibitors
      • …… .
      Histology-driven targeted therapy
    • 78. Gastrointstinal stromal tumors (GIST)
    • 79. Target therapy in GIST Imatinib SCF
    • 80.  
    • 81.  
    • 82. Imatinib chemotherapy OS months
    • 83.  
    • 84. KIT (CD 117)
    • 85. Lasota J et al, Histopathology 2008 exon 9 (~10%) exon 11 (~70%) exon 13 (~5%) exon 17 (~5 %) PDGFRA (~10%) KIT (~80%) WT (~10%)
    • 86. KIT exon 9
    • 87. KIT exon 9 PDGFRA
    • 88.  
    • 89. PDGFRA Corless CL, J Clin Oncol 2005, 23: 5357
    • 90. GIST in syndromes GIST in children 0 – 18+ yrs
    • 91.  
    • 92.  
    • 93.  
    • 94. Tumor response
    • 95.  
    • 96. Tumor response: Choi’s criteria 10% 15%
    • 97. 5 HU 57 HU 39 HU 13 HU 61 HU 15 HU 83 HU 36 HU 57 HU 9 HU 52 HU 3 HU - 2 HU - 18 HU -34 HU 9 HU 5 HU -9 HU -13 HU 3 HU 20 HU 10 HU
    • 98. PET scan
    • 99. 0 +3-4 wks +12 mos +18 mos
    • 100. 50 mg/day, 4 weeks on, 2 weeks off SUNITINIB
    • 101. Van den Abbeele AD et al, ECCO Ann meet 2005
    • 102. Sunitinib: interval progression
    • 103. Imatinib: interval progression
    • 104. t
    • 105. BFR14 study R stop Imatinib continue Imatinib Imatinib CR PR SD
      • 12 mos
      • surgery if feasible
    • 106. from: ASCO 2009 Virtual Meeting Duffaud F et al, ASCO Ann meet 2009; #10508
    • 107. Duffaud F et al, ASCO Ann meet 2009; #10508 from: ASCO 2009 Virtual Meeting
    • 108. Time to secondary resistance…
    • 109.  
    • 110. Secondary resistance
    • 111. Sunitinib VEGFR-2 VEGFR-1 VEGFR-3 PDGFR-  KIT FLT-3 PDGFR-  RET N H O N H F H 3 C CH 3 N H O N CH 3 CH 3
    • 112.  
    • 113. Negri T al, J Natl Cancer Inst 2009;101:194
    • 114. Secondary resistance: molecular heterogeneity Liegl B, J Pathol, 2008;216:64
    • 115. KIT PDGRA VEGFR …… ..
    • 116. KIT PDGRA VEGFR …… ..
    • 117. KIT PDGRA VEGFR PI3K AKT mTOR …… ..
    • 118. KIT PDGRA VEGFR Hsp90 …… ..
    • 119. GIST: rechallenge with Imatinib 0 +1 mos
    • 120. Surgery of responding residual disease 
    • 121. n = 27 n = 8 Gronchi A, Ann Surg 2007; 245:341
    • 122. Raut CP, J Clin Oncol 2006;24:2325
    • 123.  
    • 124. DeMatteo R et al, Lancet 2009
    • 125. OS RFS
    • 126. R OS relapse RFS OS Imatinib Imatinib
    • 127. R R relapse R relapse Imatinib Imatinib Imatinib
    • 128. R R relapse R relapse Imatinib Imatinib Imatinib
    • 129. R R relapse R relapse Imatinib Imatinib Imatinib
    • 130. R R relapse R relapse Imatinib Imatinib Imatinib
    • 131. Paolo G. Casali Study Chair & ISG Coordinator Jean-Yves Blay EORTC Coordinator Axel Le Cesne FSG Coordinator Andres Poveda GEIS Coordinator John Zalcberg AGITG Coordinator Martine van Glabbeke Study Statistician Sandrine Marraud Coordinating Physician Anne Kirkpatrick Study Data Manager Intermediate and high risk localized , completely resected, gastrointestinal stromal tumors ( GIST ) expressing KIT receptor: a controlled randomized trial on adjuvant Imatinib mesylate (Glivec ™ ) versus no further therapy after complete surgery
    • 132. R Imatinib x 2 yrs control
    • 133. German/Scandinavian trial R Imatinib x 3 yrs Imatinib x 1 yr
    • 134. Risk stratification Miettinen M. Semin Diagn Pathol 2006; 23: 70 cm M/50HPF gastric jejunal/ ileal duodenal rectal 1 < 2 < 5 0 none 0 none 0 none 0 none 2 >2 < 5 < 5 1.9% very low 4.3% low 8.3% low 8.5% low 3a >5 < 10 < 5 3.6% low 24% moderate 3b >10 < 5 12% moderate 52% high 34% high 57% high 4 < 2 >5 0 50% 54% high 5 >2 < 5 >5 16% moderate 73% high 50% high 52% high 6a >5 < 10 >5 55% high 85% high 6b >10 >5 86% high 90% high 86% high 71% high
    • 135. Corless C et al, ASCO 2010 (from: ASCO Virtual meeting)
    • 136. Corless C et al, ASCO 2010 (from: ASCO Virtual meeting)
    • 137. Corless C et al, ASCO 2010 (from: ASCO Virtual meeting)
    • 138. Corless C et al, ASCO 2010 (from: ASCO Virtual meeting)
    • 139. Osteosarcoma
    • 140. Osteosarcoma
    • 141.  
    • 142. N Engl J Med 1986;314:1600
    • 143. Cancer 1979; 43: 2163-2177
    • 144. Cancer 1979; 43: 2163-2177
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    • 151.  
    • 152.  
    • 153. + IFX + IFX + MTP + MTP + IFX + MTP P<0.05 + IFX + MTP
    • 154. Ewing’s sarcoma
    • 155. Ewing’s sarcoma
    • 156.  
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    • 166. [email_address]