EORTC STBSG EORTC STBSG 8th PMH Conference: New developments in cancer management Contributions of EORTC trials to Contributions of EORTC trials to the management of sarcoma the management of sarcoma the management of sarcoma the management of sarcoma Ole Steen Nielsen Ole Steen Nielsen Ole Steen Nielsen Ole Steen Nielsen on behalf of the EORTC STBSG on behalf of the EORTC STBSG STBSG PMH/OSN
EORTC STBSG EORTC STBSG Not 50 years but 20 years Not 50 years but 20 years since I was at PHM! STBSG PMH/OSN
EORTC STBSG EORTC STBSG Molecular biological knowledge Molecular biological knowledge in sarcomas increases • Genetic involvement • Genetic involvement. • Many genes are affected: – p53 Rb ras myc MDM2 CDK4 GLI etc p53, Rb, ras, myc, MDM2, CDK4, GLI etc. • Genetic changes ( cytogenetic aberrationer ): – t(X;18) (p11;q11) - SSX1&2 SYT: Synovial sarcomas t(X;18) (p11;q11) - SSX1&2, SYT: Synovial sarcomas – t(12;22) (q13;q12) - ATF1, EWS: Clear Cell sarcomas – t(12;16) (q13;p11) - CHOP, TLS: Myxoid liposarcomas – t(2;13)(q37;q14) - PAX3, FKHR: Rhabdomyosarcomas (2 13)( 37 14) PAX3 FKHR Rh bd – t(11;22) (q24;q12) - FLI-1, EWS: Ewing family (EFT) – Others (lipomas, fibrosis, schwannomas, chondros. etc.) f • Etc …….. STBSG PMH/OSN
EORTC STBSG EORTC STBSG SARCOMAS SARCOMAS Treatment and research problems p • A rare disease • Too few patients locally! • Many subtypes! • Many subtypes! • Molecular biological knowledge! • Nationally: Centralisation! • Internationally: Collaboration! • Internationally: Collaboration! STBSG PMH/OSN
EORTC STBSG EORTC STBSG European Organization for Research and Treatment of Cancer A An example of International l f I t ti l Cooperation: EORTC STBSG Cooperation: EORTC STBSG • To develop stimulate and coordinate • To develop, stimulate and coordinate studies on all aspects of sarcomas within the framework of the EORTC framework of the EORTC. • To organize congresses, conferences and s mposia to promote these st dies symposia to promote these studies. STBSG PMH/OSN
EORTC STBSG EORTC STBSG EORTC Soft Tissue and Bone EORTC Soft Tissue and Bone Sarcoma Group • 52 member institutions from 13 countries • > 500 patients / year in clinical trials • > 3000 patients in the central database p • 58 clinical trials conducted so far • Strict quality control programs • Strict quality control programs – Strict membership policy (site visits, recruitment, data quality) Strict membership policy (site visits, recruitment, data quality) – Review of pathology and response Review of pathology and response – On site visits On site visits STBSG PMH/OSN
EORTC STBSG EORTC STBSG Patient recruitment 1200 1200 Phase I 1000 Phase II Phase III - Advanc.dis. 800 Phase III - Adjuvant 600 600 400 200 0 <86 0 1 2 3 4 5 6 7 86 87 88 89 90 91 92 93 94 95 96 97 98 99 STBSG PMH/OSN
EORTC STBSG EORTC STBSG (Neo)-adjuvant phase III trials in STS ( ) j p • The STBSG has conducted the largest adjuvant trials: – CYVADIC vs observation after surgery +/- radiotherapy (77-88: 468 pts) Advantage of CYVADIC only in delaying local recurrences for pts with localizations other than limbs No proof of effect! No proof of effect! – Neo-adjuvant DOXO-IFOS vs immediate surgery (88-95: 150 pts) No advantage in survival – DOXO-IFOS-GCSF vs observation after surgery (95-03: 351 pts) No advantage in survival – Neo-adjuvant VP16-IFOS-DOXO±hyperthermia (97-06: 341 / 340 pts) Neo adjuvant VP16 IFOS DOXO±hyperthermia (97 06: 341 / 340 pts) Advantage in disease free survival for the hyperthermia arm – Imatinib vs observation after surgery in GIST (05-ongoing: 879 / 900 pts) with ISG, FSG, GEIS, AGITG STBSG PMH/OSN
EORTC STBSG EORTC STBSG Projects based on the STBSG j database of adjuvant studies • Data originating from centers with a large recruitment (> 5 pts in a study) is of better quality • Validation of the Trojani grading system • Development of a prognostic index based on mitotic count, necrosis and tumor size necrosis and tumor size • Inclusion of the results of the CYVADIC study in the Sarcoma Meta-Analysis Collaborative group project • Patients with marginal resection, males, and patients older P ti t ith i l ti l d ti t ld than 40 years benefit more from chemotherapy than others; tumor size and histological grade have no predictive value. di ti l STBSG PMH/OSN
EORTC STBSG EORTC STBSG EORTC STBSG STUDY STRATEGY EORTC STBSG STUDY STRATEGY ADVANCED/METASTATIC STS • Standard is doxorubicin • Only multicenter studies. • Study strategy: Study strategy: – Phase 1: Selected centres – Phase 2: 2nd line chemotherapy – Phase 2: 2nd line chemotherapy – Phase 2: 1st line chemotherapy – Phase 3: New drug vs standard Phase 3: New drug vs standard STBSG PMH/OSN
EORTC STBSG EORTC STBSG Phase I-II trials in STS (1977-2008) Phase I II trials in STS (1977 2008) Examples 1st and 2nd line chemotherapy • • ACNU ACNU • Cisplatin Cisplatin • Fotemustine • Chlorozotocin • Miltefosine • Methotrexate • Docetaxel • PALA PALA • Lipo. doxorubicin • Ellipticinium • Temozolomide • Mitomycin • Raltitrexed • Etoposide (iv/oral) p ( ) • • Gemcitabine Gemcitabine • DTIC (high dose) • Ecteinascidin-743 • TGU • Brostallicin • Exatecan • MDS • Gefitinib fi i ib • MT-PPE • Razopanib • Mitozolomide • Eribulin mesylate • MZPES • And more … And more … NEW DRUGS STILL NEEDED! STBSG PMH/OSN
EORTC STBSG EORTC STBSG Phase III trials in advanced STS Phase III trials in advanced STS E Examples 1st line chemotherapy Examples 1st line chemotherapy E l l 1 1 l l h h h h CYVADIC CYVADIC (comparison of 2 schedules) • (comparison of 2 schedules) Oct 76 Mar 80 (312 pts) Oct 76 Oct 76 - Mar 80 (312 pts) Oct 76 Mar 80 (312 pts) Mar 80 (312 pts) DOXORUBICIN DOXORUBICIN (75 mg/m vs EPIRUBICIN EPIRUBICIN (75 mg/m (75 mg/m 2 ) (75 mg/m 2 ) • ) vs Dec 80 Dec 80 - - Jun 83 (210 pts) Jun 83 (210 pts) NO SUPERIORITY IN SURVIVAL CYVADIC CYVADIC vs vs DOX DOX- - IFOS IFOS vs vs DOX DOX • Oct 85 Oct 85 - - Jun 90 (729 pts) Jun 90 (729 pts) COMPARED TO SINGLE AGENT DOX DOX (75) vs EPI EPI (150) vs EPI EPI (3 x 50) • (75) vs (150) vs (3 x 50) DOXORUBICIN Nov 90 Nov 90 - - Nov 94 (334 pts) Nov 94 (334 pts) DOX DOX (50) DOX (50) DOX (50) - IFOS IFOS IFOS (5) IFOS (5) vs DOX DOX (75) DOX (75) DOX - IFOS IFOS (5) IFOS (5) IFOS • (50) (5) vs (5) (75) (75) - (5) (5) - - Gm Gm- G -CSF CSF CSF CSF Mar 92 Mar 92 - - Jan 95 (296 pts) Jan 95 (296 pts) IFOS (5 g/m 2 /24 h) vs IFOS (3 x 3 g/m 2 /4h • Mar 92 Mar 92 Mar 92 Mar 92 - Jul 96 (182 pts) Jul 96 (182 pts) Jul 96 (182 pts) Jul 96 (182 pts) DOX (75) vs DOX (75) vs DOX (75) DOX (75) - - IFOS (9 g/m IFOS (9 g/m 2 /72h) /72h) • Feb 98 Feb 98 – – Oct 01 (326 pts) Oct 01 (326 pts) DOX (75) vs DOX (75) DOX (75) DOX (75) vs vs IFOS (3 x 3 g/m vs IFOS (3 x 3 g/m IFOS (3 x 3 g/m 2 IFOS (3 x 3 g/m /4h) 2 /4h) /4h) vs /4h) vs vs IFOS (9 g/m vs IFOS (9 g/m IFOS (9 g/m 2 /72h) IFOS (9 g/m /72h) /72h) /72h) • • Mar 03 Mar 03 – – ongoing ongoing STBSG PMH/OSN
EORTC STBSG Summary EORTC STBSG Ad Advanced STS - 1st line therapy d STS 1 li h • Systematic evaluation in phase II and phase III trials of : y p p – CYVADIC (Doxo, CPH, DTIC) – Doxorubicin, 75 mg/m2 – Epirubicin, 75 mg/m2 and 150 mg/m2 Epirubicin 75 mg/m2 and 150 mg/m2 – Ifosfamide, 5 g/m2, 9 g/m2, 12 g/m2 – Doxorubicin – Ifosfamide combinations – Docetaxel – Liposomal doxorubicin • Doxorubicin, 75 mg/m2, q 3 weeks remains the “golden Doxorubicin, 75 mg/m2, q 3 weeks remains the golden standard” • On-going phase III trial – Doxo 75 mg/m2 vs Doxo 75 mg/m2 + Ifos 9 g/m2 + GCSF • Accumulation of a database of > 3000 cases STBSG PMH/OSN
EORTC STBSG EORTC STBSG Projects based on the STBSG database of 1st line studies A potentially curable disease… ( EJC 39, 2003, p.64 ) ( , , p ) OS OS 100 90 5 years survival: 8% y 80 80 70 - Long terms survivors observed 60 in all prognostic groups 50 40 30 20 10 0 (years) 0 2 4 6 8 10 12 O N Number of patients at risk : All DB patients 1832 2187 406 112 44 11 2 All STBSG PMH/OSN
EORTC STBSG EORTC STBSG Summary Summary Advanced STS 2 nd and 3rd line therapy • 28 phase II trials on various drugs • Accumulation of a database of 380 patients A l ti f d t b f 380 ti t treated with active and inactive drugs • Reference values for phase II trials using R f l f h II t i l i PFR as the primary end-point (i.e. for cytostatic drugs or targeted therapies) cytostatic drugs or targeted therapies) STBSG PMH/OSN
EORTC STBSG EORTC STBSG Progression free rate observed in STBSG 100 100 2 nd /3 rd line phase II studies in STS 90 80 70 Agents 3 mon. 6 mon. 60 s.e. Estim. s.e Estim. 50 50 Active (4 trials) Active (4 trials) 39 % 39 % 14 % 14 % 4 % 4 % 3 % 3 % 40 Inactive (9 trials) 21 % 8 % 3 % 2 % 30 20 10 0 0 (months) (months) 0 3 6 9 12 15 O N Number of patients at risk : 221234 221234 47 47 16 16 5 5 1 1 Inactive agents I ti t 136146 55 18 14 11 Active agents STBSG PMH/OSN
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