docAppendix A – International
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Appendix A – International
Appendix A – International A.1 A.2 A.3 A.4 A.5 A.6 Addresses Pathology guidelines Molecular biological studies Alternative high-dose therapy in case of busulfan inapplicability: ME-ME Experimental phase I/II studies Forms Form 0 Study policy commitment Form 1 Registration Form 2 Clinical extent at diagnosis Form 3 Histopathology Form 4 Tumour biology Form 5.1 Randomisation R1 Form 5.2 Randomisation R2loc Form 5.1 Randomisation R2pulm Form 6 Induction chemotherapy – VIDE Form 7 Response to therapy Form 8 Surgery of primary tumour Form 9 Surgery of initial lung metastases Form 10 Consolidation chemotherapy – VAI or VAC Form 11 Stem cell apheresis / collection Form 12 High-dose chemotherapy – Bu-Mel Form 13.1 Radiotherapy of the primary tumour, clinician's report Form 13.2 Radiotherapy of the primary tumour, radiotherapist's report Form 14.1 Radiotherapy of the lungs, clinician's report Form 14.2 Radiotherapy of the lungs, radiotherapist's report Form 15 Report of severe adverse event under treatment Form 16 End of treatment Form 17.1 Event report – First event Form 17.2 Event report – Subsequent event(s) Form 17.3 Secondary malignancy Form 18 Follow-up Form 20 Late Effects File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc EURO-E.W.I.N.G. 99 – Appendix A.1 Appendix A.1 – Addresses Paediatric Oncology Albritton, MD, K. Primary Childrens Medical Center Huntsman Cancer Center 2000 Circle of Hope, Suite 2143 Salt Lake City UT 84112 Phone +1 801-585-0255 Fax +1 801 585-0159 [email protected] USA Bielack, Prof. Dr. St. Klinikum Stuttgart Kinderklinik Olgahospital, Pädiatrie 5 Bismarckstr. 8 D-70176 Stuttgart Phone +49 (0)711 992 3881 Fax +49 (0)711 992 2749 [email protected] GER Brennan, Dr. B. Royal Manchester Children's Hospital Hospital Road Manchester M27 Phone +44 161 727 2227 Fax +44 161 728 2589 [email protected] UK Burdach, Prof. Dr. St. Kinderklinik der Technischen Universität Kölner Platz 1 D-80804 München Phone +49(89)3086-2260/2261 Fax+49(89)3086-3954 [email protected] GER Craft, Professor A.W. The Royal Victoria Infirmary, Inst. of Child Health Queen Victoria Road Newcastle upon Tyne NE1 4LP Phone +44 191 202 3010 Fax +44 191 202 3022 [email protected] UK Dirksen, PD Dr. U. Univ.-Klinik und Poliklinik für Kinder- und Jugendmedizin GER Päd. Hämatologie und Onkologie Albert-Schweitzer-Str. 33 D-48149 Münster Phone +49 (0)251 83 56484 Fax +49 (0)251 83 56489 [email protected], [email protected] Gadner, Prof. Dr. H. St. Anna Kinderspital, Päd. Hämatologie/ Onkologie Kinderspitalgasse 6 A-1090 Wien Phone +43 1 40170 250 Fax +43 1 40170 430 [email protected] Göbel, Prof. Dr. U. Univ.-Klinik und Poliklinik für Kinderheilkunde Päd. Hämatologie/ Onkologie Moorenstr. 5 D-40225 Düsseldorf Phone +49 (0)211 811 7680 Fax +49 (0)211 811 6206 Hartmann, Prof. Dr. O. Institut Gustave Roussy Rue Camille Desmoulins F-94800 Villejuif Cédex Phone +33 1 455 941 70 [email protected] A GER F Fax +33 1 455 964 51 File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc EURO-E.W.I.N.G. 99 – Appendix A.1 Paediatric Oncology continued Hawkins, MD, D. Children's Hospital and Regional Medical Center Dept. of Hematology/Oncology 4800 Sand Pt Way NE, MS: 6D-1 Seattle WA 98105 Phone 206 987-3096 Fax 206 987-3946 [email protected] Hjorth, Dr. L. Lund University Hospital Dept. of Pediatric Oncology SE-22185 Lund Phone +46 461 782 73 [email protected] USA S Fax +46 461 305 73 Jakobson, M.D., Ph.D., Dr. Å. Astrid Lindgren Children's Hospital Karolinska Hospital Pediatric Oncology Unit SE-17176 Stockholm Phone +46 8 5177 9576 Fax +46 8 5177 3184 [email protected] S Jürgens, Prof. Dr. H. Univ.-Klinik und Poliklinik für Kinder- und Jugendmedizin GER Päd. Hämatologie und Onkologie Albert-Schweitzer-Str. 33 D-48149 Münster Phone +49 (0)251 83 47742 Fax +49 (0)251 83 47828 [email protected], [email protected] Klingebiel, Prof. Dr. Th. Univ.-Kinderklinik, Päd. Hämatologie/Onkologie Theodor-Stern-Kai 7 D-60590 Frankfurt Phone +49 (0)69 6301 5094 Fax +49 (0)69 6301 6700 [email protected] GER Koscielniak, Prof. Dr. E. Kinderklinik Olgahospital, Onkologie Bismarckstr. 8 D-70176 Stuttgart Phone +49 711 992 2461 Fax +49 711 992 22462 [email protected] GER Ladenstein, Univ.-Doz. Dr. R. St.Anna-Kinderspital, Päd. Hämatologie / Onkologie Kinderspitalgasse 6 A-1090 Wien IX Phone +43 1 40 170 Kl. 475 Fax +43 1 40 170 437 [email protected] A Lewis, Dr. I. Regional Paediatric Oncology Unit, Children's Day Hospital UK St.James University Hospital Beckett Street Leeds LS9 7TF Phone +44 113 243 3144 Fax +44 113 247 0248 [email protected] Michon, Dr. J. Institut Curie 26 Rue d'Ulm F-75231 Paris Cédex Phone +33 1 443 245 58 [email protected] F Fax +33 1 433 240 05 File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc EURO-E.W.I.N.G. 99 – Appendix A.1 Paediatric Oncology continued Morland, Dr. B. Birmingham Children's Hospital NHS Trust Dept. of Oncology Steelhouse Lane Birmingham B4 6NH Phone +44 121 333 8233 Fax +44 121 333 8241 [email protected] Oberlin, Dr. O. Institut Gustave Roussy Rue Camille Desmoulins F-94800 Villejuif Cédex Phone +33 1 455 941 73 [email protected] UK F Fax +33 1 455 964 51 Paulussen, Prof. Dr. M. University Children's Hospital Basel (UKBB) Pediatric Haematology/Oncology CH-4005 Basel Phone +41 (0)61 685 6267 Fax +41 (0)61 685 6010 [email protected] CH Thomson, MD, B. University of Washington Medical Center Cancer Center 1959 NE Pacific Seattle, WA 98195 USA van den Berg, Dr. H. Emma Children's Hospital Academisch Medisch Centrum Dept. Paediatric Oncology P.O. Box 22700 NL-1100 DD Amsterdam Phone + 31 20 566 3050 Fax + 31 20 691 2231 [email protected] Zoubek, Univ.-Doz. Dr.A. St.Anna-Kinderspital, Päd. Hämatologie / Onkologie Kinderspitalgasse 6 A-1090 Wien IX Phone +43 1 40170 250 Fax +43 1 40170 70 [email protected] File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc NL A EURO-E.W.I.N.G. 99 – Appendix A.1 Medical Oncology Berdel, Prof. Dr. W. Univ.-Klinik und Poliklinik f. Innere Medizin A Hämatologie/ Onkologie Albert-Schweitzer-Str. 33 D-48129 Münster Phone +49 251 83 47586 Bernstein, MD, M. Hopital Sainte-Justine Hematology Oncology 3175 Cote Ste. Catherine Road Montreal QC H3T1C5 Phone +1 514 345-4931 x2771 Fax: +1 514 345-4792 [email protected] Bui, Dr. B. Fondation Bergonie 180 rue de Saint Genes F-33 076 Bordeaux Phone +33 5 5633 3333 E-mail [email protected] GER CA F Fax +33 5 5633 3330 Goldsby, MD, R. UCSF School of Medicine Division of Pediatric Hematology/Oncology 505 Parnassus Avenue San Francisco CA 94143-0106 Phone +1 415 476-3831 [email protected] Honegger, Prof. Dr. H.P. Stadtspital Triemli Zürich Abt. für Innere Medizin, Onkologie Birmensdorferstr. 497 CH-8063 Zürich Phone +41 1 466 1111 / 2330 Fax +41 1 466 2747 / 2739 CH Judson, Dr. I. The Institute of Cancer Research 15 Cotswold Road, Belmont Sutton, Surrey SM2 5NG Phone +44 208 722 4302 Fax +44 208 642 7979 [email protected] UK Marina, MD, N. Stanford University Medical Center Pediatric Hematology/Oncology 300 Pasteur Drive Stanford CA 94305-5208 Phone +1 650 723-5535 Fax +1 650 723-5231 [email protected] USA Merino, MD, M.E. Walter Reed Army Medical Center Pediatric Hem-Onc 6900 Georgia Ave., NW Washington DC 20307 Phone +1 202 782-9451 Fax +1 202 782-7020 [email protected] USA File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc USA EURO-E.W.I.N.G. 99 – Appendix A.1 Medical Oncology continued van Coevorden, Dr. F. Netherlands Cancer Institute Plesmanlaan 121 NL-1066 CX Amsterdam, The Netherlands Phone + 31 20 512 2553 Fax + 31 20 512 2554 [email protected] NL Whelan, Dr. J. Middlesex Hospital, Dept. of Oncology Mortimer Street London W1N 8AA Phone+44 207 380 9302 Fax +44 207 436 0160 [email protected] UK File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc EURO-E.W.I.N.G. 99 – Appendix A.1 Pathology / Molecular Biology Amann, Ass.-Prof. Dr. G. Institut für Klinische PathologieA Währinger Gürtel 18-20 A-1090 Wien, Austria Phone + 43 1 40 400 3654 Fax + 43 1 40 53402 [email protected] Burchill, Dr. S. St.James University Hospital, Cancer Research UK, Cancer Medicine Research Unit Beckett Street Leeds LS9 7TF Phone +44 113 283 7034 Fax +44 113 242 9886 [email protected] UK Daugaard, Dr. Rigshospitalet Dept. of Pathology Blegdamsvej DK-2100 Copenhagen [email protected] Laboratoire de Genetique des Tumeurs Pavillon Trouillet Rossignol, , Institut Curie F-Paris 75005 Phone +33 1 4234 6679 Fax +33 1 4234 6630 DK Delattre, Dr. O. F Delling, Prof. Dr. Institut für Pathologie der Universität Martinistr. 52 D-20246 Hamburg GER Dickman, MD, P. Phoenix Childrens Hospital Department of Pathology 1919 East Thomas Road Phoenix AZ 85016 Phone +1 602 546-1286 Fax +1 602 546-1273 [email protected] USA Fisher, MD, C. The Institute of Cancer Research Royal Marsden Downs Road Sutton, Surrey SM2 5PT [email protected] UK Flanagan, MD, A.M. University College of London Department of Pathology Gower Street London WC1E 6BT [email protected] UK Guinbretière, Dr. J.M. Service de Pathologie Centre Reni-Huguenin 35, rue Dailly F-92210 Saint-Cloud Phone +33 1 4711 1511 Fax +33 1 4711 1516 [email protected] File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc F EURO-E.W.I.N.G. 99 – Appendix A.1 Pathology / Molecular Biology continued Hogendoorn, Prof. Dr. P. Dept. of Pathology, L1-Q Leiden University Medical Center P.O.Box 9600 2300 RC Leiden Phone +31 71 526 6639 Fax +31 71 524 8158 [email protected] Jänig, Dr. U. Patholog. Institut der Universität, Paidopathologie Michaelisstr. 11 D-24105 Kiel Jundt, Prof. Dr. G. Kantonspital Basel Institut für Pathologie Schönbeinstr. 40 CH-4003 Basel Phone +41 61 265 2757 [email protected] NL GER CH Fax +41 61 265 3194 Köhler, Prof. Dr. G. Gerhard-Domagk-Institut für Pathologie der Universität Münster Domagkstr. 17 D-48129 Münster Phone +49 (0)251 83 52094 Fax +49 (0)251 83 55460 [email protected] Kovar, Assoc. Prof. Dr. H. St.Anna-Kinderspital, Forschungsinstitut für Krebskranke Kinder Kinderspitalgasse 6 A-1090 Wien IX Phone +43 1 40 470 Fax +43 1 40 87230 [email protected] Leuschner, PD Dr. I. Institut für Pathologie der Universität Michaelisstr. 11 D-24105 Kiel Phone +49 (0)431 597 3444 Fax +49 (0)431 597 3486 [email protected] Malcolm, Dr. A.J. University of Newcastle upon Tyne Royal Victoria Infirmary Dept. of Pathology Newcastle upon Tyn Ne1 4LP, UK Phone + 44 191 232 5131 Fax + 44 191 222 8100 UK Mangham, Dr. D.C. Dept. of Pathology Univ. of Birmingham Medical School Edgbaston, Birmingham B15 2//, UK [email protected] UK Poremba, Prof. Dr. C. Univ.-Klinikum Düsseldorf Institut für Pathologie Moorenstr. 5 D-40225 Düsseldorf Phone +49 (0)211 81 18 339 Fax +49 (0)211 81 18 353 [email protected] File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc GER A GER GER EURO-E.W.I.N.G. 99 – Appendix A.1 Pathology / Molecular Biology continued Russo, MD, P. Childrens Hospital of Philadelphia Dept of Pediatric Pathology 324 South 34th Street Philadelphia PA 19104 Phone +1 215 590-1733 Fax +1 215 590-1736 [email protected] von Hochstetter, PD Dr. A.R. Pathologie Institut Enge Tödistr. 48 CH-8039 Zürich Phone +41 1 287 3838 [email protected] Wejde, Dr. J. USA CH Fax +41 1 287 3839 Klinisk patologi/cytologi Karolinska Universitetssjukhuset i. solna S-17176 Stockholm [email protected] File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc S EURO-E.W.I.N.G. 99 – Appendix A.1 Radiology / Radiotherapy Carrie, Dr. Ch. Centre Leon Berard Dept of Radiation Oncology 28 rue laennec F-69008 Lyon Phone 33-4-78-78-26-52 [email protected] F Fax 33-4-78-78-26-26 Cassoni, Dr. A. Middlesex Hospital, Meyerstein Inst. of Clinical Oncology Mortimer Street London W1N 8AA Phone +44 171 636 8333 Fax +44 171 436 0160 [email protected] UK Douglas, M.D., J.G. University of Washington Medical Center Cancer Center Department of Radiation Oncology,Pediatrics, and Neurological Surgery UW Box 356043 Seattle, WA 98195 [email protected] USA Dunst, Prof. Dr. J. Universität Lübeck Klinik für Strahlentherapie Ratzeburger Allee 160 D-23538 Lübeck Phone +49 (0)451 500 6660 Fax +49 (0)451 500 3324 [email protected] GER Habrand, Prof. Dr. J.L. Institut Gustave Roussy Département de radiothérapie Rue Camille Desmoulins 94 805 Villejuif cedex Phone +33 1 4211 4211 [email protected] F Fax +33 1 4211 5253 Pape, Dr. H. Klinikum der Heinrich-Heine-Universität, Strahlentherapie GER Moorenstr. 5 D-40225 Düsseldorf Phone +49 (0)211 811 7992 Fax +49 (0)211 811 8057 [email protected] Pötter, Prof. Dr. R. Klinik für Strahlentherapie, Allg. Krankenhaus der Stadt Wien A Währinger GürPhone 19-20 A-1090 Wien Phone +43 1 40400 2694 Fax +43 1 40400 2693 [email protected] Rübe, Prof. Dr. Ch Univ. des Saarlandes Klinik für Strahlentherapie, Haus 26 D-66421 Homburg Phone +49 (0)6841 164 606 Fax +49 (0)6841 164 699 [email protected] GER Schuck, Prof. Dr. A. Univ.-Klinikum Münster Klinik für Strahlentherapie Albert-Schweitzer-Str. 33 D-48129 Münster Phone +49 (0)251 83 47384 [email protected] GER Fax +49 (0)251 83 47355 File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc EURO-E.W.I.N.G. 99 – Appendix A.1 Radiology / Radiotherapy continued Spooner, Dr. D. Willich, Prof. Dr. N. Consultant Radiotherapist Queen Elisabeth II Hospital Edgbaston Birmingham B15 2TH, UK Phone + 44 121 472 1311 Univ.-Klinikum Münster Klinik für Strahlentherapie Albert-Schweitzer-Str. 33 D-48129 Münster Phone +49 251 834 7384 [email protected] UK Fax + 44 121 627 2386 GER Fax +49 251 834 7355 File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc EURO-E.W.I.N.G. 99 – Appendix A.1 Surgery / Orthopedic Surgery Cannon, Dr. S.R. Consultant Orthopaedic Surgeon Royal National Orthopaedic Hospital Brokley Hill, Stanmore Middlesex HA7 4LP Phone +44 181 954 2300 Fax +44 181 420 7115 Ewerbeck, Prof. Dr. Orthopäd. Univ.-Klinik Schlierbacher Landstraße 200 a D-69118 Heidelberg Phone +49 (0)6221 96 5 Fax +49 (0)6221 96 6347 Exner, LA Prof. Dr. U. Orthopäd. Univ.-Klinik Balgrist Forchstr. 340 CH-8008 Zürich Phone +41 1 386 3090 / 3095 Fax +41 1 386 3099 [email protected] CH Grimer, Dr. R.J. The Royal Orthopaedic Hospital Woodlands, Northfield Birmingham B31 2AP Phone +44 121 627 8350 Fax +44 121 627 8644 UK Kotz, Prof. Dr. Allg. Krankenhaus der Stadt Wien, Orthopäd. Klinik Währinger Gürtel 18-20 A-1090 Wien A Mascard, Dr. E. Clinique Labrouste 64 rue Labrouste F-75015 Paris Phone +33 1 44 19 50 00 [email protected] F Missenard, Dr. G. Clinique Arago 95 bd Arago F-75 014 Paris Phone +33 1 4408 0400 / 0403 Fax +33 1 4331 1653 F Randall, MD, R.L. Primary Childrens Medical Center Dept. of Orthopaedic Surgery 100 North Medical Drive Salt Lake City UT 84113-1100 Phone +1 801 588-2680 Fax +1 801 588-2662 [email protected] USA Semik, Prof. Dr. M. Univ.-Klinikum Münster GER Klinik für Thorax-, Herz- und Gefäßchirurgie D-48129 Münster Phone +49 (0)251 83 47481 Fax +49 (0)251 83 47 48316 [email protected] van Coevorden, Dr. F. The Netherlands Cancer Institute Antoni van Leeuwenhoek-Ziekenhuis Dept. of Surgery Plesmanlaan 121 NL-1066 CX Amsterdam File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc UK GER NL EURO-E.W.I.N.G. 99 – Appendix A.1 Surgery / Orthopedic Surgery continued Winkelmann, Prof. Dr. W. Univ.-Klinikum Münster, Orthopäd. Univ.-Klinik Albert-Schweitzer-Str. 33 D-48129 Münster Phone +49 (0)251 83 47902 / 47901 File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc GER EURO-E.W.I.N.G. 99 – Appendix A.1 Late effects / Quality of Life Calaminus, Dr. G. Univ.-Kinderklinik, Päd. Hämatologie/Onkologie Postfach 10 10 07 D-40001 Düsseldorf Phone +49 (0)211 811 6100 Fax +49 (0)211 811 6206 [email protected] GER Langer, Dr. Th. Univ.-Kinderklinik, Päd. Immunologie/Onkologie Loschgestr. 15 D-91054 Erlangen Phone +49 (0)9131 853 731 Fax +49 (0)9131 853 113 [email protected] GER Rossi, CA Prof. Dr. R. Städtisches Krankenhaus Neukölln, Kinderklinik Mariendorfer Weg 28 D-12051 Berlin Phone +49 (0)30 6294 2269 Fax +49 (0)30 6294 2364 [email protected] GER File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc EURO-E.W.I.N.G. 99 – Appendix A.1 Data Monitoring Committee Chairman Souhami, Professor R.L. U.C.L. Medical School Administration Gowre Street London WC1E 6BT Phone +44 207 679 5454 [email protected] UK Fax +44 207 383 2462 Babiker, Dr. A. MRC HIV Clinical Trials Centre Royal Free and University College Medical School Mortimer Market Centre Capper Street London WC1E 6AU Meyers, Dr. P. Dept. of Pediatrics Memorial Sloan-Kettering Cancer Center 1275 York Avenue New York, N.Y. 10021 Phone +1 212 639 5952 Fax +1 212 717 3447 [email protected] File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc UK U.S.A. EURO-E.W.I.N.G. 99 – Appendix A.1 Associated Studies Nowak-Göttl, Prof. Dr. U. Univ.-Klinik und Poliklinik für Kinder- und Jugendmedizin GER Pädiatrische Hämatologie/Onkologie Albert Schweitzer Str. 33 D-48129 Münster Phone: + 49 251 834 7936 Fax: +49 251 834 7828 Schweigerer, Prof. Dr. L. Univ.-Klinikum Göttingen Zentrum für Kinderheilkunde Forschungslabor Pädiatrie I, D3 646 Robert-Koch-Str. 40 D-37075 Göttingen Phone +49 (0)551 39 6200 Fax +49 (0)551 39 12 664 [email protected] File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc GER EURO-E.W.I.N.G. 99 – Appendix A.1 Phase I/II Studies, Pharmacology Bernstein, MD, M. Hopital Sainte-Justine Hematology Oncology 3175 Cote Ste. Catherine Road Montreal QC H3T1C5 Phone +1 514 345-4931 x2771 Fax: +1 514 345-4792 [email protected] Boos, Prof. Dr. J. Univ-Klinik und Poliklinik für Kinder- und Jugendmedizin GER Päd. Hämatologie/ Onkologie Albert-Schweitzer-Str. 33 D-48129 Münster Phone +49 251 83 47865 Fax +49 251 83 47828 [email protected] Morland, Dr. B. Birmingham Children's Hospital NHS Trust Dept. of Oncology Steelhouse Lane Birmingham B4 6NH Phone +44 121 333 8233 Fax +44 121 333 8241 [email protected] Vassal, Dr. G. Institut Gustave Roussy Clinical Pharmacology Lab. and Paediatric Oncology Dept. Rue Camille Desmoulins F-94805 Villejuif Phone +33 142 114 947 Fax +33 142 115275 [email protected] File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc CA UK F EURO-E.W.I.N.G. 99 – Appendix A.1 Statistics Devidas, PhD, M. Children's Oncology Group - Data Center 104 North Main Street, Suite 600 Gainesville FL 32601-3330 Phone +1 352 392-5198 x339 Fax +1 352 392-8162 [email protected] USA Heinecke, Dr. A. Universitätsklinikum Münster Koordinierungszentrum für Klinische Studien Von-Esmarch-Str. 62 D-48149 Münster Phone +49 (0)251 83 57111 Fax +49 (0)251 83 57026 [email protected] GER Kaatsch, Dr. P. Institut für Medizinische Biometrie, Epidemiologie und Informatik der Universität Mainz Deutsches Kinderkrebsregister Langenbeckstr. 1 D-55101 Mainz Phone +49 (0)6131 173 111 Fax +49 (0)6131 172 968 [email protected] GER Köpcke, Prof. Dr. W. Inst. für Med. Informatik und Biomathematik d. Universität GER Domagkstr. 9 D-48129 Münster Phone +49 (0)251 83 55261 Fax +49 (0)251 83 55277 Le Deley, Dr. M.-C. Institut Gustave Roussy Département de Biostatistique 39 Rue Camille Desmoulins F-94805 Villejuif Cédex, France Phone + 33 1 4211 5444 Fax + 33 1 4211 5207 [email protected] Machin, Dr. D. UKCCSG Data Centre University of Leicester, Dept. of Epidemiology 22-28 Princess Road West Leicester LE1 6TP UK Maibach, R. Leitender Statistiker SIAK SIAK Koordinationsstelle Effingerstraße 40 CH-3008 Bern Phone +41 31 389 9191 [email protected] CH F Fax +41 31 389 9200 Ranft, A. Universitätsklinikum Münster Koordinierungszentrum für Klinische Studien Von-Esmarch-Str. 62 D-48149 Münster Phone +49 (0)251 83 57464 Fax +49 (0)251 83 56489 [email protected] Stevens, S. UKCCSG Data Centre University of Leicester Dept. of Cancer Studies and Molecular Medicine 9 Princess Road West Leicester LE1 6TH [email protected] File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc GER UK EURO-E.W.I.N.G. 99 – Appendix A.1 Statistics continued van Glabbeke, M. EORTC Data center Avenue E. Mounier, 83 Bte 11 B-1200 Brussels, Belgium Phone +32 2 774 1625 Fax +32 2 772 3545 [email protected] Weston, C. UKCCSG Data Centre University of Leicester, Dept. of Epidemiology 22-28 Princess Road West Leicester LE1 6TH [email protected] File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc EORTC UK EURO-E.W.I.N.G. 99 – Appendix A.1 Data management Douglas, C. UKCCSG Data Centre University of Leicester, Dept. of Epidemiology Hearts of Oak House 9 Princess Road West Leicester LE1 6TH Phone +44 116 249 4464 Fax +44 116 254 9504 [email protected] Kirkpatrick, A. EORTC Data center Avenue E. Mounier, 83 Bte 11 B-1200 Brussels, Belgium Phone +32 2 774 1691 Fax +32 2 771 3810 [email protected] Ny Tovo, N. Institut Gustave Roussy Rue Camille Desmoulins F-94800 Villejuif Cédex Brussels, Belgium Phone +33 1 4211 5443 Fax +33 1 4211 5302 [email protected] Ranft, A. Universitätsklinikum Münster Koordinierungszentrum für Klinische Studien Von-Esmarch-Str. 62 D-48149 Münster Phone +49 (0)251 83 57464 Fax +49 (0)251 83 56489 [email protected]; [email protected] Steiner, S. Medizinische Dokumentation SIAK Koordinationsstelle Effingerstraße 40 CH-3008 Bern Phone +41 31 389 9191 [email protected] UK EORTC FR GER CH Fax +41 31 389 9200 File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc EURO-E.W.I.N.G. 99 – Appendix A.1 Trial offices Braun-Munzinger, G. Univ.-Klinik u. Poliklinik f. Kinder- u. Jugendmedizin GER Päd. Hämatologie/ Onkologie D-48129 Münster, Germany T + 49 251 83 57749 F + 49 251 83 56489 [email protected], [email protected] Douglas, C. UKCCSG Data Centre University of Leicester, Dept. of Epidemiology Hearts of Oak House 9 Princess Road West Leicester LE1 6TH Phone +44 116 249 4464 Fax +44 116 254 9504 [email protected] Stefani, Dr. E. St. Anna Kinderspital Abteilung für Dokumentation und Statistik Kinderspitalgasse 6 A-1090 Wien Phone +43 1 40470 438 Fax +43 1 40470 437 [email protected] File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc UK A EURO-E.W.I.N.G. 99 – Appendix A.2 Appendix A.2 – Pathology guidelines Procedures at biopsy The diagnosis has to be histologically confirmed in every patient. Either open biopsy or needle core biopsy of the primary tumour must be performed in order to obtain sufficient material for histological diagnosis and concomitant studies outlined below. The later inclusion of the biopsy channel/scar into the final local treatment must be considered. The fresh surgical specimens should be sent rapidly to the local Department of Pathology. Fresh tumour tissue (deep frozen) must be saved for additional diagnostic investigations such as genetic analyses (molecular cytogenetics, FISH, CGH, electron microscopy). Imprints (touch preparations) should also be made and stored at –20° until further examination (e.g. cytology, FISH). The diagnosis is based on the examination of routinely stained material supplemented with additional diagnostic methods as outlined below. Hematoxylin and eosin (HE) and periodic-acidSchiff (PAS) are necessary for preliminary classification, followed and supplemented by immuno-histochemistry and molecular biology. Immuno-histochemistry Although CD99 (MIC-2 antigen) expression is not unique in Ewing tumours, - CD 99 immunohistochemistry is obligatory in the diagnostic work-up of Ewing tumours, because >95% of Ewing tumours are positive. (Note that a positive staining reaction has been reported in synovial sarcoma, myelosarcoma, precursor lymphoma, Burkitt's lymphoma, alveolar rhabdomyosarcoma, thymocytes in thymoma, and others.) To distinguish Ewing’s Sarcoma versus atypical Ewing’s Sarcoma and peripheral neuroectodermal tumour (PNET) an obligatory imunohistochemical examination of neuronal expression has to be performed by means of at least the following antigens - Synaptophysin - S-100 protein - NSE (neuron-specific enolase) File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc EURO-E.W.I.N.G. 99 – Appendix A.2 As useful markers for differential diagnosis within the group of small round cell tumours the following antigens can be used to identify myogenic, fibrogenic, and hematopoetic origin - Vimentin - Desmin - Smooth-muscle actin - CD45 (leukocyte common antigen) Pan B-cell antibodies, pan T-cell antibodies are recommended in suspected haematological malignancies, and TdT (terminal deoxynucleotidyl transferase) and MPO (myeloperoxidase) in tumours suspected for precursor lymphoma, Burkitt's lymphoma, and myelosarcoma. Additional diagnostic methods • Molecular genetic analyses are strongly suggested for molecular tumour classification Systematic investigations of Ewing tumours' molecular biological features are integrated part of the EURO-E.W.I.N.G. 99 concept. Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) based detection of chromosomal transloactions, Fluorescence In Situ Hybridisation (FISH), and/or Comparative Genomic Hybridisation (CGH) investigations of tumour samples (and bone marrow specimen and stem cell preparations) are performed in reference laboratories. A small fresh (deep frozen) tissue sample, together with a small conventional paraffin-embedded representative tissue sample, should be sent to a laboratory capable of these methods, see separate protocol below. • Conventional cytogenetics and cell culture (optional) Fresh small tumour samples kept in RPMI should be sent to reference laboratories. • Electron microscopy (optional) A small sample should be immediately fixed in 2% glutaraldehyde. Definitive diagnosis The definitive diagnosis may be based on examination of routinely stained material plus the obligatory immunohistochemistry panel as outlined above, or plus two out of the following three investigations 81,94,95: a) molecular/cytogenetic analysis (chromosome 22 rearrangement) b) CD 99 (Mic-2) positivity c) electron microscopy File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc EURO-E.W.I.N.G. 99 – Appendix A.2 Each case should be signed by one of the EURO-E.W.I.N.G. 99 pathology board members. Special cases will be reviewed by the pathology board. Names and addresses of the pathology board members are listed in appendix A.1, and are available from the national study centres. (For definition of histological response at surgery following neoadjuvant treatment, see protocol section XVI) File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc EURO-E.W.I.N.G. 99 – Appendix A.2 File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc EURO-E.W.I.N.G. 99 – Appendix A.3 Appendix A.3 – Molecular biological studies Background: EWS gene rearrangements, involving the EWS gene and one of several ETS transcription factor genes (Fli1 85%, ERG 10%,<1% ETV1, E1AF, FEV), have been described in over 90% of tumours of the Ewing tumour family and are currently used to aid in the classification of these tumours. The gene rearrangement results in expression of a chimeric RNA product which varies in length dependent on the breakpoint in the genes. These encode aberrant transcription factors, which are thought to be involved in the pathogenesis of these tumours. The identification of these fusion products by reverse transcriptase polymerase chain reaction (RT-PCR) has been used for the differential diagnosis of Ewing family tumours. For patients with localised Ewing tumours two studies have suggested that specific EWS-ETS fusion types may be of prognostic significance. RT-PCR for EWS-ETS fusion products is a sensitive and specific method for the identification of small numbers of circulating tumour cells, and may therefore be valuable to detect micrometastatic disease. Preliminary results suggest that in patients with localised Ewing tumour infiltration of bone marrow identified by RT-PCR may be of poor prognostic significance. Patients with bone metastases are almost always positive for bone marrow disease detected by RT-PCR and conventional cytological methods. Circulating tumour cells in peripheral blood has rarely been observed, and appeared not to correlate with extent of disease or with outcome in all studies performed so far. Aims of this prospective, blinded, multicentre, quality controlled study: • To evaluate the independent prognostic significance of individual EWS-ETS fusion types. • To determine the prognostic impact of RT-PCR detectable tumour cells in the bone marrow of patients with Ewing tumours taken at diagnosis. • To investigate the clinical significance of disease detected by RT-PCR in bone marrow samples taken at time of PBSC harvest and at suspected relapse. • To define the frequency of RT-PCR detectable tumour cells in PBPC harvests and to evaluate their potential clinical significance. File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc EURO-E.W.I.N.G. 99 – Appendix A.3 Samples Samples are requested from all newly diagnosed patients with Ewing tumours. • Fresh frozen tumour material is requested from all patients at the time of diagnostic biopsy or primary tumour resection. This material should be snap frozen in liquid nitrogen and stored in either liquid nitrogen or at – 80°C until transported to the reference laboratory. • Bone marrow aspirates (0.5-1ml samples into EDTA, from at least two sites excluding the involved side) to be taken at :Time of diagnosis (essential) PBPC harvest Suspected relapse • Two peripheral stem cell harvest samples (0.5-1ml into EDTA) to be taken at the time of leukapheresis. Bone marrow and PBPC samples should be either shipped immediately at room temperature to the reference centre to be received within 24h (Germany, Austria, Switzerland, France, Belgium, Netherlands) or placed into GT buffer (tubes will be provided to participating centres) and stored at –80°C until transported on dry ice to reference laboratory (UK). Bone marrow and tumour pathology will be reviewed centrally. File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc EURO-E.W.I.N.G. 99 – Appendix A.3 Established reference laboratories: • Austria Dr. H. Kovar, Dr. A. Zoubek E-mail: [email protected]; [email protected] • France Dr. O. Delattre E-mail: [email protected] • Germany Prof. Dr. G. Köhler, E-mail [email protected] Prof. Dr. C. Poremba Email [email protected] • Netherlands, Belgium Prof. Dr. Pancras C.W. Hogendoorn E-mail: [email protected] • United Kingdom Ms S. Brownhill, Dr. S.A. Burchill E-mail: [email protected] Details on transportation can be obtained from the reference laboratory. For full addresses see appendix A1. File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc EURO-E.W.I.N.G. 99 – Appendix A.3 File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc EURO-E.W.I.N.G. 99 – Appendix A.4 Appendix A.4 – Alternative high-dose therapy in case of busulfan inapplicability: Any patient who has received radiotherapy to central axial sites (e.g. chest, pelvis) is ineligible for busulfan high-dose therapy and randomisation for reasons of anticipated toxicity. As an alternative, these patients may receive either Treo–Mel or Me-Me. TREOSULFAN – MELPHALAN (Treo-Mel) Treosulfan intravenous (i.v.) 12 g/m²/dose D -5 D -4 D -3 X X X D -2 D -1 D0 single hour infusion X Melphalan i.v. 140 mg/m² i.v. infusion, 30 min. Stem cell re-infusion (min. 3 x 106/kg CD 34+) X Please note: The cumulative treosulfan dose is 36 g/m². Treosulfan powder for infusion is to be reconstituted in warm water for injection (ca. 30°C). The treosulfan solution is compatible with sterile physiologic NaCl solution (saline) but NOT with buffered media! Anticonvulsive prophylactic treatment is not considered necessary with high dose treosulfan. Hydration 2000ml/24h using a standard hydration solution according to the institution's guidelines is recommended. G-CSF support 5µg/kg/d is recommended e.g. from d+4. In patients receiving Treo-Mel, radiation doses planned or administered involving spinal cord or brain must not exceed 20 Gy. The safety of Treo-Mel in patients receiving radiation to spinal cord or brain or axial sites has not been clarified. File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc EURO-E.W.I.N.G. 99 – Appendix A.4 ME-ME In patients ineligible for Bu-Mel high-dose therapy a phase II study applying the ME-ME instead of the Bu-Mel strategy is available. This therapy is to follow 6 courses of VIDE induction and one course of VAI. ME consolidation Melphalan, 35 mg/m²/d i.v. infusion, 30 min. D -7 D -6 D -5 D -4 X X X X Etoposide phosphate, 60 mg/kg/d i.v. infusion, 4 h D -3 D -2 D -1 D0 X Stem cell re-infusion (min.3 x 106/kg CD 34+) X NOTE: In case of contraindications for Bu-Mel, this high-dose therapy is compatible with early radiotherapy to central axial sites. A second course of ME should follow approx. 6 weeks later. This alternative approach is co-ordinated by: Prof. Dr. Stefan Burdach E-mail: [email protected] For full address see appendix A1 Patients treated with this approach will be analysed for the impact of aplasiogenic high-dose chemotherapy combined with involved compartment irradiation followed by myeloablative intensification on the prognosis of patients with extrapulmonary (with or without additional pulmonary) metastatic and early relapsed Ewing Tumours (relapse < 24 month from initial diagnosis). Multimodal therapy will be arrayed in three phases as (1) systemic induction, (2) involved compartment intensification and (3) systemic intensification. 1) Systemic induction treatment will be 6 courses of VIDE, with stem cell harvest. 2) Local therapy to all involved sites, i.e. primary tumour and all metastases is recommended. Involved compartment irradiation of all such sites performed with the last two conventional courses prior to HDT will usually require stem cell support of its own, and hence should be performed in institutions well experienced in these techniques. 3) A systemic intensification consolidation regimen of ME-ME high-dose therapy will then be applied. File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc EURO-E.W.I.N.G. 99 – Appendix A.4 Specifically the analysis will address four issues: 1. Can patients with high risk (extrapulmonary metastatic and early relapsed) Ewing tumours be cured of their malignancy? 2. Does involved compartment irradiation improve results? 3. Is long term monitoring by PCR of the EWS/Fli-1 transcript in the bone marrow predictive of relapse? 4. Does tumour cell contamination of the grafts impact on the event free survival? The main measurable objective of the study is EFS. In addition, feasibility and toxicity of treatment and prediction of relapse by PCR of the EWS/Fli-1 transcript will be measured. Patients will be entered via registration to EURO-E.W.I.N.G. 99 and to the ME-ME coordinator. A complete protocol will be available through the ME-ME coordinator. File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc EURO-E.W.I.N.G. 99 – Appendix A.4 File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc EURO-E.W.I.N.G. 99 – Appendix A.5 Appendix A.5 – Experimental phase I/II studies As prognosis in group 3 Ewing tumour patients is expected to be very limited (<15% 5-year EFS), additional phase II studies are warranted. These may either be studies of "window" treatment in addition to the regular therapy (e.g. comparable to the treatment of the localised disease, with high-dose consolidation), or may be studies of treatment options replacing part of such a treatment. As patient numbers are only few, and treatment may be highly toxic, it was decided that enrolment of Ewing tumour patients into such studies should be performed via the national EURO-E.W.I.N.G. 99 study centres in close collaboration with the national phase II study centres. An update of active phase II studies will be available from your national study centre. • For the UK-CCSG group, Dr. Bruce Morland co-ordinates phase I/II studies in the field of paediatric oncology. UK participants should contact him via their EURO-E.W.I.N.G. 99 study centre for information on active studies. • For the GPOH group, Prof. Dr. Joachim Boos co-ordinates phase I/II studies in the field of paediatric oncology. German participants should contact the EURO-E.W.I.N.G. 99 study centre for information on active studies. • For the SFCE group, Dr. Gilles Vassal co-ordinates phase I/II studies in the field of paediatric oncology. French participants should contact him via their EURO-E.W.I.N.G. 99 study centre for information on active studies. • For the COG group, Dr. Mark Bernstein co-ordinates phase I/II studies in the field of paediatric oncology. COG participants should contact him via their COG study centre for information on active studies. For full addresses see appendix A.1. It is strongly recommended that each patient should be discussed with the national study centre in order to get access to active phase II studies. File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc EURO-E.W.I.N.G. 99 – Appendix A.5 File name EE99 App A1-5 International_Treo_amend_2006_02_14.doc
