Adjuvant High-Dose Thiotepa and Stem Cell Rescue Associated With Conventional Chemotherapy in Relapsed Osteosarcoma

Summary

Approximately 150 new cases of osteosarcoma are reported each year in France, of which 15 to 20% are metastatic. Further to the initial standard care, about 45% of the patients relapse within a median duration of 20 months. Result of the OS94 study results and of the investigation performed within the CRLCC, indicate that 25 to 30 patients (children and adults) experience an osteosarcoma relapse each year in FRANCE. According to several studies, the 5-year overall survival rate of patients in first relapse is 23-28%,with a median post relapse survival of 10 to 17 months. Multiple relapse cases are also reported in the COSS study, with a median time to second relapse of 0.8 year. At present, there is no reference treatment for the standard care of osteosarcoma relapse in FRANCE. Thiotepa is known for its antitumor effect in numerous malignant tumors. In 2007, a study from our institution reported that about 35% of all osteosarcoma relapses are treated with a high-dose thiotepa while the efficacy and tolerance of this therapeutic strategy have never been assessed. These results highlight the need to the evaluate the efficacy and tolerance of this high-dose of thiotepa within a clinical trial and its inclusion in the standard care of the osteosarcoma at relapse.

Timeline

Start

2009-07

Primary completion

2018-10-29

Completion

2018-10-29

Publications

• Background Desandes E, Lacour B, Sommelet D, Buemi A, Danzon A, Delafosse P, Grosclaude P, Mace-Lesech J, Raverdy-Bourdon N, Tretarre B, Velten M, Brugieres L. Cancer incidence among adolescents in France. Pediatr Blood Cancer. 2004 Dec;43(7):742-8. doi: 10.1002/pbc.20106.
• Background Widhe B, Widhe T. Initial symptoms and clinical features in osteosarcoma and Ewing sarcoma. J Bone Joint Surg Am. 2000 May;82(5):667-74. doi: 10.2106/00004623-200005000-00007.
• Background Jaffe N, Paed D, Farber S, Traggis D, Geiser C, Kim BS, Das L, Frauenberger G, Djerassi I, Cassady JR. Favorable response of metastatic osteogenic sarcoma to pulse high-dose methotrexate with citrovorum rescue and radiation therapy. Cancer. 1973 Jun;31(6):1367-73. doi: 10.1002/1097-0142(197306)31:63.0.co;2-6. No abstract available.
• Background Gasparini M, Rouesse J, van Oosterom A, Wagener T, Somers R, Russel JA, Voute PA, Bramwell V, Thomas D, Sylvester R, et al. Phase II study of cisplatin in advanced osteogenic sarcoma. European Organization for Research on Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Cancer Treat Rep. 1985 Feb;69(2):211-3.
• Background Marti C, Kroner T, Remagen W, Berchtold W, Cserhati M, Varini M. High-dose ifosfamide in advanced osteosarcoma. Cancer Treat Rep. 1985 Jan;69(1):115-7.
• Background Cores EP, Holland JF, Wang JJ, Sinks LF. Doxorubicin in disseminated osteosarcoma. JAMA. 1972 Sep 4;221(10):1132-8. doi: 10.1001/jama.221.10.1132. No abstract available.
• Background Rosen G, Caparros B, Huvos AG, Kosloff C, Nirenberg A, Cacavio A, Marcove RC, Lane JM, Mehta B, Urban C. Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer. 1982 Mar 15;49(6):1221-30. doi: 10.1002/1097-0142(19820315)49:63.0.co;2-e.
• Background Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, Kotz R, Salzer-Kuntschik M, Werner M, Winkelmann W, Zoubek A, Jurgens H, Winkler K. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol. 2002 Feb 1;20(3):776-90. doi: 10.1200/JCO.2002.20.3.776.
• Background Souhami RL, Craft AW, Van der Eijken JW, Nooij M, Spooner D, Bramwell VH, Wierzbicki R, Malcolm AJ, Kirkpatrick A, Uscinska BM, Van Glabbeke M, Machin D. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet. 1997 Sep 27;350(9082):911-7. doi: 10.1016/S0140-6736(97)02307-6.
• Background Claude L, Rousmans S, Carrie C, Breteau N, Dijoud F, Gentet JC, Giammarile F, Jouve JL, Kind M, Marec-Berard P, Mascard E, Bataillard A, Philip T; Institut National du Cancer; Fedeation nationale des centres de lutte contre le cancer (FNCLCC); Standards, Options et Recommendations; Ligue nationale contre le cancer; SFCE; Fedeation hospitaliere de France; FNCHRU; Fedeation francaise de cancerologie. [Standards and Options for the use of radiation therapy in the management of patients with osteosarcoma. Update 2004]. Bull Cancer. 2005 Oct;92(10):891-906. French.
• Background Franzius C, Schuck A, Bielack SS. High-dose samarium-153 ethylene diamine tetramethylene phosphonate: low toxicity of skeletal irradiation in patients with osteosarcoma and bone metastases. J Clin Oncol. 2002 Apr 1;20(7):1953-4. doi: 10.1200/JCO.2002.20.7.1953. No abstract available.
• Background Harris MB, Gieser P, Goorin AM, Ayala A, Shochat SJ, Ferguson WS, Holbrook T, Link MP. Treatment of metastatic osteosarcoma at diagnosis: a Pediatric Oncology Group Study. J Clin Oncol. 1998 Nov;16(11):3641-8. doi: 10.1200/JCO.1998.16.11.3641.
• Background Mialou V, Philip T, Kalifa C, Perol D, Gentet JC, Marec-Berard P, Pacquement H, Chastagner P, Defaschelles AS, Hartmann O. Metastatic osteosarcoma at diagnosis: prognostic factors and long-term outcome--the French pediatric experience. Cancer. 2005 Sep 1;104(5):1100-9. doi: 10.1002/cncr.21263.
• Background Crompton BD, Goldsby RE, Weinberg VK, Feren R, O'Donnell RJ, Ablin AR. Survival after recurrence of osteosarcoma: a 20-year experience at a single institution. Pediatr Blood Cancer. 2006 Sep;47(3):255-9. doi: 10.1002/pbc.20580.
• Background Ferrari S, Briccoli A, Mercuri M, Bertoni F, Cesari M, Longhi A, Bacci G. Late relapse in osteosarcoma. J Pediatr Hematol Oncol. 2006 Jul;28(7):418-22. doi: 10.1097/01.mph.0000212944.82361.1d.
• Background Shi XB, Chen AM, Cai XH, Guo FJ, Liao GN, Ma D. Establishment and characterization of cell sublines with high and low metastatic potential derived from human osteosarcoma. Chin Med J (Engl). 2005 Apr 20;118(8):687-90. No abstract available.
• Background Bacci G, Briccoli A, Longhi A, Ferrari S, Mercuri M, Faggioli F, Versari M, Picci P. Treatment and outcome of recurrent osteosarcoma: experience at Rizzoli in 235 patients initially treated with neoadjuvant chemotherapy. Acta Oncol. 2005;44(7):748-55. doi: 10.1080/02841860500327503.
• Background Ferrari S, Briccoli A, Mercuri M, Bertoni F, Picci P, Tienghi A, Del Prever AB, Fagioli F, Comandone A, Bacci G. Postrelapse survival in osteosarcoma of the extremities: prognostic factors for long-term survival. J Clin Oncol. 2003 Feb 15;21(4):710-5. doi: 10.1200/JCO.2003.03.141.
• Background Huth JF, Eilber FR. Patterns of recurrence after resection of osteosarcoma of the extremity. Strategies for treatment of metastases. Arch Surg. 1989 Jan;124(1):122-6. doi: 10.1001/archsurg.1989.01410010132026.
• Background Kempf-Bielack B, Bielack SS, Jurgens H, Branscheid D, Berdel WE, Exner GU, Gobel U, Helmke K, Jundt G, Kabisch H, Kevric M, Klingebiel T, Kotz R, Maas R, Schwarz R, Semik M, Treuner J, Zoubek A, Winkler K. Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol. 2005 Jan 20;23(3):559-68. doi: 10.1200/JCO.2005.04.063.
• Background Saeter G, Hoie J, Stenwig AE, Johansson AK, Hannisdal E, Solheim OP. Systemic relapse of patients with osteogenic sarcoma. Prognostic factors for long term survival. Cancer. 1995 Mar 1;75(5):1084-93. doi: 10.1002/1097-0142(19950301)75:53.0.co;2-f.
• Background Tabone MD, Kalifa C, Rodary C, Raquin M, Valteau-Couanet D, Lemerle J. Osteosarcoma recurrences in pediatric patients previously treated with intensive chemotherapy. J Clin Oncol. 1994 Dec;12(12):2614-20. doi: 10.1200/JCO.1994.12.12.2614.
• Background Jeffree GM, Price CH, Sissons HA. The metastatic patterns of osteosarcoma. Br J Cancer. 1975 Jul;32(1):87-107. doi: 10.1038/bjc.1975.136.
• Background Weeden S, Grimer RJ, Cannon SR, Taminiau AH, Uscinska BM; European Osteosarcoma Intergroup. The effect of local recurrence on survival in resected osteosarcoma. Eur J Cancer. 2001 Jan;37(1):39-46. doi: 10.1016/s0959-8049(00)00362-2.
• Background Lucidarme N, Valteau-Couanet D, Oberlin O, Couanet D, Kalifa C, Beaujean F, Lapierre V, Hartmann O. Phase II study of high-dose thiotepa and hematopoietic stem cell transplantation in children with solid tumors. Bone Marrow Transplant. 1998 Sep;22(6):535-40. doi: 10.1038/sj.bmt.1701395.
• Background Hagen B, Walseth F, Walstad RA, Iversen T, Nilsen OG. Single and repeated dose pharmacokinetics of thio-TEPA in patients treated for ovarian carcinoma. Cancer Chemother Pharmacol. 1987;19(2):143-8. doi: 10.1007/BF00254567.
• Background Hart RD, Perloff M, Holland JF. One-day VATH (vinblastine, Adriamycin, thiotepa, and Halotestin) therapy for advanced breast cancer refractory to chemotherapy. Cancer. 1981 Oct 1;48(7):1522-7. doi: 10.1002/1097-0142(19811001)48:73.0.co;2-g.
• Background Heideman RL, Cole DE, Balis F, Sato J, Reaman GH, Packer RJ, Singher LJ, Ettinger LJ, Gillespie A, Sam J, et al. Phase I and pharmacokinetic evaluation of thiotepa in the cerebrospinal fluid and plasma of pediatric patients: evidence for dose-dependent plasma clearance of thiotepa. Cancer Res. 1989 Feb 1;49(3):736-41.
• Background Lazarus HM, Reed MD, Spitzer TR, Rabaa MS, Blumer JL. High-dose i.v. thiotepa and cryopreserved autologous bone marrow transplantation for therapy of refractory cancer. Cancer Treat Rep. 1987 Jul-Aug;71(7-8):689-95.
• Background Kletzel M, Kearns GL, Wells TG, Thompson HC Jr. Pharmacokinetics of high dose thiotepa in children undergoing autologous bone marrow transplantation. Bone Marrow Transplant. 1992 Aug;10(2):171-5.
• Background Kalifa C, Hartmann O, Demeocq F, Vassal G, Couanet D, Terrier-Lacombe MJ, Valteau D, Brugieres L, Lemerle J. High-dose busulfan and thiotepa with autologous bone marrow transplantation in childhood malignant brain tumors: a phase II study. Bone Marrow Transplant. 1992 Apr;9(4):227-33.
• Background Finlay JL, Goldman S, Wong MC, Cairo M, Garvin J, August C, Cohen BH, Stanley P, Zimmerman RA, Bostrom B, Geyer JR, Harris RE, Sanders J, Yates AJ, Boyett JM, Packer RJ. Pilot study of high-dose thiotepa and etoposide with autologous bone marrow rescue in children and young adults with recurrent CNS tumors. The Children's Cancer Group. J Clin Oncol. 1996 Sep;14(9):2495-503. doi: 10.1200/JCO.1996.14.9.2495.
• Background Entz-Werle N, Stoetzel C, Berard-Marec P, Kalifa C, Brugiere L, Pacquement H, Schmitt C, Tabone MD, Gentet JC, Quillet R, Oudet P, Lutz P, Babin-Boilletot A, Gaub MP, Perrin-Schmitt F. Frequent genomic abnormalities at TWIST in human pediatric osteosarcomas. Int J Cancer. 2005 Nov 10;117(3):349-55. doi: 10.1002/ijc.21068.
• Background Bertolini F, Mancuso P, Shaked Y, Kerbel RS. Molecular and cellular biomarkers for angiogenesis in clinical oncology. Drug Discov Today. 2007 Oct;12(19-20):806-12. doi: 10.1016/j.drudis.2007.08.011. Epub 2007 Sep 27.
• Background Oliveira ID, Petrilli AS, Tavela MH, Zago MA, de Toledo SR. TNF-alpha, TNF-beta, IL-6, IL-10, PECAM-1 and the MPO inflammatory gene polymorphisms in osteosarcoma. J Pediatr Hematol Oncol. 2007 May;29(5):293-7. doi: 10.1097/MPH.0b013e3180587e69.
• Background Nardin A, Lefebvre ML, Labroquere K, Faure O, Abastado JP. Liposomal muramyl tripeptide phosphatidylethanolamine: Targeting and activating macrophages for adjuvant treatment of osteosarcoma. Curr Cancer Drug Targets. 2006 Mar;6(2):123-33. doi: 10.2174/156800906776056473.
• Background Entz-Werle N, Schneider A, Kalifa C, Voegeli AC, Tabone MD, Marec-Berard P, Marcellin L, Pacquement H, Terrier P, Boutard P, Meyer N, Gaub MP, Lutz P, Babin A, Oudet P. Genetic alterations in primary osteosarcoma from 54 children and adolescents by targeted allelotyping. Br J Cancer. 2003 Jun 16;88(12):1925-31. doi: 10.1038/sj.bjc.6600968.
• Background Entz-Werle N, Marcellin L, Gaub MP, Guerin E, Schneider A, Berard-Marec P, Kalifa C, Brugiere L, Pacquement H, Schmitt C, Tabone MD, Jeanne-Pasquier C, Terrier P, Dijoud F, Oudet P, Lutz P, Babin-Boilletot A. Prognostic significance of allelic imbalance at the c-kit gene locus and c-kit overexpression by immunohistochemistry in pediatric osteosarcomas. J Clin Oncol. 2005 Apr 1;23(10):2248-55. doi: 10.1200/JCO.2005.03.119.
• Background Freedman LS. Tables of the number of patients required in clinical trials using the logrank test. Stat Med. 1982 Apr-Jun;1(2):121-9. doi: 10.1002/sim.4780010204.
• Background Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin Trials. 1996 Aug;17(4):343-6. doi: 10.1016/0197-2456(96)00075-x. No abstract available.
• Background Rialland F.Treatment and outcome of relapsed osteosarcoma:experience of the societe française des cancers de l'enfant.(in press). 2008. Ref type:in press
• Background Sutow WW, Herson J, Perez C. Survival after metastasis in osteosarcoma. Natl Cancer Inst Monogr. 1981 Apr;(56):227-31.
• Background Gelderblom H, Jinks RC, Sydes M, Bramwell VH, van Glabbeke M, Grimer RJ, Hogendoorn PC, McTiernan A, Lewis IJ, Nooij MA, Taminiau AH, Whelan J; European Osteosarcoma Intergroup. Survival after recurrent osteosarcoma: data from 3 European Osteosarcoma Intergroup (EOI) randomized controlled trials. Eur J Cancer. 2011 Apr;47(6):895-902. doi: 10.1016/j.ejca.2010.11.036. Epub 2011 Jan 6.
• Background Leary SE, Wozniak AW, Billups CA, Wu J, McPherson V, Neel MD, Rao BN, Daw NC. Survival of pediatric patients after relapsed osteosarcoma: the St. Jude Children's Research Hospital experience. Cancer. 2013 Jul 15;119(14):2645-53. doi: 10.1002/cncr.28111. Epub 2013 Apr 26.
• Background Beron G, Euler A, winkley K.pulmonary metastase from osteogenic sarcoma: Complete resection and effective chemotherapy contributing to improved prognosis.Eur Paediatr Haematol Oncol 1985; 2:77-85
• Background Kaplan EL MP.Nonparametric estimation from incomplete observations.J Am Stat Assoc 1958

Drugs

Indications