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3 38% 26% A) Response to ifosfamide and mesna: 124 previously treated patients with metastatic or unresectable sarcoma 124 (J Clin Oncol 7: , 1989) II 1 2,000mg/m 2 x 4 8g/m % CR 4 PR p= % 1,2 19 performance status p<0.01 p<0.01 WBC 1,000/ul - 3 -

4 49 B) An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas / / / III (J Clin Oncol 11: , 1993) Southwest Oncology Group(SWOG) 60mg/m 2 1,000mg/m 2 60mg/m 2 1,000mg/m 2 7,500mg/m 2 III 10,000mg/m / 170 / / p<0.002 p<0.02 / / 84 7,500mg/m 2 6,000mg/m 2 / 13 / / / European Organization for Research and Treatment of Cancer (EORTC) / CYVADIC / / / III Proc Am Soc Clin Oncol 9: 309, 1990 Eastern Cooperative Oncology Group (ECOG) / III 20% vs. 34%, p<0.03 vs.12 Proc Am Soc Clin Oncol 11: 413, 1992 C) Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: Results of the Italian randomized cooperative trial (J Clin Oncol 19: , 2001) 104 III / / 1-4 -

5 60mg/m 2 x 2 120mg/m 2 1 1,800mg/m 2 x 5 g/m p= p=0.03 / p=0.04 D) Long-term results of the co-operative German-Austrian-Swiss osteosarcoma study group s protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs - - COSS-86 (Ann Oncol 9: , 1998) COSS low-risk 41 high-risk 128 Low-risk 90mg/m 2, 4 12g/m 2, mg/m 2, 4 3 High-risk 90mg/m 2, 12g/m 2, mg/m 2, 6g/m 2, Low-risk High-risk high-risk 3 2 E) Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial II/III (J Clin Oncol 20: , 2002) Pediatric Oncology Group (POG) 1 100mg/m 2 x 500mg/m 2 1 3,500mg/m 2 x 17.5g/m 2 II/III G-CSF 6 5,000/uL CR PR Grade Fanconi 5 2 / - 5 -

6 2 F) Addition of ifosfamide and etoposide to standard chemotherapy for Ewing s sarcoma and primitive neuroectodermal tumor of bone / (N Engl J Med 348: , 2003) / Children s Cancer Group (CCG) Pediatric Oncology Group (POG) 4 1 1,800 mg/m 2 x 9g/m mg/m 2 x 500mg/m 2 III % 34% 58 22% 35% % 61% % 72% p< / (i) Cancer 35: , 1975 Cancer 49: , 1982, J Clin Oncol 10: 5-15, ,800mg/m 2 x 9g/m 2 33 Cancer Treat Rep 69: , (Ann Oncol 9: , 1998) (J Clin Oncol 20: , - 6 -

7 2002) 3 (ii) VAC ,800 mg/m 2 x 9g/m mg/m 2 x 500mg/m 2 94% J Clin Oncol 5: , 1987 III 4 p<0.01 (N Engl J Med 348: , 2003) 1 (iii) 20% 2 II % Hematology and Oncology Clinics of North America 9: , % 12% 13% Hematology and Oncology Clinics of North America 9: , 1995 Cancer 73: , Eastern Cooperative Oncology Group(ECOG) 80mg/m 2 60mg/m 2 7.5g/m 2 20% 34% p=0.03 J Clin Oncol 11: , 1993 European Organization for the Research and Treatment of Cancer (EORTC) 663 III 75mg/m 2 50mg/m 2 5g/m 2 23% 28% J Clin Oncol 13: , 1995 Southwest Oncology Group(SWOG) 60mg/m 2 1,000mg/m 2 60mg/m 2 1,000mg/m 2 7.5g/m 2 III / - 7 -

8 / / p<0.002 p<0.02 (J Clin Oncol 11: , 1993) G-CSF, GM-CSF Ann Oncol 9: , 1998, Am J Clin Oncol 21: , 1998 Cancer 80: , 1997 dose intensity Lancet 350: , III 1 60mg/m 2 x 2 120mg/m 2 1 1,800mg/m 2 x 5 9g/m p=0.04 (J Clin Oncol 19: , 2001) Web ifosfamide, adriamycin 49: , : , 1999 ifosfamide Int J Clin Oncol : 36-40, 1999 Ifosfamide 37:

9 43: , 2000 mesna, adriamycin, ifosfamide, dacarbazine (MAID) 51: , 2000 CYVADACT MAI(ifosfamide-adriamycin ) 52: , : , : , 2003 Ifosfamide, Doxorubicin and Cyclophosfamide Chemotherapy for Advanced Adult Soft Tissue Sarcoma: a Japanese Musculoskeletal Oncology Group Study. Proceedings Am Soc Clin Oncol 22, 825, 2003 acrolein sodium-2-mercapto-ethanesulfonate / (w/w) 60% J Clin Oncol 11: , 1993, J Clin Oncol 15: , 1997, J Clin Oncol 19: , % J Clin Oncol 13: , % J Clin Oncol 11: , %(J Clin Oncol 5: , 1987) 175% Ann Oncol 9: , % g/m 2 J Clin Oncol 11: , 1993, Lancet 348: , 1996, Br J Cancer 82: , 2000 J Clin Oncol 9: , 1991, J Clin Oncol 11: ,

10 Curr Opin Pediatr 7: , 1995 Curr Opin Pediatr 7: , 1995 Med Pediatr Oncol 41: , 2003 performance status (J Clin Oncol 7: , 1989, Hematology and Oncology Clinics of North America 9: , 1995) g/m 2 g/m 2 x 147 3,4 76 3,4 10 3, J Clin Oncol 13: , mg/m 2 g/m 2 1.8g/m 2 x 5 3,4 58 3,4 11 3, (J Clin Oncol 19: , 2001) mg/m g/m 2 3.5g/m 2 x 3,4 85 3,4 44 3, (J Clin Oncol 20: , 2002) G-CSF

11 (i) EORTC 135 II g/m % 1.5g/m 2 Eur J Cancer Clin Oncol 23: , 1987 Antman II 2,000mg/m 2 x 4 g/m 2 21 (J Clin Oncol 7: , 1989) J Clin Oncol 8: , 1990, Cancer Chemother Pharmacol 31: S , 1993, Semin Oncol 23: 22-26, 1996 Le Cesne ~10g/m 2 g/m 2 x 12g/m 2 33 PR 22 J Clin Oncol 13: , 1995 MD Shreyaskumar 14g/m 2 J Clin Oncol 15: , g/m g/m g/m ~10g/m 2 12g/m 2 (ii) 40 75mg/m 2 10g/m Eur J Cancer 26: , 1990, J Clin Oncol 11: 15-21, 1993, J Clin Oncol 11: , 1993, J Chemother 8: , 1996 G-CSF dose intensity Ann Oncol 9: , 1998, Am J Clin Oncol 21: ,

12 90mg/m g/m 2 Souhami RL, ed. Oxford Textbook of Oncology 2 nd ed. p2516 POG 500mg/m g/m 2 II/III 59 CR 10%, PR (J Clin Oncol 20: , 2002) - ~10g/m 2 12g/m 2 14g/m mg/m 2 10g/m 2 G-CSF

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