Objective: This study compared outcomes between doublet (AP) and triplet (IAP) neoadjuvant chemotherapy for nonmetastatic osteosarcoma of the extremity. Methods: A total of 124 patients were enrolled. In the AP group, a doublet regimen of intraarterial cisplatin and intravenous doxorubicin was given to 77 patients from 1991 to 1999. In the IAP group, a triplet regimen of additional intravenous ifosfamide was given to 47 patients from 2000 to 2007. After completion of 3 cycles of chemotherapy, patients underwent surgery. We assessed tumor response according to pathologic tumor necrosis, and treated patients with further adjuvant chemotherapy. Results: The overall pathologic response was excellent with more than 90% tumor necrosis in 74.8% of patients. Total necrosis of tumors was also found in 46 (37.4%) patients. There was no difference between the 2 groups in pathologic response (75.3 vs. 72.3%; p = 0.52) or other clinicopathologic parameters. There was no difference between the 2 groups in recurrence rate (31.2 vs. 31.9%; p = 0.17) or lung metastasis (28.6 vs. 23.4%; p = 0.53). Moreover, there were no statistical differences in median disease-free survival and overall survival between the groups. There was more hematologic toxicity in the IAP group (neutropenia, p = 0.002; thrombocytopenia, p = 0.001; febrile neutropenia, p < 0.001). Conclusions: The addition of ifosfamide to doxorubicin and cisplatin in neoadjuvant chemotherapy did not show improved outcomes in this study. Further trials are required to elucidate optimal neoadjuvant chemotherapy and effective salvage regimens.

1.
Friedman MA, Carter SK: The therapy of osteogenic sarcoma: Current status and thoughts for the future. J Surg Oncol 1972;4:482–510.
2.
Link MP, Goorin AM, Miser AW, Green AA, Pratt CB, Belasco JB, Pritchard J, Malpas JS, Baker AR, Kirkpatrick JA, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 1986;314:1600–1606.
3.
Eilber F, Giuliano A, Eckardt J, Patterson K, Moseley S, Goodnight J: Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial. J Clin Oncol 1987;5:21–26.
4.
Rosen G, Marcove RC, Caparros B, Nirenberg A, Kosloff C, Huvos AG: Primary osteogenic sarcoma: the rationale for preoperative chemotherapy and delayed surgery. Cancer 1979;43:2163–2177.
5.
Ferrari S, Palmerini E: Adjuvant and neoadjuvant combination chemotherapy for osteogenic sarcoma. Curr Opin Oncol 2007;19:341–346.
6.
Chou AJ, Gorlick R: Chemotherapy resistance in osteosarcoma: current challenges and future directions. Expert Rev Anticancer Ther 2006;6:1075–1085.
7.
Tunn PU, Reichardt P: Chemotherapy for osteosarcoma without high-dose methotrexate: a 12-year follow-up on 53 patients. Onkologie 2007;30:228–232.
8.
van Dalen EC, de Camargo B: Methotrexate for high-grade osteosarcoma in children and young adults. Cochrane Database Syst Rev 2009:CD006325.
9.
Enneking WF, Spanier SS, Goodman MA: A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop Relat Res 1980;153:106–120.
10.
Pratt CB, Horowitz ME, Meyer WH, Etcubanas E, Thompson EI, Douglass EC, Wilimas JA, Hayes FA, Green AA: Phase II trial of ifosfamide in children with malignant solid tumors. Cancer Treat Rep 1987;71:131–135.
11.
Goorin AM, Harris MB, Bernstein M, Ferguson W, Devidas M, Siegal GP, Gebhardt MC, Schwartz CL, Link M, Grier HE: Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial. J Clin Oncol 2002;20:426–433.
12.
Bacci G, Lari S: Current treatment of high grade osteosarcoma of the extremity: review. J Chemother 2001;13:235–243.
13.
Huvos AG, Rosen G, Marcove RC: Primary osteogenic sarcoma: Pathologic aspects in 20 patients after treatment with chemotherapy en bloc resection, and prosthetic bone replacement. Arch Pathol Lab Med 1977;101:14–18.
14.
Ferguson WS, Goorin AM: Current treatment of osteosarcoma. Cancer Invest 2001;19:292–315.
15.
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;49:1221–1230.
16.
Bielack S, Carrle D, Jost L: Osteosarcoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2008;19(suppl 2):ii94–ii96.
17.
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;350:911–917.
18.
Jaffe N, Knapp J, Chuang VP, Wallace S, Ayala A, Murray J, Cangir A, Wang A, Benjamin RS: Osteosarcoma: Intra-arterial treatment of the primary tumor with cis-diammine-dichloroplatinum II (CDP). Angiographic, pathologic, and pharmacologic studies. Cancer 1983;51:402–407.
19.
Hugate RR, Wilkins RM, Kelly CM, Madsen W, Hinshaw I, Camozzi AB: Intraarterial chemotherapy for extremity osteosarcoma and MFH in adults. Clin Orthop Relat Res 2008;466:1292–1301.
20.
Choi HS, Kang HJ, Lee JA, Han HH, Park HJ, Yoo ES, Kim WS, Shin HY, Kim IO, Lee SH, Ahn HS, Lee HK: Treatment result of pediatric osteosarcoma with intraarterial cisplatin. J Korean Cancer Assoc 1998;30:169–177.
21.
Jaffe N, Prudich J, Knapp J, Wang YM, Bowman R, Cangir A, Ayala A, Chuang V, Wallace S: Treatment of primary osteosarcoma with intra-arterial and intravenous high-dose methotrexate. J Clin Oncol 1983;1:428–431.
22.
Rha SY, Gong SJ, Chung HC, Shim KY, Ahn JB, Yoo NC, Chung HC, Kim JH, Roh HK, Min JS, Kim BS, Shin KH, Yang WI, Lee CI: The efficacy of pre-operative chemotherapy with intra-arterial cisplatin and intravenous adriamycin for high grade osteosarcoma. J Korean Cancer Assoc 1999;31:134–143.
23.
Sohn JH, Rha SY, Jeung HC, Shin HJ, Goo YS, Chung HC, Yang WI, Hahn SB, Shin KH, Min JS, Kim BS, Roh JK, Jang WI: Efficacy of pre- and postoperative chemotherapy in patients with osteosarcoma of the extremities. Cancer Res Treat 2001;33:520–526.
24.
Benjamin RS: Regional chemotherapy for osteosarcoma. Semin Oncol 1989;16:323–327.
25.
Dirix LY, Van Oosterom AT: The role of ifosfamide in the treatment of sarcomas. Semin Oncol 1989;16:39–45.
26.
Marti C, Kroner T, Remagen W, Berchtold W, Cserhati M, Varini M: High-dose ifosfamide in advanced osteosarcoma. Cancer Treat Rep 1985;69:115–117.
27.
Patel SR, Vadhan-Raj S, Papadopolous N, Plager C, Burgess MA, Hays C, Benjamin RS: High-dose ifosfamide in bone and soft tissue sarcomas: results of phase II and pilot studies – dose-response and schedule dependence. J Clin Oncol 1997;15:2378–2384.
28.
Marina N, Gebhardt M, Teot L, Gorlick R: Biology and therapeutic advances for pediatric osteosarcoma. Oncologist 2004;9:422–441.
29.
Huvos AG, Rosen G, Bretsky SS, Butler A: Telangiectatic osteogenic sarcoma: a clinicopathologic study of 124 patients. Cancer 1982;49:1679–1689.
30.
Bacci G, Picci P, Ferrari S, Ruggieri P, Casadei R, Tienghi A, Brach del Prever A, Gherlinzoni F, Mercuri M, Monti C: Primary chemotherapy and delayed surgery for nonmetastatic osteosarcoma of the extremities. Results in 164 patients preoperatively treated with high doses of methotrexate followed by cisplatin and doxorubicin. Cancer 1993;72:3227–3238.
31.
Salzer-Kuntschik M, Delling G, Beron G, Sigmund R: Morphological grades of regression in osteosarcoma after polychemotherapy – study COSS 80. J Cancer Res Clin Oncol 1983;106(suppl):21–24.
32.
Kim MS, Lee SY, Lee TR, Cho WH, Song WS, Koh JS, Lee JA, Yoo JY, Jeon DG: Prognostic nomogram for predicting the 5-year probability of developing metastasis after neo-adjuvant chemotherapy and definitive surgery for AJCC stage II extremity osteosarcoma. Ann Oncol 2009;20:955–960.
33.
Picci P, Bacci G, Campanacci M, Gasparini M, Pilotti S, Cerasoli S, Bertoni F, Guerra A, Capanna R, Albisinni U: Histologic evaluation of necrosis in osteosarcoma induced by chemotherapy. Regional mapping of viable and nonviable tumor. Cancer 1985;56:1515–1521.
34.
Winkler K, Beron G, Delling G, Heise U, Kabisch H, Purfürst C, Berger J, Ritter J, Jürgens H, Gerein V: Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol 1988;6:329–337.
35.
Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, Kotz R, Salzer-Kuntschik M, Werner M, Winkelmann W, Zoubek A, Jürgens 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;20:776–790.
36.
Ferrari S, Bertoni F, Mercuri M, Picci P, Giacomini S, Longhi A, Bacci G: Predictive factors of disease-free survival for non-metastatic osteosarcoma of the extremity: an analysis of 300 patients treated at the Rizzoli Institute. Ann Oncol 2001;12:1145–1150.
37.
Bacci G, Longhi A, Versari M, Mercuri M, Briccoli A, Picci P: Prognostic factors for osteosarcoma of the extremity treated with neoadjuvant chemotherapy: 15-year experience in 789 patients treated at a single institution. Cancer 2006;106:1154–1161.
38.
Lewis IJ, Nooij MA, Whelan J, Sydes MR, Grimer R, Hogendoorn PC, Memon MA, Weeden S, Uscinska BM, van Glabbeke M, Kirkpatrick A, Hauben EI, Craft AW, Taminiau AH: Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst 2007;99:112–128.
39.
Basaran M, Bavbek ES, Saglam S, Eralp L, Sakar B, Atalar AC, Bilgic B, Ozger H, Onat H: A phase II study of cisplatin, ifosfamide and epirubicin combination chemotherapy in adults with nonmetastatic and extremity osteosarcomas. Oncology 2007;72:255–260.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.