Abstract
Osteosarcoma was initially resistant to chemotherapy that worked for Ewing sarcoma and rhabdomyosarcoma as well as other chemotherapeutic agents available in the 1960s. In the early 1970s, responses of osteosarcoma to adriamycin were reported, and at about the same time, so were responses of osteosarcoma to high-dose methotrexate. These agents were introduced into adjuvant therapy due to the dire prognosis associated with apparently localized osteosarcoma. After initial questions regarding the role of chemotherapy delayed its uniform acceptance, there is now general agreement that chemotherapy is primarily responsible for the cure of patients with osteosarcoma when combined with surgical elimination of the primary tumor. Advances with combination chemotherapy later adding cisplatin and ifosfamide have improved ultimate survival. The history of the development of effective chemotherapy combinations at Memorial Sloan Kettering Cancer Center, UT MD Anderson Cancer Center, and the Rizzoli Institute are highlighted, and recent large cooperative group studies are reviewed in the context of those findings.
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References
Antman KH, Ryan L, Elias A, Sherman D, Grier HE (1989) Response to ifosfamide and mesna: 124 previously treated patients with metastatic or unresectable sarcoma. J Clin Oncol 7:126–131
Ayala A, Mackay B, Jaffe N, Sutow W, Benjamin R, Murray J (1980) Osteosarcoma: the pathological study of specimens from en bloc resection in patients receiving preoperative chemotherapy. In: van Eys J, Sullivan MP (eds) Status of curability of childhood cancers. Raven Press, New York, pp 127–144
Ayala A, Raymond A, Jaffe N (1984) The pathologist’s role in the diagnosis and treatment of osteosarcoma in children. Hum Pathol 15:258–266
Bacci G, Briccoli A, Ferrari S, Longhi A, Mercuri M, Capanna R, Donati D, Lari S, Forni C, DePaolis M (2001) Neoadjuvant chemotherapy for osteosarcoma of the extremity: long-term results of the Rizzoli’s 4th protocol. Eur J Cancer 37(16):2030–2039
Bacci G, Campanacci M, Picci P, Pagani P (1979) Adjuvant multiple drug chemotherapy for osteosarcoma of the extremity: a 6 year report. Tumori 65(5):587–600
Bacci G, Ferrari S, Bertoni F, Ruggieri P, Picci P, Longhi A, Casadei R, Fabbri N, Forni C, Versari M, Campanacci M (2000) Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the Istituto Ortopedico Rizzoli according to the Istituto Ortopedico Rizzoli/Osteosarcoma-2 protocol: an updated report. J Clin Oncol 18(24):4016–4027
Bacci G, Loro L, Longhi A, Bertoni F, Bacchini P, Versari M, Picci P, Serra M (2006) No correlation between methotrexate serum level and histologic response in the pre-operative treatment of extremity osteosarcoma. Anti-Cancer Drugs 17(4):411–415
Bacci G, Picci P, Ferrari S, Ruggieri P, Casadei R, Tienghi A, Prever ABD, Gherlinzoni F, Mercuri M, Monti C (1993) 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 72(11):3227–3238
Bacci G, Picci P, Ruggieri P, Mercuri M, Avella M, Capanna R, Brach Del Prever A, Mancini A, Gherlinzoni F, Padovani G, Leonessa C, Biagini R, Ferraro A, Ferruzzi A, Cazzola A, Manfrini M, Campanacci M (1990) Primary chemotherapy and delayed surgery (neoadjuvant chemotherapy) for osteosarcoma of the extremities the istituto rizzoli experience in 127 patients treated preoperatively with intravenous methotrexate (high versus moderate doses) and intraarterial cisplatin. Cancer 65(11):2539–2553
Bacci G, Picci P, Gherlinzoni F, Van Horn JR, Orlandi M, Normand AR, Manfrini M, Pignatti G, Campanacci M (1986) Neoadjuvant chemotherapy for high grade osteosarcoma of the extremities: is a good response to preoperative treatment an indication to reduce postoperative chemotherapy? Chemioterapia 5(2):140–143
Bacci G, Ruggieri P, Picci P, Mercuri M, Ferraro A, Tella G, Ferrari S, Bertoni F, Comandone A (1996) Intra-arterial versus intravenous Cisplatinum (in addition to systemic Adriamycin and high dose methotrexate) in the neoadjuvant treatment of osteosarcoma of the extremities. Results of a randomized study. J Chemother 8(1):70–81
Baum ES, Gaynon P, Greenberg L, Krivit W, Hammond D (1979) Phase II study of cis-dichlorodiammineplatinum(II) in childhood osteosarcoma: children’s cancer study group report. Cancer Treat Rep 63(9–10):1621–1627
Benjamin R (1989) Regional chemotherapy for osteosarcoma. Semin Oncol 16:323–327
Benjamin R, Murray J, Carrasco C, Raymond A, Chawla S, Wallace S, Ayala A, Papadopoulos N, Plager C, Romsdahl M (1984) Preoperative chemotherapy for osteosarcoma: a treatment approach facilitating limb salvage with major prognostic implications. In: Jones S, Salmon S (eds) Adjuvant therapy of cancer IV. Grune & Stratton, Orlando, pp 601–610
Benjamin RS, Legha SS, Patel SR, Nicaise C (1993) Single-agent ifosfamide studies in sarcomas of soft tissue and bone: the M. D. Anderson experience. Cancer Chemother Pharmacol 31(Suppl 2):S174–S179
Benjamin RS, Patel SR (2010) Pediatric and adult osteosarcoma: comparisons and contrasts in presentation and therapy. In: Jaffe N, Bruland OS, Bielack S (eds) Pediatric and adolescent osteosarcoma. Springer US, Boston, pp 355–363
Bielack SS, Smeland S, Whelan JS, Marina N, Jovic G, Hook JM, Krailo MD, Gebhardt M, Pápai Z, Meyer J, Nadel H, Randall RL, Deffenbaugh C, Nagarajan R, Brennan B, Letson GD, Teot LA, Goorin A, Baumhoer D, Kager L, Werner M, Lau CC, Hall KS, Gelderblom H, Meyers P, Gorlick R, Windhager R, Helmke K, Eriksson M, Hoogerbrugge PM, Schomberg P, Tunn P-U, Kühne T, Jürgens H, van den Berg H, Böhling T, Picton S, Renard M, Reichardt P, Gerss J, Butterfass-Bahloul T, Morris C, Hogendoorn PCW, Seddon B, Calaminus G, Michelagnoli M, Dhooge C, Sydes MR, Bernstein M (2015) Methotrexate, Doxorubicin, and Cisplatin (MAP) plus maintenance pegylated interferon alfa-2b versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative MAP: first results of the EURAMOS-1 good response randomized controlled trial. J Clin Oncol 33(20):2279–2287
Cade S (1955) Osteogenic sarcoma; a study based on 133 patients. J R Coll Surg Edinb 1(2):79–111
Calvo D, Patt Y, Wallace S, Chuang V, Benjamin R, Pritchard J, Hersh E, Body G, Mavligit G (1980) Phase I-II trial of percutaneous intra-arterial cis-diamminedichloro platinum (II) for regionally confined malignancy. Cancer 45:1278–1283
Campanacci M, Bacci G, Bertoni F, Picci P, Minutillo A, Franceschi C (1981) The treatment of osteosarcoma of the extremities: twenty years’ experience at the Instituto Ortopedico Rizzoli. Cancer 48:1569–1581
Chary KK, Higby DJ, Henderson ES, Swinerton KD (1977) Phase I study of high-dose cis-dichlorodiammineplatinum(II) with forced diuresis. Cancer Treat Rep 61(3):367–370
Chuang V, Wallace S, Benjamin R, Jaffe N, Ayala A, Murray J, Zornoza J, Patt Y, Mavligit G, Charnsangavej C, Soo C (1981) The therapy of osteosarcoma by intra-arterial cis-platinum and limb preservation. Cardiovasc Intervent Radiol 4:229–235
Cortes E, Holland J, Wang J, Sinks L, Blom J, Senn H, A. Bank, Glidewell O (1974) Amputation and adriamycin in osteosarcoma. N Engl J Med 291:998–1000
Cortes EP, Holland JF, Glidewell O (1978) Amputation and adriamycin in primary osteosarcoma: a 5-year report. Cancer Treat Rep 62(2):271–277
Delepine N, Delepine G, Cornille H, Brion F, Arnaud P, Desbois JC (1995) Dose escalation with pharmacokinetics monitoring in methotrexate chemotherapy of osteosarcoma. Anticancer Res 15(2):489–494
Delepine N, Delepine G, Jasmin C, Desbois JC, Cornille H, Mathé G (1988) Importance of age and methotrexate dosage: prognosis in children and young adults with high-grade osteosarcomas. Biomed Pharmacother 42(4):257–262
Delepine N, Desbois JC, Delepine G, Cornille H, Astier A, Alkallaf S (1989) Individualization of the dosage of high-dose methotrexate by assaying plasma concentration. Therapeutic value in osteogenic sarcoma. Bull Cancer 76(8):913–918
Edmonson J, Fleming T, Irvins J, Burgert EJ, Soule E, O'Connell M, Sim FH, Ahmann D (1984) Randomized study of systemic chemotherapy following complete excision of nonosseous sarcomas. J Clin Oncol 2:1390–1396
Eilber F, Giuliano A, Eckardt J, Patterson K, Moseley S, Goodnight J (1987) Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial. J Clin Oncol 5:21–26
Ettinger L, Douglass H, Higby D, Mindell E, Nime F, Ghoorah J, Freeman A (1981) Adjuvant adriamycin and cis-diamminedichloroplatinum (cis-platinum) in primary osteosarcoma. Cancer 47:248–254
Ettinger L, Douglass H, Mindell E, Sinks L, Tebbi C, Risseeuw D, Freeman A (1986) Adjuvant adriamycin and cisplatin in newly diagnosed, nonmetastatic osteosarcoma of the extremity. J Clin Oncol 4:353–362
Ferrari S, Palmerini E, Staals EL, Mercuri M, Franco B, Picci P, Bacci G (2010) The treatment of nonmetastatic high grade osteosarcoma of the extremity: review of the Italian Rizzoli experience. Impact on the future. In: Jaffe N, Bruland OS, Bielack S (eds) Pediatric and adolescent osteosarcoma. Springer US, Boston, pp 275–287
Ferrari S, Smeland S, Mercuri M, Bertoni F, Longhi A, Ruggieri P, Alvegard TA, Picci P, Capanna R, Bernini G, Müller C, Tienghi A, Wiebe T, Comandone A, Böhling T, Del Prever AB, Brosjö O, Bacci G, Sæter G (2005) Neoadjuvant chemotherapy with high-dose ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups. J Clin Oncol 23(34):8845–8852
Gherlinzoni F, Picci P, Bacci G, Campanacci D (1992) Limb sparing versus amputation in osteosarcoma: correlation between local control, surgical margins and tumor necrosis: Istituto Rizzoli experience. Ann Oncol 3(suppl_2):S23–S27
Huvos A, Rosen G, Marcove R (1977) Primary osteogenic sarcoma: pathologic aspect in 20 patients treated with chemotherapy, en bloc resection, and prosthetic bone replacement. Arch Pathol Lab Med 101:14–18
Jaffe N (1972) Recent advances in the chemotherapy of metastatic osteogenic sarcoma. Cancer 30(6):1627–1631
Jaffe N, Frei E, Traggis D, Bisop Y (1974) Adjuvant methotrexate and citrovorum-factor treatment of osteogenic sarcoma. N Engl J Med 291:994–997
Jaffe N, Frei E, Watts H, Traggis D (1978) High-dose methotrexate in osteogenic sarcoma: a 5-year experience. Cancer Treat Rep 62:259–264
Jaffe N, Knapp J, Chuang V, Wallace S, Ayala A, Murray J, Cangir A, Wang A, Benjamin R (1983) Osteosarcoma: intra-aterial treatment of the primary tumor with cis-diamminedichloroplatinum II (CDP). Angiographic, pathologic, and pharmacologic studies. Cancer 51:402–407
Jaffe N, Robertson R, Ayala A, Wallace S, Chuang V, Anzai T, Cangir A, Wang Y-M, Chen T (1985) Comparison of intra-arterial cis-diamminedichloroplatinum II with high-dose methotrexate and citrovorum factor rescue in the treatment of primary osteosarcoma. J Clin Oncol 3:1101–1104
Kamalakar P, Freeman AI, Higby DJ, Wallace HJ Jr, Sinks LF (1977) Clinical response and toxicity with cis-dichlorodiammineplatinum(II) in children. Cancer Treat Rep 61(5):835–839
Lee ES, Mackenzie DH (1964) Osteosarcoma. A study of the value of preoperative megavoltage radiotherapy. Br J Surg 51(4):252–274
Link M, Goorin A, Miser A, Green A, Pratt C, Belasco J, Pritchard J, Malpas J, Baker A, Kirkpatrick J, Ayala A, Shuster J, Abelson H, Simone J, Vietti T (1986) The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 314:1600–1602
Marcove RC, Miké V, Hajek JV, Levin AG, Hutter RV (1970) Osteogenic sarcoma under the age of twenty-one. A review of one hundred and forty-five operative cases. J Bone Joint Surg Am 52(3):411–423
Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, Hook JM, Arndt C, van den Berg H, Brennan B, Brichard B, Brown KLB, Butterfass-Bahloul T, Calaminus G, Daldrup-Link HE, Eriksson M, Gebhardt MC, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier HE, Hale JP, Hall KS, Hardes J, Hawkins DS, Helmke K, Hogendoorn PCW, Isakoff MS, Janeway KA, Jürgens H, Kager L, Kühne T, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Meyers PA, Mottl H, Nathrath M, Papai Z, Randall RL, Reichardt P, Renard M, Safwat AA, Schwartz CL, Stevens MCG, Strauss SJ, Teot L, Werner M, Sydes MR, Whelan JS (2016) Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. Lancet Oncol 17(10):1396–1408
Marti C, Kroner T, Remagen U (1985) High dose ifosfamide in advanced osteosarcoma. Cancer Treat Rep 69:115–117
Mavligit G, Benjamin R, Patt Y, Jaffe N, Chuang V, Wallace S, Murray J, Ayala A, Johnston S, Hersh E, Calvo D (1981) Intra-arterial cis-platinum for patients with inoperable skeletal tumors. Cancer 48:1–4
Meyers PA, Schwartz CL, Krailo M, Kleinerman ES, Betcher D, Bernstein ML, Conrad E, Ferguson W, Gebhardt M, Goorin AM, Harris MB, Healey J, Huvos A, Link M, Montebello J, Nadel H, Nieder M, Sato J, Siegal G, Weiner M, Wells R, Wold L, Womer R, Grier H (2005) Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol 23(9):2004–2011
Meyers PA, Schwartz CL, Krailo MD, Healey JH, Bernstein ML, Betcher D, Ferguson WS, Gebhardt MC, Goorin AM, Harris M, Kleinerman E, Link MP, Nadel H, Nieder M, Siegal GP, Weiner MA, Wells RJ, Womer RB, Grier HE (2008) Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival—a report from the Children’s Oncology Group. J Clin Oncol 26(4):633–638
Mosende C, Gutierrez M, Caparros B, Rosen G (1977) Combination chemotherapy with bleomycin, cyclophosphamide and dactinomycin for the treatment of osteogenic sarcoma. Cancer 40:2779–2786
Murphy W, Benjamin R, Eyre H, Thigpen T, Whitecar J, Uribe-Bkotero G, Baker L, Gehan E, Gottlieb J (1977) Adjuvant chemotherapy in osteosarcoma of adults. A Southwest Oncology Group Study. In: Salmon S, Jones S (eds) Adjuvant therapy of cancer. North Holland Press, Amsterdam
Ochs J, Freeman A, Douglass H Jr, Higby D, Mindell E, Sinks L (1978) Cis-dichlorodiammine-platinum (II) in advanced osteogenic sarcoma. Cancer Treat Rep 62:239–245
Patel S, Vadhan-Raj S, Papadopoulos N, Plager C, Burgess M, Hays C, Benjamin R (1997) High-dose ifosfamide in bone and soft tissue sarcomas: results of phase II and pilot studies – dose response and schedule dependence. J Clin Oncol 15:2378–2384
Picci P, Capanna R, Bacci G, Mercuri M, Biagini R, Ruggieri P, Ferraro A, De Cristofaro R, Ferruzzi A, Campanacci M (1990) Margins, necrosis and local recurrence after conservative surgery in osteosarcoma. Chir Organi Mov 75:82–85
Platt H, Cade S, Baker SL (1952) Symposium on sarcoma of bone. Proc R Soc Med 45(5):265–265
Pratt CB, Horowitz ME, Meyer WH, Etcubanas E, Thompson EI, Douglass EC, Wilimas JA, Hayes FA, Green AA (1987) Phase II trial of ifosfamide in children with malignant solid tumors. Cancer Treat Rep 71(2):131–135
Pritchard J, Mavligit G, Benjamin R, Patt Y, Calvo D, Hall S, Bodey G, Wallace S (1979) Regression of regionally confined melanoma with intra-arterial cis-dichloro-diammineplatinum (II). Cancer Treat Rep 63:555–558
Raymond A, Chawla S, Carrasco C, Ayala A, Fainning C, Grice B, Armen T, Plager C, Papadopoulos N, Edeiken J, Wallace S, Jaffe N, Murray J, Benjamin R (1987) Osteosarcoma chemotherapy effect: a prognostic factor. Sem Diag Path 4:212–236
Rosen G, Caparros B, Huvos AG, Kosloff C, Nirenberg A, Cacavio A, Marcove RC, Lane JM, Mehta B, Urban C (1982) Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer 49(6):1221–1230
Rosen G, Marcove RC, Caparros B, Nirenberg A, Kosloff C, Huvos AG (1979) Primary osteogenic sarcoma. The rationale for preoperative chemotherapy and delayed surgery. Cancer 43(6):2163–2177
Rosen G, Murphy M, Huvos A, Guttierrez M, Marcove R (1976) Chemotherapy, en bloc resection, and prosthetic bone replacement in the treatment of osteogenic sarcoma. Cancer 37:1–11
Rosen G, Suwansirikul S, Kwon C, Tan C, Wu SJ, Beattie EJ Jr, Murphy ML (1974) High-dose methotrexate with citrovorum factor rescue and adriamycin in childhood osteogenic sarcoma. Cancer 33(4):1151–1163
Rosen G et al (1990) The successful management of metastatic osteogenic sarcoma: a model for the treatment of primary osteogenic sarcoma. In: Oosterom ATV, Muggia FM, Cleton FJ (eds) Therapeutic progress in ovarian cancer, testicular cancer and the sarcomas. Leiden University Press, Hingham, pp 244–265
Stewart D, Benjamin R, Zimmerman S, Caprioli R, Wallace S, Chuang V, Calvo D 3rd, Samuels M, Bonura J, Loo T (1983) Clinical pharmacology of intra-arterial cis-diamminedichloroplatinum(II). Cancer Res 43:917–920
Sutow W, Gehan E, Dyment P (1978) Multidrug adjuvant chemotherapy for osteosarcoma: interim report of the Southwest Oncology Group studies. Cancer Treat Rep 62:265
Sutow W, Sullivan M, Fernbach D, Cangir A, George S (1975) Adjuvent chemotherapy in primary treatment of osteogenic sarcoma. A Southwest Oncology Group study. Cancer 36:1598–1602
Taylor W, Ivins J, Dahlin D, Edmonson J, Pritchard D (1978) Trends and variability in survival from osteosarcoma. Mayo Clin Proc 53:695–700
Taylor W, Ivins J, Pritchard D, Dahlin D, Gilchrist G, Edmonson J (1985) Trends and variability in survival among patients with osteosardoma: a 7-year update. Mayo Clin Proc 60:91–104
Vietti TJ, Nitschke R, Starling KA, van Eys J (1979) Evaluation of cis-dichlorodiammineplatinum(II) in children with advanced malignant diseases: Southwest Oncology Group Studies. Cancer Treat Rep 63(9–10):1611–1614
Wang JJ, Cortes E, Sinks LF, Holland JF (1971) Therapeutic effect and toxicity of adriamycin in patients with neoplastic disease. Cancer 28(4):837–843
Winkler K, Bielack S, Delling G, Salzer-Kuntschik M, Kotz R, Greenshaw C, Jürgens H, Ritter J, Kusnierz-Glaz C, Erttmann R, Gädicke G, Graf N, Ladenstein R, Leyvraz S, Mertens R, Weinel P (1990) Effect of intraarterial versus intravenous cisplatin in addtion to systemic doxorubicin, high-dose methotrexate, and ifosfamide on histologic tumor response in osteosarcoma (study COSS-86). Cancer 66:1703–1710
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Benjamin, R.S. (2020). Adjuvant and Neoadjuvant Chemotherapy for Osteosarcoma: A Historical Perspective. In: Kleinerman, E.S., Gorlick, R. (eds) Current Advances in Osteosarcoma . Advances in Experimental Medicine and Biology, vol 1257. Springer, Cham. https://doi.org/10.1007/978-3-030-43032-0_1
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