Perspectives of the Role of Chemotherapy in the Management of Osteosarcoma

Jyoti Bajpai, Norman Jaffe

Children’s Cancer Hospital, University of Texas M.D. Anderson Cancer Center, Houston, USA..
Department of Medical Oncology, Tata Memorial Cancer Center, Mumbai, India.

DOI: 10.4236/jct.2012.36154                

Abstract

Background: Multimodality management of osteosarcoma has significantly improved the 5-year-survival rate for localized disease over the past 40 years: from 5% - 10% (in historical controls) to 65% - 75% and 20% - 30% in metastatic disease. These results were achieved with doxorubicin, cisplatin, high-dose methotrexate and ifosfamide (or cyclophosphamide). In the absence of new and effective agents the results have remained stationary for at least the past 30 years. No standard second line therapy exists for patients who relapse. In these circumstances surgery when feasible, constitutes the main therapeutic option. Questions/Purposes: To understand the present approach to therapy and determine the possibilities for improvement a review of the chemotherapeutic agents currently deployed in the treatment of Osteosarcoma was undertaken. Methods: The review focused on the results achieved with the evolution of therapy following the discovery of effective chemotherapeutic agents. Results: There was an improvement in survival during the first decade following the introduction of effective chemotherapy and limb salvage replaced amputation in the majority of patients. Attempts to rescue pulmonary metastases patients with surgical intervention were also enhanced but produced only minor improvement in survival. An international collaborative study, EURAMOS has been launched to investigate the utility of neoadjuvant chemotherapeutic agents in improving survival based upon their efficacy in the treatment of the primary tumor. Conclusions: New agents and or new strategies are urgently required to improve the outcome in Osteosarcoma.

Keywords

Osteosarcoma; Chemotherapy; Prognostic-Parameters

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	P. A. Meyers, G. Heller, J. Healey, A. Huvos, J. Lane and R. Marcove, “Chemotherapy for Nonmetastatic Osteogenicsarcoma: The Memorial Sloan-Kettering Experience,” Journal of Clinical Oncology, Vol. 10, 1992, pp. 5-15.
[2]	G. Bonadonna, S. Monfardini, M. De Lena, F. Fossati-Bellani and G. Beretta, “Phase I and Preliminary Phase II Evaluation of Adriamycin (NSC/123127),”Cancer Research, Vol. 30, 1970, pp. 2527-2582.
[3]	N. Jaffe, “Recent Advances in the Chemotherapy of Osteogenicsarcoma,” Cancer, Vol. 30, 1972, pp. 1627-1631. doi:10.1002/1097-0142(197212)30:6<1627::AID-CNCR2820300631>3.0.CO;2-H
[4]	W. W. Sutow, “Combination Chemotherapy with Adriamycin (NSC-123127) in Primary Treatment of Osteogenicsarcoma (Part III),” Cancer Chemotherapy Reports, Vol. 6, 1975, pp. 315-317.
[5]	W. W. Sutow, E. A. Gehan and P. C. Dyment, “Multi-Drug Adjuvant Chemotherapy in Osteosarcoma. Interim Report of the Southwest Oncology Group Studies,” Cancer Chemotherapy Reports, Vol. 62, No. 2, 1978, pp. 265-269.
[6]	J. Herson, W. W. Sutow, K. Elder, T. J. Vietti, J. M. Falletta and W. M. Crist, “Adjuvant Chemotherapy in Non Metastatic Osteosarcoma: A Southwest Oncology Group Study,” Medical and Pediatric Oncology, Vol. 8, No. 4, 1980, pp. 343-352. doi:10.1002/mpo.2950080405
[7]	T. Philip, C. Iliescu, M. C. Demaille, H. Pacquement, J. C. Gentet and I. Krakowski, “High-Dose Methotrexate and HELP [Holoxan (Ifosfamide), Eldesine (Vindesine), Platinum]—Doxorubicin in Non-Metastatic Osteosarcoma of the Extremity: A French Multicentre Pilot Study,” Annals of Oncology, Vol. 10, No. 9, 1999, pp. 1065-1071. doi:10.1023/A:1008395126800
[8]	N. Jaffe, “Osteosarcoma: Review of the Past, Impact on the Future: The American Experience Pediatric and Adolescent Osteosarcoma,” Cancer Treatment and Research, Vol. 152, 2010, pp. 239-262. doi:10.1007/978-1-4419-0284-9_12
[9]	K. M. Leu, L. J. Ostruszka, D. Shewach, M. Zalupski, V. Sondak and J. S. Biermann, “Laboratory and Clinical Evidence of Synergistic Cytotoxicity of Sequential Treatment with Gemcitabine Followed by Docetaxel in the Treatment of Sarcoma,” Journal of Clinical Oncology, Vol. 22, No. 9, 2004, pp. 1706-1712. doi:10.1200/JCO.2004.08.043
[10]	E. Fox, R. Aplenc, R. Bagatell, M. K. Chuk, E. Dombi and W. Goodspeed, “A Phase 1 Trial and Pharmakinetic Study of Cediranib, an Orally Bioavailable Pan-Vascular Endothelial Growth Factor Receptor Inhibitor, in Children and Adolescents with Refractory Solid Tumors,” Journal of Clinical Oncology, Vol. 28, No. 35, 2010, pp. 5174-5181. doi:10.1200/JCO.2010.30.9674
[11]	G. Rosen, M. L. Murphy, A. G. Huvos, M. Gutierrez and R. C. Marcove, “Chemotherapy, En bloc Resection, and Prosthetic Bone Replacement in the Treatment of Osteogenicsarcoma,” Cancer, Vol. 37, No. 1, 1976, pp. 1-11. doi:10.1002/1097-0142(197601)37:1<1::AID-CNCR2820370102>3.0.CO;2-3
[12]	G. Rosen, R. C. Marcove, B. Caparros, A. Nirenberg, C. Kosloff and A. G. Huvos, “Primary Osteogenicsarcoma: The Rationale for Preoperative Chemotherapy and Delayed Surgery,” Cancer, Vol. 43, No. 6, 1979, pp. 2163-2177. doi:10.1002/1097-0142(197906)43:6<2163::AID-CNCR2820430602>3.0.CO;2-S
[13]	G. Rosen, B. Caparros, A. G. Huvos, C. Kosloff, A. Nirenberg and A. Cacavio, “Preoperative Chemotherapy for Osteogenicsarcoma: Selection of Postoperative Adjuvant Chemotherapy Based on the Response of the Primary Tumor to Preoperative Chemotherapy,” Cancer, Vol. 49, No. 6, 1982, pp. 1221-1230. doi:10.1002/1097-0142(19820315)49:6<1221::AID-CNCR2820490625>3.0.CO;2-E
[14]	A. G. Huvos, G. Rosen and R. C. Marcove, “Primary Osteogenicsarcoma: Pathologic Aspects in 20 Patients after Treatment with Chemotherapy, En bloc Resection, and Prosthetic Bone Replacement,” Archives of Pathology & Laboratory Medicine, Vol. 101, No. 1, 1977, pp. 14-18.
[15]	G. Saeter, T. A. Alveg?rd, I. Elomaa, A. E. Stenwig, T. Holmstram and O. P. Solheim, “Treatment of Osteosarcoma of the Extremities with the T-10 Protocol, with emphasis on the Effects of Preoperative Chemotherapy with Single-agent High-dose Methotrexate: A Scandinavian Sarcoma Group Study,” Journal of Clinical Oncology, Vol. 9, No. 10, 1991, pp. 1766-1775.
[16]	A. J. Provisor, L. J. Ettinger, J. B. Nachman, M. D. Krailo, J. T. Makley and E. J. Yunis, “Treatment of Nonmetastatic Osteosarcoma of the Extremity with Preoperative and Postoperative Chemotherapy: A Report from the Children’s Cancer Group,” Journal of Clinical Oncology, Vol. 15, No. 1, 1997, pp. 76-84.
[17]	N. Fuchs, S. S. Bielack, D. Epler, P. Bieling, G. Delling and D. K?rholz, “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,” Annals of Oncology, Vol. 9, No. 8, 1998, pp. 893-899. doi:10.1023/A:1008391103132
[18]	G. Bacci, P. Picci, S. Ferrari, P. Ruggieri, R. Casadei and A. Tienghi, “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, Vol. 72, No. 11, 1993, pp. 3227-3238. doi:10.1002/1097-0142(19931201)72:11<3227::AID-CNCR2820721116>3.0.CO;2-C
[19]	V. H. Bramwell, M. Burgers, R. Sneath, R. Souhami, A. T. van Oosterom and P. A. Vo?te, “A Comparison of Two Short Intensive Adjuvant Chemotherapy Regimens in Operable Osteosarcoma of Limbs in Children and Young Adults: The First Study of the European Osteosarcoma Intergroup,” Journal of Clinical Oncology, Vol. 10, No. 10, 1992, pp. 1579-1591.
[20]	I. J. Lewis, M. A. Nooij, J. Whelan, M. R. Sydes, R. Grimer and P. C. Hogendoorn, “MRC BO06 and EORTC 80931 Collaborators; European Osteosarcoma Intergroup: Randomized Trial of Two Regimens of Chemotherapy in Operable Osteosarcoma: A Study of the European Osteosarcoma Intergroup,” Lancet, Vol. 350, No. 9082, 1997, pp. 911-917.
[21]	I. J. Lewis and M. Nooij, “Chemotherapy at Standard or Increased Dose Intensity in Patients with Operable Osteosarcoma of the Extremity; a Randomized Controlled trial Conducted by the European Osteosarcoma Intergroup (ISRCTN 86294690),” Proceedings of the Annual Meeting of the American Society of Clinical Oncology, Chicago, 31 May-3 June 2003.
[22]	P. A. Meyers, C. L. Schwartz, M. Krailo, E. S. Kleinerman and D. Betcher, “Osteosarcoma: A Randomized, Prospective Trial of the Addition of Ifosfamide and/or Muramyl Tripeptide to Cisplatin, Doxorubicin, and High-Dose Methotrexate,” Journal of Clinical Oncology, Vol. 26, No. 18, 2005, pp. 2004-2011. doi:10.1200/JCO.2005.06.031
[23]	A. M. Goorin, D. J. Schwartzentruber, M. Devidas, M. C. Gebhardt, A. G. Ayala, M. B. Harris and Pediatric Oncology Group, “Presurgical Chemotherapy Compared with Immediate Surgery and Adjuvant Chemotherapy for Nonmetastatic Osteosarcoma: Pediatric Oncology Group Study POG-8651,” Journal of Clinical Oncology, Vol. 21, No. 8, 2003, pp. 1574-1580. doi:10.1200/JCO.2003.08.165
[24]	G. Bacci, S. Ferrari, A. Longhi, C. Forni, P. Ruggieri and A. Briccoli, “Preoperative Therapy versus Immediate Surgery in Nonmetastatic Osteosarcoma,” Journal of Clinical Oncology, Vol. 21, No. 24, 1993, pp. 4662-4663. doi:10.1200/JCO.2003.99.157
[25]	N. Jaffe, H. Watts, K. E. Fellows and G. Vawter, “Local En bloc Resection for Limb Preservation,” Cancer Treatment and Research, Vol. 62, No. 2, 1978, pp. 217-223.
[26]	N. Jaffe, A. K. Raymond, A. Ayala, S. Wallace, C. H. Carrasco and Y. M. Wang, “Analysis of the Efficacy of Intra-Arterial Cis-diammine-dichloroplatinum-II and High-Dose Methotrexate with Citrovorum Factor Rescue in the Treatment of Primary Osteosarcoma,” Regional Cancer Treatment, Vol. 2, 1989, pp. 157-163.
[27]	N. Jaffe, D. Jaffe, A. Raymond, P. Pearson, R. Robertson and E. Kim, “Pediatric Osteosarcoma: Treatment of the Primary Tumor with Intravenous Cis diamminedichloroplatinum-II (CDP). Comparison of the Results with the Reported Efficacy of Intra-arterial CDP,” International Journal of Oncology, Vol. 3, 1993, pp. 273-278.
[28]	N. Jaffe, J. Knapp, V. P. Chuang, S. Wallace, A. Ayala and J. Murray, “Osteosarcoma Intra-Arterial Treatment of the Primary Tumor with Cis-diamminedichloroplatinum-II (CDP). Angiographic, Pathologic and Pharmacologic Studies,” Cancer, Vol. 51, 1983, pp. 402-407. doi:10.1002/1097-0142(19830201)51:3<402::AID-CNCR2820510308>3.0.CO;2-P
[29]	E. S. Kleinerman, “Biologic Therapy for Osteosarcoma using Liposome-encapsulated Muramyl tripeptide,” Hematology/Oncology Clinics of North America, Vol. 9, No. 4, 1995, pp. 927-938.
[30]	C. R. Müller, S. Smeland, H. C. Bauer, G. Saeter and H. Strander, “Interferon Alpha as the Only Adjuvant Treatment in High-Grade Osteosarcoma: Long Term Results of the Karolinska Hospital Series,” Acta Oncologica, Vol. 44, No. 5, 2005, pp. 475-480. doi:10.1080/02841860510029978
[31]	L. L. Worth, N. Jaffe, R. S. Benjamin, N. E. Papadopoulos, S. Patel and A. K. Raymond, “Phase II Study of Recombinant Interleukin la and Etoposide in Patients with Relapsed Osteosarcoma,” Clinical Cancer Research, Vol. 3, 1997, pp. 1721-1729.
[32]	H. Masui, T. Kawamoto, J. D. Sato, B. Wolf, G. Sato and J. Mendelsohn, “Growth Inhibition of Human Tumor Cells in Athymic Mice by Anti-Epidermal Growth Factor Receptor Monoclonal Antibodies,” Cancer Research, Vol. 44, No. 3, 1984, pp. 1002-1007.
[33]	R. M. Hudziak, G. D. Lewis, M. Winget, B. M. Fendly, H. M. Shepard and A. Ullrich,“p185HER2 Monoclonal Antibody Has Antiproliferative Effects in Vitro and Sensitizes Human Breast Tumor Cells to Tumor Necrosis Factor,” Molecular and Cellular Biology, Vol. 9, No. 3, 1989, pp. 1165-1172.
[34]	Y. Hirata, M. Uchihashi, H. Nakashima, T. Fujita, S. Matsukura and K. Matsui,“ Speci?c Receptors for Epidermal growth factor in Human Bone Tumour Cells and Its Effect on Synthesis of Prostaglandin E2 by Cultured Osteosarcoma Cell Line,” Acta Endocrinologica (Copenhagen), Vol. 107, 1984, pp. 125-130.
[35]	S. Ferrari, F. Bertoni, L. Zanella, E. Setola, P. Bacchini and M. Alberghini, “Evaluation of P-Glycoprotein, HER-2/ErbB-2, p53, and Bcl-2 in Primary Tumor and Metachronous Lung Metastases in Patients with High-Grade Osteosarcoma,” Cancer, Vol. 100, No. 9, 2004, pp. 1936-1942. doi:10.1002/cncr.20151
[36]	R. Gorlick, A. G. Huvos, G. Heller, A. Aledo, G. P. Beardsley and J. H. Healey, “Expression of HER2/erbB-2 Correlates with Survival in Osteosarcoma,” Journal of Clinical Oncology, Vol. 17, No. 9, 1999, pp. 2781-2788.
[37]	T. Akatsuka, T. Wada, Y. Kokai, S. Kawaguchi, K. Isu and K. Yamashiro, “ErbB2 Expression Is Correlated with Increased Survival of Patients with Osteosarcoma,” Cancer, Vol. 94, No. 5, 2002, pp. 1397-1404. doi:10.1002/cncr.10360
[38]	T. Akatsuka, T. Wada, Y. Kokai, S. Kawaguchi, K. Isu and K. Yamashiro, “Over Expression of the HER-2 Oncogene Does Not Play a Role in High-Grade Osteosarcomas,” European Journal of Cancer, Vol. 40, No. 7, 2004, pp. 963-970. doi:10.1016/j.ejca.2003.10.025
[39]	D. P. Hughes, D. G. Thomas, T. J. Giordano, L. H. Baker and K. T. McDonagh, “Cell Surface Expression of Epidermal Growth Factor Receptor and Her-2 with Nuclear Expression of Her-4 in Primary Osteosarcoma,” Cancer Research, Vol. 64, No. 6, 2004, pp. 2047-2053. doi:10.1158/0008-5472.CAN-03-3096
[40]	D. P. Hughes, D. G. Thomas, T. J. Giordano, K. T. McDonagh and L. H. Baker, “Essential erbB Family Phosphorylation in Osteosarcoma as a Target for CI-1033 Inhibition,” Pediatric Blood Cancer, Vol. 46, No. 5, 2006, pp. 614-623. doi:10.1002/pbc.20454
[41]	M. A. Witlox, V. W. Van Beusechem, J. Grill, H. J. Haisma, G. Schaap and J. Bras, “Epidermal Growth Factor Receptor Targeting Enhances Adenoviral Vector Based Suicide Gene Therapy of Osteosarcoma,” Journal of Gene Medicine, Vol. 4, No. 5, 2002, pp. 510-516. doi:10.1002/jgm.308
[42]	Y. H. Wen, H. Koeppen, R. Garcia, L. Chiriboga, B. D. Tarlow and B. A. Peters, “Epidermal Growth Factor Receptor in Osteosarcoma: Expression and Mutational Analysis,” Human Pathology, Vol. 38, No. 8, 2007, pp. 1184-1191. doi:10.1016/j.humpath.2007.01.002
[43]	S. P. Chawla, V. S. Chua, L. Fernandez, D. Quon, A. Saralou and W. C. Blackwelder, “Phase I/II and Phase II Studies of Targeted Gene Delivery in Vivo: Intravenous Rexin-G for Chemotherapy-Resistant Sarcoma and Osteosarcoma,” Molecular Therapy, Vol. 17, No. 9, 2009, pp. 1651-1657. doi:10.1038/mt.2009.126
[44]	C. R. Dass, L. M. Khachigian and P. F. Choong, “c-Jun Knockdown Sensitizes Osteosarcoma to Doxorubicin,” Molecular Cancer Therapeutics, Vol. 7, No. 7, 2008, pp. 1909-1912. doi:10.1158/1535-7163.MCT-08-0086
[45]	P. M. Anderson, G. A. Wiseman, L. Erlandson, V. Rodriguez, B. Trotz and S. A. Dubansky, “Gemcitabine Radiosensitization after High-Dose Samarium for Osteoblastic Osteosarcoma,” Clinical Cancer Research, Vol. 11, No. 1, 2005, pp. 6895-6900. doi:10.1158/1078-0432.CCR-05-0628
[46]	A. Mahajan, S. Y. Woo, D. G. Kornguth, D. Hughes, W. Huh and E. L. Chang, “Multimodality Treatment of Osteosarcoma: Radiation in a High-Risk Cohort,” Pediatric Blood & Cancer, Vol. 50, No. 5, 2008, pp. 976-982. doi:10.1002/pbc.21451
[47]	P. M. Anderson, G. A. Wiseman, A. Dispenzieri, C. A. Arndt, L. C. Hartmann and W. A. Smithson, “High-Dose Samarium-153 Ethylene Diamine Tetramethylene Phosphonate: Low Toxicity of Skeletal Irradiation in Patients with Osteosarcoma and Bone Metastases,” Journal of Clinical Oncology, Vol. 20, No. 1, 2002, pp. 189-196. doi:10.1200/JCO.20.1.189
[48]	D. E. Heron, A. Brufsky, S. Beriwal and M. Kurman, “Myelotoxicity of Samarium Sm 153 Lexidronam in Patients Receiving Prior Treatment with Chemotherapy or Radiotherapy,” Annals of Oncology, Vol. 19, No. 9, 2008, pp. 1639-1643. doi:10.1093/annonc/mdn178
[49]	C. MacLean, S. Newberry, M. Maglione, M. McMahon, V. Ranganath and M. Suttorp, “Systematic Review: Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis,” Annals of Internal Medicine, Vol. 148, No. 11, 2008, pp. 197-213.
[50]	T. Iguchi, Y. Miyakawa, K. Saito, C. Nakabayashi, M. Nakanishi and H. Saya, “Zoledronate-Induced S Phase Arrest and Apoptosis accompanied by DNA Damage and Activation of the ATM/Chk1/cdc25 Pathway in Human Osteosarcoma Cells,” International Journal of Oncology, Vol. 31, 2007, pp. 285-291.
[51]	B. Kubista, K. Trieb, F. Sevelda, C. Toma, F. Arrich and P. Heffeter, “Anticancer Effects of Zoledronic Acid against Anticancer Cells,” Journal of Orthopaedic Research, Vol. 24, 2006, pp. 1145-1152. doi:10.1002/jor.20129
[52]	A. McTiernan and J. S. Whelan, “A Phase II Study of Docetaxel for the Treatment of Recurrent Osteosarcoma,” Sarcoma, Vol. 8, No. 2-3, 2004, pp. 71-76. doi:10.1155/2004/762736
[53]	C. Laverdiere, E. A. Kolb, J. G. Supko, R. Gorlick, P. A. Meyers and R. G. Maki, “Phase II Study of Ecteinascidin 743 in Heavily Pretreated Patients with Recurrent Osteosarcoma,” Cancer, Vol. 98, No. 4, 2003, pp. 832-840. doi:10.1002/cncr.11563
[54]	S. J. Strauss, A. McTiernan and J. S. Whelan, “Late Relapse of Osteosarcoma: Implications for Follow-Up and Screening,” Pediatric Blood Cancer, Vol. 43, No. 6, 2004, pp. 692-697. doi:10.1002/pbc.20154
[55]	W. H. Meyer, C. B. Pratt, C. A. Poquette, B. N. Rao, D. M. Parham and N. M. Marina, “Carboplatin/Ifosfamide Window Therapy for Osteosarcoma: Results of the St Jude Children’s Research Hospital OS-91 Trial,” Journal of Clinical Oncology, Vol. 19, No. 1, 2001, pp. 171-182.
[56]	C. A. Arndt, N. V. Koshkina, C. Y. Inwards, D. S. Hawkins, M. D. Krailo and D. Villaluna, “Inhaled GM-CSF for First Pulmonary Recurrence of Osteosarcoma; Immunologic and Surgical Findings,” CTOS, 2010, Abstr 54-830406.
[57]	A. J. Chou, M. D. Bell, C. Mackinson, R. Gupta, P. A. Meyers and R. Gorlick, “Phase Ib/IIa Study of Sustained Release Lipid Inhalation Targeting Cisplatin by Inhalation in the Treatment of Patients with Relapsed/Progressive Osteosarcoma Metastatic to the Lung,” Journal of Clinical Oncology, Vol. 25, No. 18S, 2007, pp. 9525.
[58]	B. Kempf-Bielack, S. S. Bielack, H. Jürgens, D. Branscheid, W. E. Berdel and G. U. Exner, “Osteosarcoma Relapse after Combined Modality Therapy: An Analysis of Unselected Patients in the Cooperative Osteosarcoma Study Group (COSS),” Journal of Clinical Oncology, Vol. 23, 2005, pp. 559-568. doi:10.1200/JCO.2005.04.063
[59]	G. Bacci, A. Briccoli, A. Longhi, S. Ferrari, M. Mercuri and F. Faggioli, “Treatment and Outcome of Recurrent Osteosarcoma: Experience at Rizzoli in 235 Patients Initially Treated with Neoadjuvant Chemotherapy,” Acta Oncologica, Vol. 44, No. 7, 2005, pp. 748-755. doi:10.1080/02841860500327503
[60]	G. Bacci, A. Longhi, F. Bertoni, A. Briccoli, M. Versari and E. Pignotti, “Bone Metastases in Osteosarcoma Patients Treated with Neoadjuvant or Adjuvant Chemotherapy: The Rizzoli Experience in 52 Patients,” Acta Orthopaedica, Vol. 77, No. 6, 2006, pp. 938-943. doi:10.1080/17453670610013268
[61]	J. S. Miser, T. J. Kinsella, T. J. Triche, M. Tsokos, P. Jarosinski and R. Forquer, “Ifosfamide with Mesna Uroprotection and Etoposide: An Effective Regimen in the Treatment of Recurrent Sarcomas and Other Tumors of Children and Young Adults” Journal of Clinical Oncology, Vol. 5, No. 8, 1987, pp. 1191-1198.
[62]	F. Navid, J. R. Willert, M. B. McCarville, W. Furman, A. Watkins and W. Roberts, “Combination of Gemcitabine and Docetaxel in the Treatment of Children and Young Adults with Refractory Bone Sarcoma,” Cancer, Vol. 113, No. 2, 2008, pp. 419-425. doi:10.1002/cncr.23586
[63]	M. Berger, G. Grignani, S. Ferrari, E. Biasin, P. A. del Brach and S. Aliberti, “Cyclophosphamide and Etoposide for Relapsed High-Risk Osteosarcoma Patients,” Cancer, Vol. 115, No. 13, 2009, pp. 2980-2987. doi:10.1002/cncr.24368
[64]	F. Fagioli, M. Aglietta, A. Tienghi, S. Ferrari, P. A. del Brach and E. Vassallo, “High-Dose Chemotherapy in the Treatment of Relapsed Osteosarcoma: An Italian Sarcoma Group Study,” Journal of Clinical Oncology, Vol. 20, No. 8, 2002, pp. 2150-2156. doi:10.1200/JCO.2002.08.081
[65]	E. C. van Dalen, J. W. van As and B. de Camargo, “Methotrexate for High-grade Osteosarcoma in Children and Young Adults. Cochrane Database of Systematic Reviews, No. 5, 2011, Article No. CD006325.
[66]	N. Jaffe, R. Robertson, A. Ayala, S. Wallace, V. Chuang and T. Anzai, “Comparison of Intra-Arterial Cis-diamminedichloroplatinum II with High-Dose Methotrexate and Citrovorum Factor Rescue in the Treatment of Primary Osteosarcoma,” Journal of Clinical Oncology, Vol. 3, No. 8, 1985, pp. 1101-1104.
[67]	A. M. Goorin, M. Delorey and R. D. Gelber, “The Dana Farber Cancer Institute/The Children’s Hospital Adjuvant Chemotherapy Trials for Osteosarcoma: Three Sequential Studies,” Cancer Treatment Symposium, Vol. 3, 1985, pp. 155-159.
[68]	G. Rosen, “Role of Chemotherapy in the Treatment of Primary Osteogenicsarcoma: A Five-Year Follow-Up of T-10 Neoadjuvant Chemotherapy,” In: K. Kimura, Y.-M. Wang, Eds., Methotrexate in Cancer Therapy, Raven Press, New York, 1986, pp. 227-238.
[69]	G. Bacci, F. Gherlinzoni, P. Picci, J. R. Van Horn, N. Jaffe and A. Guerra, “Doxorubicin-Methotrexate High-Dose versus Doxorubicin-Methotrexate Moderate dose as Adjuvant Chemotherapy for Osteosarcoma of the Extremities: A Randomized Study,” European Journal of Cancer and Clinical Oncology, Vol. 22, 1986, pp. 1337-1345. doi:10.1016/0277-5379(86)90142-2
[70]	N. Delepine, G. Delepine, C. Jasmin, J. C. Desbois, H. Cornille and G. Mathé, “The Importance of Age and Methotrexate Dosage: Prognosis in Children and Young Adults with High grade Osteosarcoma,” Biomedicine & Pharmacotherapy, Vol. 42, No. 4, 1988, pp. 257-262.
[71]	N. Graf, K. Winkler, M. Betlemovic, N. Fuchs and U. Bode, “Methotrexate Pharmakinetics and Prognosis in Osteosarcoma,” Journal of Clinical Oncology, Vol. 12, No. 7, 1994, pp. 1443-1451.
[72]	N. Jaffe and R. Gorlick, “High-Dose Methotrexate in Osteosarcoma: Let the Questions Surcease—Time for Final Acceptance,” Journal of Clinical Oncology, Vol. 26, No. 27, 2008, pp. 4365-4366. doi:10.1200/JCO.2007.14.7793
[73]	N. Jaffe, Eds., “Osteosarcoma: Review of the Past, Impact on the Future. The American Experience. Pediatric and Adolescent Osteosarcoma,” Cancer Treatment and Research, Vol. 152, 2009, pp. 239-262.
[74]	J. Bajpai, R. Kumar, V. Sreenivas, M. C. Sharma, S. A. Khan and S. Rastogi, “Prediction of Chemotherapy Response by PET-CT in Osteosarcoma: Correlation with Histologic Necrosis,” Journal of Pediatric Hematology/ Oncology, Vol. 33, No. 7, 2011, pp. e271-e278.
[75]	J. Bajpai, S. Gamnagatti, R. Kumar, V. Sreenivas, M. C. Sharma and S. A. Khan, “Role of MRI in Osteosarcoma for Evaluation and Prediction of Chemotherapy Response: Correlation with Histological Necrosis,” Pediatric Radiology, Vol. 41, No. 4, 2011, pp. 441-450. doi:10.1007/s00247-010-1876-3
[76]	J. Bajpai, M. Sharma, V. Sreenivas, R. Kumar, S. Gamnagatti and S. A. Khan, “VEGF Expression as a Prognostic Marker in Osteosarcoma,” Pediatric Blood & Cancer, Vol. 53, No. 6, 2009, pp. 1035-1039. doi:10.1002/pbc.22178
[77]	J. Bajpai, S. Gamanagatti, M. C. Sharma, R. Kumar, S. Vishnubhatla and S. A. Khan, “Noninvasive Imaging Surrogate of Angiogenesis in Osteosarcoma,” Pediatric Blood & Cancer, Vol. 54, No. 4, 2010, pp. 526-531.
[78]	“The European and American Osteosarcoma Study Group: The EURAMOS I Trial,” 2006. http://www.euramos.org
[79]	J. K. Anninga, H. Gelderblom, M. Fiocco, J. R. Kroep, A. H. Taminiau and P. C. Hogendoorn, “Chemotherapeutic Adjuvant Treatment for Osteosarcoma: Where Do We Stand?” European Journal of Cancer, Vol. 47, No. 16, 2011, pp. 2431-2445. doi:10.1016/j.ejca.2011.05.030
[80]	B. Kempf-Bielack, S. S. Bielack, H. Jürgens, D. Branscheid, W. E. Berdel and G. U. Exner, “Osteosarcoma Relapse after Combined Modality Therapy: An Analysis of Unselected Patients in the Cooperative Osteosarcoma Study Group (COSS),” Journal of Clinical Oncology, Vol. 23, 2005, pp. 559-568. doi:10.1200/JCO.2005.04.063