Targeted Chemotherapy in Bone and Soft-Tissue Sarcoma




Historically surgical intervention has been the mainstay of therapy for bone and soft-tissue sarcomas, augmented with adjuvant radiation for local control. Although cytotoxic chemotherapy revolutionized the treatment of many sarcomas, classic treatment regimens are fraught with side effects while outcomes have plateaued. However, since the approval of imatinib in 2002, research into targeted chemotherapy has increased exponentially. With targeted therapies comes the potential for decreased side effects and more potent, personalized treatment options. This article reviews the evolution of medical knowledge regarding sarcoma, the basic science of sarcomatogenesis, and the major targets and pathways now being studied.




  • •

    The most common targets and pathways are discussed with relevant updates and clinical trials.




  • •

    The most common targets and pathways are discussed with relevant updates and clinical trials.




    • In conclusion, current systemic treatment strategies are marginally effective for most bone sarcomas and STS, underscoring the need for more effective and individualized regimens. Table 2 lists several relevant completed and ongoing clinical trials and studies.



    Table 2

    Current and recently completed clinical trials






























































































































































































































































    Trial/Reference Date Phase Tumor Mechanism of Action/Target Agent(s) Tested Route/Frequency Number Treated Results
    NCT01524926 /(Schöffski, 2012) — II AKT and/or MET altered tumors to include alveolar soft-part sarcoma, clear cell sarcoma, and alveolar rhabdomyosarcoma (≥15 y old) Alk/MET Crizotinib PO/daily 582 (estimate) Recruiting
    NCT00093080 (Chawla et al, 2012) 2004 II Metastatic/unresectable soft-tissue or bone sarcoma mTOR inhibitor Ridaforolimus IV/daily 212 28.8% achieved clinical benefit response (CR, PR, or SD for >16 wk)
    (Yoo et al, 2013) — II Metastatic or recurrent bone and STS after the failure of anthracycline- and ifosfamide-containing regimens mTOR inhibition Everolimus PO/daily 38 28.9% reached 16-wk PFS. Median PFS was 1.9 mo and median OS was 5.8 mo
    NCT01614795 (Wagner, 2015, #8372) 2012 II STS (1–30 y old) IGF-1R + mTOR Cixutumumab + Temsirolimus IV/weekly 43 No responses. 16% PF at 12 wk
    NCT01016015 (Schwartz et al, 2013) 2009 II STS (1–30 y old) IGF-1R + mTOR Cixutumumab + Temsirolimus IV/weekly 174 Combination therapy with clinical activity. 39% were PF at 12 wk. IGF-1R expression not predictive of outcome
    NCT00831844 (Weigel, 2014) 2009 II Solid tumors (7–30 y old) IGF-1R Cixutumumab IV/weekly 114 Limited activity noted. 4.4% with PR. 12.3% with SD
    NCT00563680 (Tap et al, 2012) 2007–2012 II Ewing family tumors, DSRCTs (≥16 y old) IGF-1R monoclonal antibody Ganitumab — 38 ORR was primary end point and seen in 6% of patients. CBR (seen in 17% of patients) and safety were secondary end points. 49% had SD. 63% experienced adverse events
    NCT00642941 (Pappo et al, 2014) 2007–2010 II Recurrent/refractory rhabdomyosarcoma, osteosarcoma, and synovial sarcoma (≥2 y old) IGF-1R monoclonal antibody R1507 IV/weekly 228 ORR was 2.5%. Partial responses were seen in 4 patients. 4 patients had >50% reduction in tumor size that lasted <4 wk. Median PFS was 5.7 wk. Median OS was 11 mo
    NCT00385203 (Judson et al, 2014) 2006–2009 II GIST + STS progressing on imatinib/sunitinib VEGF Cediranib Daily 34 Some activity noted by 18 FDG-PET in 5 patients, but no statistical reduction in SUV max across the cohort. 4 of 6 patients with ASPS saw confirmed and durable partial responses
    NCT00942877 (Kummar et al, 2013) 2009 II ASPS VEGFR inhibitor Cediranib PO/daily 43 Partial response seen in 35% of patients. SD seen in 60%. Disease control rate of 84% at 24 wk
    NCT00288015 (Agulnik et al, 2013) 2006 II Angiosarcoma and epithelioid hemangioendotheliomas VEGF antibody Bevacizumab IV 32 Therapy was well tolerated in 15 patients with SD at 26 wk
    NCT00070109 (Baruchel et al, 2012) 2008–2013 II Recurrent rhabdomyosarcoma, ES, and nonrhabdomyosarcoma STS Unknown, suspect superoxide-induced apoptosis Trabectedin IV/every 3 wk 50 1 RMS patient had PR; 1 with RMS, 1 with SCS, and 1 with ES had SD at 2, 3, and 15 cycles
    NCT01189253 (Butrynski, 2015), EORTC 2011 III Advanced/metastatic-related sarcomas Unknown, suspect superoxide-induced apoptosis Trabectedin vs doxorubicin-based chemotherapy (DXCT) IV/every 3 wk 121 PFS and survival curves with no significant differences between arms. Response rate was higher in DXCT arm
    (Cesne et al, 2013) — II Recurrent/advanced STS Unknown, suspect superoxide-induced apoptosis Trabectedin — 350 Pooled analysis of 5 phase II studies. RR (10.1% in younger, 9.6% in older), PFS (2.5 vs 3.7 mo), and OS (13 vs 14 mo) did not differ among young and elderly cohorts
    NCT01303094 (Le Cesne et al, 2015, #71639) 2011 II Advanced STS (≥18 y old) Unknown, suspect superoxide-induced apoptosis Trabectedin IV/every 3 wk 178 91 patients (51%) had not progressed. Of these 53 were randomly assigned to continuation (C) vs interruption (I). PFS at 6 mo was 51.9% in the C group and 23.1% in the I group
    NCT00928525 (Grignani, 2011) — II Chondrosarcoma COL1A1-PDGFB Imatinib IM 26 PFS at 4 mo was 35%, median OS was 11 mo. No long-lasting disease-free progression or clinical benefit was observed. Temporary dose reduction required in 60%
    (Ugurel et al, 2014) — II Dermatofibrosarcoma protuberans COL1A1-PDGFB Imatinib Daily 16 Primary end point was response with secondary end points as safety, tumor relapse, and response biomarkers. Median therapy duration was 3.1 mo. Median tumor shrinkage was 31.5%. CR of 7.1%, PR of 50%, 35.7% SD, and 7.1% PD was seen. Neoadjuvant use was efficacious and well tolerated
    (Sugiura et al, 2010) — II Metastatic unresectable or refractory KIT+/PDGFR+ sarcoma (12–75 y old) Multitargeted tyrosine kinase inhibitor Imatinib Daily 22 1 PR (4.5%). 50% PFS at 61 d
    NCT01209598 (Dickson, 2013) 2010–current II CDK-4-amplified liposarcoma (≥18 y old) CDK4/CDK6 inhibitor PD0332991 PO/daily 29 At 12 wk, PFS was 66%, exceeding the 40% needed to consider the study positive
    NCT00023998 (Ebb, 2012) 2001–current II HER2+ osteosarcoma Monoclonal antibody that interferes with HER2/neu receptor Trastuzumab + chemotherapy — 96 received chemotherapy (41 of these were HER+ and received trastuzumab) Outcomes were poor. No significant difference between HER2− and HER2+ patients (EFS at 30 mo of 32% in both groups, OS 50% and 59%, respectively)
    NCT00217620 (Von Mehren, Demetri, 2012) — II STS Multitargeted tyrosine kinase inhibitor Sorafenib BID 37 No responses in any of the cohorts. Median PFS was 3 mo. Median OS was 17 mo
    NCT00889057 (Grignani et al, 2012) 2008–2011 II Osteosarcoma (15–75 y old) Multitargeted tyrosine kinase inhibitor Sorafenib BID 35 PFS at 4 mo was 46%. Median PFS was 4 mo. Median OS of 7 mo. CBR 29%. PR in 8%. Minor response in 6%. SD in 34%. PR/SD >6 mo in 17%
    NCT01804374 /SERIO (Aglietta, 2015) 2011–2014 II Unresectable advanced and metastatic osteosarcoma (≥18 y old) Multitargeted tyrosine kinase inhibitor/mTOR Sorafenib + Everolimus Daily 38 Dose reduction/interruptions were required in 66%. 6-mo PFS was 45%, shy of the 50% threshold to call the study positive
    NCT00297258 (Sleijfer et al, 2009) 2005–2012 II STS Multitargeted tyrosine kinase inhibitor Pazopanib PO/daily 148 Primary end point of PFS at 12 wk and secondary end points of response, safety, and OS were reached in leiomyosarcoma, synovial sarcoma, and other cohorts. End points were not reached in the adipocytic STS cohort

    Abbreviations: ASPS, alveolar soft-part sarcoma; BID, twice daily; CBR, clinical benefit rate; CR, complete response; EFS, event-free survival; ES, Ewing sarcoma; FDG, fluorodeoxyglucose; GIST, gastrointestinal stromal tumor; IM, intramuscular; IV, intravenous; ORR, overall response rate; OS, overall survival; PD, progressive disease; PF, progression free; PFS, progression-free survival; PO, by mouth; PR, partial response; RMS, rhabdomyosarcoma; RR, response rate; SCS, synovial cell sarcoma; SD, stable disease; STS, soft-tissue sarcoma; SUV max , standardized uptake value; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.






    References



    1. 1. Link M.P., Goorin A.M., Miser A.W., et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 1986; 314: pp. 1600-1606

    2. 2. Eilber F., Giuliano A., Eckardt J., et al: Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial. J Clin Oncol 1987; 5: pp. 21-26

    3. 3. Bernthal N.M., Federman N., Eilber F.R., et al: Long-term results (>25 years) of a randomized, prospective clinical trial evaluating chemotherapy in patients with high-grade, operable osteosarcoma. Cancer 2012; 118: pp. 5888-5893

    4. 4. Bramwell V.H., Burgers M., Sneath R., et al: 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. J Clin Oncol 1992; 10: pp. 1579-1591

    5. 5. Souhami R.L., Craft A.W., Van der Eijken J.W., et al: Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet 1997; 350: pp. 911-917

    6. 6. Lewis I.J., Nooij M.A., Whelan J., et al: 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: pp. 112-128

    7. 7. Le Deley M.C., Guinebretière J.M., Gentet J.C., et al: SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. Eur J Cancer 2007; 43: pp. 752-761

    8. 8. Collins M., Wilhelm M., Conyers R., et al: Benefits and adverse events in younger versus older patients receiving neoadjuvant chemotherapy for osteosarcoma: findings from a meta-analysis. J Clin Oncol 2013; 31: pp. 2303-2312

    9. 9. Bacci G., Picci P., Ruggieri P., et al: 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 1990; 65: pp. 2539-2553

    10. 10. Ferrari S., Ruggieri P., Cefalo G., et al: Neoadjuvant chemotherapy with methotrexate, cisplatin, and doxorubicin with or without ifosfamide in nonmetastatic osteosarcoma of the extremity: an Italian sarcoma group trial ISG/OS-1. J Clin Oncol 2012; 30: pp. 2112-2118

    11. 11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Bone Cancer. Version 1. 2015. Available online at: http://www.nccn.org/professionals/physician_gls/pdf/bone.pdf. Accessed 28 July, 2015.

    12. 12. Bacci G., Briccoli A., Rocca M., et al: Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Ann Oncol 2003; 14: pp. 1126-1134

    13. 13. Navid F., Willert J.R., McCarville M.B., et al: Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer 2008; 113: pp. 419-425

    14. 14. Goorin A.M., Harris M.B., Bernstein M., et al: 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: pp. 426-433

    15. 15. Berger M., Grignani G., Ferrari S., et al: Phase 2 trial of two courses of cyclophosphamide and etoposide for relapsed high-risk osteosarcoma patients. Cancer 2009; 115: pp. 2980-2987

    16. 16. Esiashvili N., Goodman M., and Marcus R.B.J.: Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: Surveillance Epidemiology and End Results data. J Pediatr Hematol Oncol 2008; 30: pp. 425-430

    17. 17. Herzog C.E.: Overview of sarcomas in the adolescent and young adult population. J Pediatr Hematol Oncol 2005; 27: pp. 215-218

    18. 18. Cotterill S.J., Ahrens S., Paulussen M., et al: Prognostic factors in Ewing’s tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing’s Sarcoma Study Group. J Clin Oncol 2000; 18: pp. 3108-3114

    19. 19. Nesbit M.E.J., Gehan E.A., Burgert E.O., et al: Multimodal therapy for the management of primary, nonmetastatic Ewing’s sarcoma of bone: a long-term follow-up of the First Intergroup study. J Clin Oncol 1990; 8: pp. 1664-1674

    20. 20. Burgert E.O.J., Nesbit M.E., Garnsey L.A., et al: Multimodal therapy for the management of nonpelvic, localized Ewing’s sarcoma of bone: intergroup study IESS-II. J Clin Oncol 1990; 8: pp. 1514-1524

    21. 21. Evans R.G., Nesbit M.E., Gehan E.A., et al: Multimodal therapy for the management of localized Ewing’s sarcoma of pelvic and sacral bones: a report from the second intergroup study. J Clin Oncol 1991; 9: pp. 1173-1180

    22. 22. Paulussen M., Ahrens S., Dunst J., et al: Localized Ewing tumor of bone: final results of the cooperative Ewing’s Sarcoma Study CESS 86. J Clin Oncol 2001; 19: pp. 1818-1829

    23. 23. Grier H.E., Krailo M.D., Tarbell N.J., et al: Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 2003; 348: pp. 694-701

    24. 24. Maheshwari A.V., and Cheng E.Y.: Ewing sarcoma family of tumors. J Am Acad Orthop Surg 2010; 18: pp. 94-107

    25. 25. Granowetter L., Womer R., Devidas M., et al: Dose-intensified compared with standard chemotherapy for nonmetastatic Ewing sarcoma family of tumors: a Children’s Oncology Group Study. J Clin Oncol 2009; 27: pp. 2536-2541

    26. 26. Womer R.B., West D.C., Krailo M.D., et al: Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children’s Oncology Group. J Clin Oncol 2012; 30: pp. 4148-4154

    27. 27. Oberlin O., Patte C., Demeocq F., et al: The response to initial chemotherapy as a prognostic factor in localized Ewing’s sarcoma. Eur J Cancer Clin Oncol 1985; 21: pp. 463-467

    28. 28. Bacci G., Ferrari S., Bertoni F., et al: Prognostic factors in nonmetastatic Ewing’s sarcoma of bone treated with adjuvant chemotherapy: analysis of 359 patients at the Istituto Ortopedico Rizzoli. J Clin Oncol 2000; 18: pp. 4-11

    29. 29. Lin P.P., Jaffe N., Herzog C.E., et al: Chemotherapy response is an important predictor of local recurrence in Ewing sarcoma. Cancer 2007; 109: pp. 603-611

    30. 30. Wunder J.S., Paulian G., Huvos A.G., et al: The histological response to chemotherapy as a predictor of the oncological outcome of operative treatment of Ewing sarcoma. J Bone Joint Surg Am 1998; 80: pp. 1020-1033

    31. 31. Paulussen M., Ahrens S., Burdach S., et al: Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies. Ann Oncol 1998; 9: pp. 275-281

    32. 32. Miser J.S., Krailo M.D., Tarbell N.J., et al: Treatment of metastatic Ewing’s sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide—a Children’s Cancer Group and Pediatric Oncology Group study. J Clin Oncol 2004; 22: pp. 2873-2876

    33. 33. Magnan H., Goodbody C.M., Riedel E., et al: Ifosfamide dose-intensification for patients with metastatic Ewing sarcoma. Pediatr Blood Cancer 2015; 62: pp. 594-597

    34. 34. Hamilton S.N., Carlson R., Hasan H., et al: Long-term outcomes and complications in pediatric Ewing sarcoma. Am J Clin Oncol 2015; undefined:

    35. 35. Gelderblom H., Hogendoorn P.C., Dijkstra S.D., et al: The clinical approach towards chondrosarcoma. Oncologist 2008; 13: pp. 320-329

    36. 36. Patrikidou A., Domont J., Cioffi A., et al: Treating soft tissue sarcomas with adjuvant chemotherapy. Curr Treat Options Oncol 2011; 12: pp. 21-31

    37. 37. Cormier J.N., and Pollock R.E.: Soft tissue sarcomas. CA Cancer J Clin 2004; 54: pp. 94-109

    38. 38. Pisters P.W., Harrison L.B., Leung D.H., et al: Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 1996; 14: pp. 859-868

    39. 39. Yang J.C., Chang A.E., Baker A.R., et al: Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998; 16: pp. 197-203

    40. 40. Eilber F.C., Rosen G., Nelson S.D., et al: High-grade extremity soft tissue sarcomas: factors predictive of local recurrence and its effect on morbidity and mortality. Ann Surg 2003; 237: pp. 218-226

    41. 41. Kang S., Kim H.S., Kim S., et al: Post-metastasis survival in extremity soft tissue sarcoma: a recursive partitioning analysis of prognostic factors. Eur J Cancer 2014; 50: pp. 1649-1656

    42. 42. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Sarcoma Meta-analysis Collaboration. Lancet 1997; 350: pp. 1647-1654

    43. 43. Buesa J.M., López-Pousa A., Martín J., et al: Phase II trial of first-line high-dose ifosfamide in advanced soft tissue sarcomas of the adult: a study of the Spanish Group for Research on Sarcomas (GEIS). Ann Oncol 1998; 9: pp. 871-876

    44. 44. Casali P.G., and Blay J.Y.: Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21: pp. v198-v203

    45. 45. Pervaiz N., Colterjohn N., Farrokhyar F., et al: A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer 2008; 113: pp. 573-581

    46. 46. Penel N., Bui B.N., Bay J.O., et al: Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX Study. J Clin Oncol 2008; 26: pp. 5269-5274

    47. 47. Kollar A., and Benson C.: Current management options for liposarcoma and challenges for the future. Expert Rev Anticancer Ther 2014; 14: pp. 297-306

    48. 48. Rosen G., Forscher C., Lowenbraun S., et al: Synovial sarcoma. Uniform response of metastases to high dose ifosfamide. Cancer 1994; 73: pp. 2506-2511

    49. 49. Sleijfer S., Ouali M., van Glabbeke M., et al: Prognostic and predictive factors for outcome to first-line ifosfamide-containing chemotherapy for adult patients with advanced soft tissue sarcomas: an exploratory, retrospective analysis on large series from the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG). Eur J Cancer 2010; 46: pp. 72-83

    50. 50. Leahy M., Garcia Del Muro X., Reichardt P., et al: Chemotherapy treatment patterns and clinical outcomes in patients with metastatic soft tissue sarcoma. The SArcoma treatment and Burden of Illness in North America and Europe (SABINE) study. Ann Oncol 2012; 23: pp. 2763-2770

    51. 51. Hanahan D., and Weinberg R.A.: The hallmarks of cancer. Cell 2000; 100: pp. 57-70

    52. 52. van Oosterom A.T., Judson I., Verweij J., et al: Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 2001; 358: pp. 1421-1423

    53. 53. Waller C.F.: Imatinib mesylate. Recent Results Cancer Res 2014; 201: pp. 1-25

    54. 54. Cronin M., and Ross J.S.: Comprehensive next-generation cancer genome sequencing in the era of targeted therapy and personalized oncology. Biomark Med 2011; 5: pp. 293-305

    55. 55. Roukos D.H., and Ku C.S.: Clinical cancer genome and precision medicine. Ann Surg Oncol 2012; 19: pp. 3646-3650

    56. 56. Workman P., Al-Lazikani B., and Clarke P.A.: Genome-based cancer therapeutics: targets, kinase drug resistance and future strategies for precision oncology. Curr Opin Pharmacol 2013; 13: pp. 486-496

    57. 57. Linch M., Miah A.B., Thway K., et al: Systemic treatment of soft-tissue sarcoma-gold standard and novel therapies. Nat Rev Clin Oncol 2014; 11: pp. 187-202

    58. 58. Kansara M., Teng M.W., Smyth M.J., et al: Translational biology of osteosarcoma. Nat Rev Cancer 2014; 14: pp. 722-735

    59. 59. Jo V.Y., and Fletcher C.D.: WHO classification of soft tissue tumours: an update based on the 2013 (4th) edition. Pathology 2014; 46: pp. 95-104

    60. 60. Vogelstein B., Papadopoulos N., Velculescu V.E., et al: Cancer genome landscapes. Science 2013; 339: pp. 1546-1558

    61. 61. Ognjanovic S., Olivier M., Bergemann T.L., et al: Sarcomas in TP53 germline mutation carriers: a review of the IARC TP53 database. Cancer 2012; 118: pp. 1387-1396

    62. 62. MacCarthy A., Bayne A.M., Brownbill P.A., et al: Second and subsequent tumours among 1927 retinoblastoma patients diagnosed in Britain 1951-2004. Br J Cancer 2013; 108: pp. 2455-2463

    63. 63. Toguchida J., Ishizaki K., Sasaki M.S., et al: Preferential mutation of paternally derived RB gene as the initial event in sporadic osteosarcoma. Nature 1989; 338: pp. 156-158

    64. 64. Chen X., Bahrami A., Pappo A., et al: Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep 2014; 7: pp. 104-112

    65. 65. Wunder J.S., Gokgoz N., Parkes R., et al: TP53 mutations and outcome in osteosarcoma: a prospective, multicenter study. J Clin Oncol 2005; 23: pp. 1483-1490

    66. 66. van Oosterwijk J.G., Anninga J.K., Gelderblom H., et al: Update on targets and novel treatment options for high-grade osteosarcoma and chondrosarcoma. Hematol Oncol Clin North Am 2013; 27: pp. 1021-1048

    67. 67. Hieken T.J., and Das Gupta T.K.: Mutant p53 expression: a marker of diminished survival in well-differentiated soft tissue sarcoma. Clin Cancer Res 1996; 2: pp. 1391-1395

    68. 68. Hayden J.B., and Hoang B.H.: Osteosarcoma: basic science and clinical implications. Orthop Clin North Am 2006; 37: pp. 1-7

    69. 69. Ito M., Barys L., O’Reilly T., et al: Comprehensive mapping of p53 pathway alterations reveals an apparent role for both SNP309 and MDM2 amplification in sarcomagenesis. Clin Cancer Res 2011; 17: pp. 416-426

    70. 70. Ray-Coquard I., Blay J.Y., Italiano A., et al: Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol 2012; 13: pp. 1133-1140

    71. 71. Shangary S., Qin D., McEachern D., et al: Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc Natl Acad Sci U S A 2008; 105: pp. 3933-3938

    72. 72. Pishas K.I., Al-Ejeh F., Zinonos I., et al: Nutlin-3a is a potential therapeutic for Ewing sarcoma. Clin Cancer Res 2011; 17: pp. 494-504

    73. 73. Frith A.E., Hirbe A.C., and Van Tine B.A.: Novel pathways and molecular targets for the treatment of sarcoma. Curr Oncol Rep 2013; 15: pp. 378-385

    74. 74. Graves B., Thompson T., Xia M., et al: Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization. Proc Natl Acad Sci U S A 2012; 109: pp. 11788-11793

    75. 75. Hartmann C., and Tabin C.J.: Dual roles of Wnt signaling during chondrogenesis in the chicken limb. Development 2000; 127: pp. 3141-3159

    76. 76. Hoang B.H.: Wnt, osteosarcoma, and future therapy. J Am Acad Orthop Surg 2012; 20: pp. 58-59

    77. 77. Cai Y., Mohseny A.B., Karperien M., et al: Inactive Wnt/beta-catenin pathway in conventional high-grade osteosarcoma. J Pathol 2010; 220: pp. 24-33

    78. 78. Kansara M., Tsang M., Kodjabachian L., et al: Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice. J Clin Invest 2009; 119: pp. 837-851

    79. 79. Mandal D., Srivastava A., Mahlum E., et al: Severe suppression of Frzb/sFRP3 transcription in osteogenic sarcoma. Gene 2007; 386: pp. 131-138

    80. 80. Vijayakumar S., Liu G., Rus I.A., et al: High-frequency canonical Wnt activation in multiple sarcoma subtypes drives proliferation through a TCF/beta-catenin target gene, CDC25A. Cancer Cell 2011; 19: pp. 601-612

    81. 81. Lin C.H., Ji T., Chen C.F., et al: Wnt signaling in osteosarcoma. Adv Exp Med Biol 2014; 804: pp. 33-45

    82. 82. Yang Q., and Guan K.L.: Expanding mTOR signaling. Cell Res 2007; 17: pp. 666-681

    83. 83. Brun J., Dieudonné F.X., Marty C., et al: FHL2 silencing reduces Wnt signaling and osteosarcoma tumorigenesis in vitro and in vivo. PLoS One 2013; 8: pp. e55034

    84. 84. Tao J., Jiang M.M., Jiang L., et al: Notch activation as a driver of osteogenic sarcoma. Cancer Cell 2014; 26: pp. 390-401

    85. 85. Mu X., Isaac C., Greco N., et al: Notch signaling is associated with ALDH activity and an aggressive metastatic phenotype in murine osteosarcoma cells. Front Oncol 2013; 3: pp. 143

    86. 86. Samuel A.M., Costa J., and Lindskog D.M.: Genetic alterations in chondrosarcomas – keys to targeted therapies? Cell Oncol (Dordr) 2014; 37: pp. 95-105

    87. 87. Lo W.W., Wunder J.S., Dickson B.C., et al: Involvement and targeted intervention of dysregulated Hedgehog signaling in osteosarcoma. Cancer 2014; 120: pp. 537-547

    88. 88. Kelleher F.C., Cain J.E., Healy J.M., et al: Prevailing importance of the hedgehog signaling pathway and the potential for treatment advancement in sarcoma. Pharmacol Ther 2012; 136: pp. 153-168

    89. 89. Martin J.W., Zielenska M., Stein G.S., et al: The Role of RUNX2 in osteosarcoma oncogenesis. Sarcoma 2011; 2011: pp. 282745

    90. 90. Lahat G., Zhang P., Zhu Q.S., et al: The expression of c-Met pathway components in unclassified pleomorphic sarcoma/malignant fibrous histiocytoma (UPS/MFH): a tissue microarray study. Histopathology 2011; 59: pp. 556-561

    91. 91. Scotlandi K., Baldini N., Oliviero M., et al: Expression of Met/hepatocyte growth factor receptor gene and malignant behavior of musculoskeletal tumors. Am J Pathol 1996; 149: pp. 1209-1219

    92. 92. Wallenius V., Hisaoka M., Helou K., et al: Overexpression of the hepatocyte growth factor (HGF) receptor (Met) and presence of a truncated and activated intracellular HGF receptor fragment in locally aggressive/malignant human musculoskeletal tumors. Am J Pathol 2000; 156: pp. 821-829

    93. 93. Patane S., Avnet S., Coltella N., et al: MET overexpression turns human primary osteoblasts into osteosarcomas. Cancer Res 2006; 66: pp. 4750-4757

    94. 94. Wagner A.J., Goldberg J.M., Dubois S.G., et al: Tivantinib (ARQ 197), a selective inhibitor of MET, in patients with microphthalmia transcription factor-associated tumors: results of a multicenter phase 2 trial. Cancer 2012; 118: pp. 5894-5902

    95. 95. Egas-Bejar D., Anderson P.M., Agarwal R., et al: Theranostic profiling for actionable aberrations in advanced high risk osteosarcoma with aggressive biology reveals high molecular diversity: the human fingerprint hypothesis. Oncoscience 2014; 1: pp. 167-179

    96. 96. Wang Y.H., Han X.D., Qiu Y., et al: Increased expression of insulin-like growth factor-1 receptor is correlated with tumor metastasis and prognosis in patients with osteosarcoma. J Surg Oncol 2012; 105: pp. 235-243

    97. 97. Krueger D.A., Care M.M., Holland K., et al: Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 2010; 363: pp. 1801-1811

    98. 98. Franz D.N., Belousova E., Sparagana S., et al: Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study. Lancet Oncol 2014; 15: pp. 1513-1520

    99. 99. Bissler J.J., Kingswood J.C., Radzikowska E., et al: Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2013; 381: pp. 817-824

    100. 100. Pazdur R, et al. FDA Approval for everolimus. 2013. Available at: http://www.cancer.gov/about-cancer/treatment/drugs/fda-everolimus. Accessed June 23, 2015.

    101. 101. Demetri G.D., Chawla S.P., Ray-Coquard I., et al: Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy. J Clin Oncol 2013; 31: pp. 2485-2492

    102. 102. Rikhof B., de Jong S., Suurmeijer A.J., et al: The insulin-like growth factor system and sarcomas. J Pathol 2009; 217: pp. 469-482

    103. 103. Steigen S.E., Schaeffer D.F., West R.B., et al: Expression of insulin-like growth factor 2 in mesenchymal neoplasms. Mod Pathol 2009; 22: pp. 914-921

    104. 104. Cironi L., Riggi N., Provero P., et al: IGF1 is a common target gene of Ewing’s sarcoma fusion proteins in mesenchymal progenitor cells. PLoS One 2008; 3: pp. e2634

    105. 105. Mora J., Rodríguez E., de Torres C., et al: Activated growth signaling pathway expression in Ewing sarcoma and clinical outcome. Pediatr Blood Cancer 2012; 58: pp. 532-538

    106. 106. van de Luijtgaarden A.C., Versleijen-Jonkers Y.M., Roeffen M.H., et al: Prognostic and therapeutic relevance of the IGF pathway in Ewing’s sarcoma patients. Target Oncol 2013; 8: pp. 253-260

    107. 107. Sun Y., Gao D., Liu Y., et al: IGF2 is critical for tumorigenesis by synovial sarcoma oncoprotein SYT-SSX1. Oncogene 2006; 25: pp. 1042-1052

    108. 108. Ayalon D., Glaser T., and Werner H.: Transcriptional regulation of IGF-I receptor gene expression by the PAX3-FKHR oncoprotein. Growth Horm IGF Res 2001; 11: pp. 289-297

    109. 109. Makawita S., Ho M., Durbin A.D., et al: Expression of insulin-like growth factor pathway proteins in rhabdomyosarcoma: IGF-2 expression is associated with translocation-negative tumors. Pediatr Dev Pathol 2009; 12: pp. 127-135

    110. 110. van de Luijtgaarden A.C., Roeffen M.H., Leus M.A., et al: IGF signaling pathway analysis of osteosarcomas reveals the prognostic value of pAKT localization. Future Oncol 2013; 9: pp. 1733-1740

    111. 111. Kolb E.A., Kamara D., Zhang W., et al: Kamara D, Zhang W, R1507, a fully human monoclonal antibody targeting IGF-1R, is effective alone and in combination with rapamycin in inhibiting growth of osteosarcoma xenografts. Pediatr Blood Cancer 2010; 55: pp. 67-75

    112. 112. Rainusso N., Wang L.L., and Yustein J.T.: The adolescent and young adult with cancer: state of the art—bone tumors. Curr Oncol Rep 2013; 15: pp. 296-307

    113. 113. Stegmaier K., Wong J.S., Ross K.N., et al: Signature-based small molecule screening identifies cytosine arabinoside as an EWS/FLI modulator in Ewing sarcoma. PLoS Med 2007; 4: pp. e122

    114. 114. Erkizan H.V., Kong Y., Merchant M., et al: A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing’s sarcoma. Nat Med 2009; 15: pp. 750-756

    115. 115. Grohar P.J., Woldemichael G.M., Griffin L.B., et al: Identification of an inhibitor of the EWS-FLI1 oncogenic transcription factor by high-throughput screening. J Natl Cancer Inst 2011; 103: pp. 962-978

    116. 116. Gautreau A., Poullet P., Louvard D., et al: Ezrin, a plasma membrane-microfilament linker, signals cell survival through the phosphatidylinositol 3-kinase/Akt pathway. Proc Natl Acad Sci U S A 1999; 96: pp. 7300-7305

    117. 117. Louvet-Vallee S.: ERM proteins: from cellular architecture to cell signaling. Biol Cell 2000; 92: pp. 305-316

    118. 118. Bretscher A., Edwards K., and Fehon R.G.: ERM proteins and merlin: integrators at the cell cortex. Nat Rev Mol Cell Biol 2002; 3: pp. 586-599

    119. 119. Pujuguet P., Del Maestro L., Gautreau A., et al: Ezrin regulates E-cadherin-dependent adherens junction assembly through Rac1 activation. Mol Biol Cell 2003; 14: pp. 2181-2191

    120. 120. Geissler K.J., Jung M.J., Riecken L.B., et al: Regulation of Son of sevenless by the membrane-actin linker protein ezrin. Proc Natl Acad Sci U S A 2013; 110: pp. 20587-20592

    121. 121. Khanna C., Wan X., Bose S., et al: The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat Med 2004; 10: pp. 182-186

    122. 122. Hunter K.W.: Ezrin, a key component in tumor metastasis. Trends Mol Med 2004; 10: pp. 201-204

    123. 123. Yu Y., Davicioni E., Triche T.J., et al: The homeoprotein six1 transcriptionally activates multiple protumorigenic genes but requires ezrin to promote metastasis. Cancer Res 2006; 66: pp. 1982-1989

    124. 124. Krishnan K., Bruce B., Hewitt S., et al: Ezrin mediates growth and survival in Ewing’s sarcoma through the AKT/mTOR, but not the MAPK, signaling pathway. Clin Exp Metastasis 2006; 23: pp. 227-236

    125. 125. Weng W.H., Ahlen J., Astrom K., et al: Prognostic impact of immunohistochemical expression of ezrin in highly malignant soft tissue sarcomas. Clin Cancer Res 2005; 11: pp. 6198-6204

    126. 126. Carneiro A., Bendahl P.O., Åkerman M., et al: Ezrin expression predicts local recurrence and development of metastases in soft tissue sarcomas. J Clin Pathol 2011; 64: pp. 689-694

    127. 127. Kim M.S., Cho W.H., Song W.S., et al: Prognostic significance of ezrin expression in pleomorphic malignant fibrous histiocytoma. Anticancer Res 2007; 27: pp. 1171-1178

    128. 128. Huang H.Y., Li C.F., Fang F.M., et al: Prognostic implication of ezrin overexpression in myxofibrosarcomas. Ann Surg Oncol 2010; 17: pp. 3212-3219

    129. 129. Soderstrom M., Palokangas T., Vahlberg T., et al: Expression of ezrin, Bcl-2, and Ki-67 in chondrosarcomas. APMIS 2010; 118: pp. 769-776

    130. 130. Ogino W., Takeshima Y., Mori T., et al: High level of ezrin mRNA expression in an osteosarcoma biopsy sample with lung metastasis. J Pediatr Hematol Oncol 2007; 29: pp. 435-439

    131. 131. Ferrari S., Zanella L., Alberghini M., et al: Prognostic significance of immunohistochemical expression of ezrin in non-metastatic high-grade osteosarcoma. Pediatr Blood Cancer 2008; 50: pp. 752-756

    132. 132. Wang Z., He M.L., Zhao J.M., et al: Meta-analysis of associations of the ezrin gene with human osteosarcoma response to chemotherapy and prognosis. Asian Pac J Cancer Prev 2013; 14: pp. 2753-2758

    133. 133. Mu Y., Zhang H., Che L., et al: Clinical significance of microRNA-183/Ezrin axis in judging the prognosis of patients with osteosarcoma. Med Oncol 2014; 31: pp. 821

    134. 134. Ren L., and Khanna C.: Role of ezrin in osteosarcoma metastasis. Adv Exp Med Biol 2014; 804: pp. 181-201

    135. 135. Bulut G., Hong S.H., Chen K., et al: Small molecule inhibitors of ezrin inhibit the invasive phenotype of osteosarcoma cells. Oncogene 2012; 31: pp. 269-281

    136. 136. Schwertschlag U.S., Trepicchio W.L., Dykstra K.H., et al: Hematopoietic, immunomodulatory and epithelial effects of interleukin-11. Leukemia 1999; 13: pp. 1307-1315

    137. 137. Li T.M., Wu C.M., Huang H.C., et al: Interleukin-11 increases cell motility and up-regulates intercellular adhesion molecule-1 expression in human chondrosarcoma cells. J Cell Biochem 2012; 113: pp. 3353-3362

    138. 138. Lewis V.O., Ozawa M.G., Deavers M.T., et al: The interleukin-11 receptor alpha as a candidate ligand-directed target in osteosarcoma: consistent data from cell lines, orthotopic models, and human tumor samples. Cancer Res 2009; 69: pp. 1995-1999

    139. 139. Aggarwal B.B., Kunnumakkara A.B., Harikumar K.B., et al: Signal transducer and activator of transcription-3, inflammation, and cancer: how intimate is the relationship? Ann N Y Acad Sci 2009; 1171: pp. 59-76

    140. 140. Chen C.L., Loy A., Cen L., et al: Signal transducer and activator of transcription 3 is involved in cell growth and survival of human rhabdomyosarcoma and osteosarcoma cells. BMC Cancer 2007; 7: pp. 111

    141. 141. David D., Rajappan L.M., Balachandran K., et al: Prognostic significance of STAT3 and phosphorylated STAT3 in human soft tissue tumors – a clinicopathological analysis. J Exp Clin Cancer Res 2011; 30: pp. 56

    142. 142. Wang X., Goldstein D., Crowe P.J., et al: Impact of STAT3 inhibition on survival of osteosarcoma cell lines. Anticancer Res 2014; 34: pp. 6537-6545

    143. 143. Bendell J.C., Hong D.S., Burris H.A., et al: Phase 1, open-label, dose-escalation, and pharmacokinetic study of STAT3 inhibitor OPB-31121 in subjects with advanced solid tumors. Cancer Chemother Pharmacol 2014; 74: pp. 125-130

    144. 144. Kim K.J., Li B., Winer J., et al: Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993; 362: pp. 841-844

    145. 145. Takahashi H., and Shibuya M.: The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clin Sci (Lond) 2005; 109: pp. 227-241

    146. 146. Lin C.Y., Hung S.Y., Chen H.T., et al: Brain-derived neurotrophic factor increases vascular endothelial growth factor expression and enhances angiogenesis in human chondrosarcoma cells. Biochem Pharmacol 2014; 91: pp. 522-533

    147. 147. Wakamatsu T., Naka N., Sasagawa S., et al: Deflection of vascular endothelial growth factor action by SS18-SSX and composite vascular endothelial growth factor- and chemokine (C-X-C motif) receptor 4-targeted therapy in synovial sarcoma. Cancer Sci 2014; 105: pp. 1124-1134

    148. 148. Katuri V., Gerber S., Qiu X., et al: WT1 regulates angiogenesis in Ewing Sarcoma. Oncotarget 2014; 5: pp. 2436-2449

    149. 149. Miyoshi K., Kohashi K., Fushiujmi F., et al: Close correlation between CXCR4 and VEGF expression and frequent CXCR7 expression in rhabdomyosarcoma. Hum Pathol 2014; 45: pp. 1900-1909

    150. 150. Yang J., Zhao L., Tian W., et al: Correlation of WWOX, RUNX2 and VEGFA protein expression in human osteosarcoma. BMC Med Genomics 2013; 6: pp. 56

    151. 151. Itakura E., Yamamoto H., Oda Y., et al: Detection and characterization of vascular endothelial growth factors and their receptors in a series of angiosarcomas. J Surg Oncol 2008; 97: pp. 74-81

    152. 152. Young R.J., Fernando M., Hughes D., et al: Angiogenic growth factor expression in benign and malignant vascular tumours. Exp Mol Pathol 2014; 97: pp. 148-153

    153. 153. Kummar S., Allen D., Monks A., et al: Cediranib for metastatic alveolar soft part sarcoma. J Clin Oncol 2013; 31: pp. 2296-2302

    154. 154. Agulnik M., Yarber J.L., Okuno S.H., et al: An open-label, multicenter, phase II study of bevacizumab for the treatment of angiosarcoma and epithelioid hemangioendotheliomas. Ann Oncol 2013; 24: pp. 257-263

    155. 155. Graeven U., Andre N., Achilles E., et al: Serum levels of vascular endothelial growth factor and basic fibroblast growth factor in patients with soft-tissue sarcoma. J Cancer Res Clin Oncol 1999; 125: pp. 577-581

    156. 156. Yoon S.S., Segal N.H., Olshen A.B., et al: Circulating angiogenic factor levels correlate with extent of disease and risk of recurrence in patients with soft tissue sarcoma. Ann Oncol 2004; 15: pp. 1261-1266

    157. 157. van Oosterwijk J.G., Meijer D., van Ruler M.A., et al: Screening for potential targets for therapy in mesenchymal, clear cell, and dedifferentiated chondrosarcoma reveals Bcl-2 family members and TGFbeta as potential targets. Am J Pathol 2013; 182: pp. 1347-1356

    158. 158. Hoffman A., Ghadimi M.P., Demicco E.G., et al: Localized and metastatic myxoid/round cell liposarcoma: clinical and molecular observations. Cancer 2013; 119: pp. 1868-1877

    159. 159. Ho A.L., Vasudeva S.D., Laé M., et al: PDGF receptor alpha is an alternative mediator of rapamycin-induced Akt activation: implications for combination targeted therapy of synovial sarcoma. Cancer Res 2012; 72: pp. 4515-4525

    160. 160. Llombart B., Monteagudo C., Sanmartín O., et al: Dermatofibrosarcoma protuberans: a clinicopathological, immunohistochemical, genetic (COL1A1-PDGFB), and therapeutic study of low-grade versus high-grade (fibrosarcomatous) tumors. J Am Acad Dermatol 2011; 65: pp. 564-575

    161. 161. Walluks K., Chen Y., Woelfel C., et al: Molecular and clinicopathological analysis of dermatofibrosarcoma protuberans. Pathol Res Pract 2013; 209: pp. 30-35

    162. 162. O’Brien K.P., Seroussi E., Dal Cin P., et al: Various regions within the alpha-helical domain of the COL1A1 gene are fused to the second exon of the PDGFB gene in dermatofibrosarcomas and giant-cell fibroblastomas. Genes Chromosomes Cancer 1998; 23: pp. 187-193

    163. 163. Takagi S., Takemoto A., Takami M., et al: Platelets promote osteosarcoma cell growth through activation of the platelet-derived growth factor receptor-Akt signaling axis. Cancer Sci 2014; 105: pp. 983-988

    164. 164. Rutkowski P., Van Glabbeke M., Rankin C.J., et al: Imatinib mesylate in advanced dermatofibrosarcoma protuberans: pooled analysis of two phase II clinical trials. J Clin Oncol 2010; 28: pp. 1772-1779

    165. 165. Kasper B., Sleijfer S., Litière S., et al: Long-term responders and survivors on pazopanib for advanced soft tissue sarcomas: subanalysis of two European Organisation for Research and Treatment of Cancer (EORTC) clinical trials 62043 and 62072. Ann Oncol 2014; 25: pp. 719-724

    166. 166. van der Graaf W.T., Blay J.Y., Chawla S.P., et al: Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2012; 379: pp. 1879-1886

    167. 167. de Souza R.R., Oliveira I.D., del Giúdice Paniago M., et al: Investigation of IGF2, Hedgehog and fusion gene expression profiles in pediatric sarcomas. Growth Horm IGF Res 2014; 24: pp. 130-136

    168. 168. Crozat A., Aman P., Mandahl N., et al: Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature 1993; 363: pp. 640-644

    169. 169. Rodriguez R., Tornin J., Suarez C., et al: Expression of FUS-CHOP fusion protein in immortalized/transformed human mesenchymal stem cells drives mixoid liposarcoma formation. Stem Cells 2013; 31: pp. 2061-2072

    170. 170. Kobos R., Nagai M., Tsuda M., et al: Combining integrated genomics and functional genomics to dissect the biology of a cancer-associated, aberrant transcription factor, the ASPSCR1-TFE3 fusion oncoprotein. J Pathol 2013; 229: pp. 743-754

    171. 171. Reis H., Hager T., Wohlschlaeger J., et al: Mammalian target of rapamycin pathway activity in alveolar soft part sarcoma. Hum Pathol 2013; 44: pp. 2266-2274

    172. 172. Charytonowicz E., Matushansky I., Doménech J.D., et al: PAX7-FKHR fusion gene inhibits myogenic differentiation via NF-kappaB upregulation. Clin Transl Oncol 2012; 14: pp. 197-206

    173. 173. Bovee J.V., van den Broek L.J., Cleton-Jansen A.M., et al: Up-regulation of PTHrP and Bcl-2 expression characterizes the progression of osteochondroma towards peripheral chondrosarcoma and is a late event in central chondrosarcoma. Lab Invest 2000; 80: pp. 1925-1934

    174. 174. van Oosterwijk J.G., Herpers B., Meijer D., et al: Restoration of chemosensitivity for doxorubicin and cisplatin in chondrosarcoma in vitro: BCL-2 family members cause chemoresistance. Ann Oncol 2012; 23: pp. 1617-1626

    175. 175. Morii T., Ohtsuka K., Ohnishi H., et al: BH3 mimetics inhibit growth of chondrosarcoma–a novel targeted-therapy for candidate models. Anticancer Res 2014; 34: pp. 6423-6430

    176. 176. Schöffski P. CREATE: Cross-tumoral Phase 2 With Crizotinib. ClinicalTrials.gov Identifier NCT01524926. Available at: https://clinicaltrials.gov/ct2/show/NCT01524926?term=nct01524926&rank=1. Accessed July 28, 2015.

    177. 177. Chawla SP, Staddon AP, Baker LH, et al. Study of AP23573/MK-8669 (Ridaforolimus), A Mammalian Target of Rapamycin (mTOR) Inhibitor, in Participants With Advanced Sarcoma (MK-8669–018 AM1). ClinicalTrials.gov Identifier NCT00093080. Available at: https://clinicaltrials.gov/ct2/show/NCT00093080?term=NCT00093080&rank=1. Accessed July 28, 2015.

    178. 178. Yoo C., Lee J., Rha S.Y., et al: Multicenter phase II study of everolimus in patients with metastatic or recurrent bone and soft-tissue sarcomas after failure of anthracycline and ifosfamide. Invest New Drugs 2013; 31: pp. 1602-1608

    179. 179. Wagner L. Cixutumumab and Temsirolimus in Treating Younger Patients With Recurrent or Refractory Sarcoma. ClinicalTrials.gov Identifier NCT01614795. Available at: https://clinicaltrials.gov/ct2/show/NCT01614795?term=nct01614795&rank=1. Accessed July 28, 2015.

    180. 180. Schwartz GK, Tap WD, Qin LX, et al. Temsirolimus and Cixutumumab in Treating Patients With Locally Advanced, Metastatic, or Recurrent Soft Tissue Sarcoma or Bone Sarcoma. ClinicalTrials.gov Identifier NCT01016015. Available at: https://clinicaltrials.gov/ct2/show/NCT01016015?term=NCT01016015&rank=1. Accessed July 28, 2015.

    181. 181. Weigel B. Cixutumumab in Treating Patients With Relapsed or Refractory Solid Tumors. ClinicalTrials.gov Identifier NCT00831844. Available at: https://clinicaltrials.gov/ct2/show/NCT00831844?term=NCT00831844&rank=1. Accessed July 28, 2015.

    182. 182. Tap WD, Demetri G, Barnette P, et al. A Phase 2 Study of AMG 479 in Relapsed or Refractory Ewing’s Family Tumor and Desmoplastic Small Round Cell Tumors. ClinicalTrials.gov Identifier NCT00563680. Available at: https://clinicaltrials.gov/ct2/show/NCT00563680?term=00563680&rank=1. Accessed July 28, 2015.

    183. 183. Pappo AS, Patel SR, Crowley J, et al. A Study of R1507 in Patients With Recurrent or Refractory Sarcoma. ClinicalTrials.gov Identifier NCT00642941. Available at: https://clinicaltrials.gov/ct2/show/NCT00642941?term=00642941&rank=1. Accessed July 28, 2015.

    184. 184. Judson I, Scurr M, Gardner K, et al. The Biological Activity of Cediranib (AZD2171) in Gastro-Intestinal Stromal Tumours(GIST). ClinicalTrials.gov Identifier NCT00385203. Available at: https://clinicaltrials.gov/ct2/show/NCT00385203?term=00385203&rank=1. Accessed July 28, 2015.

    185. 185. Kummar S, Allen D, Monks A, et al. Phase II Study of Cediranib (AZD2171) in Patients With Alveolar Soft Part Sarcoma. ClinicalTrials.gov Identifier NCT00942877. Available at: https://clinicaltrials.gov/ct2/show/NCT00942877?term=00942877&rank=1. Accessed July 28, 2015.

    186. 186. Agulnik M. Bevacizumab in Treating Patients With Angiosarcoma. ClinicalTrials.gov Identifier NCT00288015. Available at: https://clinicaltrials.gov/ct2/show/NCT00288015?term=00288015&rank=1. Accessed July 28, 2015.

    187. 187. Baruchel S, Pappo A, Krailo M, et al. Trabectedin in Treating Young Patients With Recurrent or Refractory Soft Tissue Sarcoma or Ewing’s Family of Tumors. ClinicalTrials.gov Identifier: NCT00070109. Available at: https://clinicaltrials.gov/ct2/show/NCT00070109?term=00070109&rank=1. Accessed July 28, 2015.

    188. 188. Butrynski JE. Doxorubicin Hydrochloride or Trabectedin in Treating Patients With Previously Untreated Advanced or Metastatic Soft Tissue Sarcoma. ClinicalTrials.gov Identifier NCT01189253. Available at: https://clinicaltrials.gov/ct2/show/NCT01189253?term=NCT01189253&rank=1. Accessed July 28, 2015.

    189. 189. Cesne A.L., Judson I., Maki R., et al: Trabectedin is a feasible treatment for soft tissue sarcoma patients regardless of patient age: a retrospective pooled analysis of five phase II trials. Br J Cancer 2013; 109: pp. 1717-1724

    190. 190. Le Cesne A, Blay JY, Domont J, et al. Continuing vs Intermittent Trabectedin-regimen in Patients With Advanced Soft Tissue Sarcoma Experiencing Response or Stable Disease After the 6th Cycle (T-DIS). ClinicalTrials.gov Identifier: NCT01303094. Available at: https://clinicaltrials.gov/ct2/show/NCT01303094?term=01303094&rank=1. Accessed July 28, 2015.

    191. 191. Grignani G. Imatinib in Patients With Desmoid Tumor and Chondrosarcoma (Basket 1). ClinicalTrials.gov Identifier: NCT00928525. Available at: https://clinicaltrials.gov/ct2/show/NCT00928525?term=grignani+imatinib&rank=1. Accessed July 28, 2015.

    192. 192. Ugurel S., Mentzel T., Utikal J., et al: Neoadjuvant imatinib in advanced primary or locally recurrent dermatofibrosarcoma protuberans: a multicenter phase II DeCOG trial with long-term follow-up. Clin Cancer Res 2014; 20: pp. 499-510

    193. 193. Sugiura H., Fujiwara Y., Ando M., et al: Multicenter phase II trial assessing effectiveness of imatinib mesylate on relapsed or refractory KIT-positive or PDGFR-positive sarcoma. J Orthop Sci 2010; 15: pp. 654-660

    194. 194. Dickson M. PD0332991 in Patients With Advanced or Metastatic Liposarcoma. ClinicalTrials.gov Identifier: NCT01209598. Available at: https://clinicaltrials.gov/ct2/show/NCT01209598?term=NCT01209598&rank=1. Accessed July 28, 2015.

    195. 195. Ebb D. Chemotherapy With or Without Trastuzumab in Treating Patients With Metastatic Osteosarcoma. ClinicalTrials.gov Identifier: NCT00023998. Available at: https://clinicaltrials.gov/ct2/show/NCT00023998?term=NCT00023998&rank=1. Accessed July 28, 2015.

    196. 196. Von Mehren M, Demetri GD. S0505 Sorafenib in Treating Patients With Advanced Soft Tissue Sarcomas. ClinicalTrials.gov Identifier: NCT00217620. Available at: https://clinicaltrials.gov/ct2/show/NCT00217620?term=00217620&rank=1. Accessed July 28, 2015.

    197. 197. Grignani G. Sorafenib in Relapsed High Grade Osteosarcoma. ClinicalTrials.gov Identifier: NCT00889057. Available at: https://clinicaltrials.gov/ct2/show/NCT00889057?term=NCT00889057&rank=1. Accessed July 28, 2015.

    198. 198. Aglietta M. Phase II Open Label, Non-randomized Study of Sorafenib and Everolimus in Relapsed and Non-resectable Osteosarcoma (SERIO). ClinicalTrials.gov Identifier: NCT01804374. Available at: https://clinicaltrials.gov/ct2/show/NCT01804374?term=NCT01804374&rank=1. Accessed July 28, 2015.

    199. 199. Sleijfer S, Ray-Coquard I, Papai Z, et al. Pazopanib In Patients With Relapsed Or Refractory Soft Tissue Sarcoma. ClinicalTrials.gov Identifier: NCT00297258. Available at: https://clinicaltrials.gov/ct2/show/NCT00297258?term=NCT00297258&rank=1. Accessed July 28, 2015.

    Only gold members can continue reading. Log In or Register to continue

    Related posts:

    Default ThumbnailLiposomal Bupivacaine Discoid Meniscus Default ThumbnailThe Effect of Osteoporosis on Healing of Distal Radius Fragility Fractures Default ThumbnailTraumatic Knee Dislocations Default ThumbnailPercutaneous Sacroiliac Screw Fixation of the Posterior Pelvic Ring Default ThumbnailScapholunate Ligament Tears

    Stay updated, free articles. Join our Telegram channel
    Tags:
    Feb 23, 2017 | Posted by in ORTHOPEDIC | Comments Off on Targeted Chemotherapy in Bone and Soft-Tissue Sarcoma

    Full access? Get Clinical Tree
    Get Clinical Tree app for offline access