Abstract
Unresectable or metastatic disease occurs in 40% to 60% of soft-tissue sarcoma (STS) patients and portends a poor prognosis. For decades, doxorubicin has formed the backbone of systemic treatment, with response rates of approximately 26%. Patients progressing following first-line therapy were left with few proven options. No other cytotoxic chemotherapy agent or combination has demonstrated superiority to doxorubicin. Advances in targeted therapy of STS have been hindered by STS heterogeneity and poorly understood disease biology. Despite challenges, progress has been made in specific STS subtypes. Here, we highlight the challenges, progress, and lessons learned from STS trials published in the last 20 to 25 years.
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References
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Jemal A et al. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277–300.
Nascimento AF, Raut CP. Diagnosis and management of pleomorphic sarcomas (so-called “MFH”) in adults. J Surg Oncol. 2008;97(4):330–9.
Weitz J, Antonescu CR, Brennan MF. Localized extremity soft tissue sarcoma: improved knowledge with unchanged survival over time. J Clin Oncol. 2003;21(14):2719–25.
Wunder JS et al. Opportunities for improving the therapeutic ratio for patients with sarcoma. Lancet Oncol. 2007;8(6):513–24.
Karavasilis V et al. Significant clinical benefit of first-line palliative chemotherapy in advanced soft-tissue sarcoma: retrospective analysis and identification of prognostic factors in 488 patients. Cancer. 2008;112(7):1585–91.
• Van Glabbeke, M., et al. Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: an analysis of 2,185 patients treated with anthracycline-containing first-line regimens—a European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol. 1999;17(1):150–7. A large meta-analysis to determine the efficacy of anthracycline regimens in treatment of sarcoma in the first-line setting.
Lehnhardt M et al. MFH revisited: outcome after surgical treatment of undifferentiated pleomorphic or not otherwise specified (NOS) sarcomas of the extremities—an analysis of 140 patients. Langenbecks Arch Surg. 2009;394(2):313–20.
Poremba C. Soft tissue sarcomas: the role of histology and molecular pathology for differential diagnosis. Verh Dtsch Ges Pathol. 2006;90:59–72.
Iwasaki H et al. Pathology of soft-tissue tumors: daily diagnosis, molecular cytogenetics and experimental approach. Pathol Int. 2009;59(8):501–21.
Borden EC et al. Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas. J Clin Oncol. 1987;5(6):840–50.
Gelderblom H, et al. Brostallicin versus doxorubicin as first-line chemotherapy in patients with advanced or metastatic soft tissue sarcoma: an EORTC Soft Tissue and Bone Sarcoma Group randomized phase II study. ASCO Meeting Abstracts. 2010;28(15_suppl):10037.
Judson I et al. Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2001;37(7):870–7.
Lorigan P et al. Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol. 2007;25(21):3144–50.
Maurel J et al. Efficacy of sequential high-dose doxorubicin and ifosfamide compared with standard-dose doxorubicin in patients with advanced soft tissue sarcoma: an open-label randomized phase II study of the Spanish group for research on sarcomas. J Clin Oncol. 2009;27(11):1893–8.
Mouridsen HT et al. Adriamycin versus epirubicin in advanced soft tissue sarcomas. A randomized phase II/phase III study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer Clin Oncol. 1987;23(10):1477–83.
Nielsen OS et al. High-dose epirubicin is not an alternative to standard-dose doxorubicin in the treatment of advanced soft tissue sarcomas. A study of the EORTC soft tissue and bone sarcoma group. Br J Cancer. 1998;78(12):1634–9.
• Santoro A, et al. Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol. 1995;13(7):1537–45. A large randomized phase 3 study demonstrating no statistically significant difference in ORR or OS between doxorubicin alone compared to doxorubicin plus ifosfamide.
Verweij J et al. Randomized phase II study of docetaxel versus doxorubicin in first- and second-line chemotherapy for locally advanced or metastatic soft tissue sarcomas in adults: a study of the european organization for research and treatment of cancer soft tissue and bone sarcoma group. J Clin Oncol. 2000;18(10):2081–6.
• Edmonson JH, et al. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol. 1993;11(7):1269–75. A randomized phase 3 study demonstrating that ifosfamide plus doxorubicin yields a statistically significant increase in ORR compared to doxorubicin alone, but both regimens lead to similar overall survival outcomes.
• Sleijfer S 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(1):72–83. An important meta-analysis that establishes the prognostic and predictive factors for outcome of ifosfamide-containing regimens compared to doxorubicin-containing therapy in the first-line setting. Also important for benchmarks of single-agent doxorubicin.
Adriamycin, [package insert]. USA: Pharmacia & Upjohn, 1997.
• Smith LA, et al. Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials. BMC Cancer. 2010;10:337. A systematic review and meta-analysis to identify the risk of cardiotoxicity of anthracycline agents.
Casper ES et al. A prospective randomized trial of adjuvant chemotherapy with bolus versus continuous infusion of doxorubicin in patients with high-grade extremity soft tissue sarcoma and an analysis of prognostic factors. Cancer. 1991;68(6):1221–9.
Zalupski M et al. Phase III comparison of doxorubicin and dacarbazine given by bolus versus infusion in patients with soft-tissue sarcomas: a Southwest Oncology Group study. J Natl Cancer Inst. 1991;83(13):926–32.
Nielsen OS et al. Epirubicin is not superior to doxorubicin in the treatment of advanced soft tissue Sarcomas. The Experience of the EORTC Soft Tissue and Bone Sarcoma Group. Sarcoma. 2000;4(1–2):31–5.
Bull FE et al. Phase II trial of mitoxantrone in advanced sarcomas: a Southwest Oncology Group study. Cancer Treat Rep. 1985;69(2):231–3.
Quirt I et al. Phase II study of mitoxantrone in untreated and previously minimally treated patients with metastatic soft tissue sarcomas. Cancer Treat Rep. 1987;71(11):1109–10.
Huh WW et al. Comparison of doxorubicin cardiotoxicity in pediatric sarcoma patients when given with dexrazoxane versus as continuous infusion. Pediatr Hematol Oncol. 2010;27(7):546–57.
Lopez M et al. Randomized prospective clinical trial of high-dose epirubicin and dexrazoxane in patients with advanced breast cancer and soft tissue sarcomas. J Clin Oncol. 1998;16(1):86–92.
Chidiac T et al. Phase II trial of liposomal doxorubicin (Doxil) in advanced soft tissue sarcomas. Invest New Drugs. 2000;18(3):253–9.
Skubitz KM. Phase II trial of pegylated-liposomal doxorubicin (Doxil) in sarcoma. Cancer Investig. 2003;21(2):167–76.
Toma S et al. Liposomal doxorubicin (Caelyx) in advanced pretreated soft tissue sarcomas: a phase II study of the Italian Sarcoma Group (ISG). Anticancer Res. 2000;20(1B):485–91.
Casper ES et al. Phase I trial of dose-intense liposome-encapsulated doxorubicin in patients with advanced sarcoma. J Clin Oncol. 1997;15(5):2111–7.
McTiernan A et al. A Phase II nonrandomised open-label study of liposomal Daunorubicin (DaunoXome) in advanced soft tissue Sarcoma. Sarcoma. 2006;2006(1):41080.
D’Adamo DR et al. Phase II study of doxorubicin and bevacizumab for patients with metastatic soft-tissue sarcomas. J Clin Oncol. 2005;23(28):7135–42.
Tascilar M et al. The pharmacologic basis of ifosfamide use in adult patients with advanced soft tissue sarcomas. Oncologist. 2007;12(11):1351–60.
Bramwell VH et al. Cyclophosphamide versus ifosfamide: a randomized phase II trial in adult soft-tissue sarcomas. The European Organization for Research and Treatment of Cancer [EORTC], Soft Tissue and Bone Sarcoma Group. Cancer Chemother Pharmacol. 1993;31 Suppl 2:S180–4.
Lopez M et al. Single-agent ifosfamide in the treatment of anthracycline-refractory adult sarcomas. Clin Ter. 1998;149(5):331–3.
van Oosterom AT et al. Results of randomised studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) with two different ifosfamide regimens in first- and second-line chemotherapy in advanced soft tissue sarcoma patients. Eur J Cancer. 2002;38(18):2397–406.
Buesa JM 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(8):871–6.
Palumbo R et al. Phase II study of continuous-infusion high-dose ifosfamide in advanced and/or metastatic pretreated soft tissue sarcomas. Ann Oncol. 1997;8(11):1159–62.
Patel SR et al. High-dose ifosfamide in bone and soft tissue sarcomas: results of phase II and pilot studies—dose-response and schedule dependence. J Clin Oncol. 1997;15(6):2378–84.
Cerny T et al. Saturable metabolism of continuous high-dose ifosfamide with mesna and GM-CSF: a pharmacokinetic study in advanced sarcoma patients. Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol. 1999;10(9):1087–94.
Verweij J. High-dose ifosfamide for soft tissue sarcomas: set the scene, or senescence? Ann Oncol. 1998;9(8):807–9.
Rosen G et al. Synovial sarcoma. Uniform response of metastases to high dose ifosfamide. Cancer. 1994;73(10):2506–11.
D’Amato GZ, et al. Preliminary efficacy and safety results of glufosfamide (GLU) in relapsed soft tissue sarcoma: results of a phase II trial. ASCO Meeting Abstracts. 2008;26(15_suppl):10591.
Verschraegen CF, et al. A phase II, randomized, controlled trial of palifosfamide plus doxorubicin versus doxorubicin in patients with soft tissue sarcoma (PICASSO). ASCO Meeting Abstracts. 2010;28(15_suppl):10004.
Chevallier B et al. Epirubicin and ifosfamide in advanced soft tissue sarcoma: a phase II study. Cancer Investig. 1993;11(2):135–9.
Le Cesne A et al. Randomized phase III study comparing conventional-dose doxorubicin plus ifosfamide versus high-dose doxorubicin plus ifosfamide plus recombinant human granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: A trial of the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group. J Clin Oncol. 2000;18(14):2676–84.
Leyvraz S et al. Treatment of advanced soft-tissue sarcomas using a combined strategy of high-dose ifosfamide, high-dose doxorubicin and salvage therapies. Br J Cancer. 2006;95(10):1342–7.
Schutte J et al. Ifosfamide plus doxorubicin in previously untreated patients with advanced soft tissue sarcoma. The EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 1990;26(5):558–61.
Siehl JM et al. Ifosfamide/liposomal daunorubicin is a well tolerated and active first-line chemotherapy regimen in advanced soft tissue sarcoma: results of a phase II study. Cancer. 2005;104(3):611–7.
Worden FP et al. Randomized phase II evaluation of 6 g/m2 of ifosfamide plus doxorubicin and granulocyte colony-stimulating factor (G-CSF) compared with 12 g/m2 of ifosfamide plus doxorubicin and G-CSF in the treatment of poor-prognosis soft tissue sarcoma. J Clin Oncol. 2005;23(1):105–12.
• Antman K. et al. An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol. 1993;11(7):1276–85. A randomized phase 3 study to determine the effects of adding ifosfamide to doxorubicin/dacarbazine. While addition of ifosfamide doubles ORR in a statistically significant manner, it increased toxicity and had no impact on overall survival.
van Hoesel QG et al. Phase II study with docetaxel (Taxotere) in advanced soft tissue sarcomas of the adult. EORTC Soft Tissue and Bone Sarcoma Group. Ann Oncol. 1994;5(6):539–42.
Casper ES et al. Phase II trial of paclitaxel in patients with soft-tissue sarcoma. Cancer Investig. 1998;16(7):442–6.
• Penel N, et al. Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX Study. J Clin Oncol. 2008;26(32):5269–74. Although this is a small phase 2 study, it confirmed observations in other trials which suggested that paclitaxel single agent is active in angiosarcoma.
Gradishar WJ. Albumin-bound paclitaxel: a next-generation taxane. Expert Opin Pharmacother. 2006;7(8):1041–53.
• Butrynski JE, et al. A phase II study of nanoparticle albumin-bound (nab) paclitaxel in the treatment of patients with unresectable or metastatic sarcoma. CTOS Meeting Abstracts, 2010(Abstract #901186). Despite the negative data in this study for nab-paclitaxel as a single agent, this agent may hold potential if used as part of a combination regimen.
Pivot X et al. Phase II trial of paclitaxel-epirubicin in patients with recurrent soft-tissue sarcoma. Am J Clin Oncol. 2002;25(6):561–4.
Bafaloukos D et al. Combination of pegylated liposomal doxorubicin (PLD) and paclitaxel in patients with advanced soft tissue sarcoma: a phase II study of the Hellenic Cooperative Oncology Group. Br J Cancer. 2004;91(9):1639–44.
Ferraresi V et al. Gemcitabine at fixed dose-rate in patients with advanced soft-tissue sarcomas: a mono-institutional phase II study. Cancer Chemother Pharmacol. 2008;63(1):149–55.
Hartmann JT et al. An open label, non-comparative phase II study of gemcitabine as salvage treatment for patients with pretreated adult type soft tissue sarcoma. Invest New Drugs. 2006;24(3):249–53.
Patel SR et al. Phase II clinical investigation of gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation. J Clin Oncol. 2001;19(15):3483–9.
Spath-Schwalbe E et al. Phase II trial of gemcitabine in patients with pretreated advanced soft tissue sarcomas. Anticancer Drugs. 2000;11(5):325–9.
Von Burton G et al. Phase II trial of gemcitabine as first line chemotherapy in patients with metastatic or unresectable soft tissue sarcoma. Am J Clin Oncol. 2006;29(1):59–61.
Dileo P et al. Gemcitabine and vinorelbine combination chemotherapy for patients with advanced soft tissue sarcomas: results of a phase II trial. Cancer. 2007;109(9):1863–9.
Losa R et al. Phase II study with the combination of gemcitabine and DTIC in patients with advanced soft tissue sarcomas. Cancer Chemother Pharmacol. 2007;59(2):251–9.
• Garcia Del Muro X, et al. Randomized phase II study of dacarbazine plus gemcitabine versus DTIC alone in patients with advanced soft tissue sarcoma: a Spanish Group for Research on Sarcomas (GEIS) study. ASCO Meeting Abstracts. 2009;27(15S):10529. The combination of gemcitabine and dacarbazine appears very promising. It may have lower toxicity and similar efficacy to gemcitabine and docetaxel-based regimens. Awaiting publication of these results in formal manuscript.
• Leu KM, et al. Laboratory and clinical evidence of synergistic cytotoxicity of sequential treatment with gemcitabine followed by docetaxel in the treatment of sarcoma. J Clin Oncol. 2004;22(9):1706–12. Interesting in vitro data demonstrating that the sequential treatment of gemcitabine followed by docetaxel was synergistic, whereas simultaneous treatment led to antagonistic effects. Another component of this study is a retrospective analysis to identify the efficacy of gemcitabine/docetaxel by histologic subtype.
Maki RG. Gemcitabine and docetaxel in metastatic sarcoma: past, present, and future. Oncologist. 2007;12(8):999–1006.
• Maki RG, et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected]. J Clin Oncol. 2007;25(19):2755–63. Randomized phase 2 trial of gemcitabine and docetaxel indicating significant activity over single-agent gemcitabine. Novel adaptive randomization strategy.
Ahn J, et al. Phase II study of weekly docetaxel and fixed-dose rate gemcitabine in patients with previously treated advanced soft tissue and bone sarcoma. CTOS Meeting Abstracts, 2010(Abstract #897230).
Ganjoo KN, et al. A phase II study of low dose TAG (taxotere, adriamycin, gemcitabine) as salvage therapy for soft tissue sarcoma. CTOS Meeting Abstracts, 2010(Abstract #896893).
Seddon BM, et al. Phase II study of gemcitabine and docetaxel as first-line chemotherapy in locally advanced/metastatic leiomyosarcoma. ASCO Meeting Abstracts. 2009;27(15S):10528.
• D’Incalci M, Galmarini CM. A review of trabectedin (ET-743): a unique mechanism of action. Mol Cancer Ther. 2010:9(8):2157–63. Detailed description of the unique mechanisms of actions of this novel compound.
Garcia-Carbonero R et al. Ecteinascidin-743 (ET-743) for chemotherapy-naive patients with advanced soft tissue sarcomas: multicenter phase II and pharmacokinetic study. J Clin Oncol. 2005;23(24):5484–92.
Blay J, et al. Trabectedin for advanced sarcomas failing doxorubicin: analysis of 189 unreported patients in a compassionate use program. ASCO Meeting Abstracts. 2009;27(15S):10574.
Garcia-Carbonero R et al. Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy. J Clin Oncol. 2004;22(8):1480–90.
Le Cesne A et al. Phase II study of ET-743 in advanced soft tissue sarcomas: a European Organisation for the Research and Treatment of Cancer (EORTC) soft tissue and bone sarcoma group trial. J Clin Oncol. 2005;23(3):576–84.
Mohan V, et al. Updated results of Phase II study of trabectedin (ET-743) in pretreated patients with advanced/metastatic soft tissue sarcoma from a single institute. ASCO Meeting Abstracts. 2008;26(15_suppl):21506.
Samuels BL, et al. Trabectedin (Tr) as single agent for advanced soft tissue sarcomas (STS) failing standard of care: Interim analysis of 1,400 patients (pts) in an expanded access program study. ASCO Meeting Abstracts. 2010;28(15_suppl):10027.
Yovine A et al. Phase II study of ecteinascidin-743 in advanced pretreated soft tissue sarcoma patients. J Clin Oncol. 2004;22(5):890–9.
Demetri GD et al. Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules. J Clin Oncol. 2009;27(25):4188–96.
Grosso F, et al. Long-term benefit from trabectedin (T) in myxoid liposarcoma (MLS) patients. ASCO Meeting Abstracts. 2008;26(15_suppl):10582.
D’Adamo D. Advances in the treatment of gastrointestinal stromal tumor. Adv Ther. 2009;26(9):826–37.
Demetri GD et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347(7):472–80.
Dematteo RP et al. Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol. 2002;33(5):466–77.
Hirota S et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279(5350):577–80.
Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol. 2004;22(18):3813–25.
Grignani G, et al. A phase II trial of imatinib (IM) in relapsed, nonresectable chondrosarcoma (CS) expressing platelet-derived growth factor receptor-{alpha} or -{beta} (PDGFR-{alpha}/PDGFR-{beta}): An Italian Sarcoma Group study. ASCO Meeting Abstracts. 2010;28(15_suppl):10060.
Sugiura H 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(5):654–60.
Verweij J et al. Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study. Eur J Cancer. 2003;39(14):2006–11.
Chugh R et al. Phase II multicenter trial of imatinib in 10 histologic subtypes of sarcoma using a bayesian hierarchical statistical model. J Clin Oncol. 2009;27(19):3148–53.
Blay JY et al. Complete response to imatinib in relapsing pigmented villonodular synovitis/tenosynovial giant cell tumor (PVNS/TGCT). Ann Oncol. 2008;19(4):821–2.
Casali PG et al. Imatinib mesylate in chordoma. Cancer. 2004;101(9):2086–97.
Chugh R, et al. A SARC phase II multicenter trial of imatinib mesylate (IM) in patients with aggressive fibromatosis. ASCO Meeting Abstracts. 2006;24(18_suppl):9515.
Rutkowski P et al. Imatinib mesylate in advanced dermatofibrosarcoma protuberans: pooled analysis of two phase II clinical trials. J Clin Oncol. 2010;28(10):1772–9.
George S et al. Multicenter phase II trial of sunitinib in the treatment of nongastrointestinal stromal tumor sarcomas. J Clin Oncol. 2009;27(19):3154–60.
Vigil CE, et al. Phase II study of sunitinib malate (SM) in subjects with metastatic and/or surgically unresectable non-GIST soft tissue sarcomas. ASCO Meeting Abstracts. 2008;26(15_suppl):10535.
Ryan CW, et al. Phase II intergroup study of sorafenib (S) in advanced soft tissue sarcomas (STS): SWOG 0505. ASCO Meeting Abstracts. 2008;26(15_suppl):10532.
Maki RG et al. Phase II study of sorafenib in patients with metastatic or recurrent sarcomas. J Clin Oncol. 2009;27(19):3133–40.
Sleijfer S et al. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). J Clin Oncol. 2009;27(19):3126–32.
Schuetze S, et al. Results of a Sarcoma Alliance for Research through Collaboration (SARC) phase II trial of dasatinib in previously treated, high-grade, advanced sarcoma. ASCO Meeting Abstracts. 2010;28(15_suppl):10009.
Sleijfer S, van der Graaf WT, Blay JY. Angiogenesis inhibition in non-GIST soft tissue sarcomas. Oncologist. 2008;13(11):1193–200.
Agulnik M, et al. An open-label multicenter phase II study of bevacizumab for the treatment of angiosarcoma. ASCO Meeting Abstracts. 2009;27(15S):10522.
• Verschraegen CF, et al. Phase I/II study of docetaxel (D), gemcitabine (G), and bevacizumab (B) in patients (pts) with advanced or recurrent soft tissue sarcoma (STS). ASCO Meeting Abstracts. 2008;26(15_suppl):10534. Although a small phase 2 trial, the combination of docetaxel, gemcitabine, and bevacizumab appears very promising.
• Ray-Coquard I, et al. A phase II study of gefitinib for patients with advanced HER-1 expressing synovial sarcoma refractory to doxorubicin-containing regimens. Oncologist 2008;13(4):467–73. A study where the targeted agent is not active despite the presence of molecular target in tumors. Underscores the significance of understanding the underlying biological mechanisms driving tumor progression.
• Ha HT, et al. Phase II trial of cetuximab in patients (pts) with metastatic and/or locally advanced soft tissue and bone sarcomas. ASCO Meeting Abstracts. 2008;26(15_suppl):10537. A study where the targeted agent is not active despite the presence of molecular target in tumors. Underscores the significance of understanding the underlying biological mechanisms driving tumor progression.
Rikhof B et al. The insulin-like growth factor system and sarcomas. J Pathol. 2009;217(4):469–82.
Patel S, et al. A SARC global collaborative phase II trial of R1507, a recombinant human monoclonal antibody to the insulin-like growth factor-1 receptor (IGF1R) in patients with recurrent or refractory sarcomas. ASCO Meeting Abstracts. 2009;27(15S):10503.
Pappo A, et al. A Phase II trial of R1507, a monoclonal antibody to the insulin-like growth factor-1 receptor (IGF1R) in patients with recurrent or refractory bone and soft tissue sarcomas excluding ESFT. CTOS Meeting Abstracts, 2010(Abstract #900715).
Olmos D et al. Biological rationale and current clinical experience with anti-insulin-like growth factor 1 receptor monoclonal antibodies in treating sarcoma: twenty years from the bench to the bedside. Cancer J. 2010;16(3):183–94.
Blay JY. Updating progress in sarcoma therapy with mTOR inhibitors. Ann Oncol. 2010;22(2):280–7.
Richter S, et al. Multicenter, triple-arm, single-stage, phase II trial to determine the efficacy and safety of everolimus (RAD001) in patients with refractory bone or soft tissue sarcomas including GIST. ASCO Meeting Abstracts. 2010;28(15_suppl):10038.
• Chawla SP, et al. Survival results with AP23573, a novel mTOR inhibitor, in patients (pts) with advanced soft tissue or bone sarcomas: Update of phase II trial. ASCO Meeting Abstracts. 2007;25(18_suppl):10076. An example of a well-designed phase 2 trial that is based on promising evidence from phase 1 and 2 trials, Simon’s two-stage design, sound statistical methods (enrolling an adequate number of patients), and segregated patients into cohorts based on their STS histological subtype.
Waehler R, Russell SJ, Curiel DT. Engineering targeted viral vectors for gene therapy. Nat Rev Genet. 2007;8(8):573–87.
Chawla SP et al. Phase I/II and phase II studies of targeted gene delivery in vivo: intravenous Rexin-G for chemotherapy-resistant sarcoma and osteosarcoma. Mol Ther. 2009;17(9):1651–7.
Ganjoo K, et al. Advanced phase I/II evaluation of tumor-targeted gene delivery: intravenous Rexin-G as stand alone therapy for chemotherapy-resistant bone and soft tissue sarcoma. CTOS Meeting Abstracts. 2010(Abstract #896893).
Brizel DM et al. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res. 1996;56(5):941–3.
Duan JX et al. Potent and highly selective hypoxia-activated achiral phosphoramidate mustards as anticancer drugs. J Med Chem. 2008;51(8):2412–20.
Cranmer LD, et al. Phase I/II study of TH-302 combined with doxorubicin in soft tissue sarcoma. ASCO Meeting Abstracts. 2010;28(15_suppl):10036.
Korn EL et al. Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. J Clin Oncol. 2008;26(4):527–34.
• Baird K, et al. Gene expression profiling of human sarcomas: insights into sarcoma biology. Cancer Res. 2005;65(20):9226–35. These references [124–126] highlight the potential of using high-throughput approaches to help understand the underlying biology of STS subtypes.
• Skubitz KM, Skubitz AP. Role of gene expression arrays in sarcomas. Curr Oncol Rep. 2004;6(4):309–14. These references [124–126] highlight the potential of using high-throughput approaches to help understand the underlying biology of STS subtypes.
• West RB, van de Rijn M. The role of microarray technologies in the study of soft tissue tumours. Histopathology. 2006;48(1):22–31. These references [124–126] highlight the potential of using high-throughput approaches to help understand the underlying biology of STS subtypes.
• Choi H. Critical issues in response evaluation on computed tomography: lessons from the gastrointestinal stromal tumor model. Curr Oncol Rep. 2005;7(4):307–11. This paper addresses lessons learned from GIST on how response to targeted agents is measured and evaluated.
• Korn EL, et al. Clinical trial designs for cytostatic agents: are new approaches needed? J Clin Oncol. 2001;19(1):265–72. A critical evaluation of appropriate end points, statistical considerations, and clinical trial designs for testing cytostatic agents.
• Van Glabbeke M, et al. Progression-free rate as the principal end-point for phase II trials in soft-tissue sarcomas. Eur J Cancer. 2002;38(4):543–9. An important paper characterizing the use of progression-free rate as a primary end point in STS trials.
Acknowledgments
We would like to thank Jennie Brown for assistance in preparation and submission of the manuscript. This work is supported in part by a Career Development Award from the Phoenix Friends of the Arizona Cancer Center.
Disclosure
S. S. Morgan: none; L. D. Cranmer: honoraria from Merck and Amgen for speakers’ bureau activities; unpaid consultant for Threshold Pharmaceuticals.
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Morgan, S.S., Cranmer, L.D. Systematic Therapy for Unresectable or Metastatic Soft-Tissue Sarcomas: Past, Present, and Future. Curr Oncol Rep 13, 331–349 (2011). https://doi.org/10.1007/s11912-011-0182-z
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DOI: https://doi.org/10.1007/s11912-011-0182-z