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.


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