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.


Key points








  • The evolution of our medical knowledge regarding sarcoma is explored, with special emphasis on its application to targeted chemotherapy as a treatment modality.



  • The basic science behind sarcomatogenesis is discussed to identify common links among disparate tumor types. These common links offer targets that are being increasingly studied as novel treatments in sarcoma.



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






Introduction


Bone sarcomas and soft-tissue sarcomas (STS) encompass a heterogeneous group of human cancers that derive from the embryonic mesoderm. The diversity of sarcomas, with respect to histology, natural history, therapeutic sensitivities, and metastatic potential, stems in part from the diversity of mesodermic tissue, which includes bone, cartilage, adipose, muscle, vasculature, and hematopoietic. In the orthopedic literature, sarcomas tend to be broadly categorized as either of bone or soft tissue in origin. However, recent genomic and molecular discoveries ( Table 1 ) have enabled us to reclassify these tumors and expand our therapeutic breadth to include optimized (and often personalized) cytotoxic chemotherapeutic regimens, radiopharmaceuticals, oncolytic viruses, immune-modulating therapies, and—the focus of this review—targeted chemotherapeutic agents. Although the mainstay of therapy for localized sarcoma remains surgical resection, neoadjuvant and adjuvant chemotherapy, and radiation, play an essential role in both local and systemic control.



Table 1

Molecular characterization of STS with specific genetic alterations

































































































Genetic Aberration Histotype Translocation a Genes Involved b
Chromosomal Translocations (10%–15%)
Aberrant transcription Myxoid liposarcoma t(12;16) (q13;p11)
t(12;22) (q13;q11–q12)
FUS-DDIT3EWSR1-DDIT3
Synovial sarcoma t(X;18) (p11;q11)
t(X;18) (p11;q11)
SS18-SSX1
SS18-SSX2
ASPS t(X;17) (p11.2;q25) ASPL-TFE3
Low-grade ESS t(7;17) (p15;q21) JAZF1-SUZ12
Ewing sarcoma/PNET t(11;22) (q24;q12)
t(21;22) (q22;q12)
EWSR1-FLI1
EWSR1-ERG
DSRCT t(11;22) (p13;q12) WT1-EWSR1
Clear-cell sarcoma t(12;22) (q13;q12) ATF1-EWSR1
Alveolar rhabdomyosarcoma t(2;13) (p36;q14)
t(1;13) (p36;q14)
PAX3-FOXO1
PAX7-FOXO1
IMT t(2;19) (p23;p13.1)
t(1:2) (q22–23;p23)
TPM4-ALK
TPM3-ALK
Low-grade fibromyxoid sarcoma t(7;16) (q32–34;p11)
t(11;16) (p11;p11)
FUS-CREB3L2
FUS-CREB3L1
Fusion (increased expression of kinase) Dermatofibrosarcoma t(17;22) (q22;q13) COL1A1-PDGFB
Chimeric (ligand independent kinase activation) Infantile fibrosarcoma t(12;15) (p13;q25) ETV6-NTRK3
Oncogenic Mutations (20%)
Activating GIST NA c-KIT, PDGFA, BRAF
MRCLS NA PI3CA
Inactivating MPNST NA NF-1
Rhabdoid tumors NA INI1
PEComa family NA TSC1/2
Gene Amplification (10%–15%)
NA WDLS/DDLS NA MDM2
CDK4
c-JUN
Intimal sarcomas NA MDM2
CDK4

Abbreviations: DDLS, dedifferentiated liposarcoma; DSRCT, desmoplastic small round cell tumor; ESS, endometrial stromal tumor; GIST, gastrointestinal stromal tumor; IMT, inflammatory myofibroblastic tumor; MPNST, malignant peripheral nerve sheath tumor; MRCLS, myxoid round cell liposarcoma; NA, not available/applicable; EComa, perivascular epithelioid cell tumor; PNET, primitive neuroectodermal tumor; WDLS, well-differentiated liposarcoma.

From Linch M, Miah AB, Thway K, et al. Systemic treatment of soft-tissue sarcoma—gold standard and novel therapies. Nat Rev Clin Oncol 2014;11(4):189; with permission.

a Translocations with a prevalence of greater than 5% are included.


b Sarcomas with specific genetic alterations (40%–50%). The approximate percentage of STS made up by the specified genomic group is shown in parentheses. Sarcoma with complex genomics (50%–60%) comprises the following: leiomyosarcoma, myofibrosarcoma, pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma, undifferentiated pleomorphic sarcoma.



The effect of chemotherapy has been most profound in the management of localized primary bone sarcomas, including osteosarcoma and Ewing sarcoma (ES). Link and colleagues conducted one of the first randomized controlled trials showing the benefit of adjuvant chemotherapy in patients with localized osteosarcoma. At 2 years, patients who received chemotherapy had improved relapse-free survival of 66% compared with 17%; however, because of the short duration, they were unable to show an improvement in overall survival. Similar results were demonstrated by Eilber and colleagues in 1987, recently validated with long-term follow-up showing a durable improvement in overall survival with adjuvant chemotherapy. In the decades following, clinical research has focused primarily on optimizing adjuvant cytotoxic regimens, including the initiation of neoadjuvant chemotherapy. Current National Comprehensive Cancer Network guidelines recommend 1 of 4 first-line regimens including cisplatin/doxorubicin, high-dose methotrexate/cisplatin/doxorubicin with or without ifosfamide, or ifosfamide/cisplatin/epirubicin. Despite the relative success in the treatment of nonmetastatic osteosarcoma, progression-free survival (PFS) and overall survival in metastatic osteosarcoma remains poor and an area that demands innovation.


Similarly to osteosarcoma, ES of bone has a predilection for adolescents and a tendency to have subclinical micrometastases at the time of presentation. More specifically, analysis of a large cohort of ES patients demonstrated that 18.4% presented with metastatic disease. The addition of chemotherapy to the treatment algorithm in ES similarly revolutionized treatment outcomes in localized ES. After further studies optimizing sequencing and timing of the chemotherapeutic agents, current treatment regimens involve neoadjuvant chemotherapy with a combination of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide, followed by surgery and adjuvant chemotherapy with or without radiation. This treatment strategy results in a 5-year relapse-free and overall survival of 52% to 78% in localized ES, with outcomes closely tied to the histologic response to neoadjuvant therapy and the presence of metastatic disease. Unfortunately, as with osteosarcoma, despite the optimization of cytotoxic regimens the 10-year overall survival in patients with metastatic ES is only 27% to 39%.


Chondrosarcoma, a heterogeneous group of malignant cartilaginous tumors most commonly seen in the adult population, has traditionally been considered both chemoresistant and radiation resistant. At present, surgical resection is the primary treatment modality; however, in patients with high-grade/metastatic disease or certain histologic subtypes adjuvant therapy may be considered, underscoring the importance of novel targeted therapies in high-risk patients. STS are traditionally considered to be chemoresistant tumors, and therapy relies heavily on surgical resection and, if a high-grade lesion, localized radiation to improve local control. The 5-year survival of nonmetastatic high-grade STS of the extremity is approximately 70%, with local recurrence having the greatest effect on survival. However, in the setting of metastatic high-grade extremity STS, survival is dismal, with 3-year survival rates less than 20%. There are, however, certain groups of patients that do benefit from systemic chemotherapy. Meta-analysis of doxorubicin-based adjuvant chemotherapy has demonstrated an improvement in time to recurrence and overall recurrence-free survival, an effect that was more significant in extremity STS. Unfortunately, this improvement in recurrence rate did not translate into an increased overall survival. Additional studies and a recent meta-analysis have supported the use of high-dose ifosfamide as an additional first-line agent.


Further evaluation of specific histologic subtypes has shown a small number of STS that are particularly responsive to adjuvant chemotherapy. The ANGIOTAX study, a phase II clinical trial investigating the effect of paclitaxel in patients with metastatic or unresectable angiosarcoma, demonstrated a modest clinical benefit. With the addition of paclitaxel the PFS at 2 months was 74%, however, this was not a durable response with only a 24% PFS at 6 months and an overall 18-month survival of 21%. In patients with liposarcoma, doxorubicin remains the agent of choice; interestingly the myxoid liposarcoma variant is particularly sensitive to cytotoxic regimens. Finally, historical data show that synovial cell sarcoma is sensitive to high-dose ifosfamide therapy, a finding that was further supported by a large retrospective analysis of patients with STS treated in the European Organization for Research and Treatment of Cancer (EORTC)/Soft Tissue and Bone Sarcoma Group. A common constraint with the aforementioned regimens is discontinuation secondary to dosing limitations with long-term therapy, possibly leading to relapse with poor outcomes. In a 2011 review by Patrikidou and colleagues, several key limitations with the use of adjuvant chemotherapy in STS were discussed. Specifically, the lack of homogenous subtype studies attributable to the rarity of STS and the need for subtype targeted therapy was highlighted.


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.




Introduction


Bone sarcomas and soft-tissue sarcomas (STS) encompass a heterogeneous group of human cancers that derive from the embryonic mesoderm. The diversity of sarcomas, with respect to histology, natural history, therapeutic sensitivities, and metastatic potential, stems in part from the diversity of mesodermic tissue, which includes bone, cartilage, adipose, muscle, vasculature, and hematopoietic. In the orthopedic literature, sarcomas tend to be broadly categorized as either of bone or soft tissue in origin. However, recent genomic and molecular discoveries ( Table 1 ) have enabled us to reclassify these tumors and expand our therapeutic breadth to include optimized (and often personalized) cytotoxic chemotherapeutic regimens, radiopharmaceuticals, oncolytic viruses, immune-modulating therapies, and—the focus of this review—targeted chemotherapeutic agents. Although the mainstay of therapy for localized sarcoma remains surgical resection, neoadjuvant and adjuvant chemotherapy, and radiation, play an essential role in both local and systemic control.



Table 1

Molecular characterization of STS with specific genetic alterations

































































































Genetic Aberration Histotype Translocation a Genes Involved b
Chromosomal Translocations (10%–15%)
Aberrant transcription Myxoid liposarcoma t(12;16) (q13;p11)
t(12;22) (q13;q11–q12)
FUS-DDIT3EWSR1-DDIT3
Synovial sarcoma t(X;18) (p11;q11)
t(X;18) (p11;q11)
SS18-SSX1
SS18-SSX2
ASPS t(X;17) (p11.2;q25) ASPL-TFE3
Low-grade ESS t(7;17) (p15;q21) JAZF1-SUZ12
Ewing sarcoma/PNET t(11;22) (q24;q12)
t(21;22) (q22;q12)
EWSR1-FLI1
EWSR1-ERG
DSRCT t(11;22) (p13;q12) WT1-EWSR1
Clear-cell sarcoma t(12;22) (q13;q12) ATF1-EWSR1
Alveolar rhabdomyosarcoma t(2;13) (p36;q14)
t(1;13) (p36;q14)
PAX3-FOXO1
PAX7-FOXO1
IMT t(2;19) (p23;p13.1)
t(1:2) (q22–23;p23)
TPM4-ALK
TPM3-ALK
Low-grade fibromyxoid sarcoma t(7;16) (q32–34;p11)
t(11;16) (p11;p11)
FUS-CREB3L2
FUS-CREB3L1
Fusion (increased expression of kinase) Dermatofibrosarcoma t(17;22) (q22;q13) COL1A1-PDGFB
Chimeric (ligand independent kinase activation) Infantile fibrosarcoma t(12;15) (p13;q25) ETV6-NTRK3
Oncogenic Mutations (20%)
Activating GIST NA c-KIT, PDGFA, BRAF
MRCLS NA PI3CA
Inactivating MPNST NA NF-1
Rhabdoid tumors NA INI1
PEComa family NA TSC1/2
Gene Amplification (10%–15%)
NA WDLS/DDLS NA MDM2
CDK4
c-JUN
Intimal sarcomas NA MDM2
CDK4

Abbreviations: DDLS, dedifferentiated liposarcoma; DSRCT, desmoplastic small round cell tumor; ESS, endometrial stromal tumor; GIST, gastrointestinal stromal tumor; IMT, inflammatory myofibroblastic tumor; MPNST, malignant peripheral nerve sheath tumor; MRCLS, myxoid round cell liposarcoma; NA, not available/applicable; EComa, perivascular epithelioid cell tumor; PNET, primitive neuroectodermal tumor; WDLS, well-differentiated liposarcoma.

From Linch M, Miah AB, Thway K, et al. Systemic treatment of soft-tissue sarcoma—gold standard and novel therapies. Nat Rev Clin Oncol 2014;11(4):189; with permission.

a Translocations with a prevalence of greater than 5% are included.


b Sarcomas with specific genetic alterations (40%–50%). The approximate percentage of STS made up by the specified genomic group is shown in parentheses. Sarcoma with complex genomics (50%–60%) comprises the following: leiomyosarcoma, myofibrosarcoma, pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma, undifferentiated pleomorphic sarcoma.



The effect of chemotherapy has been most profound in the management of localized primary bone sarcomas, including osteosarcoma and Ewing sarcoma (ES). Link and colleagues conducted one of the first randomized controlled trials showing the benefit of adjuvant chemotherapy in patients with localized osteosarcoma. At 2 years, patients who received chemotherapy had improved relapse-free survival of 66% compared with 17%; however, because of the short duration, they were unable to show an improvement in overall survival. Similar results were demonstrated by Eilber and colleagues in 1987, recently validated with long-term follow-up showing a durable improvement in overall survival with adjuvant chemotherapy. In the decades following, clinical research has focused primarily on optimizing adjuvant cytotoxic regimens, including the initiation of neoadjuvant chemotherapy. Current National Comprehensive Cancer Network guidelines recommend 1 of 4 first-line regimens including cisplatin/doxorubicin, high-dose methotrexate/cisplatin/doxorubicin with or without ifosfamide, or ifosfamide/cisplatin/epirubicin. Despite the relative success in the treatment of nonmetastatic osteosarcoma, progression-free survival (PFS) and overall survival in metastatic osteosarcoma remains poor and an area that demands innovation.


Similarly to osteosarcoma, ES of bone has a predilection for adolescents and a tendency to have subclinical micrometastases at the time of presentation. More specifically, analysis of a large cohort of ES patients demonstrated that 18.4% presented with metastatic disease. The addition of chemotherapy to the treatment algorithm in ES similarly revolutionized treatment outcomes in localized ES. After further studies optimizing sequencing and timing of the chemotherapeutic agents, current treatment regimens involve neoadjuvant chemotherapy with a combination of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide, followed by surgery and adjuvant chemotherapy with or without radiation. This treatment strategy results in a 5-year relapse-free and overall survival of 52% to 78% in localized ES, with outcomes closely tied to the histologic response to neoadjuvant therapy and the presence of metastatic disease. Unfortunately, as with osteosarcoma, despite the optimization of cytotoxic regimens the 10-year overall survival in patients with metastatic ES is only 27% to 39%.


Chondrosarcoma, a heterogeneous group of malignant cartilaginous tumors most commonly seen in the adult population, has traditionally been considered both chemoresistant and radiation resistant. At present, surgical resection is the primary treatment modality; however, in patients with high-grade/metastatic disease or certain histologic subtypes adjuvant therapy may be considered, underscoring the importance of novel targeted therapies in high-risk patients. STS are traditionally considered to be chemoresistant tumors, and therapy relies heavily on surgical resection and, if a high-grade lesion, localized radiation to improve local control. The 5-year survival of nonmetastatic high-grade STS of the extremity is approximately 70%, with local recurrence having the greatest effect on survival. However, in the setting of metastatic high-grade extremity STS, survival is dismal, with 3-year survival rates less than 20%. There are, however, certain groups of patients that do benefit from systemic chemotherapy. Meta-analysis of doxorubicin-based adjuvant chemotherapy has demonstrated an improvement in time to recurrence and overall recurrence-free survival, an effect that was more significant in extremity STS. Unfortunately, this improvement in recurrence rate did not translate into an increased overall survival. Additional studies and a recent meta-analysis have supported the use of high-dose ifosfamide as an additional first-line agent.


Further evaluation of specific histologic subtypes has shown a small number of STS that are particularly responsive to adjuvant chemotherapy. The ANGIOTAX study, a phase II clinical trial investigating the effect of paclitaxel in patients with metastatic or unresectable angiosarcoma, demonstrated a modest clinical benefit. With the addition of paclitaxel the PFS at 2 months was 74%, however, this was not a durable response with only a 24% PFS at 6 months and an overall 18-month survival of 21%. In patients with liposarcoma, doxorubicin remains the agent of choice; interestingly the myxoid liposarcoma variant is particularly sensitive to cytotoxic regimens. Finally, historical data show that synovial cell sarcoma is sensitive to high-dose ifosfamide therapy, a finding that was further supported by a large retrospective analysis of patients with STS treated in the European Organization for Research and Treatment of Cancer (EORTC)/Soft Tissue and Bone Sarcoma Group. A common constraint with the aforementioned regimens is discontinuation secondary to dosing limitations with long-term therapy, possibly leading to relapse with poor outcomes. In a 2011 review by Patrikidou and colleagues, several key limitations with the use of adjuvant chemotherapy in STS were discussed. Specifically, the lack of homogenous subtype studies attributable to the rarity of STS and the need for subtype targeted therapy was highlighted.


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

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Oct 6, 2017 | Posted by in ORTHOPEDIC | Comments Off on Targeted Chemotherapy in Bone and Soft-Tissue Sarcoma
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