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Table of Contents
INTERESTING ONGOING TRIALS
Year : 2018  |  Volume : 1  |  Issue : 2  |  Page : 121-138

Current treatment landscape and emerging management options for extremity sarcoma


Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication17-May-2019

Correspondence Address:
Siddharth Turkar
Room 1102 HBB, Department of Medical Oncology, Tata Memorial Hospital, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_9_19

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  Abstract 


Malignant tumors of extremity are mostly of mesenchymal origin and arise from bone or extraskeletal soft tissue. Combination chemotherapy has greatly increased the survival of non-metastatic localized osteosarcoma and Ewing's sarcoma; however, there is conflicting evidence regarding the role of neoadjuvant and adjuvant chemotherapy in soft tissue sarcoma due to the rarity and heterogeneous population. Despite intensive multimodal therapy and valiant efforts, most of the patients with relapsed and metastatic sarcoma will succumb to their disease. Molecular studies like next-generation sequencing have revealed various targetable biomarkers which can be further explored in the therapeutic landscape with specific targeted therapies. We reviewed all ongoing and completed clinical trials involving chemotherapy, targeted therapy, and immunotherapy valid for patients with extremity sarcoma. We present the current viable therapeutic options for such a cohort of patients in routine clinical practice.

Keywords: Ewing Sarcoma, extremity, osteogenic sarcoma, sarcoma


How to cite this article:
Turkar S. Current treatment landscape and emerging management options for extremity sarcoma. Cancer Res Stat Treat 2018;1:121-38

How to cite this URL:
Turkar S. Current treatment landscape and emerging management options for extremity sarcoma. Cancer Res Stat Treat [serial online] 2018 [cited 2019 Aug 24];1:121-38. Available from: http://www.crstonline.com/text.asp?2018/1/2/121/258547




  Introduction Top


Malignant tumors of extremity are mostly of mesenchymal origin and arise from bone or extraskeletal soft tissue, including the peripheral nervous system, and comprise less than 1% of all adult malignancies and 12% of pediatric cancers.[1] Osteosarcoma (OGS), chondrosarcoma (CS), and Ewing's sarcoma (ES) are the three most common form of bone cancers. Distinct patterns of incidence are observed in different bone tumor subtypes and have no more than 0.3 incident cases per 100,000 per year.[1] OGS and ES have a relatively high incidence in the second decade of life, whereas CS is more common in older age group. Soft tissue sarcomas (STSs) comprise heterogeneous group of rare tumors that arise from mesenchymal cells at all body sites. Three-fourths of the STS seen in adults (>29 years) are high-grade pleomorphic sarcoma, liposarcoma, leiomyosarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumor (MPNST). STSs are categorized as adipocytic tumors, fibroblastic/myofibroblastic, smooth muscle tumors, pericytic (perivascular) tumors, skeletal muscle tumors, vascular tumors of soft tissue, chondro-osseous tumors, gastrointestinal stromal tumors (GIST), nerve sheath tumors, tumors of uncertain differentiation, and undifferentiated/unclassified sarcomas.

Although multimodal chemotherapy treatment of nonmetastatic localized OGS and ES has significantly improved disease-free survival, there is conflicting evidence of the role and choices of chemotherapy regimens in STS.

Although the prognosis of localized extremity tumor is good with multimodality treatment, metastatic disease still has poor outcome, and treatment relies mainly on systemic chemotherapy for palliation.

The primary focus of this review is to highlight the recent advances and new therapeutic developments for these neoplasms. We reviewed the available literature on completed and ongoing registered clinical trials for newer chemotherapeutic approach and cytotoxic drugs, targeted agents, and immunotherapeutic regimens in various extremity sarcomas.


  Materials and Methods Top


We accessed the online available database of privately funded and public-funded clinical studies conducted around the world at https://clinicaltrials.gov/, which is maintained by the National Library of Medicine at the National Institute of Health. This website contains summary information on study participants and study outcomes including adverse events for clinical trials registered in its database. We used the search terms “extremity tumor,” “sarcoma,” “osteosarcoma,” “Ewings sarcoma,” and “bone tumors” under disease or condition, without any filters. The studies selected for the current review included Phase III, Phase II, and Phase I with Phase II extension trials, including chemotherapy, targeted therapy, radiation therapy, and immunotherapy enrolling patients with extremity soft tissue and bone sarcoma [Figure 1]. We performed a Medline search for results of completed studies. The references of various review articles were also reviewed for additional information. We included in the final list all ongoing, completed, and active (non-recruiting and recruiting) clinical trials. We excluded studies that were registered but withdrawn, prematurely terminated, having unknown status, or pure Phase I dose finding/maximum tolerated dose trials. Studies exploring chemotherapeutic interventions having firm role in treatment were excluded from the results and are discussed briefly in the discussion section.
Figure 1: Flowchart depicting search methodology

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  Results Top


This review included 66 clinical Phase III, Phase II, and Phase I with Phase II extension studies evaluating various treatment interventions in STS,[21] osteogenic sarcoma,[21] and ES [10] [Table 1], [Table 2], [Table 3]. We also included the studies [14] evaluating drugs in a broad variety of tumor types (including soft tissue tumors and bone tumors) [Table 4].
Table 1: Ongoing trials in soft tissue sarcoma

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Table 2: Ongoing trials in osteogenic sarcoma

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Table 3: Ongoing trials in Ewing's sarcoma (soft tissue sarcomas)

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Table 4: Ongoing trials including broad group of tumors

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  Discussion Top


Bone tumors

Bone tumors are mostly benign and are usually discovered incidentally. Among young people, primary malignant bone tumors are a significant cause of cancer morbidity and mortality. The peak incidence is between 10 and 15 years of age for both ES and OGS, coinciding with the time of adolescent growth spurt. Remarkable progress in surgical techniques and multidisciplinary management of bone tumors, most notably the ES family of tumors (EFT) and OGS, has resulted in significant improvements in the likelihood of cure and limb salvage; however, the treatment of bone tumors is largely unchanged since last 3 decades. The treatment relies on conventional multiagent chemotherapeutic regimens depending on the subtype in combination with surgery or radiotherapy or both. The purpose of preoperative chemotherapy used in primary bone tumors is [1] to eradicate any micrometastases that exist at the time of diagnosis,[2] to reduce the volume of the tumor to facilitate its excision, and [3] to provide prognostic information.

Ewing's sarcoma

ES is a highly malignant tumor of unknown origin comprising small round cells which often express a balanced translocation involving the EWS gene on chromosome 22 and a member of the ETS family of transcription factors. Local control for EFT can be achieved by surgery, radiation, or both. The choice of radiotherapy or surgery usually represents a tradeoff between functional result and the risk of a secondary radiation-induced malignancy. The first Intergroup ES Study (IESS) in the 1970s showed that chemotherapy, with primary tumor treatment involving surgery or radiotherapy, is necessary for successful treatment of ES and related tumors.[67]

IESS-I demonstrated the importance of doxorubicin (DOX) in ES chemotherapy, whereas IESS-II and subsequent meta-analyses showed the importance of doxorubicin dose intensity.[68],[69] The North American intergroup ES study INT-0091 revealed that a regimen of alternating vincristine–doxorubicin–cyclophosphamide (VDC) and ifosfamide–etoposide was superior to VDC alone. Later on, Children's Oncology Group (COG) demonstrated improvement in EFS at a median of 5 years from 65% in the standard 3-weekly chemotherapy arm to 73% in the 2 weekly dose-dense arm (P = 0.048) with similar toxicity.[70]

The current chemotherapy protocols used to treat ES include various combinations of the following six drugs: doxorubicin, cyclophosphamide, vincristine, actinomycin-D, ifosfamide, and etoposide. Local ES lesions are usually treated through surgical excision or radiotherapy, or a combination of both.

The prognosis of ES patients has improved markedly due to improvement in intensive chemotherapy with 5- and 10-year survival rates up to 70% and 50%, respectively.[67],[71],[72],[73],[74],[75],[76],[77],[78],[79]

Despite intensive multimodal therapy and valiant efforts, 70% of patients with relapsed and metastatic ES will succumb to their disease. However, aggressive multimodality therapy can relieve pain, prolong the progression-free interval, and cure some patients of their disease. For patients with isolated lung and pleural metastases, EFS rates up to 40% are reported with multimodality therapy; for metastases involving bone or bone marrow, EFS rates fall to 10%–20% and for combined sites, to <15%.[71] Most patients with recurrent disease will receive systemic therapy before attempts at additional local control measures. For patients with an initial recurrence, a camptothecin-based regimen (irinotecan/temozolomide or topotecan/cyclophosphamide) is most commonly used.[80],[81],[82] Role of high-dose chemotherapy with hematopoietic cell support is unclear due to conflicting results in prospective non-randomized studies, and this approach outside of the context of a clinical trial is not recommended.[83],[84],[85],[86] Patients with recurrent and metastatic ES should be considered for participation in clinical trials investigating newer agents such as monoclonal antibodies and small molecule inhibitors targeting the insulin-like growth factor 1 [IGF-1] receptor or polyadenosine diphosphate ribose polymerase inhibitors.

In a phase I/II study, conducted to evaluate the efficacy of anti-IGF-1 receptor antibody figitumumab in advanced ES, 15 had partial response (ORR, 14.2%) and 25 had stable disease. Median overall survival was 8.9 months. In this study, statistically significant survival difference (3.6 months vs. 10.4 months; P < 0.001) was observed based on pretreatment serum IGF-1 levels (<0.65 ng/mL or ≥0.65 ng/mL).[87],[88]

Few randomized trials have been conducted in this population as it accounts for only 25%–30% of patients with ES. Whenever possible, patients with newly diagnosed metastatic ES should be prioritized for enrollment in open clinical trials evaluating novel approaches.

Osteogenic sarcoma

OGSs are primary malignant tumors of bone that are characterized by the production of osteoid or immature bone by the malignant cells. It commonly arises from metaphysis of long bones, especially the distal femur, proximal tibia, and proximal humerus. Although it is the most common tumor of bone, OGS is still a rare disease, accounting for mere 0.2% of all human malignant cancers. It has a bimodal age distribution for incidence, with peaks in early adolescence and in adults over the age of 65 years.[1]

In children, the majority of OGSs are sporadic, while inherited predisposition accounts for a minority of cases. In older adults, approximately one-third of cases arise in the setting of Paget's disease of bone or as a second or later cancer.

Unlike other sarcomas, there are no characteristic translocations or other molecular genetic abnormalities in OGSs. Most OGSs have a complex unbalanced karyotype. Combined inactivation of the retinoblastoma and p53 tumor suppressor pathways is common in OGSs.

The survival of patients with malignant bone sarcomas has improved dramatically with effective chemotherapy.[89] Surgery and systemic chemotherapy are the mainstays of current treatment for patients with OGS. There is no role for adjuvant radiation therapy, except in patients with incompletely resected OGSs and possibly in the rare patient with a small cell OGS.[90] Definitive radiation can be considered in patients with sacrum, spine, or skull as primary site where complete resection is not possible. The optimal timing of chemotherapy (i.e., preoperative vs. postoperative) has not been established. Although response to neoadjuvant chemotherapy is a major prognostic factor, there is no evidence that outcomes in poor histologic responders to neoadjuvant chemotherapy can be improved by altering the postoperative chemotherapy regimen. There is no definite survival benefit for neoadjuvant as compared with adjuvant chemotherapy, but many centers preferentially utilize preoperative chemotherapy, particularly if a limb-sparing procedure is being contemplated for an extremity OGS, because of the time needed for fabrication of custom metallic endoprostheses. Methotrexate plus doxorubicin and cisplatin (MAP) regimen that was used in the control arm of the American Osteosarcoma Study Group (AOST) 0331 (EURAMOS-1) protocol is the current standard chemotherapy in most parts of the world.[91]

In a single, large Phase III study involving 677 patients (age up to 30 years) with non-metastatic OGS, the addition of mifamurtide significantly improved the overall survival rate (78 vs. 70% at 6 years), but there was no statistically significant improvement in EFS (67 vs. 61%).[92]

Long-term survival can be expected in <20% of all other patients who present with or develop overt metastatic disease; however, up to 35%–40% of those with limited pulmonary metastases may be cured with multimodality therapy.

Several strategies, including conventional chemotherapy agents, small molecule kinase inhibitors, such as sorafenib, mTOR inhibitors, eribulin, and antibody-drug conjugates such as glembatumumab, that target glycoprotein NMB are under active study.[93]

Sorafenib, a multitargeted kinase inhibitor, has some activity as a second- or third-line agent in OGS, with one study demonstrating 46% progression-free survival (PFS) at 4 months, which compares favorably with historical data.[94],[95] Gemcitabine-based regimens also have modest activity.[96]

Multiple lines of evidence point to the importance of phosphoinositide 3-kinase/mTOR pathway activation in OGS.[97] Two phase II trials, one examining sorafenib plus everolimus (6 months PFS – 45%) and the second examining gemcitabine plus sirolimus (4 months PFS – 44%), suggest modest activity for both combinations;[98],[99] however, the contribution of the mTOR inhibitor to the efficacy of therapy was unclear in either of these studies due to lack of a control arm not receiving an mTOR inhibitor.

Multiple in vitro and xenograft studies had suggested that bisphosphonates have activity against OGS alone or in combination with chemotherapy however, benefit of bisphosphonates in early-stage disease could not be confirmed in a randomized trial which showed no benefit from the addition of zoledronic acid in terms of 3-year event-free survival (57% vs. 63%), risk of failure, or orthopedic complications.[100]

A variety of immunotherapeutic approaches for patients with advanced OGS have been explored.

The addition of Bacille Calmette–Guerin (BCG) and interferon did not improve survival when added to multiagent chemotherapy.[101],[102] However, liposomal muramyl tripeptide phosphatidylethanolamine (MTP-PE; mifamurtide), an agent derived from BCG that activates macrophages and increases circulating cytokine levels, had significantly improved overall survival when added to standard chemotherapy. However, when the analysis was restricted to the 91 patients with metastatic disease at diagnosis, there was only a non-statistically significant trend toward improved 5-year event-free survival (42% vs. 26%) and overall survival (53% vs. 40%) that favored mifamurtide.[103]

Another immunotherapeutic approach evaluated for pulmonary metastatic disease is inhalation of aerosolized granulocyte-macrophage colony-stimulating factor (GM-CSF) based on potential efficacy in a variety of cancers with pulmonary metastasis.[104],[105] However, no benefit was demonstrated in a trial of inhaled GM-CSF in OGS patients with pulmonary relapse in the AOST protocol 0221.[106]

A trial exploring the activity of antibodies against GD2 is being conducted by COG.[107]

There are preliminary signs of modest activity for immune checkpoint inhibitors in OGS. Pembrolizumab (SARC28 study) in patients with advanced soft tissue or bone sarcoma led to only 1 partial response among the 22 patients with OGS entered into the study, and median PFS was 8 weeks.[108] Prospective data from trials involving other immune checkpoint inhibitors are awaited.

Samarium-153 lexidronam is a bone-seeking radiopharmaceutical that can be used for palliating pain in patients with an unresectable local recurrence or skeletal metastases.[109],[110]

Soft tissue sarcoma

STSs are a heterogeneous group of rare solid tumors of mesenchymal origin. STSs account for approximately 1% of adult cancers, with an annual incidence of 5/100,000 population. Although STS can arise anywhere in the body, the majority occur in the limb or limb girdle (60%) or within the abdomen (retroperitoneal and intraperitoneal, 20%).

Localized STSs have traditionally been managed by wide excisional surgery with or without radiotherapy. The use of chemotherapy or targeted therapy has mostly been reserved for advanced disease, aiming to achieve disease palliation and control.

The profound heterogeneity of STS subtypes complicates the conduct and interpretation of clinical trials. Most STS subtypes are treated in a similar fashion.

Around 50% of STS patients eventually develop metastases and die of metastatic disease despite optimal local treatment.[111],[112] Several trials of adjuvant chemotherapy for adult STSs were conducted to improve outcome in localized STS. A meta-analysis of 14 trials of adjuvant chemotherapy published in 1997[113] showed that doxorubicin-based chemotherapy significantly improves time to local and distant relapse. However, there was no statistically significant improvement in OS. Later, an update of this meta-analysis,[114] including 4 newer randomized trials and more than 1900 patients, demonstrated a 10% reduction of overall recurrence and a 6% improvement in OS with adjuvant chemotherapy, which was statistically significant. There is a broad consensus on superiority of combination of ifosfamide and anthracycline combination chemotherapy over single-agent anthracycline in terms of antitumoral activity despite the fact that its superiority has not been formally demonstrated in terms of efficacy in advanced disease.[115],[116],[117]

In the first Italian trial, the full dose anthracycline + ifosfamide regimen was administered [118] that provided evidence of a benefit from adjuvant chemotherapy in high-risk extremity primary sarcoma. Based on these results, Italian sarcoma group conducted a new randomized trial without a no-chemotherapy control arm, comparing 3 and 5 courses of the full-dose combined anthracyclines + ifosfamide regimen.[119]

Recently, advances in biological and clinical understanding have indicated that different histotypes of STSs may have differential sensitivity to chemotherapy, and distinct histotypes can be more sensitive to specific cytotoxic agents [Table 5].
Table 5: Alternative conventional chemotherapy options in advanced soft tissue sarcoma

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Based on these considerations, a randomized study comparing histotype-tailored approach and standard chemotherapy with ifosfamide and adriamycin was conducted. This study was terminated after third futility analysis as standard chemotherapy was found to be superior to histotype-tailored approach.[125]

Given the limited efficacy of conventional cytotoxic chemotherapy, STS remains fertile ground for the field of drug development. Clinical trials in a number of areas have shown promise in metastatic STS.

Trabectedin (ecteinascidin 743 [ET-743)), which is now synthesized but was originally isolated from the Caribbean sea sponge Ecteinascidia turbinata, kills cells by poisoning the DNA nucleotide excision repair machinery.[126] Experience with this agent has also underscored the relevance of stable disease as a beneficial endpoint for metastatic STS.[11],[12],[13],[15],[127],[128]

Phase II studies of trabectedin (1.2–1.5 mg/m2 over 24 h every 21 days), performed in both treatment-naive and pretreated disease, have shown promising results.[9],[11],[12],[13],[16] In a randomized, open-label, phase II study, in 76 patients with advanced, predominantly pretreated translocation-associated sarcoma (the main subtypes were myxoid/round cell liposarcoma and synovial sarcoma), trabectedin showed improvement in median PFS (5.6 vs. 0.9 months, hazard ratio [HR] 0.07, 95% confidence interval [CI] 0.03–0.16).[16]

In randomized, phase III, multicenter United States trial that compared trabectedin with dacarbazine in 518 pretreated patients with advanced leiomyosarcoma (LMS) or adipocytic sarcoma, median overall survival (the primary endpoint) was not significantly different with trabectedin (12.4 vs. 12.9 months), despite significant improvement in PFS with trabectedin (median 4.2 vs. 1.5 months).[129]

High response rate has been observed in a retrospective study in patients with pretreated advanced myxoid/round cell liposarcoma (51% had complete or partial response and 88% were progression free at 6 months).[130]

A phase II non-randomized study reported a high objective response rate (60%) and a high rate of disease control overall (92%), with a tolerable side effect profile, for trabectedin in combination with doxorubicin for first-line treatment of LMS.[131] Median overall survival was 20.2 months in the uterine LMS cohort and 34.5 months in the soft tissue LMS cohort. Another randomized phase II trial failed to confirm a survival benefit for combined trabectedin plus doxorubicin versus doxorubicin alone as first-line therapy in 115 patients with advanced STS of a variety of histologic subtypes (median overall survival 13.3 vs. 13.7 months).[132] This study was underpowered to assess outcomes in patients with LMS (35 of the 115 enrolled patients) and had better median PFS (7 vs. 3.9 months) and overall survival (24.2 vs. 10.3 months) as compared with other histologies. In the preliminary report presented at the 2018 American Society of Clinical Oncology (ASCO) annual meeting of phase III TSAR trial, there were no objective tumor responses with trabectedin in the non-liposarcoma/LMS subset (compared with 19% in the liposarcoma/LMS group), and median PFS was similar to that in the group receiving best supportive care (1.8 vs. 1.5 months, compared with 5.1 vs. 1.4 months in the liposarcoma/LMS subgroup).[48]

Pazopanib is an oral antiangiogenic drug that inhibits vascular endothelial growth factor receptor, platelet-derived growth factor receptor, fibroblast growth factor receptor (VEGFR, PDGFR, FGFR), c-kit, and many other tyrosine kinases. In the phase II study EORTC 62043, progression-free rate at 12 weeks was 44% in leiomyosarcoma cohort, 49% in synovial sarcoma, 26% in liposarcoma, and 39% in other histologies.[133] Based on those results, phase III study (the PALETTE trial) was done for patients with a variety of histologic subtypes (LMS, fibrosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, vascular STS, and sarcoma not otherwise specified, but not adipocytic sarcomas or GIST) post first-line chemotherapy which revealed that median PFS was significantly higher in the pazopanib group (4.6 vs. 1.6 months), and benefit was consistent across all histologic subtypes; however, there was no significant difference in overall survival (12.5 vs. 10.7 months, HR 0.86, 95% CI 0.67–1.1).[134],[135] The phase II study of pazopanib for liposarcoma, in which well-differentiated liposarcoma was excluded, showed 68.3% progression-free rate at 12 weeks and median PFS of 4.4 months.[136]

In a randomized phase II trial (REGOSARC), regorafenib was evaluated in four cohorts (leiomyosarcoma, synovial sarcoma, liposarcoma, and other histologies); three cohorts other than the liposarcoma cohort showed PFS prolongation (median PFS 4 months vs. 1 month) compared to the placebo arm and the OS of 13.4 months. Moreover, regorafenib showed benefit in quality-adjusted survival.[137]

In a phase II trial, cediranib (known as a potent VEGFR inhibitor) showed 35% partial response in alveolar soft parts sarcoma patients which is known to be resistant to cytotoxic chemotherapy.[19] Also, median PFS was improved by cediranib to 10.8 versus 3.7 months in placebo.[136]

In a phase II trial, anlotinib (multi-target TKI that inhibits VEGFR2/3, FGFR 1–4, PDGFR α/β, c-Kit, and Ret) showed median PFS and OS of 5.6 and 12 months, respectively.[138]

Olaratumab is a novel monoclonal antibody against platelet-derived growth factor receptor alpha (PDGFRα). Olaratumab in combination with doxorubicin in a phase Ib/randomized phase II trial showed prolongation of overall survival by 11.8 months (26.5 months vs. 14.7 months; P = 0.0003) compared to doxorubicin alone [23] However, the recently reported results of ANNOUNCE phase III trial did not confirm the clinical benefit of olaratumab in combination with doxorubicin as compared to doxorubicin alone.[139] A randomized, double blind, placebo-controlled phase II study of Olaratumab in combination with gemcitabine and docetaxel in advanced soft-tissue sarcoma is also ongoing.[24]

Eribulin inhibits microtubules through a mechanism that is distinct from other microtubule-targeting agents, such as taxanes. In a Phase II trial in which 128 patients with a variety of sarcoma histotypes were treated with eribulin, PFS at 12 weeks was 32% in LMS, 47% in adipocytic sarcoma, 21% in synovial sarcoma, and 19% for other sarcoma histotypes.

In a multicenter Phase III trial comparing eribulin with dacarbazine in 452 patients with advanced LMS or adipocytic sarcoma previously treated with an anthracycline, median overall survival was improved with eribulin (13.5 vs. 11.5 months, HR for death 0.77, 95% CI 0.62–0.95), although median PFS was the same in both arms (2.6 months).[140] In a preplanned exploratory subgroup analysis, the treatment benefits for eribulin were limited to patients with liposarcoma (median overall survival 15.6 vs. 8.4 months) and was regardless of histologic liposarcoma subtypes.[141]

Based on the fact that more than 90% of well-differentiated or dedifferentiated liposarcomas have amplification of cyclin-dependent kinase 4, an open-label phase II trial with palbociclib was conducted which showed 12-week PFS 57% and 1 complete response.[142]

Nivolumab (anti-PD-1 MoAb) with or without ipilimumab (anti-CTLA-4 MoAb) was administered in an open-label, multicenter, noncomparative, randomized, phase II trial of 85 pretreated patients with advanced STS or bone sarcoma that showed minimal activity with nivolumab alone (median PFS – 2.6), but there was modest antitumor activity with combined therapy (median PFS – 4.5 months).[143]

Pembrolizumab was used in an open-label phase II trial (SARC028 trial) conducted with 10 patients in each of four cohorts, namely undifferentiated pleomorphic sarcoma, poorly differentiated/dedifferentiated liposarcoma, synovial sarcoma, and LMS demonstrated 18% objective response rate and 55% 12-week PFS.[108] Differential clinical activity in each histologic type was 40% (4 of 10) objective response rate in undifferentiated pleomorphic sarcoma, 20% in poorly differentiated/dedifferentiated liposarcoma, 10% in synovial sarcoma, and no responses in LMS. The reason for dissociation of PD-L1 expression and clinical responses in sarcomas are not clear as not all trials targeting PD-1 in advanced STS have been favorable.[144] Given the uncertainty of benefit, appropriately selected patients should be referred for clinical trials exploring these strategies.

Immunotherapy with chimeric antigen receptor-modified T cells or dendritic cells is also being investigated.[145],[146] Targeted immunotherapy with the cancer-testis antigen NY-ESO-1 for synovial sarcoma has shown an objective response in 61% patients (11 of 18); a limitation is that the indication for this immunotherapy is limited to patients with a specific human leukocyte antigen (HLA) haplotype, HLA-A*0201.[147]

Several ongoing trials (e.g., the National Cancer Institute Molecular Analysis for Therapy Choice and the ASCO Targeted Agent and Profiling Utilization Registry [TAPUR] trials) are using next-generation sequencing of multiple genes (gene panel tests) to identify molecular abnormalities in the tumors of patients with refractory cancers that may potentially match molecularly targeted therapies that are either in clinical trials or approved for treatment of other cancer types.

The primary utility of next-generation sequencing in metastatic STS is to identify potential clinical trial candidates. As an example, a subset of pediatric and adult STS have gene fusions involving one of the neurotrophic tropomyosin receptor kinase (NTRK) genes.[148],[149],[150] Larotrectinib (NTRK inhibitor) in an analysis of 55 patients with various tropomyosin receptor kinase fusion-positive malignancies showed overall response rate of 75%, with 86% of responders continuing on treatment at a median follow-up of 9.4 months.[151]

Performing valid clinical trials in STS is challenging because the different histologic types can behave differently; as a result, clinical trials should be stratified by histologic subtype for adequate interpretation of results. To generate studies of sufficient size and power, large-scale collaborations are required on a national and international level. With these collaborations, it is hoped that further research will rapidly translate research findings into the novel therapeutics that are so desperately required by patients with sarcoma.


  Conclusion Top


Chemotherapeutic and targeted therapy options exist for STS, and selection criteria differ depending on histology in STS. Due to rarity of disease, there are not enough ongoing trials in metastatic and relapsed disease setting in these tumors. In symptomatic metastatic disease, combination or single-agent chemotherapy provides effective and durable palliation. Targeted therapy with small molecule inhibitors (sorafenib and pazopanib) can be used in palliative setting for disease control. Immunotherapy is still not recommended as standard strategy for advanced STS due to uncertain benefit in any of the histologic types. Further results of ongoing Phase II studies with chemotherapy, immunotherapy, and targeted therapy are awaited.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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