Treatment Of Soft Tissue Sarcomas Research Articles

1549P Pazopanib exposure in advanced soft tissue and bone sarcoma: A pharmacokinetic/pharmacodynamic analysis

Pazopanib (PAZ) is an angiogenesis inhibitor approved for the treatment of renal cell carcinoma (RCC) and soft tissue sarcoma (STS). A relationship was reported between PAZ trough concentration (Cmin) and progression free survival (PFS) in RCC (Suttle A.B. 2015; Verheijen R.B. 2017). However, information on the exposure-efficacy relationship in sarcoma remains sparse. A PAZ Cmin threshold of 27 mg/L was determined in an exploratory study (Bellesoeur A. 2017).

1533P Gene expression-based prediction of pazopanib benefit in sarcomas

The multi-tyrosine kinase inhibitor pazopanib is approved for the treatment of advanced soft-tissue sarcoma and has also shown activity in other sarcoma subtypes. However, biomarkers to prospectively identify patients who will benefit from the drug are lacking.

The evolving role of precision medicine in the management of advanced sarcomas – A mini review

Sarcomas are a heterogenous group of cancers, traditionally with dismal outcomes. They were initially treated with histology agnostic chemotherapy-based regimens usually centered around anthracyclines. With the availability of molecular diagnostics especially next-generation sequencing, the advanced genomics of sarcomas was slowly unveiled. Precision medicine not only enables a better diagnosis in sarcomas but also allows in identifying better targets for treatment of sarcoma subtypes. GENSARC study proved that using correct molecular diagnostics, enabled in a better diagnosis and treatment of soft tissue sarcomas (STSs). Notable examples of targeted therapies with great success in sarcomas include imatinib and other tyrosine kinase inhibitors in gastrointestinal stromal tumors, neurotrophic tyrosine receptor kinase inhibitors infantile fibrosarcoma, and crizotinib in inflammatory myofibroblastic tumors. Thus, treatment of sarcomas has been gradually changing from traditional chemotherapy-based treatments to the modern targeted therapy. In this review, we hope to impress on the evolving role of precision medicine in sarcoma subtypes especially STS.

Comparison of Different Systemic Therapeutic Regimes in Resectable Soft Tissue Sarcoma – Results of a Network Meta-Analysis

Background: The standard treatment of high-risk soft tissue sarcoma consists of surgical resection followed by risk-adapted radiation therapy. Further treatment options which may improve local and systemic tumor control, including chemotherapy, are not well established. Due to the heterogeneity of the disease, different systemic approaches as well as their application at different time points have been attempted. Methods: We conducted a systematic literature search for randomized clinical trials in the treatment of localized, resectable high-risk adult soft tissue sarcoma comparing different treatment modalities according to the PRISMA guidelines. We extracted published hazard ratios and number of events for the endpoints overall and disease-free survival (OS; DFS) as well as local and distant recurrence-free interval (LRFI; DRFI). The different modalities were compared in a network meta-analysis against the defined standard treatment surgery ± radiotherapy using the inverse-variance heterogeneity model. Results: The literature search identified 25 trials including 3453 patients. Five different treatment modalities were compared in the network meta-analysis. The addition of adjuvant chemotherapy significantly improves OS compared to surgery ± radiotherapy alone (HR =0.86; CI-95%: 0.75-0.97; p=0.017). Likewise, neoadjuvant chemotherapy combined with regional hyperthermia (naCTx+HTx) also led to superior OS (HR =0.45; CI-95%: 0.20-1.00; p=0.049). Neoadjuvant chemotherapy alone (naCTx) and perioperative chemotherapy (periCTx) both did not improve OS (HR =0.61; CI-95%: 0.29-1.29; p=0.195) and (HR=0.66; CI-95%: 0.30-1.48; p=0.317), respectively. Histology-tailored chemotherapy (htCTx) also did not improve survival compared to surgery ± radiotherapy (HR =1.08; CI-95%: 0.45-2.61; p=0.868). The network analysis of DFS, LRFI and DRFI revealed a similar pattern between the different treatment regimens. Adjuvant chemotherapy significantly improved DFS, LRFI and DRFI compared to surgery ± radiotherapy The subgroup analysis of adjuvant chemotherapy was In direct comparison this advantage of adjuvant chemotherapy was restricted to male patients (HR=0.78; CI-95%: 0.65-0.92; p=0.004) with no effect for female patients (HR=1.08; CI-95%: 0.90-1.29; p=0.410). Conclusions: Standardized chemotherapy in high-risk soft tissue sarcoma appears to be of added value irrespective of timing. The benefit of adjuvant chemotherapy seems to be restricted to male patients. The addition of regional hyperthermia to neodjuvant chemotherapy achieved the best effect sizes and might warrant further investigation. Funding: None to declare. Declaration of Interest: None to declare.

SP-0665 Multi-modality treatment of soft tissue sarcoma

SP-0665 Multi-modality treatment of soft tissue sarcoma

Real-World Outcome and Prognostic Factors of Pazopanib in Advanced Soft Tissue Sarcoma.

PurposePazopanib has been approved for treating soft tissue sarcomas (STS) after chemotherapy. We aimed to evaluate the prognostic factors, clinical outcomes, and tolerability of pazopanib in patients with STS.Patients and MethodsForty-five patients treated between June 2015 and August 2019 were reviewed. Clinical outcome was measured by assessing the disease control rate (DCR) using Response Evaluation Criteria in Solid Tumors (version 1.1). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Adverse effects were assessed using the Common Terminology Criteria for Adverse Events (version 5.0).ResultsThe median age of patients at diagnosis was 28 (interquartile range (IQR), 23–45) years. Pazopanib was used as the second-line treatment in 46.7% and the subsequent line in 53.3% of patients. The overall DCR was 55.6%, and at 8 and 12 weeks, it was 52.3% and 35.5%, respectively; the median duration of response was 7 (IQR: 2–18) months. Pazopanib-induced hypothyroidism was associated with DCR, with an odds ratio of 7 (95% confidence interval [95% CI: 1.7–27.5], p<0.01). The median PFS and OS were 4.1 (95% CI: 0.85–7.42) and 12.4 months (95% CI: 6.5–18.36), respectively. Hypothyroidism and response to pazopanib, better ECOG PS, histological subtypes desmoid tumor/aggressive fibromatosis (DT/AF), and alveolar soft part sarcoma (ASPS) were favorable prognostic factors for PFS. Hypothyroidism and response to pazopanib were significant favorable factors for OS. There was no statistical difference in the OS between patients using pazopanib as the second-line therapy and those using it as the subsequent-line therapy.ConclusionPazopanib is an effective treatment for STS. However, it showed variability in the clinical outcome in favor of ASPS and an outstanding response in the DT/AF subtype. Pazopanib-induced hypothyroidism is a good prognostic factor for disease control and is associated with prolonged PFS and OS.

American Brachytherapy Society (ABS) consensus statement for soft-tissue sarcoma brachytherapy

PurposeGrowing data supports the role of radiation therapy in the treatment of soft tissue sarcoma (STS). Brachytherapy has been used for decades in the management of STS and can be utilized as monotherapy or as a boost to external beam radiation. We present updated guidelines from the American Brachytherapy Society regarding the utilization of brachytherapy in the management of STS. Methods and MaterialsMembers of the American Brachytherapy Society with expertise in STS and STS brachytherapy created an updated clinical practice guideline including step-by-step details for performing STS brachytherapy based on a literature review and clinical experience. ResultsBrachytherapy monotherapy should be considered for lower-recurrence risk patients or after a local recurrence following previous external beam radiation; a brachytherapy boost can be considered in higher-risk patents meeting implant criteria. Multiple dose/fractionation regimens are available, with determination based on tumor location and treatment intent. Techniques to limit wound complications are based on the type of wound closure; wound complication can be mitigated with a delay in the start of brachytherapy with immediate wound closure or by utilizing a staged reconstruction technique, which allows an earlier treatment start with a delayed wound closure. ConclusionsThese updated guidelines provide clinicians with data on indications for STS brachytherapy as well as guidelines on how to perform and deliver high quality STS brachytherapy safely with minimal toxicity.

Combined treatment of soft tissue sarcomas

Soft tissue sarcomas (STS) are rare and heterogeneous group of mesenchymal cell tumors, accounting for only 1% of all malignances. Every year about 3700 new cases of STS are registered in Russia, while the annual increase rate was 6.45% in 2019. Randomized studies confirm the feasibility of combination therapy for STS. The review contains a comprehensive description of the proposed methods of combined treatment of STS. Advantages, disadvantages, directions and features of various methods of radiation therapy for STS are shown on the examples of scientific research of recent years.

Analysis of clinical factors associated with survival in patients with soft-tissue sarcoma receiving trabectedin.

Soft-tissue sarcomas (STSs) are a heterogeneous group of rare malignancies. Treatment for advanced STS usually starts with anthracycline-based therapies, with no clear sequence for further treatment. A preferred option is trabectedin, especially for liposarcoma and leiomyosarcoma (L-sarcoma). However, due to severe side effects and few clinical trials, further research of the parameters affecting survival is necessary for the optimal selection of patients. We retrospectively analyzed 73 consecutive patients with STS treated with trabectedin at the University Hospital Centers at Zagreb and Osijek from 2014 to 2021. Our primary goals were evaluating factors affecting progression-free survival (PFS) and overall survival (OS). The median PFS and OS for trabectedin were 3.6 months and 13.7 months, respectively. Patients with L-sarcoma exhibited longer PFS and a trend towards longer OS compared to those with non-L-sarcoma. However, these effects were primarily a result of the myxoid liposarcoma subtype, which exhibited a median PFS of 21.1 months and a median OS of 33.3 months, both significantly longer compared to non-myxoid L-sarcoma. Additionally, patients with three or more sites of metastases exhibited shorter median PFS (3.1 months vs. 3.6 months) and OS (5.7 months vs. 23.8 months) compared to only one metastatic site. There was no correlation between the PFS values of trabectedin and pazopanib and no difference in survival, regardless of the treatment sequence. Trabectedin treatment yields the greatest survival benefit in patients with myxoid liposarcoma and low metastatic burden, whereas the additional use of pazopanib provides further clinical benefit, regardless of treatment sequence.

Abstract 2163: Molecular characteristics of CDK4 and/or MDM2 amplification in Chinese soft tissue sarcoma (STS) patients

Abstract Background: Cyclin-dependent kinase 4 (CDK4) and mouse double minute 2 homolog (MDM2) amplification occur at high frequency in well-differentiated liposarcoma and dedifferentiated liposarcoma, which are generally considered to be diagnostic criteria for these tumors. Studies have also reported that CDK4 and/or MDM2 amplification can emerge in STS subtypes, such as Ewing's sarcoma (ES) and fibrosarcoma (FS). However, the clinical pathological and molecular characteristics of CDK4 and/or MDM2 amplification in STS are still unclear. We systematically depicted the clinical characteristics of MDM2 and CDK4 gene amplification in Chinese STS patients (pts), aiming to assist the precise diagnosis and treatment of STS. Methods: Totally 184 Chinese pts with different STS subtypes were included in this study. In terms of subtypes distribution, the cohort contained multiple STS subtypes including myofibroblastic sarcoma (MFS, n = 23), liposarcoma (LPS, n = 21), FS (n = 20), rhabdomyosarcoma (RMS, n = 19), liomyosarcoma (LMS, n = 12), undifferentiated pleomorphic sarcoma (n = 11), clear cell sarcoma (n = 10), synovial sarcoma (n = 8), ES (n = 7), hemangiosarcoma (n=7), other rare subtypes (n = 37) and unknown types (n = 9). The amplification status of CDK4 and MDM2 in the tumor tissues of these pts was reviewed by the DNA and RNA next generation sequencing method. Results: Totally 16.8% (31/184) of the Chinese STS pts harbored CDK4 and/or MDM2 amplification. Among the 31 pts, 17 were with co-amplification of CDK4 and MDM2, including 12 LPSs, two RMSs, one MFS, one LMS and one FS. Fourteen pts were with single amplification of MDM2 or CDK4, including LPS (n = 4), RMS (n = 3), MFS (n = 3), FS (n = 2), ES (n = 1), and malignant peripheral nerve sheath tumor (n = 1). In LPS, the ratios of co-amplification and single amplification of CDK4/MDM2 were 57.1% (12/21) and 19.0% (4/21) respectively. Other STS subtypes with high frequency of CDK4 and/or MDM2 amplification included RMS (26.3%, 5/19) and MFS (19.4%, 4/23). Meanwhile, our study revealed that co-amplification of CDK4 and MDM2 appeared to be a strong driver event in STS, which mutated exclusively with other driver genes, such as TP53, MYOD1, ATRX and PTEN. Pts with co-amplification of CDK4 and MDM2 were likely to benefit from the treatment of CDK4 and/or MDM2 inhibitors. However, more than half of the pts with single amplification of CDK4 or MDM2 were accompanied by mutations in other driven genes, such as FLI1-EWSR1 fusion, PAX3-FOXO1 fusion, MYOD1 p.L122R, TP53 p.R273S, and NRAS p.G13C. In these pts, single amplification of CDK4 or MDM2 may not be the main driver event, who may be less likely to benefit from CDK4 or MDM2 inhibitor monotherapy. Conclusion: Our study revealed the clinicopathologic and molecular features of CDK4 and/or MDM2 amplification in Chinese STS pts, which can guide the selection of personalized treatment strategies in STS pts. Citation Format: Gu Jin, Chunyang Wang, Xiaojuan Wang, Qifan He, Tonghui Ma. Molecular characteristics of CDK4 and/or MDM2 amplification in Chinese soft tissue sarcoma (STS) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2163.

Abstract 2630: Meta-analysis of pazopanib and trabectedin in 2L+ metastatic synovial sarcoma (2L+ mSS)

Abstract Background: Pazopanib (P) and trabectedin (T) are approved targeted treatments for metastatic soft tissue sarcoma (mSTS). Our objective was to evaluate the efficacy (from clinical trials [CT]) and effectiveness (from real-world studies [RW]) of P and T in second line (2L+) mSS. Methods: This meta-analysis included all English language studies assessing P or T efficacy/effectiveness in patients with 2L+ mSS, 1999 onwards, identified by a systematic literature review. Outcomes were overall response rate (ORR) representing the proportion of patients who have achieved CR or PR during the study and median overall survival (mOS) in months (mos) from start of study medication. Proportions from studies were pooled using generalized linear mixed models to account for small sample sizes, zero events and random site effects. Medians were combined using the weighted median of the medians method with 95% confidence intervals from an inverted sign test. Results: 16 studies with 405 patients with 2L+ mSS met the inclusion criteria. Response was measured variably across studies (CT: RECIST v1.0, v1.1; RW: modified RECIST or clinician assessment). ORR estimates were higher in RW than CTs (Table). OS results were consistent across CTs and RW (Table). Conclusions: This is the first study to provide estimates for patients with mSS in the 2L+ setting, distinct from mSTS and pool outcomes of targeted therapies. RW estimates of ORR for both treatments were higher than those observed in trials likely due to variable definition of response and in underlying prognostic factors. mOS was consistent across both types of studies and was similar to mOS seen on placebo (10.7 mos in PALETTE study) suggesting a high unmet need in this population. Funding: GSK (213368). Outcomes with pazopanib (P) and trabectedin (T) in clinical trials (CT) and real-world (RW) studiesPTP &amp; T pooledORR-ALL (%)N=6, n=96, 18.9 (8.5, 41.8)N=7, n=162, 12.3 (8.0, 18.9)N=13, n=258, 14.7 (9.2, 23.4)ORR-CT (%)N=1, n=38, 13.2 (2.4, 23.9)†N=3, n=57, 7.0 (2.7, 18.1)N=4, n=95, 9.5 (5.1, 17.6)ORR-RW (%)N=5, n=58, 20.2 (7.4, 54.8)N=4, n=105, 15.2 (9.7, 23.9)N=9, n=163, 17.7 (9.9, 31.5)mOS-ALL (mos)N=4, n=96, 10.3 (8.7, 13.8)N=4, n=165, 9.9 (1.5, 13.9)N=8, n=261, 9.9 (9.2, 13.9)mOS-CT (mos)ND*ND*N=3, n=113, 10.3 (8.7, 13.9)mOS-RW (mos)ND*ND*N=5, n=148, 9.9 (9.2, 13.9)*Not done due to small sample size; †results of study since N=1. N=number of studies; n=number of patients. Estimates presented with 95% confidence intervals. Citation Format: Charlotte Carroll, Nashita Patel, Necdet B. Gunsoy, Dan Parks, Heide A. Stirnadel-Farrant, Shibani Pokras. Meta-analysis of pazopanib and trabectedin in 2L+ metastatic synovial sarcoma (2L+ mSS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2630.

Comparison of preoperative and postoperative radiation therapy for extremity soft-tissue sarcoma: a randomized clinical trial

Background: The optimal sequencing of radiotherapy and surgery for the treatment of soft-tissue sarcoma (STS) is an ongoing source of controversy. In this study, the authors compared preoperative and postoperative radiotherapy in patients with extremity STS. Methods: Eighty patients with localized extremity STS were randomly assigned to either preoperative or postoperative radiotherapy group. Baseline characteristics of the patients were not significantly different between the two study groups. Primary outcome measures were pain, acute complications (wound dehiscence and infection), and late complications (limb edema, subcutaneous fibrosis, and joint stiffness). The severity of late complications was evaluated using the radiation therapy oncology group criteria. Secondary outcome measures were oncologic outcomes, including local recurrence and distant metastasis. Results: The mean pain level was not significantly different between the two groups (P=0.1). Infection was not seen in any of the patients. The rate of wound dehiscence and infection was not significantly different between the two groups (P=0.32 for both). Of the late complications, the rate of limb edema and subcutaneous fibrosis was similar in the two groups (P=0.16 and P=0.35, respectively). In contrast, the rate of joint stiffness was significantly more in the postoperative radiotherapy group (P&lt;0.001). The severity of all three late complications also was more in the postoperative radiotherapy group at 6 and 12 mo. There were no significant differences between the two groups regarding local recurrence and distant metastasis (P=0.99 and P=0.77, respectively). Conclusions: The authors suggest preoperative radiotherapy in patients with localized extremity STS because of its lower rate of and less severe complications, particularly joint stiffness. Level of Evidence: Level I.

Paediatric non-rhabdomyosarcoma soft tissue sarcomas: the prospective NRSTS 2005 study by the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG)

A standardised approach to treatment of paediatric non-rhabdomyosarcoma soft tissue sarcomas (NRSTS), which account for about 4% of childhood cancers, is still lacking. We report the results of the NRSTS 2005 protocol developed specifically by the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) to determine a risk-adapted multimodal standard of care for this group of tumours. The EpSSG NRSTS 2005 study included two prospective, non-randomised, historically controlled trials (one on localised adult-type NRSTS and the other on localised synovial sarcoma) done at 100 academic centres and hospitals in 14 countries. Patients younger than 21 years with a pathologically proven diagnosis of synovial sarcoma or an adult-type NRSTS, no evidence of metastatic disease, no previous treatment other than primary surgery, and diagnostic specimens available for pathological review were included. Patients were stratified by surgical stage, tumour size, nodal involvement, tumour grade (for adult-type NRSTS), and tumour site (for synovial sarcoma). Patients were then divided into four treatment groups: surgery alone, adjuvant radiotherapy, adjuvant chemotherapy (with or without radiotherapy), or neoadjuvant chemotherapy (with or without radiotherapy). The main chemotherapy regimen was ifosfamide (3·0 g/m2 intravenously per day for 3 days) plus doxorubicin (37·5 mg/m2 intravenously per day for 2 days); only ifosfamide (3·0 g/m2 intravenously per day for 2 days) was given concomitantly with radiotherapy (delivered with three-dimensional conformal external beam technique, using conventional fractionation [1·8 daily fractions, 5 days per week] at a dose of 50·4 Gy or 54·0 Gy, to a maximum of 59·4 Gy). The number of chemotherapy cycles ranged from three to seven depending on the stage of the disease. The primary outcomes were event-free survival and overall survival. This study has been completed, and is registered under EudraCT, 2005-001139-31. Between May 31, 2005, and Dec 31, 2016, 1321 patients were enrolled, of whom 569 (206 with synovial sarcoma and 363 with adult-type NRSTS), with a median age of 12·6 years (IQR 8·2-14·9), were included in this analysis. With a median follow-up of 80·0 months (IQR 54·3-111·3) for the 467 patients alive, 5-year event-free survival was 73·7% (95% CI 69·7-77·2) and 5-year overall survival was 83·8% (95% CI 80·3-86·7). 5-year event-free survival was 91·4% (95% CI 87·0-94·4) and 5-year overall survival was 98·1% (95% CI 95·0-99·3) in the surgery alone group (n=250); 75·5% (46·9-90·1) and 88·2% (60·6-96·9) in the adjuvant radiotherapy group (n=17); 65·6% (54·8-74·5) and 75·8% (65·3-83·5) in the adjuvant chemotherapy group (n=93); and 56·4% (49·3-63·0) and 70·4% (63·3-76·4) in the neoadjuvant chemotherapy group (n=209). Reported severe adverse events included one case of generalised seizures (probably related to ifosfamide) and six cases of secondary tumours. Findings from the EpSSG NRSTS 2005 study help to define the risk-adapted standard of care for this patient population. Adjuvant treatment can be safely omitted in the low-risk population (classified here as the surgery alone group). Improving the outcome for patients with high-risk, initially resected adult-type NRSTS and those with initially unresectable disease remains a major clinical challenge. Fondazione Città della Speranza.

Efficacy and Safety of Hypofractionated Preoperative Radiotherapy for Primary Locally Advanced Soft Tissue Sarcomas of Limbs or Trunk Wall.

Simple SummaryThe primary treatment of soft tissue sarcomas (STS) is radical resection. The use of adjuvant radiotherapy showed a significantly decreased incidence of local recurrence. In our previous study, we presented that preoperative hypofractionated radiotherapy is safe and efficient for treating an unselected group of patients with STS. This study aimed to assess the treatment scheme’s use in patients with primary STS treated at one institution. The preoperative radiotherapy (RT) scheme consisted of 5 Gy per fraction for a total dose of 25 Gy. Surgery was performed within 2–4 days from the last day of RT. We included 311 patients in this prospective study. In this group, with a significant percentage of patients with extensive, high-grade STS, hypofractionated preoperative radiotherapy was associated with similar local control compared to published studies dedicated to this population. The early tolerance was good, with a small number of late complications. Background: The use of adjuvant radiotherapy (RT) shows a significantly decreased incidence of local recurrence (LR) in soft tissue sarcomas (STS). This study aimed to assess the treatment scheme’s effect in patients with primary STS treated at one institution. Methods: In this phase 2 trial, 311 patients aged ≥18 years with primary, locally advanced STS of the extremity or trunk wall were assigned to multimodal therapy conducted at one institution. The preoperative RT scheme consisted of 5 Gy per fraction for a total dose of 25 Gy. Surgery was performed within 2–4 days from the last day of RT. The primary endpoint was LR-free survival (LRFS). Adverse events of the treatment were assessed. Results: We included 311 patients with primary locally advanced STS. The median tumor size was 11 cm. In total, 258 patients (83%) had high-grade tumors. In 260 patients (83.6%), clear surgical margins (R0) were obtained. Ninety-six patients (30.8%) had at least one type of treatment adverse event. LR was observed in 13.8% patients. The 5-year overall survival was 63%. Conclusion: In this group, with a significant percentage of patients with extensive, high-grade STS, hypofractionated preoperative RT was associated with good local control and tolerance.

Effectiveness criteria for application of the isolated limb perfusion in soft tissue sarcoma

It perdormed the literature data analysis on the criteria and methods for assessing the clinical efficacy of the isolated limb perfusion method in the treatment of soft tissue sarcoma. It is noted that the use of isolated limb perfusion is a rather effective method providing local control of the tumor process in locally advanced forms of soft tissue sarcoma. It has been demonstrated that the use of such a neoadjuvant treatment regimen allows administration of the drug with the achievement of high local concentrations of chemotherapeutic drugs with a relatively low incidence of systemic side effects. Criteria for tumor response to therapy, in particular RECIST (Response Evaluation Criteria In Solid Tumors), Choi criteria, adapted for magnetic resonance imaging, are presented. It is noted that a number of studies have studied the possibility of using positron emission tomography with fluorodeoxyglucose labeled with 18F (18F-FDG) to assess the response to treatment in sarcomas. At the same time, it was shown that the results of studying the metabolic response are superior in accuracy to the method of assessment using the RECIST criteria and the assessment performed by the dynamics of the tumor tissue volume has significant potential in assessing the response to isolated limb perfusion in patients with soft tissue sarcoma. The importance of a one-time assessment of positron emission tomography with 18F-FDG parameters and Magnetic Resonance Imaging for soft tissue sarcoma is confirmed by the results of a combined analysis that takes into account both morphological characteristics and quantitative metabolic parameters of the tumor. The high potential of the combined assessment of metabolic and volume-morphological parameters obtained using these methods was demonstrated; it was noted that the combination of positron emission tomography data with 18F-FDG and Magnetic Resonance Imaging enhances the reliability and efficiency of planning and monitoring of soft tissue sarcoma treatment using the isolated limb perfusion method.

Prospective Evaluation of Quality of Life and Functional Outcomes after Carbon Ion Radiotherapy for Inoperable Bone and Soft Tissue Sarcomas.

Simple SummaryQuality of life (QOL) and functional outcomes in patients with inoperable bone and soft tissue sarcoma treated with definitive carbon-ion radiotherapy (CIRT) were prospectively investigated. CIRT showed favorable clinical efficacy and safety, maintaining the physical component of QOL and functional outcomes, and improving the mental component of QOL. The physical component of QOL was positively correlated with functional outcomes. Poor performance status at diagnosis and female gender were independent predictors of the physical component of QOL and functional outcomes after CIRT.Carbon-ion radiotherapy (CIRT) represents a definitive treatment for inoperable bone and soft tissue sarcoma (BSTS). This prospective study analyzed 61 patients with inoperable BSTS who were treated with CIRT to evaluate QOL, functional outcomes, and predictive factors in patients with inoperable BSTS treated with definitive CIRT. The Musculoskeletal Tumor Society (MSTS) scoring system and the Short Form (SF)-8 questionnaire were completed before and at 1, 3, 6, 12, and 24 months after CIRT. The median follow-up period was 38 months. The main site of primary disease was the pelvis (70.5%), and the most common pathologic diagnosis was chordoma (45.9%). The 3-year overall survival and local control rates were 87.8% and 83.8%, respectively. The MSTS score and physical component score (PCS) of SF-8 did not change significantly between the baseline and subsequent values. The mental component score of SF-8 significantly improved after CIRT. Multivariate analysis showed that the normalized MSTS and normalized PCS of SF-8 at the final follow-up were significantly affected by performance status at diagnosis and sex. CIRT showed clinical efficacy, preserving the physical component of QOL and functional outcomes and improving the mental component of QOL, suggesting its potential value for the treatment of patients with inoperable BSTS.

Efficacy and safety of anlotinib plus TQB2450 in patients with advanced soft tissue sarcoma: A multicenter, single armed, phase 1b trial.

11547 Background: Anlotinib, a multitargeted tyrosine kinase inhibitor, had been prove to be effective for the treatment of advanced or metastatic soft tissue sarcoma(STS) faild anthracycline chemotherapy. With the lack of prospective data of combination of PDL-1 inhibitor and antiangiogenic agent, we designed a phase 1b study to investigated the efficacy and safety of anlotinib plus TQB2450 in patients with STS. Methods: Eligible patients (age 18-70, ECOG 0-1, with histopathologically confirmed advanced STS, at least one measurable lesion according to RECIST 1.1, and previously received front-line anthracycline chemotherapy) were included and received anlotinib (12mg qd, D1-14, 21d/cycle) plus TQB2450 (1200 mg, IV, D1, 21d/cycle) until disease progression or intolerable toxicities.The primary endpoint was objective response rate (ORR), secondary endpoints included safety, overall survival (OS), progression-free survival (PFS), disease control rate (DCR). Results: From January 2019 to January 2021, 30 pts were enrolled1, 12 alveolar soft part sarcoma and 18 others (7 synovial sarcoma, 4 leiomyosarcoma, 5 undifferentiated pleomorphic sarcoma, 1 fibrosarcoma and 1 epithelioid sarcoma). ORR by RECIST was 36.7%, DCR was 83.3%, 11/30 pts had PR, 14/30 (46.7%) had SD, 5/30 (16.7%) PD. Median PFS was 9.6 m in all pts and 4.9m. in non-ASPS, respectively. Median OS in non-ASPS was 10.27m, while mOS in all pts and both mPFS and mOS in ASPS had not been reached. Notably, to ASPS pts, ORR was 75%, and DCR was 100%. The most common 1-2 grade treatment-related adverse reaction (TRAE) was hypothyroidism (19/30,63.3%)，hypercholesterolemia (16/30, 53.3%) and hypertriglyceridemia (16/30, 53.3%), the most common ≥3 grade TRAEs were hypertriglyceridemia (3/30, 10%). 6 SAE (20%) occurred, including 2 pneumothorax, 1 Immune associated hapatic injury, 1 hypotension, 1 Immune myocarditis and 1 diabetic ketoacidosis. Conclusions: The combination of anlotinib and TQB2450 showed promising activity in second-line treatment of advanced STS, especially in ASPS, with well tolerance and acceptable toxicity.

A phase II study of epirubicin combined with anlotinib followed by anlotinib in the first-line treatment of advanced unresectablesoft tissue sarcoma.

e23536 Background: Anlotinib, a multi-target TKI,showed well efficiency and tolerance for the treatment of recurrent or metastatic soft tissue sarcoma (STS). Moreover, the synergistic activity of anlotinib plus epirubicin on the sarcoma PDX modelwas confirmed in our previous preclinical study. This phase II clinical study was designed to assess the efficacy and safety of epirubicin combined with anlotinib followed by anlotinib in the first-line treatment of advanced unresectable STS. Methods: This study is an open-label, prospective, single-arm phase II clinical study. Patients (pts) with locally advanced or metastatic soft tissue sarcomas confirmed by histopathology and not suitable for surgery were recruited, and treated with 6 cycles of anlotinib and epirubicin (epirubicin 90mg/m2 CIV for 48 hours on day 1 and anlotinib 12 mg QD on day1-14, 21 days per cycle), followed by anlotinib alone unless the pts experienced progression or intolerance. Tumor imaging evaluations and echocardiography were performed every 2 cycles during combined therapy, and were performed every 3 cycles during the sequential anlotinib treatment. The primary end point was the progression-free rate at 12 weeks (PFR12w) and 6 months (PFR6m), secondary endpoints included ORR, PFS, safety, DCR and OS. Results: 33 eligible pts were enrolled from June 2019 to August 2020, and 3 pts dropped out without completing one cycle of treatment. Of 30efficacy-evaluable pts,10 were man, median age was 48 (range 18-74). The main subtypes included 10 leiomyosarcoma, 8 fibrosarcoma, 5 dedifferentiated liposarcoma, 4 synovial sarcoma, 2 undifferentiated pleomorphic sarcoma, and 1 epithelioid sarcoma. The average number of combined treatment cycle is 4.7 (range 2-6), 13 pts had entered into anlotinib maintenance treatment. The PFR12w, PFR6m, ORR, DCR were 70%,53.8%, 13.3%, and 80%,respectively. Median PFS was 11.5 months (95%CI: 5.0-NA), median OS has not been reached. As cut-off on Jan 20th 2020, 6 pts are still in treatment. The other pts discontinued trial due to disease progression (16/24), adverse events (AEs) (3/24), changes in treatment strategy because of tumor shrinkage (3/24), cytoreductive surgery (1/24), and opt-out (1/24). The main AEs were grade III-IV neutropenia (8/30, 26.7%), and 7 of them were febrile neutropenia (7/30, 23.3%). Until now, no cardiac-related AEswere observed. Conclusions: Advanced unresectable STS pts could benefit from epirubicin combined with anlotinib followed by anlotinibtreatment in first line. And it is generally well tolerated especially with no short-term cardiac toxicity. Clinical trial information: ChiCTR1900024928.

Efficacy and safety of anlotinib hydrochloride in the treatment of advanced bone and soft tissue sarcoma after failure of first-line chemotherapy.

e23504 Background: There were limit treatments for bone and soft tissue sarcomas that have failed chemotherapy. Anlotinib hydrochloride is a multi-targeted receptor of tyrosine kinase inhibitors (TKI), which has shown therapeutic effects on soft tissue sarcoma. Methods: This is a single-arm, prospective, single-center clinical study. The included criteria were patients with pathological diagnose of bone and soft tissue sarcoma, at least one measurable lesion (criteria of RECIST 1.1), failed of more than one line therapy (except for sarcoma subtypes insensitive to chemotherapy), with the normal function of main organs. All patients received 12mg of anlotinib once daily, 2 weeks on and 1 week off until progression or unacceptable toxicity. The primary endpoint was ORR. We also observed PFS, OS, DCR and AEs. Results: From October 2018to October 2020, a total of 40 patients were enrolled. 25 were men and the median age of the patients was 43.28 (8-79) years. The tumor was located on the trunk in 14 cases, on the limbs in 24 cases and on the abdominal wall in 2 cases. 77.5%, 10%, 7.5% and 5% of patients have lung metastases, bone metastasis, liver metastasis and lymph node metastasis, respectively. The main subtypes included synovial sarcoma (20%), alveolar soft tissue sarcoma (15%), osteosarcoma (12.5%), fibrosarcoma (10%), undifferentiated pleomorphic sarcoma (7.5%). 32.5% of patients had received for at least second-line prior therapy and 25% of patients had received apatinib as a previous treatment. The ORR was 15% and the DCR was 77.5%. Patients who had received apatinib had an ORR of 10% and a DCR of 80% in this group. mPFS were 7.0 months (95%CI = 5.07-8.93) and 7.13 months (95%CI = 5.28-8.98) in overall patients and patients who had received apatinib respectively. The mPFS of ASPS, synovial sarcoma, fibrosarcoma, and osteosarcoma were 17.0 months, 8.2 months, 7.1 months, 2.9 months (p = 0.017). The mOS has not been reached. Adverse events were mainly in grades I and II, The ≥3 AEs were hypertension (2.5%), proteinuria (2.5%), leukopenia (2.5%), thrombocytopenia (2.5%), anorexia (2.5%) and elevated transaminase (5.0%). Conclusions: Anlotinib is effective and safe in the treatment of bone and soft tissue sarcoma, and its efficacy is positively correlated with special types (such as ASPS, synovial sarcoma), effectiveness can also be observed in patients who have failed in other targeted therapy. Clinical trial information: NCT04223583.

Efficacy and safety of nivolumab and trabectedin in pretreated patients with advanced soft tissue sarcomas (STS): Preliminary results of a phase II trial of the German Interdisciplinary Sarcoma Group (GISG-15, NitraSarc) for the non-L sarcoma cohort.

11545 Background: Single-agent PD-1 inhibitors have modest activity in the treatment of most STS. Potential strategies to increase efficacy include combination therapies targeting the tumor microenvironment. Considering that apart from direct growth inhibition and death of malignant cells, trabectedin (Tr) also induces macrophage depletion and/or different immunologic effects, suggesting a possible synergistic effect of combined Tr plus anti-PD-1 treatment. We therefore aimed to evaluate the efficacy and safety of combined Tr and nivolumab (Ni) as a second-line treatment in STS. Methods: The prospective, explorative, two group, non-randomized phase II NiTraSarc trial enrolled pretreated patients (pt) with advanced STS (Group A: lipo- or leiomyosarcomas, Group B: non-L-sarcomas). Pt were initially treated with 3 cycles of Tr 1.5 mg/m2, followed by the combination of Tr 1.5 mg/m2 + Ni 240 mg (“late combination cohort” (LCC)) for up to 16 cycles. After positive results of a preplanned interim analysis, pt received the combination therapy starting with cycle 2 (“early combination cohort” (ECC)). 92 pt were recruited to the trial (55 in Group A, 37 in Group B). Primary efficacy endpoint is progression-free survival rate after 6 months (PFSR6) according to RECIST v.1.1. This is a first analysis of the primary efficacy endpoint in Group B based on a modified intention-to-treat (mITT) population of evaluable 36 pt: 23 and 13 pt from the LCC and ECC, respectively. Results: The most common Group B subtypes comprised undifferentiated pleomorphic/not otherwise specified sarcoma (UPS/NOS, 13pt) and fibromyxoid sarcoma (FMS, 6pt). After a median follow-up of 5 months (m) PFSR6 was 13.9% for all pt, 8.7% in LCC and 23.1% in ECC. Median duration of disease stabilization (DoDS) was 4m in all pt, the LCC and the ECC. Two pt had a partial response (PR), 10 had disease stabilization (SD), while 13 pt progressed, and 11 had missing data. By subtype: PR- UPS/NOS=2 (DoDS 12.7m/12.5m). SD: UPS/NOS=3, epithelioid=2, synovial=2, FMS=1, fibrosarcoma=1, other=1. All 36 pt experienced at least one adverse event (AE) reaching a total of 579 AEs, 141 (24.4%) of which were considered to be grade ≥3 treatment-related AEs. The main grade ≥3 AEs were: leukopenia (47.2% of pt), neutropenia (41.7% of pt), thrombocytopenia (33.3% of pt), increased ALT (30.6% of pt), and anemia (27.8% of pt). Conclusions: Tr+Ni was well tolerated and showed activity in at least some patients with non-L-sarcomas (mostly UPS/NOS) especially in the ECC. Analyses of the collected data, including PD-L1 expression profile, with the goal to establish whether Tr+Ni should be further pursued in these patients, are ongoing. ClinicalTrials.gov Identifier: NCT03590210; EudraCT: 2017-001083-38. Clinical trial information: NCT03590210.