Advanced Soft Tissue Sarcoma Patients Research Articles

Impact of metronomic trabectedin combined with low-dose cyclophosphamide on sarcoma microenvironment and correlation with clinical outcome: results from the TARMIC study.

Soft tissue sarcomas (STS) are diverse mesenchymal tumors with few therapeutic options in advanced stages. Trabectedin has global approval for treating STS patients resistant to anthracycline-based regimens. Recent pre-clinical data suggest that trabectedin's antitumor activity extends beyond tumor cells to influencing the tumor microenvironment (TME), especially affecting tumor-associated macrophages and their pro-tumoral functions. We present the phase I/II results evaluating a combination of metronomic trabectedin and low-dose cyclophosphamide on the TME in patients with advanced sarcomas. 50 patients participated: 20 in phase I and 30 in phase II. Changes in the TME were assessed in 28 patients using sequential tumor samples at baseline and day two of the cycle. Treatment notably decreased CD68 + CD163 + macrophages in biopsies from tumor lesions compared to pre-treatment samples in 9 of the 28 patients after 4 weeks. Baseline CD8 + T cell presence increased in 11 of these patients. In summary, up to 57% of patients exhibited a positive immunological response marked by reduced M2 macrophages or increased CD8 + T cells post-treatment. This positive shift in the TME correlated with improved clinical benefit and progression-free survival. This study offers the first prospective evidence of trabectedin's immunological effect in advanced STS patients, highlighting a relationship between TME modulation and patient outcomes.This study was registered with ClinicalTrial.gov, number NCT02406781.

Pneumothorax in lung metastasis of advanced soft tissue sarcoma patients treated with oral pazopanib

Abstract Aim: Data on occurrence of pneumothorax after the use of oral pazopanib in advanced soft tissue sarcoma (STS) with lung metastases are scarce in literature. We aimed to evaluate those in our patients. Methods: This was a single center retrospective study of incidence of pneumothorax in patients with lung metastases in advanced STS treated with oral pazopanib between July, 2016 and December, 2020. Patients were treated with pazopanib usually from 2nd line onwards with a dose ranging from 400 mg to 800 mg once daily. Results: Total of 34 patients with lung metastasis in a setting of advanced STS were treated with oral pazopanib during the study period. The setting of pazopanib use was 2nd line in four and 1st line in one of them. The starting dose was 600 mg once daily in three patients, 400 mg OD in one patient, and 800 mg OD in one patient. Five patients developed pneumothorax with duration on pazopanib of 6, 7, 24, 6, and 2.5 months, respectively. Three patients had symptoms and required chest tube drainage. None of them were smokers or had any other underlying lung disease. The disease response of those patients was stable disease in four and partial response in one during treatment with pazopanib. One patient had a rechallenge with further pazopanib course without any recurrence of pneumothorax. Conclusions: Pneumothorax is a rare pulmonary complication after pazopanib use in patients with lung metastasis. Clinicians should be aware of this rare complication as literature is scarce. Rechallenge with pazopanib is feasible after pneumothorax.

Pegylated liposomal doxorubicin combined with ifosfamide for advanced soft tissue sarcomas: A phase I dose-escalation study.

e23525 Background: Doxorubicin combined with ifosfamide (IFO) is one of the preferred treatment options for non-specific soft tissue sarcomas (STS), but is limited by cumulative cardiotoxicity and severe myelosuppression. Pegylated liposomal doxorubicin (PLD) provides an effective alternative to conventional anthracyclines with reduced toxicity. However, there is no standard dose recommendation for PLD combined with IFO for STS. The present study aimed to investigate the maximum tolerated dose (MTD) of PLD combined with IFO in advanced STS patients. Methods: This was a phase I, open-label, single-center, dose-escalation study. Patients with locally advanced or metastatic STS were enrolled, except for gastrointestinal stromal tumors, Ewing's sarcomas, embryonal rhabdomyosarcomas, and alveolar rhabdomyosarcomas. We used a standard 3 + 3 dose-escalation design with progressively increasing PLD and IFO (3 g/m2 per day for 3 days, q3w) for one cycle, with a dose escalation ranged from 30 to 70 mg/m2 (5mg/m2 increment per step). The primary endpoint was determination of the MTD, and the secondary endpoint was the incidence/severity of adverse events (AEs). Results: From January 2020 to September 2022, 23 patients were enrolled in this study, including 3 patients at doses 30-45 mg/m2, 6 patients at dose 50 mg/m2, and 5 patients at 55 mg/m2. The median age was 49 years (ranges from 30 to 68 years), the male/female ratio was 12/11, and 22 (95.65%) patients had stage IV disease (AJCC staging system). Initially, no DLT was observed at doses of 30-50 mg/m2, with 3 patients in each dose phase. Two patients developed DLTs at the 55 mg/m2 dose, resulting in the 50 mg/m2 dose extending to a total of 6 patients who completed treatment without DLT. The DLTs at dose 55 mg/m2 of the first patient were grade 4 neutropenia lasting ≥ 5 days and grade 3 thrombocytopenia with hemorrhage tendency; the second patient had grade 4 neutropenia lasting ≥ 5 days, grade 4 thrombocytopenia relapsed after platelet transfusion, and grade 3 increased alanine aminotransferase. Therefore, the MTD of PLD was 50 mg/m2. The most common (≥ 10%) grade 3-4 AEs in all patients were lymphopenia (56.52%), neutropenia (82.61%), leukopenia (86.96%), and thrombocytopenia (13.04%). Conclusions: For patients with locally advanced or metastatic STS, single cycle PLD combined with IFO had a tolerable AE profile, with an MTD of 50 mg/m2 for PLD. Further researches are needed to confirm the multi-cycle recommendation. Clinical trial information: ChiCTR1900028270 .

Efficacy and safety of anlotinib combined with anthracycline and ifosfamide followed by anlotinib maintenance in advanced soft tissue sarcoma: A single-arm, phase 2 trial.

11553 Background: Anthracycline plus ifosfamide is the standard first line treatment regime for advanced soft tissue sarcoma (STS). Anlotinib, a multikinase angiogenesis inhibitor, has evolved as a standard second line treatment option in Chinese advanced STS patients. This study was performed to evaluate the efficacy and safety of anlotinib combined with anthracycline and ifosfamide followed by anlotinib maintenance in the first line treatment of patients with advanced STS. Methods: This prospective, open-label, single-arm, phase 2 trial was conducted in Shandong Cancer Hospital and Institute (ChiCTR2100054711). The key inclusion criteria included: (a) age was 18-70 years; (b) ECOG performance state of 0-1; (c) histologically confirmed high-grade STS; (d) unresectable or metastatic STS; (e) previously untreated, and sensitive to chemotherapy; (f) having measurable lesions according to RECIST 1.1. All patients received up to 6 cycles of anlotinib (12 mg QD on day1-14, 21 days per cycle) combined with anthracycline (epirubicin 40mg/m2/d on day 1-2, 21 days per cycle; or liposomal doxorubicin 30mg/m2/d on day 1, 21 days per cycle) and ifosfamide (2g/m2/d on day 1-3, 21 days per cycle) followed by anlotinib maintenance until disease progression, unacceptable toxicity or death. Pegylated recombinant human granulocyte colony-stimulating factor was administered following chemotherapy. The primary endpoint was objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse effect (AE). Results: From December 2021 to December 2022, 31 patients (median [range] age, 53 [18-69] years; 20 [64.5%] male) were enrolled. 29 were evaluable for objective response, and the ORR and DCR were 31.03% (95%CI, 17.28-49.23%) and 82.76% (95%CI, 65.45-92.4%), respectively. With a median follow-up duration of 6.3 months (range, 0.8–14.0), the median PFS for all 31 patients was 6.9 months (95% CI, 2.62-11.17). The median OS was not reached. Treatment-related AEs of any grade occurred in all patients. The most common AEs included nausea/vomiting (88.46%), anemia (23.08%), leukopenia (19.23%), venous thrombosis (15.38%), hand-foot syndrome (11.54%) and elevated alanine aminotransferase or aspartate aminotransferase (11.54%). The most frequent ≥ grade 3 AEs were leukopenia (11.54%) and thrombocytopenia (7.69%). 2 serious AEs (1 left heart failure and 1 intestinal obstruction) were recorded. No treatment-related death occurred. Conclusions: This study suggested that anlotinib combined with anthracycline and ifosfamide followed by anlotinib maintenance demonstrated encouraging efficacy with a manageable safety profile in the first line treatment of patients with advanced STS. Clinical trial information: ChiCTR2100054711 .

SPRINT trial: Preoperative chemotherapy and IMRT SIB in locally advanced sarcoma.

e23548 Background: In Soft Tissue Sarcoma (STS) patients with high risk features, preoperative radiotherapy (RT) associated with anthracyclines-based chemotherapy is delivered to downstage the tumor and improve resectability, although at the expense of increased risk of skin toxicity and wound dehiscence that hinder further dose escalation. Modern IMRT may overcome this limitation due to precise dose modulation that allows selectively spare radiation-sensitive structure (skin) while increasing dose to selected target volumes. The aim of this study is to assess the safety and effectiveness of the addition of a preoperative IMRT boost to the potential sites of suboptimal resection in STS patients receiving neoadjuvant chemotherapy and RT. We report hereby the dosimetric and safety results from the first 5 patients enrolled in this trial. Methods: We designed a monocentric interventional single-arm Phase II study to investigate the use of preoperative chemotherapy and RT with Simultaneous Integrated Boost (SIB) in a prospective cohort of locally advanced STS patients eligible for surgery. Epirubicin 60 mg/m2 per day (days 1,2) plus Ifosfamide 3 g/m2 per day (days 1-3), repeated every 21 days, were administered up to three cycles. RT will be administered in 25 daily fractions to include the tumor and peritumoral tissue at risk of microscopic spread (PTV1) to a dose of 50 Gy (2Gy/fraction), with SIB intensification to the tumor/dissection plane interface (PTV2) to a dose of 60 Gy (2.4 Gy/fraction). Response evaluation will be performed by MRI at 4 weeks and on the surgical specimen. Primary endpoint is R0 resection rate. Secondary endpoints include pathologic complete response rate, objective response rate, overall survival, local and distant progression-free survival, acute and chronic toxicity rate. To assess an increase in R0 rate from 81% to 97% assuming β = 80% e α = 0.05, 33 patients will be included. Results: Five patients were included. Tumor was located in the limbs and in the trunk in respectively 4 and 1 patient. Mean age was 47 years (range: 19-67). Mean tumor volume was 228.6 cm3 (range: 59.8-314.5). Mean PTV coverage by the 95% of the dose prescription was 98% (95-100) and 97% (95-100) in PTV1 and PTV2, respectively. Mean Bone Dmax was 55 Gy (56.6-61.8 Gy). Dmax to the skin corridor exceeded 20 Gy in 1 patient (range 12.5-58.1) . At the time of this report, no Grade ≥3 acute skin toxicity was observed. All patients completed the associated treatment, one patient had a G2 anaemia after the first CT cycle and two patients developed Grade 3 neutropenia. Two patients underwent surgery with a radiological partial response (RECIST) and pathological complete response. No major wound complication was reported. Conclusions: Planning goals of the first 5 enrolled patients are achieved in most cases. Preliminary results show a benign safety profile and promising tumor response rate.

Predictive Biomarkers of Pathological Response to Neoadjuvant Chemoradiotherapy for Locally Advanced Soft Tissue Sarcomas.

Marginally resectable and unresectable soft tissue sarcomas (STS) remain a therapy challenge due to the lack of highly active treatment. The aim of the study was to identify a biomarker to predict the pathological response (PR) to preplanned treatment of these STSs. In the phase II clinical trial (NCT03651375), locally advanced STS patients received preoperative treatment with a combination of doxorubicin-ifosfamide chemotherapy and 5 × 5 Gy radiotherapy. PR to the treatment was classified using the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group recommendations. We have chosen HIF-1α, CD163, CD68, CD34, CD105, and γH2AFX proteins, rendering different biological phenomena, for biomarker study. Nineteen patients were enrolled and in four cases a good PR was reported. The high expression of HIF-1α before surgery showed a negative correlation with PR, which means a poor response to therapy. Furthermore, the samples after surgery had decreased expression of HIF-1α, which confirmed the correlation with PR. However, high expression of γH2AFX positively correlated with PR, which provides better PR. The high number of positive-staining TAMs and the high IMVD did not correlate with PR. HIF1α and γH2AFX could be potential biomarkers for PR prediction after neoadjuvant treatment in STS.

Efficacy and safety of fruquintinib as third- or further-line therapy for patients with advanced bone and soft tissue sarcoma: a multicenter retrospective study.

Fruquintinib is an oral small-molecule angiogenesis inhibitor, markedly specifically inhibited vascular endothelial growth factor 2 (VEGFR2). This retrospective study aimed to evaluate the safety and efficacy of fruquintinib, or in combination with immunotherapy or chemotherapy in patients with bone and soft tissue sarcoma (STS), who have failed at least secondary-line treatment. We performed a retrospective analysis of advanced bone and STS patients who received fruquintinib containing third- or further-line therapy in Shanghai Jiao Tong University Affiliated Sixth People's and the Affiliated Hospital of Jiangxi University of Traditional Chiese Medicine from September 2019 to February 2022. All of them had accepted at least anthracyclines-based chemotherapy. For the experimental group, 25 cases, the patients took a basic dose of fruquintinib 3-5 mg once a day for 21 days per 4 weeks as a cycle until the disease progression or intolerable toxicity. The other 20 patients in the control group received the best supportive care. The patients were evaluated by computed tomography (CT) or MRI once 2 months or symptoms worse. The DCR, progression-free survival (PFS), and adverse reactions of the drug were recorded and reviewed. The DCR in patients receiving fruquintinib therapy was 80.0%. The median PFS (mPFS) in the fruquintinib-containing therapy group was significantly longer than that in the control group (4.8 vs. 1.4 months; P < 0.001). The mPFS in the fruquintinib group, the fruquintinib-OI group and the fruquintinib-chemotherapy group were 3.2 months [95% confidence interval (CI), 2.0-7.9], 4.9 months (95% CI, 3.0-9.9) and 4.2 months (95% CI, 2.6-6.6) respectively, all of them were longer than the mPFS of 1.4 months (95% CI, 0.3-2.5) in the control group (P < 0.001). Fruquintinib was reported for the first time to have favorable efficacy and safety as an optional treatment for patients with advanced bone and STS who failed in multi-line therapies.

Efficacy and safety of angiogenesis inhibitors plus immune checkpoint inhibitors in advanced soft tissue sarcoma: a real-world, single-center study

Angiogenesis inhibitors (AIs) and immune checkpoint inhibitors (ICIs) are new treatment options for advanced soft tissue sarcoma (STS) patients. This study evaluated the efficacy and safety of AIs plus ICIs in patients with advanced STS. A retrospective cohort study was performed on STS patients treated with AIs and ICIs at Shandong Cancer Hospital and Institute between August 2020 and December 2021. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and adverse events. Thirty-three patients were enrolled; 27 were evaluable for objective response. The ORR and DCR were 48.1% (95% CI 30.7–66.0%) and 85.2% (95% CI 67.5–94.1%). With a median follow-up of 7.6 months (range, 0.8–25.5), the median PFS for all 33 patients was 8.90 months (95% CI 5.98–11.82). The median OS was not reached. The most common treatment-related adverse events (TRAEs) of any grade were hypertension (50.0%), ECG T-wave abnormality (30.0%), hypothyroidism (26.7%), elevated alanine aminotransferase or aspartate aminotransferase (23.3%), elevated thyroid-stimulating hormone (23.3%), and fatigue (16.7%). The most common grade 3–4 TRAE was hypertension (27.3%). Three serious TRAEs (two myocarditis and one rapid atrial fibrillation) were recorded. This study suggests that adding AIs to ICIs is beneficial in STS.

Efficacy of Eribulin Plus Gemcitabine Combination in L-Sarcomas.

Although the overall survival of advanced soft-tissue sarcoma (STS) patients has increased in recent years, the median progression-free survival is lower than 5 months, meaning that there is an unmet need in this population. Among second-line treatments for advanced STS, eribulin is an anti-microtubule agent that has been approved for liposarcoma. Here, we tested the combination of eribulin with gemcitabine in preclinical models of L-sarcoma. The effect in cell viability was measured by MTS and clonogenic assay. Cell cycle profiling was studied by flow cytometry, while apoptosis was measured by flow cytometry and Western blotting. The activity of eribulin plus gemcitabine was evaluated in in vivo patient-derived xenograft (PDX) models. In L-sarcoma cell lines, eribulin plus gemcitabine showed to be synergistic, increasing the number of hypodiploid events (increased subG1 population) and the accumulation of DNA damage. In in vivo PDX models of L-sarcomas, eribulin combined with gemcitabine was a viable scheme, delaying tumour growth after one cycle of treatment, being more effective in leiomyosarcoma. The combination of eribulin and gemcitabine was synergistic in L-sarcoma cultures and it showed to be active in in vivo studies. This combination deserves further exploration in the clinical context.

Abstract 3100: XenoSarc: patient-derived xenograft (PDX) models of soft tissue sarcoma (STS) and their histopathological and molecular characterization

Abstract STS constitutes a family of rare mesenchymal tumors with more than 70 subtypes described. The limited treatment options available for advanced STS patients underline the need for reliable preclinical models to test new therapeutic approaches. We established a panel of PDX models (XenoSarc) by subcutaneous implantation of fresh tumor specimens in athymic mice (nu/nu NRMI). Once tumor growth was observed, pieces of tumor were re-transplanted to next generations of animals. At each passage tumor fragments were collected for histopathological and molecular characterization. In an ongoing effort 493 STS samples from 414 consenting patients treated at the University Hospitals, Leuven (Belgium) have been transplanted. A total of 67 PDX models from 20 STS subtypes have been established, meaning they have stable morphological, immunohistochemical and genetic characteristics over at least 2 passages. The PDX platform includes more common STS subtypes such as myxofibrosarcoma (n=12 models), gastrointestinal stromal tumors (9), dedifferentiated liposarcoma (10), and leiomyosarcoma (8), as well as models from ultra-rare subtypes, e.g. pulmonary intimal sarcoma, extraskeletal osteosarcoma, mesenchymal chondrosarcoma, myxoinflammatory fibroblastic sarcoma and others. All relevant details about the donor patient and tumor characteristics, including sensitivity to the standard treatments, are known for every model. The models are well-characterized, with availability of molecular information on genomic profile (by low-coverage whole genome sequencing), and expression profile (by RNA sequencing). Xenografts are accompanied by ready to use tissue microarrays (TMA) from the models, which can be exploited for target identification and model selection for preclinical studies. Ex-mouse material can also be used to establish primary cell cultures and 3D organoids for in vitro screening purposes. The XenoSarc platform offers opportunities for studying the biology of various sarcoma subtypes including ultra-rare entities and was found to be a very reliable tool for early drug screening in STS in preparation of clinical testing of novel compounds. The platform is available for collaborative preclinical projects with academic and industrial partners. Citation Format: Agnieszka Wozniak, Luna De Sutter, Lore De Cock, Britt Van Renterghem, Che-Jui Lee, Yannick Wang, Ulla Vanleeuw, Kimberly Verbeeck, Daphne Hompes, Friedl Sinnaeve, Hazem Wafa, Baki Topal, Joris Jaekers, Dirk Van Raemdonck, Maria Debiec-Rychter, Raf Sciot, Patrick Schöffski. XenoSarc: patient-derived xenograft (PDX) models of soft tissue sarcoma (STS) and their histopathological and molecular characterization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3100.

A nomogram to predict the prognosis of advanced soft tissue sarcoma patients treated with anlotinib: A real-world population-based study.

e23550 Background: The ALTER0203 randomized controlled trial proved the antitumor activity of anlotinib, a multitargeted tyrosine kinase inhibitor, in 8 subtypes of advanced refractory soft tissue sarcoma (STS). Our previous studies have shown that anlotinib showed antitumor activity in more than 30 STS pathological subtypes in the real world. This study further constructed a nomogram to predict the prognosis of advanced STS patients treated with anlotinib based on real-world data. Methods: We retrospectively analyzed the data of patients with unresectable locally advanced or metastatic STS who received at least one dose of anlotinib from June 2018 to March 2021. A nomogram was developed to predict the survival probability based on the multivariate analysis. The performance of the nomogram was evaluated by concordance index, bootstrap resampling calibration curve and time-dependent ROC curve. Results: A total of 209 patients were included in this study. The median age was 48 years (range 11-85 years), and the median follow-up time was 18.7 months. Based on five independent prognostic factors including ECOG performance status, FNCLCC grade G2-3, poor nutrition, increased neutrophil count, and treatment patterns according to the multivariate analysis, we constructed a nomogram to predict the prognosis of advanced STS patients treated with anlotinib. The concordance index was 0.780. For the prediction of 1-year and 2-year overall survival probability according to the nomogram, the area under the receiver operating characteristic curve was 0.833 and 0.829, respectively. Conclusions: The nomogram based on ECOG performance status, FNCLCC grade, nutritional status, neutrophil count, and treatment patterns can accurately predict the 1-year and 2-year OS probability for advanced STS patients treated with anlotinib.

Anlotinib rechallenge combined with immune checkpoint inhibitor for advanced soft tissue sarcoma after the failure of anlotinib.

e23541 Background: The anti-angiogenic tyrosine kinase inhibitor (TKI) anlotinib has been approved for the treatment of advanced clear cell sarcoma, alveolar soft-part sarcoma, and other anthracycline-failed advanced soft tissue sarcoma (STS) in China. However, the management of refractory STS is still an unmet medical need. The formation of immunosuppressive microenvironment is one of the resistance mechanisms of anti-angiogenic therapy. This retrospectively observational study investigated the efficacy and safety of anlotinib rechallenge combined with immune checkpoint inhibitor (ICI) for advanced STS after progression on anlotinib treatment. Methods: A cohort of STS patients who had progressed after the anlotinib treatment were prescribed with anlotinib plus ICI were enrolled. Other concurrent systemic treatments were not allowed. Demographic features and clinical outcomes were reviewed and analyzed. Results: A total of 10 STS patients were included. The median of previous systemic treatment regimens was 3 (range, 1-5). Two cases (20%) were observed a partial response, including anlotinib plus nivolumab for a leiomyosarcoma and anlotinib plus toripalimab for an angiosarcoma. Another 4 patients achieved stable disease lasting more than 6 weeks. The median progression-free survival (PFS) were 4.8 months (95% CI: NA-12.5 months). Three (30%) patients developed grade 3 or higher adverse events including toxicity of skin/mucosal(n = 2) and neutrophile granulocyte decreased(n = 1). Conclusions: ICIs plus anlotinib rechallenges maybe a potential treatment for advanced STS patients after progression on anlotinib with acceptable adverse events.

Prognostic value of EZH2 expression for immunotherapy-based schemes in advanced soft-tissue sarcoma: A translational research from Spanish Group of Research on Sarcoma (GEIS).

11549 Background: Immunotherapy-based treatments had shown to be active in several solid tumors, including in selected subtypes of sarcomas. IMMUNOSARC (NCT03277924) is a phase Ib/II trial [from Spanish (GEIS) and Italian (ISG) sarcoma groups], that tested the combination of nivolumab (anti-PD-1 inhibitor) plus sunitinib (anti-angiogenic agent) in advanced sarcomas. Among the 65 soft-tissue sarcoma (STS) patients (pts) enrolled, 48% were free of progression at 6 months, meeting the trial’s primary endpoint. EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 and it has been described to play an important role in the transcriptional repression of genes involved in T-cell migration and T-cell-mediated anti-tumor activity. The aim of this study was to explore the value of EZH2 gene expression as potential prognostic biomarker of the activity of immunotherapy-based schemes. Methods: The expression of EZH2 was evaluated in 64 paraffin tumor blocks, by direct transcriptomics, using HTG EdgeSeq Oncology Biomarkers Panel (HTG Molecular Diagnostics, Inc.; Tucson, AZ, USA). Data was normalized with DESeq2 and the cut-off of EZH2 expression was calculated with MAXSTAT R package. Gene expression was correlated with progression-free survival (PFS) by RECIST, overall survival (OS) and clinical benefit (patients with response or stable disease vs patients with progressive disease as best response). Results: Among the 64 pts analyzed, 52 (81%) showed overexpression of EZH2, considering a cut-off of 570.15 read counts. Undifferentiated pleomorphic sarcoma (UPS) and epithelioid sarcoma were the subtypes with higher expression of EZH2 with a median of read counts of 1888.04 (n = 10) and 1261.79 (n = 7), respectively. The lowest expressions were observed in extraskeletal myxoid chondrosarcoma (ECM) and alveolar soft-part sarcoma (ASPS) with a median of read counts of 461.42 (n = 4) and 680.84 (n = 7), respectively. Low expression of EZH2 was associated with better PFS (16.8 months vs. 3.9 months; p = 0.001) and better OS (NR vs. 20.0 months; p = 0.006). Moreover, low expression of EZH2 was also significantly associated with a clinical benefit of the patients treated with nivolumab plus sunitinib [relative risk (RR): 13; 95% CI: 3.0-56.9; p = &lt; 0.001). Conclusions: Low expression of EZH2 was associated with better outcome in advanced STS patients treated with immunotherapy-based schemes. These results might support the rationale for the combination of EZH2 inhibitors with immune-modulating agents for future studies.

Does the Use of Peripheral Immune-Related Markers Indicate Whether to Administer Pazopanib, Trabectedin, or Eribulin to Advanced Soft Tissue Sarcoma Patients?

Pazopanib, trabectedin, and eribulin are administered for the treatment of soft tissue sarcomas (STSs); however, there is little consensus on which agent should be preferentially used in a clinical setting. This study assessed whether peripheral immune-related markers served as a useful reference when selecting pazopanib, trabectedin, or eribulin. This study included 63 patients who were administered pazopanib, trabectedin, or eribulin for advanced STSs between March 2015 and December 2020. Patients were divided into three groups based on the first drug administered among these three drugs. Differences in overall survival (OS) or progression-free survival (PFS) among the three groups were analyzed. OS showed no significant differences among the drugs administered first. For patients with low neutrophil-to-lymphocyte ratio (NLR), the OS of patients administered pazopanib as the first choice was shorter than the others (hazard ratio [HR] = 9.53, 95% confidence interval [CI] = 1.94–18.13, p = 0.0018). In the low platelet-to-lymphocyte ratio (PLR) subgroup, the OS of the patients administered eribulin for the first choice was longer than that of the others (HR = 0.32, 95%CI = 0.10–0.98, p = 0.046). Therefore, NLR and PLR might be used as prognostic indicators to dictate whether STS patients receive pazopanib, trabectedin, or eribulin.

Priorities and preferences of advanced soft tissue sarcoma patients starting palliative chemotherapy: baseline results from the HOLISTIC study

IntroductionPalliative chemotherapy is the principal treatment of patients with advanced soft tissue sarcomas (STS); however prognosis is limited (median overall survival 12-19 months). In this setting, patient values and priorities are central to personalised treatment decisions.Patients and methodsThe prospective HOLISTIC study was conducted in the UK and the Netherlands assessing health-related quality of life in STS patients receiving palliative chemotherapy. Participants completed a questionnaire before starting chemotherapy, including attitudes towards quality of life (QoL) versus length of life (LoL), decisional control preferences, and decisional conflict. Chi-square and Fisher’s exact tests were used to evaluate associations between patient characteristics and preferences.ResultsOne hundred and thirty-seven patients with advanced STS participated (UK: n = 72, the Netherlands: n = 65). Median age was 62 (27-79) years. Preference for extended LoL (n = 66, 48%) was slightly more common than preference for QoL (n = 56, 41%); 12 patients (9%) valued LoL and QoL equally (missing: n = 3). Younger patients (age <40 years) prioritised LoL, whereas two-thirds of older patients (aged ≥65 years) felt that QoL was equally or more important than LoL (P = 0.020). Decisional conflict was most common in patients who prioritised QoL (P = 0.024). Most patients preferred an active (n = 45, 33%) or collaborative (n = 59, 44%) role in treatment decisions. Gender, performance status, and country were significantly associated with preferred role. Concordance between preferred and actual role in chemotherapy decision was high (n = 104, 76%).ConclusionsHeterogeneous priorities and preferences among advanced STS patients support personalised decisions about palliative treatment. Considering individual differences during treatment discussions may enhance communication and optimise patient-centred care.

Real-World Outcomes of Advanced Soft Tissue Sarcoma Patients Treated with Pazopanib

Background: Pazopanib is an oral multitarget tyrosine kinase inhibitor that is currently approved for the treatment of select subtypes of advanced Soft Tissue Sarcoma (STS) in patients who have progressed on prior anthracyclinebased chemotherapy regimens. In this study, we examine data from multiple centers to assess the efficacy of pazopanib in practice outside of a clinical trial setting. Methods: A retrospective chart analysis was conducted for pre-treated, advanced soft tissue sarcoma patients who began treatment with pazopanib in Alberta, Canada and Cairo, Egypt (2012-2018). Results: In total, 39 predominantly male (56.4%) patients received pazopanib. The median age was 51, 67% of whom had an ECOG of one or less. The predominant sarcoma subtype was leiomyosarcoma (30.8%), and all patients had received at least one prior line of systemic therapy. Thirtytwo of the 39 patients (82%) were initially given the full dose of 800mg with a median time on treatment of 116 days. Seven of the 39 (18%) patients required a dose reduction while on treatment. A majority (94.9%) of patients ultimately discontinued pazopanib treatment for reasons including death (21.6%), disease progression (62.2%), and toxicity (16.4%). The median progression-free and overall survival for these patients was 4.1 months (95%CI, 3.6-4.5) and 8.4 months (95% CI, 4.3-12.5), respectively. Conclusion: Pazopanib is an efficient and generally well-tolerated oral systemic therapy for the treatment of advanced, pre-treated, non-adipocytic soft tissue sarcoma. These results show the efficacy of pazoponib outside of a clinical trial setting.

A Growth Modulation Index-Based GEISTRA Score as a New Prognostic Tool for Trabectedin Efficacy in Patients with Advanced Soft Tissue Sarcomas: A Spanish Group for Sarcoma Research (GEIS) Retrospective Study.

Simple SummarySoft tissue sarcomas (STS) are an uncommon and heterogeneous group of tumors, with scarce options for treatment in advanced cases. There is no consensus regarding which is the best treatment sequence for these patients. Although trabectedin is an approved drug for STS treatment, after progression to anthracyclines, the clinical profile of the patients that most benefit from this drug it is not defined. We have retrospectively analyzed a sample of 357 nonselected sarcoma patients from real-world experience, treated homogeneously with trabectedin, confirming and validating results from previous clinical trials and other retrospective studies. After analyzing clinical prognostic factors, we selected those which predicted a better growth modulation index (GMI > 1.33), and we defined the GEISTRA score, an easy to obtain and reproducible clinical tool, that can help us to optimize the use of trabectedin in advanced sarcoma patients.The aim of this study was to identify an easily reliable prognostic score that selects the subset of advanced soft tissue sarcoma (ASTS) patients with a higher benefit with trabectedin in terms of time to progression and overall survival. A retrospective series of 357 patients with ASTS treated with trabectedin as second- or further-line in 19 centers across Spain was analyzed. First, it was confirmed that patients with high growth modulation index (GMI > 1.33) were associated with the better clinical outcome. Univariate and multivariate analyses were performed to identify factors associated with a GMI > 1.33. Thus, GEISTRA score was based on metastasis free-interval (MFI ≤ 9.7 months), Karnofsky < 80%, Non L-sarcomas and better response in the previous systemic line. The median GMI was 0.82 (0–69), with 198 patients (55%) with a GMI < 1, 41 (11.5%) with a GMI 1–1.33 and 118 (33.1%) with a GMI > 1.33. The lowest GEISTRA score showed a median of time-to-progression (TTP) and overall survival (OS) of 5.7 and 19.5 months, respectively, whereas it was 1.8 and 3.1 months for TTP and OS, respectively, for the GEISTRA 4 score. This prognostic tool can contribute to better selecting candidates for trabectedin treatment in ASTS.

Expression and prognostic significance of PDGF ligands and receptors across soft tissue sarcomas

BackgroundWhile the anti-PDGFRA antibody olaratumab failed to confirm an impact on survival in unselected advanced soft tissue sarcoma (STS) patients, the level of expression and the prognosis of platelet-derived growth factor (PDGF) receptors and ligands in STS remain unclear.Patients and methodsWe analyzed PDGF ligands and receptors' expression levels in a series of 255 patients with different histologies of STS [gastrointestinal stromal tumor (GIST), myxoid liposarcoma (MLPS), sarcoma with complex genomics, synovial sarcoma (SyS)] with Agilent single-color micro-arrays. We explored expression levels as prognostic values in univariate and multivariate analysis using R software (version 3.4.2).ResultsComplex patterns of correlation of expression between ligands and receptors were observed for each histotype. PDGFA levels were highest in SyS and lowest in MLPS (P < 4 × 10−9), PDGFB and C levels were lower in GIST (P < 2 × 10−15 and P < 3 × 10−9) while PDGFD expression was similar across histological subtypes. PDGF receptor (PDGFR) A expression was lowest in MLPS (P < 0.002), whereas PDGFRB and L expressions were lowest in GIST and SyS (P < 0.0004). Interestingly, high PDGFA expression levels were associated with higher risk of metastasis (P = 0.006), whereas PDGFD levels above average were associated with a reduced risk of metastasis (P = 0.01) in univariate and multivariate analysis.ConclusionsThe expression of PDGF ligands and receptors varies across sarcoma histological subtypes. PDGFA and D expression levels independently and inversely correlate with the risk of metastatic relapse.

Trabectedin Plus Radiotherapy for Advanced Soft-Tissue Sarcoma: Experience in Forty Patients Treated at a Sarcoma Reference Center.

Simple SummaryActive therapeutic options in advanced sarcomas, able to induce durable objective responses, are scarce beyond first line. New strategies for disease and symptomatic control are thus needed. Our aim was to analyze the activity of the combination of trabectedin and palliative radiotherapy in the real-life setting, in patients with pretreated metastatic sarcoma. Our findings on 40 pretreated metastatic soft-tissue sarcoma patients, in terms of objective responses (overall response rate by RECIST of 32.5%) and outcome (median progression-free survival of 7.5 months and median overall survival of 23.5 months), confirm the activity of this regimen, which is a valuable option to consider, especially in patients in which a dimensional response could help for symptomatic control.Symptomatic control and tumoral shrinkage is an unmet need in advanced soft-tissue sarcoma (STS) patients beyond first-line. The combination of trabectedin and radiotherapy showed activity in a recently reported clinical trial in this setting. This retrospective series aims to analyze our experience with the same regimen in the real-life setting. We retrospectively reviewed advanced sarcoma patients treated with trabectedin concomitantly with radiotherapy with palliative intent. Growth-modulation index (GMI) was calculated as a surrogate of efficacy. Forty metastatic patients were analyzed. According to RECIST, there was one (2.5%) complete response, 12 (30%) partial responses, 18 (45%) disease stabilizations, and nine (22.5%) progressions. After a median follow-up of 15 months (range 2–38), median progression-free survival (PFS) and overall survival (OS) were 7.5 months (95% CI 2.8–12.2) and 23.5 months (95% CI 1.1–45.8), respectively. Median GMI was 1.42 (range 0.19–23.76), and in 16 (53%) patients, it was >1.33. In patients with GMI >1.33, median OS was significantly longer than in those with GMI 0–1.33 (median OS 52.1 months (95% CI not reached) vs. 8.9 months (95% CI 6.3–11.6), p = 0.028). The combination of trabectedin plus radiotherapy is an active therapeutic option in patients with advanced STS, especially when tumor shrinkage for symptomatic relief is needed.

The Efficacy and Safety of Apatinib in Advanced Synovial Sarcoma: A Case Series of Twenty-One Patients in One Single Institution.

BackgroundSynovial sarcoma (SS) is a highly aggressive soft-tissue sarcoma (STS) with poor prognosis. Tyrosine kinase inhibitor (TKI) has shown a promising impact on advanced STS patients. This study aimed to evaluate the efficacy and safety of apatinib, an oral multi-TKI, which especially inhibited vascular endothelial growth factor receptor, as second-line therapy for patients with advanced SS.Patients and MethodsThis retrospective analysis included 21 advanced SS patients, who had a poor response to anthracycline-based chemotherapy alone or combined with ifosfamide at least one cycle. All the patients received an apatinib containing regimen between May 2016 and October 2019 in our institution. Apatinib 500–750 mg (250 mg for patients younger than 10) was given daily. Tumor responses were assessed by response evaluation criteria in solid tumors. Survival analysis was performed by the Kaplan–Meier test, and a safety profile was recorded.ResultsThe median follow-up was 15.2 months (95% CI, 12.2-NE). Nine (42.9%) patients had partial response (PR), and eight (38.1%) had stable disease. The median progression-free survival (PFS) was 13.1 months (95% CI, 6.7-NE). The 6- and 12-month PFS rates were 76.2% (95% CI, 60.0–96.8) and 55.4% (95% CI, 37.3–82.3), respectively. Additionally, the median overall survival (OS) was 15.5 months (95% CI, 10.7-NE). The 6- and 12-month OS rates were 81.0% (95% CI, 65.8, 99.6) and 64.9% (95% CI, 46.9–90.0), respectively. Moreover, the objective response rate was 42.9% (9/21) for advanced SS patients. The disease control rate was 81.0% (17/21). For the nine patients with the best response of PR, the median duration of response was 7.7 months.ConclusionApatinib was proved to be a potential second-line treatment option for advanced SS patients with chemo-resistance. Apatinib showed promising efficacy and acceptable safety profile in advanced SS, with considerable OS and particularly PFS. Indeed, further multicenter studies with a longer follow-up time are needed to fully determine the clinical application of apatinib in advanced SS.