Chemotherapy For Soft Tissue Sarcomas Research Articles

Factors predictive of second-line chemotherapy in soft tissue sarcoma: An analysis of the National Genomic Profiling Database.

Of the drugs used in second-line chemotherapy for soft tissue sarcoma (STS), trabectedin is effective for liposarcoma and leiomyosarcoma (L-sarcoma), eribulin for liposarcoma, and pazopanib for non-liposarcoma. The indications for these drugs in STS other than L-sarcoma have not been established. Here we explored the prognosis, mutation profiles, and drug-response factors in STS using real-world big data. Clinicogenomic data on 1761 patients with sarcoma who underwent FoundationOne CDx were obtained from a national database in Japan. Patients with TP53 and KDM2D mutations had a significantly shorter survival period of 253 (95% CI, 99-404) and 330 (95% CI, 20-552) days, respectively, than those without mutations. Non-supervised clustering based on mutation profiles generated 13 tumor clusters. The response rate (RR) to trabectedin was highest in an MDM2-amplification cluster (odds ratio [OR]: 2.2; p = 0.2). The RR was lowest for eribulin in an MDM2-amplification cluster (OR: 0.4; p = 0.03) and highest in a TERT-mutation cluster (OR: 3.0; p = 0.03). The RR was highest for pazopanib in a PIK3CA/PTEN-wild type cluster (OR: 2.1; p = 0.03). In particular, patients harboring mutations in genes regulating the PI3K/Akt/mTOR pathway had a lower RR than patients without mutations (OR: 0.3; p = 0.04). In STS, mutation profiles were more useful in predicting the drug response than histology. The present study demonstrated the potential of tailored therapy guided by mutation profiles established by comprehensive genomic profiling testing in optimizing second-line chemotherapy for STS. The findings of this study will hopefully contribute some valuable insights into enhancing STS treatment strategies and outcomes.

Anlotinib as a maintenance treatment for advanced soft tissue sarcoma after first-line chemotherapy (ALTER-S006): a multicentre, open-label, single-arm, phase 2 trial

No standard maintenance treatment has been obtained to prolong the response duration of soft tissue sarcoma (STS) after first-line chemotherapy. In this study, we aimed to evaluate the efficacy and safety of anlotinib as a maintenance treatment after chemotherapy in STS. In this multicentre, open-label, single-arm phase 2 trial, patients with advanced STS who achieved partial response or stable disease after first-line anthracycline-based chemotherapy were enrolled between April 2019 and January 2022. All patients received anlotinib as a maintenance treatment. The primary endpoint was progression-free survival (PFS) of anlotinib maintenance treatment. Other endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. This study is registered with ClinicalTrials.gov, NCT03890068. At the data cut-off date (August 8, 2022), 49 patients were enrolled, including 17 with liposarcoma (35%) and 15 with leiomyosarcoma (31%). After a median follow-up of 17.1 months (IQR 9.0-27.2), the median PFS from the beginning of maintenance treatment was 9.1 months (95% CI 5.7-12.5), and the median OS was not reached, and the 1-year OS rate for anlotinib maintenance treatment was 98.0%. The best ORR and DCR were 16% (8/49, 95% CI 7-30) and 94% (46/49, 95% CI 83-99), respectively. Most of the treatment-related adverse events were grade 1-2. Of the grade 3-4 adverse events, the most common were hypertension (10%) and hand-foot syndrome reaction (6%). Postchemotherapy maintenance treatment with anlotinib exhibits promising efficacy and tolerable toxicity in patients with advanced STS. Chia Tai Tianqing Pharmaceutical Group Co., Ltd., the National Key Research and Development Program of China, and the National Natural Science Foundation of China.

Deep learning with whole slides images to predict histological response to neoadjuvant chemotherapy in patients with resectable high grade soft-tissue sarcomas: A multicenter study.

11512 Background: Two recent randomized trials have confirmed the potential benefit of neoadjuvant anthracycline-based chemotherapy in patients with high-grade soft-tissue sarcomas (STS) (Issels et al 2018, Gronchi et al 2017). However, as for adjuvant chemotherapy, the main issue with neoadjuvant treatment of STS patients is the identification of predictive factors of response to chemotherapy that could avoid for a majority of patients ineffective and potentially toxic treatment with impaired quality of life. Histological response, defined as the percentage of stainable tumor cells on the surgical specimen, has been shown to be a reliable surrogate for metastasis-free survival and overall survival in bone but also in soft-tissue sarcomas (Crombe et al JCO Clin Inf 2021). Developing a tool to help medical oncologists predict the potential benefit of neoadjuvant chemotherapy prior to starting the treatment would be of great value for precision medicine in sarcomas. To address this need, we propose a deep learning-based approach to predict histological response to neoadjuvant chemotherapy patients from routine histological whole slide images sampled at diagnosis. Methods: A cohort of 220 patients with high grade limb and trunk wall STS enrolled in the NEOSARCOMICS study (NCT02789384, sponsor: Institut Bergonié, Bordeaux, France) was used to train a model to predict the binarized histological response from diagnostic biopsies. Responders are defined by a histological response inferior or equal to 10%. Digitized hematoxylin/eosin slides were preprocessed to segment the tissue and decompose the image into patches of smaller resolution. Features were extracted from each patch using a Vision Transformer pretrained in a self-supervised fashion on histology slides. A Multiple Instance Learning model was trained on the resulting features to compute a prediction at the patient level. The algorithm was trained and validated through a 5-fold, 5-repeat cross-validation scheme. Finally, external validation is performed on an unseen cohort from Centre Léon Bérard to assess the robustness of the model. Results: To predict histological response to neoadjuvant chemotherapy, a model using only diagnostic biopsies achieved an AUC of 0.69 (95% confidence interval, 0.60-0.76). External validation is ongoing and shows promising preliminary results with an AUC of 0.67 (95% confidence interval with bootstrapping, 0.45-0.89). Conclusions: This multi-center study demonstrates that deep-learning models can accurately predict the histological response to neoadjuvant chemotherapy from routine histological whole slide images sampled at diagnosis. This model could be used as a pre-screening tool to improve patient selection for neoadjuvant chemotherapy in STS.

Neoadjuvant pazopanib in nonrhabdomyosarcoma soft tissue sarcomas (ARST1321): A report of major wound complications from the Children's Oncology Group and NRG Oncology.

The impact upon wound healing of targeted molecular therapies, when incorporated into neoadjuvant therapy of soft tissue sarcoma, is largely unknown. Here, we describe wound complications following addition of pazopanib, a tyrosine kinase inhibitor (TKI), to neoadjuvant radiotherapy (RT) +/- chemotherapy for soft tissue sarcoma. Wound complications were evaluated on dose-finding and randomized arms of ARST1321, a phase II/III study incorporating neoadjuvant RT, +/- pazopanib, +/- ifosfamide/doxorubicin (ID) for sarcoma therapy. Of 85 evaluable patients, 35 (41%) experienced postoperative wound complications. Most (57%) were grade III. Randomization to pazopanib + RT + ID carried a 50% wound complication rate (17/34, with 47% grade III), compared to 22% (5/23) with ID + RT alone. In nonchemotherapy study arms, pazopanib + RT resulted in a 59% wound complication rate versus 25% for those receiving RT alone. Grade III wound complications occurred among 26% (15/58) of all patients receiving pazopanib. Wound complications occurred a median of 35 days postoperatively. Some occurred following diagnostic biopsies and at remote surgical sites. The addition of pazopanib to neoadjuvant chemotherapy and RT resulted in a higher wound complication rate following therapy of soft tissue sarcoma. The rate of grade III complications remained comparable to that reported in contemporary literature.

A novel inflammatory signature for evaluating immune microenvironment status in soft tissue sarcoma.

BackgroundTumorigenesis and progression are intimately associated with inflammation. However, the inflammatory landscape in soft tissue sarcoma (STS) and its clinical consequences are yet unknown, and more investigation is needed.MethodsRNA-seq expression data for STS and corresponding normal tissues were downloaded from The Cancer Genome Atlas database and the Genotype-Tissue Expression Portal. Differential and prognostic analyses were performed based on known inflammatory response genes from Gene Set Enrichment Analysis (GSEA). We utilized LASSO-Cox analysis to determine hub genes and built an inflammatory score (INFscore) and risk stratification model. Furthermore, a nomogram, including the risk stratification model, was established to predict the prognosis. We further elucidated the characteristics among different risk STS patients by GSEA, gene set variation analysis, and detailed immune infiltration analysis. Finally, the INFscore and risk stratification model in predicting prognosis and depicting immune microenvironment status were verified by pan-cancer analysis.ResultsFive hub genes (HAS2, IL1R1, NMI, SERPINE1, and TACR1) were identified and were used to develop the INFscore. The risk stratification model distinguished the immune microenvironment status and evaluated the efficacy of immunotherapy and chemotherapy in STS. The novel nomogram had good efficacy in predicting the prognosis of STS patients. Finally, a pan-cancer investigation verified the association of INFscore with prognosis and immunity.ConclusionsAccording to the present study, the risk stratification model can be used to evaluate STS prognosis, tumor microenvironment status, immunotherapy, and chemotherapy efficacy. The novel nomogram has an excellent predictive value. Thus, the INFscore and risk stratification model has potential value in assessing the prognosis and immune status of multiple malignancies.

M6A-related metabolism molecular classification with distinct prognosis and immunotherapy response in soft tissue sarcoma.

N6-methyladenosine (m6A) methylation, one of the most crucial RNA modifications, has been proven to play a key role that affect prognosis of soft tissue sarcoma (STS). However, m6A methylation potential role in STS metabolic processes remains unknown. We comprehensively estimated the m6A metabolic molecular subtypes and corresponding survival, immunity, genomic and stemness characteristics based on 568 STS samples and m6A related metabolic pathways. Then, to quantify the m6A metabolic subtypes, machine learning algorithms were used to develop the m6A-metabolic Scores of individual patients. Finally, two distinct m6A metabolic subtypes (Cluster A and Cluster B) among the STS patients were identified. Compared to Cluster B subtype, the Cluster A subtype was mainly characterized by better survival advantages, activated anti-tumor immune microenvironment, lower gene mutation frequency and higher anti-PD-1 immunotherapy response rates. We also found that the m6A-metabolic Scores could accurately predict the molecular subtype of STS, prognosis, the abundance of immune cell infiltration, tumor metastasis status, sensitivity to chemotherapeutics and immunotherapy response. In general, this study revealed that m6A-regulated tumor metabolism processes played a key role in terms of prognosis of STS, tumor progression, and immune microenvironment. The identification of metabolic molecular subtypes and the construction of m6A-metabolic Score will help to more effectively guide immunotherapy, metabolic therapy and chemotherapy in STS.

Analysis of Multiple Drug Resistance Mechanism in Different Types of Soft Tissue Sarcomas: Assessment of the Expression of ABC-Transporters, MVP, YB-1, and Analysis of Their Correlation with Chemosensitivity of Cancer Cells

Chemotherapy of soft tissue sarcomas (STS) is restricted by low chemosensitivity and multiple drug resistance (MDR). The purpose of our study was the analysis of MDR mechanism in different types of STS. We assessed the expression of ABC-transporters, MVP, YB-1, and analyzed their correlation with chemosensitivity of cancer cells. STS specimens were obtained from 70 patients without metastatic disease (2018–2020). Expression level of MDR-associated genes was estimated by qRT-PCR and cytofluorimetry. Mutations in ABC-transporter genes were captured by exome sequencing. Chemosensitivity (SI) of STS to doxorubicin (Dox), ifosfamide (Ifo), gemcitabine (Gem), and docetaxel (Doc) was analyzed in vitro. We found strong correlation in ABCB1, ABCC1, and ABCG2 expression. We demonstrated strong negative correlations in ABCB1 and ABCG2 expression with SI (Doc) and SI (Doc + Gem), and positive correlation of MVP expression with SI (Doc) and SI (Doc + Gem) in undifferentiated pleomorphic sarcoma. Pgp expression was shown in 5 out of 44 STS samples with prevalence of synovial sarcoma relapses and it is strongly correlated with SI (Gem). Mutations in MDR-associated genes were rarely found. Overall, STS demonstrated high heterogeneity in chemosensitivity that makes reasonable in vitro chemosensitivity testing to improve personalized STS therapy, and classic ABC-transporters are not obviously involved in MDR appearance.

A Systematic Review and Meta-Analysis of Malignant Rhabdoid and Small Cell Undifferentiated Liver Tumors: A Rational for a Uniform Classification

Simple SummaryMalignant rhabdoid tumors of the liver are very rare pediatric liver tumors with a devastating prognosis. It is currently unclear which histological subtypes of pediatric liver tumors belong to this entity and how these tumors should be treated. In this systematic review with meta-analysis, we analyzed all reports on pediatric patients with malignant rhabdoid liver tumors, but also with so-called small cell undifferentiated liver tumors. This is another rare liver tumor subtype that has recently been regarded to belong to the entity of rhabdoid tumors by some authors. The main result of this study is that these two tumor subtypes show large overlap on several levels and even mixtures of both histological patterns have been documented. Our meta-analysis provides an evidence base for the recommendation to classify these two tumor subtypes as one entity. We showed that treatment of these tumors with hepatoblastoma directed chemotherapy is ineffective and that a therapy with chemotherapy regimens initially applied for soft tissue sarcoma is associated with a significantly better survival. This study represents the highest level of evidence available for these rare liver tumors.Background: Rhabdoid liver tumors in children are rare and have a devastating prognosis. Reliable diagnosis and targeted treatment approaches are urgently needed. Immunohistochemical and genetic studies suggest that tumors formerly classified as small cell undifferentiated hepatoblastoma (SCUD) belong to the entity of malignant rhabdoid tumors of the liver (MRTL), in contrast to hepatoblastomas with focal small cell histology (F-SCHB). This may have relevant implications on therapeutic approaches. However, studies with larger cohorts investigating the clinical relevance of the histological and genetic similarities for patients are lacking. Purpose: To analyze possible similarities and differences in patient characteristics, tumor biology, response to treatment, and clinical course of patients with MRTL, SCUD and F-SCHB. Applied therapeutic regimens and prognostic factors are investigated. Methods: A systematic literature search of MEDLINE, Web of Science, and CENTRAL was performed for this PRISMA-compliant systematic review. All studies of patients with MRTL, SCUD and F-SCHB that provided individual patient data were included. Demographic, histological, and clinical characteristics of the three subgroups were compared. Overall survival (OS) was estimated with the Kaplan–Meier method and prognostic factors investigated in a multivariable Cox regression model. Protocol registered: PROSPERO 2021 CRD42021258760. Results: Fifty-six studies with a total of 118 patients were included. The two subgroups MRTL and SCUD did not differ significantly in baseline patient characteristics. However, heterogenous diagnostic and therapeutic algorithms were applied. Large histological and clinical overlap between SCUD and MRTL could be shown. Two-year OS was 22% for MRTL and 13% for SCUD, while it was significantly better in F-SCHD (86%). Chemotherapeutic regimens for hepatoblastoma proved to be ineffective for both SCUD and MRTL, but successful in F-SCHB. Soft tissue sarcoma chemotherapy was associated with significantly better survival for MRTL and SCUD, but was rarely applied in SCUD. Patients who did not undergo surgical tumor resection had a significantly higher risk of death. Conclusions: While F-SCHB is a subtype of HB, SCUD should be classified and treated as a type of MRTL. Surgical tumor resection in combination with intensive, multi-agent chemotherapy is the only chance for cure of these tumors. Targeted therapies are highly needed to improve prognosis. Currently, aggressive regimens including soft tissue sarcoma chemotherapy, extensive resection, radiotherapy or even liver transplantation are the only option for affected children.

Trabectedin in the treatment of soft tissue sarcomas: up to date data

Soft tissue sarcomas are a rare heterogeneous group of malignant tumors with mesenchymal nature. Soft tissue sarcomas accounts for less than 1 % of all cancers. Low efficiency of chemotherapy for soft tissue sarcomas, especially in advanced disease, is a burning issue. Trabectedin is one of the active agents approved for the treatment of advanced soft tissue sarcomas after the failure of standard chemotherapy. The article provides a literature review of the latest world-wide data of the effectiveness and role of trabectedin in the modern approach of soft tissue sarcomas treatment.

Neoadjuvant chemotherapy in high-risk soft tissue sarcomas: A Sarculator-based risk stratification analysis of the ISG-STS 1001 randomized trial.

The value of neoadjuvant chemotherapy in soft tissue sarcoma (STS) is not completely understood. This study investigated the benefit of neoadjuvant chemotherapy according to prognostic stratification based on the Sarculator nomogram for STS. This study analyzed data from ISG-STS 1001, a randomized study that tested 3 cycles of neoadjuvant anthracycline plus ifosfamide (AI) or histology-tailored (HT) chemotherapy in adult patients with STS. The 10-year predicted overall survival (pr-OS) was estimated with the Sarculator and was stratified into higher (10-year pr-OS < 60%) and lower risk subgroups (10-year pr-OS ≥ 60%). The median pr-OS was 0.63 (interquartile range [IQR], 0.51-0.72) for the entire study population, 0.62 (IQR, 0.51-0.70) for the AI arm, and 0.64 (IQR, 0.51-0.73) for the HT arm. Three- and 5-year overall survival (OS) were 0.86 (95% confidence interval [CI], 0.82-0.93) and 0.81 (95% CI, 0.71-0.86) in lower risk patients and 0.69 (95% CI, 0.70-0.85) and 0.59 (95% CI, 0.51-0.72) in the higher risk patients (log-rank test, P = .004). In higher risk patients, the 3- and 5-year Sarculator-predicted and study-observed OS rates were 0.68 and 0.58, respectively, and 0.85 and 0.66, respectively, in the AI arm (P = .04); the corresponding figures in the HT arm were 0.69 and 0.60, respectively, and 0.69 and 0.55, respectively (P > .99). In lower risk patients, the 3- and 5-year Sarculator-predicted and study-observed OS rates were 0.85 and 0.80, respectively, and 0.89 and 0.82, respectively, in the AI arm (P = .507); the corresponding figures in the HT arm were 0.87 and 0.81, respectively, and 0.86 and 0.74, respectively (P = .105). High-risk patients treated with AI performed better than predicted, and this adds to the evidence for the efficacy of neoadjuvant AI in STS. People affected by soft tissue sarcomas of the extremities and trunk wall are at some risk of developing metastasis after surgery. Preoperative or postoperative chemotherapy has been tested in clinical trials to reduce the chances of distant metastasis. However, study findings have not been conclusive. This study stratified the risk of metastasis for people affected by sarcomas who were included in a clinical trial testing neoadjuvant chemotherapy. Exploiting the prognostic nomogram Sarculator, it found a benefit for chemotherapy when the predicted risk, based on patient and tumor characteristics, was high.

A randomized phase II trial of second-line treatment for advanced soft tissue sarcoma comparing trabectedin, eribulin and pazopanib (2ND-STEP, JCOG1802).

TPS11580 Background: Soft tissue sarcomas (STS) are a rare type of malignancy, which comprises of a variety of histologies. Chemotherapy is the standard treatment for patients with advanced STS. Doxorubicin alone or in combination with ifosfamide is widely accepted as the first-line chemotherapy for advanced STS. While a combination with gemcitabine and docetaxel is regarded as a standard regimen of the second-line chemotherapy after failure of doxorubicin-based first-line regimen, the efficacy is not sufficient. Trabectedin, eribulin, and pazopanib are the candidates of the second-line chemotherapy for advanced STS, although there is no clear evidence showing which is better among those agents. The purpose of this clinical trial conducted by Bone and Soft Tissue Tumor Study Group of Japan Clinical Oncology Group (JCOG) is to determine the most promising regimen among trabectedin, eribulin and pazopanib as the test arm regimen in the future phase III trial of the second-line treatment for patients with advanced STS. Methods: The study, JCOG1802, is a multicenter, selection design, randomized phase II trial comparing trabectedin (1.2 mg/m2 IV, every 3 weeks), eribulin (1.4 mg/m2 IV, days 1 and 8, every 3 weeks) and pazopanib (800 mg PO, everyday) for patients with unresectable or metastatic STS refractory to doxorubicin-based first-line chemotherapy. Eligibility criteria include 16 year-old or older, unresectable and/or metastatic STS, an exacerbation within 6 months prior to registration, histological diagnosis of STS other than Ewing sarcoma, well-differentiated liposarcoma and myxoid liposarcoma, a history of chemotherapy for STS other than doxorubicin-based regimen, ECOG (Eastern Cooperative Oncology Group) performance status 0 to 2, and sufficient organ function. Primary endpoint is progression-free survival (PFS), and secondary endpoints include overall survival, disease-control rate, response rate, and adverse events. To select the most promising regimen in median PFS (3 months in the worst regimen and 4 months in the best regimen) with a probability of at least 80%, a total of 120 patients will be enrolled from 37 institutions in Japan. After JCOG1802, a subsequent phase III trial comparing the winner of this study and a combination of gemcitabine and docetaxel will be planned. The study was activated at December 5, 2019 and 22 of planned 120 patients have been enrolled as of February 15, 2021. Clinical trial information: jRCTs031190152.

Adjuvant and neoadjuvant chemotherapy for soft tissue sarcomas: JCOG Bone and Soft Tissue Tumor Study Group.

The standard therapy for all localized soft tissue sarcomas is surgical resection of the tumor. For patients with soft tissue sarcomas who are at high risk for recurrence and/or metastasis, perioperative chemotherapy is a potential treatment option. Adriamycin plus ifosfamide is currently the most promising chemotherapy regimen for localized soft tissue sarcomas. Randomized controlled trials and meta-analyses of adjuvant postoperative chemotherapy for soft tissue sarcomas have suggested that adjuvant chemotherapy may provide an advantage, however small, compared with surgery alone. On the other hand, recent randomized trials have demonstrated the efficacy of neoadjuvant preoperative chemotherapy using full-dose anthracycline plus ifosfamide for high-risk soft tissue sarcomas and showed survival benefits in patients with large, deep-seated and high-grade soft tissue sarcomas of the trunk and extremities. In this review, adjuvant and neoadjuvant chemotherapies for soft tissue sarcomas and future perspectives are discussed.

Abstract 12913: Trabectedin Related Reversible Cardiogenic Shock: A Rare Side Effect of Anti-neoplastic Drug

Trabectedin, an alkylating agent, is used as palliative chemotherapy of soft-tissue sarcoma after failure of first-line treatment. It is labeled as a low cardiac risk profile. We present a case of a lady with metastatic synovial sarcoma with a pre-treatment normal echocardiography, who received 3 cycles of Trabectedin, and presented in cardiogenic shock which reversed back to normal function with vasopressor, diuresis and inotrope support. Case report: A 66-year-old female with metastatic synovial sarcoma of lungs (post right upper lobectomy and chemotherapy), with positive mediastinal and hilar nodes improvement, was transferred in with hypotension and respiratory distress. She was recently started on trabectedin as palliative chemotherapy, about 2 months prior to this admission, received 3 cycles, the last cycle was 4 days prior to admission. There was an elevation of high-sensitivity troponin (peaked to 2000) which trended down. With metastatic disease and ongoing thrombocytopenia (post-chemotherapy), cardiac catheterization was not deemed appropriate, managed medically with inotrope, and pressor support for cardiogenic shock. A nuclear stress test done after weaning off all intravenous medicine showed an LVEF of 55% without any area of ischemic defect. As no other precipitants were identified and with reversibility of cardiac function over time, we considered these events were related to trabectedin toxicity. Discussion: For the use of Trabectedin, there is no specific caution for patients with cardiac disease or risk factors hence labeled as low cardiac risk profile by comprehensive analysis. This case highlights a rare but life-threatening side effect of this drug. It is important to balance the potential of an increase in progression-free survival with chemotherapy versus a life-threatening adverse effect which may counter-effect the mortality benefit and highlights a need for close serial monitoring.

Deep vein thrombosis of the upper extremity caused by central venous port in a patient with soft tissue sarcoma: A case report.

Deep vein thrombosis (DVT) more commonly occurs in the lower extremities, whereas involvement of the upper extremities is rare. The present case report describes the clinical course of the development and treatment of upper extremity DVT (UEDVT) following insertion of an indwelling central venous (CV) port in a patient with soft tissue sarcoma (STS) of the thigh. A 66-year-old man was referred to our hospital for STS treatment. The indwelling CV port was placed via the left subclavian vein, and two courses of neoadjuvant chemotherapy were administered. Two months after the catheter placement, DVT was detected from the left upper arm to the left internal jugular vein. Anticoagulation therapy with warfarin was started and DVT was undetectable at 5 months after surgery. In conclusion, DVT may occur in cancer patients who undergo treatment with indwelling CV ports. Therefore, screening should be conducted concurrently with surgical resection and chemotherapy for STS.

1657P Pazopanib treatment outcome in advanced soft tissue sarcoma: Real-world data

Background Pazopanib is approved for use after the failure of chemotherapy for soft tissue sarcoma. We aimed to evaluate the clinical outcome and tolerability in a real-world setting. Methods Patients treated between June 2015 and August 2019 were reviewed. The response was assessed at 8 and 12 weeks using the Response Evaluation Criteria in Solid Tumors version 1.1. Survival analysis was performed using the Kaplan-Meier method. Toxicity was assessed using the Common Terminology Criteria v. 5.0. Results Forty-five patients (51% male) were identified; the median age at diagnosis was 28 years (IQR 23–45 years). The histology subtypes were 26.7% undifferentiated pleomorphic sarcoma (UPS), 15.6% synovial sarcoma (SS), 17% leiomyosarcoma, 8.9% alveolar soft part sarcoma, 8.9% fibrosarcoma, 6.7% epithelioid sarcoma, and 13.3% other types. The most common site for metastases was the lung (55.6%) and liver (13.3%). Pazopanib was used as the second-line and subsequent-line therapy in 46.7% and 53.3% of patients, respectively. At 8 weeks, the clinical benefits rate was 48.9% (7 partial response (PR), 15 stable diseases (SD)), and at 12 weeks, it was 35.5% (6 PR, 10 SD). The median duration of response was 7 months and 3 patients maintained a response more than 12 months; two UPS and 1 SS. The median progression-free survival (PFS) was 3 months (95% confidence interval (CI): 0.75–6.), and the median overall survival was 13 months (95% CI: 7–18.9). There was no statistical difference between using pazopanib as a second- or subsequent line therapy, 5 vs. 2.9 months (p = 0.44). Totally, 71% of patients were maintained on the full dose (800 mg) and led to discontinuation in 9.5% patients because of transaminitis, interstitial lung disease, or fatigue. The reported grade III/IV toxicities (9 patients) were hypertension, neutropenia, thrombocytopenia, anemia, diarrhea, and fatigue. The most common grade I and II toxicities were anemia 35.5%, hypothyroidism 35.1%, transaminitis 28.9%, thrombocytopenia 24.5%, neutropenia 22.2%, hypophosphatemia 21.6%, and hypertension 15.9%. Conclusions Pazopanib was found to be tolerable and effective with outcomes comparable to those reported in clinical trials. No difference in PFS was observed when used either as a second- or subsequent line therapy.

Value of peri-operative chemotherapy in patients with CINSARC high-risk localized grade 1 or 2 soft tissue sarcoma: study protocol of the target selection phase III CHIC-STS trial

BackgroundThe value of chemotherapy in soft tissue sarcoma (STS) remains controversial. Several expert teams consider that chemotherapy provides a survival advantage and should be proposed in high-risk (HR) patients. However, the lack of accuracy in identifying HR patients with conventional risk factors (large, deep, FNCLCC grade 3, extremity STS) is an issue that cannot be neglected. For example, while the FNCLCC grading system is a powerful tool, it has several limitations. CINSARC, a 67-gene signature, has proved to be an additional independent factor for predicting metastatic spread and outperforms histological grade. Regardless of FNCLCC grade, CINSARC stratifies patients into two separate prognostic groups: one with an excellent prognosis (low-risk (LR) CINSARC) and the other with a worse outcome (HR-CINSARC) in terms of metastatic relapse. Here we evaluate the role of chemotherapy in grade 1–2 STS patients with HR-CINSARC and assess the prognostic value of CINSARC in patients treated with standard of care.MethodsCHIC is a parallel, randomized, open-label, multicenter study evaluating the effect on metastasis-free survival of adding perioperative chemotherapy to standard of care in patients with grade ½ STS sarcoma defined as HR by CINSARC. In this target selection design, 600 patients will be screened with CINSARC to randomize 250 HR-CINSARC patients between standard of care and standard of care plus chemotherapy (4 cycles of 3 weeks of intravenous chemotherapy with doxorubicin in combination with dacarbazine or ifosfamide according to histologic subtype). LR-CINSARC patients will be treated by standard of care according to the investigator. The primary endpoint is metastasis-free survival. Secondary endpoints include overall survival, disease-free survival and safety. Furthermore, the prognostic value of CINSARC will be evaluated by comparing LR-CINSARC patients to HR-CINSARC patients randomized in standard of care.DiscussionCHIC is a prospective randomized phase III trial designed to comprehensively evaluate the benefit of chemotherapy in HR-CINSARC patients and to prospectively validate the prognostic value of CINSARC in grade ½ STS sarcoma patients.Trial registrationClinicalTrials.gov identifier: NCT04307277 Date of registration: 13 March 2020

The \u03b2-adrenergic receptor antagonist propranolol offsets resistance mechanisms to chemotherapeutics in diverse sarcoma subtypes: a pilot study

Standard chemotherapy for soft tissue sarcomas has shown limited efficacy. Here, we sought to evaluate whether β-adrenergic receptor (β-AR) signalling contributed to the progression of sarcomas and therapy resistance. To assess the translational potential of β-adrenergic receptors, we performed immunohistochemical detection of β1-AR, β2-AR and β3-AR in leiomyosarcoma, liposarcoma and angiosarcoma tissue specimens, reporting the results scored for the intensity. By using established and patient-derived sarcoma cells, we demonstrated the antitumour potential of the pharmacological targeting of β-ARs with the nonselective β-blocker propranolol in such sarcomas. Of note, pharmacological β-AR inhibition synergized with doxorubicin in inhibiting the cell viability of liposarcoma and leiomyosarcoma cells and increased the response to docetaxel in angiosarcoma- and solitary fibrous tumour (SFT)-patient-derived cells. Notably, the SFT patient was treated with the combination of propranolol and docetaxel, reporting prolonged disease control. Mechanistically, we found that propranolol reduced the activity of the multidrug resistance efflux pump P-gp, thereby increasing the intracellular doxorubicin concentration and antitumour activity. In addition, propranolol attenuated the Akt-dependent survival signal induced by doxorubicin and strongly reduced the activation of the NF-kB/COX-2 pathway, increasing cell sensitivity to docetaxel. Overall, our study highlighted the therapeutic potential of propranolol, alone or in rational combination therapies, for sarcoma treatment.

Molecular Imaging with 3'-deoxy-3'[(18)F]-Fluorothymidine (18F-FLT) PET/CT for Early Response to Targeted Therapies in Sarcomas: A Pilot Study.

Although 3′-deoxy-3′[(18)F]-fluorothymidine (FLT)-positron emission tomography (PET) has been utilized for tumor response assessment to neoadjuvant chemotherapy in soft tissue sarcomas, it has not been exploited for the assessment of early response to systematically targeted therapies. Herein, we investigated the 18F-FLT PET/CT kinetics in patients with sarcoma who received targeted therapies. Among 15 patients with sarcoma who underwent 18F-FLT PET/CT, 5 patients (33%) patients were imaged at three time points: At baseline and at 1–15 weeks (MDM2-inhibitor treatment), and 10 patients (67%) were imaged twice: At baseline and at 1–4 weeks (MDM2 inhibitor, n = 5; c-met inhibitor n = 5). The patients with sarcoma had a total of 18 identifiable tumors. Twelve of 15 patients (80%) demonstrated 18F-FLT concentrations changes early, i.e., at 1–4 weeks. Eight patients responded (53.3%), four patients progressed (26.7%) based on FLT change of more than 10% increase, and three patients (20%) demonstrated no change. 18F-FLT PET/CT may be used for early response imaging to molecularly targeted therapies in patients with sarcoma. Further larger studies in specific sarcoma sub-types are warranted.

A phase II multi-strata study of lurbinectedin as a single agent or in combination with conventional chemotherapy in metastatic and/or unresectable sarcomas

Chemotherapy objective response rates (ORRs) in metastatic soft tissue sarcoma (STS) are typically 20–40% with median progression-free survival (PFS) less than 6 months. Lurbinectedin is a new anticancer agent under investigation. The primary objective of this three-arm, phase II study was to determine the disease control rate (DCR = ORR + stable disease [SD]) at 24 weeks of lurbinectedin alone or with chemotherapy in STS. Eligible patients included adults with ≤2 prior cytotoxic therapies. Study cohorts were: stratum A (StrA; anthracycline-naive), lurbinectedin/doxorubicin; stratum B (StrB; prior anthracycline), lurbinectedin/gemcitabine; stratum C (StrC; prior anthracycline/gemcitabine) lurbinectedin monotherapy. Each stratum was analysed separately by Simon two-stage design. Forty-two patients were accrued (StrA = 20, StrB = 10, StrC = 12) including leiomyosarcoma [LMS] (n = 20), synovial sarcoma [SS](n = 4), malignant peripheral nerve sheath tumour (n = 3) and other STS histologies (n = 15). For StrA there were seven partial responses (PR) plus one stable disease (SD) at 24 weeks. For StrB, two patients met the 24-week DCR including one PR (leiomyosarcoma) and one SD (desmoplastic small round cell tumour [DSRCT]). StrB did not continue to the second stage. In StrC, no patients met the primary end-point. Median progression-free survival (PFS) was: StrA = 4.2 months (90% CI 1.4–7.8), StrB = 1.7 months (90% confidence interval (CI) 1.0–7.4), and StrC = 1.3 months (90% CI 1.1–3.0). Lurbinectedin as a single agent or with chemotherapy was well tolerated with haematologic adverse events (AE's) as the most common toxicity. There were no treatment-related deaths. The combination of lurbinectedin/doxorubicin reached the DCR end-point with seven PR and one patient with SD (ORR 35.0%, 24-week DCR 40.0%). Evidence of drug benefit was seen in leiomyosarcoma, dedifferentiated liposarcoma (DDLS), myxoid liposarcoma (MLS), synovial sarcoma (SS), and desmoplastic small round cell tumour (DSRCT). Trial registrationclinicaltrials.gov; NCT02448537

Three-phase scintigraphy in evaluation of preoperative chemotherapy of soft tissue sarcomas of extremities

Purpose. To determine the diagnostic value of threephase scintigraphy in the evaluation of the preoperative chemotherapy of soft tissue sarcomas of the extremities on different diagnostic stages. Material and methods. We analyzed the data of 76 patients with extremity soft tissue sarcomas. The study included data from 28 patients who underwent three-phase scintigraphy with Technetril 99mTc. Scintigraphic data before and after neoadjuvation chemotherapy were analyzed in 16 patients, before and during chemotherapy — in 6 patients, only during chemotherapy — in 1 and only after all courses of chemotherapy — in 5 patients. Results. The sensitivity of the method (prediction of grade III–IV pathologic response) was 100 %, specificity (prediction of grade I–II pathologic response) was 87%. The predictive value of positive and negative results was 63 and 100%, respectively. Conclusion. A three-phase scintigraphy with Technetril 99mTc is a highly informative method for evaluating the effectiveness of preoperative chemotherapy in patients with sarcomas of soft tissues of the extremities.