Treatment Of Soft Tissue Sarcomas Research Articles

Omics technologies in diagnosis and treatment of soft tissue sarcomas

Omics technologies in diagnosis and treatment of soft tissue sarcomas

1743P A phase II study of fruquintinib in the 1L or 2L treatment of unresectable metastatic soft tissue sarcoma

1743P A phase II study of fruquintinib in the 1L or 2L treatment of unresectable metastatic soft tissue sarcoma

S-p-bromobenzyl-glutathione cyclopentyl diester (BBGC) as novel therapeutic strategy to enhance trabectedin anti-tumor effect in soft tissue sarcoma preclinical models.

Trabectedin, approved for the treatment of soft tissue sarcoma (STS), interferes with cell division and genetic transcription processes. Due to its strong anti-tumor activity in only certain histotypes, several studies on trabectedin combinations are currently ongoing to improve its efficacy. In this study, we aimed to investigate novel potential therapeutic strategies to enhance the anti-tumor effect of trabectedin using integrated in silico, in vitro, and in vivo approaches. For in silico analysis, we screened two public datasets, GSEA M5190 and TCGA SARC. Fibrosarcoma, leiomyosarcoma, dedifferentiated, and myxoid liposarcoma cell lines were used for in vitro studies. For in vivo experiments, fibrosarcoma orthotopic murine model was developed. In silico analysis identified Glo1 as the only druggable target upregulated after trabectedin treatment and correlated with poor prognosis. The specific Glo1 inhibitor, S-p-bromobenzylglutathione cyclopentyl diester (BBGC), increased trabectedin cytotoxicity in STS cells, and restored drug sensitivity in myxoid liposarcoma cells resistant to trabectedin. Moreover, the combined treatment with BBGC and trabectedin had a synergistic antitumor effect in vivo without any additional toxicity to mice. Based on these results, we believe that BBGC warrants further investigation to evaluate its potential clinical use in combination with trabectedin.

Histology-Tailored Approach to Soft Tissue Sarcoma.

Soft tissue sarcomas are a diverse and heterogeneous group of cancers of mesenchymal origin. Each histological type of soft tissue sarcoma has unique clinical particularities, which makes them challenging to diagnose and treat. Multidisciplinary management of these rare diseases is thus key for improved survival. The role of surgery has been well established, and it represents the cornerstone curative treatment for soft tissue sarcomas. To date, local recurrence is the leading cause of death in low-grade sarcomas located at critical sites, and distant metastasis in high-grade sarcomas, regardless of the site of origin. Management must be tailored to each individual histologic type. We describe the most common types of extremity, trunk, abdominal, and retroperitoneal soft tissue sarcoma along with characteristics to consider for optimized management.

Mapping the Course of Recovery Following Limb-Salvage Surgery for Soft-Tissue Sarcoma of the Extremities.

Despite the goal of an acceptable functional result, the surgical treatment of soft-tissue sarcoma can portend a prolonged course of recovery. More comprehensive data on the expected course of recovery following extremity sarcoma surgery are needed to help to inform physicians and patients. The purpose of the present study was to describe the typical course of functional recovery following limb-salvage resection of a soft-tissue sarcoma and to identify factors associated with a delayed postoperative course of recovery. A retrospective review of a prospectively maintained institutional database was performed for all patients undergoing surgical treatment with limb salvage of a soft-tissue sarcoma of the extremities or pelvis with at least 1 year of follow-up after the definitive surgical procedure. All patients were required to have preoperative functional outcomes recorded for either the Toronto Extremity Salvage Score (TESS) or the Musculoskeletal Tumor Society (MSTS) score and functional outcome measures at 1 year postoperatively. The primary outcome measures were time to recovery and maximal functional improvement. In this study, 916 patients met inclusion criteria following surgical resection of a soft-tissue sarcoma of the extremities. The median follow-up was 74 months. Patients typically achieved a return to their baseline preoperative level of function for all functional outcome measures by 1 to 2 years and achieved maximal functional recovery by 2 years postoperatively. Older age, female sex, deep tumor location, larger tumor size, pelvic location, osseous resection, motor nerve resection, free and/or rotational soft-tissue coverage, and postoperative complications were independently associated with worse TESS and/or MSTS scores (p ≤ 0.05). Tumor recurrence was associated with worse functional outcomes scores. An analysis was performed to determine which patients had a prolonged course of recovery (i.e., were considered to still be recovering). Older age, female sex, larger tumor size, osseous resection, and motor nerve resection were associated with a delayed course of recovery (p ≤ 0.04). Complications and tumor recurrence were associated with delayed functional recovery across all domains. Most patients will achieve maximal recovery by 2 to 3 years following surgical resection for soft-tissue sarcoma of the extremities. Older age, female sex, larger tumor size, osseous resection, motor nerve resection, postoperative complications, and tumor recurrence portend poorer functional outcomes and a delayed course of recovery. Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Immediate and delayed flap reconstruction have equivalent outcomes and associated costs following soft tissue sarcoma surgery.

Surgical treatment of soft tissue sarcoma (STS) involves wide resection of the tumor, which can necessitate soft tissue reconstruction with local or free tissue flaps. This retrospective study compares cost, surgical and oncologic outcomes between patients undergoing reconstruction with immediate versus delayed flap coverage following STS resection. Thirty-four patients who underwent planned flap reconstruction following resection of primary STS were identified retrospectively. Twenty-four (71%) received immediate reconstruction during the index surgery and 10 (29%) underwent planned delayed reconstruction. Preoperative patient-specific metrics, tumor characteristics, and surgical and patient outcomes were collected. Total hospital charges associated with every encounter during the perioperative period were obtained. Patient demographics, comorbidities, tumor metrics, and surgical characteristics were equivalent between groups. Postoperative wound complications, reoperations, readmissions, and disease-specific survival did not differ between cohorts. Costs associated with each reconstruction strategy were equivalent on bivariate and multivariate testing, when accounting for operating room time, hospital length of stay, and reoperation rate. Our study identifies no significant difference in patient outcome measures or cost between planned immediate and delayed flap reconstruction following STS resection. These results support the implementation of either treatment strategy in keeping with patient-centered, multidisciplinary care principles.

Mental Health Disorders and Surgical Outcomes in Patients With Bone and Soft Tissue Sarcoma.

We conducted a study to investigate the relationship between a mental health diagnosis (MHD) and postoperative outcomes in orthopedic patients with bone and soft tissue sarcoma. We hypothesized that patients with sarcoma with a preoperative MHD would have worse outcomes and more postoperative complications. A retrospective review was performed of 356 patients who underwent surgical treatment for bone or soft tissue sarcoma. Patients were divided into two groups: those with a diagnosis of depression, anxiety, bipolar disorder, and/or schizophrenia and those with no previous MHD. Statistical analysis was performed using independent t, Mann-Whitney U, and chi-square tests. Statistical analysis demonstrated significant differences between the MHD group and the control group in three outcomes: length of stay, 90-day readmission rate, and incidence of surgical site infections. Subgroup analysis of the MHD group yielded significantly higher 90-day readmission rates for patients who were diagnosed during sarcoma treatment. Patients with sarcoma and an MHD had a longer postoperative hospital stay, an increased 90-day readmission rate, and a greater risk of surgical site infection. Given the rising prevalence of mental health disorders nationwide, orthopedic surgeons should be aware of differences in postoperative outcomes between patients with sarcoma with and without mental illness. [Orthopedics. 20XX;4X(X):XXX-XXX.].

Safety and Efficacy of Percutaneous Cryoablation for Recurrent or Metastatic Soft Tissue Sarcoma in Adult Patients.

Background: Treatment options are limited in patients with recurrent or metastatic disease after initial treatment of soft tissue sarcoma (STS) by surgical resection, radiation, or systemic therapy. Percutaneous cryoablation may provide a complementary minimally invasive option in this setting. Objective: To assess the safety and efficacy of percutaneous cryoablation performed for local control of treatment-refractory recurrent or metastatic STS. Methods: This single-institution retrospective study included adult patients who underwent percutaneous cryoablation from March 2016 to April 2023 to achieve local control of recurrent or metastatic STS after earlier treatment (surgery, radiation, or chemotherapy). For each treated lesion, a single interventional radiologist re-reviewed intraprocedural images to assess for adequate coverage by the ice ball of the entire lesion and a ≥5-mm margin in all dimensions. Complications and outcomes were extracted from medical records. The primary endpoint for procedure efficacy was 1-year local progression-free survival. Results: The study included 141 patients (median age, 66 years; 90 female, 51 male) who underwent 217 cryoablation procedures to treat 250 recurrent or metastatic STS lesions. The most common STS histologic types were leiomyosarcoma (56/141) and liposarcoma (39/141). Lesions had a mean long-axis diameter of 2.0 cm (range, 0.4-11.0 cm). Adequate ice-ball coverage was achieved for 82% (204/250) of lesions. The complication rate was 2% (4/217), entailing three major complications and one minor complication. Patients' median post-ablation follow-up was 25 months (range, 3-80 months). Local progression-free survival was 86% at 1 year and 79% at 2 years. Chemotherapy-free survival was 45% at 1 year and 31% at 2 years. Overall survival (OS) was 89% at 1 year and 80% at 2 years. In Kaplan-Meier analysis, leiomyosarcoma, in comparison with liposarcoma, had significantly higher local progression-free survival, but no significant difference in OS. In multivariable analysis, factors independently associated with an increased risk for local progression included inadequate ice-ball coverage (HR=7.73) and a lesion location of peritoneum (HR=3.63) or retroperitoneum (HR=3.71) relative to lung. Conclusion: Percutaneous cryoablation has a favorable safety and efficacy profile in patients with recurrent or metastatic STS after earlier treatments. Clinical Impact: Percutaneous cryoablation should be considered for local control of treatment-refractory STS.

Preoperative Ultrahypofractionated Radiation Therapy for Soft Tissue Sarcomas: Low Rate of Wound Complications

Background: Normofractionated pre-operative radiotherapy (nRT) with 50 Gy applied in 25 fractions represents the most widely used radiotherapy (RT) regimen in combined local treatment of soft tissue sarcomas (STS). STS are characterized by a low α/β ratio of 4-5 Gy, which may translate into a higher sensitivity for hypofractionation. Increasing data from cohorts and phase II trials on ultra-hypofractionated RT (uhRT) regimens is available. We prospectively assessed our preoperative uhRT sarcoma patient cohort with a focus on short term wound complications (WC). Methods: This is a prospective registry analysis of a single center patient cohort, treated from 03.2020-10.2023 with uhRT (25 Gy in 5 fractions in 1 week). The same radiation oncologists (GS/CG) and surgeon (BF) performed the treatment (61/61 and 58/60), as well as the same reference pathologist (BB) confirmed all histopathological diagnoses. WC (according to CAN-NCIC-SR2 trial) and intermediate local control (LC) rates were assessed and compared with outcome data of a previously published cohort of 67 extremity/trunk sarcoma patients treated with nRT by the same authors (7% WC, 98% LC at 3 years). Results: After a mean/median follow-up (FU) of 19/19 months (range 0-46), LC at 1.5y was 94%. Surgery was performed at a mean/median of 20/16 days (range 4-60) after uhRT completion. WC were observed in 7/60 operated patients (12%), and in 5/51 (10%) extremity/trunk lesions. Early tolerance was excellent, limited to G0-1, even in 3 patients with prior RT to the same region. Clear resection margins were achieved in 55/60 patients (92%). Pathologic necrosis of ≥95% was reported in 5%, 75% achieved less than <50% necrosis. Conclusion: These results show low rates of WC and high LC for uhRT and are comparable to our previously published nRT data. This study supports the routine use of preoperative uhRT for STS.

Evaluating [225Ac]Ac-FAPI-46 for the treatment of soft-tissue sarcoma in mice.

Fibroblast Activation Protein (FAP) is an emerging theranostic target that is highly expressed on cancer-associated fibroblasts and on certain tumor cells including sarcoma. We investigated the anti-tumor efficacy of [225Ac]Ac-FAPI-46 as monotherapy or in combination with immune checkpoint blockade (ICB) in immunocompetent murine models of sarcoma sensitive or resistant to ICB. [68Ga]Ga- and [225Ac]Ac-FAPI-46 were tested in subcutaneous FAP+ FSA fibrosarcoma bearing C3H/Sed/Kam mice. The efficacy of up to three cycles of 60 kBq [225Ac]Ac-FAPI-46 was evaluated as monotherapy and in combination with an anti-PD-1 antibody. Efficacy of [225Ac]Ac-FAPI-46 and/or ICB was further compared in FAP-overexpressing FSA (FSA-F) tumors that were sensitive to ICB or rendered ICB-resistant by tumor-induction in the presence of Abatacept. [225Ac]Ac-FAPI-46 was well tolerated up to 3 × 60 kBq but had minimal effect on FSA tumor growth. The combination of three cycles [225Ac]Ac-FAPI-46 and ICB resulted in growth delay in 55% of mice (6/11) and partial tumor regression in 18% (2/11) of mice. In FSA-F tumors with FAP overexpression, both [225Ac]Ac-FAPI-46 and ICB were effective without additional benefits from the combination. In locally immunosuppressed and ICB resistant FAP-F tumors, however, [225Ac]Ac-FAPI-46 restored responsiveness to ICB, resulting in significant tumor regression and tumor-free survival of 56% of mice in the combination group up to 60 days post treatment. [225Ac]Ac-FAPI-46 efficacy is correlated with tumoral FAP expression levels and can restore responsiveness to PD-1 ICB. These data illustrate that careful patient selection based on target expression and rationally designed combination therapies are critically important to maximize the therapeutic impact of FAP-targeting radioligands.

Introduction and impact of routine whole genome sequencing in the diagnosis and management of sarcoma

BackgroundSarcomas are diverse neoplasms with highly variable histological appearances in which diagnosis is often challenging and management options for metastatic/unresectable disease limited. Many sarcomas have distinctive molecular alterations, but the range of alterations is large, variable in type and rapidly increasing, meaning that testing by limited panels is unable to capture the broad spectrum of clinically pertinent genomic drivers required. Paired whole genome sequencing (WGS) in contrast allows comprehensive assessment of small variants, copy number and structural variants along with mutational signature analysis and germline testing.MethodsIntroduction of WGS as a diagnostic standard for all eligible patients with known or suspected soft tissue sarcoma over a 2-year period at a soft tissue sarcoma treatment centre.ResultsWGS resulted in a refinement in the diagnosis in 37% of cases, identification of a target for personalised therapy in 33% of cases, and a germline alteration in 4% of cases.ConclusionIntroduction of WGS poses logistical and training challenges, but offers significant benefits to this group of patients.

P-344 Systematic review of the gonadotoxicity and risk of infertility of soft tissue sarcoma chemotherapies in pre- and postpubertal females and males

Abstract Study question What is the gonadotoxicity of soft tissue sarcoma chemotherapies to better counsel females and males about the risk of infertility? Summary answer Limited data about the gonadotoxicity indicate a rather high risk with an average suspected infertility in females of 71% and in males of 54%. What is known already There is increasing awareness of the need to counsel young female and male cancer patients about the gonadotoxicity of chemotherapies and the risk of infertility. In addition, fertility preservation measures are offered in most countries. However, our knowledge of the gonadotoxicity of most cancer diseases and chemotherapies is still limited making it difficult to indicate fertility preservation measures. Soft tissue and mesothelial cancer are such a types of cancer for which data is very poor. The gonadotoxicity and risk of infertility of soft tissue and mesothelial cancer has not yet been systematically reviewed. Study design, size, duration This review is part of the FertiTOX project (www.fertitox.com) which aims to close the gap of data regarding gonadotoxicity of cancer therapies to enable more accurate counselling regarding fertility preservation. A systematic literature search considering papers on gonadotoxicity of treatment of soft tissue sarcoma and mesothelial cancer was performed. A total of 2801 records were identified for abstract screening. The review was performed from December 2022 until October 2023. Participants/materials, setting, methods A literature search of papers published in the databases of MEDLINE, Embase, and Cochrane Library since 2000 was performed. Only females and males without metastases or recurrent disease were considered. Due to limited infertility data the outcome parameter “Suspected infertility” was defined based on reported low ovarian reserve parameters, low inhibin B, high gonadotropin concentration, gonadal dysfunction, amenorrhea, oligomenorrhea, azoospermia or oligozoospermia. Main results and the role of chance The database search yielded a total of 2801 abstracts, 136 of which were included in the full-text analysis. Of these, 7 studies, each on soft tissue sarcomas, could be included in the review. Studies on mesothelial cancer could not be identified. Two of the 7 soft tissue sarcoma studies were retrospective and 5 were prospective. Of the 7 studies, 3 provided data on women, 3 on men and 1 on both genders. A total of 28 women and 50 men, a total of 78, were included. The pubertal status could not be determined for all patients. Suspected infertility was found in 20 of 28 (71.4%, range 0-100%) of females (4 studies) and in 27 of 50 (54%, range 34.8-100%) of males (4 studies) soft tissue sarcoma patients. Limitations, reasons for caution The weakness is the inclusion of prepubertal and pubertal females and males, and the unknown pubertal status in some cases. A further weakness is the heterogenous spectrum of infertility markers and the limited number of studies which required to define for the analysis the rather vague outcome parameter “suspected infertility”. Wider implications of the findings Our data suggest a high risk of infertility due to chemotherapies in soft tissue sarcomas. This appears to be more pronounced in females than in males, although precise information cannot be given due to limited data. However, even though the study emphasizes the importance to consider fertility preservation measures. Trial registration number PROSPERO (Registry number CRD42023385402)

Enhancing Diagnosis and Prognosis by Assessing the Clinical, Morphological, and Behavior Aspects in Soft Tissue Sarcomas.

Soft-tissue sarcomas (STSs) are an uncommon and diverse group of cancers, consisting of more than 80 different kinds, each showing unique mesenchymal differentiation as described by the World Health Organization (WHO). The prognostic factors at the time of diagnosis mostly depend on the size, depth, and histological grade of the lymphatic involvement. Improved prognostic indicators are necessary to identify patients at high risk who may derive advantages from adjuvant therapy and those at low risk who might avoid treatment-related side effects. Over a period of five years, a considerable number of patients experience the recurrence of the tumor in the same area or the metastasis of the disease to other parts of the body, even after the complete removal of the localized tumor through surgery. To further personalize and focus medicines, it is critical to enhance prediction accuracy and uncover new therapy targets. This is particularly important considering the high mortality and morbidity rate associated with metastatic STS. The significant diversity of STS poses difficulty in comprehending its pathobiology and in converting biological progress into therapeutic application. This prospective cohort study was carried out at a major university hospital to ascertain adult patients who were diagnosed with STS of the extremities between the period from 2018 to 2023. The inclusion criteria were individuals who were 18 years of age or older with a histological diagnosis of STS. The exclusion criteria encompassed individuals with malignancies other than STS and those with inadequate data on essential factors. Thorough assessments were conducted to analyze patient demographics, tumor features (including site, size, depth, neurovascular or bone invasion), and histologic type and grade (according to the French Federation of Cancer Centers (FNCLCC) grading system). The purpose was to find predictive markers and evaluate results. The results are consistent with previous research and enhance our current knowledge of STS prognosis. Key prognostic markers for metastasis and mortality risk include tumor size larger than 5 cm, histologic grade, and sarcoma subtype. Radical surgical procedures, such as amputation or disarticulation, did not show any survival advantage, probably because they were used in situations where the disease had already progressed locally and had significant involvement in the blood vessels. Histologic grading has been identified as the most important factor in predicting the likelihood of metastasis in adult STSs. The study found that most tumors were of high grade, and there was a statistically significant association between tumor grade, Ki67 levels, and overall survival. A small proportion of patients experienced prolonged longevity beyond five years, emphasizing the connection between early detection, tumors of lesser severity, and enhanced results. These observations emphasize the significance of accurate prognostic assessments and customized therapeutic approaches in the treatment of STS.

Clinical Outcomes After Definitive Treatment of Soft Tissue Sarcoma of the Hand: A Retrospective Cohort Study of 109 Patients

The purpose of this study was to provide updated data on oncologic outcomes following definitive surgical treatment of soft tissue sarcoma of the hand in a cohort of 109 patients, as well as to characterize risk factors for poor oncologic and functional outcomes. We analyzed data from 109 consecutive patients who had definitive surgical treatment for soft tissue sarcoma of the hand performed between 1996 and 2019 by a single surgeon at a sarcoma center. Primary outcomes included functional outcome (assessed by Musculoskeletal Tumor Society scores), disease-free survival (DFS), and overall survival (OS). We compiled descriptive data and used a multivariable linear model to identify factors associated with functional outcomes. Kaplan-Meier methods were used to estimate 5- and 10-year DFS and OS. Patients had a median age of 36 years at presentation. Median follow-up was 6.1 years among patients alive at the end of follow-up. The median Musculoskeletal Tumor Society score was 29; functional outcome was worse among patients with high-grade tumors or complications. Among the 107 patients who became disease-free, there were four local recurrences (one with metastasis), six distant recurrences, and one death without recurrence. All local recurrences were deep tumors (two myxofibrosarcoma and two myxoinflammatory fibrosarcoma). Estimated 5- and 10-year DFS rates were 89% (95% confidence interval [CI]: 83% to 96%) and 88% (95% CI: 80% to 95%). There were seven deaths, and the estimated 5- and 10-year OS rates were 95% (95% CI: 90% to 100%) and 92% (95% CI: 84% to 100%). Larger tumor size and higher stage at diagnosis were associated with shorter DFS and OS in univariable analyses; low event rates precluded multivariable analysis of survival. Aggressive disease-specific surgical and multidisciplinary treatment can yield long DFS and OS, and good functional outcomes. However, complications and high-grade tumors are associated with worse functional scores. Prognostic II.

Mesna, Doxorubicin, Ifosfamide and Dacarbazine (MAID) Combination Chemotherapy for Retroperitoneal Sarcoma: A Single-center Experience.

There is limited evidence regarding the systemic treatment of retroperitoneal soft-tissue sarcoma, and the current Japanese guidelines fail to make definitive suggestions. Here, we report our experience with combination chemotherapy of mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) in this population. We retrospectively reviewed the records of eight patients (three male and five female) who received MAID for pathologically diagnosed metastatic unresectable retroperitoneal sarcoma (either leiomyosarcoma or pleomorphic sarcoma) between October 2019 and January 2022. Treatment efficacy, tolerability (need for dose reduction), and safety profiles were evaluated and summarized. At initiation, the median age was 56.0 years, and the body mass index was 20.0 kg/cm2 Six patients had Eastern Cooperative Oncology Group performance status scores of 0. The net clinical benefit was a partial response in three (37.5%) patients, stable disease in four (50.0%), and progressive disease in one (12.5%). During the median 90.8 weeks of follow-up, disease in five patients progressed, resulting in a median progression-free survival of 48.4 weeks, and five deaths occurred, resulting in an overall survival of 95.1 weeks. Commonly observed adverse events were neutropenia (eight patients), anemia (eight patients), and decreased platelet count (seven patients), which led to dose reduction (60-80%) in six patients. MAID combination therapy may be an acceptable option for advanced retroperitoneal sarcoma; however, its benefits must be carefully assessed owing to its not insignificant toxicity.

Preoperative sequential chemotherapy and hypofractionated radiotherapy combined with comprehensive surgical resection for high-risk soft tissue sarcomas: a retrospective study.

The management of soft tissue sarcomas presents considerable therapeutic challenges. This study was designed to assess the efficacy of neoadjuvant sequential chemotherapy and hypofractionated radiotherapy in conjunction with extensive surgical resection for the treatment of high-risk soft tissue sarcomas. We performed a retrospective review of 31 high-risk soft tissue sarcoma patients treated at our institution from June 2021 to June 2023. The cohort consisted of 21 males and 10 females with a mean age of 55.7 years and included both initial and recurrent disease presentations. Our treatment regimen comprised two to three cycles of neoadjuvant chemotherapy coupled with hypofractionated radiotherapy, delivered at 5 Gy per fraction to a total dose of 25-35 Gy across 5-7 days, prior to surgical resection aimed at achieving wide margins. Data collection was systematic, covering surgical outcomes, chemoradiotherapy-related complications, and prognostic factors. All patients completed the prescribed course of neoadjuvant chemoradiotherapy. 29% patients experienced grade 3+ chemotherapy toxicity, necessitating a reduction or interruption in their chemotherapy regimen. Limb preservation was accomplished in 30 patients finally. Response evaluation using RECIST 1.1 criteria post-neoadjuvant therapy revealed 9.7% with PD, 58.1% with SD, 29% with a PR, and 3.2% with a CR, culminating in an ORR of 32.2%. Postoperative complications included superficial wound infections in four patients and deep incisional infections in another four. 6 patients had developed metastasis, and 3 patients were still alive. Two experienced local recurrence. One-year DFS was 79.3%, with a one-year OS rate of 89.6%. Neoadjuvant sequential chemotherapy and hypofractionated radiotherapy followed by extensive surgical resection represents an effective treatment paradigm for high-risk soft tissue sarcomas. This multimodal approach not only facilitates tumor reduction but also significantly reduces the risks of local recurrence and distant metastasis.

Correlation of ctDNA and LDH levels in patients with soft tissue sarcoma: A single-center experience.

e23535 Background: Our study aims to examine the relationship between the presence of circulating tumor DNA (ctDNA) and lactate dehydrogenase (LDH) in patients diagnosed with soft tissue sarcoma (STS). There is emerging yet limited data on the applicability of ctDNA in STS. LDH is a cheaper readily available test that has been associated with unfavorable overall survival in different malignancies. This research aims to understand the correlation between ctDNA and LDH as a tool to assess its utility as indirect markers of response to treatment in STS. Methods: This was a single-center retrospective chart review on patients diagnosed with STS. Eligibility criteria included a confirmed diagnosis and available measurements of both ctDNA and LDH levels. Correlation was compared between Non-hispanic whites (NHW) and Hispanics (H). Data was sourced from our electronic medical record and Signatera™ assay to obtain the primary endpoints. Specimens were standardized in accordance to Natera’s™ specifications. Study endpoints included the correlation coefficients between ctDNA and LDH levels. A two-stage study design was applied for a robust analysis. Spearman's rank correlation coefficient (denoted as r) was employed for statistical analysis, assessing the strength and direction of the monotonic relationship between ctDNA and LDH levels. Marker values were treated as continuous variables in these analyses. All analyses were executed in GraphPad Prism software. Results: The cohort comprised 33 patients with STS (14 NHW, 19 H). The median LDH in H was 189 (interquartile range (IQR) = 184) vs 184 (IQR = 105) in NHW. Comparatively, the median ctDNA in H was 0 (IQR = 39.3) and also 0 (IQR = 11.1) in NHW. The overall correlation between ctDNA and LDH levels was moderate positive (r = 0.5, p = 0.002), indicating a consistent, though not necessarily linear, relationship. Subgroup analysis showed r = 0.19 (p = 0.52) in NHW and r = 0.43 (p = 0.1) in H groups, suggesting ethnic variability in the ctDNA-LDH correlation. These findings were statistically significant within the predefined confidence limits and probability values. Conclusions: Our study demonstrated a significant correlation between ctDNA levels and LDH in STS patients, implying that higher ctDNA may be associated with higher LDH levels. This association can lead clinicians in monitoring LDH more frequently as an indirect marker of response to treatment in STS. This correlation suggests an increased tumor burden with a higher inflammatory response, with variations across different racial groups. The wider availability of LDH testing compared to ctDNA in many centers highlights LDH's potential as an indirect marker for STS. Further research with larger prospective cohorts is essential to confirm LDH's role paired with ctDNA in guiding treatment decisions in STS, enhancing its utility in clinical practice.

Assessing response and adherence to neoadjuvant treatment in soft tissue sarcomas of the extremities.

e23559 Background: The standard treatment for large, intermediate, and high-grade extremity soft tissue sarcoma (ESTS) involves surgery and radiotherapy. The addition of chemotherapy has improved oncological outcomes, such as reduced recurrence and prolonged survival. However, the relationship between neoadjuvant treatment and tumor response in ESTS is not well understood. Pathological evaluation of viable tumor cells after treatment is an indicator of tumor response, yet the proportion of viable tumor cells remains high, particularly in high-risk sarcomas. Combining radiotherapy with chemotherapy may enhance the response of tumor cells. Objective: This study aims to evaluate the effects of neoadjuvant chemotherapy (NCT) and chemoradiotherapy (CRT) on patients with high-risk ESTS and to determine its impact on the pathological response. Methods: We enrolled adult patients with high-risk ESTS (SARCULATOR OS &lt; 60%) at a single center in Latin America. The study was designed to analyze the pathological response in patients with high-risk sarcomas who underwent neoadjuvant CRT and resection and to correlate these responses with various variables. The treatment response was evaluated using the EORTC–STBSG criteria. Results: Thirty-four patients were recruited, with a median age of 44 years (IQR 23-74). Fifty-two percent had T3 tumors (mean size 18 cm), and 79.4% were diagnosed at stage III. The predominant histological subtypes were synovial sarcoma (35.3%) and dedifferentiated liposarcoma (29.4%). The most used NCT regimen was doxorubicin/ifosfamide (84.4%), with 62.5% receiving a dosage intensity of Q4W, affected by overcapacity, and 25% received Q3W. Concurrent CRT was administered to 64.7% of patients, with a median delay to onset of 36 days due to overcapacity (43.5%). Only 79.4% completed three preoperative cycles of treatment. As for the response, 41.2% had an EORTC-E response, and 17.6% had an EORTC-D response. Grade 3 neutropenia and anemia occurred in 17.2% and 8.8% of patients, respectively. Disease progression during NCT was observed in six patients. No significant difference was found in the pathological response between the Q4W and Q3W dosage intensities (p = 0.62). Conclusions: The impact of NCT on pathological responses was not significantly high, which may be due to the predominant histological type in our series. The main cause of treatment delay at our center was due to overcapacity; however, this did not influence the pathological response relative to dose intensity. Additional follow-up assessments are required to determine the influence on relapse-free and overall survival based on the response after preoperative CRT.

A phase I/II trial of neoadjuvant pegylated arginine deiminase (ADI-PEG 20) with ifosfamide and radiotherapy in soft tissue sarcomas (STS) of the trunk or extremity.

TPS11591 Background: Outcomes for the treatment of metastatic STS remain poor. Better therapies are needed for local and distant control. Arginine is essential to neoplastic growth, yet up to 88% of STS do not express argininosuccinate synthetase (ASS1), an enzyme necessary to produce arginine. ADI-PEG 20 is a microbial enzyme that degrades arginine causing auxotrophy in cancer cells that are ASS1 negative. Pre-clinical data demonstrates that arginine deprivation shunts glutamine towards oxidation via the TCA cycle, thus depleting glutathione stores and increasing oxidative stress to the cell. We hypothesize that the combination of ADI-PEG 20, ifosfamide, and radiation therapy can potentiate cellular death. The encouraging safety and clinical data from the ADI-PEG 20 + radiation + temozolomide trial (NCT04587830) further support this combination. We are conducting a phase I/II trial examining the safety and tolerability to determine the recommended phase II dose (R2PD) and evaluate the efficacy of ADI-PEG 20 in combination with ifosfamide and radiation in patients with high-grade STS. Methods: Eligible patients include untreated intermediate or high-grade extremity or truncal STS planned for definitive resection with performance status 0-1 and adequate organ function. Metastatic disease is exclusionary as well as receiving prior treatment for the study cancer. The total number of patients to be enrolled is approximately 35. Up to 15 patients will be enrolled in the phase I portion with a 3 + 3 dose escalation design with ADI-PEG 20 in combination with escalating doses of ifosfamide and radiation. The primary objectives include determining safety and tolerability as well as the recommended phase II dose (RP2D). Patients will be treated neoadjuvantly with ADI-PEG 20 dosed once weekly starting on Cycle 1 Day -7 with ifosfamide for up to three cycles in combination with standard radiotherapy given over approximately 5 weeks. Ifosfamide will be administered on Days 1 - 5 of all 3 cycles. The phase II participants will receive the combination with ifosfamide at the RP2D determined during phase I. The primary objective of the phase II portion is to determine the percent necrosis and pathologic complete response (pCR) at the time of resection. These endpoints will be summarized by proportions along with the associated 2-sided exact 95% CIs. Assuming the true pCR rate is 25%, enrolling 20 patients will result in a 90% CI for estimating the pCR (10%, 45%). The trial has begun accrual and is soon to open at multiple sites. Clinical trial information: NCT05813327 .

The efficacy of immune checkpoint inhibitors as a part of multimodality treatment in soft tissue and bone sarcoma in an academic community setting.

e23564 Background: Prior studies have shown response to immune checkpoint inhibitors (ICI) in a variety of sarcoma subtypes, however, much is still unknown about ICI use in specific sarcoma subtypes due to disease rarity. Patients (pts) are often treated with these agents as part of clinical trials, and real world data in the community setting is lacking. The aim of this study is to report real world efficacy and safety of ICI in sarcoma either alone or with radiation (RT) and/or surgery. Methods: A retrospective cohort review was conducted to identify pts with soft tissue and bone sarcoma who were administered ICI at Kellogg Cancer Center at NorthShore University HealthSystem/Endeavor Health. Pts who received ICI as part of a clinical trial were excluded. Results: A total of 29 pts receiving ICI were identified. Pts had a median of 1 prior systemic therapy. ICI included pembrolizumab (n = 23), nivolumab (n = 5), and ipilimumab/nivolumab (n = 1). Treatment was discontinued in 28 pts due to disease progression (n = 18), toxicities (n = 3), death (n = 2), and maximal response (n = 5). One patient is still undergoing treatment. Median progression-free survival (PFS) was 4.9 months. Median overall survival (OS) was 14 months. Overall response rate (ORR) is 31%. Median duration of response was not reached (44+ months). Complete response (CR) (n = 5) reported in 3 pts with undifferentiated pleomorphic sarcoma (UPS), 1 pt with SMARCA4 deficient undifferentiated sarcoma, and 1 pt with dedifferentiated chondrosarcoma. Partial response (PR) (n = 4) reported in 1 pt with UPS, 1 pt with dedifferentiated liposarcoma, 1 pt with high grade spindle sarcoma of bone, and 1 pt with malignant peripheral nerve sheath tumor. Of those pts with a CR, 2 patients received only pembrolizumab, 1 pt was administered concomitant RT, and 2 pts had administered concomitant surgery. Of the pts who had PR, 3 were also treated with concomitant RT. Grade 3 immune related adverse effects were reported in 5 of the 29 patients. Of these patients, 2 had documented CR and 3 documented PR. Conclusions: This study expands on the real world efficacy of ICI in a variety of sarcoma subtypes. CR and PR rates in this setting were high, and responses were durable, although selection bias for treatment may have played a role. This data supports the treatment of metastatic sarcoma with ICI, especially with concomitant RT and surgery, in a variety of subtypes.