High-risk Soft Tissue Sarcoma Research Articles

Study protocol: randomized phase III trial of neo-adjuvant and adjuvant chemotherapy vs. immediate surgery and adjuvant chemotherapy for localized soft tissue sarcoma: Japan Clinical Oncology Group study JCOG2102 (NACLESS).

The optimal timing of surgery and the number of courses of perioperative chemotherapy for high-risk soft tissue sarcoma patients are still controversial. Tumour growth during neoadjuvant chemotherapy led to limb amputation in some patients. This study aims to confirm the non-inferiority of surgery and three courses of adjuvant chemotherapy with adriamycin (30mg/m2, days 1 and 2) plus ifosfamide (2g/m2, days 1-5) compared with our standard treatment of three courses of neoadjuvant chemotherapy and surgery followed by two courses of adjuvant chemotherapy with adriamycin plus ifosfamide for localized high-risk soft tissue sarcoma patients. This is a multi-center, two-arm, open-label, randomized phase III trial. The primary aim is to confirm the non-inferiority in overall survival (margin: hazard ratio of 1.61). This is the first randomized controlled trial to compare neoadjuvant chemotherapy and immediate surgery for soft tissue sarcoma. This trial was initiated on 16 November 2022 and registered with the Japan Clinical Trials Registry (jRCTs031220446).

Safety and efficacy of pembrolizumab, radiation therapy, and surgery versus radiation therapy and surgery for stage III soft tissue sarcoma of the extremity (SU2C-SARC032): an open-label, randomised clinical trial.

Approximately half of patients with localised, high-risk soft tissue sarcoma of the extremity develop metastases. We aimed to assess whether the addition of pembrolizumab to preoperative radiotherapy and surgery would improve disease-free survival. We completed an open-label, randomised clinical trial in patients with grade 2 or 3, stage III undifferentiated pleomorphic sarcoma or dedifferentiated or pleomorphic liposarcoma of the extremity and limb girdle. Patients were enrolled at 20 academic institutions in Australia, Canada, Italy, and the USA. Patients were randomly assigned to preoperative radiotherapy then surgery (control group) or preoperative pembrolizumab with radiotherapy (initiated 1-14 days after the first dose of pembrolizumab) then surgery and postoperative pembrolizumab (experimental group). Pembrolizumab (200 mg intravenously every 3 weeks) was administered as three neoadjuvant cycles (before, during, and after radiotherapy) and 14 or less adjuvant cycles. Primary endpoint was disease-free survival. This study is registered with ClincialTrials.gov (NCT03092323). Between Nov 18, 2017, and Nov 14, 2023, 143 participants were randomly assigned to treatment. A modified intention-to-treat analysis of 127 patients with median follow-up of 43 months showed that the experimental group (n=64) had significantly longer disease-free survival than the control group (n=63; log-rank one-sided p=0·035; hazard ratio [HR] 0·61; 90% CI 0·39-0·96). The 2-year disease-free survival increased by 15% with addition of pembrolizumab: 52% (90% CI 42-64) and 67% (90% CI 58-78) for the control and experimental groups, respectively. Disease-free survival was similarly improved with pembrolizumab for the intention-to-treat patient population (HR 0·61 [90% CI 0·39-0·95]). Grade 3 or higher adverse events occurred more frequently in the experimental group (56%) than the control group (31%). Addition of pembrolizumab to preoperative radiotherapy and surgery improves disease-free survival for patients with stage III undifferentiated pleomorphic sarcoma and pleomorphic or dedifferentiated liposarcoma of the extremity, which establishes a promising new treatment option for these patients. Stand Up to Cancer and Merck Sharp & Dohme.

Results of an Integrated Phase I/II Prospective Clinical Trial (NEXIS) for Neoadjuvant Anti-PD-L1 (Durvalumab) and Anti-CTLA-4 (Tremelimumab) With Radiation for High-Risk Soft-Tissue Sarcoma of the Trunk and Extremities

Results of an Integrated Phase I/II Prospective Clinical Trial (NEXIS) for Neoadjuvant Anti-PD-L1 (Durvalumab) and Anti-CTLA-4 (Tremelimumab) With Radiation for High-Risk Soft-Tissue Sarcoma of the Trunk and Extremities

Spatial distribution of tumour immune infiltrate predicts outcomes of patients with high-risk soft tissue sarcomas after neoadjuvant chemotherapy

BackgroundAnthracycline-based neoadjuvant chemotherapy (NAC) may modify tumour immune infiltrate. This study characterized immune infiltrate spatial distribution after NAC in primary high-risk soft tissue sarcomas (STS) and investigate association with prognosis. MethodsThe ISG-STS 1001 trial randomized STS patients to anthracycline plus ifosfamide (AI) or a histology-tailored (HT) NAC. Four areas of tumour specimens were sampled: the area showing the highest lymphocyte infiltrate (HI) at H&E; the area with lack of post-treatment changes (highest grade, HG); the area with post-treatment changes (lowest grade, LG); and the tumour edge (TE). CD3, CD8, PD-1, CD20, FOXP3, and CD163 were analyzed at immunohistochemistry and digital pathology. A machine learning method was used to generate sarcoma immune index scores (SIS) that predict patient disease-free and overall survival (DFS and OS). FindingsTumour infiltrating lymphocytes and PD-1+ cells together with CD163+ cells were more represented in STS histologies with complex compared to simple karyotype, while CD20+ B-cells were detected in both these histology groups. PD-1+ cells exerted a negative prognostic value irrespectively of their spatial distribution. Enrichment in CD20+ B-cells at HI and TE areas was associated with better patient outcomes. We generated a prognostic SIS for each tumour area, having the HI-SIS the best performance. Such prognostic value was driven by treatment with AI. InterpretationThe different spatial distribution of immune populations and their different association with prognosis support NAC as a modifier of tumour immune infiltrate in STS.Funding: Pharmamar; Italian Ministry of Health [RF-2019-12370923; GR-2016-02362609]; 5x1000 Funds—2016, Italian Ministry of Health; AIRC Grant [ID#28546].

Proteomic profiling improves prognostic risk stratification of the Sarculator nomogram in soft tissue sarcomas of the extremities and trunk wall.

High-risk soft tissue sarcomas of the extremities and trunk wall (eSTS), as defined by the Sarculator nomogram, are more likely to benefit from (neo)adjuvant anthracycline-based therapy compared to low/intermediate-risk patients. The biology underpinning these differential treatment outcomes remain unknown. We analysed proteomic profiles and clinical outcomes of 123 eSTS patients. A Cox model for overall survival including the Sarculator was fitted to individual data to define four risk groups. A DNA replication protein signature-Sarcoma Proteomic Module 6 (SPM6) was evaluated for association with clinicopathological factors and risk groups. SPM6 was added as a covariate together with Sarculator in a multivariable Cox model to assess improvement in prognostic risk stratification. DNA replication and cell cycle proteins were upregulated in high-risk versus very low-risk patients. Evaluation of the functional effects of CRISPR-Cas9 gene knockdown of proteins enriched in high-risk patients using the cancer cell line encyclopaedia database identified candidate drug targets. SPM6 was significantly associated with tumour malignancy grade (p = 1.6e-06), histology (p = 1.4e-05) and risk groups (p = 2.6e-06). Cox model analysis showed that SPM6 substantially contributed to a better calibration of the Sarculator nomogram (Index of Prediction Accuracy = 0.109 for Sarculator alone versus 0.165 for Sarculator + SPM6). Risk stratification of patient with STS is defined by distinct biological pathways across a range of cancer hallmarks. Incorporation of SPM6 protein signature improves prognostic risk stratification of the Sarculator nomogram. This study highlights the utility of integrating protein signatures for the development of next-generation nomograms.

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.

CXCR4 Expression as a Prognostic Biomarker in Soft Tissue Sarcomas.

Poor long-term survival in localized high-risk soft tissue sarcomas (STSs) of the extremities and trunk highlights the need to identify new prognostic factors. CXCR4 is a chemokine receptor involved in tumor progression, angiogenesis, and metastasis. The aim of this study was to evaluate the association between CXCR4 expression in tumor tissue and survival in STSs patients treated with neoadjuvant therapy. CXCR4 expression was retrospectively determined by immunohistochemical analysis in serial specimens including initial biopsies, tumors post-neoadjuvant treatment, and tumors after relapse. We found that a positive cytoplasmatic expression of CXCR4 in tumors after neoadjuvant treatment was a predictor of poor recurrence-free survival (RFS) (p = 0.003) and overall survival (p = 0.019) in synovial sarcomas. We also found that positive nuclear CXCR4 expression in the initial biopsies was associated with poor RFS (p = 0.022) in undifferentiated pleomorphic sarcomas. In conclusion, our study adds to the evidence that CXCR4 expression in tumor tissue is a promising prognostic factor for STSs.

Neoadjuvant treatment with camrelizumab in combination with doxorubicin and ifosfamide: A phase II clinical study of high-risk soft tissue sarcoma.

e23548 Background: Surgery remains the cornerstone in the management of non-metastatic soft tissue sarcomas. However, high rate of recurrence and metastasis are not uncommon in patients(pts) with high-risk soft tissue sarcoma. Although doxorubicin plus ifosfamide resulted in better tumor shrinkage which facilitate surgical resection, approaches of reducing recurrence and metastasis are still needed. Chemotherapy combined with PD-1 antibodies showed promising activity in several tumors. To date, there is no study to evaluate the efficacy and safety of camrelizumab combined with chemotherapy for high-risk Soft Tissue Sarcoma. Methods: This is a phase II, open-label single-arm study (NCT04606108), aimed to include pts aged 14-65 with histopathologically confirmed high risk soft tissue sarcoma and ECOG 0-1, at least one measurable lesion. One course of treatment every three weeks (camrelizumab 200 mg on day 1, doxorubicin 37.5 mg/m2 or liposomal doxorubicin 25 mg/m2 on days 1-2, and ifosfamide 3 g/m2 on days 1-3). After completing the 2nd course of chemotherapy, the drug will be stopped for 14 days, and surgery or the next stage of treatment will be carried out according to the efficacy of the treatment. Six courses of preoperative chemotherapy will be administered 2 weeks ± 5 days after surgery based on the effectiveness, followed by radiotherapy (50 Gy in 25 fractions or 60 Gy in 30 fractions.) within 3 months after surgery. The primary objective is the Objective response rate (ORR). Using the Simon minimax 2 stage design, planned sample size is 62 pts with 80% power and alpha of 5% to detect an increase in ORR from 27% to 42%. Interim analysis requiring at least 9 confirmed responses in the first 30 pts to proceed to full accrual. Results: 35 pts completed neoadjuvant therapy and surgery, 30 pts received postoperative adjuvant therapy and 1 patient achieved partial response (PR). Median age was 36.4 years (14-61), 62.8% were females, and 57.1% were ECOG-PS 0. Surgery was performed in 35 pts including 16/35 Synovial Sarcoma (SS), 5/35 Liposarcoma (LPS), 2/35 Myxofibrosarcoma (MFS), 2/35 Undifferentiated pleomorphic sarcoma (UPS), 1/35 Leiomyosarcoma (LMS), 5/35 Malignant mesenchymal tumors and 4/35 other pathologic subtype. The 2-year PFS rate was 84.9%, the 2-year OS rate was 96.77%, and the 2-year RFS rate was 72.6%. The most common grade 3-4 adverse events included leukopenia (37.7%), Neutrophil count decreased (37.7%), Platelet count decreased (20.0%), Blennisthmia (3.1%), and Aspartate aminotransferase increased (0.8%). Conclusions: Camrelizumab combined with doxorubicin, liposomal doxorubicin, and ifosfamide in the perioperative treatment of soft tissue sarcoma pts were safe and tolerable. Survival follow-up is still ongoing to analyze the effect of perioperative immunotherapy combined with chemotherapy on long-term outcomes of pts with soft tissue sarcoma. Clinical trial information: NCT04606108 .

Regional hyperthermia for soft tissue sarcoma – a survey on current practice, controversies and consensus among 12 European centers

Purpose To analyze the current practice of regional hyperthermia (RHT) for soft tissue sarcoma (STS) at 12 European centers to provide an overview, find consensuses and identify controversies necessary for future guidelines and clinical trials. Methods In this cross-sectional survey study, a 27-item questionnaire assessing clinical subjects and procedural details on RHT for STS was distributed to 12 European cancer centers for RHT. Results We have identified seven controversies and five consensus points. Of 12 centers, 6 offer both, RHT with chemotherapy (CTX) or with radiotherapy (RT). Two centers only offer RHT with CTX and four centers only offer RHT with RT. All 12 centers apply RHT for localized, high-risk STS of the extremities, trunk wall and retroperitoneum. However, eight centers also use RHT in metastatic STS, five in palliative STS, eight for superficial STS and six for low-grade STS. Pretherapeutic imaging for RHT treatment planning is used by 10 centers, 9 centers set 40–43 °C as the intratumoral target temperature, and all centers use skin detectors or probes in body orifices for thermometry. Discussion There is disagreement regarding the integration of RHT in contemporary interdisciplinary care of STS patients. Many clinical controversies exist that require a standardized consensus guideline and innovative study ideas. At the same time, our data has shown that existing guidelines and decades of experience with the technique of RHT have mostly standardized procedural aspects. Conclusions The provided results may serve as a basis for future guidelines and inform future clinical trials for RHT in STS patients.

Review on Lymph Node Metastases, Sentinel Lymph Node Biopsy, and Lymphadenectomy in Sarcoma.

Soft tissue sarcomas (STS) originating from connective tissue rarely affect the lymph nodes. However, involvement of lymph nodes in STS is an important aspect of prognosis and treatment. Currently, there is no consensus on the diagnosis and management of lymph node metastases in STS. The key risk factor for nodal involvement is the histological subtype of sarcoma. Radiological and pathological evaluation seems to be the most effective method of assessing lymph nodes in these neoplasms. Thus, sentinel lymph node biopsy (SLNB), which has been shown to be valuable in the management of melanoma or breast cancer, may also be a beneficial diagnostic option in some high-risk STS subtypes. This review summarizes data on the risk factors and clinical characteristics of lymph node involvement in STS. Possible management and therapeutic options are also discussed.

What is the optimal (neo)adjuvant strategy of extremity high-risk soft tissue sarcomas (ESTS)?

Currently, the standard treatment for extremity high-risk soft tissue sarcomas (ESTS) combines surgery and pre- or post-op radiation therapy (RT). In some selected cases, chemotherapy (CT) is incorporated into the therapeutic algorithm as a neoadjuvant approach to enable conservative management. Given the risk of local or metastatic relapse, this paper discusses the potential benefits of CT and RT in high-grade ESTs. The role of adjuvant chemotherapy in addition to neoadjuvant CT, the prognostic value of the pathological response to neoadjuvant treatment, and the role for an adjuvant "boost" following resection after pre-operative radiotherapy will be discussed.

Surgical Outcomes in Patients Treated with 5-Day Preoperative Radiotherapy for Soft Tissue Sarcoma

Treatment for high-risk soft tissue sarcoma (STS) of the extremity/trunk includes radiation therapy (RT) and surgical resection. Initial results of a phase 2 single arm trial of 5-day preoperative RT demonstrated acceptable safety and local control. Here we report an update of detailed surgical outcomes among patients treated with 5-day preoperative RT alone on the original phase 2 study, as well as an ongoing expansion cohort. We conducted an updated analysis of surgical complications from a previously reported phase 2 trial of 50 patients with high-risk extremity/trunk STS treated with 5-day preoperative RT (30 Gy over 5 consecutive daily fractions) and surgery. The current analysis includes additional patients from an ongoing IRB-approved expansion cohort of the phase 2 study, which was designed to compare wound complication rates between patients receiving neoadjuvant chemotherapy and those receiving RT alone. However, given that the primary endpoint of this study has not matured, here we present only the data for patients treated with 5-day preoperative RT alone (n = 44; data cutoff date: February 17, 2022). We generated a secure prospective patient database and extracted data including demographic variables, cancer characteristics and surgical outcomes. Minimum post-operative follow-up was 90 days. Statistical analysis was performed using R (v4.2). From a total of 94 patients, mean age was 57 (17-90), 40 (42.5%) were female, 10 (10.6%) were diabetic and 8 patients (8.5%) were active smokers or had a >10 pack-year smoking history. Median follow up was 24 months (IQR 10.6-41.8). The most common histologic diagnosis was undifferentiated pleomorphic sarcoma (n = 38, 40.4%). The most common location was the lower extremity (n = 57, 60.6%). Overall, 26 (27.7%) patients experienced surgical wound complications. In the lower extremity, wound complications occurred in 18 patients (31.6%). In all other sites, wound complications occurred in 8 patients (21.6%) (p = 0.41). Twenty-seven (28.7%) cases required local tissue advancement for primary closure and 12 of these patients (44.4%) experienced a wound complication (p = 0.04). Wound dehiscence occurred in 18 patients at a median duration of 43.5 days (IQR 40.3-85.3) from surgery, comprising 69.2% of all wound complications. Secondary surgical intervention was required in 28 patients (29.8%), of which 7 were oncologic re-excisions and 15 were irrigation and debridement. On multivariate analysis, the use of advancement flaps (OR = 5.39; p = 0.004) and diabetes (OR = 4.08; p = 0.07) were associated with wound complications. Five-day preoperative RT for STS results in rates of wound complications comparable to standard fractionation. We identified local advancement flaps as the primary factor associated with wound complications. STS of the lower extremity that require complex closure warrant close attention for dehiscence.

Molecular residual disease (MRD) detection using bespoke circulating tumor DNA (ctDNA) assays in localized soft tissue sarcoma (STS).

11509 Background: Surgery and (neo)adjuvant radiotherapy (RT) are the mainstay curative treatments for localized STS. Despite treatment, up to 50% of STS patients experience metastatic relapse, and routine use of adjuvant systemic therapy (AST) remains controversial. The presence of ctDNA following curative-intent treatment of STS is a potential biomarker for MRD and may identify patients who are likely to benefit from AST. Given the genomic heterogeneity of STS, a histology-agnostic approach to ctDNA detection in this population is desirable. Methods: Patients (pts) with localized, high risk (size ≥ 5cm, grade ≥ 2) STS were enrolled prior to (neo)adjuvant RT and surgery. Pts who received (neo)adjuvant systemic treatment were excluded. Blood samples for ctDNA analysis were collected at diagnosis, post-RT, post-surgery and every 3 months for up to 2 years. Whole exome sequencing (WES) of archival tumor and matched normal were carried out to identify patient-specific, somatic, single nucleotide variants. Personalized and tumor-informed, multiplex PCR next generation sequencing-based ctDNA (Signatera) assays were then developed to track ctDNA in serially collected plasma samples. ctDNA levels were expressed as mean tumor molecules per milliliter (MTM/ml) of plasma. Radiologic surveillance was performed every 3 months following surgery. The primary endpoint was a ctDNA detection rate of >70% at diagnosis. Secondary endpoints included MRD detection after local therapy and correlation of ctDNA levels with disease relapse. Results: A total of 140 plasma samples from 22 pts [18 male and 4 female; median age: 65 years, range: 30 – 84] were obtained. RT was preoperative in 19/22 pts. Of the 22 tumor samples, 20 had adequate tissue quality for WES to enable ctDNA assay design. Tumor histologic subtypes included undifferentiated pleomorphic sarcoma (n = 6), myxofibrosarcoma (n = 5), and liposarcoma (n = 9). A median of 7 plasma samples per patient (range: 2 – 10) were analyzed. ctDNA was detected in 80% of pts (16/20) at diagnosis, with median ctDNA level of 3.4 MTM/mL (range: 0.2 – 1393.9). Of these 16 pts, 15 (94%) became ctDNA negative at the immediate post-surgical timepoint. In addition, ctDNA was detected in 4 pts (80%) prior to or around radiologic relapse with a median lead time of 92 days. Conclusions: Personalized, tumor-informed ctDNA assays can detect MRD after definitive local therapy and/or prior to radiologic recurrence in patients with localized high-risk STS. As such, serial ctDNA monitoring provides prognostic value and may further identify patients that will benefit from AST treatment. Additional studies evaluating ctDNA as a predictive biomarker for AST benefit are ongoing.

A phase III randomized trial of neo-adjuvant chemotherapy in high-risk soft tissue sarcoma (ISG-STS 1001): Feasibility and activity of concurrent chemotherapy and radiation therapy.

11506 Background: The ISG-STS 1001 was an international, randomized, phase III, clinical trial for localized, high-risk, soft tissue sarcoma comparing neoadjuvant chemotherapy (ChT) with a standard regimen of epirubicin plus ifosfamide (EI) versus an histology-tailored regimen (HT) in five histologic types, within the context of an integrated multimodality strategy. In addition, in this study, a parallel group of patients (pts) was not randomized but just registered and treated with EI. Radiation-therapy (RT) could be delivered either pre-operatively (concurrent to ChT) or post-operatively, according to clinical judgement. Final results of ISG-STS 1001, published in 2020, showed a benefit in favor of EI, in terms of overall survival, in comparison to HT. Herein, we analyzed tolerability and activity of ChT with EI either in the standard arm of the trial or in the parallel group, whether alone and concurrent to RT. Methods: The EI regimen was made up of epirubicin 120 mg/m² plus ifosfamide 9 g/m². RT was delivered at a dose of 44-50 Gy pre-operatively or 60-66 Gy post-operatively. In the current analysis, toxicities related to EI were analyzed separately in the group receiving concurrent pre-operative ChT and RT and in the group treated with pre-operative ChT alone and receiving RT post-operatively. Surgical complications and radiological response according to RECIST were analyzed in the above mentioned two groups. Data on ChT dose-intensity will be provided. Results: Among the 548 pts (287 randomized and 261 registered) included in the ISG-STS 1001, 289 pts were considered for the current analyses (111 pts randomized in the EI arm and 178 pts just registered). 146 pts were treated with pre-operative RT and 143 with post-operative RT. In regard to toxicities, no statistically significant differences were found between pts treated with pre-operative concurrent ChT and RT and pts treated with pre-operative ChT alone. When surgical post-operative complications were considered, a higher number of wound dehiscence (9% vs 3.5%, respectively, p = 0.053) and seroma (10.5% vs 3%, respectively, p = 0.009) were observed in pts treated with pre-operative concurrent ChT and RT compared to pts treated with pre-operative ChT alone. Finally, a statistically significant association between RECIST response and pre-operative RT was found (p = 0.041), RECIST partial responses (PR) being 19% and 10% in pts receiving concurrent pre-operative ChT plus RT and in pts treated with pre-operative ChT alone, respectively. Conclusions: The concurrent administration of EI and RT was confirmed to be feasible and safe, resulting in an increased number of PR. Also given the final results of this randomized trial, favoring the EI arm, this combination may help when tumors are of borderline resectability or function preservation is a goal.

Histopathological response (HR) after neoadjuvant chemotherapy (ChT) for high-risk soft tissue sarcomas (STS): A planned analysis of the ISG-STS-1001 trial.

11511 Background: HR after neoadjuvant ChT for high-risk STS has not been prospectively characterized and the prognostic implications remain unclear. This planned analysis of the ISG-STS-1001 trial, which compared neoadjuvant anthracycline plus ifosfamide (AI) and a histology-tailored (HT) ChT, was aimed at characterizing HR after neoadjuvant ChT and investigating association with the risk of recurrence. Methods: Patients registered in the ISG-STS-1001 study (ID: NCT01710176) were included if they had the per-protocol assessment of HR in surgical specimens. The following morphological post-treatment changes were considered: residual stainable tumor cells, necrosis, hemorrhage, sclerosis, sclerohyalinosis, and fibrohistiocytic reaction with haemosiderin. Pathologists at each study site analyzed and expressed each of these changes as a rate within each tumor. Disease-free survival (DFS), which was the trial primary end-point, was the outcome variable. Results: HR was assessed in 201 of 287 randomized patients (47 had re-excision, 7 did not have surgery, and 32 were not evaluable after wide excision), who were followed up for a median of 89 months (IQR 75-102 months). Presence (>1%) of stainable tumor cells (N=194, 96%) was not associated with DFS (HR=1.47, 95%CI 0.36–5.98, P= 0.591). Conversely, presence (≥1%) of necrosis (N=169, 84%) was associated with shorter DFS (HR=3.11, 95%CI 1.36–7.14, P=0.007) and sclerohyalinosis >20% (N=42, 21%) was associated with a lower risk of recurrence (HR=0.51, 95%CI 0.28–0.94, P=0.031). These findings were confirmed when patients who had preoperative radiotherapy (N=32) were excluded. In patients randomized to AI with tumors evaluable for HR (N=98), sclerohyalinosis >20% (N=24, 24.5%) maintained the association with a lower risk of recurrence (HR=0.24, 95%CI 0.09 – 0.67, P=0.007). Finally, the prognostic value of necrosis and sclerohyalinosis for DFS held also when patients registered in the study (187/361 evaluable for HR) were selected in addition to randomized patients. Conclusions: This is the first study that prospectively evaluated HR after neoadjuvant ChT in high-risk STS. Previous classifications of HR were based on expert consensus and had limited prognostic relevance. In this study residual stainable tumor cells, which is often considered the most relevant post-treatment change, did not stratify patient risk, while sclerohyalinosis (>20%) singled out patients with the best outcome after neoadjuvant ChT. Clinical trial information: NCT01710176 .

A phase ll study on the neoadjuvant treatment of resectable high-risk soft tissue sarcoma with anlotinib and doxorubicin.

e23542 Background: Anthracycline and ifosfomide-based chemotherapy is the main neoadjuvant treatment option for resectable high-risk STS with severe myelosuppression and other side effects. Anlotinib has been approved as second-line treatment for most of advanced STS by the Chinese agency. This study was conducted to evaluate the efficacy and safety of anlotinib in combination with doxorubicin in the neoadjuvant treatment of patients with resectable high-risk STS to reduce the toxicity of chemotherapy. Methods: This is a single-center, prospective study. Eligible patients were those ≥18years old, ECOG performance state of 0-1, with histologically confirmed locally resectable high-risk STS. All patients received a preoperative combination of anlotinib (12mg once daily, on for 2 weeks, off for 1 week) and doxorubicin (75mg /m2, IV, D1-2, every 3 weeks) .The combination treatment was repeated 2 to 3 cycles before operation. The primary endpoint was objective response rate (ORR), and the second endpoints were Disease control rate (DCR), and side effects. Results: Between December 2020 and December 2022, 13 patients were evaluated, including 4 synovial sarcoma, 3 undifferentiated sarcoma, 3 spindle cell sarcoma, 2 liposarcoma, 1 angiosarcoma. The median age was 35 years. 1 patients (7.69%) achieved a confirmed partial response (PR) and 7 (53.85%) had stable disease (SD). The ORR and DCR were 7.69% and 61.54% respectively. All patients underwent marginal or extensive excision of the tumor and none underwent amputation. Most of Treatment-related adverse events included neutropenia 5 (38.46%), hypothyroidism 3 (23.08%), anemia 2(15.38%). Three patients experienced grade 3 or 4 adverse events, neutropenia (1/13, 7.69%) and tumor hemorrhage (2/13, 15.38%). No wound complications such as infection, delayed healing or haematoma occurred. Conclusions: This study suggested that the combination of anlotinib and doxorubicin might be a option for neoadjuvant therapy for patients with resectable high-risk STS due to the anti-tumor activity and acceptable toxicity.

TIM-3 Qualifies as a Potential Immunotherapeutic Target in Specific Subsets of Patients with High-Risk Soft Tissue Sarcomas (HR-STS).

(1) Background: The expression of T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), an immune checkpoint receptor on T cells, has been associated with dismal outcomes and advanced tumor stages in various solid tumors. The blockade of TIM-3 is currently under examination in several clinical trials. This study examines TIM-3 expression in high-risk soft tissue sarcomas (HR-STS). (2) Methods: Tumor cell expression of TIM-3 on protein level was analyzed in pre-treatment biopsies of patients with HR-STS. TIM-3 expression was correlated with clinicopathological parameters including tumor-infiltrating lymphocyte (TIL) counts, programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PDL-1) expression in patients with HR-STS. Survival dependent on the expression of TIM-3 was analyzed. (3) Results: TIM-3 expression was observed in 101 (56%) out of 179 pre-treatment biopsies of patients with HR-STS. TIM-3 expression was significantly more often observed in undifferentiated pleomorphic sarcomas (UPS) compared to other histological subtypes (p < 0.001), high TIL counts (p < 0.001), and high PD-1 (p < 0.001) and PD-L1 expression (p < 0.001). TIM-3 expression did not have a prognostic impact on survival in patients with HR-STS. (4) Conclusions: This is the first study to demonstrate a significant tumor cell expression of TIM-3 in specific subsets of patients with HR-STS. TIM-3 qualifies as a potential immunotherapeutic target in HR-STS.

Neoadjuvant chemotherapy in patients undergoing neoadjuvant radiation for trunk and extremity soft tissue sarcoma.

Many patients with high-risk soft tissue sarcoma (STS) develop distant metastases. Meta-analyses suggest that chemotherapy confers a small survival benefit, though few studies focus on neoadjuvant chemotherapy (NCT). There has been more frequent use of neoadjuvant radiation therapy (NRT) in STS, but the utility of NCT for these patients remains unclear. Patients with stage II-III trunk/extremity STS who underwent NRT and resection were identified using the National Cancer Database (2006-2019). Predictors of NCT were analyzed using logistic regression. Change in rate of NCT use over time was assessed using log-linear regression modeling. Survival was examined using Kaplan-Meier (KM) and Cox proportional hazard modeling. Of 5740 patients, 25% underwent NCT. The overall median age was 62, 55% of patients were male, and 67% had stage III disease. The most common histological subtypes were fibrosarcoma/myxofibrosarcoma (39%) and liposarcoma (16%). Use of NCT decreased by 4.0% per year throughout the study period (p < 0.01). Predictors of NCT included younger age (median 54, IQR 42-64 vs. median 65, IQR 53-75, p < 0.01), treatment at an academic center (odds ratio [OR] 1.5, p < 0.01), and stage III disease (OR 2.2, p < 0.01). Histologic predictors of NCT included synovial sarcoma (52%) and angiosarcoma (45%). With a median follow-up time of 77 months, NCT was associated with improved 5-year survival compared to NRT alone on KM analysis (70% vs. 63%, p < 0.01). This difference persisted on multivariate analysis (hazard ratio 0.86, p = 0.027) and after propensity matching (70% vs. 65%, p = 0.0064). Despite risk of distant failure in high-risk STS, use of NCT has decreased over time in patients receiving NRT. In this retrospective analysis, NCT was associated with a modestly improved overall survival.

Quality Measurement for Soft Tissue Sarcomas in Germany: First Results of the Certified Sarcoma Centres

Introduction: Soft tissue sarcomas (STSs) are rare diseases. A high level of standardization and centralization was lacking in Germany until 2018. Methods: By developing an evidence-based guideline and a certification system for sarcoma centres, foundations for structured, guideline-based, and centralized sarcoma care were defined. First results of the certified sarcoma centres are presented. Results: The first 3 years of data collection show good results for case volume, presentation rates in pretherapeutic and postoperative tumour boards, psycho-oncological counselling, and study rates. However, other indicators (e.g., preoperative or postoperative radiotherapy for operated high-risk STS without GIST, counselling rates social services) still have potential for improvement. Based on these results, the set of indicators could be further improved. Conclusions: A sarcoma-specific quality assurance scheme that includes guideline-derived quality indicators was developed. In future, a broader database will allow further insights into sarcoma care in Germany.

Postoperative complications and oncologic outcomes after multimodal therapy of localized high risk soft tissue sarcoma

BackgroundStandard therapy for localized high-risk soft tissue sarcoma includes surgical resection and neoadjuvant or adjuvant radiation therapy (± chemotherapy and locoregional hyperthermia). No difference in oncologic outcomes for patients treated with neoadjuvant and adjuvant radiation therapy was reported, whereas side effect profiles differ. The aim of this analysis was to analyse oncologic outcomes and postoperative complications in patients treated with multimodal treatment.MethodsOncologic outcomes and major wound complications (MWC, subclassified as wound healing disorder, infection, abscess, fistula, seroma and hematoma) were evaluated in 74 patients with localized high-risk soft tissue sarcoma of extremities and trunk undergoing multimodal treatment, and also separately for the subgroup of lower extremity tumors. Clinical factors and treatment modalities (especially neoadjuvant vs. adjuvant radiotherapy) were evaluated regarding their prognostic value and impact on postoperative wound complications.ResultsOncologic outcomes were dependent on number of high risk features (tumor size, depth to superficial fascia and grading), but not on therapy sequencing (however with higher risk patients in the neoadjuvant group). Different risk factors influenced different subclasses of wound healing complications. Slightly higher MWC-rates were observed in patients treated with neoadjuvant therapy, compared to adjuvant radiotherapy, although only with a trend to statistical significance (31.8% vs. 13.3%, p = 0.059). However, except for wound infections, no significant difference for other subclasses of postoperative complications was observed between neoadjuvant and adjuvant therapy. Diabetes was confirmed as a major risk factor for immune-related wound complications.ConclusionRates of major wound complications in this cohort are comparable to published data, higher rates of wound infections were observed after neoadjuvant radiotherapy. Tumor localization, patient age and diabetes seem to be major risk factors. The number of risk factors for high risk soft tissue sarcoma seem to influence DMFS. Neoadjuvant treatment increases the risk only for wound infection treated with oral or intravenous antibiotic therapy and appears to be a safe option at an experienced tertiary center in absence of other risk factors.