High-risk Soft Tissue Sarcoma Research Articles

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.

Abstract IA025: Using genetically engineered mouse models to study sarcoma metastasis

Abstract Despite aggressive conventional therapy, many patients with high-risk soft-tissue sarcoma develop metastatic disease. To investigate mechanism(s) of sarcoma metastasis, our lab has utilized genetically engineered mouse models. For example, we injected an adenovirus expressing Cre recombinase (adeno-Cre) into the gastrocnemius muscle of LSL-KrasG12D; p53Flox/Flox (KP) mice to initiate high grade undifferentiated pleomorphic sarcomas, and after amputation approximately 40% of the mice develop lung metastasis. Using a genetic approach, we found that miR-182, NEAT-1, and HIF-1a regulate metastasis to the lung. We also performed lineage tracing with complementary fluorescent proteins and CRISPR-generated bar codes to find that lung metastases from KP sarcomas arise from clones with specific gene expression profiles. Although the KP sarcoma model is useful for studying metastasis, one limitation of this model is that there are few non-synonymous mutations to engage the immune system. Therefore, we generated a high mutational load primary mouse model of soft tissue sarcoma by injecting adeno-Cre into the gastrocnemius muscle of p53Flox/Flox mice to delete p53 and also injected 3-methylcholanthrene (MCA) to generate primary p53/MCA undifferentiated pleomorphic sarcomas. In this p53/MCA model, the overall rate of lung metastasis after amputation was surprisingly low (~12%). We hypothesized that the immune system suppressed lung metastasis in this model. However, when we generated p53/MCA sarcomas in Rag2 −/− mice that lack mature B and T cells, we still observed a low rate of lung metastasis after amputation. These data suggest that mutations caused by MCA may have disabled tumor intrinsic factors needed to drive sarcoma metastasis. We are currently performing genome-wide screens in the p53/MCA model to search for genes required for sarcoma metastasis. Citation Format: David G. Kirsch, Rutulkumar Patel, Sophie R. Finkelstein, Joy Ban, Yuning J Tang, Jianguo Huang, Benjamin A. Alman, Yvonne M. Mowery. Using genetically engineered mouse models to study sarcoma metastasis [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr IA025.

1525TiP TORNADO: A randomized multicenter open-label phase II study evaluating retifanlimab in combination with neoadjuvant chemotherapy in patients with selected retroperitoneal sarcomas

Despite optimal surgery, up to 40% of patients with retroperitoneal sarcomas (RPS) will develop locoregional and/or distant relapse. Peri-operative radiotherapy has failed to improve outcome of these patients (Bonvalot et al Lancet Oncol 2020). Innovative strategies are urgently needed in this setting. Recent studies have shown the positive impact on overall survival of neoadjuvant systemic therapy in high-risk soft-tissue sarcoma (STS) of the extremities or trunk wall (Issels et al Lancet Oncol 2010; Gronchi et al Lancet Oncol 2017).

Perioperative Adriamycin plus ifosfamide vs. gemcitabine plus docetaxel for high-risk soft tissue sarcomas: randomised, phase II/III study JCOG1306

BackgroundThis randomised phase II/III trial aimed to determine whether perioperative chemotherapy with gemcitabine plus docetaxel (GD) is non-inferior to the standard Adriamycin plus ifosfamide (AI) in terms of overall survival (OS) in patients with soft tissue sarcoma (STS).MethodsPatients with localised high-risk STS in the extremities or trunk were randomised to receive AI or GD. The treatments were repeated for three preoperative and two postoperative courses. The primary endpoint was OS.ResultsAmong 143 enrolled patients who received AI (70 patients) compared to GD (73 patients), the estimated 3-year OS was 91.4% for AI and 79.2% for GD (hazard ratio 2.55, 95% confidence interval: 0.80–8.14, P = 0.78), exceeding the prespecified non-inferiority margin in the second interim analysis. The estimated 3-year progression-free survival was 79.1% for AI and 59.1% for GD. The most common Grade 3–4 adverse events in the preoperative period were neutropenia (88.4%), anaemia (49.3%), and febrile neutropenia (36.2%) for AI and neutropenia (79.5%) and febrile neutropenia (17.8%) for GD.ConclusionsAlthough GD had relatively mild toxicity, the regimen—as administered in this study—should not be considered a standard treatment of perioperative chemotherapy for high-risk STS in the extremities and trunk.Clinical trial registrationjRCTs031180003.

Neoadjuvant chemotherapy in high-risk soft tissue sarcomas: Results of the expanded cohort of myxoid liposarcoma of the randomized clinical trial from the Italian Sarcoma Group (ISG), the Spanish Sarcoma Group (GEIS), the French Sarcoma Group (FSG), and the Polish Sarcoma Group (PSG).

11508 Background: An ISG, GEIS, FSG and PSG randomized trial on 3 cycles of neoadjuvant epirubicine+ifosfamide (EI) versus a histology-tailored (HT) regimen in selected localized high-risk STS showed some superiority of EI in all histologies with the exception of Myxoid Liposarcoma (MLPS) where EI and HT regimens seemed equivalent (J Clin Oncol 2020; 38:2178-86). This MLPS cohort was expanded with the aim to assess the non-inferiority of the HT regimen compared to EI. Methods: This was a multicenter European randomized trial comparing EI versus a HT regimen. Patients (pts) had localized high-risk (grade = 3; size &gt;5 cm; deeply seated) undifferentiated pleomorphic sarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, synovial sarcoma or MLPS of extremities or trunk wall. Primary end-point was Disease Free Survival (DFS). Secondary end-point was Overall Survival (OS). The MLPS cohort was expanded after the results of the 3rd interim analysis (Lancet Oncol 2017; 18:812-22) in order to reject the hypothesis that HT regimen trabectedin is associated with a HR of relapse = 1.25 with a non-inferiority design. To this aim, a Bayesian monitoring approach was used until the probability that the true HR is higher than 1.25 was greater than 80% or smaller than 5%. Results: From May 2011 to June 2020, 101 pts affected by high-risk MLPS were randomized, 56 to EI and 45 to HT regimen. The median follow-up was 66 months (IQ range 37-89). Median size was 107 mm (IQ range 84-143), 108 mm (IQ range 86-150) in the EI and 106 mm (IQ range75-135) in the HT arm. The DFS and OS probabilities at 60 months were 0.86 and 0.73 (HR:0.60; 95%CI: 0.24-1.46; log rank p = 0.26 for DFS) and 0.88 and 0.90 (HR:1.20; 95%CI:0.37-3.93; log rank p = 0.77 for OS), in the HT and EI arm, respectively. 5-yr observed and Sarculator-predicted OS were 0.89 (95% CI 0.82-0.97) and 0.80 in all patients (p = 0.020), 0.90 (95% CI 0.81-1.00) and 0.79 in the EI arm (p = 0.049) and 0.88 (95% CI 0.77-1.00) and 0.81 in the HT arm (p = 0.204) respectively. Conclusions: In the expanded cohort of MLPS, the HT neoadjuvant therapy trabectedin was not inferior to EI. While survival in both arms was better than predicted by Sarculator, it is left to understand whether this patient population, who had on average a lower Sarculator-predicted risk of death compared with the rest of the trial population, may benefit from a neoadjuvant therapy. Clinical trial information: NCT01710176.

In vitro evidence that combination treatment with anti-PD-1 and anti-CD47 immunotherapy may not be efficient in human soft tissue sarcoma.

e23560 Background: Soft tissue sarcomas (STSs) are rare mesenchymal tumors. With more than 70 histological subtypes of STSs, studies defining robust biomarkers of therapeutic value are lacking. Even with the improvements in local control rates, metastases and death occur in 50% of patients that are diagnosed with high-risk STSs. Across nearly all sarcoma types, macrophages dominate the immune landscape of STSs. While immune checkpoint inhibitors (ICIs) represent the major immunotherapeutic approach in malignancies with a high load of T cells, the anti-CD47 anti-cancer therapy mostly promotes macrophage-mediated phagocytosis. The efficacy of both therapies is critically dependent on the composition of the tumor microenvironment. Methods: In our study, we evaluated the potential additive effects of combining the anti-PD-1 immunotherapy and anti-CD47 immunotherapy ex vivo. The proportions of tumor cells and tumor-infiltrating lymphocytes were characterized ex vivo from resected tumors of 73 patients who underwent surgery for STS. The expression of CD47 on tumor cells was analyzed by immunohistochemistry. Cell suspensions were obtained from freshly resected tumors and the proportions of CD45+, CD45-, CD3+, CD4+, and CD8+ cells were measured by flow cytometry. The effect of the anti-PD-1 blockade, anti-CD47 blockade, and the combinatorial application of anti-PD-1 and anti-CD47 therapies on the immune cell activation in vitro was investigated by culturing of cell suspensions at a concentration 0.3x106/ul in the presence/absence of therapeutic monoclonal antibody (Nivolumab 2 ug/ml; anti-CD47 clone MIAP410 20ug/ml) and evaluated by a cytokine Luminex assay (Milliplex® MAP Human Cytokine Bead Panel (Sigma Aldrich) for TNFα, IFNγ, and IL-2 cytokines analysis). Results: The addition of anti-PD1 to CD3/CD28 stimulation drastically increased the production of all cytokines analyzed. This increase in pro-inflammatory cytokine secretion was even more pronounced after adding an anti-CD47 monoclonal antibody to the cell culture. However, a combinatorial application of anti-PD-1 and anti-CD47 agents in vitro was found to limit rather than potentiate the immune activation in the TME of human STS. On an individual level, the most profound response to anti-PD-1 was observed in high-grade leiomyosarcoma and the most profound response to anti-CD47 therapy was observed in an undifferentiated pleiomorphic sarcoma. Conclusions: Our data suggest that combinatorial strategies based on ICIs and anti-CD47 blockade may not provide the desired outcome in STSs. Both therapies, anti-PD-1, and anti-CD47 alone, could however bear a therapeutic potential in selected tumors after close evaluation of the CD47 and PD-1 expression status, as well as the extent of T cell/macrophage infiltration.

Trabectedin and hypofractionated radiation for high-risk, localized, and metastatic soft tissue sarcoma: A retrospective study.

11564 Background: Soft tissue sarcomas (STSs) are a heterogeneous group of cancers with high unmet need. Trabectedin (T) is an FDA-approved chemotherapy that blocks cell cycling and DNA repair pathways. Combination T and conventional radiation (XRT) in STS nonrandomized phase 1/2 trials demonstrated objective response rates (ORR) of 36-72% in localized and low burden metastatic disease, while pre-treated metastatic STS treated with T alone has an ORR of 10-14%. We hypothesize that the combination of T and hypofractionated radiation (hXRT) will exhibit a tolerable safety profile and improve ORR relative to historical outcomes with T or hXRT alone. Here we report our experience in the treatment of oligometastatic STS with combined T and hXRT. Methods: We reviewed our institutional experience to identify patients treated with T and XRT. We included patients with high risk localized or metastatic STS (majority of patients had metastatic disease at time of treatment). All patients received at least 1 cycle of T and concurrent XRT to at least 1 lesion. ORR and local control rate (LCR) were determined for irradiated lesions by RECIST 1.1. Results: Between 2020 – 2021, 9 STS patients with 21 tumors were treated at the University of Colorado with XRT and concurrent T. The median age was 39.2 (range 26.0 – 64.6) years. 8 patients had metastatic disease at the time of treatment. Treated tumor sites included 1 lung,1 extremity, 2 liver, 2 retroperitoneal, 5 bone, and 10 peritoneal. The following histologic subtypes were included: myxoid liposarcoma (3), uterine leiomyosarcoma (2), non-uterine leiomyosarcoma (1), dedifferentiated liposarcoma (1), undifferentiated pleomorphic sarcoma (1), and synovial sarcoma (1). All metastatic patients were pre-treated with a median of 3 lines of systemic therapy. The median number of T cycles delivered was 5 (range 1 – 20). The median XRT prescription dose was 3000cGy (range 2000cGy – 5000cGy), with 8 patients having received hXRT (5 -10 fractions) and 1 having received conventionally fractionated XRT. 8 patients underwent 1 course of XRT, while 1 received 3 courses in combination with T. All patients had a Karnofsky performance status equal to or greater than 60. After a median follow-up 5.4 months, the LCR of treated lesions was 90.5%. The ORR (CR or PR) was 57.1% and median decrease in tumor diameter at time of maximum response was 52.0%. The median time until maximum response was 3.7 months. 2 patients experienced grade 3 toxicity (LFT elevation) attributable to T, and 2 patients experienced grade 3 toxicity due to XRT. There were no grade 4 or 5 toxicities. Conclusions: T in combination with hXRT appears to be safe and feasible in this patient population. Based on these data, a phase 1/2 prospective clinical trial is being planned in oligometastatic and high risk localized STS. [Table: see text]

Circulating tumor DNA (ctDNA) detection of molecular residual disease (MRD) as a potential biomarker in localized soft tissue sarcoma (STS).

11547 Background: Surgery and (neo)adjuvant radiotherapy are the mainstay curative treatments for localized STS. Despite treatment, approximately 50% of STS patients (pts) experience metastatic relapse and routine use of adjuvant systemic therapy (AST) remains controversial. The presence of ctDNA following curative treatment of STS is a potential biomarker for MRD and may identify patients who benefit from AST. Given the genomic heterogeneity of STS, a histology-agnostic approach to ctDNA detection in this population is desirable. Methods: Pts with localized, high risk (size ≥ 5cm, grade ≥ 2) disease were enrolled prior to (neo) adjuvant radiotherapy and surgery. Blood for ctDNA was collected at diagnosis; post-radiotherapy, post-surgery and every 3 months for up to 2 years. Whole exome sequencing (WES) of archival tumor- and matched buffy coat-DNA were carried out to identify somatic variants. Personalized and tumor-informed, multiplex PCR next generation sequencing-based ctDNA assay (Signatera™ assay) was performed on plasma obtained at the serial timepoints. A sample level positive call required ≥ 2 variants above a confidence calling threshold. Absolute ctDNA levels were expressed as mean tumor molecules per milliliter (MTM/ml) of plasma, based on variant allele frequencies and quantity of cell free DNA. Standard radiologic surveillance (every 3 months) was performed following surgery. The primary endpoint was a ctDNA detection rate of 70% at diagnosis. Secondary endpoints included MRD detection and correlation of ctDNA levels with disease relapse. Results: Seventy-six plasma samples from 10 pts [8 males and 2 females; median age 64 years (range 46–84)] were obtained prospectively. STS subtypes were undifferentiated pleomorphic sarcoma (n = 4), myxofibrosarcoma (n = 2), dedifferentiated liposarcoma (n = 2), myxoid liposarcoma (n = 1), and pleomorphic liposarcoma (n = 1). All tumors successfully underwent WES with adequate data quality for Signatera™ assay design. The personalized ctDNA assay was performed on a median of 7 plasma samples per patient (range: 5 – 10). ctDNA was detected in 7 pts (70%) at diagnosis, with median ctDNA level of 1.6 MTM/ml (range: 0.2 – 137.8), achieving the study primary endpoint. Immediate post-surgery samples were negative in all pts. However, ctDNA was detected in 2 out of 2 pts who developed metastatic disease during follow-up. Conclusions: Personalized tumor-informed ctDNA assays in localized high-risk STS at diagnosis are feasible. In this series, all patients had undetectable levels of ctDNA post-surgery and patients who experienced disease relapse demonstrated a detectable rise in ctDNA levels. Further interrogation of this approach for detection of post-treatment MRD as a possible biomarker of benefit from AST is ongoing.

Pharmacogenetic Profiling in High-Risk Soft Tissue Sarcomas Treated with Neoadjuvant Chemotherapy.

Neoadjuvant chemotherapy based on anthracyclines and ifosfamide for high-risk soft tissue sarcomas (STS) of the extremities and trunk is a controversial treatment option. There are substantial interindividual differences in clinical outcomes in patients treated with neoadjuvant chemotherapy. The aim of this study was to evaluate, as biomarkers, polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters, or drug targets and their association with toxicity and survival in STS patients treated with neoadjuvant chemotherapy. We analysed variants in genes involved in anthracycline metabolism (ABCB1, ABCC2, NQO1, CBR3, and SLC22A16) and in ifosfamide catabolism (ALDH1A1) in 79 treated patients. Two genes showed significant association after adjusted multivariate analysis: ABCC2 and ALDH1A1. In patients treated with anthracyclines, ABCC2 rs3740066 was associated with risk of febrile neutropenia (p = 0.031), and with decreased overall survival (OS) (p = 0.024). ABCC2 rs2273697 was associated with recurrence-free survival (RFS) (p = 0.024). In patients treated with ifosfamide, ALDH1A1 rs3764435 was associated with RFS (p = 0.046). Our pharmacogenetic study shows for the first time that variants in genes regulating the metabolism of neoadjuvant chemotherapy may be helpful to predict toxicity and survival benefit in high-risk STS treated with neoadjuvant chemotherapy. Further validation studies are needed to establish their clinical utility.