Treatment Of Soft Tissue Sarcomas Research Articles

Blockade of beta-adrenergic receptors reduces cancer growth and enhances the response to anti-CTLA4 therapy by modulating the tumor microenvironment

The development of immune checkpoint inhibitors (ICI) marks an important breakthrough of cancer therapies in the past years. However, only a limited fraction of patients benefit from such treatments, prompting the search for immune modulating agents that can improve the therapeutic efficacy. The nonselective beta blocker, propranolol, which for decades has been prescribed for the treatment of cardiovascular conditions, has recently been used successfully to treat metastatic angiosarcoma. These results have led to an orphan drug designation by the European Medicines Agency for the treatment of soft tissue sarcomas. The anti-tumor effects of propranolol are suggested to involve the reduction of cancer cell proliferation as well as angiogenesis. Here, we show that oral administration of propranolol delays tumor progression of MCA205 fibrosarcoma model and MC38 colon cancer model and increases the survival rate of tumor bearing mice. Propranolol works by reducing tumor angiogenesis and facilitating an anti-tumoral microenvironment with increased T cell infiltration and reduced infiltration of myeloid-derived suppressor cells (MDSCs). Using T cell deficient mice, we demonstrate that the full anti-tumor effect of propranolol requires the presence of T cells. Flow cytometry-based analysis and RNA sequencing of FACS-sorted cells show that propranolol treatment leads to an upregulation of PD-L1 on tumor associated macrophages (TAMs) and changes in their chemokine expression profile. Lastly, we observe that the co-administration of propranolol significantly enhances the efficacy of anti-CTLA4 therapy. Our results identify propranolol as an immune modulating agent, which can improve immune checkpoint inhibitor therapies in soft tissue sarcoma patients and potentially in other cancers.

Lymphatic Complications Prevention and Soft Tissue Reconstruction after Soft Tissue Sarcoma Resection in the Limbs.

Background and Objectives: The definitive treatment of soft tissue sarcomas (STS) requires a radical surgical removal of the tumor, which often leads to large soft tissue defects. When they are located in the limbs, significant damage to the lymphatic pathways is not uncommon. In the present article, we present different techniques aimed at both reconstructing the defect and restoring sufficient lymph drainage, thus preventing short- and long-term lymphatic complications. Materials and Methods: Between 2018 and 2020, 10 patients presenting a soft tissue defect with lymphatic impairment received a locoregional reconstruction by means of either pedicled or free SCIP flap. Seven patients required a second flap to reach a good dead space obliteration. In six cases, we performed an interpositional flap, namely a soft tissue transfer with lymphatic tissue preservation, and in four cases a lymphatic flow-through flap. In all cases, the cause of the defect was STS surgical excision. The average age was 60.5 years old (ranging 39–84), seven patients were females and six were males. Results: All the patients were successfully treated. In two cases, minor post-operative complications were encountered (infected seroma), which were conservatively managed. No secondary procedures were required. The average follow-up was 8.9 months (ranging 7–12 months). No signs of lymphedema were reported during this time. In all cases, complete range of motion (ROM) and a good cosmetic result were achieved. Conclusions: A reconstructive procedure that aims not only to restore the missing volume, but also the lymphatic drainage might successfully reduce the rate of postoperative complications. Both lymphatic interpositional flaps and lymphatic flow-through flaps could be effective, and the right choice must be done according to each patient’s needs.

Risk Factors of Early Distant Metastasis After Primary Tumor Treatment in Soft Tissue Sarcoma.

Distant metastasis has a strong influence on prognosis in patients with soft tissue sarcoma (STS). While various risk factors have been reported for distant metastases, risk factors for distant metastases early after treatment of primary tumor have not been investigated. This study aimed to evaluate the factors of early distant metastasis after primary tumor resection in patients with STS. We retrospectively identified patients with STS involving the extremities or trunk without any metastasis at the first visit. Data on clinical information and detailed assessment were collected. We evaluated clinical information as a risk factor for distant or lung metastases. Additionally, we evaluated risk factors for metastases in patients with distant metastases as early as 6 months after the initial resection of the primary tumor. A total of 337 patients were included in the study. Multivariate analysis revealed that the size of the primary tumor (p=0.0011 and p=0.0167), consultation in a short period after onset (p=0.0325 and p=0.0402), histological high grade (p=0.0006 and p=0.0002), and inadequate surgical margin (p=0.0151 and p=0.0055) were significant predictors for poor prognosis for all distant and lung metastases, respectively. However, the only risk factor for early metastases within 6 months was young age (p=0.0148). The only risk factor for early distant metastasis after primary tumor resection in patients with STS was young age, even though large tumor diameter and histological high grade were risk factors for distant metastasis.

Preoperative Radiation for Soft Tissue Sarcomas: How Much Is Needed?

Preoperative radiation therapy is an important component of curative treatment for extremity and superficial trunk soft tissue sarcomas. It has traditionally been delivered to a dose of 50 Gy in 2 Gy fractions over 5 weeks. With significant advances in the multidisciplinary approach to soft tissue sarcomas, preoperative radiation therapy may be omitted for certain cases, delivered over a shortened period of time (1-3 weeks), deintensified for myxoid liposarcomas, or combined with systemic therapy to improve the therapeutic ratio. This article reviews the innovative preoperative radiation therapy strategies currently used to treat extremity and superficial trunk soft tissue sarcomas.

Ингибитор АКТ-сигнального пути потенцирует цитотоксическую активность доксорубицина в отношении клеток остеосарком in vitro

Activation of receptor and nonreceptor tyrosyne kinases (TK) is detected in a broad spectrum of human malignancies, including soft tissue sarcomas (STS) and osteosarcomas (OS) and in some cases correlates with poor prognosis and clinical outcomes. Despite the topoisomerase II inhibitor doxorubicin is broadly used for treatment of STS and OC as mono- and as a component of the combined chemotherapeutic regimens, rapid development of tumor resistance to doxorubicin is considered to be most significant factor of poor prognosis and bad clinical outcome, especially for the patients with metastatic and reccurent forms of disease. This, in turn, remains a driving force to develop novel effective approaches to increase sensitivity of tumor cells to this chemotherapeutic agent and overcome drug resistance. Our current data illustates activation of c-Met-, FGFR-, AKT-, и МAPK-kinases in OS cells, whereas inhibition of their activities with corresponding TK inhibitors (TKIs) (crizotinib, BGJ398, MK-2206, and U0126, respectively) enhances cytotoxic activity of doxorubicin against OS cells. The most prominent synergism between doxorubicin and TKIs inhibitors was found for AKT inhibitor MK- 2206. We found that MK-2206 significantly enhanced sensitivity of OS cells to doxorubicin and induced their apoptosis. Thus, activation of AKT signaling in OS might be an attractive therapeutic target to increase OS sensitivy to chemotherapeutic agents, in particular, doxorubicin. This in turn provide the molecular basis for the effective further use of the combined (AKT- and topoisomerase II inhibitors) therapy for patinets with OS.

Treatment at Specialized Cancer Centers Is Associated with Improved Survival in Adolescent and Young Adults with Soft Tissue Sarcoma.

Background: Soft tissue sarcomas (STS) are a heterogeneous group of tumors whose management benefits from a multidisciplinary therapeutic approach. Published data suggest that cancer treatment at a specialized cancer center (SCC) can improve survival in other cancers. Therefore, we examined the impact of the location of treatment on survival in children and adolescents and young adults (AYAs) with STS. Methods: We performed a population-based analysis of children and AYAs hospitalized within 1 year of diagnosis with first primary STS (2000-2014) using the California Cancer Registry linked with hospitalization data. Patients were categorized based on receiving all inpatient treatments at a SCC versus part/none. Multivariable Cox proportional hazards regression identified factors associated with overall and STS-specific survival by age group. Results are presented as adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Of the 1,674 patients with STS, 142 were children (0-14) and 1,532 were AYAs (15-39) and 89.4% and 40.4% received all inpatient treatments at a SCC, respectively. Overall, the 5-year survival was improved for patients who received all inpatient care at a SCC (59.8% vs. those who received part/none, 50.7%). Multivariable regression analysis found that having all treatments at a SCC was associated with better overall survival (HR, 0.79, CI: 0.65-0.95) in AYAs, but not in children. Conclusions: Our findings demonstrate that treatment for STS at a SCC is associated with better survival in AYAs. Eliminating barriers to treatment of AYAs with STS at SCCs could improve survival in this population.

Multimodality treatment of undifferentiated pleomorphic soft tissue sarcoma of the extremity (eUPS) in the elderly

IntroductionThis subgroup analysis of undifferentiated pleomorphic soft tissue sarcoma of the extremity (eUPS) from the PERSARC collaborative group aimed to achieve a more personalized multimodality treatment approach for primary eUPS in elderly patients. Material and methodsA multicenter retrospective study including primary high-grade eUPS surgically treated with curative intent between 2000 and 2016. Overall survival (OS), local recurrence (LR) and distant metastasis (DM) curves were calculated by Kaplan Meier analysis. Cox proportional hazard models were used to determine the effect of radiotherapy. ResultsFrom a total of 2511 patients with extremity soft tissue sarcoma (eSTS) of the PERSARC study collaborative; 703 patients with eUPS were included in this study. In elderly patients with eUPS 5-year OS, LR and DM were 35.4 (95%CI 29.3–42.8), 17.7 (95%CI 12.7–22.6) and 24.6 (95%CI 19.1–30.1). eUPS was significantly less treated with radiotherapy compared with other eSTS, especially in elderly patients. Patients with R1-R2 margins treated with radiotherapy had about half the risk of developing LR compared with patients treated without radiotherapy (HR = 0.454, p = 0.033). ConclusionElderly patients with eUPS were less often treated with radiotherapy and showed higher LR. Nowadays, given an increasing life expectancy in elderly patients, multimodality treatment should be considered.

Pre-Treatment Neutrophil-to-Lymphocyte Ratio (NLR) as a Predictive Marker of Pazopanib Treatment for Soft-Tissue Sarcoma.

Simple SummarySecond-line systematic therapy options for soft-tissue sarcoma (STS) have remained unchanged for decades due to the rarity and various histological types associated with STS. Challenges with molecular-targeted treatments for STS led to the approval of pazopanib and its wide use for STS. However, predictive markers of pazopanib treatment for STS have not been identified. Baseline neutrophil-to-lymphocyte ratio (NLR) is known as a candidate biomarker for several cancers. In this retrospective study, we investigated the use of the NLR as a predictor for the efficacy and prognosis of pazopanib in patients with STS. Our findings could be useful for the development of biomarker-targeted therapies for STS.Pazopanib with trabectedin and eribulin is widely used to treat soft-tissue sarcoma (STS). We have shown that baseline neutrophil-to-lymphocyte ratio (NLR) may predict the efficacy and patient prognosis of eribulin. Changes in NLR, but not baseline NLR, can predict patient prognosis of trabectedin. However, prognostic factors of pazopanib for STS have not been identified. We present a retrospective analysis of 141 patients treated with pazopanib for recurrent or metastatic non-round cell STS. Univariate and multivariate analyses were performed to determine the predictive factors of durable clinical benefit (DCB), overall survival (OS), and progression-free survival. L-sarcoma histology (odds ratio [OR] = 0.31, 95% CI = 0.12–0.79; p = 0.014) and pre-treatment NLR < 3.0 (OR = 2.03, 95% CI = 1.02–6.67; p = 0.045) were independent predictive factors of DCB. Pre-treatment NLR < 3.0 (hazard ratio [HR] = 0.55, 95% CI = 0.36–0.84; p = 0.0057), liposarcoma histology (HR = 1.78, 95% CI = 1.09–2.91; p = 0.022), primary extremity site (HR = 0.48, 95% CI = 0.31–0.75; p = 0.0010), ECOG PS ≥ 1 (HR = 1.62, 95% CI = 1.08–2.42; p = 0.019), and CRP < 0.3 (HR = 0.52, 95% CI = 0.33–0.82; p = 0.0050) were independent predictive factors of OS. These findings indicate that baseline NLR predicts the efficacy and patient prognosis of pazopanib for STS.

Free Functional Latissimus Dorsi Reconstruction of the Quadriceps and Hamstrings following Oncologic Resection of Soft Tissue Sarcomas of the Thigh

Background Limb-salvage surgery combined with radiotherapy has become the primary treatment for soft tissue sarcomas of the extremity. Free functional latissimus flaps (FFLF) are an option to restore function in the setting of volumetric muscle loss. The purpose of the current study was to examine the use of FFLF in patients undergoing resection of thigh sarcoma. Methods Twelve patients with a sarcoma involving the hamstring (n = 6), quadriceps (n = 5), or combined (n = 1) defects which included multiple muscle groups were reviewed. This included 9 males and 3 females with a mean age and body mass index of 56 ± 12 years and 31.3 ± 5.7 kg/m2. Results The mean defect volume and operative time was 3,689 ± 2,314 cm3 and 587 ± 73 minutes. Following reconstruction, the mean knee range of motion (ROM), MSTS93 score, and muscle strength was 89 ± 24°, 90 ± 15%, and 4 ± 1; with 75% of patients ambulating without gait aids. Seven (58%) patients sustained a complication, namely, delayed wound healing (n = 2). Conclusion Although there was a high incidence of complications, FFLF can restore active knee ROM and function, with most patients ambulating without gait aids following reconstruction of large oncologic defects in the thigh.

Medicinal treatment of retroperitoneal soft tissue sarcomas

Retroperitoneal soft tissue sarcomas represent extreme challenges for interdisciplinary treatment teams. The sarcoma-specific experience of surgeons has the greatest impact on the survival of patients; however, too many patients still die despite optimal local treatment. The role of chemotherapy is undisputed only for patients with highly malignant bone sarcomas or rhabdomyosarcomas. For soft tissue sarcomas in adult patients, especially liposarcomas and leiomyosarcomas, the evidence situation is very unsatisfactory. This overview article discusses the complex data situation and controversial aspects that are relevant for current treatment decisions in interdisciplinary treatment teams.

Comparison between trabectedin and doxorubicin in soft-tissue sarcomas: a systematic review and meta-analysis.

BackgroundThis study sought to evaluate the differences between trabectedin and doxorubicin in the treatment of soft-tissue sarcoma (STS).MethodsMultiple databases, including PubMed, Web of Science, Cochrane Library, and China National Knowledge Infrastructure, were searched to retrieve relevant articles. Ultimately, the full text of 10 studies involving the use of trabectedin and doxorubicin in STS were reviewed. Review Manager 5.2 was used to evaluate the heterogeneity of the results of the selected articles. Forest plot, bias, and sensitivity analyses were carried out on the included articles.ResultsTen papers that met the criteria were included in this analysis. STS patients receiving trabectedin had longer progression-free survival than those receiving doxorubicin [overall mean difference (MD) =1.36, 95% confidence interval (CI): 1.04, 1.68, I2=6%, fixed-effects model]. The experimental group also had a longer overall survival period than the control group (MD =3.92, 95% CI: 0.23, 7.60, P=0.04 and I2=83%, random-effects model), and the experimental group had a better disease control rate than the control group (relative risk =1.2, P=0.03 and I2=45%, fixed-effects model). From the publication bias analysis and sensitivity analysis, we can guarantee the results are robust and unbiased.DiscussionOur research showed that STS patients who received trabectedin had better clinical effects and a longer survival time than those who received doxorubicin.

143P Novel anti-PD-L1 antibody TQB2450 (T) in combination with anlotinib (A) in patients with advanced soft tissue sarcoma (STS), the results from the expanded sample size and updated data

T is a novel anti-PD-L1 antibody and A is a multi-kinase inhibitor. This study aims to evaluate the efficacy and safety of T in combination with A in the treatment of advanced STS. Preliminary results had disclosed the potential of this regimen, here we report the results based on the expanded sample size and updated data.

Doxorubicin Combined With Ifosfamide for Sarcoma Induces Muscle Atrophy and Sleep Disruption

There are no reports evaluating sleep disturbance and skeletal muscle loss in response to the treatment of soft tissue sarcoma (STS) with chemotherapy. This study investigated the effects of combined doxorubicin (DXR) and ifosfamide (IFM) on sleep and skeletal muscle. This retrospective cohort study included 14 patients with high-grade STS. Participants underwent five 7-day hospitalizations during which they received chemotherapy for 5 consecutive days. Sleep analysis and muscle-volume evaluation were investigated using a wearable device during hospitalization and by bioelectrical impedance analysis at each chemotherapy course. Chemotherapy significantly impeded sleep, increased wake-time after sleep onset, and aggravated movement index during hospitalization. In long-term body composition assessment, chemotherapy induced muscle-mass loss and fat-mass gain. Combination of DXR and IFM for STS induces skeletal muscle loss and sleep disruption.

MiR-197-5p increases Doxorubicin-mediated anticancer cytotoxicity of HT1080 fibrosarcoma cells by decreasing drug efflux

Doxorubicin (Dox) is one of the most used drugs in the treatment of Soft tissue sarcoma. However, acquired resistance linked with poor survival and numerous side effects are the major challenges. Meanwhile, miRNAs are reported to influence the chemotherapeutic responses. However, there is hardly any evidence on the involvement of tumor-suppressive miR-197 reported in our previous study in augmenting the sensitivity of fibrosarcoma cells to Dox. Therefore, in this study, we intend to decipher if miR-197–5p combined with Dox could increase the anticancer cytotoxicity. For this, we evaluated the antitumorigenic effects of Dox and miR-197–5p individually and in combination by performing a series of molecular assays. We noticed that the sub-lethal concentration of miR-197–5p markedly enhanced the sensitivity of HT1080 fibrosarcoma cells to Dox by promoting apoptosis and G2/M cell cycle arrest. We also observed miR-197–5p sensitizes HT1080 cells to Dox by increasing drug influx, possibly due to suppression of MDR genes (ABCC1, MVP). Moreover, we found that KIAA0101, a target of miR-197–5p is inhibited by Dox, which is further repressed when treated in combination with miRNA. We also observed a marked upregulation of p53, known to be negatively correlated with KIAA0101 in Dox and miR-197–5p combination treatment compared to Dox alone. Taken together, our study revealed that Dox chemotherapy in combination with miR-197–5p could overcome the problem of drug efflux and enhance its antitumor effects on fibrosarcoma.

ASO Visual Abstract: National Trends in Treatment for Retroperitoneal Soft Tissue Sarcoma—A Modern Appraisal of Variability in Therapeutic Strategies

ASO Visual Abstract: National Trends in Treatment for Retroperitoneal Soft Tissue Sarcoma—A Modern Appraisal of Variability in Therapeutic Strategies

Preoperative Stereotactic Body Radiation Therapy for Soft-Tissue Sarcoma: Results of Phase 2 Study

PurposePreoperative radiation followed by surgical resection is a standard treatment for soft-tissue sarcomas (STS). We report on 2 consecutive, phase 2, single-arm studies evaluating 5 fraction stereotactic body radiation therapy (SBRT) treatments followed by surgical resection for STS (clinical trails.gov NCT02706171). Methods and MaterialsA total of 16 patients were treated with preoperative SBRT. Tumor size in the greatest dimension was a median 6.7 cm (maximum: 14 cm) and the majority of STS were in the extremities. SBRT consisted of 35 to 40 Gy in 5 fractions every other day. ResultsMedian follow-up time was 1719 days (4.7 years). Grade ≥3 acute toxicity occurred in 1 patient (grade 3 skin changes). Fifteen patients proceeded with surgical resection. Three patients had a wound complication after surgery, 1 patient had grade ≥3 late toxicity (grade 4 requiring surgical intervention). There was 1 local recurrence and 5 distant recurrences. ConclusionsLong-term follow-up on SBRT for STS found acceptable control and toxicity rates, and warrants further evaluation.

A demographic and clinical panorama of a sixteen-year cohort of soft tissue sarcoma patients in Brazil

Little is known about soft tissue sarcomas (STS) in Brazil, once the federal statistics regarding estimates on incidence and mortality of the most common cancers that affect the Brazilian population currently do not include STS. This study aims to perform a broad evaluation and description of the epidemiological profile, access to treatment and main clinical outcomes of the Brazilian STS patient. A population-based cohort study of 66,825 patients who underwent procedures related to STS treatment registered in the Brazilian public health system (Sistema Único de Saúde, SUS) databases. Median age was 57 years, 30% of them older than 65 years and 50.7% of the cohort was female. The majority, 50,383 patients (75.4%), was diagnosed between 2008 and 2015. Most prevalent anatomic sites were upper and lower limbs (12.6%) and the registry of sarcomas without a specific location comprehended 29.7% of the cohort. The majority of patients resided in the Northeast (40.2% of the patients). Surgery was the first treatment modality in 77.7% of the cases. For survival analysis, only patients with stage and histological grade information were included. The 1-, 5- and 10-year survival rate of the patients was, respectively, 75.4% (95% CI = 74.1–76.7%), 43.4% (95% CI = 41.5–45.5%) and 18.6% (95% CI = 14.8–23.3%).

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

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

Is Metformin Use Associated with Prolonged Overall Survival in Patients with Soft Tissue Sarcoma? A SEER-Medicare Study.

Metformin, an oral drug used to treat patients with diabetes, has been associated with prolonged survival in patients with various visceral carcinomas. Although the exact mechanisms are unknown, preclinical translational studies demonstrate that metformin may impair tumor cellular metabolism, alter matrix turnover, and suppress oncogenic signaling pathways. Currently used chemotherapeutic agents have not been very successful in the adjuvant setting or for treating patients with metastatic sarcomas. We wanted to know whether metformin might be associated with improved survival in patients with a soft tissue sarcoma. In patients treated for a soft tissue sarcoma, we asked: (1) Is there an association between metformin use and longer survival? (2) How does this association differ, if at all, among patients with and without the diagnosis of diabetes? The Surveillance, Epidemiology, and End Results-Medicare (SEER-Medicare) database was used to identify patients with a diagnosis of soft tissue sarcoma from 2007 to 2016. Concomitant medication use was identified using National Drug Codes using the Medicare Part D event files. This database was chosen because of the large number of captured sarcoma patients, availability of tumor characteristics, and longitudinal linkage of Medicare data. A total of 14,650 patients were screened for inclusion. Patients with multiple malignancies, diagnosis at autopsy, or discrepant linkage to the Medicare database were excluded. Overall, 4606 patients were eligible for the study: 598 patients taking metformin and 4008 patients not taking metformin. A hazard of mortality (hazard ratio) was analyzed comparing patients taking metformin with those patient groups not taking metformin and expressed in terms of a 95% confidence interval. Cox regression analysis was used to control for patient-specific, disease-specific, and treatment-specific covariates. Having adjusted for disease-, treatment-, and patient-specific characteristics, patients taking metformin experienced prolonged survival compared with all patients not taking metformin (HR 0.76 [95% CI 0.66 to 0.87]). Associated prolonged survival was also seen when patients taking metformin were compared with those patients not on metformin irrespective of a diabetes diagnosis (HR 0.79 [95% CI 0.66 to 0.94] compared with patients with a diagnosis of diabetes and HR 0.77 [95% CI 0.67 to 0.89] compared with patients who did not have a diagnosis of diabetes). Without suggesting causation, we found that even after controlling for confounding variables such as Charlson comorbidity index, tumor grade, size, stage, and surgical/radiation treatment modalities, there was an association between metformin use and increased survival in patients with soft tissue sarcoma. When considered separately, this association persisted in patients not on metformin with and without a diabetes diagnosis. Although metformin is not normally prescribed to patients who do not have a diabetes diagnosis, these data support further study, and if these findings are substantiated, it might lead to the performance of multicenter, prospective clinical trials about the use of metformin as an adjuvant therapy for the treatment of soft tissue sarcoma in patients with and without a preexisting diabetes diagnosis. Level III, therapeutic study.

Comparison of Different Systemic Therapeutic Regimes in Resectable Soft-Tissue Sarcoma-Results of a Network Meta-Analysis.

Simple SummaryThis analysis was conducted to compare different systemic treatment options in the therapy of localized and resectable soft-tissue sarcoma. We tested these in a network against the current standard of resection with or without radiotherapy, which allowed direct and indirect comparisons. Chemotherapy given after the local therapy and chemotherapy added to regional hyperthermia before the operation were associated with a longer survival and likeliness of being disease free and alive. Chemotherapy tailored to the specific subtype of sarcoma did not improve outcomes. Adjuvant chemotherapy might be more helpful in male rather than female patients.Background: The standard treatment of high-risk soft-tissue sarcoma consists of surgical resection followed by risk-adapted radiation therapy. Further treatment options that may improve local and systemic tumor control, including chemotherapy, are not well established. Due to the heterogeneity of the disease, different systemic approaches as well as their application at different time points have been attempted. Methods: We conducted a systematic literature search for randomized clinical trials in the treatment of localized, resectable high-risk adult soft-tissue sarcoma comparing different treatment modalities according to the PRISMA guidelines. We extracted published hazard ratios and number of events for the endpoints overall and disease-free survival (OS; DFS) as well as local and distant recurrence-free interval (LRFI; DRFI). The different modalities were compared in a network meta-analysis against the defined standard treatment surgery ± radiotherapy using the inverse-variance heterogeneity model. Results: The literature search identified 25 trials including 3453 patients. Five different treatment modalities were compared in the network meta-analysis. The addition of adjuvant chemotherapy significantly improved OS compared to surgery ± radiotherapy alone (HR = 0.86; CI-95%: 0.75–0.97; p = 0.017). Likewise, neoadjuvant chemotherapy combined with regional hyperthermia (naCTx + HTx) also led to superior OS (HR = 0.45; CI-95%: 0.20–1.00; p = 0.049). Both neoadjuvant chemotherapy alone (naCTx) and perioperative chemotherapy (periCTx) did not improve OS (HR = 0.61; CI-95%: 0.29–1.29; p = 0.195 and HR = 0.66; CI-95%: 0.30–1.48; p = 0.317, respectively). Histology-tailored chemotherapy (htCTx) also did not improve survival compared to surgery ± radiotherapy (HR = 1.08; CI-95%: 0.45–2.61; p = 0.868). The network analysis of DFS, LRFI, and DRFI revealed a similar pattern between the different treatment regimens. Adjuvant chemotherapy significantly improved DFS, LRFI, and DRFI compared to surgery ± radiotherapy. In direct comparison, this advantage of adjuvant chemotherapy was restricted to male patients (HR = 0.78; CI-95%: 0.65–0.92; p = 0.004) with no effect for female patients (HR = 1.08; CI-95%: 0.90–1.29; p = 0.410). Conclusions: Standardized chemotherapy in high-risk soft-tissue sarcoma appears to be of added value irrespective of timing. The benefit of adjuvant chemotherapy seems to be restricted to male patients. The addition of regional hyperthermia to neodjuvant chemotherapy achieved the best effect sizes and might warrant further investigation.