New Trends in the Management of Soft Tissue Sarcoma

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ACHAIKI IATRIKI | 2025; 44(2):71–75

Review

Anastasios Kyriazoglou, Anna Boulouta

Second Department of Internal Medicine, Oncology Unit, Attikon University Hospital, Athens, Greece

Received: 29 May 2024; Accepted: 11 Sep 2024

Corresponding author: Anna Boulouta, Second Department of Internal Medicine, Oncology Unit, Attikon University Hospital, Athens, Greece. E-mail: annitaboulouta@gmail.com

Key words: Soft tissue sarcoma, treatment, chemotherapy, radiotherapy, immunotherapy, pathologic complete response.

 

Abstract

Soft tissue sarcomas (STS) are a heterogeneous group of tumors originating from connective tissues. The management of STS has historically been challenging due to their rarity, heterogeneity, and complex anatomical locations. Surgical excision remains the standard treatment for localized STS, often supplemented by radiotherapy and chemotherapy to control recurrence and metastasis. Recent advancements in the era of immunotherapy and precision medicine have introduced novel therapeutic strategies, including neoadjuvant combination treatments and immune checkpoint inhibitors. Neoadjuvant therapies incorporating chemotherapy agents and tyrosine kinase inhibitors (TKIs), often combined with radiotherapy and regional hyperthermia, have improved surgical outcomes and survival rates. In metastatic STS, immune checkpoint inhibitors have shown promising efficacy, particularly in specific histologic subtypes. The identification of biomarkers such as tumor mutational burden (TMB) and tertiary lymphoid structures (TLS) has the potential to guide and personalize immunotherapy, improving prognostic accuracy and treatment efficacy. This review highlights these emerging trends, emphasizing the importance of integrating novel therapeutic approaches and precision medicine in the management of STS to optimize patient outcomes.

Introduction

Soft tissue sarcomas (STS) are a heterogeneous group of malignant tumors originating in connective tissues, including muscles, fat, blood vessels, nerves, and fibrous tissues, and accounting for approximately 1% of malignant tumors in adults [1]. Historically, the management of STS has been challenging due to their rarity, heterogeneity, and the complex anatomical locations they often involve. Surgical excision remains the standard treatment for early disease. However, due to high recurrence rates, the addition of perioperative systemic therapies and/or radiotherapy (RT) has been integrated [2,3]. RT has been a standard adjunct to surgery, particularly for high-grade and large tumors, aiming to control local disease. Chemotherapy plays a well-established role in managing metastatic disease and serves as a perioperative treatment for certain high-risk patients [2]. With the advent of immunotherapy and precision medicine, significant advances have been made in the management of STS, such as neoadjuvant combination treatments and immune checkpoint inhibitors. New trends in STS therapeutics emphasize improving treatment efficacy and tailoring therapeutic strategies to individual patients.

Materials and methods

This review aims to highlight and evaluate the emerging trends and advancements in the management of STS, including an analysis of novel therapeutic approaches, the role of precision medicine, and the integration of multimodal treatment strategies. To achieve this, we conducted a bibliographic search of the PubMed database using the following terms: “Soft tissue sarcoma” AND (“treatment”) AND (“chemotherapy” OR “radiotherapy” OR “hyperthermia” OR “TKI”) AND (“neoadjuvant” OR “adjuvant” OR “perioperative”). We included phase I, II or III clinical trials, reviews, as well as the ESMO–EURACAN–GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up of soft tissue and visceral sarcomas.

Results

Early disease

Surgery is the standard treatment for all patients with localized STS, with en-bloc excision with R0 margins being the standard procedure [3]. For high-grade tumors, RT is the classic adjunct treatment. While it was historically preferred postoperatively, it is nowadays used as a preoperative treatment with or without chemotherapy [5]. Neoadjuvant treatment for STS can facilitate surgical resection and lower rates of local relapse and distant metastases, compared to adjuvant treatment. There is no standard neoadjuvant chemotherapy treatment for STS, however, among expert centers, a combination of doxorubicin and ifosfamide is preferred [3].

Radiotherapy and hyperthermia

For patients with localized high-risk STS, incorporating regional hyperthermia (RHT) into neoadjuvant therapy has led to improved survival rates and better local progression-free survival. Therefore, for those eligible for neoadjuvant therapy, adding RHT to the treatment regimen may be beneficial [6]. Another issue that is under investigation is the hypofractionation of RT, meaning an RT schedule that is given over a shorter period of time than standard RT. The standard-of-care preoperative RT dose regimen for STS remains 25 × 2 Gy [7]. Recent studies on moderate hypofractionation and ultra-hypofractionation for STS have demonstrated that these alternative schedules generally achieve comparable local control outcomes to the conventional RT regimen [8]. In addition, a phase II study of hypofractionated RT combined with chemotherapy for extremity STS resulted in a disease-free survival (DFS) of 72%, with a median follow-up of 29 months [9].

Chemotherapy and TKIs

A chemotherapeutic agent that has demonstrated promising activity in the neoadjuvant treatment of STS, especially in myxoid liposarcoma (MLS), is trabectedin. In a recent phase II clinical trial, 51% of patients treated with preoperative trabectedin combined with RT achieved over 90% necrosis in the tumor specimen [10]. Another agent showing promising results in combination with RT is pazopanib. In the ARST1321 randomized phase II trial, the addition of pazopanib to neoadjuvant chemoradiotherapy improved the rate of pathologic complete response, increasing to 58% compared to 22% [11]. A similar study of neoadjuvant pazopanib plus chemotherapy in patients with high-grade localized soft tissue sarcoma more than double the historical pathologic complete response (pCR) rates observed with neo-adjuvant RT alone [12].

Pathologic complete response

pCR is a marker that is used in daily clinical practice in other neoplasms, such as breast and urothelial cancers. Even though it is not yet integrated into the therapeutic approach of STS, there are recent data that indicate a correlation between pCR and clinical outcomes in these patients. A study of neoadjuvant RT for STS had shown a positive correlation between the rate of pCR and distant recurrence-free survival (DRFS) [13]. The RTOG 9514 and RTOG 0630 trials of neoadjuvant chemoradiotherapy proved that pCR after preoperative treatment is correlated with a superior five-year overall survival (OS) [14,16]. Additionally, a study evaluating neoadjuvant chemotherapy versus chemoradiotherapy for retroperitoneal STS, concluded in a superior five-year disease specific survival (DSS) in the group of patients that achieved pCR [15]. The above results show that pCR is a marker that needs to be investigated further and utilized in therapeutic decisions for localized STS.

Metastatic disease

Immunotherapy

Several immune checkpoint inhibitors have been, and are currently being, investigated, showing promising results in certain subtypes of STS.

The SARC028 phase II trial enrolled 84 patients with both bone sarcoma (BS) and soft tissue sarcoma (STS). The STS group included patients with undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), leiomyosarcoma (LMS), and synovial sarcoma (SS). All participants were administered pembrolizumab at a dose of 200 mg every 21 days. There was a notably high objective response rate (ORR) in the UPS subgroup, with one patient achieving a complete response and two others achieving partial responses. Additionally, 20% of patients with LPS exhibited partial responses. The median progression-free survival (mPFS) was 30 weeks for UPS and 25 weeks for LPS [17].

The AcSe trial, a phase II multicenter study, also evaluated the effectiveness of pembrolizumab monotherapy across different sarcoma subtypes. The updated results demonstrated an ORR of 6.2%, with a mPFS of 2.8 months and a median OS of 19.7 months. There was notable heterogeneity in responses among different histotypes, with alveolar soft part sarcoma (ASPS) and SMARCA4-deficient sarcoma or malignant rhabdoid tumor showing favorable outcomes, achieving partial response rates of 50% and 25%, respectively. One patient with ASPS (7%) and one patient with epithelioid sarcoma (17%) achieved complete responses [18].

A phase II study investigating the effect of atezolizumab in patients with ASPS reported an ORR of 37%, including one complete response and 18 partial responses. The mPFS was 20.8 months. Interestingly, seven patients discontinued treatment after two years and their responses were maintained [19].

In a Chinese phase I clinical trial, toripalimab was administered to patients with advanced or refractory tumors, including 12 with ASPS. Among the ASPS patients, the ORR was 25.0%, the mOS was 34.7 months and the mPFS was 11.1 months [20].

The randomized Alliance A091401 trial demonstrated that the combination of nivolumab and ipilimumab was more effective for treating metastatic, locally advanced, or unresectable sarcomas compared to nivolumab alone. The study’s primary endpoint was met, with a response rate of 16%. Responses to the combination therapy were noted in patients with ASPS, UPS, LMS, myxofibrosarcoma (MFS), and angiosarcoma (AS), with five (12%) partial responses and two (5%) complete responses [21].

Immune checkpoint inhibitors and TKI combinations

In the phase Ib/II IMMUNOSARC trial, nivolumab plus sunitinib was tested in 16 patients with STS. The ORR was 21%, while the 18-month OS was 100% for patients who had an objective response and 75% for those who had stable disease. One patient with AS achieved a complete response, while two patients with ASPS, one with AS, one with SS, and one with extraskeletal myxoid CS experienced a partial response [22].

A phase II, single-arm clinical trial of pembrolizumab combined with axitinib for advanced soft tissue sarcoma, including ASPS, showed a ​​three-month progression-free survival of 65.6% for all evaluable patients, with a three-month progression-free survival being 72.7%, especially for patients with ASPS [23].

Alliance A091902 is a multicenter phase II study of cabozantinib plus nivolumab for patients with advanced AS previously treated with a taxane. Preliminary data from this trial show an ORR of 62%, with 11 partial responses and two complete responses. Median PFS was 9.6 months, and OS 20.5 months [24].

Recently, the combination of durvalumab plus pazopanib was tested in metastatic and/or recurrent STS. The ORR was 30.4%, meeting the prespecified endpoint and the median PFS was 7.7 months [25].

Biomarkers for immunotherapy response

PD-L1 is known to predict responses to immune checkpoint inhibitors in several solid tumors. However, its role as a prognostic and predictive biomarker in STS is controversial [26]. A marker that has shown a stronger correlation with ICI response is tumor mutational burden (TMB). High TMB values are observed in UPS, LMS, and SS [27].

Tertiary lymphoid structures (TLS), which include T cells, follicular dendritic cells, and B cells, are part of the tumor microenvironment and appear to be better predictors of prognosis and response to therapy. Recent findings from the PEMBROSARC trial showed that STS rich in TLS and intratumoral plasma cells exhibited a better response to pembrolizumab [28].

Discussion

The management of soft tissue sarcomas (STS) has evolved significantly over the past decades, with advancements in surgical techniques, the incorporation of multimodal therapies, and the advent of precision medicine and immunotherapy. This review has highlighted several key trends and innovations in the treatment of STS, particularly focusing on the roles of neoadjuvant therapies, hyperthermia, and immune checkpoint inhibitors, as well as the exploration of biomarkers to guide therapy. These trends represent a move towards more personalized, precise, and effective management of soft tissue sarcomas, aimed at improving outcomes and quality of life for patients. Future research should focus on refining these therapeutic strategies and validating biomarkers to further improve clinical outcomes for patients with soft tissue sarcomas. The continued collaboration between clinical researchers, oncologists, and multidisciplinary teams will be essential in translating these advancements into standard practice, ultimately enhancing the prognosis and quality of life for patients with STS. Table 1 summarizes the new therapeutic options in the management of STS.

Conclusion

The landscape of STS management is rapidly evolving, with significant advancements in both neoadjuvant and metastatic disease treatments. The integration of new radiotherapy regimens, hyperthermia, novel chemotherapeutic agents, TKIs, immune checkpoint inhibitors and combinations of the above, have enhanced the efficacy of traditional treatment regimens. Moreover, the identification of predictive biomarkers for therapy response represents a significant step towards personalized medicine in STS.

Conflict of interest disclosure

None to declare.

Declaration of funding sources

None to declare.

Author contributions

AB, conceptualization, methodology, writing – original draft, investigation, data curation, systematic review search; AK, conceptualization, methodology, writing – review and editing, supervision, investigation, data curation, systematic review search.

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