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Cancers
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Sarcoma: Clinical Trials and Management
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Sarcoma: Clinical Trials and Management

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Clinical Research of Cancer".

Deadline for manuscript submissions: 30 November 2025 | Viewed by 5791

Special Issue Editors

Prof. Dr. Mohammed M. Milhem

E-Mail Website
Guest Editor
Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, USA
Interests: immunotherapy; melanoma; sarcoma; epigenetics; injectable intratumoral therapy
Dr. John Rieth

E-Mail Website
Co-Guest Editor
Holden Comprehensive Cancer Center, University of Iowa Hospitals & Clinics, 200 Hawkins Drive, Iowa City, IA 52242, USA
Interests: cancer; melanoma; oncology; sarcoma

Special Issue Information

Dear Colleagues,

Sarcoma represents a heterogenous collection of mesenchymal neoplasms originating in the soft tissue and bone. There are over 50 different histologic subtypes of sarcoma, and these differ by differentiation, clinical behavior, genetics, age of occurrence, and response to different therapies.  The optimal treatment of sarcoma can vary significantly between different histologic subtypes. 

Over the past decade, several innovative therapies have revolutionized the field of oncology and have challenged conventional notions of cancer treatment. New molecular targets have been identified, and immunotherapy has dramatically changed the treatment landscape for multiple malignancies, including several sarcoma subtypes. 

In this present Special Issue, we are particularly interested in manuscripts reporting original findings or updated literature reviews concerning the treatment of sarcoma. We seek to highlight innovative strategies that may lead to improvements in the management of bone and soft tissue sarcomas.

Prof. Dr. Mohammed M. Milhem
Dr. John Rieth
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • soft tissue sarcoma
  • bone sarcoma
  • chemotherapy
  • immunotherapy
  • targeted therapy
  • radiotherapy
  • pediatric sarcoma
  • adult sarcoma

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Published Papers (6 papers)

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Research

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11 pages, 252 KiB  
Article
Clinical Benefit of Pegylated Liposomal Doxorubicin and High Prevalence of Pre-Existing Psychiatric Conditions in Patients with Desmoid-Type Fibromatosis
by Andrea P. Espejo Freire and Keith M. Skubitz
Cancers 2025, 17(2), 293; https://doi.org/10.3390/cancers17020293 - 17 Jan 2025
Viewed by 1064
Abstract
Background/Objectives: Desmoid-type fibromatosis (DTF) is a locally invasive tumor composed of myofibroblast-like cells and collagen; it does not metastasize but can cause significant local morbidity. Most sporadic cases are associated with mutations in the CTNNB1 gene, which encodes beta-catenin. Various treatments have been [...] Read more.
Background/Objectives: Desmoid-type fibromatosis (DTF) is a locally invasive tumor composed of myofibroblast-like cells and collagen; it does not metastasize but can cause significant local morbidity. Most sporadic cases are associated with mutations in the CTNNB1 gene, which encodes beta-catenin. Various treatments have been used with differing efficacy and toxicity profiles. At our institution, pegylated liposomal doxorubicin (PLD) has become the preferred treatment for patients with DTF. We aim to describe our experience using PLD in patients with DTF who require treatment. Methods: A retrospective review of 61 DTF patients (41 females, 20 males) treated between 2000 and 2023 was conducted to assess the efficacy and toxicity of PLD. Results: Of the 26 patients treated with PLD, 23 had follow-up clinical data to assess benefit. Twenty-one showed clinical benefit, and only one progressed. Two patients did not benefit from PLD due to infusion reactions and chose alternative therapies. The primary side effect of PLD was hand-foot syndrome (HFS), but dose reduction and extended intervals allowed most patients to tolerate treatment. Other treatments, such as methotrexate, vinblastine/vinorelbine, and sorafenib, also showed activity but had significant toxicities, including severe HFS, malaise, and hypertension. Interestingly, 31 out of 61 patients had a pre-existing history of psychiatric conditions (primarily depression and anxiety), and 6 of 41 women had personal or family history of polycystic ovary syndrome (PCOS). Additionally, 15 patients had obesity, and 4 had hypothyroidism. Conclusions: PLD is an effective and well-tolerated treatment for DTF, with good clinical responses at lower, tolerable doses. The association of pre-existing psychiatric diagnoses, PCOS, and obesity warrants further investigation. Full article
(This article belongs to the Special Issue Sarcoma: Clinical Trials and Management)
10 pages, 1000 KiB  
Article
Primary Mediastinal Ewing’s Sarcoma: Post Hoc Analysis from Two International Multicenter Prospective Randomized Trials
by Theresa Stork, Andreas Ranft, Clemens Aigner, Heribert Jurgens, Ruth L. Ladenstein, Beate Timmermann, Henk Van den Berg, Uta Dirksen and Stéphane Collaud
Cancers 2025, 17(1), 118; https://doi.org/10.3390/cancers17010118 - 2 Jan 2025
Viewed by 870
Abstract
Objective: Ewing sarcoma (EWS) of the mediastinum is extremely rare, with only a few cases reported in the literature. We aimed to gain a better understanding of primary mediastinal EWS, describing patients treated within two international, multicenter, prospective, randomized EWS trials. Methods: Data [...] Read more.
Objective: Ewing sarcoma (EWS) of the mediastinum is extremely rare, with only a few cases reported in the literature. We aimed to gain a better understanding of primary mediastinal EWS, describing patients treated within two international, multicenter, prospective, randomized EWS trials. Methods: Data from patients with primary mediastinal EWS were retrieved from the database of the EURO-E.W.I.N.G.99 (ClinicalTrials.gov identifier: NCT00020566) and EWING 2008 (ClinicalTrials.gov identifier: NCT00987636) trials. Patient and treatment characteristics were analyzed. Results: Out of 2969 patients with EWS, 9 (0.3%) had primary mediastinal EWS. The median age at diagnosis was 30.5 years (4 to 49). At the time of diagnosis, n = 3 (33%) patients had synchronous metastases. All patients underwent multiagent chemotherapy. Local therapy for non-metastatic patients was surgery (n = 2, 22%), surgery and radiotherapy (n = 2, 22%) or radiotherapy alone (n = 2, 22%). Surgery consisted of extended resections in most patients (n = 3, 33%). Five-year survival for the whole cohort was 64%. Apart from one patient who was lost to follow-up, all patients (n = 4) who had undergone surgery were alive at the end of follow-up. Conclusions: Primary mediastinal ES is extremely rare, with a prevalence of 0.3% among EWS. Five-year survival was favorable compared to primary mediastinal sarcoma of all histologies and in line with EWS of different origin. Full article
(This article belongs to the Special Issue Sarcoma: Clinical Trials and Management)
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Review

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23 pages, 1237 KiB  
Review
Review of Adoptive Cellular Therapies for the Treatment of Sarcoma
by James J. Fradin and John A. Charlson
Cancers 2025, 17(8), 1302; https://doi.org/10.3390/cancers17081302 - 12 Apr 2025
Viewed by 297
Abstract
Sarcomas are a heterogeneous group of malignancies with limited therapeutic options, particularly in the metastatic setting. Adoptive cellular therapies (ACTs), including tumor-infiltrating lymphocyte (TIL) therapy, chimeric antigen receptor (CAR) T-cell therapy, and T-cell receptor (TCR) gene-modified T-cell therapy, offer promising novel approaches for [...] Read more.
Sarcomas are a heterogeneous group of malignancies with limited therapeutic options, particularly in the metastatic setting. Adoptive cellular therapies (ACTs), including tumor-infiltrating lymphocyte (TIL) therapy, chimeric antigen receptor (CAR) T-cell therapy, and T-cell receptor (TCR) gene-modified T-cell therapy, offer promising novel approaches for these refractory tumors. TIL-based therapy has demonstrated early efficacy in melanoma and myeloma, with ongoing trials exploring its role in sarcoma. CAR T-cell strategies targeting HER2, GD2, and B7-H3 antigens are in development, though challenges such as tumor microenvironment-mediated resistance and antigen escape remain significant. Engineered TCRs, particularly those targeting MAGE-A4 and NY-ESO-1, have shown promising clinical results in synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCLS), leading to the recent FDA approval of afamitresgene autoleucel (afami-cel) and letetresgene autoleucel (lete-cel). Despite encouraging preliminary data, ACT implementation faces barriers including limited antigen specificity, off-tumor toxicity, immune evasion, and manufacturing scalability. Future research will focus on optimizing lymphodepleting regimens, mitigating toxicity, enhancing in vivo persistence, and combining ACT with other therapeutic agents. As clinical trials expand, ACT holds the potential to revolutionize sarcoma treatment by offering durable, targeted therapies for previously refractory disease. Full article
(This article belongs to the Special Issue Sarcoma: Clinical Trials and Management)
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17 pages, 717 KiB  
Review
A Sequencing Overview of Malignant Peripheral Nerve Sheath Tumors: Findings and Implications for Treatment
by Kangwen Xiao, Kuangying Yang and Angela C. Hirbe
Cancers 2025, 17(2), 180; https://doi.org/10.3390/cancers17020180 - 8 Jan 2025
Viewed by 1226
Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are rare but aggressive malignancies with a low 5-year survival rate despite current treatments. MPNSTs frequently harbor mutations in key genes such as NF1, CDKN2A, TP53, and PRC2 components (EED or SUZ12) [...] Read more.
Malignant peripheral nerve sheath tumors (MPNSTs) are rare but aggressive malignancies with a low 5-year survival rate despite current treatments. MPNSTs frequently harbor mutations in key genes such as NF1, CDKN2A, TP53, and PRC2 components (EED or SUZ12) across different disease stages. With the rapid advancement of high-throughput sequencing technologies, the molecular characteristics driving MPNST development are becoming clearer. This review summarizes recent sequencing studies on peripheral nerve sheath tumors, including plexiform neurofibromas (PNs), atypical neurofibromatous neoplasm with uncertain biologic potential (ANNUBP), and MPNSTs, highlighting key mutation events in tumor progression from the perspectives of epigenetics, transcriptomics, genomics, proteomics, and metabolomics. We also discuss the therapeutic implications of these genomic findings, focusing on preclinical and clinical trials targeting these alterations. Finally, we conclude that overcoming tumor resistance through combined targeted therapies and personalized treatments based on the molecular characteristics of MPNSTs will be a key direction for future treatment strategies. Full article
(This article belongs to the Special Issue Sarcoma: Clinical Trials and Management)
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24 pages, 1156 KiB  
Review
UBR5 in Tumor Biology: Exploring Mechanisms of Immune Regulation and Possible Therapeutic Implications in MPNST
by Diana Akinyi Odhiambo, Selina Fan and Angela C. Hirbe
Cancers 2025, 17(2), 161; https://doi.org/10.3390/cancers17020161 - 7 Jan 2025
Viewed by 1221
Abstract
Malignant peripheral nerve sheath tumor (MPNST) is a rare but aggressive soft-tissue sarcoma characterized by poor response to therapy. The primary treatment remains surgical resection with negative margins. Nonetheless, in the setting of neurofibromatosis type 1 (NF1), the five-year survival rate is at [...] Read more.
Malignant peripheral nerve sheath tumor (MPNST) is a rare but aggressive soft-tissue sarcoma characterized by poor response to therapy. The primary treatment remains surgical resection with negative margins. Nonetheless, in the setting of neurofibromatosis type 1 (NF1), the five-year survival rate is at 20–50%, with recurrence occurring in up to 50% of individuals. For patients with metastatic and unresectable disease, current treatment options include cytotoxic chemotherapy, which offers minimal benefit, and most patients die within five years of diagnosis. Despite advances in targeted therapy focusing on inhibiting Ras signaling and its downstream effectors, clinical trials report minimal clinical benefit, highlighting the need to explore alternative pathways in MPNST pathogenesis. Here, we discuss the role of the E3 ubiquitin ligase, UBR5, in cancer progression and immune modulation across various malignancies, including breast, lung, and ovarian cancer. We focus on mechanisms by which UBR5 contributes to tumorigenesis, focusing on its influence on tumor microenvironment and immune modulation. Additionally, we explore UBR5’s roles in normal tissue function, DNA damage response, metastasis, and therapeutic resistance, illustrating its multifaceted contribution to cancer biology. We discuss evidence implicating UBR5 in immune evasion and highlight its potential as a therapeutic target to enhance the efficacy of immune checkpoint blockade (ICB) therapy in MPNST, a tumor typically characterized by an immune cold microenvironment. We outline current immune-based strategies and challenges in MPNST management, ongoing efforts to shift the immune landscape in MPNST, and ultimately, we suggest that targeting UBR5 could be a novel strategy to potentiate ICB therapy-mediated anti-tumor immune response and clinical outcomes, particularly in MPNST patients with inoperable or metastatic disease. Full article
(This article belongs to the Special Issue Sarcoma: Clinical Trials and Management)
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Other

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10 pages, 237 KiB  
Commentary
The Decline and Fall of the Current Chemotherapy Paradigm in Soft Tissue Sarcoma
by John Rieth, Varun Monga and Mohammed Milhem
Cancers 2025, 17(7), 1203; https://doi.org/10.3390/cancers17071203 - 1 Apr 2025
Viewed by 347
Abstract
Background/Objectives: Despite conventional cytotoxic chemotherapy treatments, soft tissue sarcoma continues to remain a terminal diagnosis for most patients. Numerous chemotherapeutic agents have been trialed in soft tissue sarcoma, with marginal improvement in overall survival. Novel therapeutic approaches are needed to improve outcomes for [...] Read more.
Background/Objectives: Despite conventional cytotoxic chemotherapy treatments, soft tissue sarcoma continues to remain a terminal diagnosis for most patients. Numerous chemotherapeutic agents have been trialed in soft tissue sarcoma, with marginal improvement in overall survival. Novel therapeutic approaches are needed to improve outcomes for this entity. Methods: the literature was reviewed, including a summary of pertinent adjuvant/neoadjuvant clinical trials and trials for metastatic disease. Results: Chemotherapeutic agent use in adjuvant/neoadjuvant trials provided limited if any evidence of the benefit of chemotherapy in this space. Despite multiple trials in the metastatic space, novel chemotherapeutic agents appear to have limited long-term benefits for the management of soft tissue sarcoma. Suggestions for further research, particularly with neoadjuvant clinical trials, were made. Conclusions: Chemotherapy remains an inadequate treatment option for soft tissue sarcoma, and novel therapies are needed. The neoadjuvant space provides an excellent opportunity to study the effects of innovative treatments in soft tissue sarcoma. Full article
(This article belongs to the Special Issue Sarcoma: Clinical Trials and Management)
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