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Cancers
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New Directions for Treating Soft Tissue Sarcomas
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New Directions for Treating Soft Tissue Sarcomas

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

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 52162

Special Issue Editors

Dr. Winan J. van Houdt

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Guest Editor
Department of surgical oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
Interests: soft tissue sarcoma; neo-adjuvant treatment for soft tissue sarcoma; translational research; retroperitoneal sarcoma; gastrointestinal stromal cell tumor; desmoid tumors; melanoma; cutaneous squamous cell carcinoma; surgical oncology
Prof. Dr. Bernd Kasper

E-Mail Website
Guest Editor
University of Heidelberg, Mannheim University Medical Center, Sarcoma Unit, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany
Interests: bone and soft tissue sarcomas; gastrointestinal stromal tumors; desmoid tumors; translational research; clinical trials; drug development; medical oncology

Special Issue Information

Dear Colleagues,

In recent decades, there have been several developments in treatment strategies for soft tissue sarcomas (STS) to improve patient outcomes. Currently, there is more insight into the differences in biological behavior and molecular background between the different sarcoma histotypes leading to more focused treatment strategies for specific subtypes. The centralization of sarcoma care and more (international) collaboration in sarcoma research also seem to improve the quality of care.

However, given the heterogeneity of the disease and the rarity of the different subtypes, setting up clinical trials for STS remains challenging. Furthermore, there have been no major breakthroughs with new targeted agents or immuno-oncology strategies when compared to other cancer types. To further improve cure and care for sarcoma patients, this Special Issue will highlight new research directions and multi-disciplinary treatment strategies for patients with STS, in primary, recurrent, and metastatic settings.

Dr. Winan J. van Houdt
Prof. Dr. Bernd Kasper
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 short 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

  • Diagnosing STS
  • Neo-adjuvant strategies for STS
  • Response prediction in STS
  • Recurrent STS
  • Centralization of STS treatment
  • Follow up after treatment of primary STS
  • Immuno oncology for STS
  • New targets for STS
  • Quality of life for STS patients

Published Papers (16 papers)

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Research

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10 pages, 1430 KiB  
Article
Analysis of the Effect of Tumor-Grade Change on the Prognosis of Retroperitoneal Sarcoma
by Sung Jun Jo, Kyeong Deok Kim, So Hee Lim, Jinseob Kim, Min Jung Kim, Jae Berm Park and Kyo Won Lee
Cancers 2022, 14(12), 3020; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14123020 - 19 Jun 2022
Cited by 2 | Viewed by 1508
Abstract
In retroperitoneal sarcoma (RPS), the change in the tumor grade from the primary tumor to the first local recurrence, and the effect of this change on prognosis, are unknown. The aim of this study is to analyze whether these changes affect the prognosis [...] Read more.
In retroperitoneal sarcoma (RPS), the change in the tumor grade from the primary tumor to the first local recurrence, and the effect of this change on prognosis, are unknown. The aim of this study is to analyze whether these changes affect the prognosis of RPS. Patients who underwent surgery for a first locally recurrent RPS at Samsung Medical Center from January 2001 to February 2020 were included. The pathologic features of primary and recurrent tumors were compared, and the outcomes were measured. A total of 49 patients were investigated. There were 25 patients with different grades of primary and recurrent tumors. The improving, stable, and worsening groups contained 16 (32.7%), 24 (49%), and 9 (18.3%) patients, respectively. There was no significant difference in the prognosis between the three groups. In the analyses of the factors that affect the OS, a high grade of the primary tumor (p = 0.023) and the size of the recurrent tumor (p = 0.032) were statistically significant in both univariate and multivariate analyses. In a factor analysis of the second LR, a high-grade recurrent tumor (p = 0.032) was the only significant factor. There were tumor-grade changes between the primary tumor and recurrent tumor in RPS. However, the most important factor in prognosis is a high grade of the primary tumor. Full article
(This article belongs to the Special Issue New Directions for Treating Soft Tissue Sarcomas)
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18 pages, 285 KiB  
Article
Development of a Disease-Specific Health-Related Quality of Life Questionnaire (DTF-QoL) for Patients with Desmoid-Type Fibromatosis
by Anne-Rose W. Schut, Emma Lidington, Milea J. M. Timbergen, Eugenie Younger, Winette T. A. van der Graaf, Winan J. van Houdt, Johannes J. Bonenkamp, Robin L. Jones, Dirk. J. Grünhagen, Stefan Sleijfer, Cornelis Verhoef, Spyridon Gennatas and Olga Husson
Cancers 2022, 14(3), 709; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030709 - 29 Jan 2022
Cited by 9 | Viewed by 1828
Abstract
Sporadic desmoid-type fibromatosis (DTF) is a rare, non-metastasising soft-tissue tumour. Patients can experience a variety of disease-specific issues related to the unpredictable clinical course and aggressiveness of DTF, which negatively impacts health-related quality of life (HRQoL). These DTF-specific issues are not captured by [...] Read more.
Sporadic desmoid-type fibromatosis (DTF) is a rare, non-metastasising soft-tissue tumour. Patients can experience a variety of disease-specific issues related to the unpredictable clinical course and aggressiveness of DTF, which negatively impacts health-related quality of life (HRQoL). These DTF-specific issues are not captured by generic HRQoL tools. A 102-item provisional DTF-specific HRQoL tool, the DTF-QoL, was previously developed. The aim of this study was to pre-test the psychometric properties of the DTF-QoL by administering it together with the EORTC Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) to 236 DTF patients from the United Kingdom and the Netherlands. Construct validity and reliability were determined based on factor analysis, multi-trait scaling analysis, Cronbach’s alpha, and correlations with the EORTC QLQ-C30 scales. Ninety-six items were selected, conceptualised into three symptom scales, eleven disease-impact scales and six single items, together forming the final DTF-QoL. Scaling assumptions were fully or moderately met for ten out of fourteen scales. Cronbach’s alpha ranged from 0.551–0.908. Most scales of the DTF-QoL were weakly or moderately correlated with the EORTC QLQ-C30. The DTF-QoL is a promising tool capturing the whole spectrum of DTF-specific issues. Implementation of the DTF-QoL in research and clinical practice will help to personalise HRQoL measurement and clinical care for DTF patients. Full article
(This article belongs to the Special Issue New Directions for Treating Soft Tissue Sarcomas)
15 pages, 827 KiB  
Article
Clinical Impact of Prospective Whole Genome Sequencing in Sarcoma Patients
by Luuk J. Schipper, Kim Monkhorst, Kris G. Samsom, Linda J.W. Bosch, Petur Snaebjornsson, Hester van Boven, Paul Roepman, Lizet E. van der Kolk, Winan J. van Houdt, Winette T.A. van der Graaf, Gerrit A. Meijer and Emile E. Voest
Cancers 2022, 14(2), 436; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020436 - 16 Jan 2022
Cited by 10 | Viewed by 3049
Abstract
With more than 70 different histological sarcoma subtypes, accurate classification can be challenging. Although characteristic genetic events can largely facilitate pathological assessment, large-scale molecular profiling generally is not part of regular diagnostic workflows for sarcoma patients. We hypothesized that whole genome sequencing (WGS) [...] Read more.
With more than 70 different histological sarcoma subtypes, accurate classification can be challenging. Although characteristic genetic events can largely facilitate pathological assessment, large-scale molecular profiling generally is not part of regular diagnostic workflows for sarcoma patients. We hypothesized that whole genome sequencing (WGS) optimizes clinical care of sarcoma patients by detection of diagnostic and actionable genomic characteristics, and of underlying hereditary conditions. WGS of tumor and germline DNA was incorporated in the diagnostic work-up of 83 patients with a (presumed) sarcomas in a tertiary referral center. Clinical follow-up data were collected prospectively to assess impact of WGS on clinical decision making. In 12/83 patients (14%), the genomic profile led to revision of cancer diagnosis, with change of treatment plan in eight. All twelve patients had undergone multiple tissue retrieval procedures and immunohistopathological assessments by regional and expert pathologists prior to WGS analysis. Actionable biomarkers with therapeutic potential were identified for 30/83 patients. Pathogenic germline variants were present in seven patients. In conclusion, unbiased genomic characterization with WGS identifies genomic biomarkers with direct clinical implications for sarcoma patients. Given the diagnostic complexity and high unmet need for new treatment opportunities in sarcoma patients, WGS can be an important extension of the diagnostic arsenal of pathologists. Full article
(This article belongs to the Special Issue New Directions for Treating Soft Tissue Sarcomas)
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17 pages, 771 KiB  
Article
Efficacy and Safety of Trans-Arterial Yttrium-90 Radioembolization in Patients with Unresectable Liver-Dominant Metastatic or Primary Hepatic Soft Tissue Sarcomas
by Stefano Testa, Nam Q. Bui, David S. Wang, John D. Louie, Daniel Y. Sze and Kristen N. Ganjoo
Cancers 2022, 14(2), 324; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020324 - 10 Jan 2022
Cited by 4 | Viewed by 2865
Abstract
Patients with liver-dominant metastatic or primary hepatic soft tissue sarcomas (STS) have poor prognosis. Surgery can prolong survival, but most patients are not surgical candidates, and treatment response is limited with systemic chemotherapy. Liver-directed therapies have been increasingly employed in this setting, and [...] Read more.
Patients with liver-dominant metastatic or primary hepatic soft tissue sarcomas (STS) have poor prognosis. Surgery can prolong survival, but most patients are not surgical candidates, and treatment response is limited with systemic chemotherapy. Liver-directed therapies have been increasingly employed in this setting, and Yttrium-90 trans-arterial radioembolization (TARE) is an understudied yet promising treatment option. This is a retrospective analysis of 35 patients with metastatic or primary hepatic STS who underwent TARE at a single institution between 2006 and 2020. The primary outcomes that were measured were overall survival (OS), liver progression-free survival (LPFS), and radiologic tumor response. Clinical and biochemical toxicities were assessed 3 months after the procedure. Median OS was 20 months (95% CI: 13.9–26.1 months), while median LPFS was 9 months (95% CI: 6.2–11.8 months). The objective response rate was 56.7%, and the disease control rate was 80.0% by mRECIST at 3 months. The following correlated with better OS post-TARE: liver disease control (DC) at 6 months (median OS: 40 vs. 17 months, p = 0.007); LPFS ≥ 9 months (median OS: 50 vs. 8 months, p < 0.0001); ECOG status 0–1 vs. 2 (median OS: 22 vs. 6 months, p = 0.042); CTP class A vs. B (median OS: 22 vs. 6 months, p = 0.018); and TACE post-progression (median OS: 99 vs. 16 months, p = 0.003). The absence of metastases at diagnosis was correlated with higher median LPFS (7 vs. 1 months, p = 0.036). Two grade 4 (5.7%) and ten grade 3 (28.6%) laboratory toxicities were identified at 3 months. There was one case of radioembolization-induced liver disease and two cases of radiation-induced peptic ulcer disease. We concluded that TARE could be an effective and safe treatment option for patients with metastatic or primary hepatic STS with good tumor response rates, low incidence of severe toxicity, and longer survival in patients with liver disease control post-TARE. Full article
(This article belongs to the Special Issue New Directions for Treating Soft Tissue Sarcomas)
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21 pages, 2633 KiB  
Article
PARP1 Inhibitor and Trabectedin Combination Does Not Increase Tumor Mutational Burden in Advanced Sarcomas—A Preclinical and Translational Study
by Ymera Pignochino, Giovanni Crisafulli, Giorgia Giordano, Alessandra Merlini, Enrico Berrino, Maria Laura Centomo, Giulia Chiabotto, Silvia Brusco, Marco Basiricò, Elena Maldi, Alberto Pisacane, Valeria Leuci, Dario Sangiolo, Lorenzo D’Ambrosio, Massimo Aglietta, Bernd Kasper, Alberto Bardelli and Giovanni Grignani
Cancers 2021, 13(24), 6295; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13246295 - 15 Dec 2021
Viewed by 3256
Abstract
Drug-induced tumor mutational burden (TMB) may contribute to unleashing the immune response in relatively “immune-cold” tumors, such as sarcomas. We previously showed that PARP1 inhibition perpetuates the DNA damage induced by the chemotherapeutic agent trabectedin in both preclinical models and sarcoma patients. In [...] Read more.
Drug-induced tumor mutational burden (TMB) may contribute to unleashing the immune response in relatively “immune-cold” tumors, such as sarcomas. We previously showed that PARP1 inhibition perpetuates the DNA damage induced by the chemotherapeutic agent trabectedin in both preclinical models and sarcoma patients. In the present work, we explored acquired genetic changes in DNA repair genes, mutational signatures, and TMB in a translational platform composed of cell lines, xenografts, and tumor samples from patients treated with trabectedin and olaparib combination, compared to cells treated with temozolomide, an alkylating agent that induces hypermutation. Whole-exome and targeted panel sequencing data analyses revealed that three cycles of trabectedin and olaparib combination neither affected the mutational profiles, DNA repair gene status, or copy number alterations, nor increased TMB both in homologous recombinant-defective and proficient cells or in xenografts. Moreover, TMB was not increased in tumor specimens derived from trabectedin- and olaparib-treated patients (5–6 cycles) when compared to pre-treatment biopsies. Conversely, repeated treatments with temozolomide induced a massive TMB increase in the SJSA-1 osteosarcoma model. In conclusion, a trabectedin and olaparib combination did not show mutagenic effects and is unlikely to prime subsequent immune-therapeutic interventions based on TMB increase. On the other hand, these findings are reassuring in the increasing warning of treatment-induced hematologic malignancies correlated to PARP1 inhibitor use. Full article
(This article belongs to the Special Issue New Directions for Treating Soft Tissue Sarcomas)
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15 pages, 1637 KiB  
Article
Long-Term Follow-Up of Patients Receiving Neoadjuvant Treatment Modalties for Soft Tissue Sarcomas of the Extremities
by Miriam Rauch, Abbas Agaimy, Sabine Semrau, Alexander Willner, Oliver Ott, Rainer Fietkau, Werner Hohenberger, Roland S. Croner, Robert Grützmann, Katja Fechner and Nikolaos Vassos
Cancers 2021, 13(20), 5244; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205244 - 19 Oct 2021
Cited by 1 | Viewed by 1690
Abstract
Background: Neoadjuvant treatment modalities in soft tissue sarcoma (STS) of the extremities have become more popular in recent years, but because of the rarity and heterogeneity of STS, there are yet few studies on the long-term impact of neoadjuvant treatment modalities, especially in [...] Read more.
Background: Neoadjuvant treatment modalities in soft tissue sarcoma (STS) of the extremities have become more popular in recent years, but because of the rarity and heterogeneity of STS, there are yet few studies on the long-term impact of neoadjuvant treatment modalities, especially in terms of neoadjuvant radiochemotherapy. Methods: The study enrolled 136 patients with primary STS of the extremities who underwent surgery with curative intent or neoadjuvant therapy, followed by surgery in a 15-year period. Neoadjuvant treatment consisted of radiotherapy (RT) with 60 Gy and in most cases simultaneous chemotherapy (CTx) with ifosfamide (1.5 g/m2/d, d1–5, q28) and doxorubicine (50 mg/m2/d, d3, q28). We investigated the clinical, (post)-operative and histopathological data and the oncological follow-up as well. The median follow-up period was 82 months (range 6–202). Results: A total of 136 patients (M:F = 73:63) with a mean age of 62 years (range; 21–93) was observed. Seventy-four patients (54.4%) received neoadjuvant therapy (NT), 62 patients (45.6%) received primary surgery (PS). When receiving NT, patients with high-risk STS had a lower risk to develop distant metastasis (p = 0.025). Age, histological type, tumor size and surgical margins (R0 vs. R1) had no influence on any survival rates. There was an association between NT and the occurrence of postoperative complications (p = 0.001). The 5-year local recurrence free survival (LRFS), metastasis free survival (MFS), disease free survival (DFS) and overall survival (OS) rate of the whole cohort was 89.9%, 77.0%, 70.6% and 72.6%; whereas the 5-year LRFS, MFS, DFS and OS rate was 90.5%, 67.2%, 64.1% and 62.8% for the NT group and 89.5%, 88.3%. 78.4% and 83.8% for the PS group. Conclusions: Multimodal treatment strategies in patients with STS of extremities lead to excellent oncological outcomes. Patients with high-risk STS had a significantly better MFS when receiving NT than patients with low-risk STS. NT was associated with a higher probability of postoperative but well-manageable complications. Full article
(This article belongs to the Special Issue New Directions for Treating Soft Tissue Sarcomas)
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12 pages, 4910 KiB  
Article
The Lymph-Sparing Quotient: A Retrospective Risk Analysis on Extremity Radiation for Soft Tissue Sarcoma Treatment
by Iqbal Sarif, Khaled Elsayad, Daniel Rolf, Christopher Kittel, Georg Gosheger, Eva Wardelmann, Uwe Haverkamp and Hans Theodor Eich
Cancers 2021, 13(9), 2113; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13092113 - 27 Apr 2021
Cited by 3 | Viewed by 1672
Abstract
Radiation therapy (RT) for extremity soft tissue sarcoma is associated with lymphedema risk. In this study, we analyzed the influence of lymph-sparing volume on the lymphedema occurrence in patients who received adjuvant extremity RT. The lymph-sparing quotient (LSQ) was calculated by dividing the [...] Read more.
Radiation therapy (RT) for extremity soft tissue sarcoma is associated with lymphedema risk. In this study, we analyzed the influence of lymph-sparing volume on the lymphedema occurrence in patients who received adjuvant extremity RT. The lymph-sparing quotient (LSQ) was calculated by dividing the lymph-sparing volume by the total extremity volume with double weightingfor the narrowest lymph-sparing region. A total of 34 patients were enrolled in this analysis. The median applied total radiation dose was 66.3 Gy in 36 fractions. Acute lymphedema appeared in 12 patients (35%). Most of them (n = 8) were lymphedema grade 1 and five patients had grade 2 to 3 lymphedema. Chronic lymphedema appeared in 22 patients (65%). 17 of these patients had at least a grade 2 lymphedema. In 13 of 14 patients with an LSQ ≤ 0.2 and 11 of 20 patients with an LSQ > 0.2, an acute or chronic lymphedema ≥ grade 2 was observed. A Kaplan–Meier Analysis of the two groups with the endpoint of a two-year lymph edema-free survival (=2-YLEFS) was estimated with an univariate, significant result (2-YLEFS LSQ ≤ 0.2 vs. LSQ > 0.2: 0% vs. 39%; p = 0.006; hazard ratio LSQ ≤ 0.2 vs. > 0.2 2-YLEFS 2.822 (p = 0.013); 95% confidence interval (CI): 1.24–6.42). Maximizing the potential oncologically-justifiable lymph-sparing volume should be considered to reduce the risk of high-grade lymphedema when applying RT to extremities. Full article
(This article belongs to the Special Issue New Directions for Treating Soft Tissue Sarcomas)
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10 pages, 1500 KiB  
Article
Impact of Pathological Stratification on the Clinical Outcomes of Advanced Well-Differentiated/Dedifferentiated Liposarcoma Treated with Trabectedin
by Chiara Fabbroni, Giovanni Fucà, Francesca Ligorio, Elena Fumagalli, Marta Barisella, Paola Collini, Carlo Morosi, Alessandro Gronchi, Angelo Paolo Dei Tos, Paolo Giovanni Casali and Roberta Sanfilippo
Cancers 2021, 13(6), 1453; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13061453 - 22 Mar 2021
Cited by 13 | Viewed by 2071
Abstract
Background. We previously showed that grading can prognosticate the outcome of retroperitoneal liposarcoma (LPS). In the present study, we aimed to explore the impact of pathological stratification using grading on the clinical outcomes of patients with advanced well-differentiated LPS (WDLPS) and dedifferentiated LPS [...] Read more.
Background. We previously showed that grading can prognosticate the outcome of retroperitoneal liposarcoma (LPS). In the present study, we aimed to explore the impact of pathological stratification using grading on the clinical outcomes of patients with advanced well-differentiated LPS (WDLPS) and dedifferentiated LPS (DDLPS) treated with trabectedin. Patients: We included patients with advanced WDLPS and DDLPS treated with trabectedin at the Fondazione IRCCS Istituto Nazionale dei Tumori between April 2003 and November 2019. Tumors were categorized in WDLPS, low-grade DDLPS, and high-grade DDLPS according to the 2020 WHO classification. Patients were divided in two cohorts: Low-grade (WDLPS/low-grade DDLPS) and high-grade (high-grade DDLPS). Results: A total of 49 patients were included: 17 (35%) in the low-grade cohort and 32 (65%) in the high-grade cohort. Response rate was 47% in the low-grade cohort versus 9.4% in the high-grade cohort (logistic regression p = 0.006). Median progression-free survival (PFS) was 13.7 months in the low-grade cohort and 3.2 months in the high-grade cohort. Grading was confirmed as an independent predictor of PFS in the Cox proportional-hazards regression multivariable model (adjusted hazard ratio low-grade vs. high-grade: 0.45, 95% confidence interval: 0.22–0.94; adjusted p = 0.035). Conclusions: In this retrospective case series, sensitivity to trabectedin was higher in WDLPS/low-grade DDLPS than in high-grade DDLPS. If confirmed in larger series, grading could represent an effective tool to personalize the treatment with trabectedin in patients with advanced LPS. Full article
(This article belongs to the Special Issue New Directions for Treating Soft Tissue Sarcomas)
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15 pages, 3361 KiB  
Article
Trabectedin for Patients with Advanced Soft Tissue Sarcoma: A Non-Interventional, Retrospective, Multicenter Study of the Italian Sarcoma Group
by Emanuela Palmerini, Roberta Sanfilippo, Giovanni Grignani, Angela Buonadonna, Antonella Romanini, Giuseppe Badalamenti, Virginia Ferraresi, Bruno Vincenzi, Alessandro Comandone, Antonio Pizzolorusso, Antonella Brunello, Fabio Gelsomino, Tommaso De Pas, Toni Ibrahim, Federica Grosso, Francesca Zanelli, Maria Abbondanza Pantaleo, Laura Milesi, Libero Ciuffreda, Vittorio Ferrari, Emanuela Marchesi, Irene Quattrini, Alberto Righi, Elisabetta Setola, Elisa Carretta, Piero Picci and Stefano Ferrariadd Show full author list remove Hide full author list
Cancers 2021, 13(5), 1053; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13051053 - 02 Mar 2021
Cited by 15 | Viewed by 3365
Abstract
The Italian Sarcoma Group performed this retrospective analysis of patients with advanced soft tissue sarcoma, pretreated with ≥1 anthracycline-based treatment, and treated with trabectedin every three weeks. Primary endpoint was to describe real-life use of trabectedin across Italy. Secondary endpoints included objective response [...] Read more.
The Italian Sarcoma Group performed this retrospective analysis of patients with advanced soft tissue sarcoma, pretreated with ≥1 anthracycline-based treatment, and treated with trabectedin every three weeks. Primary endpoint was to describe real-life use of trabectedin across Italy. Secondary endpoints included objective response rate (ORR) and safety. Overall, 512 patients from 20 Italian centers were evaluated. Leiomyosarcoma (37.7%)/liposarcoma (30.3%) were the most prevalent histological types (abbreviated as L-sarcoma). Patients received a median of four trabectedin cycles (range: 1–40), mostly as a second-line treatment (~60% of patients). The ORR was 13.7% superior (p < 0.0001) in patients with L-sarcoma compared with patients with non-L-sarcoma (16.6% vs. 9.0%). Median progression-free survival (PFS) was 5.1 months, whereas median overall survival (OS) was 21.6 months. Significantly better PFS and OS were observed in patients with L-sarcoma, those with objective responses and/or disease stabilization, treated in an early line and treated with reduced dose. Bone marrow toxicity (61.4%) and transaminase increases (21.9%) were the most common grade 3/4 adverse events. The results of this real-life study suggest that trabectedin is an active treatment, which is mostly given as a second-line treatment to patients with a good performance status and high-grade, metastatic L-sarcoma (clinical trial information: NCT02793050). Full article
(This article belongs to the Special Issue New Directions for Treating Soft Tissue Sarcomas)
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19 pages, 3077 KiB  
Article
The Health-Related Quality of Life of Sarcoma Patients and Survivors in Germany—Cross-Sectional Results of a Nationwide Observational Study (PROSa)
by Martin Eichler, Leopold Hentschel, Stephan Richter, Peter Hohenberger, Bernd Kasper, Dimosthenis Andreou, Daniel Pink, Jens Jakob, Susanne Singer, Robert Grützmann, Stephen Fung, Eva Wardelmann, Karin Arndt, Vitali Heidt, Christine Hofbauer, Marius Fried, Verena I. Gaidzik, Karl Verpoort, Marit Ahrens, Jürgen Weitz, Klaus-Dieter Schaser, Martin Bornhäuser, Jochen Schmitt, Markus K. Schuler and the PROSa Study Groupadd Show full author list remove Hide full author list
Cancers 2020, 12(12), 3590; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123590 - 30 Nov 2020
Cited by 33 | Viewed by 3462
Abstract
Sarcomas are rare cancers with high heterogeneity in terms of type, location, and treatment. The health-related quality of life (HRQoL) of sarcoma patients has rarely been investigated and is the subject of this analysis. Adult sarcoma patients and survivors were assessed between September [...] Read more.
Sarcomas are rare cancers with high heterogeneity in terms of type, location, and treatment. The health-related quality of life (HRQoL) of sarcoma patients has rarely been investigated and is the subject of this analysis. Adult sarcoma patients and survivors were assessed between September 2017 and February 2019 in 39 study centers in Germany using standardized, validated questionnaires (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)). Associated factors were analyzed exploratively using multivariable linear regressions. Among 1113 patients, clinically important limitations and symptoms were most pronounced in emotional (63%, 95% CI 60–66%), physical (60%, 95% CI 57–62%), role functioning (51%, 95% CI 48–54%), and pain (56%, 95% CI 53–59%) and fatigue (51%, 95% CI 48–54%). HRQoL differed between tumor locations with lower extremities performing the worst and sarcoma types with bone sarcoma types being most affected. Additionally, female gender, higher age, lower socioeconomic status, recurrent disease, not being in retirement, comorbidities, and being in treatment were associated with lower HRQoL. Sarcoma patients are severely restricted in their HRQoL, especially in functioning scales. The heterogeneity of sarcomas with regard to type and location is reflected in HRQoL outcomes. During treatment and follow-up, close attention has to be paid to the reintegration of the patients into daily life as well as to their physical abilities and emotional distress. Full article
(This article belongs to the Special Issue New Directions for Treating Soft Tissue Sarcomas)
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Review

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13 pages, 1159 KiB  
Review
Status of the Current Treatment Options and Potential Future Targets in Uterine Leiomyosarcoma: A Review
by Hiroshi Asano, Toshiyuki Isoe, Yoichi M. Ito, Naoki Nishimoto, Yudai Watanabe, Saki Yokoshiki and Hidemichi Watari
Cancers 2022, 14(5), 1180; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14051180 - 24 Feb 2022
Cited by 9 | Viewed by 5452
Abstract
Uterine leiomyosarcoma (uLMS) is the most common subtype of mesenchymal tumors in the uterus. This review aims to summarize the current standard therapies and the molecular properties of uLMS for novel molecular-targeted therapies. Although 65% of uLMS cases are diagnosed in stage I, [...] Read more.
Uterine leiomyosarcoma (uLMS) is the most common subtype of mesenchymal tumors in the uterus. This review aims to summarize the current standard therapies and the molecular properties of uLMS for novel molecular-targeted therapies. Although 65% of uLMS cases are diagnosed in stage I, the 5-year overall survival rate is less than 60%. The only effective treatment for uLMS is complete and early resection, and chemotherapy is the main treatment for unresectable advanced or recurrent cases. No chemotherapy regimen has surpassed doxorubicin monotherapy as the first-line chemotherapy for unresectable advanced or recurrent cases in terms of overall survival in phase 3 trials. As a second-line treatment, pazopanib, trabectedin, and eribulin are used, but their therapeutic effects are not sufficient, highlighting the urgent need for development of novel treatments. Recent developments in gene analysis have revealed that homologous recombination deficiency (HRD), including breast cancer susceptibility gene 2 (BRCA2) mutations, are frequently observed in uLMS. In preclinical studies and several case series, poly(adenosine diphosphate-ribose)polymerase inhibitors showed antitumor effects on uLMS cell lines with BRCA2 mutations or HRD and in recurrent or persistent cases of uLMS with BRCA2 mutations. Thus, HRD, including BRCA mutations, may be the most promising therapeutic target for uLMS. Full article
(This article belongs to the Special Issue New Directions for Treating Soft Tissue Sarcomas)
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19 pages, 780 KiB  
Review
Unmet Medical Needs and Future Perspectives for Leiomyosarcoma Patients—A Position Paper from the National LeioMyoSarcoma Foundation (NLMSF) and Sarcoma Patients EuroNet (SPAEN)
by Bernd Kasper, Annie Achee, Kathrin Schuster, Roger Wilson, Gerard van Oortmerssen, Rebecca A. Gladdy, Matthew L. Hemming, Paul Huang, Matthew Ingham, Robin L. Jones, Seth M. Pollack, Denise Reinke, Roberta Sanfilippo, Scott M. Schuetze, Neeta Somaiah, Brian A. Van Tine, Breelyn Wilky, Scott Okuno and Jonathan Trent
Cancers 2021, 13(4), 886; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040886 - 20 Feb 2021
Cited by 16 | Viewed by 6834
Abstract
As leiomyosarcoma patients are challenged by the development of metastatic disease, effective systemic therapies are the cornerstone of outcome. However, the overall activity of the currently available conventional systemic treatments and the prognosis of patients with advanced or metastatic disease are still poor, [...] Read more.
As leiomyosarcoma patients are challenged by the development of metastatic disease, effective systemic therapies are the cornerstone of outcome. However, the overall activity of the currently available conventional systemic treatments and the prognosis of patients with advanced or metastatic disease are still poor, making the treatment of this patient group challenging. Therefore, in a joint effort together with patient networks and organizations, namely Sarcoma Patients EuroNet (SPAEN), the international network of sarcoma patients organizations, and the National LeioMyoSarcoma Foundation (NLMSF) in the United States, we aim to summarize state-of-the-art treatments for leiomyosarcoma patients in order to identify knowledge gaps and current unmet needs, thereby guiding the community to design innovative clinical trials and basic research and close these research gaps. This position paper arose from a leiomyosarcoma research meeting in October 2020 hosted by the NLMSF and SPAEN. Full article
(This article belongs to the Special Issue New Directions for Treating Soft Tissue Sarcomas)
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10 pages, 409 KiB  
Perspective
Global Patient Involvement in Sarcoma Care—A Collaborative Initiative of the Connective Tissue Oncology Society (CTOS) & Sarcoma Patients EuroNet (SPAEN)
by Bernd Kasper, Kathrin Schuster, Roger Wilson, Sorrel Bickley, Jean-Yves Blay, Denise Reinke, Markus Wartenberg and Rick Haas
Cancers 2022, 14(4), 854; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14040854 - 09 Feb 2022
Cited by 2 | Viewed by 2669
Abstract
Sarcomas are a grouping of rare cancers with a wide variety of histological types that are difficult to diagnose and treat. This leads to many varying challenges not only for sarcoma patients, but also for doctors, researchers, and caregivers. Patient advocacy groups have [...] Read more.
Sarcomas are a grouping of rare cancers with a wide variety of histological types that are difficult to diagnose and treat. This leads to many varying challenges not only for sarcoma patients, but also for doctors, researchers, and caregivers. Patient advocacy groups have an important role to play in rare cancers such as sarcomas, especially in collaboration with experts and their medical societies. To this end, patients and patient advocates from Sarcoma Patients EuroNet (SPAEN), a global network of national Sarcoma Patient Advocacy Groups, and medical experts from the scientifically driven Connective Tissue Oncology Society (CTOS) came together on 9 November 2021 at an official ancillary event to the CTOS 2021 Annual Meeting. At the event, representatives of CTOS and SPAEN jointly discussed gaps and challenges in global sarcoma care and management. This resulting position paper highlights the main findings and possible future steps. Full article
(This article belongs to the Special Issue New Directions for Treating Soft Tissue Sarcomas)
11 pages, 250 KiB  
Study Protocol
The Evaluation of Health-Related Quality of Life Issues Experienced by Patients with Desmoid-Type Fibromatosis (The QUALIFIED Study)—A Protocol for an International Cohort Study
by Anne-Rose W. Schut, Milea J. M. Timbergen, Emma Lidington, Dirk J. Grünhagen, Winette T. A. van der Graaf, Stefan Sleijfer, Winan J. van Houdt, Johannes J. Bonenkamp, Eugenie Younger, Alison Dunlop, Robin L. Jones, Cornelis Verhoef, Spyridon Gennatas and Olga Husson
Cancers 2021, 13(13), 3068; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13133068 - 22 Jun 2021
Cited by 9 | Viewed by 2006
Abstract
Sporadic desmoid-type fibromatosis (DTF) is a rare soft tissue tumour with an unpredictable clinical course. These tumours are incapable of metastasising, but their local aggressive tumour growth and tendency to recur locally can result in a substantial symptom burden. Measuring the impact of [...] Read more.
Sporadic desmoid-type fibromatosis (DTF) is a rare soft tissue tumour with an unpredictable clinical course. These tumours are incapable of metastasising, but their local aggressive tumour growth and tendency to recur locally can result in a substantial symptom burden. Measuring the impact of DTF on health-related quality of life (HRQoL) can be challenging due to the variable clinical presentation of the disease. Therefore, a HRQoL instrument assessing DTF-specific issues is needed. The QUALIFIED study aims to (1) pre-test a previously developed DTF-specific HRQoL tool (the DTF-QoL); (2) evaluate prevalence of HRQoL issues in adult DTF patients; and (3) identify subgroups at risk of impaired HRQoL. This study (NCT04289077) is an international, multicentre, cross-sectional, observational cohort study. Patients ≥ 18 years with sporadic DTF from the Netherlands and the United Kingdom will be invited to complete a set of questionnaires specifically composed for this patient group. Questionnaires will be completed using PROFILES (Patient Reported Outcomes Following Initial treatment and Long-term Evaluation of Survivorship). Analyses will include testing the psychometric properties of the DTF-QoL and evaluating the prevalence of HRQoL issues using the DTF-QoL, EORTC QOL-C30 and EQ-5D-5L, among other questionnaires. This study will provide insight into HRQoL issues experienced by patients with DTF. Awareness of these issues and the implementation of the DTF-QoL in research and clinical practice can help to improve overall HRQoL and to provide personalised care. Full article
(This article belongs to the Special Issue New Directions for Treating Soft Tissue Sarcomas)
11 pages, 927 KiB  
Commentary
Photodynamic Therapy Using Hippo Pathway Inhibitor Verteporfin: A Potential Dual Mechanistic Approach in Treatment of Soft Tissue Sarcomas
by Jeffrey D. Rytlewski, Nicholas Scalora, Keith Garcia, Munir Tanas, Fatima Toor, Benjamin Miller, Bryan Allen, Mohammed Milhem and Varun Monga
Cancers 2021, 13(4), 675; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040675 - 08 Feb 2021
Cited by 4 | Viewed by 4638
Abstract
Sarcoma is a widely varied and devastating oncological subtype, with overall five-year survival of 65% that drops to 16% with the presence of metastatic disease at diagnosis. Standard of care for localized sarcomas is predicated on local control with wide-local resection and radiation [...] Read more.
Sarcoma is a widely varied and devastating oncological subtype, with overall five-year survival of 65% that drops to 16% with the presence of metastatic disease at diagnosis. Standard of care for localized sarcomas is predicated on local control with wide-local resection and radiation therapy, or, less commonly, chemotherapy, depending on tumor subtype. Verteporfin has the potential to be incorporated into this standard of care due to its unique molecular properties: inhibition of the upregulated Hippo pathway that frequently drives soft tissue sarcoma and photodynamic therapy-mediated necrosis due to oxidative damage. The initial anti-proliferative effect of verteporfin is mediated via binding and dissociation of YAP/TEAD proteins from the nucleus, ultimately leading to decreased cell proliferation as demonstrated in multiple in vitro studies. This effect has the potential to be compounded with use of photodynamic therapy to directly induce cellular necrosis with use of a clinical laser. Photodynamic therapy has been incorporated into multiple malignancies and has the potential to be incorporated into sarcoma treatment. Full article
(This article belongs to the Special Issue New Directions for Treating Soft Tissue Sarcomas)
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14 pages, 280 KiB  
Study Protocol
Incorporating the Patient Voice in Sarcoma Research: How Can We Assess Health-Related Quality of Life in This Heterogeneous Group of Patients? A Study Protocol
by Dide den Hollander, Marco Fiore, Javier Martin-Broto, Bernd Kasper, Antonio Casado Herraez, Dagmara Kulis, Ioanna Nixon, Samantha C. Sodergren, Martin Eichler, Winan J. van Houdt, Ingrid M. E. Desar, Isabelle Ray-Coquard, Claire Piccinin, Hanna Kosela-Paterczyk, Aisha Miah, Leopold Hentschel, Susanne Singer, Roger Wilson, Winette T. A. van der Graaf and Olga Husson
Cancers 2021, 13(1), 1; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13010001 - 22 Dec 2020
Cited by 14 | Viewed by 3114
Abstract
Sarcomas comprise 1% of adult tumors and are very heterogeneous. Long-lasting and cumulative treatment side-effects detract from the (progression-free) survival benefit of treatment. Therefore, it is important to assess treatment effectiveness in terms of patient-reported outcomes (PROs), including health-related quality of life (HRQoL) [...] Read more.
Sarcomas comprise 1% of adult tumors and are very heterogeneous. Long-lasting and cumulative treatment side-effects detract from the (progression-free) survival benefit of treatment. Therefore, it is important to assess treatment effectiveness in terms of patient-reported outcomes (PROs), including health-related quality of life (HRQoL) as well. However, questionnaires capturing the unique issues of sarcoma patients are currently lacking. Given the heterogeneity of the disease, the development of such an instrument may be challenging. The study aims to (1) develop an exhaustive list of all HRQoL issues relevant to sarcoma patients and determine content validity; (2) determine a strategy for HRQoL measurement in sarcoma patients. We will conduct an international, multicenter, mixed-methods study (registered at clinicaltrials.gov: NCT04071704) among bone or soft tissue sarcoma patients ≥18 years, using EORTC Quality of Life Group questionnaire development guidelines. First, an exhaustive list of HRQoL issues will be generated, derived from literature and patient (n = 154) and healthcare professional (HCP) interviews (n = 30). Subsequently, another group of sarcoma patients (n = 475) and HCPs (n = 30) will be asked to rate and prioritize the issues. Responses will be analyzed by priority, prevalence and range of responses for each item. The outcome will be a framework for tailored HRQoL measurement in sarcoma patients, taking into account sociodemographic and clinical variables. Full article
(This article belongs to the Special Issue New Directions for Treating Soft Tissue Sarcomas)
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