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Surgical Resection and the Multi-Disciplinary Management of Soft Tissue Sarcomas

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

Deadline for manuscript submissions: closed (12 January 2023) | Viewed by 34055

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Special Issue Editors

Prof. Robert J. Canter

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Guest Editor

Department of Surgery, Division of Surgical Oncology, University of California Davis Medical Center, Sacramento, CA 95817, USA
Interests: soft tissue sarcoma; immunotherapy; natural killer cells; comparative oncology; canine immunotherapy; canine natural killer cells

Dr. Steven W. Thorpe

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Guest Editor

Department of Orthopedic Surgery, University of California, Davis, CA 95817, USA
Interests: orthopedic oncology; limb salvage surgery; pelvic resection and reconstructive surgery; sarcoma biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are pleased to lead this special effort addressing the surgical and multi-disciplinary management of soft tissue sarcomas. Soft tissue sarcomas comprise a heterogenous group of malignancies of mesenchymal origin. Optimizing the outcomes for this diverse family of tumors with a wide spectrum of biologic aggressiveness requires a multi-disciplinary approach. While the cornerstone of the treatment of localized soft tissue sarcoma has been wide-margin surgical resection, it is the addition of adjuvant radiotherapy that has led to limb salvage rates approaching 90–95% for extremity-based soft tissue sarcomas. The role of systemic chemotherapy in the management of localized disease has been much less clear, with the potential for seemingly modest improvements in survival when maximal dosing with traditional doxorubicin and ifosfamide regimens is administered. Investigators have pursued histology-tailored approaches to the multimodal care of locally advanced soft tissue sarcomas, including the selection of chemotherapeutic regimens, without definitive results.

For patients with metastatic disease, the prognosis remains dismal, and novel combined-modality approaches and systemic therapies are needed. It is in the settings of both metastatic disease and a high risk of metastatic disease where significant progress in new therapeutic agents is most needed. Although the data for pazopanib from the PALETTE trial were promising and, subsequently, there was much excitement for olaratumab—a human antiplatelet-derived growth factor receptor a monoclonal antibody—the enthusiasm for these agents has waned, in part because the follow-up results, especially for olaratumab, did not validate the initial enthusiasm.

Current therapeutic trials are focused on evaluating immunotherapeutic options, given the results for melanoma, lung carcinoma, and other solid tumors. Unfortunately, the results with immunotherapy for soft tissue sarcomas have been relatively incremental when using single-agent checkpoint inhibitors with PD-1-, PD-L1-, or CTLA-4-targeting agents. Newer strategies are evaluating combination-based strategies with PD-1/PD-L1 blockade and tyrosine kinase inhibitors, cytotoxic chemotherapy, and radiotherapy.

With regards to efforts to improve radiotherapy and decrease long-term complications, current trials are evaluating hypofractionated treatment regimens. Additionally, there is a prospective regimen evaluating the efficacy of IMRT in decreasing the wound complications associated with preoperative radiotherapy.

Finally, improvements in the surgical treatment of soft tissue sarcomas have been focused on mitigating wound healing complications, especially associated with preoperative radiotherapy. Technologies including the use of negative pressure wound vac therapy and the use of intraoperative SPY angiography are under current investigation. Additionally, efforts to improve surgical accuracy with regard to intraoperative margins and the adequacy of resection are underway with intraoperative near-infrared imaging with the use of indocyamine green (ICG).

Exciting developments are under investigation for soft tissue sarcomas, and the intersection of cutting-edge medical, surgical, and radiation therapy with advances in sarcoma biology, the tumor microenvironment, and immunotherapy promises to pave the way for further advances in soft tissue sarcoma outcomes.

Prof. Robert J. Canter
Dr. Steven W. Thorpe
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

soft tissue sarcoma
limb-salvage surgery
radiation therapy
immunotherapy
targeted therapy
tyrosine kinase inhibitors
chemotherapy

Published Papers (11 papers)

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Research

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11 pages, 1686 KiB

Open AccessArticle

Feasibility of Longitudinal ctDNA Assessment in Patients with Uterine and Extra-Uterine Leiomyosarcoma

by Maggie Zhou, Nam Bui, Richa Rathore, Sumedha Sudhaman, Giby V. George, Allyson K. Malashevich, Meenakshi Malhotra, Minetta C. Liu, Alexey Aleshin and Kristen N. Ganjoo

Cancers 2023, 15(1), 157; https://doi.org/10.3390/cancers15010157 - 27 Dec 2022

Cited by 2 | Viewed by 1792

Abstract

Background: Leiomyosarcomas (LMS) are aggressive malignancies with a propensity for early relapse. Current surveillance modalities include physical exam and imaging; however, radiological response to therapy may only manifest after 4–6 cycles of treatment. Herein, we evaluated the feasibility of longitudinal circulating tumor DNA (ctDNA) assessment in LMS patients to identify disease progression. Methods: We performed a retrospective review of patients with LMS who underwent treatment at Stanford Cancer Center between September 2019 and May 2022. ctDNA detection was performed using a personalized, tumor-informed ctDNA assay. Genomic analysis was conducted to characterize tumor mutation burden (TMB) and known driver mutations. Results: A total of 148 plasma samples were obtained from 34 patients with uterine (N = 21) and extrauterine (N = 13) LMS (median follow-up: 67.2 (19–346.3) weeks] and analyzed for ctDNA presence. Nineteen patients had metastatic disease. The most frequently mutated driver genes across sub-cohorts were TP53, RB1, and PTEN. Patients were stratified into four sub-cohorts (A-D) based on ctDNA kinetics. ctDNA levels tracked longitudinally with progression of disease and response to therapy. Conclusion: Our results indicate that while undetectable ctDNA may suggest a lower likelihood of relapse, ctDNA positivity may indicate progressive disease, enabling closer monitoring of patients for early clinical intervention. Full article

(This article belongs to the Special Issue Surgical Resection and the Multi-Disciplinary Management of Soft Tissue Sarcomas)

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23 pages, 1857 KiB

Open AccessArticle

Management of Patients with Newly Diagnosed Desmoid Tumors in a First-Line Setting

by Stefano Testa, Nam Q. Bui, Gregory W. Charville, Raffi S. Avedian, Robert Steffner, Pejman Ghanouni, David G. Mohler and Kristen N. Ganjoo

Cancers 2022, 14(16), 3907; https://doi.org/10.3390/cancers14163907 - 12 Aug 2022

Cited by 8 | Viewed by 2169

Abstract

The initial management of desmoid tumors (DTs) is shifting from surgery towards active surveillance, with systemic and locally ablative treatments reserved for enlarging and/or symptomatic disease. However, it remains unclear which patients would benefit most from an initial conservative rather than interventional approach. To answer this question, we retrospectively analyzed adult and pediatric patients with DTs treated at a tertiary academic cancer center between 1992 and 2022. Outcomes measured were progression-free survival (PFS) and time to next treatment (TTNT) after first-line therapy. A total of 262 treatment-naïve patients were eligible for analysis with a median age of 36.5 years (range, 0–87 years). The 5-year PFS and the median TTNT (months) after first-line treatment were, respectively: 50.6% and 69.1 mo for surgery; 64.9% and 149.5 mo for surgery plus adjuvant radiotherapy; 57.1% and 44.7 mo for surgery plus adjuvant systemic therapy; 24.9% and 4.4 mo for chemotherapy; 26.7% and 5.3 mo for hormonal therapy; 41.3% and 29.6 mo for tyrosine kinase inhibitors (TKIs); 44.4% and 8.9 mo for cryoablation and high intensity focused ultrasound; and 43.1% and 32.7 mo for active surveillance. Age

\leq

40 years (p < 0.001), DTs involving the extremities (p < 0.001), a maximum tumor diameter

>

60 mm (p = 0.04), and hormonal therapy (p = 0.03) predicted a higher risk of progression. Overall, our results suggest that active surveillance should be considered initially for patients with smaller asymptomatic DTs, while upfront TKIs, local ablation, and surgery achieve similar outcomes in those with more aggressive disease. Full article

(This article belongs to the Special Issue Surgical Resection and the Multi-Disciplinary Management of Soft Tissue Sarcomas)

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10 pages, 1424 KiB

Open AccessArticle

Definition of the Surgical Case Complexity in the Treatment of Soft Tissue Tumors of the Extremities and Trunk

by Annika Frei, Mario F. Scaglioni, Pietro Giovanoli, Stefan Breitenstein, Philip Heesen, Bruno Fuchs and on behalf of the Swiss Sarcoma Network

Cancers 2022, 14(6), 1559; https://doi.org/10.3390/cancers14061559 - 18 Mar 2022

Cited by 7 | Viewed by 1826

Abstract

Background: We intend to establish a complexity score for soft tissue tumor surgeries to compare the complexities of different soft tissue tumor surgeries and to ultimately assign affected patients to appropriate treatments. Methods: We developed a soft tissue tumor complexity score (STS-SCS) based on three pillars: in addition to patient-related factors, tumor biology and surgery-associated parameters were taken into account. The STS-SCS was applied to our sampling group of 711 patients. Results: The minimum STS-SCS was 4, the maximum score was 34 and the average score 11.4 ± 5.9. The scores of patients with malignant diagnoses were notably higher and more widely scattered than those of patients with benign or intermediate malignant tumors. To better categorize the complexities of individual surgeries, we established four categories using the collected data as a reference dataset. Each of the categories contained approximately one-quarter of the registered patients. Discussion: The STS-SCS allows soft tissue tumor surgeries to be retrospectively evaluated for their complexity and forms the basis for the creation of a prospective concept to provide patients with the right intervention in the right geographic location, which can lead to better results and provision of the most cost-effective overall treatment. Full article

(This article belongs to the Special Issue Surgical Resection and the Multi-Disciplinary Management of Soft Tissue Sarcomas)

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12 pages, 4407 KiB

Open AccessArticle

Amputation for Extremity Sarcoma: Indications and Outcomes

by Maya Kirilova, Alexander Klein, Lars H. Lindner, Silke Nachbichler, Thomas Knösel, Christof Birkenmaier, Andrea Baur-Melnyk and Hans Roland Dürr

Cancers 2021, 13(20), 5125; https://doi.org/10.3390/cancers13205125 - 13 Oct 2021

Cited by 10 | Viewed by 2768

Abstract

Background: Sarcomas are rare, malignant tumors of soft tissues or bone. Limb salvage surgery (LSS) is the standard treatment, but amputation is still an option, especially in local recurrence or complications after LSS. Methods: We retrospectively reviewed indications and oncological outcomes in patients who underwent an amputation. Two groups with either primary amputations (n = 120) or with secondary amputations after failed LSS with local recurrence or complications (n = 29) were compared with the main end points of LRFS and OS. Results: Five-year LRFS was 84% with 17 (16%) patients developing local recurrence, of which 16 (13%) occurred in group I. Forty-two (28%) patients developed metastatic disease and overall survival at five years was 44%. Overall survival (OS) was the same in both groups. In those group II patients who had a secondary amputation due to LR or insufficient margins after LSS (n = 12) the five-year OS was 33% compared to 48% in patients with amputation due to complications (n = 17) (n.s.). Conclusions: This study indicates the worse oncological outcomes with respect to OS of sarcoma patients requiring an amputation as compared to LSS. Patients with primary amputation or those who had a secondary amputation after failed LSS for whatever reason showed the same oncological results. Full article

(This article belongs to the Special Issue Surgical Resection and the Multi-Disciplinary Management of Soft Tissue Sarcomas)

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10 pages, 779 KiB

Open AccessArticle

Clinical Outcomes for Primary and Radiation-Associated Angiosarcoma of the Breast with Multimodal Treatment: Long-Term Survival Is Achievable

by Joshua P. Kronenfeld, Jessica S. Crystal, Emily L. Ryon, Sina Yadegarynia, Celeste Chitters, Raphael Yechieli, Gina D’Amato, Andrew E. Rosenberg, Susan B. Kesmodel, Jonathan C. Trent and Neha Goel

Cancers 2021, 13(15), 3814; https://doi.org/10.3390/cancers13153814 - 29 Jul 2021

Cited by 7 | Viewed by 2667

Abstract

Background: The optimal management of primary angiosarcoma (PAS) and radiation-associated angiosarcoma (RAAS) of the breast remains undefined. Available data show persistently poor survival outcomes following treatment with surgery or chemotherapy alone. The objective of this study was to evaluate long-term outcomes in patients treated with multimodality therapy. Methods: Patients diagnosed with stage I–III PAS or RAAS of the breast were identified from our local tumor registry (2010–2020). Patient demographics, tumor characteristics, and treatment were collected. Primary outcomes were local recurrence (LR), distant recurrence (DR), and median overall survival (OS). A secondary outcome was pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC). Mann–Whitney U, chi-squared, or Fisher exact tests were used to analyze data. Kaplan–Meier curves compared OS for PAS and RAAS. Results: Twenty-two patients met inclusion criteria, including 11 (50%) with RAAS and 11 (50%) with PAS. Compared to PAS patients, RAAS patients were older and had more comorbidities. For RAAS patients, median time from radiation to diagnosis was 6 years (IQR: 5–11). RAAS patients were more likely to have a pCR to NAC (40% vs. 20%, p = 0.72). RAAS patients had a higher LR rate (43% vs. 38%, p = 0.83), and PAS patients were more likely to develop a DR (38% vs. 0%, p = 0.07). Median OS was 81 months in PAS patients and 90 months in RAAS patients (p = 1.00). Discussion: Long-term survival can be achieved in patients with PAS and RAAS who undergo multimodality treatment. NAC can result in pCR. The long-term clinical implications of pCR warrant further investigation. Full article

(This article belongs to the Special Issue Surgical Resection and the Multi-Disciplinary Management of Soft Tissue Sarcomas)

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16 pages, 3165 KiB

Open AccessArticle

Unmasking BCL-2 Addiction in Synovial Sarcoma by Overcoming Low NOXA

by Carter K. Fairchild, Jr., Konstantinos V. Floros, Sheeba Jacob, Colin M. Coon, Madhavi Puchalapalli, Bin Hu, Hisashi Harada, Mikhail G. Dozmorov, Jennifer E. Koblinski, Steven C. Smith, Gregory Domson, Joel D. Leverson, Andrew J. Souers, Naoko Takebe, Hiromichi Ebi, Anthony C. Faber and Sosipatros A. Boikos

Cancers 2021, 13(10), 2310; https://doi.org/10.3390/cancers13102310 - 12 May 2021

Cited by 6 | Viewed by 2851

Abstract

Synovial sarcoma (SS) is frequently diagnosed in teenagers and young adults and continues to be treated with polychemotherapy with variable success. The SS18-SSX gene fusion is pathognomonic for the disease, and high expression of the anti-apoptotic BCL-2 pathologically supports the diagnosis. As the oncogenic SS18-SSX fusion gene itself is not druggable, BCL-2 inhibitor-based therapies are an appealing therapeutic opportunity. Venetoclax, an FDA-approved BCL-2 inhibitor that is revolutionizing care in some BCL-2-expressing hematological cancers, affords an intriguing therapeutic possibility to treat SS. In addition, there are now dozens of venetoclax-based combination therapies in clinical trials in hematological cancers, attributing to the limited toxicity of venetoclax. However, preclinical studies of venetoclax in SS have demonstrated an unexpected ineffectiveness. In this study, we analyzed the response of SS to venetoclax and the underlying BCL-2 family biology in an effort to understand venetoclax treatment failure and find a therapeutic strategy to sensitize SS to venetoclax. We found remarkably depressed levels of the endogenous MCL-1 inhibitor, NOXA, in SS compared to other sarcomas. Expressing NOXA led to sensitization to venetoclax, as did the addition of the MCL-1 BH3 mimetic, S63845. Importantly, the venetoclax/S63845 combination induced tumor regressions in SS patient-derived xenograft (PDX) models. As a very close analog of S63845 (S64315) is now in clinical trials with venetoclax in AML (NCT03672695), the combination of MCL-1 BH3 mimetics and venetoclax should be considered for SS patients as a new therapy. Full article

(This article belongs to the Special Issue Surgical Resection and the Multi-Disciplinary Management of Soft Tissue Sarcomas)

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Review

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16 pages, 2121 KiB

Open AccessReview

Surgical Principles of Primary Retroperitoneal Sarcoma in the Era of Personalized Treatment: A Review of the Frontline Extended Surgery

by Paula Munoz, Pedro Bretcha-Boix, Vicente Artigas and José Manuel Asencio

Cancers 2022, 14(17), 4091; https://doi.org/10.3390/cancers14174091 - 24 Aug 2022

Cited by 11 | Viewed by 4030

Abstract

Surgery is the key treatment in retroperitoneal sarcoma (RPS), as completeness of resection is the most important prognostic factor related to treatment. Compartmental surgery/frontline extended approach is based on soft-tissue sarcoma surgical principles, and involves resecting adjacent viscera to achieve a wide negative margin. This extended approach is associated with improved local control and survival. This surgery must be tailored to tumor histology, tumor localization, and patient performance status. We herein present a review of compartmental surgery principles, covering the oncological and technical basis, and describing the tailored approach to each tumor subtype and localization in the retroperitoneum. Full article

(This article belongs to the Special Issue Surgical Resection and the Multi-Disciplinary Management of Soft Tissue Sarcomas)

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18 pages, 840 KiB

Open AccessReview

Neoadjuvant Therapy for Primary Resectable Retroperitoneal Sarcomas—Looking Forward

by Alexandra C. Istl and Alessandro Gronchi

Cancers 2022, 14(7), 1831; https://doi.org/10.3390/cancers14071831 - 5 Apr 2022

Cited by 9 | Viewed by 3204

Abstract

The cornerstone of therapy for primary retroperitoneal sarcomas (RPS) is complete surgical resection, best achieved by resecting the tumor en bloc with adherent structures even if not overtly infiltrated. Until recently, trials designed to elucidate the role of neoadjuvant radiation or chemotherapy for RPS have been unable to achieve sufficient enrollment. The completion of the STRASS trial, which explored neoadjuvant radiotherapy for primary resectable RPS, is a major milestone in RPS research, but has prompted further questions about histology-driven treatment paradigms for RPS. Though it was ultimately a negative trial with respect to its primary endpoint of abdominal recurrence-free survival, STRASS produced a signal that suggested improved abdominal recurrence-free survival with neoadjuvant radiotherapy (RT) for patients with liposarcoma (LPS). No effect was seen for leiomyosarcoma (LMS) or high-grade dedifferentiated (DD) LPS, consistent with recent literature suggesting LMS and high-grade DD-LPS have a predominant pattern of distant rather than local failure. These results, along with those from other recent studies conducted at the bench and the bedside, emphasize the importance of a histology-specific approach to RPS research. Recent evidence for patterns of distant failure in LMS and high-grade DD-LPS has prompted the initiation of STRASS2, a study of neoadjuvant chemotherapy for these histologies. As this study unfolds, evidence may emerge for novel systemic therapy options in specific sarcoma histotypes given the explosion in targeted and immunotherapeutic applications over the last decade. This article reviews current and recent evidence around neoadjuvant radiation and chemotherapy as well as avenues for future study to optimize these treatment approaches. Full article

(This article belongs to the Special Issue Surgical Resection and the Multi-Disciplinary Management of Soft Tissue Sarcomas)

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17 pages, 1050 KiB

Open AccessReview

Retroperitoneal Sarcoma Care in 2021

by Erika Schmitz and Carolyn Nessim

Cancers 2022, 14(5), 1293; https://doi.org/10.3390/cancers14051293 - 2 Mar 2022

Cited by 18 | Viewed by 6805

Abstract

Soft-tissue sarcomas are biologically heterogenous tumors arising from connective tissues with over 100 subtypes. Although sarcomas account for <1% of all adult malignancies, retroperitoneal sarcomas are a distinct subgroup accounting for <10% of all sarcomatous tumors. There have been considerable advancements in the understanding and treatment of retroperitoneal sarcoma in the last decade, with standard treatment consisting of upfront primary surgical resection. The evidence surrounding the addition of radiation therapy remains controversial. There remains no standard with regards to systemic therapy, including immunotherapy. Adjunctive therapy remains largely dictated by expert consensus and preferences at individual centers or participation in clinical trials. In this 2021 review, we detail the anatomical boundaries of the retroperitoneum, clinical characteristics, contemporary standard of care and well as recent advancements in retroperitoneal sarcoma care. Ongoing international collaborations are encouraged to advance our understanding of this complex disease. Full article

(This article belongs to the Special Issue Surgical Resection and the Multi-Disciplinary Management of Soft Tissue Sarcomas)

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15 pages, 331 KiB

Open AccessReview

Multidisciplinary Management of Retroperitoneal Sarcoma: Diagnosis, Prognostic Factors and Treatment

by Fabio Carbone, Antonio Pizzolorusso, Giuseppe Di Lorenzo, Massimiliano Di Marzo, Lucia Cannella, Maria Luisa Barretta, Paolo Delrio and Salvatore Tafuto

Cancers 2021, 13(16), 4016; https://doi.org/10.3390/cancers13164016 - 10 Aug 2021

Cited by 14 | Viewed by 3263

Abstract

Retroperitoneal sarcomas (RPS) are rare cancers whose management can be challenging due to various presentation patterns, multiple organ involvement, and a high local and distant recurrence rate. Histopathology and prognostic factors analysis are essential to predict the behaviour of the disease and plan the best therapeutic strategy. To date, surgery is still the main therapeutic option that guarantees a chance of cure from the primary disease. While chemotherapy and radiotherapy seem to be good options for controlling metastatic and recurrent irresectable disease, their role in the treatment of primary RPS remains unclear. This literature review aims to provide a comprehensive overview of the multidisciplinary aspects of RPS management in high-volume centres, summarising the diagnostic path, the prognostic factors, and the most suitable therapeutic options. Full article

(This article belongs to the Special Issue Surgical Resection and the Multi-Disciplinary Management of Soft Tissue Sarcomas)