UK guidelines for the management of soft tissue sarcomas.

Soft tissue sarcomas (STS) are rare tumours arising in mesenchymal tissues and can occur almost anywhere in the body. Their rarity, and the heterogeneity of subtype and location, means that developing evidence-based guidelines is complicated by the limitations of the data available. This makes it more important that STS are managed by expert multidisciplinary teams, to ensure consistent and optimal treatment, recruitment to clinical trials, and the ongoing accumulation of further data and knowledge. The development of appropriate guidance, by an experienced panel referring to the evidence available, is therefore a useful foundation on which to build progress in the field. These guidelines are an update of the previous versions published in 2010 and 2016 [1, 2]. The original guidelines were drawn up by a panel of UK sarcoma specialists convened under the auspices of the British Sarcoma Group (BSG) and were intended to provide a framework for the multidisciplinary care of patients with soft tissue sarcomas. This iteration of the guidance, as well as updating the general multidisciplinary management of soft tissue sarcoma, includes specific sections relating to the management of sarcomas at defined anatomical sites: gynaecological sarcomas, retroperitoneal sarcomas, breast sarcomas, and skin sarcomas. These are generally managed collaboratively by site specific multidisciplinary teams linked to the regional sarcoma specialist team, as stipulated in the recently published sarcoma service specification [3]. In the UK, any patient with a suspected soft tissue sarcoma should be referred to a specialist regional soft tissues sarcoma service, to be managed by a specialist sarcoma multidisciplinary team. Once the diagnosis has been confirmed using appropriate imaging and a tissue biopsy, the main modality of management is usually surgical excision performed by a specialist surgeon, combined with pre- or post-operative radiotherapy for tumours at higher risk for local recurrence. Systemic anti-cancer therapy (SACT) may be utilised in cases where the histological subtype is considered more sensitive to systemic treatment. Regular follow-up is recommended to assess local control, development of metastatic disease, and any late effects of treatment.

Low local recurrence rates following marginal surgical resection of non-coelomic Atypical Lipomatous Tumours/Well-differentiated Liposarcomas.

INTRODUCTION: High rates of local recurrence (LR) have been reported following resection of extremity Atypical lipomatous tumours/Well-differentiated liposarcomas (ALTs). This retrospective study of patients who underwent resection of primary deep extremity and trunk ALTs at a specialist sarcoma centre aims to assess morbidity and factors associated with low local recurrence rates (LRR). METHODS: To review a homogeneous cohort of patients with low-grade disease, tumours with known high-risk histological features were excluded. Prognostic variables potentially influencing local recurrence (LR) (age, size, site, margin status, and histological findings) were analysed. Endpoints were LR, distant recurrence (DR) and local disease-free survival (LDFS). RESULTS: 127 patients were identified, with median follow-up of 54 months (0-235). Median tumour size was 17.5 cm (5-36). 85 % occurred in the lower limb. 93.7 % underwent marginal resection. No patients received radiotherapy. Median hospital stay was 3 days (0-16). 7.9 % returned to theatre for evacuation of haematoma or infected seroma and 18.1 % had outpatient seroma aspiration. Surgical margins were R0/R1 in 93.7 % of patients and R2 in 6.3 % with a LR rate of 8.4 % and 75 % respectively at median time of 54 months. One- and 5-year LDFS was 100 % and 88.4 %, respectively. DR rate was 0.8 % (1/127) this patient had pleomorphic liposarcomatous transformation on recurrence and subsequently developed distant metastases. No patients died of disease. CONCLUSION: Function-preserving marginal resection of non-coelomic ALTs has low morbidity, low LR and extremely low rates of distant relapse. Patients with lower limb ALT were found to have significantly lower LR, which may impact follow-up protocols.

New Sarculator Prognostic Nomograms for Patients With Primary Retroperitoneal Sarcoma: Case Volume Does Matter.

OBJECTIVE: To update the current Sarculator retroperitoneal sarcoma (RPS) prognostic nomograms considering the improvement in patient prognosis and the case volume effect. BACKGROUND: Survival of patients with primary RPS has been increasing over time, and the volume-outcome relationship has been well recognized. Nevertheless, the specific impact on prognostic nomograms is unknown. METHODS: All consecutive adult patients with primary localized RPS treated at 8 European and North American sarcoma reference centers between 2010 and 2017 were included. Patients were divided into 2 groups: high-volume centers (HVC, ≥13 cases/year) and low-volume centers (LVC, <13 cases/year). Primary end points were overall survival (OS) and disease-free survival (DFS). Multivariable analyses for OS and DFS were performed. The nomograms were updated by recalibration. Nomograms performance was assessed in terms of discrimination (Harrell C index) and calibration (calibration plot). RESULTS: The HVC and LVC groups comprised 857 and 244 patients, respectively. The median annual primary RPS case volume (interquartile range) was 24.0 in HVC (15.0-41.3) and 9.0 in LVC (1.8-10.3). Five-year OS was 71.4% (95% CI: 68.3%-74.7%) in the HVC cohort and 63.3% (56.8%-70.5%) in the LVC cohort ( P =0.012). Case volume was associated with both OS (LVC vs. HVC hazard ratio 1.40, 95% CI: 1.08-1.82, P =0.011) and DFS (hazard ratio 1.93, 95% CI: 1.57-2.37, P <0.001) at multivariable analyses. When applied to the study cohorts, the Sarculator nomograms showed good discrimination (Harrell C index between 0.68 and 0.73). The recalibrated nomograms showed good calibration in the HVC group, whereas the original nomograms showed good calibration in the LVC group. CONCLUSIONS: New nomograms for patients with primary RPS treated with surgery at high-volume versus low-volume sarcoma reference centers are available in the Sarculator app.

Risk Factors for the Development of Early Recurrence in Patients with Primary Retroperitoneal Sarcoma.

BACKGROUND: Disease recurrence after retroperitoneal sarcoma (RPS) surgery is common, and resection may offer no benefit for patients who experience recurrence early. This study examined the incidence of early recurrence (EREC) in RPS patients, and the association between EREC and prognosis, aiming to identify the factors associated with EREC. METHODS: Patients undergoing surgery for primary RPS from 2008 to 2019 at two tertiary RPS centers were analyzed. The study defined EREC as any evidence of local recurrence and/or distant metastases on the CT scan up to 6 months after surgery. Overall survival (OS) was calculated using the Kaplan-Meier method. A multivariable analysis was performed to identify independent predictors of EREC. RESULTS: Of the 692 patients who underwent surgery during the study period, 657 were included in the analysis. Sixty-five of these patients (9.9%; 95% confidence interval [CI], 7.7-12.4%) developed EREC. Five-year OS was 3% for the patients with EREC versus 76% for those without EREC (p < 0.001). Patient characteristics were compared between the EREC and non-EREC patients, and EREC was found to be significantly associated with Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.006), tumor histology (p = 0.002), tumor grading (p < 0.001), radiotherapy (p = 0.04), and postoperative complications measured as a comprehensive complications index value (p = 0.003). However, the only significant independent predictor of EREC in the multivariable analysis was grade 3 tumors, with an odds ratio of 14.8 (95% CI, 4.44-49.2; p < 0.001). CONCLUSION: Early recurrence is associated with a poor prognosis, and a high tumor grade is an independent predictor for the development of EREC. Patients with EREC may benefit the most from new therapeutic options such as neoadjuvant chemotherapy.

Oncological Outcome After Lymph Node Dissection for Cutaneous Squamous Cell Carcinoma.

BACKGROUND: Although cutaneous squamous cell carcinoma (cSCC) is common, lymph node metastases are relatively rare and are usually treated with lymph node dissection (LND). The aim of this study was to describe the clinical course and prognosis after LND for cSCC at all anatomical locations. METHODS: A retrospective search at three centres was performed to identify patients with lymph node metastases of cSCC who were treated with LND. Prognostic factors were identified by uni- and multivariable analysis. RESULTS: A total of 268 patients were identified with a median age of 74. All lymph node metastases were treated with LND, and 65% of the patients received adjuvant radiotherapy. After LND, 35% developed recurrent disease both locoregionally and distantly. Patients with more than one positive lymph node had an increased risk for recurrent disease. 165 (62%) patients died during follow-up of whom 77 (29%) due to cSCC. The 5-year OS- and DSS rate were 36% and 52%, respectively. Disease-specific survival was significantly worse in immunosuppressed patients, patients with primary tumors >2cm and patients with more than one positive lymph node. CONCLUSIONS: This study shows that LND for patients with lymph node metastases of cSCC leads to a 5-year DSS of 52%. After LND, approximately one-third of the patients develop recurrent disease (locoregional and/or distant), which underscores the need for better systemic treatment options for locally advanced cSCC. The size of the primary tumor, more than one positive lymph node, and immunosuppression are independent predictors for risk of recurrence and disease-specific survival after LND for cSCC.

Prognosis of Patients with Cutaneous Angiosarcoma After Surgical Resection with Curative Intent: Is There a Difference Between the Subtypes?

BACKGROUND: The etiology of cutaneous angiosarcoma (cAS) may be idiopathic (I-cAS), or arise secondary to radiotherapy (RT-cAS), in chronic lymphedema (ST-cAS), or related to UV exposure (UV-cAS). The aim of this study was to evaluate oncological outcomes of different cAS subtypes. PATIENTS AND METHODS: Non-metastatic cAS patients, treated with surgery for primary disease with curative intent, were retrospectively analyzed for oncological outcome, including local recurrence (LR), distant metastases (DM), and overall survival (OS). RESULTS: A total of 234 patients were identified; 60 I-cAS, 122 RT-cAS, 9 ST-cAS, and 43 UV-cAS. The majority was female (78%), the median age was 66 years (IQR 57-76 years), the median tumor size was 4.4 cm (IQR 2.5-7.0 cm), and most common site of disease was the breast (59%). Recurrence was identified in 66% (44% LR and/or 41% DM), with a median follow up of 26.5 months (IQR 12-60 months). The 5-year OS was estimated at 50%, LRFS at 47%, and DMFS at 50%. There was no significant difference in LR, DM, or OS between the subtypes. Age < 65 years and administration of radiotherapy (RT) were significantly associated with lower LR rates (HR 0.560, 95% CI 0.3373-0.840, p = 0.005 and HR 0.421, 95% CI 0.225-0.790, p = 0.007, respectively), however no prognostic factors were identified for development of DM. Development of DM, but not LR (p = 0.052), was significantly associated with decreased OS (HR 6.486, 95% CI 2.939-14.318 p < 0.001). CONCLUSION: We found no significant difference in oncological outcome between the different cAS subtypes. OS remains relatively poor, and RT is associated with lower LR rates.

Retrospective observational studies in ultra-rare sarcomas: A consensus paper from the Connective Tissue Oncology Society (CTOS) community of experts on the minimum requirements for the evaluation of activity of systemic treatments.

BACKGROUND: In ultra-rare sarcomas (URS) the conduction of prospective, randomized trials is challenging. Data from retrospective observational studies (ROS) may represent the best evidence available. ROS implicit limitations led to poor acceptance by the scientific community and regulatory authorities. In this context, an expert panel from the Connective Tissue Oncology Society (CTOS), agreed on the need to establish a set of minimum requirements for conducting high-quality ROS on the activity of systemic therapies in URS. METHODS: Representatives from > 25 worldwide sarcoma reference centres met in November 2020 and identified a list of topics summarizing the main issues encountered in ROS on URS. An online survey on these topics was distributed to the panel; results were summarized by descriptive statistics and discussed during a second meeting (November 2021). RESULTS: Topics identified by the panel included the use of ROS results as external control data, the criteria for contributing centers selection, modalities for ensuring a correct pathological diagnosis and radiologic assessment, consistency of surveillance policies across centers, study end-points, risk of data duplication, results publication. Based on the answers to the survey (55 of 62 invited experts) and discussion the panel agreed on 18 statements summarizing principles of recommended practice. CONCLUSIONS: These recommendations will be disseminated by CTOS across the sarcoma community and incorporated in future ROS on URS, to maximize their quality and favor their use as control data when results from prospective studies are unavailable. These recommendations could help the optimal conduction of ROS also in other rare tumors.

Radiomic Features From Diffusion-Weighted MRI of Retroperitoneal Soft-Tissue Sarcomas Are Repeatable and Exhibit Change After Radiotherapy.

Background: Size-based assessments are inaccurate indicators of tumor response in soft-tissue sarcoma (STS), motivating the requirement for new response imaging biomarkers for this rare and heterogeneous disease. In this study, we assess the test-retest repeatability of radiomic features from MR diffusion-weighted imaging (DWI) and derived maps of apparent diffusion coefficient (ADC) in retroperitoneal STS and compare baseline repeatability with changes in radiomic features following radiotherapy (RT). Materials and Methods: Thirty patients with retroperitoneal STS received an MR examination prior to treatment, of whom 23/30 were investigated in our repeatability analysis having received repeat baseline examinations and 14/30 patients were investigated in our post-treatment analysis having received an MR examination after completing pre-operative RT. One hundred and seven radiomic features were extracted from the full manually delineated tumor region using PyRadiomics. Test-retest repeatability was assessed using an intraclass correlation coefficient (baseline ICC), and post-radiotherapy variance analysis (post-RT-IMS) was used to compare the change in radiomic feature value to baseline repeatability. Results: For the ADC maps and DWI images, 101 and 102 features demonstrated good baseline repeatability (baseline ICC > 0.85), respectively. Forty-three and 2 features demonstrated both good baseline repeatability and a high post-RT-IMS (>0.85), respectively. Pearson correlation between the baseline ICC and post-RT-IMS was weak (0.432 and 0.133, respectively). Conclusions: The ADC-based radiomic analysis shows better test-retest repeatability compared with features derived from DWI images in STS, and some of these features are sensitive to post-treatment change. However, good repeatability at baseline does not imply sensitivity to post-treatment change.

Association Between Ageing and Short-Term Survival Outcomes in Patients Undergoing Surgery for Primary Retroperitoneal Sarcoma.

BACKGROUND: As the population ages, more elderly patients are receiving surgery for retroperitoneal sarcoma (RPS). However, high-quality data investigating associations between ageing and prognosis are lacking. Our study aimed to investigate whether ageing is associated with inferior short-term survival outcomes after RPS surgery. PATIENTS AND METHODS: Patients undergoing surgery for primary RPS between 2008 and 2019 at two tertiary sarcoma centres were analysed. The primary outcome was 1-year mortality, and the primary explanatory variable was patient age, classified as: < 55, 55-64, 65-74 or 75+ years. RESULTS: The 692 patients undergoing surgery (mean age 60.8 ± 13.8 years) had a 1-year mortality rate of 9.4%, which differed significantly by age (p < 0.001), with rates of 7.2%, 6.9%, 8.7% and 22.8% for the < 55, 55-64, 65-74 and 75+ years groups, respectively. The distribution of causes of death also differed significantly by age (p = 0.023), with 22% and 28% of deaths in the 65-74 and 75+ years groups caused by post-operative complications, versus none in the < 55 and 55-64 years groups. On multivariable analysis, age of 75+ years (versus < 55 years) was a significant independent predictor of 1-year mortality [odds ratio (OR) 7.05, 95% confidence interval (CI) 2.63-18.9, p < 0.001]; no significant increase in risk was observed in the 55-64 (OR 0.72, 95% CI 0.28-1.87) or 65-74 (OR 0.89, 95% CI 0.37-2.15) years groups. CONCLUSIONS: Post-operative complications are an important cause of deaths in elderly patients. These findings are relevant to decision-making and counselling when surgery is considered for patients with RPS.

Management of Locally Recurrent Retroperitoneal Sarcoma in the Adult: An Updated Consensus Approach from the Transatlantic Australasian Retroperitoneal Sarcoma Working Group.

BACKGROUND: Surgery is the mainstay of treatment for retroperitoneal sarcoma (RPS), but local recurrence is common. Biologic behavior and recurrence patterns differ significantly among histologic types of RPS, with implications for management. The Transatlantic Australasian RPS Working Group (TARPSWG) published a consensus approach to primary RPS, and to complement this, one for recurrent RPS in 2016. Since then, additional studies have been published, and collaborative discussion is ongoing to address the clinical challenges of local recurrence in RPS. METHODS: An extensive literature search was performed, and the previous consensus statements for recurrent RPS were updated after review by TARPSWG members. The search included the most common RPS histologic types: liposarcoma, leiomyosarcoma, solitary fibrous tumor, undifferentiated pleomorphic sarcoma, and malignant peripheral nerve sheath tumor. RESULTS: Recurrent RPS management was evaluated from diagnosis to follow-up evaluation. For appropriately selected patients, resection is safe. Nomograms currently are available to help predict outcome after resection. These and other new findings have been combined with expert recommendations to provide 36 statements, each of which is attributed a level of evidence and grade of recommendation. In this updated document, more emphasis is placed on histologic type and clarification of the intent for surgical treatment, either curative or palliative. Overall, the fundamental tenet of optimal care for patients with recurrent RPS remains individualized treatment after multidisciplinary discussion by an experienced team with expertise in RPS. CONCLUSIONS: Updated consensus recommendations are provided to help guide decision-making for treatment of locally recurrent RPS and better selection of patients who would potentially benefit from surgery.

Frailty in Very Elderly Patients is Not Associated with Adverse Surgical or Oncological Outcomes in Extremity Surgery for Soft Tissue Sarcoma.

BACKGROUND: While surgery remains the mainstay of treatment for limb sarcoma, extreme old age is a relative contraindication to oncological surgery. METHODS: Patients >80 years referred with primary extremity soft-tissue sarcoma (ESTS) between 2007 and 2016 were retrospectively reviewed. Prognostic variables, including ASA status and Clinical Frailty Scores, were collected. Endpoints were perioperative morbidity, locoregional (LRR) and distant recurrence (DR), disease-specific survival (DSS) adjusted using competing risk modelling, and overall survival (OS). RESULTS: A total of 141 primary tumours were identified, with 116 undergoing resections. Main motives for nonoperative management were severe frailty or significant comorbidity (56.0%). The operative group had a median age of 84 (range 80-96) years and median follow-up of 16 months (range 0-95). 45.7% of patients received radiotherapy. Median hospital stay was 7 (range 0-40) days, with frailty (p = 0.25) and ASA (p = 0.28) not associated with prolonged admission. 12.9% developed significant complications, with one perioperative mortality. 24.1% had LRR, occurring at a median of 14.5 months. All patients with reported DR (28.4%), except one, died of their disease. Frailty did not confer a significant difference in adjusted LRFS (p = 0.95) and DMFS (p = 0.84). One- and 5-year adjusted DSS and OS was 87.0% versus 74.9% and 62.3% versus 27.4%, respectively. Frailty (CFS ≥4) was associated with worse OS (hazard ratio [HR] 2.49; 95% confidence interval [CI] 1.51-4.12; p < 0.001), however not with adjusted DSS (p = 0.16). Nonoperative management conferred a 1- and 5-year adjusted DSS was 58.3% and 44.4%, respectively. CONCLUSIONS: Extremity surgery for sarcoma is well tolerated in the frail very elderly population with low morbidity and comparable oncological outcomes.

Longitudinal prognostication in retroperitoneal sarcoma survivors: Development and external validation of two dynamic nomograms.

PURPOSE: The aim of this study was to create and validate dynamic nomograms to predict overall survival (OS) and disease-free survival (DFS) at different time points during follow-up in patients who had undergone resection of primary retroperitoneal sarcoma (RPS). METHODS: Patients with primary RPS operated upon between 2002 and 2017 at four and six referral centres comprised the development and external validation cohorts, respectively. Landmark analysis and multivariable Cox models were used to develop dynamic nomograms. Variables were selected using two backward procedures based on the Akaike information criterion. The prediction window was fixed at 5 years. Nomogram performances were tested in terms of calibration and discrimination on the development and validation cohorts. RESULTS: Development and validation cohorts totalled 1357 and 487 patients (OS analysis), and 1309 and 452 patients (DFS analysis), respectively. The final OS model included age, landmark time (TLM), tumour grade, completeness of resection and occurrence of local/distant recurrence. The final DFS model included TLM, histologic subtype, tumour size, tumour grade, multifocality and the interaction terms between TLM and size, grade and multifocality. For OS, Harrell C indices were higher than 0.7 in both cohorts, indicating very good discriminative capability. For DFS, Harrell C indices were between 0.64 and 0.72 in the development cohort and 0.62 and 0.68 in the validation cohort. Calibration plots showed good agreement between predicted and observed outcomes. CONCLUSION: Validated nomograms are available to predict the 5-year OS and DFS probability at different time points throughout the first 5 years of follow-up in RPS survivors.

Gastrointestinal leiomyosarcoma demonstrate a predilection for distant recurrence and poor response to systemic treatments.

BACKGROUND: Primary leiomyosarcoma (LMS) of the gastrointestinal (GI) tract is rare. Limited literature exists regarding the clinical characteristics and outcome for patients with localised and metastatic disease. METHODS: A retrospective chart review was performed for patients greater than 18 years of age diagnosed with GI LMS at The Royal Marsden Hospital between 1 January 2000-1 May 2020. Descriptive statistics were performed. Patients were censored at data cut-off date of 27 June 2020. RESULTS: Forty-six patients with a median age at diagnosis of 54 years (range 25-85) were identified. Fifteen percent (n = 7) of patients previously received abdominal radiation for an unrelated cancer. All patients with localised disease (n = 36) had resection with oncological margins. For patients who underwent potentially curative surgery, median recurrence-free survival (mRFS) was 13 months (0.4-183 months), and half of these patients (n = 18) developed recurrent disease post resection (distant n = 16, local n = 2). Median overall survival (mOS) was 27 months for patients with distant recurrence. Twenty-one percent (n = 10) of patients presented with synchronous metastatic disease and their mOS was 19 months. Median progression-free survival (mPFS) for patients treated with conventional chemotherapy ranged from 2.0 to 8.0 months. CONCLUSION: The risk of recurrence is significant, and recurrence-free survival was short even with complete oncologic resection. The relationship of prior abdominal radiotherapy to the development of GI LMS warrants further investigation. Outcomes with systemic therapy for metastatic disease were poor and there is a need for the development of more effective systemic therapies.