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.

Correlation of radiological and histopathological response after neoadjuvant radiotherapy in soft tissue sarcoma.

BACKGROUND: The aim of this study was to assess the association between radiological and histopathological response after neoadjuvant radiotherapy (nRT) in soft tissue sarcoma (STS), as well as the prognostic value of the different response evaluation methods on the oncological outcome. METHODS: A retrospective cohort of patients with localized STS of the extremity and trunk wall, treated with nRT followed by resection were included. The radiological response was assessed by RECIST 1.1 (RECIST) and MR-adapted Choi (Choi), histopathologic response was evaluated according to the EORTC-STBSG recommendations. Oncological outcome parameters of interest were local recurrence-free survival (LRFS), disease metastases-free survival (DMFS), and overall survival (OS). RESULTS: For 107 patients, complete pre- and postoperative pathology and imaging datasets were available. Most tumors were high-grade (77%) and the most common histological subtypes were undifferentiated pleomorphic sarcoma/not otherwise specified (UPS/NOS, 40%), myxoid liposarcoma (MLS, 21%) and myxofibrosarcoma (MFS, 16%). When comparing RECIST to Choi, the response was differently categorized in 58%, with a higher response rate (CR + PR) with Choi. Radiological responders showed a significant lower median percentage of viable cells (RECIST p = .050, Choi p = .015) and necrosis (RECIST p < .001), and a higher median percentage of fibrosis (RECIST p = .005, Choi p = .008), compared to radiological non-responders (SD + PD). RECIST, Choi, fibrosis, and viable cells were not significantly associated with altered oncological outcome, more necrosis was associated with poorer OS (p = .038). CONCLUSION: RECIST, Choi and the EORTC-STBSG response score show incongruent results in response evaluation. The radiological response was significantly correlated with a lower percentage of viable cells and necrosis, but a higher percentage of fibrosis. Apart from necrosis, radiological nor other histopathological parameters were associated with oncologic outcomes.

Radiotherapy for retroperitoneal liposarcoma: A report from the Transatlantic Retroperitoneal Sarcoma Working Group.

BACKGROUND: The current study investigated the role of radiotherapy (RT) in patients with primary nonmetastatic retroperitoneal liposarcomas. METHODS: A total of 607 patients with localized retroperitoneal well-differentiated liposarcomas (WDLPS) and dedifferentiated liposarcomas (DDLPS) underwent surgical resection with or without RT at 8 high-volume sarcoma centers (234 patients with WDLPS, 242 patients with grade 1 to 2 DDLPS, and 131 patients with grade 3 DDLPS; grading was performed according to the National Federation of Centers for the Fight Against Cancer [Federation Nationale des Centres de Lutte Contre le Cancer; FNCLCC]). RT was administered in 19.7%, 34.7%, and 35.1%, respectively, of these 3 cohorts. Overall survival (OS) was estimated using the Kaplan-Meier method, and the incidences of local recurrence and distant metastasis (DM) were estimated in a competing risk framework. To account for bias consistent with nonrandom RT assignment, propensity scores were estimated. Cox univariable analysis of the association between RT and oncological endpoints was performed by applying inverse probability of treatment weighting (IPTW) using propensity scores. RESULTS: Age, tumor size, and the administration of chemotherapy were found to be significantly imbalanced between patients who did and did not undergo RT in all cohorts. IPTW largely removed imbalances in key prognostic variables. Although the 8-year local recurrence incidences in patients treated with surgery plus RT versus surgery only were 11.8% and 39.2%, respectively, for patients with WDLPS (P = .011;); 29.0% and 56.7%, respectively, for patients with grade 1 to 2 DDLPS (P = .008); and 29.8% and 43.7%, respectively, for patients with grade 3 DDLPS (P = .025), this significant benefit was lost after IPTW analyses. There were no significant differences noted with regard to DM and OS between irradiated and unirradiated patients across all 3 cohorts. CONCLUSIONS: Perioperative RT was found to be associated with better local control in univariable unadjusted analysis in all 3 cohorts, but not after accounting for imbalances in prognostic variables. RT did not impact on DM or OS. The appropriate selection of RT in this disease remains challenging. The results of the European Organization for Research and Treatment of Cancer (EORTC)-Soft Tissue and Bone Sarcoma Group (STBSG) 62092-22092 prospective randomized trial are awaited.

Adherence to Guidelines for Adult (Non-GIST) Soft Tissue Sarcoma in the Netherlands: A Plea for Dedicated Sarcoma Centers.

INTRODUCTION: Optimal management of soft tissue sarcoma (STS) remains a challenge. A nationwide survey assessed the quality of STS care in the Netherlands, thereby aiming to identify potentialities for improvement through more centralized disease management. METHODS: From the Netherlands Cancer Registry (NCR), data were obtained on 3317 adult STS patients (excluding gastrointestinal stromal tumor, GIST) diagnosed in 2006-2011. Logistic regression models were employed to compare outcomes on selected clinical indicators reflecting prevailing STS guidelines between high-volume (≥10 resections annually) and low-volume (<10 resections) hospitals, between academic and general hospitals, and between sarcoma research centers and other hospitals, adjusted for case mix. Analyses were performed on imputed datasets (m = 50), generated through multiple imputations by chained equations. RESULTS: Overall, 89% of patients underwent surgical resection. Resection status remained unknown in 24% (excluding those with metastasized disease), and grade was not documented for one-third of tumors. Microscopic residual disease was detected in 20% with an increased risk for older patients, larger and deeply located tumors, and those located in the (retro)peritoneum or upper extremity. Almost half of patients with an R1 resection received adjuvant radiotherapy. Following adjustment for case mix factors, patients treated in high-volume hospitals less often had macroscopic residual disease (R2 resection; adjusted odds ratio: 0.54). A strongly skewed distribution of surgical volumes was observed. CONCLUSIONS: These survey results indicate a potential for improving Dutch STS care. More centralized sarcoma management should improve definitive pathology reporting on tumor characteristics, adherence to treatment guidelines and overall disease outcome.

Orthovoltage X-rays for Postoperative Treatment of Resected Basal Cell Carcinoma in the Head and Neck Area.

BACKGROUND: Surgery is the golden standard for treating basal cell carcinomas. In case of positive tumor margins or recurrent disease, postoperative adjuvant or salvaging therapy is suggested to achieve good local control. OBJECTIVE: To retrospectively report on local control and toxicity of postoperative radiotherapy by means of orthovoltage X-rays for residual or recurrent basal cell carcinoma after surgery in the head and neck area. METHODS: Sixty-six surgically resected residual or recurrent basal cell carcinomas of the head and neck region were irradiated postoperatively by means of orthovoltage X-rays at the Netherlands Cancer Institute between January 2000 and February 2015. RESULTS: After a median follow-up duration of 30.5 months, only 5 recurrences were reported. The 5-year local control rates at 1, 3, and 5 years were 100%, 87%, and 87%, respectively. The 5-year local control rate was 92% for immediate postoperative radiotherapy of incompletely resected basal cell carcinomas, 90% for recurrences after 1 previously performed excision, and 71% for multiple recurrences, namely, a history of more than 1 excision ( P = .437). Acute toxicity healed spontaneously within 3 months. Late toxicities were mild. CONCLUSION: Radiotherapy by means of orthovoltage X-ray is an excellent alternative for re-excision in case of incompletely resected or recurrent basal cell carcinomas that are at risk of serious functional and cosmetic impairments after re-excision, with a 5-year local control rate of 87% and a low toxicity profile.

A phase I study on the combination of neoadjuvant radiotherapy plus pazopanib in patients with locally advanced soft tissue sarcoma of the extremities.

UNLABELLED: Accumulating evidence suggests significant synergism combining radiotherapy (RT) with angiogenesis targeted therapies. This multicenter prospective phase I clinical trial established the safety profile and recommended dose for further studies of pazopanib concurrent with preoperative RT in patients with extremity soft tissue sarcomas (ESTS) in curative setting. METHODS: Patients with deep seated intermediate and high grade sarcomas, ≥ 5 cm, received once daily pazopanib (dose-escalation cohorts 400 mg, 600 mg and 800 mg) for 6 weeks and 50 Gy preoperative RT starting Day 8. Surgery was performed 5-7 weeks later. Toxicity was scored according to CTC criteria 4.0. Dose limiting toxicities (DLT) were divided into two separate sets; DLT-I being toxicities occurring during the 6-week chemoradiotherapy period within the radiation portals until day of surgery (designated as DLT-I) and those occurring perioperatively until Day 21 after surgery (DLT-II). RESULTS: A total of 12 patients were enrolled, 11 were evaluable (3 females and 8 males, median age 58 years, range 24-78 years, median tumor size 9 cm, range 5-15 cm). Ten underwent surgery. No increased toxicity inside the radiation fields was seen, but two of 10 patients (one each in the 400 mg and 600 mg cohorts) showed delayed wound healing after surgery. None of the patients showed significant volume reductions after RT. Evaluation of the resection specimen showed pathological (near) complete responses (≥ 95% necrosis rate) in four of 10 cases. Unexpectedly, grade 3 + hepatotoxicity led to premature pazopanib interruption in three of 11 (27%) of cases. CONCLUSION: Apart from hepatotoxicity, neoadjuvant pazopanib 800 mg daily in combination with 50 Gy seems tolerable; the regimen appears to demonstrate promising activity in ESTS and is the recommended dose for further studies.

What Is a Sarcoma 'Specialist Center'? Multidisciplinary Research Finds an Answer.

The management of sarcomas in specialist centers delivers significant benefits. In much of the world, specialists are not available, and the development of expertise is identified as a major need. However, the terms 'specialist' or 'expert' center are rarely defined. Our objective is to offer a definition for patient advocates and a tool for healthcare providers to underpin improving the care of people with sarcoma. SPAGN developed a discussion paper for a workshop at the SPAGN 2023 Conference, attended by 75 delegates. A presentation to the Connective Tissue Oncology Society (CTOS) and further discussion led to this paper. Core Principles were identified that underlie specialist sarcoma care. The primary Principle is the multi-disciplinary team discussing every patient, at first diagnosis and during treatment. Principles for optimal sarcoma management include accurate diagnosis followed by safe, high-quality treatment, with curative intent. These Principles are supplemented by Features describing areas of healthcare, professional involvement, and service provision and identifying further research and development needs. These allow for variations because of national or local policies and budgets. We propose the term 'Sarcoma Intelligent Specialist Network' to recognize expertise wherever it is found in the world. This provides a base for further discussion and local refinement.

Neoadjuvant chemotherapy for radiation associated angiosarcoma (RAAS) of the breast: A retrospective single center study.

BACKGROUND: Radiation associated angiosarcoma (RAAS) of the breast is a rare malignancy with poor survival. Optimal treatment strategies remain uncertain due to a lack of data, and vary between surgery alone and a combination of surgery with (neo)adjuvant chemotherapy (NACT) and/or re-irradiation. The aim of this study was to evaluate the potential benefit of taxane based NACT. METHODS: In this retrospective single center study, all patients with RAAS of the breast treated between 1994 and 2024 are included. Since 2018, NACT is considered a treatment option for this patient population in our institute. The difference in oncological outcomes of patients with and without NACT were compared. RESULTS: Thirty-five women were included. Thirteen (37 %) received NACT of which five (39 %) also had neoadjuvant re-irradiation with hyperthermia. Eleven patients (85 %) received paclitaxel, the other two (15 %) had doxorubicine/docetaxel. Complete pathological response was found in 69 % (n = 9). Median follow up was 41 months (range 24-56) for patients with NACT and 44 (range 20-108) for patients without NACT. In the NACT group, only one patient developed a recurrence after 6.5 years. Patients with NACT had improved oncological outcomes compared to patients without NACT in terms of 3-year local recurrence free survival (100% vs. 63.9 %, p = 0.14), distant metastasis free survival (100 % vs. 47.5 %, p = 0.005), and overall survival (100% vs. 56.1 %, p = 0.016). CONCLUSION: In this study, neoadjuvant taxanes for RAAS of the breast leads to improved distant metastasis free survival and overal survival in patients treated with NACT compared to no NACT.

Complete resection of recurrent and initially unresectable dermatofibrosarcoma protuberans downsized by Imatinib.

Curative surgical treatment of recurrent, locally advanced dermatofibrosarcoma protuberans is often limited owing to a close relation of the tumor with important anatomical structures. Targeted therapy with imatinib, a tyrosine kinase inhibitor, may cause significant reduction of tumor volume, thereby enabling radical surgery. This treatment strategy, therefore, offers a chance of cure for selected patients with advanced dermatofibrosarcoma protuberans. In addition, preoperative treatment with imatinib may decrease possible disfigurement related to radical surgery for large tumors.

Histological response to radiotherapy is an early event in myxoid liposarcoma.

Compared to other sarcomas, myxoid liposarcoma (MLS) is exceptionally sensitive to radiation therapy, but the underlying mechanism remains unknown. The objective was to assess the tissue-based changes in MLS during and after neoadjuvant radiotherapy in 26 patients of the DOREMY trial. Morphological assessment was performed on biopsies pre-treatment, after 8 fractions, 16 factions, and after surgical resection and included percentage of viable tumor cells, hyalinization, necrosis, and fatty maturation. Furthermore, immunohistochemistry was performed for apoptosis (cleaved caspase-3), anti-apoptosis (Bcl-2), activity of mTOR signaling (phospho-S6), hypoxia (CAIX), proliferation (Ki67), inflammation (CD45 and CD68), and microvessel density (CD34 Chalkley count). A pronounced reduction in vital tumor cells was observed early with a drop to 32.5% (median) tumor cells (IQR 10-93.8%) after 8 fractions. This decreased further to 10% (IQR 5-30%) after 16 fractions and 7.5% (IQR 5-15%) in the surgical specimen. All but one patient had an excellent response with < 50% remaining tumor cells. Inversely, treatment response was mainly observed as hyalinization and less often as fatty maturation. Additionally, a decrease of inflammatory cells was noticed especially during the first eight fractions. Microvessel density remained stable over time. Immunohistochemical markers for apoptosis, anti-apoptosis, activity of mTOR signaling, proliferation, and hypoxia did not show any marked changes within the remaining tumor cells during and after radiotherapy. As a modest dose of neoadjuvant radiotherapy induces profound tissue changes in MLS, mainly during the first 8 fractions, current findings might suggest that in a carefully selected patient population further deintensification of radiotherapy might be explored.

Treatment Strategies for Metastatic Soft Tissue Sarcomas.

Soft tissue sarcomas (STS) are a diverse group of rare tumors of mesenchymal origin with different clinical, histologic and molecular characteristics [...].

Intra-Tumoral Pharmacokinetics of Pazopanib in Combination with Radiotherapy in Patients with Non-Metastatic Soft-Tissue Sarcoma.

There is a lack of understanding whether plasma levels of anticancer drugs (such as pazopanib) correlate with intra-tumoral levels and whether the plasma compartment is the best surrogate for pharmacokinetic and pharmacodynamic evaluation. Therefore, we aimed to quantify pazopanib concentrations in tumor tissue, to assess the correlation between tumor concentrations and plasma concentrations and between tumor concentrations and efficacy. In this clinical trial, non-metastatic STS patients were treated with neo-adjuvant concurrent radiotherapy and pazopanib. Plasma samples and tumor biopsies were collected, and pazopanib concentrations were measured using liquid chromatography-tandem mass spectrometry. Twenty-four evaluable patients were included. The median pazopanib tumor concentration was 19.2 µg/g (range 0.149-200 µg/g). A modest correlation was found between tumor concentrations and plasma levels of pazopanib (ρ = 0.41, p = 0.049). No correlation was found between tumor concentrations and percentage of viable tumor cells (p > 0.05); however, a trend towards less viable tumor cells in patients with high pazopanib concentrations in tumor tissue was observed in a categorical analysis. Possible explanations for the lack of correlation might be heterogeneity of the tumors and timing of the biopsy procedure.

Health-Related Quality of Life Issues Experienced by Thoracic and Breast Sarcoma Patients: A Rare and Understudied Group.

Thoracic and breast sarcomas constitute a rare subgroup within the sarcoma population. There is limited knowledge about their health-related quality of life (HRQoL) and a valid disease-specific HRQoL instrument is lacking. This qualitative study aimed to investigate the HRQoL issues experienced by a small group of thoracic and breast sarcoma patients. Semi-structured interviews with 19 thoracic and four breast sarcoma patients were conducted and thematically analysed. Physical issues mentioned by both groups were fatigue, sleep disturbances, pain, wound infections, and symptoms related to chemotherapy and radiotherapy. Tightness in the back and restrictions in performing tasks above arm height were specific physical issues for breast sarcoma patients, whereas respiratory problems were only mentioned by thoracic sarcoma patients. Body image issues, changes in mood, fear of recurrence, and living with uncertainty were important mental health issues for both subgroups. Social issues in both groups included challenges in work and relationships, financial difficulties, loss of independence, and limitations in social activities. The identified physical, mental, and social health challenges can significantly impact thoracic and breast sarcoma patients' HRQoL. Results of this qualitative study will guide personalised supportive care for breast and thoracic sarcoma patients and help in determining the best possible HRQoL measurement strategy for sarcoma patients with different primary sarcoma locations.

Radiotherapy resistance in chondrosarcoma cells; a possible correlation with alterations in cell cycle related genes.

BACKGROUND: Conventional chondrosarcomas are malignant cartilage tumors considered radioresistant. Nevertheless, retrospective series show a small but significant survival benefit for patients with locally advanced disease treated with radiotherapy. And, in daily practice when considered inoperable their irradiation is an accepted indication for proton beam radiotherapy. Therefore, we investigated the sensitivity of chondrosarcoma cell lines and -tissue samples towards radiotherapy and screened for biomarkers to identify predictors of radiosensitivity. METHODS: Proliferation and clonogenic assays were performed in chondrosarcoma cell lines after γ-radiation in combination with mutant IDH1 inhibitor AGI-5198. In addition, glutathione levels were measured using mass spectrometry. Chondrosarcoma tumor explants were irradiated after which γ-H2AX foci were counted. Mutation analysis was performed using the Ion AmpliSeq™ Cancer Hotspot Panel and immunohistochemical staining's were performed for P-S6, LC-3B, P53, Bcl-2, Bcl-xl and Survivin. Results were correlated with the number of γ-H2AX foci. RESULTS: Chondrosarcoma cell lines were variably γ-radiation resistant. No difference in radiosensitivity, nor glutathione levels was observed after treatment with AGI-5198. Irradiated chondrosarcoma patient tissue presented a variable increase in γ-H2AX foci compared to non-radiated tissue. Samples were divided into two groups, high and low radioresistant, based on the amount of γ-H2AX foci. All four highly resistant tumors exhibited mutations in the pRb pathway, while none of the less radioresistant tumors showed mutations in these genes. CONCLUSIONS: Chondrosarcoma cell lines as well as primary tumors are variably radioresistant, particularly in case of a defective Rb pathway. Whether selection for radiotherapy can be based upon an intact Rb pathway should be further investigated.

99mTc-HYNIC-rh-annexin-V scintigraphy: visual and quantitative evaluation of early treatment-induced apoptosis to predict treatment outcome.

AIM: To determine the reliability of visual analysis of 99mTc-HYNIC-rh-annexin-V tumour uptake (ATU) compared to quantitative tracer uptake evaluation. METHODS: Thirty-eight patients (22 male, 16 female, mean age 57) with histologically proved lymphoma (n=31), non-small cell lung cancer (NSCLC) (n=4) and head and neck squamous cell carcinoma (H&NSCC) (n=3) were examined. 99mTc-HYNIC-rh-annexin-V scintigraphy (TAS) was acquired before and within 2 days after the start of anti-cancer treatment. Maximal counts per pixel in the tumour volume (Cmax) were calculated for every target lesion. To match the quantitative and visual ATU, both were expressed as a four-grade score. Cmax as percentages of baseline values: grade 1, decrease >25%; grade 0, 1-25% decrease; grade 1, 1-25% increase; grade 2, >25% increase. Visual analysis: 0=absent, 1=weak, 2=moderate, 3=intense. Intra-observer and inter-observer variability and methodological agreement between visual and quantitative evaluation of ATU was expressed by computing Cohen's kappa statistics. RESULTS: A statistically highly significant correlation was found between the changes in ATU and therapy outcome: r=0.97 (P<0.0001) and r=0.99 (P<0.0001) for visual and quantitative analysis, respectively. Good intra-observer reproducibility, with a high kappa of 0.82 for observer 1 and a kappa of 0.90 for observer 2, was determined. Inter-observer variability was 0.82. CONCLUSION: Visual evaluation of ATU after image co-registration appears to be a reliable and reproducible method for preliminary assessment of early treatment-induced apoptosis.

Outcome of Nonsurgical Management of Extra-Abdominal, Trunk, and Abdominal Wall Desmoid-Type Fibromatosis: A Population-Based Study in the Netherlands.

INTRODUCTION: Nonsurgical management of patients with desmoid-type fibromatosis (DF) is increasing. This study tries to provide insight on type, usage, and outcome of first-line nonsurgical management strategies. PATIENTS AND METHODS: From the Dutch Pathology Registry (PALGA), patients with extra-abdominal or trunk/abdominal wall DF, diagnosed between 1993 and 2013, were identified. First-line treatment was analyzed. Best response (BR) using RECIST criteria from start of treatment/surveillance until change of treatment or last follow-up was analyzed. RESULTS: Ninety-one of the 1141 identified patients had first-line nonsurgical management. The percentage of patients treated nonsurgically increased from 0.6% in 1993-1998 to 12.8% in 2009-2013. Thirty-seven patients had surveillance (41%), 35 radiotherapy (38%), and 19 systemic treatment (21%). BR for surveillance was complete response (CR) in 2/37, partial response (PR) in 4/37, stable disease (SD) in 21/37, progressive disease (PD) in 5/37, and unknown in 5/37 patients. BR for radiotherapy was CR in 4/35, PR in 11/35, SD in 16/35, and unknown in 4/35. BR for systemic treatment was CR in 1/19, PR in 1/19, SD in 10/19, PD in 2/19, and unknown in 5/19. Totally, 91% of patients did not progress. DISCUSSION: Given the low percentage (9%) of PD of nonsurgical management, these data can be used in shared decision making with the patient regarding optimal treatment.

Radiotherapy preserves fingers in the management of subungual squamous cell carcinoma, obviating the need for amputation.

A retrospective study of the use of radiotherapy in 12 patients with subungual squamous cell carcinoma of the finger was conducted at two radiotherapy departments in the Netherlands. This malignancy has little tendency to metastasize and is usually treated by amputation. Primary radiotherapy resulted in a permanent local control of 92% with only one serious adverse effect leading to an amputation of the initially involved digit. No regional or distant failure was seen during follow-up. Radiotherapy should be considered as an alternative for amputation to treat patients with subungual squamous cell carcinoma of the finger.