Introduction Tenosynovial giant cell tumor (TGCT) is a benign mesenchymal tumor arising from the synovium of tendon sheats and joints, driven by colony-stimulating factor 1 (CSF1) over-expression. Standard treatment is surgery, but local recurrences are frequent, especially in diffuse TGCT subtype, rarely cured with surgery. When TGCT becomes a chronic condition, which may severely compromise joint function and quality of life, patients may need a systemic therapy.Areas covered: We reviewed the drugs on clinical development in TGCT, focusing on the pharmacodynamics, pharmacokinetics, efficacy, and toxicity profile of pexidartinib, the first drug approved in the US for TGCT, and on the open questions about its optimal use in clinical practice.Expert opinion CSFR1 inhibitors have opened a new avenue for treatment of TGCT patients. Pexidartinib is the first-in-class FDA approved agent for symptomatic locally advanced TGCT, based on a phase III study where pexidartinib showed high anti-tumor activity, improved patient symptoms, and functional outcome. A few cases of potentially life-threatening hepatic toxicity were observed. TGCT patients candidate to pexidartinib need to be carefully selected by the multidisciplinary board of center of expertise, balancing the expected risk-benefit ratio. Close monitoring of liver function and adequate education on the approved indication is warranted.
Background: Undifferentiated round cell sarcomas (URCSs) represent a diagnostic challenge and their optimal treatment is unknown. We aimed to define clinical characteristics, treatment and outcome of URCS patients.Methods: URCS patients treated from 1983 to 2019 at 21 worldwide sarcoma reference centers were retrospectively identified. Based on molecular assessment, cases were classified as follows 1) CIC -rearranged round cell sarcomas, 2) BCOR::CCNB3-rearranged round cell sarcomas, 3) unclassified URCSs. Treatment, prognostic factors and outcome were reviewed.Results: 148 patients were identified [88/148 (60%) CIC -rearranged sarcoma (median age 32 years, range 7-78), 33/148 (22%) BCOR :: CCNB3-rearranged (median age 17 years, range 5-91), and 27/148 (18%) unclassified URCSs (median age 37 years, range 4-70)]. One hundred-one (68.2%) cases presented with localized disease; 47 (31.8%) had metastases at diagnosis. Male prevalence, younger age, bone primary site and a low rate of synchronous metastases were observed in BCOR::CCNB3-rearranged cases. Local treatment was surgery in 67/148 (45%) patients, and surgery + radiotherapy in 52/148 (35%). Chemotherapy was given to 122/148 (82%) patients. At a 42.7-month median follow-up, the 3-year overall survival (OS) was 92.2% (95% CI 71.5-98.0) in BCOR::CCNB3 patients, 39.6% (95% CI 27.7-51.3) in CIC -rearranged sarcomas, and 78.7% in unclassified URCSs (95% CI 56.1-90.6; p<0.0001).Conclusions: This study is the largest conducted in URCS and confirms major differences in outcomes between URCS subtypes. A full molecular assessment should be undertaken when a diagnosis of URCS is suspected. Prospective studies are needed to better define the optimal treatment strategy in each URCS subtype.
Background The objective of this study was to report on a retrospective series of patients with epithelioid hemangioendothelioma (EHE) who received treatment with sirolimus within the Italian Rare Cancer Network. Methods From January 2005, 38 adult patients with advanced EHE received continuous‐dosing sirolimus, 5 mg daily, until they developed either toxicity or disease progression. Disease progression in the 6 months before the start of treatment was required. Each pathologic diagnosis was reviewed. The daily dose of sirolimus was adjusted based on plasma levels. Response was retrospectively assessed by local investigators using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST). Survival was estimated using the Kaplan‐Meier method. Results All 38 patients (WW Domain Containing Transcription Regulator 1 [WWTR1]‐positive, n = 37; transcription factor E3 [TFE3]‐positive, n = 1) had disease progression before starting sirolimus (at baseline, 13 of 38 patients had the presence of serosal effusions and systemic symptoms). Thirty‐seven patients were evaluable for response (there was 1 early interruption). The best RECIST responses were a partial response in 4 patients (10.8%), stable disease in 28 patients (75.7%), and disease progression in 5 patients (13.5%). At a 41.5‐month median follow‐up (interquartile range [IQR], 23.9‐56.8 months), the median PFS was 13 months (95% CI, 3.7 months to not estimated [NE]), and the median OS was 18.8 months (95% CI, 10.6 months to NE). In patients who had serosal effusions at baseline, the median PFS was 4.8 months (IQR, 3.5‐11.7 months), and the median OS was 10.6 months (IQR, 5.1‐13.0 months), compared with 47.8 months (IQR, 11.4 months to NE) and 47.8 months (IQR, 15.7 months to NE), respectively, in patients without serosal effusions. Overall, sirolimus was fairly well tolerated, with 10 patients reporting irregular menstruation/ovary disfunction. Conclusions The current results confirm that sirolimus is active in EHE, leading to prolonged stabilization in most patients who present without serosal effusions. Serosal effusions are confirmed as an unfavorable prognostic sign associated with short survival, and sirolimus displays limited activity in this subgroup.
This letter to the editor responds to questions about the results of the authors’ recently reported study of chemotherapy in inflammatory myofibroblastic tumors.
We surveyed the natural history of bone metastases in patients affected by soft tissue sarcoma (STS).This multicenter retrospective observational study included 135 patients. Histological subtype, characteristics of bone metastases, treatment, skeletal related events (SREs) and disease outcome were recorded.The most represented histological subtypes were leiomyosarcoma (27%) angiosarcoma (13%) and undifferentiated sarcoma (8%). Axial skeleton was the most common site for bone involvement (70%). In 27% of cases, bone metastases were present at the time of diagnosis. Fifty-four (40%) patients developed SREs and the median time to first SRE was 4 months (range 1-9). The most common SRE was the need for radiotherapy (28%) followed by pathological fracture (22%). Median survival after bone progression was 6 months (range 1-14). SREs were associated with decreased overall survival (OS) (P = 0.04). A subgroup analysis revealed that bisphosphonates significantly prolonged median time to first SRE (5 versus 2 months; P = 0.002) while they did not determine an improvement in OS, although a favourable trend was identified (median: 7 versus 5 months; P = 0.105).This study illustrates the burden of bone disease from STS and supports the use of bisphosphonates in this setting.
Sarcomas are rare malignant neoplasms that develop from mesenchymal cells and include a heterogeneous and large group of histological subtypes that may occur at any anatomical site. Soft tissue sarcomas (STS), the focus of this review, account for ≈70‒80% of sarcomas and represent <1% of all cancers. The heterogeneity of STS applies to both their topography and morphology, and 5-year survival can vary widely depending on disease stage and the complex interplay between anatomical site and histology for different STS subtypes. The rarity and heterogeneity of STS, together with other factors, such as the lack of clinical expertise often lead to difficulties and delays in making an accurate diagnosis and to the inappropriate management of each STS subtype. Therefore, this group of cancers requires special attention and approaches to diagnosis and treatment. Epidemiological data on STS are limited, and concerns have been raised regarding accurate registration of STS in cancer registries, including issues related to details of the histotypes. This review provides an overview of the epidemiology of STS in Italy, focusing on data from the Italian Association of Cancer Registries (AIRTUM), and compares findings with those from other European countries. Based on these data, and considering that STS is among the most common group of rare cancers, the relevance of multidisciplinary care for STS patients through reference centres, clinical networks and collaborative disease-specific groups is discussed.
