Solitary fibrous tumor (SFT) is a rare mesenchymal, ubiquitous tumor, with an incidence of 1 new case/million people/year. In the 2020 WHO classification, risk stratification models were recommended ...as a better tool to determine prognosis in SFT, to the detriment of “typical” or “malignant” classic terms. The risk for metastasis is up to 35–45%, or even greater, in series with a longer follow-up. Over the last few decades, advances in immunohistochemistry and molecular diagnostics identified STAT6 nuclear protein expression and the NAB2–STAT6 fusion gene as more precise tools for SFT diagnosis. Recent evidence taken from retrospective series and from two prospective phase II clinical trials showed that antiangiogenics are active and their sequential use from first line should be considered, except for dedifferentiated SFT for which chemotherapy is the best option. Since the fusion transcript driver’s first description in 2013, new insights have been brought on key molecular events in SFT. This comprehensive review mainly focuses on the superior efficacy of antiangiogenics over chemotherapeutic agents in SFT, provides the current knowledge of key molecules that could co-drive the SFT behavior, and suggests new target candidates that deserve to be explored in preclinical and clinical research in SFT.
Abstract Introduction Imatinib showed activity in 50 chordoma patients treated within a Phase II study. In that study, 70% of patients remained with stable disease (SD), median progression free ...survival (PFS) was 9 months and median overall survival (OS) was 34 months. We now report on a retrospective series of PDGFB/PDGFRB positive advanced chordoma patients treated with imatinib as a single agent within a compassionate-use programme at Istituto Nazionale Tumori, Milan, Italy (INT) between August 2002 and November 2010, when the programme was closed. Methods 48 patients were consecutively treated with imatinib 800 mg/d. All patients had inoperable and progressive disease before starting imatinib. Demographics, treatment duration, toxicity and response rate by Response Evaluation Criteria in Solid Tumors (RECIST) were retrospectively recorded. Results The median duration of therapy was 7 months (1–46.5). No patient is on therapy at present. 46 patients were evaluable for response. No partial responses were detected. Best response was: stable disease 34 (74%), progressive disease 12 (26%). At a median follow-up of 24.5 months (0.5–117), median PFS was 9.9 months (95% confidence interval (CI) 6.7–13). Eight patients (16.5%) remained on therapy >18 months and 10 patients (21%) remained progression-free >18 months. Median OS was 30 months (95% CI 20–40), with 24 (50%) patients dead at the time of the present analysis. Conclusions We confirm the activity of imatinib in locally advanced and metastatic chordoma, in terms of >70% tumour growth arrest in previously progressive patients. Median duration of response lasted almost 10 months, with >20% of patients progression-free at 18+ months.
Background
Alveolar soft part sarcoma (ASPS) is an exceedingly rare and orphan disease, without active drugs approved in the front line. Pazopanib and trabectedin are licensed for sarcoma treatment ...from second‐line, but very little and contradictory data are available on their activity in ASPS. Lacking ongoing and/or planned clinical trials, we conducted a multi‐institutional study involving the reference sites for sarcoma in Europe, U.S., and Japan, within the World Sarcoma Network, to investigate the efficacy of pazopanib and trabectedin.
Materials and Methods
From May 2007, 14 of the 27 centers that were asked to retrospectively review their databases had identified 44 advanced ASPS patients treated with pazopanib and/or trabectedin. Response was evaluated by Response Evaluation Criteria in Solid Tumors 1.1. Progression‐free survival (PFS) and overall survival (OS) were computed by Kaplan‐Meier method.
Results
Among 30 patients who received pazopanib, 18 were pretreated (13 with other antiangiogenics). Response was evaluable in 29/30 patients. Best responses were 1 complete response, 7 partial response (PR), 17 stable disease (SD), and 4 progressions. At a 19‐month median follow‐up, median PFS was 13.6 months (range: 1.6–32.2+), with 59% of patients progression‐free at 1 year. Median OS was not reached.
Among 23 patients treated with trabectedin, all were pretreated and evaluable for response. Best responses were 1 PR, 13 SD, and 9 progressions. At a 27‐month median follow‐up, median PFS was 3.7 months (range: 0.7–109), with 13% of patients progression‐free at 1 year. Median OS was 9.1 months.
Conclusion
The value of pazopanib in advanced ASPS is confirmed, with durable responses, whereas the value of trabectedin appears limited. These results are relevant to defining the best approach to advanced ASPS.
Implications for Practice
This retrospective study, conducted among the world reference centers for treatment of sarcoma, confirms the value of pazopanib in patients with advanced alveolar soft part sarcoma (ASPS), with dimensional and durable responses, whereas trabectedin shows a limited activity. Alveolar soft part sarcoma is resistant to conventional cytotoxic chemotherapy. Pazopanib and trabectedin are licensed for treatment of sarcoma from second line; in the lack of prospective clinical trials, these results are relevant to defining ASPS best management and strongly support initiatives aimed at obtaining the approval of pazopanib in the front line of the disease.
Because of the rarity of alveolar soft part sarcoma and the lack of prospective trials, a retrospective, multi‐institutional, caseseries analysis was conducted among reference centers for treatment of soft tissue sarcoma.With the support of the World Sarcoma Network, the activity and efficacy of trabectedin and pazopanib in advanced alveolar soft part sarcoma patients was investigated. The results are presented here.
Rhabdomyosarcoma (RMS) in adults is a rare and aggressive disease, which lacks standard therapies for relapsed or advanced disease. This retrospective study aimed to describe the activity of BOMP-EPI ...(bleomycin, vincristine, methotrexate and cisplatin alternating with etoposide, cisplatin and ifosfamide), an alternative platinum-based regimen, in adult patients with relapsed/metastatic RMS. In the study, 10 patients with RMS with a median age at diagnosis of 20.8 years and a female/male distribution of 6/4 received a mean of 2.5 cycles of BOMP-EPI. The best RECIST response was a complete response in 1/10 (10%) patients, a partial response in 5/10 (50%), stable disease in 3/10 (30%) and progression in 1/10 (10%). With a median follow-up in the alive patients from the start of therapy of 30.5 months (15.7-258), all patients progressed with a median progression-free survival of 8.47 months (95% CI 8.1-8.8), and 7/10 patients died with a median overall survival of 24.7 months (95% CI 13.7-35.6). BOMP-EPI was an active chemotherapy regimen in adults with pediatric-type metastatic RMS, with outcomes in terms of survival that seem superior to what was expected for this poor-prognosis population. Low HMGB1 expression level was identified as a predictive factor of better response to this treatment.
Background
Reference centers (RCs) are a key point for improving the survival of patients with soft‐tissue sarcomas (STS). The aim of this study was to evaluate selected items in the management of ...patients with STS, comparing results between RC and local hospitals (LHs).
Materials and Methods
Diagnostic and therapeutic data from patients diagnosed between January 2004 and December 2011 were collected. Correlation with outcome was performed.
Results
A total of 622 sarcomas were analyzed, with a median follow‐up of 40 months. Imaging of primary tumor preoperatively (yes vs. no) correlated with a higher probability of free surgical margins (77.4% versus 53.7%; p = .006). The provenance of the biopsy (RC vs. LH) significantly affected relapse‐free survival (RFS; 3‐year RFS 66% vs. 46%, respectively; p = .019). Likewise, 3‐year RFS was significantly worse in cases with infiltrated (55.6%) or unknown (43.4%) microscopic surgical margins compared with free margins (63.6%; p < .001). Patients managed by RCs had a better 3‐year overall survival compared with those managed by LHs (82% vs. 70.4%, respectively; p = .003). Perioperative chemotherapy in high‐risk STS, more frequently administered in RCs than in LHs, resulted in significantly better 3‐year RFS (66% vs. 44%; p = .011). In addition, patients with stage IV disease treated in RCs survived significantly longer compared with those in LHs (30.4 months vs. 18.5 months; p = .036).
Conclusion
Our series indicate that selected quality‐of‐care items were accomplished better by RCs over LHs, all with significant prognostic value in patients with STS. Early referral to an RC should be mandatory if the aim is to improve the survival of patients with STS.
Implications for Practice
This prospective study in patients diagnosed with soft‐tissue sarcoma shows the prognostic impact of reference centers in the management of these patients. The magnitude of this impact encompasses all steps of the process, from the initial management (performing diagnostic biopsy) to the advanced disease setting. This is the first prospective evidence showing improvement in outcomes of patients with metastatic disease when they are managed in centers with expertise. This study provides extra data supporting referral of patients with sarcoma to reference centers.
Management of soft‐tissue sarcoma is challenging. This article reports on sarcoma clinical management in cancer centers in Spain, based on information from a prospective registry launched by the Spanish Group for Research in Sarcoma.
Background
Aggressive angiomyxoma (AA) is a rare, locally aggressive tumor usually arising from pelvis or perineum, with a high local‐recurrence rate after complete surgery. Anecdotal responses to ...hormone therapy have been reported. In the present study we aimed at studying surgical treatment outcomes and sensitivity to hormone therapy of AA.
Materials and Methods
We conducted a multicenter, international retrospective effort including patients with AA treated at three European referral centers (Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy and the Italian Rare Cancer Network; Centre Léon Bérard, Lyon, France; and Hospital Universitario Virgen del Rocio, Seville, Spain).
Results
A total of 36 patients were included. Median follow‐up was 51.3 months. Thirty‐three patients (92%) underwent complete (R0 + R1) surgery, with a local relapse rate of 50% and a median relapse‐free survival of 39 months (95% confidence interval CI, 27–68.1). Thirteen patients received a first‐line systemic treatment with hormone therapy for locally advanced disease, with an overall response rate of 62% and a median progression‐free survival of 24.6 months (95% CI, 11.0–39.7). In two patients, adding an aromatase inhibitor (AI) on progression to first‐line GnRH agonist (GnRHa) resulted in a new tumor response.
Conclusion
Our findings confirm that in AA, surgical local control may be challenging, with a significant rate of local relapse despite complete surgery. Hormone therapy is an active treatment option, with a potential of disease control and of being combined with surgery. The addition of an AI to first‐line GnRHa could be an effective second‐line systemic therapy in premenopausal female patients with AA.
Implications for Practice
In this retrospective effort including 36 patients with aggressive angiomyxoma, local relapse rate after complete surgery was 50%, with a median relapse‐free survival of 39 months, confirming that local control is challenging. Overall response rate to first‐line hormone therapy was 62%, with a median progression‐free survival of 24.6 months. Thus, hormone therapy has a potential of disease control and of being combined with surgery.
This article reports the results of a study of the natural history of aggressive angiomyxoma, focusing on the disease's sensitivity to hormone therapy and on treatment outcomes.
Desmoid fibromatosis (DF) are mesenchymal neoplasms, with potential aggressive course and relevant clinical impact. New systemic therapy modalities are needed in this symptomatic/progressive ...population. In this multicenter, phase II trial (NCT03275818), patients with symptomatic/progressing DF received three cycles of weekly nab-paclitaxel. Brief pain inventory short form (BPI-SF) was collected at baseline and in every visit. MRI was performed every 3 months. Primary composite endpoint was RECIST 1.1 overall response rate (ORR) and/or clinical response (improvement ≥ 2 points in BPI-SF). If 40% of patients achieved clinical/radiological response, further investigation would be warranted. Toxicity, progression-free survival (PFS), pattern of response and its correlation with clinical best response and BPI, variation of physical function, and analgesic consumption were secondary endpoints. The translational research reported was not a pre-specified secondary outcome. Forty eligible patients started therapy, being 35 radiologically and clinically evaluable. The study achieved its primary endpoint, as 7(20%) patients obtained RECIST partial response, whereas 31(89%) experienced pain reduction of ≥2 points in BPI-SF worst pain. Therapy was well tolerated. With a median follow-up of 30(14-44) months, median 12 and 24-months PFS rates were 91%(CI 95%, 82-100) and 84%(CI 95%, 71-97). For clinical progression, 12 and 24-months PFS rates were 85% (CI 95%, 73-97) and 74% (CI 95%, 58-90) respectively. Short course of nab-paclitaxel is active, safe and achieves quick and durable responses in progressing/symptomatic DF patients.
Although the overall survival of advanced soft-tissue sarcoma (STS) patients has increased in recent years, the median progression-free survival is lower than 5 months, meaning that there is an unmet ...need in this population. Among second-line treatments for advanced STS, eribulin is an anti-microtubule agent that has been approved for liposarcoma. Here, we tested the combination of eribulin with gemcitabine in preclinical models of L-sarcoma. The effect in cell viability was measured by MTS and clonogenic assay. Cell cycle profiling was studied by flow cytometry, while apoptosis was measured by flow cytometry and Western blotting. The activity of eribulin plus gemcitabine was evaluated in in vivo patient-derived xenograft (PDX) models. In L-sarcoma cell lines, eribulin plus gemcitabine showed to be synergistic, increasing the number of hypodiploid events (increased subG1 population) and the accumulation of DNA damage. In in vivo PDX models of L-sarcomas, eribulin combined with gemcitabine was a viable scheme, delaying tumour growth after one cycle of treatment, being more effective in leiomyosarcoma. The combination of eribulin and gemcitabine was synergistic in L-sarcoma cultures and it showed to be active in in vivo studies. This combination deserves further exploration in the clinical context.
Approximately 15% of adult GIST patients harbor tumors that are wild-type for KIT and PDGFRα genes (KP-wtGIST). These tumors usually have SDH deficiencies, exhibit a more indolent behavior and are ...resistant to imatinib. Underlying oncogenic mechanisms in KP-wtGIST include overexpression of HIF1α high IGFR signaling through the MAPK pathway or BRAF activating mutation, among others. As regorafenib inhibits these signaling pathways, it was hypothesized that it could be more active as upfront therapy in advanced KP-wtGIST.
Adult patients with advanced KP-wtGIST after central confirmation by NGS, naïve of systemic treatment for advanced disease, were included in this international phase II trial. Eligible patients received regorafenib 160 mg per day for 21 days every 28 days. The primary endpoint was disease control rate (DCR), according to RECIST 1.1 at 12 weeks by central radiological assessment.
From May 2016 to October 2020, 30 patients were identified as KP-wtGIST by Sanger sequencing and 16 were confirmed by central molecular screening with NGS. Finally, 15 were enrolled and received regorafenib. The study was prematurely closed due to the low accrual worsened by COVID outbreak. The DCR at 12 weeks was 86.7% by central assessment. A subset of 60% experienced some tumor shrinkage, with partial responses and stabilization observed in 13% and 87% respectively, by central assessment. SDH-deficient GIST showed better clinical outcome than other KP-wtGIST.
Regorafenib activity in KP-wtGIST compares favorably with other tyrosine kinase inhibitors, especially in the SDH-deficient GIST subset and it should be taken into consideration as upfront therapy of advanced KP-wtGIST.
ClinicalTrials.gov Identifier: NCT02638766.
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