IntroductionAngiosarcoma is a rare and aggressive malignancy with a high metastatic potential and recurrence rate. Despite optimal treatment with surgery, with or without radiation, the prognosis remains poor and, therefore, new treatment strategies are warranted. Recently, propranolol has effectively been repurposed for the treatment of infantile haemangioma. Propranolol is a β3-sparing antagonist of the β-adrenergic receptor. In infantile haemangioma, the β1, β2 and β3 receptors are highly expressed. Angiosarcoma has several similarities with haemangioma, including its high β-adrenergic receptor expression and the supposedly important role of vascular endothelial growth factor in malignant growth. As a result, propranolol has been administered small scale in individual angiosarcoma cases with promising results. The precise effect of propranolol, however, is not yet established.Methods and analysisThe goal of this neoadjuvant window of opportunity study is to prospectively evaluate the activity of propranolol monotherapy in patients with cutaneous angiosarcoma. The neoadjuvant setting provides a good opportunity to rapidly evaluate both the clinical response and histological response, without a significant delay in standard anticancer treatment. Fourteen patients with primary, recurrent or metastatic cutaneous angiosarcoma will be included. Propranolol will be administered orally in an escalating dose during 3–6 weeks, before the initiation of standard treatment. The primary endpoint is clinical response according to Response Evaluation Criteria in Solid Tumours, as measured on consecutive coloured photographs or CT/MRI. The histological response will be determined as secondary endpoint, comparing the difference in proliferation index before and after propranolol by measuring the change in immunohistochemistry staining of Ki-67. The study will be considered positive when at least three patients have a response to propranolol.Ethics and disseminationEthical approval was obtained from the Medical Ethical Committee of the Netherlands Cancer Institute. Independent of the outcome, results of this study will be shared and submitted for publication in an international peer-reviewed journal.Trial registration numberNL8118; registry through the Netherlands Trial Register.
Background/Aim: Pazopanib is approved for advanced soft tissue sarcoma (STS) patients. The aim of the study was to examine the usefulness of ( 18 F)-Fluorodeoxyglucose-positron emission tomography/ computed tomography (FDG-PET/CT) imaging for early evaluation of the response of STS patients to pazopanib, as well as the association between pazopanib pharmacokinetics and early metabolic response. Patients and Methods: Twenty STS patients underwent FDG-PET scans at baseline, two-and eight-weeks following treatment with pazopanib. The FDG-PET scans were evaluated by quantitative PERCIST analysis and visually by an independent nuclear medicine physician and related to RECIST1.1 outcome at eight weeks. Results: After eight weeks of therapy, 14 out of 20 patients had discontinued pazopanib due to tumor progression identified radiologically ('non-responders' n=12) or toxicity (n=2). Quantitative FDG-PET scoring at two weeks, according to PERCIST guidelines, identified 25% (3 of 12) of the patients radiologically as non-responders versus 42% (5 of 12) identified by visual response analysis. Conclusion: In this heterogeneous STS patients' cohort, early FDG-PET/CT identified a substantial part of pazopanib non-responders.Soft tissue sarcomas (STS) represent a group of rare mesenchymal cancers that encompasses more than 70 histological subtypes (1). Based on the outcome of the PALETTE trial, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved pazopanib as the first oral targeted therapy for non-gastrointestinal stromal tumors (GIST), non-adipocytic STS patients in second line and beyond (2). Patients treated with pazopanib showed a progression-free survival (PFS) benefit of 3 months compared to placebo-treated patients. Unfortunately, 23% of patients had progressive disease and were considered as de novo resistant to pazopanib therapy (non-responders), and about 10-30% of the STS patients treated with pazopanib developed grade 3-4 toxicity (2, 3). It is, therefore, evident that easily assessable biomarkers to predict response shortly after the start of treatment with pazopanib are required to identify patients who will ultimately not benefit from therapy. This is particularly important to avoid treatment of patients with an ineffective, potentially toxic, and expensive drug over a prolonged period of time. Molecular imaging with ( 18 F)-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography (FDG-PET/CT) has shown clinical relevance for grading and staging sarcoma patients (4); reflecting outcome after (neoadjuvant) chemotherapy (5, 6); and for predicting the anti-tumor effect of imatinib in GIST patients (7, 8) at an earlier stage than is currently possible with conventional radiological imaging that solely depicts tumor morphology (CT/MRI). In addition, FDG-PET/CT has been successful in predicting the effects of angiogenesis inhibitors in metastatic renal cell carcinoma (mRCC) (9).Until now, the metabolic response depicted by FDG-PET/CT has not been related to drug pharmacokine...
Purpose: A prior phase I study showed that the neo-adjuvant combination of pazopanib and radiotherapy was well tolerated, and induced promising pathological responses in soft-tissue sarcoma patients. Results of the subsequent prospective, multicenter phase II, PASART-2 trial are presented here, further investigating the efficacy and safety of this combination. Patients and methods: Patients with high-risk, localized soft-tissue sarcoma received neo-adjuvant radiotherapy, 50 Gy in 25 fractions (PASART-2A) or with a subsequent dose de-escalation to 36 Gy in 18 fractions (PASART-2B). This was combined with 800 mg once daily pazopanib, which started one week before radiotherapy and finished simultaneously. After an interval of 4-8 weeks, surgical resection was performed. The primary endpoint was the rate of pathological complete responses (pCR), defined as 5% viable cells. Results: 25 patients were registered in the study, 21 in PASART-2A and 4 in PASART-2B. After central pathology review, the combination treatment led to a pCR in 5 patients (20%). 17 patients (68%) experienced grade 3þ toxicities during neo-adjuvant treatment, of which the most common were alanine aminotransferase (ALT) elevation, aspartate aminotransferase (AST) elevation, and hypertension, all asymptomatic. Grade 3þ acute post-operative toxicities occurred in 5 patients (20%), of which the most common was wound infection. All patients completed the full radiotherapy regimen and underwent surgery. Pazopanib was discontinued before completion in 9 patients (36%), due to elevated ALT and/or AST, and shortly interrupted in 2 patients (8%), due to hypertension. Conclusion: Apart from asymptomatic hepatotoxicity, the study regimen was well tolerated. Although the pre-specified efficacy endpoint (30% pCR) was not met, a more than doubling of historical pCR rates after neo-adjuvant radiotherapy alone was observed, which warrants further investigation.
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