pazopanib and Sarcoma--Alveolar-Soft-Part

Pazopanib shows a modest efficacy in metastatic alveolar soft part sarcoma.Clinical outcomes were comparable to those in previous studies using antiangiogenic drugs.Further prospective studies evaluating the benefit of pazopanib in alveolar soft part sarcoma with a larger sample are warranted to validate results.. Alveolar soft part sarcoma (ASPS) is a rare mesenchymal malignant tumor characterized by an unbalanced translocation, t(X;17)(p11.2;q25), which leads to the fusion of. This open-label, single-arm, multicenter, investigator-initiated phase II trial was designed to evaluate efficacy and safety of pazopanib 800 mg once daily in patients with metastatic ASPS. The primary endpoint was investigator-assessed overall response rate (ORR), and secondary endpoints were toxicity, progression-free survival (PFS), and overall survival (OS).. Six patients with histologically confirmed metastatic ASPS were enrolled between December 2013 and November 2014. Among six patients, one achieved a partial response (PR) (ORR 16.7%) and five patients showed stable disease (SD). With a median follow-up of 33 months (range 18.7-39.3 months), median PFS was 5.5 months (95% confidence interval [CI] 3.4-7.6 months), and median OS was not reached. There were no severe toxicities except one patient with grade 3 diarrhea.. Pazopanib showed modest antitumor activity with manageable toxicities for patients with metastatic ASPS.

Topics: Adult; Angiogenesis Inhibitors; Female; Humans; Indazoles; Male; Neoplasm Metastasis; Pyrimidines; Sarcoma, Alveolar Soft Part; Sulfonamides

Alveolar soft part sarcoma (ASPS) is a rare malignancy that typically arises in the trunk or extremities and preferentially metastasises to the brain. Radical resection is generally recommended for cranial metastatic ASPS, but stereotactic radiosurgery (SRS) is a recognised alternative for tumours in surgically challenging locations. Here, we present the case of a 22-year-old female, who underwent SRS and systemic therapy with pazopanib for a metastatic ASPS in the left temporal bone. The tumour was successfully controlled without further intervention over 23 months following SRS, which should be considered for metastatic ASPS when surgical resection is not appropriate.

Topics: Angiogenesis Inhibitors; Female; Humans; Indazoles; Pyrimidines; Radiosurgery; Sarcoma, Alveolar Soft Part; Skull Base Neoplasms; Sulfonamides; Temporal Bone; Young Adult

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.. 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.. 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.. 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.. 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.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Female; Follow-Up Studies; Humans; Indazoles; Male; Middle Aged; Prognosis; Pyrimidines; Retrospective Studies; Sarcoma, Alveolar Soft Part; Sulfonamides; Survival Rate; Trabectedin

Alveolar soft part sarcoma (ASPS) is an extremely rare metastatic soft tissue tumor with a poor prognosis for which no effective systemic therapies have yet been established. Therefore, the development of novel effective treatment approaches is required. Tyrosine kinases (TKs) are being increasingly used as therapeutic targets in a variety of cancers. The purpose of this study was to identify novel therapeutic target TKs and to clarify the efficacy of TK inhibitors (TKIs) in the treatment of ASPS.. To identify novel therapeutic target TKs in ASPS, we evaluated the antitumor effects and kinase activity of three TKIs (pazopanib, dasatinib, and cabozantinib) against ASPS cells using an in vitro assay. Based on these results, we then investigated the phosphorylation activities of the identified targets using western blotting, in addition to examining antitumor activity through in vivo assays of several TKIs to determine both the efficacy of these substances and accurate targets.. In cell proliferation and invasion assays using pazopanib, cabozantinib, and dasatinib, all three TKIs inhibited the cell growth in ASPS cells. Statistical analyses of the cell proliferation and invasion assays revealed that dasatinib had a significant inhibitory effect in cell proliferation assays, and cabozantinib exhibited marked inhibitory effects on cellular functions in both assays. Through western blotting, we also confirmed that cabozantinib inhibited c-MET phosphorylation and dasatinib inhibited SRC phosphorylation in dose-dependent fashion. Mice that received cabozantinib and dasatinib had significantly smaller tumor volumes than control animals, demonstrating the in vivo antitumor activity of, these substances.. Our findings suggest that cabozantinib and dasatinib may be more effective than pazopanib against ASPS cells. These in vitro and in vivo data suggest that c-MET may be a potential therapeutic target in ASPS, and cabozantinib may be a particularly useful therapeutic option for patients with ASPS, including those with pazopanib-resistant ASPS.

Topics: Anilides; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dasatinib; Female; Humans; Indazoles; Mice; Mice, Inbred BALB C; Mice, Nude; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-met; Pyridines; Pyrimidines; Sarcoma, Alveolar Soft Part; src-Family Kinases; Sulfonamides; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays

The multi-targeted tyrosine kinase inhibitors such as cediranib, sunitinib and pazopanib have been reported to be effective for alveolar soft part sarcoma (ASPS). The efficacy of pazopanib for the patient with lingual ASPS has yet to be reported.. A 23-year old man presented with articulation disorder and swelling of the tongue. Diagnosis of lingual ASPS was made after incisional biopsy and complete excision of the mass was performed. Three months later, he presented with a protruding mental region.. Computed tomography revealed mental region mass and lung metastasis.. After the failure of combination therapy of doxorubicin and ifosfamide, pazopanib was administered.. Shrinkage of both the mental region and lung mass continued for more than two months, but regrowth was confirmed at the fourth month.. Lingual ASPS is an exceedingly rare subset of ASPS with distinct molecular and histological characteristics and appropriate therapy remains to be established. Our findings suggest a possible therapeutic strategy for lingual ASPS.

Topics: Antineoplastic Agents; Humans; Indazoles; Male; Pyrimidines; Sarcoma, Alveolar Soft Part; Sulfonamides; Tongue Neoplasms; Treatment Outcome; Young Adult

Topics: Child; Female; Humans; Indazoles; Lung Neoplasms; Pyrimidines; Sarcoma, Alveolar Soft Part; Sulfonamides; Treatment Outcome