Soft Tissue Sarcoma: An Update on Systemic Treatment Options for Patients with Advanced Disease

Schöffski, Patrick; Cornillie, Jasmien; Woźniak, Agnieszka; Li, Haifu; Hompes, Daphne

doi:10.1159/000362631

Cited by 91 publications

(99 citation statements)

References 33 publications

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“…1 For patients with metastatic disease, treatment options are limited, and the median overall survival is 10 to 18 months, highlighting the need for new therapies. 2 Aberrations in tumor suppressor proteins (TSPs) have been well described in many sarcoma subtypes and are thought to contribute to tumorigenesis and drug resistance.…”

Section: Introductionmentioning

confidence: 99%

Phase IB Study of Selinexor, a First-in-Class Inhibitor of Nuclear Export, in Patients With Advanced Refractory Bone or Soft Tissue Sarcoma

Gounder

Zer

Tap

et al. 2016

JCO

143

122

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Purpose We evaluated the pharmacokinetics (PKs), pharmacodynamics, safety, and efficacy of selinexor, an oral selective inhibitor of nuclear export compound, in patients with advanced soft tissue or bone sarcoma with progressive disease. Patients and Methods Fifty-four patients were treated with oral selinexor twice per week (on days 1 and 3) at one of three doses (30 mg/m2, 50 mg/m2, or flat dose of 60 mg) either continuously or on a schedule of 3 weeks on, 1 week off. PK analysis was performed under fasting and fed states (low v high fat content) and using various formulations of selinexor (tablet, capsule, or suspension). Tumor biopsies before and during treatment were evaluated for pharmacodynamic changes. Results The most commonly reported drug-related adverse events (grade 1 or 2) were nausea, vomiting, anorexia, and fatigue, which were well managed with supportive care. Commonly reported grade 3 or 4 toxicities were fatigue, thrombocytopenia, anemia, lymphopenia, and leukopenia. Selinexor was significantly better tolerated when administered as a flat dose on an intermittent schedule. PK analysis of selinexor revealed a clinically insignificant increase (approximately 15% to 20%) in drug exposure when taken with food. Immunohistochemical analysis of paired tumor biopsies revealed increased nuclear accumulation of tumor suppressor proteins, decreased cell proliferation, increased apoptosis, and stromal deposition. Of the 52 patients evaluable for response, none experienced an objective response by RECIST (version 1.1); however, 17 (33%) showed durable (≥ 4 months) stable disease, including seven (47%) of 15 evaluable patients with dedifferentiated liposarcoma. Conclusion Selinexor was well tolerated at a 60-mg flat dose on a 3-weeks-on, 1-week-off schedule. There was no clinically meaningful impact of food on PKs. Preliminary evidence of anticancer activity in sarcoma was demonstrated.

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Section: Introductionmentioning

confidence: 99%

Phase IB Study of Selinexor, a First-in-Class Inhibitor of Nuclear Export, in Patients With Advanced Refractory Bone or Soft Tissue Sarcoma

Gounder

Zer

Tap

et al. 2016

JCO

143

122

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“…There is no widely accepted second-line treatment. However, novel therapeutic approaches have been recently identified as second-line treatments for patients with recurrent or incurable sarcoma, including HDAC inhibitors and tyrosine kinase inhibitors, such as pazopanib, which has been approved in USA and Europe since 2012 for the treatment of distinct STS subtypes (14)(15)(16)(17)(18)(19). The two patients in the present study were administered doxorubicin; however, this treatment did not prevent tumor progression.…”

Section: Chemotherapeutic Treatment Of Undifferentiated Pleomorphic Smentioning

confidence: 82%

“…The application of an anthracycline-based chemotherapy, including doxorubicin alone or in combination with ifosfamide, is often the first-line treatment of undifferentiated pleomorphic sarcoma NOS, and there are no widely recognized second-line therapies available (11)(12)(13). Recently, improved second-line drugs have been developed, including histone deacetylase (HDAC) inhibitors, trabectedin and tyrosine kinase inhibitors such as pazopanib, which are more effective than those currently available (14)(15)(16)(17)(18)(19). With these drugs, a progression-free survival time of 3-5 months may be achieved (14)(15)(16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, improved second-line drugs have been developed, including histone deacetylase (HDAC) inhibitors, trabectedin and tyrosine kinase inhibitors such as pazopanib, which are more effective than those currently available (14)(15)(16)(17)(18)(19). With these drugs, a progression-free survival time of 3-5 months may be achieved (14)(15)(16)(17)(18)(19). However, the overall survival time is not increased.…”

Section: Introductionmentioning

confidence: 99%

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Xenograft models for undifferentiated pleomorphic sarcoma not otherwise specified are essential for preclinical testing of therapeutic agents

et al. 2016

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Abstract. Undifferentiated pleomorphic sarcoma not otherwise specified belongs to the heterogeneous group of soft tissue tumors. It is preferentially located in the upper and lower extremities of the body, and surgical resection remains the only curative treatment. Preclinical animal models are crucial to improve the development of novel chemotherapeutic agents for the treatment of undifferentiated pleomorphic sarcoma. However, this approach has been hampered by the lack of reproducible animal models. The present study established two xenograft animal models generated from stable non-clonal cell cultures, and investigated the difference in chemotherapeutic effects on tumor growth between undifferentiated pleomorphic sarcoma in vivo and in vitro. The cell cultures were generated from freshly isolated tumor tissues of two patients with undifferentiated pleomorphic sarcoma. For the in vivo analysis, these cells were injected subcutaneously into immunodeficient mice. The mice were monitored for tumor appearance and treated with the most common or innovative chemotherapeutic agents available to date. Furthermore, the same drugs were administered to in vitro cell cultures. The most effective tumor growth inhibition in vitro was observed with doxorubicin and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA), also known as vorinostat. In the in vivo xenograft mouse model, the combination of doxorubicin and the tyrosine kinase inhibitor pazopanib induced a significant tumor reduction. By contrast, treatment with vorinostat did not reduce the tumor growth. Taken together, the results obtained from drug testing in vitro differed significantly from the in vivo results. Therefore, the novel and reproducible xenograft animal model established in the present study demonstrated that in vivo models are required to test potential chemotherapeutic agents for the treatment of undifferentiated pleomorphic sarcoma prior to clinical use, since animal models are more similar to humans, compared with in vitro cell cultures.

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“…Patients with local tumour recurrence have a lower disease-specific survival, and those with metastatic relapse have definitely low 5-year survival rates. 65 Prognosis is worse when the primary site is critical, like the skull base.…”

Section: Discussionmentioning

confidence: 99%

Systemic therapy for selected skull base sarcomas: Chondrosarcoma, chordoma, giant cell tumour and solitary fibrous tumour/hemangiopericytoma

Colia

Provenzano

Hindi

et al. 2016

Reports of Practical Oncology & Radiotherapy

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IntroductionSkull base tumours include a large number of benign and malignant entities. This review focuses on chondrosarcoma, chordoma, giant cell tumour of the bone (GTCB) and solitary fibrous tumour/hemangiopericytoma (SFT), i.e., those sarcomas which are relatively "typical" of the skull base. Each represents a very rare disease, with an incidence of less than 1/1,000,000/year (considering all primary sites). 1,2 Of course, * Corresponding author. Tel.: +39 0223902803; fax: +39 0223902404.E-mail address: silvia.stacchiotti@istitutotumori.mi.it (S. Stacchiotti).all sarcoma subtypes can occasionally arise from the skull base.In principle, the essential criteria for medical treatment of sarcomas arising from the skull base are basically independent from the primary site. On the other hand, as a general rule, given their rarity and heterogeneity, sarcoma patients should always be approached by a multidisciplinary team at a referral institution. 3 Chondrosarcoma, chordoma and GTCB are all bone sarcomas that can arise from the bone component of the skull base, http://dx

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Soft Tissue Sarcoma: An Update on Systemic Treatment Options for Patients with Advanced Disease

Cited by 91 publications

References 33 publications

Phase IB Study of Selinexor, a First-in-Class Inhibitor of Nuclear Export, in Patients With Advanced Refractory Bone or Soft Tissue Sarcoma

Phase IB Study of Selinexor, a First-in-Class Inhibitor of Nuclear Export, in Patients With Advanced Refractory Bone or Soft Tissue Sarcoma

Xenograft models for undifferentiated pleomorphic sarcoma not otherwise specified are essential for preclinical testing of therapeutic agents

Systemic therapy for selected skull base sarcomas: Chondrosarcoma, chordoma, giant cell tumour and solitary fibrous tumour/hemangiopericytoma

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