Dacarbazine in Solitary Fibrous Tumor: A Case Series Analysis and Preclinical Evidence vis-à-vis Temozolomide and Antiangiogenics

Abstract

Purpose: To explore the value of triazines in solitary fibrous tumor (SFT). Experimental Design: We retrospectively reviewed 8 cases of patients with SFT treated with dacarbazine (1,200 mg/m 2 every 3 weeks) as from January 2012. Then, we studied a dedifferentiated-SFT subcutaneously xenotransplanted into severe combined immunodeficient (SCID) mice. Dacarbazine, temozolomide, sunitinib, bevacizumab, and pazopanib were administered at their reported optimal doses for the mouse model when mean tumor volume (TV) was about 80 mm 3 ; each experimental groups included 6 mice. Drug activity was assessed as tumor volume inhibition percentage (TVI%). Dacarbazine was tested according to two different schedules of administration. One hunded twenty days after treatment interruption, mouse tumor samples were analyzed.Results: Among the eight patients treated with dacarbazine, best response evaluation criteria in solid tumors responses (RECIST) were three partial responses, 4 stable disease, 1 progression. Two responsive patients had paraneoplastic hypoglycemia that disappeared after 10 days from starting dacarbazine. In the dedifferentiated-SFT xenograft model, dacarbazine and temozolomide showed the highest antitumor activity (about 95% TVI), confirmed pathologically. Sunitinib and pazopanib were only marginally active (52% and 41% TVI, respectively), whereas bevacizumab caused a 78% TVI. No tumor regrowth was observed up to 100 days from end of treatment with temozolomide and dacarbazine, whereas secondary progression followed sunitinib, pazopanib, and bevacizumab interruption.Conclusions: Dacarbazine as single agent has antitumor activity in SFT. Our preclinical results suggest a cytotoxic effect of temozolomide and dacarbazine, as compared with a cytostatic role for sunitinib, pazopanib, and bevacizumab. A phase II study on dacarbazine in advanced SFT is planned.

Preclinical and clinical evidence of activity of pazopanib in solitary fibrous tumour

“…The presence of the typical NAB2-STAT6 rearrangement -recently described in human SFT [12] -was confirmed in xenograft by RT-PCR [10].…”

“…SFT represents a very rare disease and very few data are available on its sensitivity to pazopanib, that is the only antiangiogenic agent approved for STS treatment. Our preclinical results showed that pazopanib is less active compared to other antiangiogenics in a high-grade dedifferentiated-SFT mouse model [10]. By contrast regorafenib was found to be the most interesting compound.…”

“…A patient-derived human high-grade dedifferentiated-SFT xenograft model [10] was used in the study. The presence of the typical NAB2-STAT6 rearrangement -recently described in human SFT [12] -was confirmed in xenograft by RT-PCR [10].…”

“…Antiangiogenics were shown to produce durable disease stabilisation in a proportion of patients by means of tumour responses that were mostly non-dimensional [5,6]. We already reported on the activity of pazopanib in a human high-grade dedifferentiated-SFT xenotransplanted into severe combined immunodeficiency (SCID) mice [10]. When compared to dacarbazine and temozolomide, pazopanib was less active and characterised by a short lasting cytostatic effect.…”

Solitary fibrous tumors: loss of chimeric protein expression and genomic instability mark dedifferentiation

“…[7][8][9][10][11][12][13][14], and 10 as having dedifferentiated solitary fibrous tumors (nos. [15][16][17][18][19][20][21][22][23][24].…”