Phase I Trial of Preoperative Chemoradiation Plus Sorafenib for High Risk Extremity Soft Tissue Sarcomas with Dynamic Contrast-Enhanced MRI Correlates
Mené sur 18 patients présentant un sarcome des tissus mous des extrémités et devant subir une chirurgie de sauvetage du membre atteint, cet essai de phase I détermine la dose maximale tolérée de sorafenib en combinaison avec une chimioradiothérapie pré-opératoire, puis évalue la réponse au traitement par IRM dynamique quantitative de contraste
Purpose : We performed a phase I trial of the addition of sorafenib to a chemoradiotherapy regimen in patients with high-risk (intermediate/high grade, >5 cm) extremity soft tissue sarcoma (STS) undergoing limb salvage surgery. We conducted a correlative study of quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to assess response to treatment. Experimental Design : Patients were treated at increasing dose levels of sorafenib (200 mg daily, 400 mg daily, 400 mg BID) initiated 14 days prior to 3 preoperative and 3 postoperative cycles of epirubicin/ifosfamide. 28 Gy of radiation was administered during cycle 2 with epirubicin omitted. The primary objective was to determine the maximum tolerated dose (MTD) of sorafenib. DCE-MRI was performed at baseline, after 2 weeks of sorafenib, and prior to surgery. The imaging data were subjected to quantitative pharmacokinetic analyses. Results : 18 subjects were enrolled, of which 16 were evaluable. The MTD of sorafenib was 400 mg daily. Common grade 3-4 adverse events included neutropenia (94%), hypophosphatemia (75%), anemia (69%), thrombocytopenia (50%), and neutropenic fever/infection (50%). 38% developed wound complications requiring surgical intervention. The rate of ≥95% histopathologic tumor necrosis was 44%. Changes in DCE-MRI biomarker ∆Ktrans after 2 weeks sorafenib correlated with histologic response (R2=0.67, p = 0.012) at surgery. Conclusions : The addition of sorafenib to preoperative chemoradiotherapy is feasible and warrants further investigation in a larger trial. DCE-MRI detected changes in tumor perfusion after 2 weeks of sorafenib and may be a minimally-invasive tool for rapid assessment of drug effect in STS.