Phase I trial of preoperative chemoradiation plus sorafenib for high-risk extremity soft tissue sarcomas with dynamic contrast-enhanced MRI correlates Journal Article

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Authors: Meyer, J. M.; Perlewitz, K. S.; Hayden, J. B.; Doung, Y. C.; Hung, A. Y.; Vetto, J. T.; Pommier, R. F.; Mansoor, A.; Beckett, B. R.; Tudorica, A.; Mori, M.; Holtorf, M. L.; Afzal, A.; Woodward, W. J.; Rodler, E. T.; Jones, R. L.; Huang, W; Ryan, C. W.
Article Title: Phase I trial of preoperative chemoradiation plus sorafenib for high-risk extremity soft tissue sarcomas with dynamic contrast-enhanced MRI correlates
Abstract: PURPOSE: We conducted 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 undergoing limb salvage surgery. We conducted a correlative study of quantitative dynamic contrast-enhanced MRI (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 twice daily) initiated 14 days before three preoperative and three postoperative cycles of epirubicin/ifosfamide. Radiation (28 Gy) was administered during cycle 2 with epirubicin omitted. The primary objective was to determine the maximum tolerated dose (MTD) of sorafenib. DCE-MRI was conducted at baseline, after 2 weeks of sorafenib, and before surgery. The imaging data were subjected to quantitative pharmacokinetic analyses. RESULTS: Eighteen 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%). Of note, 38% developed wound complications requiring surgical intervention. The rate of >/=95% histopathologic tumor necrosis was 44%. Changes in DCE-MRI biomarker DeltaK(trans) after 2 weeks of sorafenib correlated with histologic response (R(2) = 0.67, P = 0.012) at surgery. CONCLUSION: 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 soft tissue sarcoma.
Journal Title: Clinical cancer research : an official journal of the American Association for Cancer Research
Volume: 19
Issue: 24
ISSN: 1078-0432; 1078-0432
Publisher: AACR  
Journal Place: United States
Date Published: 2013
Start Page: 6902
End Page: 6911
Language: eng
DOI/URL:

10.1158/1078-0432.CCR-13-1594
Notes: LR: 20141217; CI: (c)2013; GR: P30 CA069533/CA/NCI NIH HHS/United States; GR: P30 CA069533/CA/NCI NIH HHS/United States; GR: R01 CA120861/CA/NCI NIH HHS/United States; GR: R01 CA120861/CA/NCI NIH HHS/United States; GR: U01 CA154602/CA/NCI NIH HHS/United States; GR: U01 CA154602/CA/NCI NIH HHS/United States; GR: UL1 RR024140/RR/NCRR NIH HHS/United States; GR: UL1 RR024140/RR/NCRR NIH HHS/United States; JID: 9502500; 0 (Phenylurea Compounds); 25X51I8RD4 (Niacinamide); 9ZOQ3TZI87 (sorafenib); NIHMS532141; OID: NLM: NIHMS532141; OID: NLM: PMC3869565; 2013/10/16 [aheadofprint]; 2013/11/26 [aheadofprint]; ppublish