title: Phase I trial of preoperative chemoradiation plus sorafenib for high-risk extremity soft tissue sarcomas with dynamic contrast-enhanced MRI correlates.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 ΔK(trans) after 2 weeks of sorafenib correlated with histologic response (R(2) = 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 soft tissue sarcoma.
authors.affiliation: Authors' Affiliations: Loyola University Chicago, Maywood, Illinois; Providence Cancer Center, Newberg; Oregon Health and Science University; Oregon Health and Science University Knight Cancer Institute; Oregon Health and Science University Advanced Imaging Research Center, Portland, Oregon; and Seattle Cancer Care Alliance, Seattle, Washington.
authors.forename: Janelle M
authors.initials: JM
authors.lastname: Meyer
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Perlewitz
authors.forename: James B
authors.initials: JB
authors.lastname: Hayden
authors.forename: Yee-Cheen
authors.initials: YC
authors.lastname: Doung
authors.forename: Arthur Y
authors.initials: AY
authors.lastname: Hung
authors.forename: John T
authors.initials: JT
authors.lastname: Vetto
authors.forename: Rodney F
authors.initials: RF
authors.lastname: Pommier
authors.forename: Atiya
authors.initials: A
authors.lastname: Mansoor
authors.forename: Brooke R
authors.initials: BR
authors.lastname: Beckett
authors.forename: Alina
authors.initials: A
authors.lastname: Tudorica
authors.forename: Motomi
authors.initials: M
authors.lastname: Mori
authors.forename: Megan L
authors.initials: ML
authors.lastname: Holtorf
authors.forename: Aneela
authors.initials: A
authors.lastname: Afzal
authors.forename: William J
authors.initials: WJ
authors.lastname: Woodward
authors.forename: Eve T
authors.initials: ET
authors.lastname: Rodler
authors.forename: Robin L
authors.initials: RL
authors.lastname: Jones
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Ryan
mesh_terms: D000328:Adult; D059248:Chemoradiotherapy; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D057234:Preoperative Period; D011859:Radiography; D012509:Sarcoma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D000077157:Sorafenib; D055815:Young Adult
chemical_list: D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib