title: Phase I trial of neoadjuvant conformal radiotherapy plus sorafenib for patients with locally advanced soft tissue sarcoma of the extremity.
abstract: BACKGROUND
  Despite effective local therapy with surgery and radiotherapy (RT), ~50 % of patients with high-grade soft tissue sarcoma (STS) will relapse and die of disease. Since experimental data suggest a significant synergistic effect when antiangiogenic targeted therapies such as sorafenib are combined with RT, we chose to evaluate preoperative combined modality sorafenib and conformal RT in a phase I/II trial among patients with extremity STS amenable to treatment with curative intent.
  
  
  METHODS
  For the phase I trial, eight patients with intermediate- or high-grade STS >5 cm in maximal dimension or low-grade STS >8 cm in maximal dimension received concomitant sorafenib (dose escalation cohort 1:200 twice daily, cohort 2:200/400 daily) and preoperative RT (50 Gy in 25 fractions). Sorafenib was continued during the entire period of RT as tolerated. Surgical resection was completed 4-6 weeks following completion of neoadjuvant sorafenib/RT. Three sorafenib dose levels were planned. Primary endpoints of the phase I trial were maximal tolerated dose and dose-limiting toxicity (DLT).
  
  
  RESULTS
  Eight patients were enrolled in the phase I (five females, median age 44 years, two high-grade pleomorphic, two myxoid/round cell liposarcoma, four other). Median tumor size was 16 cm (range 8-29), and all tumors were located in the lower extremity. Two of five patients treated at dose level 2 developed DLT consisting of grade 3 rash not tolerating drug reintroduction. Other grade 3 side effects included anemia, perirectal abscess, and supraventricular tachycardia. Radiation toxicity (grade 1 or 2 dermatitis; N = 8) and post-surgical complications (three grade 3 wound complications) were comparable to historical controls and other series of preoperative RT monotherapy. Complete pathologic reponse (≥95 % tumor necrosis) was observed in three patients (38 %).
  
  
  CONCLUSIONS
  Neoadjuvant sorafenib in combination with RT is tolerable and appears to demonstrate activity in locally advanced extremity STS. Further study to determine efficacy at dose level 1 is warranted. (ClinicalTrials.gov identifier NCT00805727).
authors.affiliation: Division of Surgical Oncology, UC Davis Comprehensive Cancer Center, University of California Davis Medical Center, Sacramento, CA, USA, Robert.canter@ucdmc.ucdavis.edu.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Canter
authors.forename: Dariusz
authors.initials: D
authors.lastname: Borys
authors.forename: Abimbola
authors.initials: A
authors.lastname: Olusanya
authors.forename: Chin-Shang
authors.initials: CS
authors.lastname: Li
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Lee
authors.forename: Robert D
authors.initials: RD
authors.lastname: Boutin
authors.forename: Scott D
authors.initials: SD
authors.lastname: Christensen
authors.forename: Robert M
authors.initials: RM
authors.lastname: Tamurian
authors.forename: Arta M
authors.initials: AM
authors.lastname: Monjazeb
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D059248:Chemoradiotherapy; D005121:Extremities / Q000473:pathology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D060787:Neoplasm Grading; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D011379:Prognosis; D020266:Radiotherapy, Conformal; D012509:Sarcoma / Q000473:pathology / Q000628:therapy*; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib