title: Phase 1 Trial of Sorafenib and Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma.
abstract: OBJECTIVE
  To determine the maximally tolerated dose of sorafenib delivered before, during, and after stereotactic body radiation therapy (SBRT) in hepatocellular carinoma (HCC).
  
  
  METHODS
  Eligible patients had locally advanced Child-Pugh class A HCC, showed Eastern Cooperative Oncology Group performance status 0-1, and were ineligible for standard local-regional therapies. Sorafenib was dose escalated in 2 strata: (1) low effective irradiated liver volume (veff) < 30% and (2) high veff 30%to 60%. Sorafenib (400 mg daily = dose level 1) was administered for 12 weeks, with 6 fractions SBRT delivered weeks 2 and 3, and escalation to full dose (400 mg twice daily) after 12 weeks as tolerated. Standard 3 + 3 cohorts with dose escalation of sorafenib were planned.
  
  
  RESULTS
  Sixteen patients (4 low veff, median dose 51 Gy; 12 high veff, median dose 33 Gy) were treated at 2 sorafenib dose levels. Of those patients 75% were had Barcelona Clinic Liver Cancer stage C, and 63% had main branch portal vein invasion. In the low veff stratum, no dose-limiting toxicities (DLTs) were observed in 4 patients treated with SBRT and sorafenib 400 mg. Inb the high veff stratum: 2 of 3 evaluable patients treated with sorafenib 400 mg experienced DLT (grade 3 large bowel bleed and grade 4 bowel obstruction 51 and 27 days, respectively, after SBRT). One of 6 evaluable patients at dose level -1 (200 mg once daily) experienced a grade 3 tumor rupture at week 5. Median overall survival and in-field local progression have not been reached. Worsening of Child-Pugh liver function class was seen in 6 of 12 patients in the high veff stratum.
  
  
  CONCLUSIONS
  Significant toxicity was observed in the high veff stratum, and concurrent SBRT with sorafenib is not recommended outside a clinical trial.
authors: Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address: anthony.brade@rmp.uhn.on.ca.
authors: Anthony M
authors: AM
authors: Brade
authors: Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors: Sylvia
authors: S
authors: Ng
authors: Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors: James
authors: J
authors: Brierley
authors: Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors: John
authors: J
authors: Kim
authors: Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors: Robert
authors: R
authors: Dinniwell
authors: Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors: Jolie
authors: J
authors: Ringash
authors: Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors: Rebecca R
authors: RR
authors: Wong
authors: Department of Radiation Oncology, Southlake Regional Cancer Centre, Newmarket, Ontario, Canada.
authors: Charles
authors: C
authors: Cho
authors: Division of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors: Jennifer
authors: J
authors: Knox
authors: Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors: Laura A
authors: LA
authors: Dawson
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000601:surgery*; D019583:Dose Fractionation, Radiation; D005260:Female; D006801:Humans; D007422:Intestines / Q000187:drug effects / Q000528:radiation effects; D008099:Liver / Q000187:drug effects / Q000528:radiation effects; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000601:surgery*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects*; D016634:Radiosurgery / Q000009:adverse effects / Q000379:methods*; D011879:Radiotherapy Dosage; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib