title: A phase I clinical and pharmacology study using amifostine as a radioprotector in dose-escalated whole liver radiation therapy.
abstract: OBJECTIVE
  Diffuse intrahepatic tumors are difficult to control. Whole-liver radiotherapy has been limited by toxicity, most notably radiation-induced liver disease. Amifostine is a prodrug free-radical scavenger that selectively protects normal tissues and, in a preclinical model of intrahepatic cancer, systemic amifostine reduced normal liver radiation damage without compromising tumor effect. We hypothesized that amifostine would permit escalation of whole-liver radiation dose to potentially control microscopic disease. We also aimed to characterize the pharmacokinetics of amifostine and its active metabolite WR-1065 to optimize timing of radiotherapy.
  
  
  METHODS
  We conducted a radiation dose-escalation trial for patients with diffuse, intrahepatic cancer treated with whole-liver radiation and intravenous amifostine. Radiation dose was assigned using the time-to-event continual reassessment method. A companion pharmacokinetic study was performed.
  
  
  RESULTS
  Twenty-three patients were treated, with a maximum dose of 40 Gy. Using a logistical regression model, compared with our previously treated patients, amifostine increased liver tolerance by 3.3 ± 1.1 Gy (p = 0.007) (approximately 10%) with similar response rates. Peak concentrations of WR-1065 were 25 μM with an elimination half-life of 1.5 h; these levels are consistent with radioprotective effects of amifostine in patients.
  
  
  CONCLUSIONS
  These findings demonstrate for the first time that amifostine is a normal liver radioprotector. They further suggest that it may be useful to combine amifostine with fractionated or stereotactic body radiation therapy for patients with focal intrahepatic cancer.
authors.affiliation: Department of Radiation Oncology, School of Medicine, University of Michigan, Ann Arbor, Michigan, USA. maryfeng@umich.edu
authors.forename: Mary
authors.initials: M
authors.lastname: Feng
authors.forename: David E
authors.initials: DE
authors.lastname: Smith
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Normolle
authors.forename: James A
authors.initials: JA
authors.lastname: Knol
authors.forename: Charlie C
authors.initials: CC
authors.lastname: Pan
authors.forename: Edgar
authors.initials: E
authors.lastname: Ben-Josef
authors.forename: Zheng
authors.initials: Z
authors.lastname: Lu
authors.forename: Meihua R
authors.initials: MR
authors.lastname: Feng
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: William
authors.initials: W
authors.lastname: Ensminger
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Lawrence
mesh_terms: D000328:Adult; D000368:Aged; D004999:Amifostine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001650:Bile Duct Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D001653:Bile Ducts, Intrahepatic; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000532:radiotherapy*; D018281:Cholangiocarcinoma / Q000378:metabolism / Q000532:radiotherapy*; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D008113:Liver Neoplasms / Q000378:metabolism / Q000532:radiotherapy* / Q000556:secondary; D016015:Logistic Models; D008297:Male; D020714:Maximum Tolerated Dose; D008624:Mercaptoethylamines / Q000493:pharmacokinetics; D008875:Middle Aged; D058958:Organs at Risk / Q000528:radiation effects; D011446:Prospective Studies; D011829:Radiation Dosage; D011832:Radiation Injuries / Q000517:prevention & control; D011836:Radiation Tolerance / Q000187:drug effects; D011837:Radiation-Protective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011880:Radiotherapy Planning, Computer-Assisted; D020266:Radiotherapy, Conformal
chemical_list: D008624:Mercaptoethylamines; D011837:Radiation-Protective Agents; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; D004999:Amifostine