A Phase I Clinical and Pharmacology Study Using Amifostine as a Radioprotector in Dose-escalated Whole Liver Radiation Therapy

• Published in: International journal of radiation oncology, biology, physics Vol. 83; no. 5; pp. 1441 - 1447
• Main Authors: Feng, Mary, M.D, Smith, David E., Ph.D, Normolle, Daniel P., Ph.D, Knol, James A., M.D, Pan, Charlie C., M.D, Ben-Josef, Edgar, M.D, Lu, Zheng, Ph.D, Feng, Meihua R., Ph.D, Chen, Jun, Ph.D, Ensminger, William, M.D, Lawrence, Theodore S., Ph.D., M.D
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.08.2012; Elsevier
• Subjects: Adult; Aged; Amifostine; Amifostine - pharmacokinetics; Amifostine - therapeutic use; Bile Duct Neoplasms - metabolism; Bile Duct Neoplasms - radiotherapy; Bile Ducts, Intrahepatic; Biological and medical sciences; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - radiotherapy; Cholangiocarcinoma - metabolism; Cholangiocarcinoma - radiotherapy; Diseases of the digestive system; Female; HALF-LIFE; Hematology, Oncology and Palliative Medicine; Humans; LIVER; Liver - drug effects; Liver - metabolism; Liver - radiation effects; Liver Neoplasms - metabolism; Liver Neoplasms - radiotherapy; Liver Neoplasms - secondary; Liver radiation; Logistic Models; Male; Maximum Tolerated Dose; Medical sciences; Mercaptoethylamines - pharmacokinetics; Middle Aged; NEOPLASMS; Organs at Risk - radiation effects; PATIENTS; PHARMACOLOGY; Prospective Studies; Radiation Dosage; RADIATION DOSES; RADIATION EFFECTS; Radiation Injuries - prevention & control; Radiation Tolerance - drug effects; Radiation-Protective Agents - pharmacokinetics; Radiation-Protective Agents - therapeutic use; Radiology; RADIOLOGY AND NUCLEAR MEDICINE; Radioprotector; RADIOTHERAPY; Radiotherapy Planning, Computer-Assisted; Radiotherapy, Conformal; Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects); TOXICITY; Amifostine; Radioprotector; Liver radiation; Human; Intravenous administration; Hepatic disease; Malignant tumor; Metabolism; Radiotherapy; Liver cancer; Increasing dose; Cancerology; Treatment; Cytoprotector; Phase I trial; Digestive diseases; Pharmacokinetics; Cancer
• ISSN: 0360-3016; 1879-355X
• DOI: 10.1016/j.ijrobp.2011.10.020

Purpose 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 and Materials 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. Conclusion 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.