Radiotherapy (RT) or radiochemotherapy is the treatment of choice for patients with medically or technically inoperable non-small cell lung cancer (NSCLC) localized to the primary site and regional lymph nodes. Radiation-induced damage has been recognized as a major complication in thoracic RT. The use of concurrent chemoradiation has been associated with an increase in acute and late toxicity. Amifostine (Ethyol) is an effective cytoprotective agent and also may have a role in protecting healthy lung tissue during radiation treatment. The purpose of these 2 clinical trials was to investigate whether daily pretreatment with amifostine could reduce the incidence of esophagitis, and acute and late lung toxicity without affecting the antitumor efficacy of the treatment. The first was a phase III randomized trial of 146 patients with locally advanced lung cancer. All patients received conventional RT to a total of 55 to 60 Gy, and they were assigned randomly to pretreatment with 340 mg/m(2) of amifostine (A). Acute and late toxicities were graded according to the Radiation Therapy Oncology Group (RTOG) grading system from grades 0 to 4. Ninety-seven patients were evaluated 2 months post-RT for the incidence of pneumonitis; 43% (23 of 53) of patients in the RT arm and 9% (9 of 44) in the A plus RT arm experienced grade > or = 2 pneumonitis (P <.001). Forty-nine percent (26 of 53) of patients in the RT arm and 16% (7/44) in the A plus RT arm showed changes that were representative of grade > or = 2 lung damage in the computed tomography (CT) scan. Fibrosis was present in 53% (19 of 36) of patients receiving RT versus 28% (9 of 32) in the A plus RT arm at 6 months (P < 0.05). The incidence of esophagitis grade > or = 2 during week 4 was 42% (31 of 73) in the RT arm versus 4% (3 of 73) in the A plus RT arm (P <.001). Among 97 patients evaluable for response 2 months after RT, complete or partial responses were present in 76% (40 of 53) of patients in the RT arm and 75% (33 of 44) in the A plus RT arm (P = 1.0). The second trial was a phase II randomized study of 45 patients with NSCLC. All patients had received platinum-based induction chemotherapy before being referred for conventional radiation treatment with or without A; a total dose of 55 to 60 Gy was administered at the primary site. Acute and late toxicities were evaluated and graded according the RTOG criteria from grades 0 to 4. Forty-five patients were evaluable for response 2 months after RT. Complete or partial responses were achieved in 78% (18 of 23) of patients in the RT arm and 82% (18 of 22) in the A plus RT arm (P =.278). By week 5, 74% (17 of 23) of patients in the RT group versus 36% (8 of 22) in the A plus RT group experienced grade > or = 2 esophagitis. (During the follow-up period, pulmonary toxicity was evaluated by CT scan.) Three months after RT, 65% (15/23) of patients in the RT group and 32% (7 of 22) in the A plus RT group presented with grade > or = 2 pneumonitis (P =.038). Amifostine reduces the incidence of acute and late radiation-induced toxicities.