HOUSTON-Amifostine (Ethyol) can reduce the risk of acute pneumonitis and severe esophagitis associated with concurrent radiation and chemotherapy administered to patients with advanced non-small-cell lung cancer (NSCLC). Results of a phase III study were reported by Ritsuko Komaki, MD, professor of radiation oncology at the University of Texas M.D. Anderson Cancer Center in Houston.
HOUSTONAmifostine (Ethyol) can reduce the risk of acute pneumonitis and severe esophagitis associated with concurrent radiation and chemotherapy administered to patients with advanced non-small-cell lung cancer (NSCLC). Results of a phase III study were reported by Ritsuko Komaki, MD, professor of radiation oncology at the University of Texas M.D. Anderson Cancer Center in Houston.
"The purpose of this trial was to compare esophageal toxicity of grade 3 to 4, including severe dysphagia and odynophagia, in patients who received chemoradiotherapy with or without amifostine. The trial also compared hematologic and pulmonary toxicity. Secondary endpoints were survival, local control and distant metastasis," Dr. Komaki said. Toxicities were scored using Radiation Therapy Oncology Group (RTOG) criteria. The study was designed with the power to detect a 50% reduction in the rate of severe acute esophagitis.
Amifostine was chosen for this study because it has protective abilities against nephrotoxicity, hematologic toxicity, neurologic toxicity, and radiation-induced injury, Dr. Komaki explained.
Eligibility criteria included medically inoperable stage II and stage IIIA or IIIB NSCLC, no major weight loss, and no pleural effusion, prior chemotherapy, or prior radiation therapy. "We had only two patients with medically inoperable stage II disease. The majority of the patients were surgically inoperable stage IIIB," Dr. Komaki said.
Randomized to Two Arms
Twenty-seven patients were randomized to arm I (chemoradiation with amifostine) and 26 were randomized to arm II (chemoradiation without amifostine). Patients in arm I received amifostine, 500 mg IV over 5 minutes, 15 minutes before cisplatin (Platinol) infusion on days 1, 8, 29, and 36, and 500 mg IV over 5 minutes, 30-60 minutes before the first daily fraction of radiation on days 2, 9, 15, 16, 22, 23, 30, and 37.
"The regimen was slightly different from that in RTOG 98-01. We used oral etoposide and cisplatin and radiation therapy in 1.2 Gy twice-daily fractionations, with a 6-hour interfractional interval, and the total tumor dose of 69.6 Gy. There was no induction chemotherapy," Dr. Komaki said. "We gave the amifostine at 7 o’clock in the morning."
Acute grade 3 or worse esophagitis was observed significantly less often in the patients treated with amifostine compared to the control group (7.4% vs 31%, P = 0.03). Acute grade 3 or worse pneumonitis was also significantly reduced by amifostine (3.7% vs 23%, P = 0.037). "Interestingly, those patients who received amifostine also didn’t lose much of their hair, according to a medical oncologist. There must be some protection to the skin and hair follicles in those patients," Dr. Komaki said.
No Adverse Survival Effects
Dr. Komaki reported that treatment with amifostine increased the complete response rate and did not adversely affect overall survival. More than half of the patients in the amifostine and the control groups were alive at 24 months. Complete response was observed in 7/27 (26%) among patients in the amifostine group and 2/26 (7%) among patients in the control group (P = 0.07). Because of the small number of patients, no significant difference in median survival was observed. Among complete response groups, median survival was 26 months with amifostine vs 15 months without amifostine (P = NS). Similar effects were observed on disease-free survival and local-regional control.
"Amifostine can be administered safely with concurrent cisplatin/oral etoposide and thoracic radiation therapy," Dr. Komaki concluded. "Amifostine significantly reduced acute pneumonitis and severe esophagitis and increased the complete response rate. Amifostine also prevented reduction of the diffusion capacity of the lung for carbon monoxide (DLCO) in pretreatment and posttreatment pulmonary function testing. Hypotension appears to be the major acute problem with use of amifostine. We gave the IV very quickly, in about 3 minutes, and 70% of the patients who received amifostine developed hypotension briefly. Blood pressure returned to normal within about 2 hours. Further follow-up is needed to determine the long-term efficacy and possible cytotoxic effect of amifostine."