SAN ANTONIO Pretreatment with amifostine(Drug information on amifostine) (Ethyol) reduced the incidence of both acute and chronic xero-stomia in patients undergoing head and neck radiotherapy, David M. Brizel, MD, reported at the 41st Annual Scientific Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO).
Acute and chronic xerostomia and acute mucositis are the most common and clinically significant toxicities associated with radiotherapy for head and neck cancer.
We all know that xerostomia arises in our patients who are irradiated for head and neck cancer, and that there are often lifelong consequences from this, said Dr. Brizel, associate professor of radiation oncology, Duke University Medical Center. Xerostomia does, in fact, cause significant problems for these patients with respect to activities of daily living, dental health, and overall well being, he continued.
The study, an open-label, phase III, multi-institutional, randomized trial, was performed to test whether amifostine could protect against xerostomia and mucositis in head and neck cancer patients receiving radiotherapy without compromising the antitumor efficacy of the radiation itself.
From October 1995 to October 1997, 315 patients were randomized, of whom 303 were actually treated, Dr. Brizel reported. The median follow up is now greater than 2 years. The study population consisted of patients with newly diagnosed, previously untreated head and neck squamous cell carcinoma. Inclusion of greater than 75% of both parotid glands within the radiation fields was required. Almost half of all primary tumors originated in the oropharynx.
This was a randomized trial in which patients in both arms received once-daily standard-fraction radiation therapy to total doses of 50 Gy to 70 Gy, Dr. Brizel said.
The patients in the treatment arm received intravenous amifostine (200 mg/m²) every day, 15 to 30 minutes prior to radiotherapy.
Primary endpoints of the study included the incidence of grade 2 or higher acute xerostomia (defined as xerostomia developing during treatment and persisting to within 90 days after the completion of therapy); grade 3 or higher acute mucositis; and grade 2 or higher late xerostomia (defined as xerostomia persisting 1 year post-treatment).
Type of irradiation (definitive vs postoperative) was included in the stratification parameters, as well as treatment center, primary tumor site, and nodal status. The treatment consisted of isocentric external beam megavoltage irradiation given at 180 to 200 cGy daily, with definitive irradiation prescribed to 66 Gy to 70 Gy. Approximately two thirds of the patients received postoperative irradiation, which was further subclassified into high risk (60 Gy to 64 Gy) and low risk (50 Gy to 54 Gy).
Amifostine significantly reduced the incidence of grade 2 or higher acute xerostomia from 78% to 51% (P < .0001). Moreover, the radiation dose at which half of the patients had acute grade 2 xerostomia is significantly lower in the patients treated with radiotherapy alone. In other words, for 50% of the patients to develop grade 2 xerostomia, you needed to give much more radiation (60 Gy vs 42 Gy) if amifostine was on board each day, Dr. Brizel said.
For late xerostomia across all grades, we see a statistically significant reduction in overall xero-stomia favoring the patients who received amifostine. If we confine our analysis to the study-specific endpoint of grade 2 or higher late xero-stomia, we see that about one third of the patients treated with amifostine had late xerostomia, whereas nearly 60% of the patients treated with radiotherapy alone had this problem, Dr. Brizel said.
Unstimulated saliva production 1 year after treatment was significantly greater for patients who received amifostine (0.26 g vs 0.1 g for those patients who were treated with radiation alone). If one reviews the oral surgery and dental literature, this 0.1 g appears to be a clinically relevant quantity, Dr. Brizel said. Patients whose saliva production is below this threshold tend to have more complaints of xerostomia.
Only 49% of the patients treated with radiation alone were able to exceed this 0.1 g saliva production threshold, whereas nearly three quarters of the patients who received amifostine with radiation had clinically significant saliva production, he added.
Mucositis, grade 3 or higher, occurred in 35% of the patients in the amifostine group and in 39% of the radiotherapy-alone patients. There was no mucosal protection afforded by the drug in this trial, he said.
Improved Quality of Life
Dr. Brizel added that patients receiving amifostine also experienced improved quality of life, as indicated by their responses to a 10-item questionnaire that evaluated symptoms at baseline, during weekly treatment, and at each follow-up visit.
Overall 2-year survival was similar in both groups (71% for the amifostine patients and 66% for the radiotherapy-alone group).
So, in this trial, we demonstrated that amifostine provided significant protection against acute and late xerostomia without any compromise of antitumor efficacy, and that it was safe at the dose delivered, Dr. Brizel concluded.