Amifostine Reduces Xerostomia, Loss of Taste, Fibrosis, Pain

ZUHL, Germany—Amifostine (Ethyol) used as cytoprotective therapy can reduce the occurrence of xerostomia, loss of taste, and fibrosis associated with radiochemotherapy for head and neck cancer. Jens Buentzel, MD, PhD, reported results of three studies at The First Investigators’ Congress on Radio-protection, held at the Kimmel Cancer Center at Jefferson University, Philadelphia. Dr. Buentzel is vice chairman of the Department of Otolaryngology, Head and Neck Oncology, Zentralklinikum Zuhl, Germany.

Pilot Study

The pilot trial was a controlled phase II study involving 14 patients randomized to receive standard radiochemotherapy, with radiation administered in 2-Gy fractions to a total dose of 60 Gy, plus carboplatin (Paraplatin) 70 mg/m² as a radiosensitizer on weeks 1 and 5.

Another 14 patients received the same regimen plus amifostine 500 mg given prior to carboplatin as a short infusion over approximately 10 minutes. The time interval between amifostine administration and the end of daily irradiation was less than 60 minutes, and no cytoprotectant was given on days of radiotherapy alone.

Amifostine significantly reduced mucositis, xerostomia, dysphagia, ageusia, and dermatitis rates, as well as anemia, leukocytopenia, and thrombocytopenia.

Dr. Buentzel concluded that amifostine could reduce the typical acute chemotherapy-related toxicities and should be able to reduce radiation-induced acute toxicities but must be administered within an interval of no more than 60 minutes prior to the end of radiotherapy.

"At 5 years after treatment, the survival rate in the amifostine group is a little bit better than in the control group, and we have no sign of tumor protection," Dr. Buentzel said. "There was a surprising decrease in nonhematologic toxicities. These were the first data to show a reduction of mucositis from amifostine given prior to chemotherapy. We see similar results in clinical practice. I would like to focus attention on the reduction of severity of mucositis, dysphagia, and loss of taste. These effects should be examined in larger studies."

Dose-Intensification Study

This study was followed by a controlled, phase II dose-intensification study to evaluate the role of intensified carboplatin dosage with amifostine protection and concomitant radiochemotherapy in locally advanced pharyngeal cancer.

The trial enrolled 76 consecutive patients (mean age, 55 years) with unresectable locally advanced squamous-cell carcinoma without distant metastases. All patients had definitive radiochemotherapy with a conventional fractionation, linear accelerator using single doses of 2 Gy to a total dose of 60 Gy to the primary tumor and cervical nodes, with a boost to 70 Gy for sites of tumor.

The first 45 patients in this series received carboplatin (70 mg/m²) on days 1 to 5 and 29 to 33 of radiotherapy. Cumulative carboplatin dose was 700 mg/m². The next 31 patients received carboplatin at the same dose on days 1 to 5, 15 to 19, 29 to 33, and 43 to 47 of radiotherapy. The cumulative carboplatin dose was 1,050 to 1,400 mg/m². All patients received 500 mg of amifostine. Radiation was given immediately after completion of chemotherapy.

Initial data analysis showed no differences between the two regimens. Subgroup analysis stratified according to tumor volume showed that patients with tumors smaller than 20 cm³ had better response with the intensified regimen, especially in overall survival (median, 22 months vs 15 months) and in time to progression (median, 17 months vs 10 months). There was no effect in patients with larger tumors.

"In our opinion, there is no reason to take such a patient in such an intensified regimen of platinum derivatives, especially since leukocytopenia was increased, although rarely enough to require growth factors," Dr. Buentzel said. ‘‘Our conclusion is that it may be possible in selected cases to use a higher dosage of chemotherapy under the cytoprotection of amifostine in order to get a better outcome."

Late Toxicities

Dr. Buentzel’s group also studied the influence of cytoprotection on late toxicities in head and neck cancer. Between 1999 and 2000, his department enrolled 531 patients in a follow-up trial. They were observed and a questionnaire elicited information about xerostomia, dysphagia, and loss of taste. The researchers also assessed esophageal stenosis, pain, interstitial lymphedema, and fibrosis.

A total of 313 patients had received amifostine during primary treatment. The remaining 218 patients who had not received amifostine were the control group. Of the 143 patients who had primary radiochemotherapy, 90 received amifostine and 53 did not.

Dr. Buentzel reported that cytoprotection with amifostine reduced both xerostomia and loss of taste. "Loss of taste remains for 10 or 15 years for many patients and is a question of quality of life for long-time survivors," he said.

The development of fibrotic changes in the area of a former tumor is a problem, especially for patients treated with surgery plus radiochemotherapy. "The development of such fibrotic tissues in the head-neck area is one of the factors which lead to dysphagia," Dr. Buentzel said. Amifostine significantly reduced this problem.

Pain Significantly Reduced

Grade 2 or 3 pain during the first 2 years after radiochemotherapy was also significantly reduced in the amifostine-treated patients. Amifostine had no significant effect on interstitial lymphedema or on esophageal stenosis.

"Xerostomia, loss of taste, fibrosis, and pain are late symptoms which the data show can be prevented with the use of amifostine," Dr. Buentzel concluded.