Limited cytoprotective effects of amifostine in high-dose radioactive iodine 131-treated well-differentiated thyroid cancer patients: analysis of quantitative salivary scan. Randomized phase III trial of postoperative radiochemotherapy +/- amifostine in head and neck cancer. Is there evidence for radioprotection? Salivary gland protection by amifostine in high-dose radioiodine treatment: results of a double-blind placebo-controlled study. Effect of Amifostine to prevent radiotherapy-induced acute and late toxicity in head and neck cancer patients who had normal or mild impaired salivary gland function. Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. Randomized phase 2 study of concomitant chemoradiotherapy using weekly carboplatin/paclitaxel with or without daily subcutaneous amifostine in patients with locally advanced head and neck cancer. Prophylactic use of amifostine to prevent radiochemotherapy-induced mucositis and xerostomia in head-and-neck cancer. A randomized study of very accelerated radiotherapy with and without amifostine in head and neck squamous cell carcinoma. Subcutaneous administration of amifostine during fractionated radiotherapy: a randomized phase II study.
The aim of present study was to investigate the cytoprotective effect of amifostine on salivary glands in 131I-treated differentiated thyroid cancer (DTC) patients using serial quantitative analysis of salivary gland scans.
                Serial quantitative salivary scintigraphies were performed in 80 newly diagnosed DTC patients (9 men, 71 women; mean age, 43.2 years old; range, 21-58 years old). Forty-two patients were assigned randomly to the amifostine treatment group, which received 300 mg/m2 amifostine intravenously before 131I administration.
                In both amifostine-treated and nontreated groups statistically significant declines of functional parameters after 131I treatment were revealed by quantitative salivary scintigraphy in DTC patients. Amifostine pretreatment did not prevent the parenchymal damage to major salivary gland function after 131I treatment (F = 1.37, p = 0.2461). However, the dose of 131I had significant effects on salivary gland function after 131I treatment (F = 9.72, p = 0.0002).
                The present study did not show cytoprotective effects of amifostine for DTC patients treated with 131I. Experimental and clinical data suggest a reduction of radiation-induced acute toxicity by amifostine (A). We investigated this issue in a randomized trial comparing radiochemotherapy (RT + CT) versus radiochemotherapy plus amifostine (RC + CT + A) in patients with head and neck cancer.
                56 patients with oro-/hypopharynx or larynx cancer (T1-2 N1-2 G3, T3-4 N0-2 G1-3) were randomized to receive RC + CT alone or RC + CT + A. Patients were irradiated up to 60 Gy (R0) or 70 Gy (R1/2) and received chemotherapy (70 mg/m(2) carboplatin, day 1-5 in week 1 and 5 of radiotherapy). 250 mg amifostine were applied daily before each radiotherapy session. Acute toxicity was evaluated according to the Common Toxicity Criteria (CTC). As for acute xerostomia, patients with laryngeal cancer were excluded from evaluation.
                50 patients were evaluable (25 patients in the RC + CT, 25 patients in the RC + CT + A group). Clinical characteristics were well balanced in both treatment groups. Amifostine provided reduction in acute xerostomia and mucositis but had no obvious influence on Karnofsky performance status, body weight, cutaneous side effects, and alopecia. The differences between both groups were statistically significant for acute xerostomia and nonsignificant, but with a trend for mucositis.
                According to our results, there is a radioprotective effect on salivary glands and a potential effect on oral mucosa by amifostine in postoperative radiotherapy combined with carboplatin. To improve the radio- and chemoprotective effects of amifostine in clinical practice, the application of a higher dose (> 250 mg) seems to be necessary. Salivary gland impairment is a well-recognized side effect following high-dose radioiodine treatment (HD-RIT). Since differentiated thyroid cancer has a good prognosis, reduction of long-term side effects is important. Therefore, the effect of amifostine was studied in HD-RIT.
                Parenchymal function was assessed by quantitative salivary gland scintigraphy performed prospectively in 50 patients with differentiated thyroid cancer before and 3 months after HD-RIT with either 3 GBq iodine ((131)I) (n=21) or 6 GBq (131)I (n=29) in a double-blind, placebo-controlled study. Twenty-five patients were treated with 500 mg/m2 amifostine intravenously before HD-RIT and 25 patients served as controls, who received physiologic saline solution. Xerostomia was graded according to World Health Organization (WHO) criteria.
                Before HD-RIT in 25 control patients, uptake of technetium-99m (99mTc)-pertechnetate was 0.45%+/-0.16% and 0.42%+/-0.16% in parotid and submandibular glands, respectively. Three months after HD-RIT, parenchymal function was significantly (P < .001) reduced by 40.2%+/-14.1% and 39.9%+/-15.3% in parotid and submandibular glands, respectively. Nine control patients developed grade I and two grade II xerostomia. In 25 amifostine-treated patients, uptake of 99mTc-pertechnetate was 0.46%+/-0.16% and 0.43%+/-0.17% in parotid and submandibular glands, respectively. Three months after HD-RIT, parenchymal function of salivary glands was not significantly altered (P=.691) and xerostomia did not occur in any of these patients.
                Parenchymal damage in salivary glands caused by HD-RIT can significantly be reduced by amifostine, which may improve the quality of life of patients with differentiated thyroid cancer. Amifostine has a potential role for salivary gland protection in head and neck cancer patients who had radiotherapy.
                Sixty-seven head and neck cancer patients were randomized to receive radiotherapy or radiotherapy plus Amifostine. The efficacy of the treatment was determined by a questionnaire evaluating dryness of mouth and the oral comfort, the RTOG/EORTC acute/late radiation morbidity scoring criteria, collection of the whole saliva and the 99mTc-pertecnetate scintigraphy of the salivary glands.
                Amifostine significantly reduced the mean questionnaire scores from 6.49 to 3.73, the incidence of grade > or = 2 mucositis from 75% to 36% and acute xerostomia from 82% to 39%. The salivary gland function returned to normal at a rate of 36.3% in the Amifostine group versus 9.1% in the control group.
                Amifostine is effective in reducing the incidence and severity of acute mucositis, acute and late xerostomia in head and neck cancer patients. Radiotherapy for head and neck cancer causes acute and chronic xerostomia and acute mucositis. Amifositine and its active metabolite, WR-1065, accumulate with high concentrations in the salivary glands. This randomized trial evaluated whether amifostine could ameliorate these side effects without compromising the effectiveness of radiotherapy in these patients.
                Patients with previously untreated head and neck squamous cell carcinoma were eligible. Primary end points included the incidence of grade > or =2 acute xerostomia, grade > or =3 acute mucositis, and grade > or =2 late xerostomia and were based on the worst toxicity reported. Amifostine was administered (200 mg/m(2) intravenous) daily 15 to 30 minutes before irradiation. Radiotherapy was given once daily (1.8 to 2.0 Gy) to doses of 50 to 70 Gy. Whole saliva production was quantitated preradiotherapy and regularly during follow-up. Patients evaluated their symptoms through a questionnaire during and after treatment. Local-regional control was the primary antitumor efficacy end point.
                Nausea, vomiting, hypotension, and allergic reactions were the most common side effects. Fifty-three percent of the patients receiving amifostine had at least one episode of nausea and/or vomiting, but it only occurred with 233 (5%) of 4,314 doses. Amifostine reduced grade > or =2 acute xerostomia from 78% to 51% (P<.0001) and chronic xerostomia grade > or = 2 from 57% to 34% (P=.002). Median saliva production was greater with amifostine (0.26 g v 0.10 g, P=.04). Amifostine did not reduce mucositis. With and without amifostine, 2-year local-regional control, disease-free survival, and overall survival were 58% versus 63%, 53% versus 57%, and 71% versus 66%, respectively.
                Amifostine reduced acute and chronic xerostomia. Antitumor treatment efficacy was preserved. A randomized phase 2 study was performed to investigate the efficacy/toxicity of combining concomitant boost radiation and weekly carboplatin/paclitaxel with or without amifostine in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).
                Patients with newly diagnosed, locally advanced stage III or IV SCCHN received 4 weekly doses of carboplatin (area under the curve, 1.5) and paclitaxel (45 mg/m(2)) concurrently with concomitant boost radiation consisting of 72 grays in 42 fractions over 6 weeks (every day for 18 days, twice a day for 12 days) (grading determined according to the TNM staging system). All patients were randomized to subcutaneous daily amifostine at a dose of 500 mg (Arm A) or no amifostine (Arm B). Toxicity data were collected weekly, and saliva collection was performed with and without citric acid stimulation. To evaluate the correlation between serum cytokine levels and the severity of oral mucositis, we evaluated a subset (13 patients in Arm A and 11 patients in Arm B) of subjects at baseline and then on alternate weeks.
                Fifty-eight patients were enrolled, 29 in each arm. The majority of patients were men (90%), had stage IV disease (82%), and had the oropharynx as the primary tumor site (60%). Major toxicities encountered were similar in both arms and included grade 3 (as determined by Common Terminology Criteria for Adverse Events, version 3.0) mucositis (75% in Arm A and 70% in Arm B) and grade 2 xerostomia (41% in both arms). The median number of amifostine doses delivered was 28, with skin toxicity (grade 3 in 11 patients) as the limiting factor. Saliva production showed no difference between the arms. The median follow-up was 34 months, and only 5 failures had been encountered (2 local and 3 distant) at the time of last follow-up, with an overall survival rate of 89%. Neck dissection was performed in 25 patients; 5 patients demonstrated persistent disease and 4 patients were alive without disease recurrence at the time of last follow-up. The median time to percutaneous endoscopic gastrostomy removal was 9.6 months in Arm A and 10.4 months in Arm B. Only 1 patient remained percutaneous endoscopic gastrostomy-dependent at the time of last follow-up. A correlation was noted between levels of selected cytokines and mucositis severity, in which higher levels of proinflammatory cytokines (tumor necrosis factor, interleukin [IL]-1, and IL-6) and lower levels of anti-inflammatory cytokines (IL-13) were noted. No changes in C-reactive protein levels were noted.
                Four weekly doses of carboplatin/paclitaxel with concomitant boost radiation was found to be a highly effective regimen in this patient population with advanced SCCHN. The overall survival rate was 89%. The time to percutaneous endoscopic gastrostomy removal was prolonged. Amifostine given subcutaneously did not improve the rates of xerostomia and mucositis with this fairly intensive chemoradiotherapy regimen.
                2009 American Cancer Society. To determine the prophylactic properties of amifostine against acute and late toxicities from radiochemotherapy in patients with head-and-neck cancer.
                Fifty patients were randomized to receive conventional radiotherapy (RT) (2-Gy fractions, 5 days weekly, to a total of 60-74 Gy, depending on the tumor localization and TNM classification) and carboplatin (90 mg/m(2) infusion once per week before RT). Amifostine (300 mg/m(2)) was administered in the study group only 15-30 min before RT for 6-7.5 weeks. The primary study end point was the grading of acute and late nonhematologic toxicities (mucositis, dysphagia, xerostomia) induced by radiochemotherapy. Secondary end points included treatment duration, hematologic toxicity, and clinical outcome.
                The treatment duration was significantly shorter in the amifostine-treated group (p = 0.013), because treatment interruptions were more frequent in the control group. Acute toxicities (mucositis and dysphagia) were less severe in the amifostine-treated group. By Week 3, all in the control group experienced Grade 2 mucositis compared with only 9% in the amifostine-treated group (p <0.0001). By Week 5, 52.2% of the patients in the control group experienced Grade 4 mucositis compared with 4.5% in the amifostine-treated group (p = 0.0006). Similar results were obtained for dysphagia. At 3 months of follow-up, only 27% of patients in the study group experienced Grade 2 xerostomia compared with 73.9% in the control group (p = 0.0001). Eighteen months after cessation of therapy, the proportion of patients with Grade 2 xerostomia was 4.5% vs. 30.4% for each respective treatment group (p = 0.047). Cytoprotection with amifostine did not affect treatment outcome, with 90.9% complete responses in the amifostine-treated group compared with 78.3% in the control group (p = 0.414).
                Amifostine was effective in reducing mucositis and dysphagia resulting from radiochemotherapy in patients with head-and-neck cancer. Furthermore, amifostine reduced the severity of late xerostomia, a side effect of RT with long-lasting consequences. Amifostine treatment did not affect the clinical outcome. The aim of this study was to assess whether amifostine could minimize acute mucositis induced by a very accelerated irradiation regimen in patients with advanced head and neck squamous cell carcinoma (HNSCC).
                Between May 1996 and February 1998, 26 patients with an inoperable nonmetastatic Stage IV HNSCC were entered in this study. The treatment consisted of very accelerated radiotherapy given 64 Gy in 3.5 weeks. The patients were randomized to receive or not 150 mg/m(2), amifostine (Ethyol, U.S. Bioscience) 15-30 min prior to each radiation session.
                Of the 13 patients who received amifostine, definitive interruption of amifostine occurred in 5 cases (38%), due to tolerance problems (vomiting, liver enzyme elevation, generalized erythema). The distribution of Grade 4 mucositis (WHO) was 1 case versus 8 cases, with and without amifostine, respectively. The mean duration of "at least Grade 3" mucositis (WHO) was 25.1 days versus 49.2 days with and without amifostine (p = 0.03). In the amifostine group, 11/13 of the patients required a feeding tube (nasogastric tube or medical gastrostomy), because of acute mucositis, whereas in the control group a feeding tube was necessary in all cases. The mean duration of the use of this feeding tube was 1 month versus 2.5 months with and without amifostine respectively (p < 0.01). Local-regional control was not different between both arms with a median follow-up of 15 months.
                Despite the limited number of patients, this pilot randomized study suggests that amifostine was able to markedly reduce the severity and duration of mucositis induced by very accelerated radiotherapy. However, the tolerance of this twice daily amifostine schedule was relatively poor. Amifostine (WR-2721) is an important cytoprotective agent. Although intravenous administration is the standard route, pharmacokinetic studies have shown acceptable plasma levels of the active metabolite of amifostine (WR-1605) after subcutaneous administration. The subcutaneous route, due to its simplicity, presents multiple advantages over the intravenous route when amifostine is used during fractionated radiotherapy.
                Sixty patients with thoracic, 40 with head and neck, and 40 with pelvic tumors who were undergoing radical radiotherapy were enrolled onto a randomized phase II trial to assess the feasibility, tolerance, and cytoprotective efficacy of amifostine administered subcutaneously. A flat dose of amifostine 500 mg, diluted in 2.5 mL of normal saline, was injected subcutaneously 20 minutes before each radiotherapy fraction.
                The subcutaneous amifostine regimen was well tolerated by 85% of patients. In approximately 5% of patients, amifostine therapy was interrupted due to cumulative asthenia, and in 10%, due to a fever/rash reaction. Hypotension was never noted, whereas nausea was frequent. A significant reduction of pharyngeal, esophageal, and rectal mucositis was noted in the amifostine arm (P <.04). The delays in radiotherapy because of grade 3 mucositis were significantly longer in the group of patients treated with radiotherapy alone (P <.04). Amifostine significantly reduced the incidence of acute perineal skin and bladder toxicity (P <.0006).
                Subcutaneous administration of amifostine is well tolerated, effectively reduces radiotherapy's early toxicity, and prevents delays in radiotherapy. The subcutaneous route is much simpler and saves time compared with the intravenous route of administration and can be safely and effectively applied in the daily, busy radiotherapy practice.
Results from two randomised controlled clinical trials suggest that the amifostine has no significant radioprotective effects on salivary glands in high-dose radioactive iodine treated differentiated thyroid cancer patients. Moreover, no health-related quality of life and other patient-oriented outcomes were evaluated in the two included trials. Randomised controlled clinical trials with low risk of bias investigating patient-oriented outcomes are needed to guide treatment choice.