Tissue levels of WR-1065, the active metabolite of amifostine (Ethyol), are equivalent following intravenous or subcutaneous administration in cynomolgus monkeys

Amifostine (Ethyol) is a cytoprotective drug approved for the reduction of xerostomia in head and neck cancer when administered to patients receiving postoperative radiation therapy. Although amifostine is approved for intravenous infusion, the off-label subcutaneous route of administration has become more prevalent. Although human patient data indicate higher plasma bioavailability of the active metabolite (WR-1065) following intravenous compared to subcutaneous administration, there are no corresponding data showing human tissue levels of WR-1065 following either route of administration due to the difficulty in obtaining human specimens. In our study we compared plasma and tissue pharmacokinetics of WR-1065 in primates following both routes of administration. Monkeys received amifostine at a dose of 260 mg/m2 either intravenously or subcutaneously. Plasma samples were analyzed for total WR-1065 by reverse-phase high-pressure liquid chromatography (HPLC) and fluorescence detection up to 4 h after amifostine administration. Tissues were analyzed for free WR-1065 by reverse-phase HPLC and electrochemical detection 30 and 60 min after administration. Following intravenous administration, plasma WR-1065 levels peaked rapidly and showed a bi-exponential decline, while following subcutaneous administration WR-1065 levels rose slowly and declined exponentially. The relative plasma bioavailability of WR-1065 given subcutaneously was lower at 30 and 60 min. Interestingly, after 30 min, tissues showed equal or slightly greater concentrations of WR-1065 following subcutaneous administration. Levels following 60 min were comparable following both routes. The plasma bioavailability studies performed in primates confirm human plasma data. Expanding the study to evaluate primate tissue levels of WR-1065 revealed that despite lower plasma bioavailability following subcutaneous administration, tissue levels of the active metabolite were surprisingly greater than or equal to those measured in animals that received the drug intravenously. These studies strengthen the argument for subcutaneous administration of amifostine in radiation oncology.     

Subcutaneous administration of amifostine (ethyol) is equivalent to intravenous administration in a rat mucositis model

PURPOSE: Amifostine (Ethyol) is currently approved for intravenous (IV) administration to prevent xerostomia in patients receiving radiotherapy for head-and-neck cancer. Recently, subcutaneous (SC) administration has been explored as an alternative route. To determine whether SC administration was equivalent to IV administration, we used models to follow pharmacokinetics and oral mucosal protection in rats. METHODS: Amifostine was administered to rats at doses of 200, 100, or 50 mg/kg (1300, 650, or 325 mg/m(2)) IV or SC at various times before radiation at 15.3 Gy (protection studies) or harvest of blood and tissues for analysis by HPLC (pharmacokinetic studies). RESULTS: Amifostine administered IV or SC 1 h before radiation protected rats from mucositis, but the protective effect was more prolonged when amifostine was administered SC. Tissue levels of the active metabolite (WR-1065) were equivalent after SC administration. The correlation between tissue levels of WR-1065 and protection was strong, but that between blood levels of WR-1065 and protection was only weak. CONCLUSION: These data demonstrate that, in a rat model, SC administration of amifostine was at least as effective as that by IV.     

Amifostine (ETHYOL) protects rats from mucositis resulting from fractionated or hyperfractionated radiation exposure

PURPOSE: The cytoprotective drug amifostine (Ethyol) protects rats from oral mucositis resulting from a single dose of gamma-irradiation. We expanded earlier studies to determine whether multiple doses of amifostine protect against fractionated or hyperfractionated radiation and whether the active metabolite of amifostine (WR-1065) accumulates in tissues upon repeated administration. METHODS AND MATERIALS: Rats received amifostine daily for 5 days in conjunction with a 1-week fractionated radiation schedule and were evaluated for oral mucositis. Rats also received amifostine before the am or pm exposure or b.i.d. in conjunction with hyperfractionated radiation. To determine the pharmacokinetics of WR-1065 after repeated dosing, amifostine was given 5 days a week for 1 or 3 weeks, and rat tissue and plasma were collected at intervals during and after treatment and analyzed for WR-1065. RESULTS: Amifostine protected rats from mucositis resulting from fractionated or hyperfractionated radiation. When the number of days of amifostine administration was reduced, protection was diminished. A dose of 100 mg/kg given in the morning or 2 doses at 50 mg/kg provided the best protection against hyperfractionated radiation. WR-1065 did not accumulate in tissues or tumor upon repeated administration. CONCLUSIONS: Amifostine prevented radiation-induced mucositis in a rat model; protection was dose and schedule dependent.     

Phase III randomized trial of amifostine as a radioprotector in head and neck cancer.

PURPOSE: 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 AND METHODS: 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. RESULTS: 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. CONCLUSION: Amifostine reduced acute and chronic xerostomia. Antitumor treatment efficacy was preserved.     

Phase II multicenter randomized study of amifostine for prevention of acute radiation rectal toxicity: topical intrarectal versus subcutaneous application

PURPOSE: To investigate the cytoprotective effect of subcutaneous vs. intrarectal administration of amifostine against acute radiation toxicity. METHODS AND MATERIALS: Patients were randomized to receive amifostine either intrarectally (Group A, n = 27) or a 500-mg flat dose subcutaneously (Group B, n = 26) before irradiation. Therapy was delivered using a four-field technique with three-dimensional conformal planning. In Group A, 1,500 mg of amifostine was administered intrarectally as an aqueous solution in 40 mL of enema. Two different toxicity scales were used: the European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group (RTOG) rectal and urologic toxicity criteria and the Subjective-RectoSigmoid scale based on the endoscopic terminology of the World Organization for Digestive Endoscopy. Objective measurements with rectosigmoidoscopy were performed at baseline and 1-2 days after radiotherapy completion. The area under the curve for the time course of mucositis (RTOG criteria) during irradiation represented the mucositis index. RESULTS: Intrarectal amifostine was feasible and well tolerated without any systemic or local side effects. According to the RTOG toxicity scale, Group A had superior results with a significantly lower incidence of Grades I-II rectal radiation morbidity (11% vs. 42%, p = 0.04) but inferior results concerning urinary toxicity (48% vs. 15%, p = 0.03). The mean rectal mucositis index and Subjective-RectoSigmoid score were significantly lower in Group A (0.44 vs. 2.45 [p = 0.015] and 3.9 vs. 6.0 [p = 0.01], respectively), and the mean urinary mucositis index was lower in Group B (2.39 vs. 0.34, p < 0.028). CONCLUSIONS: Intrarectal administration of amifostine (1,500 mg) seemed to have a cytoprotective efficacy in acute radiation rectal mucositis but was inferior to subcutaneous administration in terms of urinary toxicity. Additional randomized studies are needed for definitive decisions concerning the cytoprotection of pelvic irradiated areas.     

Phase I trial of a twice-daily regimen of amifostine with ifosfamide, carboplatin, and etoposide chemotherapy in children with refractory carcinoma

BACKGROUND: Amifostine protects normal tissues against chemotherapy and radiation-induced toxicity without loss of antitumor effects. Evidence suggests that multiple daily doses of amifostine may improve its cytoprotective effects. The purpose of this study was to assess the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of twice-daily doses of amifostine with ifosfamide, carboplatin, and etoposide (ICE) chemotherapy for children with refractory malignancies and to determine the pharmacokinetic properties of amifostine, WR-1065, and the disulfide metabolites of amifostine. METHODS: Patients with refractory malignancies were treated with amifostine 15 minutes before and 2 hours after chemotherapy with ifosfamide (3 g/m(2) per dose on Days 1 and 2) and carboplatin (635 mg/m(2) on Day 3). Etoposide was administered on Days 1 and 2 (150 mg/m(2)). The starting dose of amifostine was 740 mg/m(2). Pharmacokinetic studies were performed after the first dose of amifostine. RESULTS: Twelve patients received 23 courses of ICE and amifostine. Dose-limiting toxicities for amifostine at 740 mg/m(2) were somnolence and anxiety. The other Grade 3 and 4 toxicities included asymptomatic, reversible hypocalcemia, vomiting, and reversible hypotension. At a dose of 600 mg/m(2), amifostine was well tolerated. Hypocalcemia, due to rapid, transient suppression of parathyroid hormone production, required close monitoring and aggressive intravenous calcium supplementation. Pharmacokinetic studies revealed high interpatient variability with rapid plasma clearance of amifostine and WR-1065. The median elimination half-life of amifostine (9.3 minutes) and WR-1065 (15 minutes) was much shorter than the disulfide metabolites (74.4 minutes). CONCLUSIONS: The recommended pediatric dose of amifostine for a twice-daily regimen is 600 mg/m(2) per dose (1200 mg/m(2)/day) with DLTs of anxiety and somnolence, lower than the previously recommended single dose of 1650 mg/m(2).     

Amifostine before chemotherapy: improved tolerance profile of the subcutaneous over the intravenous route.

INTRODUCTION: The i.v. administration of the cytoprotective agent amifostine is associated with reversible clinical hypotension, protracted emesis, and malaise in a various percentage of patients. We evaluated, prospectively, whether the s.c. route is a better tolerated alternative to the i.v. route in patients receiving chemotherapy. PATIENTS AND METHODS: Fifty-nine patients treated with "once every 2 weeks" regimens received 1000 mg of amifostine i.v. before chemotherapy. Patients who developed protracted vomiting and malaise and/or clinical hypotension for two consecutive i.v. administrations received the same dose of amifostine s.c. for the subsequent cycles (i.v./s.c. study). In an additional cohort of 12 patients (s.c. study), 1000 mg of amifostine were given s.c. since the first chemotherapy cycle. RESULTS: In the i.v./s.c. study, 8 (13.5%) patients showed protracted emesis/malaise and/or clinical hypotension during the first two cycles. An additional 4 (6.6%) patients developed similar side effects during the subsequent cycles. Switching to the s.c. route, an improved tolerance was noted. In the s.c. study, a total of 76 injections was administered. Protracted vomiting or clinical hypotension was absent, and this tolerance profile was significantly better than the i.v. one (P = 0.001). There were no other systemic side effects related to the s.c. administration. CONCLUSIONS: Amifostine, at a dose of 1000 mg, is better tolerated when administered s.c. Switching to the s.c. route in patients with poor tolerance using the i.v. administration allows the continuation of cytoprotection with minor side effects. Although preliminary, 1000 mg of amifostine effectively protected against the lower, still more frequently administered doses of chemotherapy given once every 2 weeks.     

Protective effect of amifostine on dental health after radiotherapy of the head and neck

Purpose: The cytoprotective agent amifostine has been shown to reduce the radiation-induced acute and chronic xerostomia in head and neck cancer patients. The purpose of this study was to evaluate whether or not amifostine also reduces the incidence of dental caries associated with the radiation-induced xerostomia.

Methods and Materials: The dental status before and 1 year after radiotherapy was retrospectively compared in 35 unselected patients treated as part of the prospective randomized and multicenter open-label Phase III study (WR-38) at the University Hospitals of Heidelberg, Freiburg, and Erlangen. The WR-38 study compared radiotherapy in head and neck cancer with and without concomitant administration of amifostine.

Results: Patient and treatment characteristics (particularly the radiation dose and percentage of parotids included in the treatment volume) were equally distributed between the patients who received (n = 17) or did not receive (n = 18) amifostine. Fifteen patients of the amifostine group showed no deterioration of the dental status 1 year after radiotherapy as compared to 7 patients who did not receive the cytoprotector (p = 0.015, two-tailed Fisher exact test).

Conclusion: Our data suggest a protective effect of amifostine on the dental health after radiotherapy of the head and neck. The dental status should be used as a primary endpoint in future studies on amifostine.     

Concurrent administration of Docetaxel and Stealth liposomal doxorubicin with radiotherapy in non-small cell lung cancer : excellent tolerance using subcutaneous amifostine for cytoprotection

The substantial augmentation of the radiation sequelae during chemo-radiotherapy with novel drugs masks the real potential of such regimens. In this study we examined whether subcutaneous administration of amifostine can reduce the toxicity of a highly aggressive chemo-radiotherapy scheme with Stealth liposomal doxorubicin (Caelyx and Docetaxel (Taxotere in non-small cell lung cancer. Twenty-five patients with stage IIIb non-small cell lung cancer were recruited in a phase I/II dose escalation trial. The starting dose of Taxotere was 20 mg m(-2) week and of Caelyx was 15 mg m(-2) every two weeks, during conventionally fractionated radiotherapy (total dose of 64 Gy). The dose of Taxotere/Caelyx was, thereafter, increased to 20/25 (five patients) and 30/25 mg m(-2) (15 patients). Amifostine 500 mg was given subcutaneously before each radiotherapy fraction, while an i.v. amifostine dose of 1000 mg preceded the infusion of docetaxel. The 'in-field' radiation toxicity was low. Grade 3 esophagitis occurred in 9 out of 25 (36%) patients. Apart from a marked reduction of the lymphocyte counts, the regimen was deprived from any haematological toxicity higher than grade 1. No other systemic toxicity was noted. The CR and CR/PR rates in 15 patients treated at the highest dose level was 40% (6 out of 15) and 87% (13 out of 15) respectively. It is concluded that the subcutaneous administration of amifostine during high dose Taxotere/Caelyx chemo-radiotherapy is a simple and effective way to render this aggressive regimen perfectly well tolerated, by reducing the systemic and the 'in-field' toxicity to the levels expected from simple conventional radiotherapy. The impressive tolerance and the high CR rate obtained encourages the conduct of a relevant randomized trial to assess an eventual survival benefit in patients with non-small cell lung cancer.     

Selective cytoprotection with amifostine in concurrent radiochemotherapy for head and neck cancer

Background: Amifostine has reduced toxicities associated with radiationtherapy and platinum-based chemotherapy. In a phase II randomized trial, weinvestigated the ability of amifostine to reduce the toxicity of carboplatinplus radiotherapy (RCT) in patients with head and neck cancer.Patients and methods: Thirty-nine patients with stage III or IV squamouscell carcinomas of the head and neck received RCT (following surgery or asprimary treatment). Radiotherapy was given five days per week with dailyfractions of 2 Gy, up to a total dose of 60 Gy in conjunction withcarboplatin 70 mg/m² on days 1 through 5 and days 21 through26. Eligible patients were randomised to receive RCT alone or preceded by arapid infusion of amifostine (500 mg) on the days when carboplatin wasadministered.Results: Patients receiving amifostine + RCT (n = 25) had significantlyreduced mucositis (P = 0.0001) and xerostomia (P = 0.0001) in comparisonwith patients receiving RCT alone (n = 14). Additionally, patients receivingamifostine + RCT had significantly less thrombocytopenia (P = 0.001) andleukopenia (P = 0.001). At 12 months following therapy, 79% ofpatients receiving amifostine + RCT had no evidence of disease compared with64% of those receiving RCT alone.Conclusions: Amifostine reduces the RCT-induced toxicities in patients withhead and neck cancer and has no negative impact on antitumour efficacy.     

Commentary: the pharmacological antioxidant amifostine -- implications of recent research for integrative cancer care

Amifostine is a pharmacological antioxidant used as a cytoprotectant in cancer chemotherapy and radiotherapy. It is thought to protect normal tissues relative to tumor tissue against oxidative damage inflicted by cancer therapies by becoming concentrated at higher levels in normal tissues. The degree to which amifostine nevertheless accumulates in tumors and protects them against cancer therapies has been debated. Guidelines have been published that direct its use in chemotherapy and radiation, taking into consideration the concerns of tumor protection. In this article, clinical studies of amifostine appearing since the publication of the most recent set of guidelines are reviewed. Randomized and nonrandomized trials of regimens involving chemo-therapeutic agents (chemotherapy, chemoradiation, conditioning regimens for bone marrow transplant) are discussed. Nineteen studies showed positive effects for amifostine reducing the level of side effects of these regimens, while 9 showed no effect and 1 had a questionable result. Clinically relevant levels of amifostine toxicity were observed in several studies, but subcutaneous administration may reduce such toxicity. Amifostine showed protection against mucositis, esophagitis, neuropathy, and other side effects, although protection against cisplatin-induced ototoxicity was not observed. No evidence of tumor protection was observed. Amifostine may enable populations unable to tolerate conventional cancer therapy to receive treatment of their cancers, even if some degree of tumor protection is eventually discovered. The authors discuss the implications of this research for patient populations seen in integrative cancer care centers and for research on phytochemical antioxidants such as vitamins and carotenoids.     

Phase I trial and pharmacokinetics of escalating doses of paclitaxel and concurrent hyperfractionated radiotherapy with or without amifostine in patients with advanced head and neck carcinoma

BACKGROUND: Amifostine was developed to protect normal tissues from radiation exposure. The current study was undertaken to determine whether amifostine would allow the delivery of greater numbers of weekly paclitaxel treatments with concomitant, hyperfractionated radiotherapy in patients with advanced head and neck carcinoma. METHODS: Patients received radiation therapy twice daily using 1.6-gray (Gy) fractions up to a total of 70.4 Gy over an elapsed time of 6.5 weeks. All patients received paclitaxel 60 mg/m(2) once weekly starting on Day 1. The number of doses of paclitaxel was escalated from three to a maximum of six in groups of three patients. For the patients who received amifostine, a dose of 400 mg/m(2) was given intravenously over 15 minutes on Days 1-5, 8, 29-33, and 36. Patients underwent surgery for persistent tumor after radiotherapy. The plasma pharmacokinetics of paclitaxel were characterized during treatment with the first weekly dose to determine the effect of concurrently administered amifostine. RESULTS: Thirty-six patients were evaluable for this study. In the absence of amifostine, a maximum of four doses of paclitaxel were tolerated in combination with the radiotherapy. With amifostine, up to five doses of paclitaxel could be given. Generally, the treatment resulted in Grade 2 and 3 stomatitis. Overall, 69% of patients had a complete remission, and 29% had a partial remission. Both progression-free survival and overall survival were 66% at 30 months. Amifostine had no effect on the pharmacokinetics of paclitaxel. CONCLUSIONS: The administration of amifostine allowed the authors to give an additional dose of paclitaxel to patients who were undergoing hyperfractionated radiotherapy for head and neck carcinoma. This treatment regimen resulted in a high frequency of complete remissions and an excellent progression-free survival pattern without compromising the plasma kinetics of paclitaxel.     

Prevention of radiation-induced central nervous system toxicity: a role for amifostine?

PURPOSE: To review the role of amifostine (WR-2721) in ameliorating radiation-induced central nervous system (CNS) toxicity. MATERIALS AND METHODS: Literature review and presentation of preliminary animal experiments designed to test the efficacy of both intrathecal and subcutaneous application of amifostine. RESULTS: Despite its inability to cross the blood-brain barrier, amifostine appears promising because it protects blood vessels against radiation-induced damage. Vascular damage is one of the most important components in the development of CNS toxicity after radiotherapy. Furthermore, the increased permeability of the blood-brain barrier during fractionated radiotherapy might allow penetration of amifostine. Three animal studies with systemic administration found positive results after brain irradiation with different fractionation schedules, total doses and amifostine doses. One study where amifostine was given after radiotherapy showed no protection, suggesting that the timing of the drug application is crucial. Further data suggest that either intrathecal or systemic administration might protect the spinal cord as well. In our experience with spinal cord irradiation, systemic administration was more effective than intrathecal. Regarding CNS protection, the optimum dose of amifostine has yet to be determined. CONCLUSION: Several independent experiments provided preliminary evidence that modulation of the radiation response of the CNS in vivo by systemic administration of amifostine is possible and feasible. Additional studies are warranted to investigate the protective effect with differing regimens of administration, more clinically relevant fractionation regimens and longer follow-up.     

Prophylactic use of amifostine to prevent radiochemotherapy-induced mucositis and xerostomia in head-and-neck cancer

PURPOSE: To determine the prophylactic properties of amifostine against acute and late toxicities from radiochemotherapy in patients with head-and-neck cancer. METHODS AND MATERIALS: 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. RESULTS: 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). CONCLUSION: 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.     

Phase I clinical and pharmacologic study of weekly cisplatin and irinotecan combined with amifostine for refractory solid tumors.

PURPOSE: This Phase I study was designed primarily to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of irinotecan and cisplatin with and without amifostine in children with refractory solid tumors. PATIENTS AND METHODS: Cisplatin, at a fixed dose of 30 mg/m(2), and escalating doses of irinotecan (starting dose, 40 mg/m(2)) were administered weekly for four consecutive weeks, every 6 weeks. After the MTD of irinotecan plus cisplatin was determined, additional cohorts of patients were enrolled with amifostine (825 mg/m(2)) support. Leukocyte DNA-platinum adducts and pharmacokinetics of cisplatin and WR-1065 (amifostine-active metabolite) were also determined. RESULTS: Twenty-four patients received 43 courses of therapy. The MTD for irinotecan administered in combination with cisplatin (30 mg/m(2)) was 50 mg/m(2). The DLTs of this combination were neutropenia and thrombocytopenia. With the addition of amifostine, at an irinotecan dose of 65 mg/m(2) and cisplatin dose of 30 mg/m(2), the DLT was hypocalcemia. Although no objective responses were observed, six patients received at least three courses of therapy. The amounts of platinum adducts (mean +/- SD) were 10 +/- 20 molecules/10(6) nucleotides. The maximum plasma concentrations (C(max)) for free cisplatin and WR-1065 were 4.5 +/- 1.6 micro M and approximately 89 +/- 10 micro M, respectively. The half-life (t(1/2)) for free plasma cisplatin was 25.4 +/- 5.4 min. The initial t(1/2) for plasma WR-1065 was approximately 7 min and terminal t(1/2) approximately 24 min. CONCLUSION: The combination of cisplatin and irinotecan administered weekly for 4 weeks in children with refractory cancer is well tolerated. Amifostine offers some myeloprotection, likely permitting >/=30% dose escalation for irinotecan, when administered in a combination regimen with cisplatin. However, effective antiemetics and calcium supplementation are necessary with the use of amifostine. Further escalation of irinotecan dosing, using these precautions for amifostine administration, may be possible.     

Chemical radioprotection: a critical review of amifostine as a cytoprotector in radiotherapy

The use of chemical radioprotectors represents an obvious strategy to improve the therapeutic index in radiotherapy. Amofostine (WR-2721) has recently been approved for use in head and neck cancer to protect against radiation-induced xerostomia. Currently, the question has arisen whether amifostine could be used for radioprotection in broader terms. Amifostine may have the potential to enable intensified treatment by ameliorating mucosal reactions that are often a limiting factor in accelerated fractionation or concomitant chemoradiation. However, it has as yet not been clarified whether sufficient amifostine to reduce mucositis can be administered before each radiation fraction without causing unacceptable toxicity. Also, the optimal dosage and schedule of amifostine in chemoradiation combinations have not yet been established. The major concern related to radioprotectiors is the potential hazard of collateral tumor protection. A number of clinical studies have concluded that amifostine does not reduce antitumor efficacy. However, not even the largest study conducted, with over 300 patients, has sufficient statistical power to detect a clinically significant reduction in tumor control rate. To put this issue ultimately to a rest, a clinical trial with a sufficient accrual to definitely rule out a tumor protective effect of amifostine needs to be conducted. Substances reducing radiation-induced toxicity by modulating the biological response to radiation injury may represent an alternative concept in radioprotection. However, such agents are still at a developmental stage.     

Serious adverse effects of amifostine during radiotherapy in head and neck cancer patients

Background and purpose: Amifostine has been shown to protect against xerostomia induced by radiotherapy for head and neck cancer, but its impact on the therapeutic index is unknown. This is the first report focusing on amifostine related adverse effects leading to discontinuation of amifostine treatment.

Patients and methods: Thirty-nine patients from two centers irradiated for head and neck cancer received i.v.-infusions of amifostine prior to each radiation fraction. In a phase III study, two daily amifostine doses, 200 mg/m² (n=21) and 340 mg/m² (n=18), were compared for protection against radiation induced toxicity. Total radiation dose was 60–70 Gy (2 Gy per fraction), nine patients received concurrent chemotherapy with cisplatin/5-FU. amifostine was usually discontinued after >1 episode of serious toxicity during subsequent treatment sessions.

Results: In 16/39 patients (41%) amifostine was discontinued due to severe adverse effects, which led to discontinuation of the phase III study. In four of 16 patients radiotherapy was delayed due to amifostine related adverse effects for 1–3 days. Discontinuation occurred more often in patients receiving chemotherapy. The results led to a literature review for amifostine treatment during radiotherapy in head and neck cancer patients. Regarding our series and published series using an amifostine schedule comparable to ours, total discontinuation rate was 27% (57/214). Discontinuation was significantly influenced by chemotherapy (P=0.007), but not by amifostine dose (P=0.156).

Conclusion: Daily i.v. administration of amifostine during radiotherapy in head and neck cancer is associated with a high rate of serious adverse effects leading to discontinuation of amifostine treatment and sometimes delay of radiotherapy.     

Efficacy and safety of subcutaneous amifostine in minimizing radiation-induced toxicities in patients receiving combined-modality treatment for squamous cell carcinoma of the head and neck

PURPOSE: To report long-term data from a prospective trial of subcutaneous (s.c.) amifostine in patients who received chemoradiotherapy for squamous cell carcinoma of the head and neck (SCCHN). METHODS AND MATERIALS: Patients >or=18 years of age with previously untreated Stage III/IV SCCHN received fractionated radiotherapy, 1.8-2.0 Gy/day, 5 days per week, to a total dose of 70-72 Gy, plus weekly paclitaxel (40 mg/m2) and carboplatin (100 mg/m2) administered intravenously (i.v.) for 6 weeks. All patients received 500 mg s.c. amifostine 30-60 min before radiotherapy with antihistamine and antiemetic prophylaxis. RESULTS: Twenty patients were evaluable (median age, 55 years). The incidence of Grade 2 xerostomia was 42% and 29% at 12 and 18 months, respectively; there were no reports of Grade >or=3 xerostomia. Grade >or=3 mucositis occurred in 30% of patients, with median time to resolution of 12.5 weeks (range, 5-17 weeks). Survival estimates at 1 and 2 years were 95% and 71%, respectively. All patients experienced Grade 2 weight loss; 7 patients (35%) experienced Grade /=3 amifostine-related adverse events. CONCLUSIONS: Subcutaneous amifostine was well tolerated by patients receiving chemoradiotherapy for SCCHN, with lower rates of nausea/vomiting than reported in trials with i.v. amifostine. Xerostomia and mucositis rates were similar to those reported in trials with i.v. amifostine.     

Impact on cytoprotective efficacy of intermediate interval between amifostine administration and radiotherapy: a retrospective analysis

PURPOSE: To evaluate the cytoprotective impact of the interval between amifostine administration and radiotherapy (RT). METHODS AND MATERIALS: In a nonrandomized study, we reviewed the records of 177 patients with tumors localized in the pelvis (prostate, bladder, or gynecologic cancer), upper abdomen (pancreas, stomach, kidney), thorax (lung and breast cancer), head and neck (nasopharynx), soft tissue (sarcomas), and central nervous system. The patient records were stratified according to whether the patients had undergone RT either 25-40 min (Group 1, 96 subjects) or 10-15 min (Group 2, 81 subjects) after i.v. amifostine administration. The mean toxicity score was the mean value of recorded acute radiation toxicity. The mean interruption time was the mean value of the recorded interruption time due to radiation toxicity. RESULTS: A significantly reduced severity of symptoms related to oral (p = 0.023), esophageal (p = 0.05) and rectal (p = 0.015) mucosa was noted in Group 2. A statistically significant reduction in the mean toxicity score (p <0.001) and mean interruption time (p = 0.001) was observed in Group 2 vs. Group 1. In terms of the incidence of radiation-induced dermatitis and alopecia, multivariate logistic analysis revealed only the total dose (p = 0.018) and the amifostine-RT interval (p = 0.002) as independent factors. CONCLUSION: A significantly better cytoprotective effect of amifostine against radiation-induced mucositis, dermatitis, and alopecia was noted if RT was administered no later than 15 min after i.v. amifostine infusion. The results presented here need additional investigation with randomized prospective trials.