Amifostine ameliorates bleomycin-induced murine pulmonary fibrosis via NAD+/SIRT1/AMPK pathway-mediated effects on mitochondrial function and cellular metabolism.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disease characterized by irreversible scarring of the lung parenchyma. Despite various interventions aimed at mitigating several different molecular aspects of the disease, only two drugs with limited clinical efficacy have so far been approved for IPF therapy. OBJECTIVE: We investigated the therapeutic efficacy of amifostine, a detoxifying drug clinically used for radiation-caused cytotoxicity, in bleomycin-induced murine pulmonary fibrosis. METHODS: C57BL6/J mice were intratracheally instilled with 3 U/kg of bleomycin. Three doses of amifostine (WR-2721, 200 mg/kg) were administered intraperitoneally on days 1, 3, and 5 after the bleomycin challenge. Bronchoalveolar lavage fluid (BALF) was collected on day 7 and day 21 for the assessment of lung inflammation, metabolites, and fibrotic injury. Human fibroblasts were treated in vitro with transforming growth factor beta 1 (TGF-ß1), followed by amifostine (WR-1065, 1-4 µg/mL) treatment. The effects of TGF-ß1 and amifostine on the mitochondrial production of reactive oxygen species (ROS) were assessed by live cell imaging of MitoSOX. Cellular metabolism was assessed by the extracellular acidification rate (ECAR), the oxygen consumption rate (OCR), and the concentrations of various energy-related metabolites as measured by mass spectrum (MS). Western blot analysis was performed to investigate the effect of amifostine on sirtuin 1 (SIRT1) and adenosine monophosphate activated kinase (AMPK). RESULTS: Three doses of amifostine significantly attenuated lung inflammation and pulmonary fibrosis. Pretreatment and post-treatment of human fibroblast cells with amifostine blocked TGF-ß1-induced mitochondrial ROS production and mitochondrial dysfunction in human fibroblast cells. Further, treatment of fibroblasts with TGF-ß1 shifted energy metabolism away from mitochondrial oxidative phosphorylation (OXPHOS) and towards glycolysis, as observed by an altered metabolite profile including a decreased ratio of NAD + /NADH and increased lactate concentration. Treatment with amifostine significantly restored energy metabolism and activated SIRT1, which in turn activated AMPK. The activation of AMPK was required to mediate the effects of amifostine on mitochondrial homeostasis and pulmonary fibrosis. This study provides evidence that repurposing of the clinically used drug amifostine may have therapeutic applications for IPF treatment. CONCLUSION: Amifostine inhibits bleomycin-induced pulmonary fibrosis by restoring mitochondrial function and cellular metabolism.

Xerostomia: From Pharmacological Treatments to Traditional Medicine-An Overview on the Possible Clinical Management and Prevention Using Systemic Approaches.

Despite high incidence rates and severe complications, the management of xerostomia lacks clinical guidelines. The aim of this overview was to summarize the clinical experience derived from the last 10 years of treatments and prevention using systemic compounds. Results showed that the cytoprotective drug amifostine, and its antioxidant agents, are the most discussed as preventive agents of xerostomia in head and neck cancer (HNC) patients. In the presence of the disease, the pharmacological treatments have been mainly directed to stimulate secretion of the damaged salivary glands, or to counteract a decreased capacity of the antioxidant system, in view of an increasing of reactive oxygen species (ROS). However, the data demonstrated low ability of the drugs, together with a great number of side effects, which strongly limit their use. Concerning traditional medicine (TM), valid clinical trials are so limited that neither the efficacy nor the absence of interferences to concomitant chemical therapies can be validated. Consequently, the management of xerostomia and its devastating complications remain a very significant void in daily clinical practice.

Preclinical Evaluation of Safety, Pharmacokinetics, Efficacy, and Mechanism of Radioprotective Agent HL-003.

Amifostine is a radioprotector with high efficacy but poor safety, short half-life, no oral formulation, and poor compliance, which limits its application. With the increasing risk of exposure to radiation, the development of new radioprotective agents is critical. We previously synthesized a new amifostine derivative, the small molecule compound HL-003. In this study, we focused on evaluating the radioprotective properties of HL-003. Using the in vitro 2,2-diphenyl-1-picrylhydrazyl assay, we initially confirmed HL-003 as a strong antioxidant and demonstrated that its free radical scavenging activity was stronger than that of amifostine. Then, we performed an acute toxicity test, a 28-day toxicity test, a 30-day survival rate test, and a pharmacokinetic study, all of which provided aggregate evidence that HL-003 functioned as a small molecule radioprotector with high efficacy, a favorable safety profile, a long half-life, and oral administration. The intestinal radioprotective mechanism of HL-003 was explored in male C57 mice after abdominal irradiation by analyzing intestinal tissue samples with hematoxylin-eosin staining, immunohistochemistry, TUNEL staining, and immunofluorescence detection. The results showed that HL-003 protected intestinal DNA from radiation damage and suppressed the expression of phosphorylated histone H2AX, phosphorylated p53, and the apoptosis-related proteins caspase-8 and caspase-9, which contributed to maintaining the normal morphology of the small intestine and provided insights into the mechanism of radioprotection. Thus, HL-003 is a small molecule radioprotector with a potential application in radiation medicine.

Feasibility and Outcome of a Phase II Study of Intensive Induction Chemotherapy in 91 Elderly Patients with AML Evaluated Using a Simplified Multidimensional Geriatric Assessment.

INTRODUCTION: We prospectively tested in a phase II study high-dose aracytin and idarubicin plus amifostine as induction regimen in 149 patients with acute myeloid leukaemia (AML) aged ≥ 60 years, evaluated by a simplified multidimensional geriatric assessment (MGA). METHODS: Ninety-one fully or partially fit patients (61%) were allocated to intensive chemotherapy and 58 (39%) frail patients to best supportive care (BSC). Intensively treated patients, showing early death and complete response (CR) rate respectively of 5.5% and 73.6%, received 61 consolidations, followed by autologous transplant (ASCT), stem cell transplantation (SCT) or gemtuzumab ozogamicin, depending on mobilization outcome and donor availability. RESULTS: The 8-year overall survival (OS) of these patients was 20.4%, with median duration of 11.4 months significantly superior to the 1.5 months of BSC arm (p < 0.001). Hyperleukocytosis and cytogenetics were predictors of survival with a relative risk of 1.8 in patients with poor karyotype without hyperleukocytosis (p = 0.02) and 3 in those with hyperleukocytosis (≥ 50,000/µl) (p = 0.002). CONCLUSION: MGA allowed tailored post-consolidation in 53.8% of patients after high-dose aracytin induction, with long-term survival doubling that reported in the literature after standard-dose cytarabine regimens. TRIAL REGISTRATION: The study was registered with the Umin Clinical Trial Registry (www.umin.ac.jp/ctr), number R000014052.

Use of Amifostine for Cytoprotection during Radiation Therapy: A Review.

BACKGROUND: Radiation therapy is a cornerstone of the therapeutic modalities used in modern oncology. However, it is sometimes limited in its ability to achieve optimal tumor control by radiation-induced normal tissue toxicity. In delivering radiation therapy, a balance must be achieved between maximizing the dose to the tumor and minimizing any injury to the normal tissues. Amifostine was the first Food and Drug Administration (FDA)-approved clinical radiation protector intended to reduce the impact of radiation on normal tissue, lessening its toxicity and potentially allowing for increased tumor dose/control. Despite being FDA-approved almost 20 years ago, Amifostine has yet to achieve widespread clinical use. SUMMARY: A thorough review of Amifostine's development, mechanism of action, and current clinical status were conducted. A brief history of Amifostine is given, from its development at Walter Reid Institute of Research to its approval for clinical use. The mechanism of action of Amifostine is explored. The results of a complete literature review of all prospective randomized trials to date involving the use of Amifostine in radiation therapy are presented. The results are arranged by treatment site and salient findings discussed. Side effects and complications to consider in using Amifostine are reviewed. Key Messages: Amifostine has been explored as a radiation protectant in most radiation treatment sites. Studies have demonstrated efficacy of Amifostine in all treatment sites reviewed, but results are heterogeneous. The heterogeneity of studies looking at Amifostine as a clinical radiation protectant has precluded a definitive answer on its efficacy. Complicating its clinical use is its toxicity and delivery requirements. Amifostine has largely fallen out of use with the advent of intensity modulated radiation therapy (IMRT). However, side effects with IMRT remain a challenge and concern. The use of Amifostine in the IMRT era has been poorly explored and is worthy of future study.

The efficacy and safety of amifostine for the acute radiation syndrome.

Introduction: A radiation countermeasure that can be used prior to radiation exposure to protect the population from the harmful effects of radiation exposure remains a major unmet medical need and is recognized as an important area for research. Despite substantial advances in the research and development for finding nontoxic, safe, and effective prophylactic countermeasures for the acute radiation syndrome (ARS), no such agent has been approved by the United States Food and Drug Administration (FDA). Area covered: Despite the progress made to improve the effectiveness of amifostine as a radioprotector for ARS, none of the strategies have resolved the issue of its toxicity/side effects. Thus, the FDA has approved amifostine for limited clinical indications, but not for non-clinical uses. This article reviews recent strategies and progress that have been made to move forward this potentially useful countermeasure for ARS. Expert opinion: Although the recent investigations have been promising for fielding safe and effective radiation countermeasures, additional work is needed to improve and advance drug design and delivery strategies to get FDA approval for broadened, non-clinical use of amifostine during a radiological/nuclear scenario.

Preventing Radiation-Induced Injury by Topical Application of an Amifostine Metabolite-Loaded Thermogel.

PURPOSE: Despite the development of high-precision radiation therapy, ionizing radiation inevitably damages healthy tissues. Radiodermatitis and radioinduced oral mucositis are frequent and significant side effects among patients with breast and head and neck cancer, respectively. These radiation-related injuries negatively affect patient quality of life and can lead to unplanned therapeutic breaks and compromise treatment outcomes. Currently, no preventive or mitigating agent has emerged to address these issues. Although amifostine, a well-known free radical scavenger, has proven efficacy against specific radio- and chemo-induced toxicities, severe adverse side effects (reversible hypotension, nausea, emesis, etc) combined with logistical hurdles are associated with its recommended intravenous route of administration, limiting its use. METHODS AND MATERIALS: We developed a thermogel containing the active thiol metabolite of amifostine (CPh-1014) that polymerizes at body temperature and serves as a matrix for topical application onto the skin or mucosa. RESULTS: Applied before irradiation, CPh-1014 greatly reduced the severity of oral mucositis and dermatitis induced by either a single dose or fractionated irradiation regimens in in vivo mouse models. The cytoprotective effect of CPh-1014 was confirmed by the decrease in DNA double-strand breaks in the irradiated epithelium. Noticeably, CPh-1014 did not affect radiation therapy efficacy against tumors grafted at submucosal and subcutaneous sites. In contrast to the intravenous administration of amifostine, CPh-1014 oral application did not induce hypotension in dogs. CONCLUSIONS: CPh-1014 confers radioprotective effects in healthy tissues with reduced systemic side effects without compromising radiation therapy efficacy. We propose CPh-1014 as an easy-to-implement therapeutic approach to alleviate radiation therapy toxicity in patients with breast and head and neck cancer.

Sustained-release microspheres of amifostine for improved radio-protection, patient compliance, and reduced side effects.

A biweekly administration of sustained-release microsphere dosage form of amifostine, a radioprotective drug used in radiotherapy, was performed to examine the feasibility to minimize injection frequency and blood concentration-associated side effects. Model animal trials indicated that this subcutaneously injecting microspheres, 50-100 µm in diameter, achieved bi-weekly prolonged radio-protective efficacy and, at the same time, significantly reduced skin irritation than the solution form of amifostine given by the same administration route. In addition, the hypertension associated with blood concentration of amifostine was not observed in the drug-treated rats. The animals given the amifostine microspheres and amifostine showed significantly differences in white blood cell, red blood cell, hematocrit, hemoglobin and spleen tissue histopathology after exposed under a cobalt-60 γ-radiation at a dose rate of 1.0 Gy/min for 6 min. The in vitro release profile of amifostine from the micropsheres showed a minor initial burst (less than 20% of total drug loading in the first day of administration), consisting with the side effects observations. The results suggest that amifostine encapsulated in sustained-release microspheres may be an ideal dosage form for prolonged radio-protective efficacy and improved patient compliance.

Potential of Amifostine for Chemoradiotherapy and Radiotherapy-associated Toxicity Reduction in Advanced NSCLC: A Meta-Analysis.

BACKGROUND/AIM: The addition of amifostine to chemoradiotherapy (CRT) or radiotherapy (RT) in advanced, inoperable NSCLC presents varying toxicity. The present study examined amifostine's effect on toxicity and efficacy of CRT or RT alone. MATERIALS AND METHODS: Database searches yielded 16 eligible trials comprising of 1,057 patients. Results of randomised trials were pooled and used to estimate the overall effect. RESULTS: Amifostine reduced the risk of >grade 2 acute oesophagitis by 26% [risk ratio (RR), 0.74; 95% confidence interval (CI)=0.65-0.86; p<0.0001] and the risk of acute pulmonary toxicity by 44% (RR, 0.56; 95%CI=0.41-0.75; p=0.0001). Risk of complete response was unchanged (RR, 1.64; 95%CI=0.99-2.73; p=0.06), partial response was unchanged (RR, 0.92; 95% CI=0.73-1.16; p=0.48). Statistical heterogeneity was high for toxicity but low for response. CONCLUSION: Statistical heterogeneity of retrived results casts doubt over amifostine's efficacy in this setting, despite decreased acute oesophageal and pulmonary toxicity. Amifostine did not compromise treatment efficacy.

Systematic review of amifostine for the management of oral mucositis in cancer patients.

PURPOSE: The aim of this study was to review the available literature from 1966 until December 31, 2010 and define clinical practice guidelines for the use of amifostine for the prevention and treatment of oral mucositis in cancer patients. METHODS: A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology. The body of evidence for the use of amifostine, in each cancer treatment setting was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, or no guideline possible. RESULTS: Thirty papers were reviewed for evidence on amifostine as an intervention for oral mucositis. No guideline was possible for amifostine in any cancer treatment setting due to inadequate and conflicting evidence. CONCLUSION: Review of the amifostine studies for the prevention and treatment of oral mucositis has found insufficient evidence to support its use in any cancer treatment setting for this purpose. Additional well-designed research is needed to clarify the role of amifostine as an intervention for oral mucositis.

Amifostine-doxorubicin association causes long-term prepubertal spermatogonia DNA damage and early developmental arrest.

BACKGROUND: In a previous study, we found that amifostine provides some protection to the seminiferous epithelium of prepubertal doxorubicin-treated male rats but does not improve their fertility status as adults. Based on these results, a long-term study was undertaken to evaluate the DNA damage caused to spermatogonia and the consequences for embryo development. METHODS: Twenty-four male prepubertal rats (30-day-old) were divided into four equal groups and treated with: doxorubicin (D--5 mg/kg), amifostine (A--400 mg/kg), amifostine/doxorubicin (AD--amifostine 15 min before doxorubicin) and control (C--0.9% saline solution). Sixty-four days after the treatment, animals were euthanized and the testes and epididymides were excised. The testes were fixed in Bouin's solution and historesin-embedded for histopathological analysis. Spermatozoa from the cauda epididymides were collected for chromatin structure analyses (Comet Assay and SCSA™). Adult rats (100-day-old) were mated with fertile females for embryo analyses on 2.5, 4.5 and 20 days post-coitum (d.p.c.). RESULTS: The seminiferous epithelium histopathology of AD group was better preserved compared with the D group. On the other hand, rats from the D and AD groups presented an increased percentage of sperm DNA strand breaks, as assessed by the comet assay, as well as an increased level of sperm chromatin denaturation, as assessed by the SCSA™ assay. In amifostine-treated groups (A and AD) there was a significant increase in the number of arrested embryos, as observed by the number of oocytes/zygotes on 2.5 d.p.c., when compared with control and doxorubicin groups; however, this number was increased when the AD group was compared with the A group. CONCLUSIONS: These results raise a concern about the effects of the association of these two drugs on the germ cell genome. Amifostine-doxorubicin-exposed rat spermatogonia produced long-term damage on sperm DNA, compromised conceptus development and reduced pregnancy outcome.

Treatment of invasive bladder cancer with conformal hypofractionated accelerated radiotherapy and amifostine (HypoARC).

INTRODUCTION: Radiotherapy (RT) for bladder cancer is as an effective alternative of cystectomy. Although rapid cancer clonogen repopulation contributes to radio-resistance, accelerated RT schemes based on ≤ 2 Gy fractions have failed to improve results. We suggest that accelerated hypofractionation (HypoARC) may be more effective, as it targets both tumors with increased clonogenic activity and tumors with low radio-sensitivity. PATIENTS AND METHODS: Eighty-two bladder cancer patients were treated with concomitant-boost conformal RT (14 × 2.7 Gy to the pelvis and 15 × 3.4 Gy to the bladder, within 19 days). Patients received a daily dose of 0/500/750/1,000 mg of amifostine using a dose-individualization algorithm (15.8%, 8.5%, 19.5%, and 56.1% of patients respectively). RESULTS: Early frequency grade 2-3, dysuria grade 1-2, diarrhea grade 2, and proctitis grade 2 appeared in 10.9%, 15.8%, 8.5%, and 13.4% of patients, respectively. The incidence of late sequelae was low (1.2% grade 2 frequency, 2.4% grade 2-3 dysuria, 2.4% grade 2-3 hematuria, 2.4% grade 2-3 incontinence). Patients receiving 1,000 mg of amifostine experienced significantly lower toxicities. The complete response rate, 3-year local control and disease specific survival rates were 86.6%, 56%, and 63%, respectively. CONCLUSIONS: HypoARC is linked with low early and late radiation toxicity, which is further reduced with the administration of high dose daily amifostine. The control and survival rates compare favorably with previously published data.

Severe allergic reactions to thiol-based cytoprotective agents mesna and amifostine in a child with a supratentorial primitive neuroectodermal tumor.

Both 2-mercaptoethane sulfonate sodium (mesna) and amifostine's active metabolite WR-1065 are thiol-based cytoprotective agents that are critical components of high-dose chemotherapy regimens used to treat various cancers in both adults and children. This case report describes a patient with a supratentorial primitive neuroectodermal tumor who developed severe drug reactions to both mesna and amifostine/WR-1065, suggesting that the thiol component of these agents triggered the adverse reactions. This report highlights the clinical presentation of drug-induced hypersensitivity syndrome in the context of pediatric oncology and the supportive care measures that, if implemented rapidly, may diminish the reaction severity and allow successful completion of chemotherapy.

Subcutaneous compared with intravenous administration of amifostine in patients with head and neck cancer receiving radiotherapy: final results of the GORTEC2000-02 phase III randomized trial.

PURPOSE: To compare compliance with and efficacy of intravenous (IV) and subcutaneous (SC) amifostine for the treatment of patients undergoing radiotherapy for head and neck cancer. PATIENTS AND METHODS: Patients with newly diagnosed squamous cell carcinoma of the head and neck, who were eligible for radiotherapy and who were not receiving concurrent chemotherapy, were randomly assigned to receive either IV amifostine (200 mg/m(2) daily for 3 minutes, 15 to 30 minutes before irradiation) or SC amifostine (500 mg; two sites; 20 to 60 minutes before irradiation). The primary end point was late xerostomia at 1 year as indicated by unstimulated and stimulated salivary flow rates, a patient benefit questionnaire score, and Radiation Therapy Oncology Group (RTOG) late toxicity grade. RESULTS: Results for IV (n = 143) versus SC (n = 148) administration were as follows. There was no significant difference in compliance (69% for IV v 71% for SC) in patients receiving a full dose of amifostine. Reasons for dose reduction were acute toxicity (25% for IV v 27% for SC; P = .51) and logistics (18% for IV v 9% for SC administration; P = .09). Acute toxicity differed significantly in terms of grade 1 to 2 hypotension (19% for IV v 8% for SC; P = .01), grade 1 to 2 skin rash (9% for IV v 21% for SC; P = .01), and local pain (0% for IV v 8% for SC; P = .003). The incidence of grade 2 or greater xerostomia was significantly higher for patients who received amifostine via SC administration (37% for IV v 62% for SC; P = .005) in the 127 patients (n = 67, IV; n = 60, SC) evaluable at 1 year but not at 2 or 3 years (36% for IV v 51% for SC administration; P = .19; 32% for IV v 41% for SC; P = .63). A generalized linear mixed-model analysis of all data revealed no significant difference in patient self-assessment of salivary function (P = .25), unstimulated or stimulated salivary flow rates (P = .054 and .82, respectively), or grade 2 or greater xerostomia (P = .23). CONCLUSION: SC amifostine administration was not significantly superior to IV amifostine administration in terms of patient compliance or efficacy.

A Phase I trial: dose escalation of melphalan in the "BEAM" regimen using amifostine cytoprotection.

With the eventual goal of reducing relapse and thus improving overall survival in selected lymphoma patients, a Phase I study was performed using the cytoprotectant amifostine to permit safe dose-augmentation of melphalan in the carmustine (BCNU), etoposide, cytarabine (arabinosylcytosine), and melphalan (BEAM) regimen before autologous hematopoietic stem cell transplantation. Between 30 July 2003 and 25 November 2008, a total of 32 lymphoma patients were entered, of which 28 were evaluable. We found the melphalan dose in BEAM could be safely escalated to at least 260 mg/m², a substantial increase from the usual dose of 140 mg/m² in BEAM while the trial was terminated early due to poor accrual, no maximal tolerated dose or dose-limiting toxicity was found. A Phase II trial is planned.

Efficacy of amifostine in treating patients with idiopathic thrombocytopenia purpura.

Idiopathic Thrombocytopenic Purpura (ITP) is an autoimmune disease characterized by the production of antibodies against platelet surface antigens, resulting in platelet destruction. ITP is generally treated using glucocorticoids, splenectomy, immunosuppressants, platelet transfusions, and also rituxan and rituximab. However, as these treatments are not effective in some refractory ITP patients, especially the elderly, who are also at greater risk of cerebral hemorrhage, we have undertaken this study to find a safe and effective way of treating these patients. In a clinical protocol, we have examined the efficacy of the cytoprotective adjuvant, amifostine, on 24 ITP patients, consisting of 21 Chinese (age: 13-92 years), and 3 Caucasians (age: 46-73 years). In order to prevent the side effects associated with amifostine treatment, an alternative dosing and anti-emetic regimen was developed as part of this protocol, which significantly improved patient acceptance. The protocol consisted of daily intravenous infusions of amifostine 5 × 400 mg per week, for a total of 4-5 weeks. All the patients experienced a long-lasting and continuing remission, defined as platelet counts greater than 100,000. Two patients relapsed: one after an upper respiratory tract infection, and another due to Helicobacter pylori. However, both these patients had complete remission, after they were treated again with amifostine. In this clinical study, we report for the first time, the successful use of amifostine for ITP treatment in refractory patients. In conclusion, amifostine may have good therapeutic effect on ITP patients, especially in refractory and/or elderly. The long-term clinical outcome and the mechanism of action of this drug still need further investigation.

Amifostine-related fever-rash during fractionated radiotherapy: diagnostic and predictive role of C-reactive protein.

INTRODUCTION: Fever/rash is a side-effect of amifostine that demands immediate interruption of the drug. Here, we focus on the role of C-reactive protein (CRP) as a putative marker linked with amifostine fever/rash. MATERIALS AND METHODS: The CRP serum values were analyzed in 496 patients receiving radiotherapy supported with amifostine (500-1000 mg/d). CRP levels were recorded before the onset of radiotherapy (day 0), on day 15 and when the fever/rash appeared. For 121 out of 496 patients, CRP values on day 7 were also available. About 79 patients (15.9%) developed fever/rash symptoms. RESULTS: The CRP levels before the onset of therapy were 0 to 20.7 mg/dL (normal, ≤0.5 mg/dL). For patients who did not develop fever/rash, the CRP levels increased from a median of 0.30 to 0.50 on day 15; P = 0.001. Patients who developed fever/rash showed a more than 7-fold increase of the median CRP levels (median, 3.50; P < 0.0001). This sharp CRP rise was specific for amifostine-related fever/rash. Initially abnormal CRP levels were linked with a 2-fold risk for fever/rash (P = 0.01), while abnormal levels on day 7 were linked with a 3-fold higher risk (P = 0.08). The occurrence of fever/rash was independent of the amifostine dose level. CONCLUSIONS: Sharp rise of CRP levels on the day after the fever/rash development suggest amifostine-related etiology of fever/rash. Abnormal initial CRP levels and/or high CRP levels on day 7 should be considered as an alert signal as the probability to develop fever/rash reaches the 30%.

Bevacizumab, capecitabine, amifostine, and preoperative hypofractionated accelerated radiotherapy (HypoArc) for rectal cancer: a Phase II study.

PURPOSE: Bevacizumab has established therapeutic activity in patients with metastatic colorectal cancer, and anti-vascular endothelial growth factor therapy enhances the activity of radiotherapy in experimental models. We assessed the feasibility and efficacy of preoperative radiochemotherapy combined with bevacizumab in patients with rectal cancer. METHODS AND MATERIALS: Nineteen patients with radiologic T3 and/or N+ rectal carcinoma were treated with preoperative conformal hypofractionated accelerated radiotherapy (3.4 Gy in 10 consecutive fractions) supported with amifostine (500-1,000 mg daily), capecitabine (600 mg/m(2) twice daily, 5 days per week), and bevacizumab (5 mg/kg every 2 weeks for 2 cycles). Surgery followed 6 weeks after the end of radiotherapy. A cohort of 14 sequential patients treated with the same regimen without bevacizumab was available for comparison. RESULTS: Grade 2 or 3 diarrhea was noted in 7 of 19 patients (36.8%), which was statistically worse than patients receiving the same regimen without bevacizumab (p = 0.01). A higher incidence of Grade 2 or 3 proctalgia was also noted (21.1%) (p = 0.03). Bladder and skin toxicity was negligible. All toxicities regressed completely within 2 weeks after the end of therapy. Pathologic complete and partial response was noted in 7 of 19 cases (36.8%) and 8 of 19 cases (42.1%). Within a median follow-up of 21 months, none of the patients has had late complications develop and only 1 of 18 evaluable cases (5.5%) has had locoregional relapse. CONCLUSIONS: Bevacizumab can be safely combined with hypofractionated radiotherapy and capecitabine as a preoperative radiochemotherapy regimen for patients with rectal cancer. The high pathologic complete response rates urges the testing of bevacizumab in randomized studies.

Does amifostine have radioprotective effects on salivary glands in high-dose radioactive iodine-treated differentiated thyroid cancer.

OBJECTIVES: To assess the effects of amifostine on salivary glands in radioactive iodine-treated differentiated thyroid cancer. METHODS: We searched the MEDLINE, EMBASE and the Cochrane Library for randomized controlled clinical trials which compared the effects of amifostine with those of placebo or acid-stimulating agents. RESULTS: Two randomized controlled clinical trials with a total of 130 patients were included. Both studies had a low risk of bias. There were no statistically significant differences between the effects of amifostine and acid-stimulating agents on the incidence of xerostomia (RR 0.24, 95% CI 0.01 to 9.52), the decrease of scintigraphically measured uptake of (99m)Tc by the parotid (RR 0.30, 95% CI -2.28 to 2.88) or submandibular glands (RR 1.90, 95% CI -1.46 to 5.26) at 12 months, or the reduction in blood pressure (RR 5.00, 95% CI 0.25 to 99.16). Neither of the included trials investigated death from any cause, morbidity, health-related quality of life or costs. CONCLUSION: The results of two randomized controlled clinical trials suggest that amifostine has no significant radioprotective effects on salivary glands in radioactive iodine treatment of differentiated thyroid cancer. The use of acid-stimulating agents to increase salivation should remain the first choice during radioactive iodine treatment of differentiated thyroid cancer. Patients should also be well informed of the importance of hydration and acid stimulation.

Radiochemotherapy with cetuximab, cisplatin, and amifostine for locally advanced head and neck cancer: a feasibility study.

PURPOSE: Radiotherapy (RT) combined with cisplatin or cetuximab is the standard of care for patients with locally advanced head/neck cancer (LA-HNC). The feasibility of radiochemotherapy with cisplatin and cetuximab, supported with amifostine, was herein investigated. METHODS AND MATERIALS: Forty-three patients with LA-HNC were recruited. Conformal hypofractionated/accelerated RT with amifostine cytoprotection (2.7 Gy/fraction, 21 fractions in 4 weeks) was combined with cisplatin (30 mg/m(2)/week) and cetuximab (standard weekly regimen) therapy. The dose of amifostine was individualized according to tolerance. RESULTS: A high daily amifostine dose (750-1,000 mg) was tolerated by 41.8% of patients, and a standard dose (500 mg) was tolerated by 34.9% of patients. A high amifostine dose was linked to reduced RT delays (p = 0.0003). Grade 3 to 4 (3-4) mucositis occurred in 7/43 (16.2%) patients, and fungal infections occurred in 18/43 (41.8%) patients. Radiation dermatitis was not aggravated. Interruption of cetuximab due to acneiform rash was necessary in 23.3% of patients, while amifostine-related fever and rash were not observed. Severe late radiation sequelae consisted of laryngeal edema (9% laryngeal cases) and cervical strictures (33% of hypopharyngeal cases). Good salivary function was preserved in 6/11 (54.5%) nasopharyngeal cancer patients. The complete response rate was 68.5%, reaching 77.2% in patients with minor radiotherapy delays. The 24-month local control and survival rates were 72.3% and 91%, respectively (median follow-up was 13 months.). CONCLUSIONS: In this feasibility study, weekly administration of cisplatin and cetuximab was safely combined with accelerated RT, supported with amifostine, at the cost of a high incidence of acneiform rash but a reduced incidence of amifostine-related fever/rash. A high daily dose of amifostine allows completion of therapy with minor delays.