Use Of Amifostine Research Articles

PROSPECTS OF THE USE OF RADIOPROTECTORS TO OVERCOME MITOCHONDRIAL DYSFUNCTION OF HEALTHY CELLS SURROUNDING THE IRRADIATED TUMOR

Radiation-induced changes in normal cells, including their mitochondria, from around the tumor can lead to the development of remote complications that negatively affect the effectiveness of radiation therapy. This determines the search for radioprotectors capable of overcoming the membrane barrier of mitochondria and suppressing their acquired dysfunction for selective protection of healthy tissues. The use of amifostine and melatonin radiomitigators, whose action is characterized by low toxicity, the ability to overcome acquired mitochondrial dysfunction, and unimpeded penetration into the mitochondria of various types of cells, is recognized as a reliable and effective means of protection. The appointment of the specified drugs to accompany radiation therapy of oncological patients is substantiated and recommended.

The protective effects of red ginseng and amifostine against renal damage caused by ionizing radiation.

This study aimed to elucidate the effects of amifostine (ethyol) (AM), a synthetic radioprotector, and red ginseng (RG), a natural radioprotective agent, against the toxic effect of ionizing radiation (IR) on kidney tissues through changes in biochemical and histopathological parameters in addition to contributions to the use of amifostine and RG in clinical studies. Five groups were established: Group I (control, receiving only saline by gavage), Group II (IR only), and Group III (IR+AM, 200mg/kg intraperitoneally (i.p.). Group IV (IR + RG, 200mg/kg orally once a day for 4weeks), and Group V (IR+RG+AM, 200mg/kg orally once/day for 4weeks before IR and 200mg/kg AM administered (i.p.) 30min before IR). All groups, except for the control group, were subject to 6-Gy whole-body IR in a single fraction. 24h after irradiation, all animals were sacrificed under anesthesia. IR enhanced MDA, 8-OHdG, and caspase-3 expression while decreasing renal tissue GSH levels (p < .05). Significant numbers of necrotic tubules together with diffuse vacuolization in proximal and distal tubule epithelial cells were also observed. The examination also revealed substantial brush boundary loss in proximal tubules as well as relatively unusual glomerular structures. While GSH levels significantly increased in the AM, RG, and AM+RG groups, a decrease in KHDS, MDA, 8-OHdG, and caspase-3 expression was observed, compared to the group subject to IR only (p < .05). Therefore, reactive oxygen species-scavenging antioxidants may represent a promising treatment for avoiding kidney damage in patients receiving radiation.

Optimizing Autologous Stem Cell Transplant for High-Risk Patients with Plasma Cell Dyscrasias

Autologous hematopoietic stem cell transplantation (ASCT) is recommended for transplant-eligible pts (pts) with newly diagnosed multiple myeloma (MM) as well as AL Amyloidosis (AA). However, melphalan-associated gastrointestinal (GI) and cardiac toxicities may limit its applicability. GI toxicity is a main limitation to ASCT in the elderly population which constitute a significant proportion of MM pts, where the median age at diagnosis is 68 years. There is an unmet need for measures to minimize non-hematological toxicities without compromising the melphalan (MEL) anti-tumor efficacy; this could lead to expansion of transplant eligibility to older pts as wells pts with high-risk cardiac AA. Also, minimizing treatment-related morbidity may allow dose-escalation or the addition of novel anti-myeloma agents to MEL conditioning; such may improve the depth of response and remission duration after ASCT. Here, we report outcomes of an integrated ASCT program for high-risk MM and AA pts.We incorporated a series of measures to decrease GI toxicity, infections and cardiac failure to our ASCT program. All pts receive amifostine 740 mg/m2 as a bolus infusion before MEL. In addition, stem cell collection is performed inpatient if pts are on hemodialysis (HD) and/or have high-risk AA. Peripheral blood stem cell (PBSC) mobilization uses plerixafor and Neupogen. The CardioMEMS HF System is used for high-risk AA with cardiac involvement to achieve more accurate fluid balance throughout the ASCT process. This device is FDA-approved for wirelessly measuring and monitoring pulmonary artery pressure and heart rate in New York Heart Association Class III heart failure pts who have been hospitalized for heart failure in the previous year. HD was done on the day before and the day of transplant and three times weekly thereafter. DMSO used for PBSC cryopreservation is washed from the infused stem cell product prior to infusion. High-risk pts are those older than age 65 years, on HD, or with high-risk AA (Mayo stage III, Kumar et al. JCO 30.9 (2012): 989-995). All pts fulfilling these criteria treated from January 2013 to Dec 2016 were retrospectively analyzed. Survival outcomes were measured from the date of ASCT until disease relapse or progression, Survival distribution was estimated using Kaplan-Meier methods.Thirty seven pts were analyzed (median age=66.6 years; range: 45-77). Thirty-five pts (95%) were older > 65. Fourteen pts were female (37%). Five pts were on HD (14%); two had AA with cardiac involvement. Six pts had light chain disease (16%), 21 IgG (56%) and eight had IgA (21%) MM, and two had AL AA. Five pts were ISS stage I (14%), 16 stage II (46%) and 14 stage III (40%). Five MM pts (14%) had extramedullary disease. Thirty pts (85%) were considered standard-risk and 5 had high-risk cytogenetics (14%). Median time from diagnosis to ASCT was 8.7 months (range: 3.2-169.4). Median number of therapy lines was 1 (range 1-7). Thirty pts (85%) had at least partial response (PR) at the time of transplant. Nine pts (24%) were collected with filgrastim only and 28 (75%) with filgrastim and Plerixafor (including all pts on HD and AA). Median number of CD34 cells collected was 6.36 x10E6/Kg (range: 2.34-23.99 x10E6/Kg). Median number of CD34 cells infused was 3.25 x10E6/Kg (range: 1.88-10.8). Fourteen pts (37%) received conditioning with MEL 140 mg/m2, and 63% received 200 mg/m2. Median length of hospital stay for ASCT was 15 days (range: 13-25). Grade II-III toxicity was seen in 13 pts (35%), with only 2 grade III and no grade IV GI toxicity. There was no difference in toxicity between MEL 140 vs. 200 (P=0.210). Median length of mucositis was 6.5 days (range: 2-18). One pt used PCA dilaudid. No pt needed total parenteral nutrition. Median time to neutrophil and platelet engraftment was 11 (range: 9-15) and 12 days (range: 8- 19), respectively. Transplant-related mortality was zero. Day 100 response rate (at least PR) occurred in 34 pts (97%), with 18 (51%) achieving near complete remission or better. Twenty eight (75%) received maintenance therapy. Median follow-up time for survivors was 38 months. At the end of follow up period, only 4 pts (10%) had died. Median PFS was not reached, 3-year PFS: 70% (Figure-1.A and B).Taken together, our results indicate the safety of the sequential approach described here. Prospective studies to examine the use of CardioMEMs and amifostine to improve clinical outcome of high-risk autologous transplant are warranted. [Display omitted] DisclosuresCooper:Novartis: Research Funding. Caimi:Abbvie: Equity Ownership; Incyte: Equity Ownership; Seattle Genetics: Equity Ownership; Celgene: Speakers Bureau. de Lima:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Research Funding. Malek:Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Amifostine is a Nephro-Protectant in Patients Receiving Treatment with Cisplatin- Myth, Mystery or Matter-of-Fact?

Despite reports of amifostine possibly protecting nephrotoxicity from cisplatin, it has not been recommended by any guidelines committees or routinely prescribed in clinical practice over the past decade. In this article, we review literature and guidelines regarding use of amifostine in oncology practice for protection against adverse effects from certain chemotherapeutic agents, in particular as a nephro-protectant in patients receiving cisplatin.

Determination of plasma levels of the active thiol form of the direct-acting PrC-210 ROS-scavenger using a fluorescence-based assay

PrC-210 is a direct-acting ROS-scavenger. It's active when administered orally, IV, or topically; it has none of the nausea/emesis nor hypotension side effects that have precluded human amifostine use. PrC-210 confers 100% survival to mice and rats that received an otherwise 100% lethal radiation dose and 36% reduction of ischemia-reperfusion-induced mouse myocardial infarct damage, and thus is a viable candidate to prevent human ROS-induced ischemia-reperfusion and ionizing radiation toxicities. We report the first assay for the pharmacologically active PrC-210 thiol in blood. PrC-210 has no double-bonds nor light absorption, so derivatizing the thiol with a UV-absorbing fluorochrome enables quantification. This assay: i) is done on the benchtop; it's read with a fluorescence plate reader, ii) provides linear product formation through 60 min, iii) quantifies μM to low mM rodent blood levels of PrC-210 that confer complete radioprotection, iv) accurately reflects PrC-210 thiol formation of mixed disulfides with other thiols in blood, and v) shows excellent between-day assay outcome with very low standard deviation and coefficient of variation. A fluorescence assay quantifying formation of a PrC-210 thiol-bimane adduct enables measurement of blood PrC-210 thiol. A blood assay will help in the development of PrC-210 for use in the human clinical setting.

Amifostine ameliorates induction of experimental autoimmune encephalomyelitis: Effect on reactive oxygen species/NLRP3 pathway

Multiple sclerosis (MS) is an autoimmune disease for which conventional treatments have limited efficacy or side effects. Free radicals are primarily involved in blood–brain barrier disruption and induce neuronal and axonal damage, thus promoting the development of MS. Amifostine, a radioprotective drug used as a cytoprotective agent, attenuates oxidative stress and improves radiation damage by acting as a direct scavenger of reactive oxygen and nitrogen species. The aim of this study was to evaluate the effects of amifostine on MS in a mouse model of experimental autoimmune encephalomyelitis (EAE), which was developed by immunizing C57BL/6 mice with myelin oligodendrocyte glycoprotein and pertussis toxin. EAE mice received intraperitoneal injections of amifostine prior to onset of clinical symptoms and were monitored up to day 15 post induction. We observed abnormal clinical behavioral scores and a decrease in body weight. Histological analysis showed severe inflammatory infiltration and demyelination in the brain and spinal cord lumbar enlargements where significant upregulation of the mRNA expression of the pro-inflammatory cytokines interleukin-6 and interleukin-8, downregulation of the anti-inflammatory cytokine interleukin-10, and obvious microgliosis were also observed. Amifostine treatment potently reversed these abnormal changes. The anti-inflammatory effect of amifostine was associated with the inhibition of reactive oxygen species generation. Furthermore, the expression of proteins involved in the NLRP3 signaling pathway and pyroptosis was decreased. In conclusion, our study showed that amifostine ameliorates induction of experimental autoimmune encephalomyelitis via anti-inflammatory and anti-pyroptosis effects, providing further insights into the use of amifostine for the treatment of MS.

Amifostine protects from the peripheral sensory neuropathy induced by oxaliplatin in mice

Sensory neuropathy is a dose-limiting side effect of oxaliplatin-based cancer treatment. This study investigated the antinociceptive effect of amifostine and its potential neuroprotective mechanisms on the oxaliplatin-related peripheral sensory neuropathy in mice. Oxaliplatin (1 mg/kg) was injected intravenously in Swiss albino male mice twice a week (total of nine injections), while amifostine (1, 5, 25, 50, and 100 mg/kg) was administered subcutaneously 30 min before oxaliplatin. Mechanical and thermal nociceptive tests were performed once a week for 49 days. Additionally, c-Fos, nitrotyrosine, and activating transcription factor 3 (ATF3) immunoexpressions were assessed in the dorsal root ganglia. In all doses, amifostine prevented the development of mechanical hyperalgesia and thermal allodynia induced by oxaliplatin (P<0.05). Amifostine at the dose of 25 mg/kg provided the best protection (P<0.05). Moreover, amifostine protected against neuronal hyperactivation, nitrosative stress, and neuronal damage in the dorsal root ganglia, detected by the reduced expression of c-Fos, nitrotyrosine, and ATF3 (P<0.05 vs the oxaliplatin-treated group). In conclusion, amifostine reduced the nociception induced by oxaliplatin in mice, suggesting the possible use of amifostine for the management of oxaliplatin-induced peripheral sensory neuropathy.

Medical interventions for the prevention of platinum-induced hearing loss in children with cancer.

Medical interventions for the prevention of platinum-induced hearing loss in children with cancer.

Radioprotective Effects of Amifostine, L-Carnitine and Vitamin E in Preventing Early Salivary Gland Injury due to Radioactive Iodine Treatment.

Standard treatment of differentiated thyroid cancer includes total thyroidectomy and high-dose Radioactive Iodine Therapy (RIT) for ablation of remnant thyroid tissue. When administered systemically, RIT can cause radiation-induced damage in non-targeted normal tissues. The aim of the present study was to compare the protective effects of amifostine (AMI), LCarnitine (LC), and Vitamin E (EVIT) against high dose radioactive iodine treatment induced Salivary Gland (SG) damage using SG scintigraphy and histopathological examination. Forty adult guinea pigs were studied. Twenty guinea pigs receive 555-660 MBq 131Iodine intraperitoneally (IP) to ablate the thyroid and impair the parenchymal function of the SGs. The animals were divided into eight groups as follows: (1) Group 1 (control): 1 mL IP PS (physiological saline); (2) Group 2: single dose of 200 mg/kg IP AMI one hour prior to 1 mL IP PS; (3) Group 3: 200 mg/kg IP LC and 1 mL IP PS for 10 days; (4) Group 4: 40 mg/kg intramuscular (IM) EVITand 1 mL IP PS for 10 days; (5) Group 5: IP RIT after premedication; (6) Group 6: Single dose of 200 mg/kg IP AMI one hour prior to RIT and IP RIT after premedication; (7) Group 7: IP RIT after premedication and 200 mg/kg IP LC for 10 days starting one day before RIT; and (8) Group 8: IP RIT after premedication and 40 mg/kg IM EVIT for 10 days starting one day before RIT. Scintigraphy was performed 1 month after treatment. SGs were examined by light microscopy and a histopathological scoring system was used to assess the degree of SG damage. There were significant differences in the body weight and thyroid hormone levels between the groups after treatment. The individual use of AMI, LC and EVIT for radioprotection yield different levels of protection against radioactive iodine treatment injury in SGs; however, none of the agents could provide absolute protection at the doses administered in this experimental model.

Robotic-Based SBRT for Prostate Cancer is Well Tolerated in Patients with a History of Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is considered a relative contraindication to radiation therapy directed to the pelvis. Previous publications have demonstrated safety of carefully delivered image guided radiation therapy (IGRT) and brachytherapy in patients with inactive disease. Stereotactic Body Radiation Therapy (SBRT) is an increasingly utilized treatment option for men with localized prostate cancer, which utilizes smaller target volumes. This study reports our initial experience in men with inactive IBD who were treated with definitive robotic-based SBRT for prostate malignancy. We conducted a retrospective query of 3295 patients in our institutional review board approved database for patients with prostate cancer who had a comorbidity of IBD and were treated with SBRT. We cross-referenced follow-up visits, EPIC-questionnaires, and dosimetry tables to assess treatment related toxicity. Between December 10, 2010 and August 11, 2017, 19 patients with IBD and prostate cancer were treated with definitive robotic-based SBRT. 12 (63.2%) were diagnosed with Ulcerative Colitis and 7 (36.8%) with Crohn’s disease. Long-term rectal toxicity was characterized as occurring ≥6 months post radiation and scored by RTOG late toxicity scale. Of the 19 patients identified, 13 patients took nonsteroidal anti-inflammatory medications for their IBD; 1 took prednisone, and 2 patients received anti-coagulation medications for unrelated comorbidities prior to treatment. For this cohort, the median pre-treatment PSA was 7.3ng/ml (3-49.1ng/ml). Based on NCCN risk categories, 31.6%, 47.4% and 21.1% had low, intermediate, and high-risk disease, respectively. 5 patients were treated with concurrent Androgen Deprivation Therapy (ADT). The median prescription dose received was 3500cGy (3500-3625) delivered in 5 fractions. Patients received intrarectal amifostine prior to each fraction. The median age was 68 years (52-84). The mean Rectal maximum point dose was 3816.7cGy (3707.2-3997.1) and the mean rectal V3600cGy was 0.9cc’s (0.1-4.0). 5 patients have follow-up greater than 12 months and the median follow-up is 6 months (1-38). Thus far, treatment has been well tolerated by this cohort. 1 patient (5.3%) experienced ≥ grade 2 toxicity, with rectal fullness 12 months post-treatment; symptoms fully responded to proctofoam, with no further episodes on subsequent encounter. No cases of grade 3 toxicity, non-hemorrhoidal bleeding, or IBD flare have been reported. With a small sample size and modest follow-up, SBRT for selected patients with IBD who have prostate cancer appears well tolerated, with long-term follow-up continuing to evolve. Judicious use of tight posterior margins and intrarectal amifostine might confer a benefit regarding acute and chronic rectal toxicity. Caution should remain employed treating this patient cohort with larger fraction sizes even in high volume clinics.

Histopathological efficiency of amifostine in radiation‑induced heart disease in rats.

Amifositine is a phosphorylated thiol that holds its radioprotective actions by several indirect mechanisms. The purpose of this study was to evaluate histopathologically whether amifositine administration prior to irradiation would have a long‑term protective effect on heart tissue in an experimental rat model. Single dose of 18 Gy radiation and sham radiation exposure were used in related groups. A dose of 200 mg/kg of amifostine was injected intraperitoneally 30 min prior to radiation exposure. Analyses were performed 6 months after irradiation. Vascular damage and vasculitis were significantly decreased in amifositine treatment group. At the same time, significant thickening of the medial layer was accompanied by vascular damage in irradiated groups. The number and severity of myocyte necrosis were diminished with amifostine.Nevertheless, it could not prevent epicardial and myocardial fibrosis. Severe myocardial fibrosis was observed prominently in three regions, particularly on the apex, tips of papillary muscles and in sites adjacent to the atrioventricular valves. The anti-inflammatory effect of amifostine was not seen. The development of vascular damage and vasculitis were prevented by the use of amifostine. There was a correlation between vascular damage and fibrosis development. According to histopathological results, amifostine could be used as a protective agent against the side effects of radiotherapy (Tab. 4, Fig. 2, Ref. 22).

Reducing Gastrointestinal Toxicity Associated with Autologous Transplantation for Multiple Myeloma without Compromising Its Anti-Myeloma Effect

Early autologous hematopoietic stem cell transplantation (auto-HCT) is recommended for transplant-eligible patients (pts) with newly diagnosed multiple myeloma (MM). However, gastrointestinal toxicities, i.e., oral mucositis (OM), nausea and diarrhea, are the major limitation to the use of auto-HCT especially in the elderly population which constitute a significant proportion of MM pts, where the median age at diagnosis is 68 years. There is an unmet need for measures to minimize non-hematological toxicities without compromising melphalan anti-myeloma efficacy; this could lead to expansion of transplant eligibility to older pts. Amifostine, a FDA-approved cytoprotective agent to prevent OM for Head and Neck cancer, may reduce HDM-associated GI toxicity. We conducted a case-control study comparing auto-HCT with or without amifostine for MM pts.Methodspre-transplant amifostine has been incorporated to standard protocol for all MM patients underwent auto-HCT at University Hospitals Cleveland Medical Center (UH) for the last decade. One hundred and seven pts treated at UH who received amifostine, from January 2007 to July 2014, were compared to 114 matched-control pts treated at MD Anderson Cancer Center (MDACC) without use of this agent. The institutional review boards at both institutions approved the study. Amifostine 740 mg/m2 was administered as a bolus infusion at 24 hours and 15 minutes before HDM. All pts received ice chips peri-melphalan infusion. Survival outcomes were measured from the date of auto-HCT to the date of disease relapse or progression, Survival distribution was estimated using Kaplan-Meier methods. The effect of treatment on OS and PFS was estimated using a Cox model after controlling for the effects of age, gender, and number of prior therapies, time from diagnosis to transplant, Eastern Cooperative Oncology Group (ECOG) performance status and number of infused CD34+ cells.ResultsPts' characteristics were similar in both groups.Median follow-up of surviving pts was 35 (range 2-100) months in both cohorts. Amifostine therapy was well tolerated without any serious adverse effects. There was no significant difference between all-grade OM, nausea or vomiting between the two cohorts. However, > grade II GI toxicities were significantly lower in the amifostine group as follows: OM: 27.1% vs 47.4% (P=0.002), diarrhea: 56.1% vs. 72.7% (P=0.006), nausea: 31.8% vs. 86.0% (P=0.0001) and vomiting: 18.7% vs. 52.6%, (P=0.0001) (Figure-1) (Table-1). Median time to platelet engraftment was similar between the two groups while neutrophil engraftment period was shorter with use of amifostine (10 vs. 11 days, P=0.011) (Table-2). Multivariable logistic regression showed that use of amifostine pre-transplant was associated with a significant decrease in OM, diarrhea, nausea and vomiting. Pts who received amifostine and melphalan developed grade ≥ II OM significantly less often than those given melphalan alone with odds ratio (OR) = 0.366 (95% CI: 0.196-0.685, P=0.001; Table 3). Female gender was associated with a significant increase in OM, nausea and vomiting. Female pts were more likely to develop grade ≥ II OM with OR of 1.967 (P=0.017). Similarly, an ECOG performance status (PS) of ≥ 2 was associated with a significant increase in OM and diarrhea. For every additional score of ECOG, the risk of having grade ≥ II OM increased 1.89 fold (p=0.015). Subgroup analysis of grade II and higher OM rates are shown in Table-4. Use of amifostine was associated with reduced grade II or higher GI toxicity after adjusting for the effects of age, gender, number of prior therapies, time from diagnosis to transplant, ECOG PS and infused CD34 cell dose. There was no detrimental effect of amifostine on progression-free or overall survival.ConclusionsOur analysis indicates that the use of two amifostine doses of 740 mg/m2 before auto-HCT is safe and associated with significant reduction in grade II and higher GI toxicities without any deleterious effect on engraftment or anti-myeloma efficacy. Amifostine use could conceivably allow further melphalan dose-intensification for pts with resistant or high-risk disease. Also, pre-treatment with amifostine potentially could expand the utilization of auto-HCT for modestly frail MM pts that might not be considered eligible for this treatment modality. The protective effect of amifostine should be confirmed in randomized trial. [Display omitted] DisclosuresMalek:Celgene: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees. Cooper:Novartis: Research Funding. Caimi:Abbvie: Equity Ownership; Incyte: Equity Ownership; Celgene: Speakers Bureau; Seattle Genetics: Equity Ownership. De Lima:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Research Funding.

Medical interventions for the prevention of platinum-induced hearing loss in children with cancer.

Platinum-based therapy, including cisplatin, carboplatin, oxaliplatin or a combination of these, is used to treat a variety of paediatric malignancies. One of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this ototoxicity, different otoprotective medical interventions have been studied. This review is the second update of a previously published Cochrane review. To assess the efficacy of medical interventions to prevent hearing loss and to determine possible effects of these interventions on anti-tumour efficacy, toxicities other than hearing loss and quality of life in children with cancer treated with platinum-based therapy. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 6), MEDLINE (PubMed) (1945 to 8 July 2016) and EMBASE (Ovid) (1980 to 8 July 2016). In addition, we handsearched reference lists of relevant articles and we assessed the conference proceedings of the International Society for Paediatric Oncology (2006 up to and including 2015), the American Society of Pediatric Hematology/Oncology (2007 up to and including 2016) and the International Conference on Long-Term Complications of Treatment of Children and Adolescents for Cancer (2010 up to and including 2015). We scanned the International Standard Randomized Controlled Trial Number (ISRCTN) Register (www.isrctn.com) and the National Institute of Health Register (www.clinicaltrials.gov) for ongoing trials (both searched on 12 July 2016). Randomized controlled trials (RCTs) or controlled clinical trials (CCTs) evaluating platinum-based therapy together with an otoprotective medical intervention versus platinum-based therapy with placebo, no additional treatment or another protective medical intervention in children with cancer. Two review authors independently performed the study selection, data extraction, risk of bias assessment and GRADE assessment of included studies, including adverse effects. We performed analyses according to the Cochrane Handbook for Systematic Reviews of Interventions. We identified two RCTs and one CCT (total number of participants 149) evaluating the use of amifostine versus no additional treatment in the original version of the review; the updates identified no additional studies. Two studies included children with osteosarcoma, and the other study included children with hepatoblastoma. Children received cisplatin only or a combination of cisplatin and carboplatin, either intra-arterially or intravenously. Pooling of results of the included studies was not possible. However, in the individual studies there was no significant difference in symptomatic ototoxicity only (that is, grade 2 or higher) and combined asymptomatic and symptomatic ototoxicity (that is, grade 1 or higher) between children treated with or without amifostine. Only one study, including children with osteosarcoma treated with intra-arterial cisplatin, provided information on tumour response, defined as the number of participants with a good or partial remission. The available data analysis (data were missing for one participant), best case scenario analysis and worst case scenario analysis all showed a difference in favour of amifostine, but this difference was significant only in the worst case scenario analysis (P = 0.04). There was no information on survival for any of the included studies. Only one study, including children with osteosarcoma treated with intra-arterial cisplatin, provided data on the number of participants with adverse effects other than ototoxicity grade 3 or higher. There was a significant difference in favour of the control group in the occurrence of vomiting grade 3 or 4 (risk ratio (RR) 9.04; 95% confidence interval (CI) 1.99 to 41.12; P = 0.004). There was no significant difference between treatment groups for cardiotoxicity and renal toxicity grade 3 or 4. None of the studies evaluated quality of life. The quality of evidence for the different outcomes was low. We found no eligible studies for possible otoprotective medical interventions other than amifostine and other types of malignancies. At the moment there is no evidence from individual studies in children with osteosarcoma or hepatoblastoma treated with different platinum analogues and dosage schedules that underscores the use of amifostine as an otoprotective intervention as compared to no additional treatment. Since pooling of results was not possible and all studies had serious methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. Based on the currently available evidence, we are unable to give recommendations for clinical practice. We identified no eligible studies for other possible otoprotective medical interventions and other types of malignancies, so no conclusions can be made about their efficacy in preventing ototoxicity in children treated with platinum-based therapy. More high quality research is needed.

Medical interventions for the prevention of platinum-induced hearing loss in children with cancer.

Platinum-based therapy, including cisplatin, carboplatin and/or oxaliplatin, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this ototoxicity, different otoprotective medical interventions have been studied. This review is an update of a previously published Cochrane review. The primary objective was to assess the efficacy of any medical intervention to prevent hearing loss in children with cancer treated with platinum-based therapy (that is including cisplatin, carboplatin and/or oxaliplatin) when compared to placebo, no additional treatment or a different protective medical intervention. Secondary objectives were to determine possible effects of these interventions on anti-tumour efficacy, toxicities other than hearing loss and quality of life. We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 1), MEDLINE (PubMed) (1945 to 17 March 2014) and EMBASE (Ovid) (1980 to 17 March 2014). In addition, we handsearched reference lists of relevant articles and the conference proceedings of the International Society for Paediatric Oncology (2006 to 2013), the American Society of Pediatric Hematology/Oncology (2007 to 2013) and the International Conference on Long-Term Complications of Treatment of Children and Adolescents for Cancer (2010 to 2013). We scanned the International Standard Randomized Controlled Trial Number (ISRCTN) Register and the National Institute of Health Register for ongoing trials (www.controlled-trials.com) (searched on 17 March 2014). Randomized controlled trials (RCTs) or controlled clinical trials (CCTs) evaluating platinum-based therapy together with an otoprotective medical intervention versus platinum-based therapy with placebo, no additional treatment or another protective medical intervention in children with cancer. Two review authors independently performed the study selection, risk of bias assessment of included studies and data extraction, including adverse effects. Analyses were performed according to the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions. We identified two RCTs and one CCT (total number of patients 149) evaluating the use of amifostine versus no additional treatment in the original version of the review; in this update no additional studies were identified. Two studies included children with osteosarcoma, and the other study included children with hepatoblastoma. Patients received cisplatin only or a combination of cisplatin and carboplatin, either administered intra-arterially or intravenously. All studies had methodological limitations. Unfortunately pooling of the results of the included studies was not possible. However, in the individual studies no significant difference was identified in symptomatic ototoxicity only (that is grade 2 or higher) and combined asymptomatic and symptomatic ototoxicity (that is grade 1 or higher) between children treated with or without amifostine. Only one study, including children with osteosarcoma treated with intra-arterial cisplatin, provided information on tumour response, defined as the number of patients with a good or partial remission. The available data analysis (data were missing for one patient), best case scenario analysis and worst case scenario analysis all showed a difference in favour of amifostine, but this difference was significant only in the worst case scenario analysis (P = 0.04). No information on survival was available for any of the included study populations. Only one study, including children with osteosarcoma treated with intra-arterial cisplatin, provided data on the number of patients with adverse effects other than ototoxicity grade 3 or higher. There was a significant difference in favour of the control group in the occurrence of vomiting grade 3 or 4 (risk ratio (RR) 9.04; 95% confidence interval (CI) 1.99 to 41.12; P = 0.004). No significant difference was identified between treatment groups for cardiotoxicity and renal toxicity grade 3 or 4. None of the studies evaluated quality of life. No eligible studies were found for possible otoprotective medical interventions other than amifostine and other types of malignancies. At the moment there is no evidence from individual studies in children with osteosarcoma or hepatoblastoma treated with different platinum analogues and dosage schedules which underscores the use of amifostine as an otoprotective intervention as compared to no additional treatment. Since pooling of results was not possible and all studies had serious methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. Based on the currently available evidence, we are not able to give recommendations for clinical practice. No eligible studies were identified for other possible otoprotective medical interventions and other types of malignancies, so no conclusions can be made about their efficacy in preventing ototoxicity in children treated with platinum-based therapy. More high quality research is needed.

Effect of amifostine in head and neck cancer patients treated with radiotherapy: a systematic review and meta-analysis based on randomized controlled trials.

BackgroundAmifostine is the most clinical used chemical radioprotector, but its effect in patients treated with radiation is not consistent.MethodsBy searching Medline, CENTRAL, EMBASE, ASCO, ESMO, and CNKI databases, the published randomized controlled trials (RCTs) about the efficacy of amifostine in HNSCC patients treated with radiotherapy were collected. The pooled efficacy and side effects of this drug were calculated by RevMan software.ResultsSeventeen trials including a total of 1167 patients (604 and 563 each arm) were analyzed in the meta-analysis. The pooled data showed that the use of amifostine significantly reduce the risk of developing Grade3–4 mucositis (relative risk [RR],0.72; 95% confidence interval [CI],0.54–0.95; p<0.00001), Grade 2–4 acute xerostomia (RR,0.70; 95%CI,0.52–0.96; p = 0.02), or late xerostomia (RR,0.60; 95%CI,0.49–0.74; p<0.00001) and Grade 3–4 dysphagia (RR,0.39; 95%CI,0.17–0.92; p = 0.03). However, subgroup analysis demonstrated that no statistically significant reduction of Grade3–4 mucositis (RR,0.97; 95% CI,0.74–1.26; p = 0.80), Grade 2–4 acute xerostomia (RR,0.35; 95%CI,0.02–5.44; p = 0.45), or late xerostomia (RR,0.40; 95%CI,0.13–1.24; p = 0.11) and Grade 3–4 dysphagia (RR,0.23; 95%CI,0.01–4.78; p = 0.35) was observed in patients treated with concomitant chemoradiotherapy. Compared with placebo or observation, amifostine does not show tumor protective effect in complete response (RR,1.02; 95%CI,0.89–1.17; p = 0.76) and partial response (RR,0.90; 95%CI, 0.56–1.44; p = 0.66). For the hematologic side effect, no statistical difference of Grade 3–4 leucopenia (RR,0.60; 95%CI,0.35–1.05; p = 0.07), anemia (RR,0.80; 95%CI, 0.42–1.53; p = 0.50) and thrombocytopenia (RR,0.43; 95%CI,0.16–1.15; p = 0.09) were found between amifostine and control groups. The most common amifostine related side effects were nausea, emesis, hypotension and allergic with an average incidence rate (Grade 3–4) of 5%, 6%, 4% and 4% respectively.ConclusionThis systematic review showed that amifostine significantly reduce the serious mucositis, acute/late xerastomia and dysphagia without protection of the tumor in HNSCC patients treated with radiotherapy. And the toxicities of amifostine were generally acceptable.

Harnessing cerium oxide nanoparticles to protect normal tissue from radiation damage

At the onset of radiation exposure, free radicals are formed through ionizing reactions that are then capable of destroying normal tissues. While cells release a level of protective molecules, such as glutathione and metallothionine, they are not capable of blocking all damage, thus resulting in the death of normal tissues and therefore, we must continue to develop strategies to protect normal tissues from radiation-induced damage. One such strategy is the development of radiation protectors. Several compounds have been described, but Amifostine (Ethyol), whose active free thiol metabolite WR-1065 has been shown to prevent both radiation-induced cell death and mutagenesis while facilitating the repair of normal cells remains the only agent currently in clinical use. Major limitations to the clinical use of Amifostine are its short half-life, daily dosing requirements, toxicity based on route of administration, and its cost. Recent studies have shown the effects of engineered cerium oxide (CeO 2 ) nanoparticles for protection against radiation-induced damage in a variety of tissue types. The role of nanoparticles as radioprotectants is a cutting-edge development in decades of scientific interest regarding the protection of normal cells and tissues from radiation. The chemistry of engineered CeO 2 nanoparticles supports a potential role as a biological free radical scavenger or antioxidant. The work presented in this review article will address the effectiveness of CeO 2 nanoparticles in radioprotection in a variety of cells and in animal models during radiation exposure which will encourage the development of innovative and new approaches to radiation protection, using nanotechnology.

Glutathione S-transferase P1 single nucleotide polymorphism predicts permanent ototoxicity in children with medulloblastoma.

Glutathione S-transferase (GST) enzymes are involved in detoxifying chemotherapy and clearing reactive oxygen species formed by radiation. We explored the relationship between the host GSTP1 105 A > G polymorphism (rs1695), tumor GSTpi protein expression, and clinical outcomes in pediatric medulloblastoma. We hypothesized that the GSTP1 105 G-allele and increased tumor GSTpi expression would be associated with lower progression-free survival and fewer adverse events. The study included 106 medulloblastoma/primitive neuroectodermal tumor (PNET) patients seen at Texas Children's Cancer Center. Genotyping was performed using an Illumina HumanOmni1-Quad BeadChip and GSTpi expression was assessed using immunohistochemistry. We used the Kaplan-Meier method for survival analyses and logistic regression for toxicity comparisons. Patients with a GSTP1 105 AG/GG genotype (vs. AA) or who had received high dose craniospinal radiation (≥34 Gy vs. <26 Gy) had a greater risk of requiring hearing aids than their counterparts (OR 4.0, 95% CI 1.2-13.6, and OR 3.1, 95% CI 1.1-8.8, respectively, n = 69). Additionally, there was a statistically significant interaction between these variables. Compared with the lowest risk group (GSTP1 105 AA-low dose radiation), patients with a GSTP1 105 AG/GG genotype who received high dose radiation were 8.4 times more likely to require hearing aids (95% CI 1.4-49.9, p-trend = 0.005, n = 69). When adjusted for age, cumulative cisplatin dose, and amifostine use, the association remained. The GSTP1 105 G-allele is associated with permanent ototoxicity in pediatric medulloblastoma/PNET and strongly interacts with radiation dose. Patients with this allele should be considered for clinical trials employing radiation dose modifications and cytoprotectant strategies.

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

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. 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. 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. 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.

Cost-utility assessment of amifostine as first-line therapy for ovarian cancer

Bennett CL, Golub R, Calhoun E, Weinstein J; Fishman D, Lurain J, Roland P, Medio F, Bukowski RM. Cost-utility assessment of amifostine as first-line therapy for ovarian cancer. Int J Gynecol Cancer 1998; 8: 64-72. Nearly 27,000 female patients were diagnosed with ovarian cancer in the United States in 1997. While chemotherapeutic agents are effective in prolonging the time to progression of disease, concerns exist over treatment- related toxicities. In addition to considerations related to effectiveness, the decision to prescribe new cytoprotective agents requires consideration of costs and cost-effectiveness. The objective of this study was to describe cost-utility estimates of a new supportive care agent, amifostine, and to illustrate these issues for patients with ovarian cancer. The phase III Food and Drug Administration (FDA) licensing trial found that pretreatment with amifostine prior to each cycle of chemotherapy resulted in reduction of cumulative toxicities with cyclophosphamide and cisplatinum. While amifostine use is approximately $3,146 more per patient, after adjustment for direct medical costs and potential health status changes from reductions in hematologic toxicity, neurotoxicity, and nephrotoxicity, its use was estimated to cost $36,161 in direct medical costs per quality-adjusted life year saved. Sensitivity analyses indicated that cost-effectiveness estimates of amifostine therapy ranged front $25,474 to $78,574. Based on the phase III FDA licensing trial, amifostine use is associated with a favorable cost-utility profile that is in the range associated with widely used cancer therapeutic and supportive care agents. The decision to use (or not use) amifostine in conjunction with cisplatin and cyclophosphamide for women with ovarian cancer should be based on clinical, not economic, considerations.

QUALITY OF LIFE/AFTERCARE

BACKGROUND: Glutathione S-transferase (GST) enzymes are involved in detoxifying chemotherapy agents and clearing reactive oxygen species formed by radiation. In this study, we explored the relationship between the host GSTP1-105 polymorphism (rs1695), tumor GSTpi protein expression, and clinical outcomes in pediatric medulloblastoma. We hypothesized that the GSTP1-105 G-allele and increased tumor GSTpi expression would be associated with lower progression-free survival and fewer adverse events. METHODS: The study included 106 medulloblastoma/primitive neuroectodermal tumor (PNET) patients seen at Texas Children’s Cancer Center. Genotyping was performed using an Illumina HumanOmni1-Quad BeadChip and tumor GSTpi expression was assessed using immunohistochemistry. We used the Kaplan-Meier method for survival analyses and multivariable logistic regression for toxicity comparisons. RESULTS: Patients with a GSTP1-105 AG/GG genotype or who had received a higher dose of craniospinal radiation (median 36 Gy) had a greater risk of requiring hearing aids than their respective counterparts (OR 4.0, 95%CI 1.2 - 13.6, and OR 3.1, 95%CI 1.1 - 8.8, respectively). Additionally, there was a statistically significant interaction between the two variables. Compared with the lowest risk group (GSTP1-105 AA-lower dose radiation) patients with a GSTP1-105 AG/GG genotype who received a higher dose radiation were 8.4 times more likely to require hearing aids (95%CI 1.4 - 49.9, p-trend ¼ 0.005). When adjusted for age, gender, and amifostine use, the association remained. CONCLUSIONS: The GSTP1-105 G-allele is associated with permanent ototoxicity in pediatric medulloblastoma/PNET and strongly interacts with radiation dose. A possible mechanism for this finding is that the GSTP1-105 G-allele leads to reduced GSTpi free radical detoxification in the setting of multimodality therapy including cisplatin and radiation. Patients with this allele should be considered for clinical trials employing radiation dose modifications and more targeted cytoprotectant strategies than are currently being used with amifostine.