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Journal of Oncology 2023Osteoradionecrosis (ORN) is described as a disease with exposed, nonviable bone that fails to heal spontaneously or by means of conservative treatment after radiotherapy... (Review)
Review
Osteoradionecrosis (ORN) is described as a disease with exposed, nonviable bone that fails to heal spontaneously or by means of conservative treatment after radiotherapy in at least 3 months. Though traditional theories in the early stage including hypoxic-hypocellular-hypovascular and fibro-atrophic in addition to new findings such as ferroptosis were put forward to explain the mechanisms of the osteoradionecrosis, the etiology of ORN is still unclear. With the high rate of occurrence in the head and neck area, especially in the mandible, this disease can disrupt the shape and function of the irradiated area, leading to a clinical presentation ranging from stable small areas of asymptomatic exposed bone to severe progressive necrosis. In severe cases, patients may experience pain, xerostomia, dysphagia, facial fistulas, and even a jaw defect. Consequently, sequence therapy and sometimes extensive surgery and reconstructions are needed to manage these sequelae. Treatment options may include pain medication, antibiotics, the removal of sequesters, hyperbaric oxygen therapy, segmental resection of the mandible, and free flap reconstruction. Microanastomosed free-flaps are considered to be promising choice for ORN reconstruction in recent researches, and new methods including three-dimensional (3-D) printing, pentoxifylline, and amifostine are used nowadays in trying increase the success rates and improve quality of the reconstruction. This review summarizes the main research progress in osteoradionecrosis and reconstruction treatment of osteoradionecrosis with mandibular defect.
PubMed: 36968640
DOI: 10.1155/2023/1440889 -
The Oncologist Jun 2007After several decades of preclinical and clinical research, the first approved radioprotective drug, amifostine, is being used in clinical practice. Amifostine has been... (Review)
Review
After several decades of preclinical and clinical research, the first approved radioprotective drug, amifostine, is being used in clinical practice. Amifostine has been shown to specifically protect normal tissues from damage caused by radiation and chemotherapy. An inactive prodrug, amifostine is converted to an active thiol by dephosphorylation by alkaline phosphatase in the normal endothelium. The hypovascularity and acidity of the tumor environment and the differential expression of alkaline phosphatase in normal and neoplastic tissues contribute to its cytoprotective selectivity. The cytoprotective mechanism of amifostine is complicated, involving free-radical scavenging, DNA protection and repair acceleration, and induction of cellular hypoxia. The U.S. Food and Drug Administration has approved the i.v. use of amifostine to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer and to reduce the incidence of moderate to severe xerostomia in patients undergoing postoperative radiation treatment for head and neck cancer, where the radiation port includes a substantial portion of the parotid glands. Nonetheless, amifostine has potential applications in many other oncologic settings. Novel schedules and routes of administration are under investigation and may further simplify the use of amifostine, reduce any undesired effects, and considerably broaden its applications. This review summarizes the clinical experience with amifostine and provides insight into future clinical directions.
Topics: Amifostine; Humans; Mucositis; Neoplasms; Radiation-Protective Agents; Radiotherapy; Treatment Outcome; Xerostomia
PubMed: 17602063
DOI: 10.1634/theoncologist.12-6-738 -
Evidence-based Complementary and... 2015The potentially life-threatening effects of total body ionizing radiation exposure have been known for more than a century. Despite considerable advances in our... (Review)
Review
The potentially life-threatening effects of total body ionizing radiation exposure have been known for more than a century. Despite considerable advances in our understanding of the effects of radiation over the past six decades, efforts to identify effective radiation countermeasures for use in case of a radiological/nuclear emergency have been largely unsuccessful. Vitamin E is known to have antioxidant properties capable of scavenging free radicals, which have critical roles in radiation injuries. Tocopherols and tocotrienols, vitamin E analogs together known as tocols, have shown promise as radioprotectors. Although the pivotal mechanisms of action of tocols have long been thought to be their antioxidant properties and free radical scavenging activities, other alternative mechanisms have been proposed to drive their activity as radioprotectors. Here we provide a brief overview of the effects of ionizing radiation, the mechanistic mediators of radiation-induced damage, and the need for radiation countermeasures. We further outline the role for, efficacy of, and mechanisms of action of tocols as radioprotectors, and we compare and contrast their efficacy and mode of action with that of another well-studied chemical radioprotector, amifostine.
PubMed: 26366184
DOI: 10.1155/2015/741301 -
International Journal of Preventive... 2017Children with cancer treated with cytotoxic drugs are frequently at risk of developing renal dysfunction. The cytotoxic drugs that are widely used for cancer treatment... (Review)
Review
Children with cancer treated with cytotoxic drugs are frequently at risk of developing renal dysfunction. The cytotoxic drugs that are widely used for cancer treatment in children are cisplatin (CPL), ifosfamide (IFO), carboplatin, and methotrexate (MTX). Mechanisms of anticancer drug-induced renal disorders are different and include acute kidney injury (AKI), tubulointerstitial disease, vascular damage, hemolytic uremic syndrome (HUS), and intrarenal obstruction. CPL nephrotoxicity is dose-related and is often demonstrated with hypomagnesemia, hypokalemia, and impaired renal function with rising serum creatinine and blood urea nitrogen levels. CPL, mitomycin C, and gemcitabine treatment cause vascular injury and HUS. High-dose IFO, streptozocin, and azacitidine cause renal tubular dysfunction manifested by Fanconi syndrome, rickets, and osteomalacia. AKI is a common adverse effect of MTX, interferon-alpha, and nitrosourea compound treatment. These strategies to reduce the cytotoxic drug-induced nephrotoxicity should include adequate hydration, forced diuresis, and urinary alkalization. Amifostine, sodium thiosulfate, and diethyldithiocarbamate provide protection against CPL-induced renal toxicity.
PubMed: 29114374
DOI: 10.4103/ijpvm.IJPVM_40_17 -
Translational Oncology Jun 2018The first tenet of medicine, "primum non nocere" or "first, do no harm", is not always compatible with oncological interventions e.g., chemotherapy, targeted therapy and... (Review)
Review
The first tenet of medicine, "primum non nocere" or "first, do no harm", is not always compatible with oncological interventions e.g., chemotherapy, targeted therapy and radiation, since they commonly result in significant toxicities. One of the more frequent and serious treatment-induced toxicities is mucositis and particularly oral mucositis (OM) described as inflammation, atrophy and breakdown of the mucosa or lining of the oral cavity. The sequelae of oral mucositis (OM), which include pain, odynodysphagia, dysgeusia, decreased oral intake and systemic infection, frequently require treatment delays, interruptions and discontinuations that not only negatively impact quality of life but also tumor control and survivorship. One potential strategy to reduce or prevent the development of mucositis, for which no effective therapies exist only best supportive empirical care measures, is the administration of agents referred to as radioprotectors and/or chemoprotectors, which are intended to differentially protect normal but not malignant tissue from cytotoxicity. This limited-scope review briefly summarizes the incidence, pathogenesis, symptoms and impact on patients of OM as well as the background and mechanisms of four clinical stage radioprotectors/chemoprotectors, amifostine, palifermin, GC4419 and RRx-001, with the proven or theoretical potential to minimize the development of mucositis particularly in the treatment of head and neck cancers.
PubMed: 29698934
DOI: 10.1016/j.tranon.2018.03.014 -
Iranian Journal of Basic Medical... 2023Acrylamide (ACR) is a toxic chemical agent that can induce hepatotoxicity through different mechanisms including oxidative stress and apoptosis. Amifostine is an...
OBJECTIVES
Acrylamide (ACR) is a toxic chemical agent that can induce hepatotoxicity through different mechanisms including oxidative stress and apoptosis. Amifostine is an important hepatoprotective and anti-oxidant compound. In this research, the hepatoprotective effect of amifostine on ACR-induced hepatotoxicity in rats has been investigated.
MATERIALS AND METHODS
Male Wistar rats were randomly divided into 7 groups, including: 1. Control group, 2. ACR (50 mg/kg, 11 days, IP), 3-5. ACR+ amifostine (25, 50, 100 mg/kg, 11 days, IP), 6. ACR+ N-acetyl cysteine (NAC) (200 mg/kg, 11 days, IP), and 7. Amifostine (100 mg/kg, 11 days, IP). At the end of the injection period, animals' liver samples were collected to determine the content of glutathione (GSH), malondialdehyde (MDA), and apoptotic proteins (B-cell lymphoma 2 (Bcl2), Bcl-2-associated X protein (Bax), and cleaved caspase-3. Serum samples were also collected to measure alanine transaminase (ALT) and aspartate transaminase (AST) levels.
RESULTS
Administration of ACR increased MDA, Bax/Bcl2 ratio, cleaved caspase-3, ALT, and AST levels, and decreased GSH content compared with the control group. The administration of amifostine with ACR decreased MDA, Bax/Bcl2 ratio, cleaved caspase-3, ALT, and AST levels, and increased GSH content compared with the ACR group. Receiving NAC along with ACR reversed the alterations induced by ACR.
CONCLUSION
This study shows that pretreatment with amifostine can reduce ACR-induced toxicity in the liver tissue of rats. Since oxidative stress is one of the most important mechanisms in ACR toxicity, amifostine probably reduces the toxicity of ACR by increasing the anti-oxidant and anti-apoptotic capacity of the hepatic cells.
PubMed: 37275759
DOI: 10.22038/IJBMS.2023.67815.14837 -
PloS One 2014Amifostine is the most clinical used chemical radioprotector, but its effect in patients treated with radiation is not consistent. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Amifostine is the most clinical used chemical radioprotector, but its effect in patients treated with radiation is not consistent.
METHODS
By 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.
RESULTS
Seventeen 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 Grade 3-4 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 Grade 3-4 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.
CONCLUSION
This 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.
Topics: Amifostine; Carcinoma, Squamous Cell; Combined Modality Therapy; Head and Neck Neoplasms; Humans; Radiation Injuries; Randomized Controlled Trials as Topic; Squamous Cell Carcinoma of Head and Neck
PubMed: 24788761
DOI: 10.1371/journal.pone.0095968 -
World Journal of Clinical Oncology Jan 2019Xerostomia, or dry mouth, is a significant problem affecting quality of life in patients treated with radiation therapy for head and neck cancer. Strategies for... (Review)
Review
Xerostomia, or dry mouth, is a significant problem affecting quality of life in patients treated with radiation therapy for head and neck cancer. Strategies for reduction of xerostomia burden vary widely, with options including: sialagogue medications, saliva substitutes, acupuncture, vitamins, hyperbaric oxygen, submandibular gland transfer, and acupuncture or associated treatments. In this review, we sought to evaluate long-term outcomes of patients treated with various interventions for radiation-induced xerostomia. A literature search was performed using the terms "xerostomia" and "radiation" or "radiotherapy"; all prospective clinical trials were evaluated, and only studies that reported 1 year follow up were included. The search results yielded 2193 studies, 1977 of which were in English. Of those, 304 were clinical trials or clinical studies. After abstract review, 23 trials were included in the review evaluating the following treatment modalities: pilocarpine (three); cevimeline (one); amifostine (eleven); submandibular gland transfer (five); acupuncture like transcutaneous electrical nerve stimulation (ALTENS) (one); hyperbaric oxygen (one); and acupuncture (one). Pilocarpine, cevimeline, and amifostine have been shown in some studies to improve xerostomia outcomes, at the cost of toxicity. ALTENS has similar efficacy with fewer side effects. Submandibular gland transfer is effective but requires an elective surgery, and thus may not always be appropriate or practical. The use of intensity-modulated radiation therapy, in addition to dose de-escalation in select patients, may result in fewer patients with late xerostomia, reducing the need for additional interventions.
PubMed: 30627521
DOI: 10.5306/wjco.v10.i1.1 -
Journal of Clinical and Experimental... Apr 2016The management of oral mucositis is a challenge, due to its complex biological nature. Over the last 10 years, different strategies have been developed for the... (Review)
Review
INTRODUCTION
The management of oral mucositis is a challenge, due to its complex biological nature. Over the last 10 years, different strategies have been developed for the management of oral mucositis caused by chemotherapy in cancer patients.
MATERIAL AND METHODS
An exhaustive search was made of the PubMed-Medline, Cochrane Library and Scopus databases, crossing the key words "oral mucositis", "prevention" and "treatment" with the terms "chemotherapy" and "radiotherapy" by means of the boolean operators "AND" and "NOT". A total of 268 articles were obtained, of which 96 met the inclusion criteria.
RESULTS
Several interventions for the prevention of oral mucositis, such as oral hygiene protocols, amifostine, benzidamine, calcium phosphate, cryotherapy and iseganan, among others, were found to yield only limited benefits. Other studies have reported a decrease in the appearance and severity of mucositis with the use of cytoprotectors (sucralfate, oral glutamine, hyaluronic acid), growth factors, topical polyvinylpyrrolidone, and low power laser irradiation.
CONCLUSIONS
Very few interventions of confirmed efficacy are available for the management of oral mucositis due to chemotherapy. However, according to the reviewed literature, the use of palifermin, cryotherapy and low power laser offers benefits, reducing the incidence and severity of oral mucositis - though further studies are needed to confirm the results obtained.
KEY WORDS
Chemotherapy-Induced Oral Mucositis Treatment.
PubMed: 27034762
DOI: 10.4317/jced.52917 -
Biomedicines Oct 2020The development of protective agents against harmful radiations has been a subject of investigation for decades. However, effective (ideal) radioprotectors and... (Review)
Review
The development of protective agents against harmful radiations has been a subject of investigation for decades. However, effective (ideal) radioprotectors and radiomitigators remain an unsolved problem. Because ionizing radiation-induced cellular damage is primarily attributed to free radicals, radical scavengers are promising as potential radioprotectors. Early development of such agents focused on thiol synthetic compounds, e.g., amifostine (2-(3-aminopropylamino) ethylsulfanylphosphonic acid), approved as a radioprotector by the Food and Drug Administration (FDA, USA) but for limited clinical indications and not for nonclinical uses. To date, no new chemical entity has been approved by the FDA as a radiation countermeasure for acute radiation syndrome (ARS). All FDA-approved radiation countermeasures (filgrastim, a recombinant DNA form of the naturally occurring granulocyte colony-stimulating factor, G-CSF; pegfilgrastim, a PEGylated form of the recombinant human G-CSF; sargramostim, a recombinant granulocyte macrophage colony-stimulating factor, GM-CSF) are classified as radiomitigators. No radioprotector that can be administered prior to exposure has been approved for ARS. This differentiates radioprotectors (reduce direct damage caused by radiation) and radiomitigators (minimize toxicity even after radiation has been delivered). Molecules under development with the aim of reaching clinical practice and other nonclinical applications are discussed. Assays to evaluate the biological effects of ionizing radiations are also analyzed.
PubMed: 33142986
DOI: 10.3390/biomedicines8110461