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Zhou C, Deng H, Yang Y, Wang F, Lin X, Liu M, Xie X, Luan T, Zhong N. Cancer therapy-related interstitial lung disease. Chin Med J (Engl) 2025; 138:264-277. [PMID: 39402974 PMCID: PMC11771665 DOI: 10.1097/cm9.0000000000003149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Indexed: 01/29/2025] Open
Abstract
ABSTRACT With the increasing utilization of cancer therapy, the incidence of lung injury associated with these treatments continues to rise. The recognition of pulmonary toxicity related to cancer therapy has become increasingly critical, for which interstitial lung disease (ILD) is a common cause of mortality. Cancer therapy-related ILD (CT-ILD) can result from a variety of treatments including chemotherapy, targeted therapy, immune checkpoint inhibitors, antibody-drug conjugates, and radiotherapy. CT-ILD may progress rapidly and even be life-threatening; therefore, prompt diagnosis and timely treatment are crucial for effective management. This review aims to provide valuable information on the risk factors associated with CT-ILD; elucidate its underlying mechanisms; discuss its clinical features, imaging, and histological manifestations; and emphasize the clinical-related views of its diagnosis. In addition, this review provides an overview of grading, typing, and staging treatment strategies used for the management of CT-ILD.
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Affiliation(s)
- Chengzhi Zhou
- State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China
| | - Haiyi Deng
- KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, Guangdong 511436, China
| | - Yilin Yang
- State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China
| | - Fei Wang
- State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230032, China
| | - Xinqing Lin
- State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China
| | - Ming Liu
- State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China
| | - Xiaohong Xie
- State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China
| | - Tao Luan
- State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, China
| | - Nanshan Zhong
- State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China
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Chen K, Li S, Chen M, Jin Z, Sun X, Zhou S, Yang H. Endostar acts as a pneumonitis protectant in patients with locally advanced non-small cell lung cancer receiving concurrent chemoradiotherapy. BMC Cancer 2024; 24:257. [PMID: 38395838 PMCID: PMC10893751 DOI: 10.1186/s12885-024-12001-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 02/13/2024] [Indexed: 02/25/2024] Open
Abstract
BACKGROUND CCRT is presently the standard treatment for LA-NSCLC. RP is one of the main obstacles to the completion of thoracic radiation therapy, resulting in limited survival benefits in NSCLC patients. This research aims to explore the role of Endostar in the occurrence of grade≥2 RP and clinical curative effect in LA-NSCLC patients. METHODS This study retrospectively analyzed 122 patients with stage III NSCLC who received CCRT from December 2008 to December 2017, or Endostar intravenous drip concurrently with chemoradiotherapy (Endostar + CCRT group). Standard toxicity of the pneumonitis endpoint was also collected by CTCAE V5.0. We further summarized other available studies on the role of Endostar in the prognosis of NSCLC patients and the incidence of RP. RESULTS There were 76 cases in the CCRT group and 46 cases in the CCRT+ Endostar group. In the CCRT+ Endostar group, the occurrence of grade ≥2 RP in patients with V20Gy ≥25% was significantly higher than that in patients with V20Gy < 25% (p = 0.001). In the cohorts with V20Gy < 25%, 0 cases of 29 patients treated with Endostar developed grade ≥2 RP was lower than in the CCRT group (p = 0.026). The re-analysis of data from other available studies indicated that Endostar plus CCRT could be more efficient and safely in the occurrence of grade≥2 RP with LA-NSCLC. CONCLUSIONS When receiving CCRT for LA-NSCLC patients, simultaneous combination of Endostar is recommended to enhance clinical benefit and reduce pulmonary toxicity.
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Affiliation(s)
- Kuifei Chen
- Taizhou hospital of Zhejiang Province, Shaoxing University, Zhejiang Province, Taizhou, 317000, China
- Department of Radiation Oncology, Key Laboratory of Radiation Oncology of Taizhou, Radiation Oncology Institute of Enze Medical Health Academy, Taizhou Hospital Affiliated to Wenzhou Medical University, Zhejiang Province, Taizhou, 317000, China
| | - Shuling Li
- Taizhou hospital of Zhejiang Province, Shaoxing University, Zhejiang Province, Taizhou, 317000, China
- Department of Radiation Oncology, Key Laboratory of Radiation Oncology of Taizhou, Radiation Oncology Institute of Enze Medical Health Academy, Taizhou Hospital Affiliated to Wenzhou Medical University, Zhejiang Province, Taizhou, 317000, China
| | - Meng Chen
- Department of Radiation Oncology, Key Laboratory of Radiation Oncology of Taizhou, Radiation Oncology Institute of Enze Medical Health Academy, Taizhou Hospital Affiliated to Wenzhou Medical University, Zhejiang Province, Taizhou, 317000, China
| | - Zhicheng Jin
- Department of Radiation Oncology, Key Laboratory of Radiation Oncology of Taizhou, Radiation Oncology Institute of Enze Medical Health Academy, Taizhou Hospital Affiliated to Wenzhou Medical University, Zhejiang Province, Taizhou, 317000, China
| | - Xuefeng Sun
- Department of Radiation Oncology, Key Laboratory of Radiation Oncology of Taizhou, Radiation Oncology Institute of Enze Medical Health Academy, Taizhou Hospital Affiliated to Wenzhou Medical University, Zhejiang Province, Taizhou, 317000, China
| | - Suna Zhou
- Department of Radiation Oncology, Key Laboratory of Radiation Oncology of Taizhou, Radiation Oncology Institute of Enze Medical Health Academy, Taizhou Hospital Affiliated to Wenzhou Medical University, Zhejiang Province, Taizhou, 317000, China.
| | - Haihua Yang
- Taizhou hospital of Zhejiang Province, Shaoxing University, Zhejiang Province, Taizhou, 317000, China.
- Department of Radiation Oncology, Key Laboratory of Radiation Oncology of Taizhou, Radiation Oncology Institute of Enze Medical Health Academy, Taizhou Hospital Affiliated to Wenzhou Medical University, Zhejiang Province, Taizhou, 317000, China.
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Yang C, Wang J, Yuan S. Chinese clinical practice guidelines for the prevention and treatment of radiation-induced esophagitis. PRECISION RADIATION ONCOLOGY 2023; 7:225-236. [PMID: 40336867 PMCID: PMC11935206 DOI: 10.1002/pro6.1210] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 08/26/2023] [Accepted: 08/27/2023] [Indexed: 05/09/2025] Open
Abstract
Acute radiation-induced esophagitis is a common complication of radiotherapy for esophageal, lung, and other malignancies. Therefore, understanding the diagnosis, grading, risk factors, prevention, and treatment of radiation-induced esophagitis is essential. Currently, there are few consensuses and guidelines on radiation-induced esophagitis worldwide, mainly the American College of Gastroenterology (ACG) clinical guideline: evidenced based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis (EoE) and the Digestive Endoscopy Society of Chinese Medical Association's "Guidelines for the Diagnosis and Treatment of Reflux Esophagitis." However, no consensus or guidelines specifically addressing radiation-induced esophagitis have been established. Efforts have been made to organize experts to draft Chinese consensus or guidelines, but the recommendations in these guidelines also vary owing to differences in expert backgrounds. The clinical practice guidelines presented herein were developed for the first time with the joint participation of Chinese radiotherapy experts. Drugs and methods with clinical significance were selected by reviewing and summarizing the prevention and treatment of radiation-induced esophagitis and combining them with China's national conditions. After multiple rounds of discussion and revision, clinical practice guidelines were established in line with the needs of Chinese clinicians, providing useful clinical guidance for the prevention and treatment of radiation-induced esophagitis.
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Affiliation(s)
- Congrong Yang
- Department of Radiation OncologyThe Fourth Hospital of Hebei Medical University
| | - Jun Wang
- Department of Radiation OncologyThe Fourth Hospital of Hebei Medical University
- Chinese Radiation Therapy Oncology Group
- China Anti‐Cancer Association Tumor Radiation Protection Committee
| | - Shuanghu Yuan
- Chinese Radiation Therapy Oncology Group
- China Anti‐Cancer Association Tumor Support Therapy Committee
- Department of RadiologyShandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanChina
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Abdelghany L, Xu Y, Sekiya R, Yan C, Jingu K, Li TS. Nicaraven Exerts a Limited Effect on Radiation-Induced Inhibition of Tumor Growth in a Subcutaneous Murine Tumor Model. Radiat Res 2023; 200:382-388. [PMID: 37702409 DOI: 10.1667/rade-22-00212.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 08/03/2023] [Indexed: 09/14/2023]
Abstract
Nicaraven selectively protects normal tissue from radiation-induced injury. To further develop the clinical application of nicaraven for mitigating the side effects of cancer radiotherapy, we investigated the potential effect of nicaraven administration in radiation-induced inhibition of tumor growth. A subcutaneous tumor model was established in mice by the injection of Lewis lung cancer cells at the back of the chest. X-ray radiation was delivered to the thoracic area and different doses of nicaraven (0, 20, 50, 100 mg/kg) were administrated intraperitoneally pre- or post-irradiation. The tumor size was measured every other day. Mice were euthanized on day 30, and the tumor weight and the levels of cytokines in tumor tissue were measured. Pre- or post-irradiation administration of nicaraven up to a dose of 100 mg/kg did not significantly diminish the radiation-induced inhibition of tumor growth, but post-irradiation administration of 20 and 50 mg/kg nicaraven resulted in relatively lower tumor weight. The levels of IL-1β, IL-6, IL-10, MCP-1, MIP-2a, TGF-β1, VEGF, p53, p21, cyclin D1 and caspase-3 in tumor tissue did not change by nicaraven administration and were not significantly associated with the tumor weights. According to our experimental data, nicaraven will not significantly diminish the radiation-induced inhibition of tumor growth, even with pre-irradiation administration at a high dose.
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Affiliation(s)
- Lina Abdelghany
- Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
- Department of Stem Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
| | - Yong Xu
- Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
- Department of Stem Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
| | - Reiko Sekiya
- Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
- Department of Stem Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
| | - Chen Yan
- Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
- Department of Stem Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
| | - Keiichi Jingu
- Department of Radiation Oncology, Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Tao-Sheng Li
- Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
- Department of Stem Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
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Deutsch E, Meziani L. [Radiation-induced pulmonary fibrosis: New potential targets]. Cancer Radiother 2023; 27:491-493. [PMID: 37596124 DOI: 10.1016/j.canrad.2023.06.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 06/29/2023] [Indexed: 08/20/2023]
Abstract
Radiation-induced pulmonary fibrosis (RIPF) is one of the major and late complications of radiotherapy (RT) with an average incidence rate between 16 and 28% after RT. RIPF significantly affects the function of the affected tissues/organs as well as the quality of life and survival of patients. The process of radiation fibrogenesis is initiated by a very complex signaling network that involves several cellular and molecular factors and the development of effective treatments relies on a better understanding of the involved mechanisms. Despite a major advance in the field, to date there is no clinical treatment that has really shown efficacy in the prevention or treatment of RIPF. In the present review, we will discuss potential new therapeutic avenues that could effectively treat RIPF.
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Affiliation(s)
- E Deutsch
- Département de radiothérapie, Gustave-Roussy cancer campus, 114, rue Édouard-Vaillant, 94805 Villejuif, France; Radiothérapie moléculaire et innovation thérapeutique, Gustave-Roussy cancer campus, université Paris-Saclay, Inserm U1030, 114, rue Édouard-Vaillant, 94805 Villejuif, France
| | - L Meziani
- Radiothérapie moléculaire et innovation thérapeutique, Gustave-Roussy cancer campus, université Paris-Saclay, Inserm U1030, 114, rue Édouard-Vaillant, 94805 Villejuif, France.
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Yang W, Pan L, Cheng Y, Wu X, Huang S, Du J, Zhu H, Zhang M, Zhang Y. Amifostine attenuates bleomycin-induced pulmonary fibrosis in mice through inhibition of the PI3K/Akt/mTOR signaling pathway. Sci Rep 2023; 13:10485. [PMID: 37380638 DOI: 10.1038/s41598-023-34060-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 04/24/2023] [Indexed: 06/30/2023] Open
Abstract
Amifostine is a normal cell protection agent, not only used in the adjuvant therapy of lung cancer, ovarian cancer, breast cancer, nasopharyngeal cancer, bone tumor, digestive tract tumor, blood system tumor and other cancers in order to reduce the toxicity of chemotherapy drugs, and recent studies have reported that the drug can also reduce lung tissue damage in patients with pulmonary fibrosis, but its mechanism of action is not yet fully understood. In this study, we explored the potential therapeutic effects and molecular mechanisms of AMI on bleomycin (BLM)-induced pulmonary fibrosis in mice. A mouse model of pulmonary fibrosis was established using BLM. We then assessed histopathological changes, inflammatory factors, oxidative indicators, apoptosis, epithelial-mesenchymal transition, extracellular matrix changes, and levels of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway-related proteins in the BLM-treated mice to determine the effect of AMI treatment on these factors. BLM-treated mice had substantial lung inflammation and abnormal extracellular matrix deposition. Overall, treatment with AMI significantly improved BLM-induced lung injury and pulmonary fibrosis. More specifically, AMI alleviated BLM-induced oxidative stress, inflammation, alveolar cell apoptosis, epithelial-mesenchymal transition, and extracellular matrix deposition by regulating the PI3K/Akt/mTOR signaling pathway. This finding that AMI can alleviate pulmonary fibrosis in a mouse model by inhibiting activation of the PI3K/Akt/mTOR signaling pathway lays a foundation for potential future clinical application of this agent in patients with pulmonary fibrosis.
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Affiliation(s)
- Wenting Yang
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Lin Pan
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Yiju Cheng
- Department of Respiratory and Critical Care Medicine, The First People's Hospital of Guiyang, Guiyang, 550004, China.
- Guizhou Medical University, Guiyang, 550004, China.
| | - Xiao Wu
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Songsong Huang
- Department of Pathology, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Juan Du
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Honglan Zhu
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Menglin Zhang
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Yuquan Zhang
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
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Cong C, Niu S, Jiang Y, Zhang X, Jing W, Zheng Y, Zhang X, Su G, Zhang Y, Sun M. Renin-angiotensin system inhibitors mitigate radiation pneumonitis by activating ACE2-angiotensin-(1-7) axis via NF-κB/MAPK pathway. Sci Rep 2023; 13:8324. [PMID: 37221286 DOI: 10.1038/s41598-023-35412-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 05/17/2023] [Indexed: 05/25/2023] Open
Abstract
Radiation pneumonitis (RP) affects both patients and physicians during radiation therapy for lung cancer. To date, there are no effective drugs for improving the clinical outcomes of RP. The activation of angiotensin-converting enzyme 2 (ACE2) improves experimental acute lung injury caused by severe acute respiratory syndrome coronavirus, acid inhalation, and sepsis. However, the effects and underlying mechanisms of ACE2 in RP remain unclear. Therefore, this study aimed to investigate the effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on RP and ACE2/angiotensin-(1-7)/Mas receptor pathway activation. We found that radiotherapy decreased the expression of ACE2 and that overexpression of ACE2 alleviated lung injury in an RP mouse model. Moreover, captopril and valsartan restored ACE2 activation; attenuated P38, ERK, and p65 phosphorylation; and effectively mitigated RP in the mouse model. Further systematic retrospective analysis illustrated that the incidence of RP in patients using renin-angiotensin system inhibitors (RASis) was lower than that in patients not using RASis (18.2% vs. 35.8% at 3 months, p = 0.0497). In conclusion, the current findings demonstrate that ACE2 plays a critical role in RP and suggest that RASis may be useful potential therapeutic drugs for RP.
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Affiliation(s)
- Changsheng Cong
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, Shandong, China
- Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, 250013, Shandong, China
| | - Shiying Niu
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
- Department of Pathophysiology, Academy of Clinical and Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250062, Shandong, China
- Department of Pathology, Linfen Central Hospital, Linfen, 041099, Shanxi, China
| | - Yifan Jiang
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
- Department of Pathophysiology, Academy of Clinical and Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250062, Shandong, China
| | - Xinhui Zhang
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
- Department of Pathophysiology, Academy of Clinical and Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250062, Shandong, China
| | - Wang Jing
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, Shandong, China
- Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, 250013, Shandong, China
| | - Yawen Zheng
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, Shandong, China
- Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, 250013, Shandong, China
| | - Xiaoyue Zhang
- Department of Pathology, Shandong Medicine and Health Key Laboratory of Clinical Pathology, Shandong Lung Cancer Institute, Shandong Institute of Nephrology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250013, Shandong, China
| | - Guohai Su
- Department of Cardiology, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, Shandong, China
| | - Yueying Zhang
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
- Department of Pathophysiology, Academy of Clinical and Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250062, Shandong, China.
| | - Meili Sun
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, Shandong, China.
- Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, 250013, Shandong, China.
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Zhao X, Cheng J, Gui S, Jiang M, Qi D, Huang J, Fu L, Liu S, Ma Y, Shi J, Wang Z, Zeng W, Li X, Liu K, Tang Y. Amifostine-Loaded Nanocarrier Traverses the Blood-Brain Barrier and Prevents Radiation-Induced Brain Injury. ACS APPLIED MATERIALS & INTERFACES 2023; 15:15203-15219. [PMID: 36917732 DOI: 10.1021/acsami.3c00502] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
Radiation-induced brain injury (RIBI) is a severe, irreversible, or even life-threatening cerebral complication of radiotherapy in patients with head and neck tumors, and there is no satisfying prevention and effective treatment available for these patients. Amifostine (AMF) is a well-known free radical scavenger with demonstrated effectiveness in preventing radiation-induced toxicity. However, the limited permeability of AMF across the blood-brain barrier (BBB) when administered intravenously reduces the effectiveness of AMF in preventing RIBI. Herein, we construct a nanoparticle (NP) platform for BBB delivery of AMF. AMF is conjugated with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-n-[poly(ethylene glycol)]-hydroxy succinamide [DSPE-PEG-NHS, PEG M 2000], and the product is DSPE-PEG-AMF. Then, the nanoparticles (DAPP NPs) were formed by self-assembly of poly(lactic-co-glycolic acid) (PLGA), DSPE-PEG-AMF, and polysorbate 80 (PS 80). PEG shields the nanoparticles from blood clearance by the reticuloendothelial system and lengthens the drug circulation time. PS 80 is used to encapsulate nanoparticles for medication delivery to the brain. The results of our study showed that DAPP NPs were able to effectively penetrate the blood-brain barrier (BBB) in healthy C57BL/6 mice. Furthermore, in a well-established mouse model of X-knife-induced brain injury, treatment with DAPP NPs (corresponding to 250 mg/kg AMF) was found to significantly reduce the volume of brain necrosis compared to mice treated with AMF (250 mg/kg). Importantly, the use of DAPP NPs was also shown to significantly mitigate the effects of radiation-induced neuronal damage and glial activation. This work presents a convenient brain-targeted AMF delivery system to achieve effective radioprotection for the brain, providing a promising strategy with tremendous clinical translation potential.
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Affiliation(s)
- XiaoHui Zhao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - JinPing Cheng
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Shushu Gui
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Meng Jiang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Dawei Qi
- MediCity Research Laboratory, University of Turku, Tykistökatu 6, 20520 Turku, Finland
| | - Jianghua Huang
- Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Liren Fu
- Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Shijie Liu
- Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Yujia Ma
- Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Juntian Shi
- Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Zairui Wang
- Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Weike Zeng
- Department of Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Xiumei Li
- Department of Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Kejia Liu
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Yamei Tang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Brain Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
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9
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Wu T, Orschell CM. The delayed effects of acute radiation exposure (DEARE): characteristics, mechanisms, animal models, and promising medical countermeasures. Int J Radiat Biol 2023; 99:1066-1079. [PMID: 36862990 PMCID: PMC10330482 DOI: 10.1080/09553002.2023.2187479] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/25/2023] [Accepted: 02/20/2023] [Indexed: 03/04/2023]
Abstract
PURPOSE Terrorist use of nuclear weapons and radiation accidents put the human population at risk for exposure to life-threatening levels of radiation. Victims of lethal radiation exposure face potentially lethal acute injury, while survivors of the acute phase are plagued with chronic debilitating multi-organ injuries for years after exposure. Developing effective medical countermeasures (MCM) for the treatment of radiation exposure is an urgent need that relies heavily on studies conducted in reliable and well-characterized animal models according to the FDA Animal Rule. Although relevant animal models have been developed in several species and four MCM for treatment of the acute radiation syndrome are now FDA-approved, animal models for the delayed effects of acute radiation exposure (DEARE) have only recently been developed, and there are no licensed MCM for DEARE. Herein, we provide a review of the DEARE including key characteristics of the DEARE gleaned from human data as well as animal, mechanisms common to multi-organ DEARE, small and large animal models used to study the DEARE, and promising new or repurposed MCM under development for alleviation of the DEARE. CONCLUSIONS Intensification of research efforts and support focused on better understanding of mechanisms and natural history of DEARE are urgently needed. Such knowledge provides the necessary first steps toward the design and development of MCM that effectively alleviate the life-debilitating consequences of the DEARE for the benefit of humankind worldwide.
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Affiliation(s)
- Tong Wu
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Christie M Orschell
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
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10
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Drishya S, Dhanisha SS, Raghukumar P, Guruvayoorappan C. Amomum subulatum mitigates experimental thoracic radiation-induced lung injury by regulating antioxidant status and inflammatory responses. Food Funct 2023; 14:1545-1559. [PMID: 36655677 DOI: 10.1039/d2fo03208b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Radiation-induced lung injury (RILI) is one of the most prominent complications of thoracic radiotherapy for which effective therapy is still lacking. This study investigates the nutraceutical potential of the culinary spice Amomum subulatum in mitigating thoracic radiation-induced pneumonitis (RP) and pulmonary fibrosis (PF). Mouse models of RP and PF were established by whole thorax irradiation at a dose of 25 gray. C57BL/6 mice were administered with 250 mg per kg body weight of methanolic extract of A. subulatum dry fruits (MEAS) for four consecutive weeks and observed for changes in lung tissue antioxidant activities, oxidative stress parameters, and expression of antioxidant, inflammation, and fibrosis-related genes by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and real-time PCR analysis, and histology analysis. MEAS administration reduced radiation-induced oxidative stress by enhancing the expression of Nrf2 and its target genes. Irradiation increased gene expression of inflammatory mediators and lung histology further confirmed the characteristics of RP, which were reduced by MEAS treatment. Immunohistochemistry analysis revealed the potential of MEAS in reducing the radiation-induced elevation of cyclooxygenase 2 expression in the lungs. The late sequel of RILI was manifested as PF, characterized by the elevated expression of pro-fibrotic genes and increased collagen content. However, MEAS administration markedly reduced radiation-induced fibrotic changes in the lungs. These effects might be attributed to the synergistic effect of bioactive polyphenols in MEAS with antioxidant, anti-inflammatory, and anti-fibrotic efficacies. Taken together, this study demonstrates the potential of MEAS in mitigating RILI, suggesting the possible nutraceutical application of A. subulatum against radiation toxicities.
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Affiliation(s)
- Sudarsanan Drishya
- Laboratory of Immunopharmacology and Experimental Therapeutics, Division of Cancer Research, Regional Cancer Centre, Medical College Campus, Thiruvananthapuram 695011 (Research Centre, University of Kerala), Kerala, India.
| | - Suresh Sulekha Dhanisha
- Laboratory of Immunopharmacology and Experimental Therapeutics, Division of Cancer Research, Regional Cancer Centre, Medical College Campus, Thiruvananthapuram 695011 (Research Centre, University of Kerala), Kerala, India.
| | - Paramu Raghukumar
- Division of Radiation Physics, Regional Cancer Centre, Medical College Campus, Thiruvananthapuram 695011, Kerala, India
| | - Chandrasekharan Guruvayoorappan
- Laboratory of Immunopharmacology and Experimental Therapeutics, Division of Cancer Research, Regional Cancer Centre, Medical College Campus, Thiruvananthapuram 695011 (Research Centre, University of Kerala), Kerala, India.
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11
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Altomare A, Fiore M, D’Ercole G, Imperia E, Nicolosi RM, Della Posta S, Pasqua G, Cicala M, De Gara L, Ramella S, Guarino MPL. Protective Role of Natural Compounds under Radiation-Induced Injury. Nutrients 2022; 14:5374. [PMID: 36558533 PMCID: PMC9786992 DOI: 10.3390/nu14245374] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/05/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
In recent years, evidence has shown the potential therapeutic effects of different natural compounds for the prevention and treatment of radiotherapy-induced mucositis (RIOM). RIOM represents one of the most frequent side effects associated with anti-neoplastic treatments affecting patients' quality of life and treatment response due to radiation therapy discontinuation. The innate radio-protective ability of natural products obtained from plants is in part due to the numerous antioxidants possessed as a part of their normal secondary metabolic processes. However, oxygen presence is a key point for radiation efficacy on cancer cells. The aim of this review is to describe the most recent evidence on radiation-induced injury and the emerging protective role of natural compounds in preventing and treating this specific damage without compromising treatment efficacy.
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Affiliation(s)
- Annamaria Altomare
- Unit of Food Science and Nutrition, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo 21, 00128 Rome, Italy
- Research Unit of Gastroenterology, Università Campus Biomedico di Roma, Via Alvaro del Portillo 21, 00128 Rome, Italy
- NBFC, National Biodiversity Future Center, 90133 Palermo, Italy
| | - Michele Fiore
- Operative Research Unit of Radiation Oncology, Fondazione Policlinico Universitario Campus Biomedico di Roma, Via Alvaro del Portillo 21, 00128 Rome, Italy
- Research Unit of Radiation Oncology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo 200, 00128 Rome, Italy
| | - Gabriele D’Ercole
- Operative Research Unit of Radiation Oncology, Fondazione Policlinico Universitario Campus Biomedico di Roma, Via Alvaro del Portillo 21, 00128 Rome, Italy
| | - Elena Imperia
- Unit of Food Science and Nutrition, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo 21, 00128 Rome, Italy
| | - Roberta Maria Nicolosi
- Department of Environmental Biology, Sapienza Università di Roma, P.le Aldo Moro 5, 00185 Rome, Italy
| | - Susanna Della Posta
- Unit of Food Science and Nutrition, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo 21, 00128 Rome, Italy
| | - Gabriella Pasqua
- Department of Environmental Biology, Sapienza Università di Roma, P.le Aldo Moro 5, 00185 Rome, Italy
| | - Michele Cicala
- Research Unit of Gastroenterology, Università Campus Biomedico di Roma, Via Alvaro del Portillo 21, 00128 Rome, Italy
- Operative Research Unit of Gastroenterology, Fondazione Policlinico Campus Bio-Medico di Roma, Via Alvaro del Portillo 200, 00128 Rome, Italy
| | - Laura De Gara
- Unit of Food Science and Nutrition, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo 21, 00128 Rome, Italy
- NBFC, National Biodiversity Future Center, 90133 Palermo, Italy
| | - Sara Ramella
- Operative Research Unit of Radiation Oncology, Fondazione Policlinico Universitario Campus Biomedico di Roma, Via Alvaro del Portillo 21, 00128 Rome, Italy
- Research Unit of Radiation Oncology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo 200, 00128 Rome, Italy
| | - Michele Pier Luca Guarino
- Research Unit of Gastroenterology, Università Campus Biomedico di Roma, Via Alvaro del Portillo 21, 00128 Rome, Italy
- Operative Research Unit of Gastroenterology, Fondazione Policlinico Campus Bio-Medico di Roma, Via Alvaro del Portillo 200, 00128 Rome, Italy
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12
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Wu T, Fu C, Deng Y, Huang W, Wang J, Jiao Y. Acupuncture therapy for radiotherapy-induced adverse effect: A systematic review and network meta-analysis. Front Public Health 2022; 10:1026971. [PMID: 36590000 PMCID: PMC9797977 DOI: 10.3389/fpubh.2022.1026971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 11/07/2022] [Indexed: 12/23/2022] Open
Abstract
Objective To evaluate the efficacy of different acupuncture therapies for radiotherapy-induced adverse effects (RIAEs) and find out the optimal scheme. Methods Eligible randomized controlled trials (RCTs) were collected from inception to June 2020 from 9 bibliographic databases. The risk of bias evaluation of the analyzed literature was carried out using the Cochrane risk-of-bias tool. Network meta-analysis was mainly performed using STATA 14.2 and OpenBUGS 3.2.3 by figuring out the network diagrams, league figures, and SUCRA values. Results A total of 41 studies with 3,011 participants reported data suitable for network meta-analysis. There was a low to moderate risk of bias in twenty of the articles. ST36 was the most widely prescribed acupoint. Based on network meta-analysis, four outcome indicators were described, namely, acupuncture + medication ranked first in treating radiation enteritis, moxibustion + medication ranked first in preventing radiotherapy-induced leukopenia, acupuncture + medication ranked first in preventing radioactive oral mucositis, and acupuncture ranked first in improving the stimulated salivary flow rate of radioactive xerostomia. Conclusion The findings of the network meta-analysis manifested that acupuncture therapy combined with medication has superiority in most RIAEs, both reducing incidence and relieving symptoms. However, high-quality studies are still needed to provide conclusive evidence. Systematic review registration https://inplasy.com/inplasy-2020-7-0054/, identifier: INPLASY202070054.
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Affiliation(s)
- Tong Wu
- Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
- Affiliated Hospital of Hubei University of Traditional Chinese Medicine, Wuhan, China
- Institute of Science, Technology and Humanities, Shanghai University of Chinese Medicine, Shanghai, China
| | - Chengwei Fu
- The Second Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yiran Deng
- Xiangyang Hospital of Traditional Chinese Medicine, Xiangyang, China
| | - Wanping Huang
- General Hospital of The Yangtze River Shipping, Wuhan, China
| | - Jieyu Wang
- Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
- Affiliated Hospital of Hubei University of Traditional Chinese Medicine, Wuhan, China
| | - Yang Jiao
- Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
- Affiliated Hospital of Hubei University of Traditional Chinese Medicine, Wuhan, China
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13
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Lai X, Najafi M. Redox Interactions in Chemo/Radiation Therapy-induced Lung Toxicity; Mechanisms and Therapy Perspectives. Curr Drug Targets 2022; 23:1261-1276. [PMID: 35792117 DOI: 10.2174/1389450123666220705123315] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 04/08/2022] [Accepted: 04/29/2022] [Indexed: 01/25/2023]
Abstract
Lung toxicity is a key limiting factor for cancer therapy, especially lung, breast, and esophageal malignancies. Radiotherapy for chest and breast malignancies can cause lung injury. However, systemic cancer therapy with chemotherapy may also induce lung pneumonitis and fibrosis. Radiotherapy produces reactive oxygen species (ROS) directly via interacting with water molecules within cells. However, radiation and other therapy modalities may induce the endogenous generation of ROS and nitric oxide (NO) by immune cells and some nonimmune cells such as fibroblasts and endothelial cells. There are several ROS generating enzymes within lung tissue. NADPH Oxidase enzymes, cyclooxygenase-2 (COX-2), dual oxidases (DUOX1 and DUOX2), and the cellular respiratory system in the mitochondria are the main sources of ROS production following exposure of the lung to anticancer agents. Furthermore, inducible nitric oxide synthase (iNOS) has a key role in the generation of NO following radiotherapy or chemotherapy. Continuous generation of ROS and NO by endothelial cells, fibroblasts, macrophages, and lymphocytes causes apoptosis, necrosis, and senescence, which lead to the release of inflammatory and pro-fibrosis cytokines. This review discusses the cellular and molecular mechanisms of redox-induced lung injury following cancer therapy and proposes some targets and perspectives to alleviate lung toxicity.
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Affiliation(s)
- Xixi Lai
- The Department of Respiratory and Critical Medicine, Sir Run Run Shaw Hospital, Affiliated with the Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China
| | - Masoud Najafi
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
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14
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Wan X, Shi X, Li M, Chen Q, Xue C, Li G, Huang Y, Yang J, Chen C, Wang Z, Ma S, Liu X. The Protective Effects and Mechanism of Doxepin on Radiation–Induced Lung Injury in Rats. Dose Response 2022; 20:15593258221107193. [PMID: 35693872 PMCID: PMC9178985 DOI: 10.1177/15593258221107193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Radiation-induced lung injuries (RILI) is one of the serious complications of radiotherapy posed by the damage of alveolar cells and inflammation over-reaction. We aimed to investigate the potential protective effects of doxepin on RILI (20 Gy total dose at 3 Gy/min of X-ray irradiation), as well as its underlying mechanism. For animal experiments, such parameters as Immunohistochemistry and hematoxylin and eosin (H&E) staining, WBC (white blood cell), CRP (C-reactive protein), Western blot, and q-PCR were detected. The results indicated that both survival status and weight increase of irradiated rats treated by doxepin (3 mg/kg/day, rat) were higher than those of treated with irradiation alone (Dosing started the day before irradiation). Further, histological examinations showed doxepin could tenuate the radiation injury, as indicated as alveolar inflammatory exudation and there was only mild interstitial inflammation infiltration. Western blotting and q-PCR showed that expression of NF-κβ in X group were higher than that in XMD group. For the first time, we reported doxepin functioned as a radioprotectant candidate, which provide a promising application of doxepin for protecting radiotherapy injuries.
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Affiliation(s)
- Xinlong Wan
- South ZheJiang Institute of Radiation Medicine and Nuclear Technology, Wenzhou Medical University, China
- School of Public Health and Management, Wenzhou Medical University, China
| | - Xuan Shi
- Department of Geriatric Medicine, The First Affiliated Hospital of Wenzhou Medical University, China
| | - Mengke Li
- South ZheJiang Institute of Radiation Medicine and Nuclear Technology, Wenzhou Medical University, China
- School of Public Health and Management, Wenzhou Medical University, China
| | - Qing Chen
- South ZheJiang Institute of Radiation Medicine and Nuclear Technology, Wenzhou Medical University, China
- School of Public Health and Management, Wenzhou Medical University, China
| | - Chang Xue
- South ZheJiang Institute of Radiation Medicine and Nuclear Technology, Wenzhou Medical University, China
- School of Public Health and Management, Wenzhou Medical University, China
| | - Guanghui Li
- South ZheJiang Institute of Radiation Medicine and Nuclear Technology, Wenzhou Medical University, China
- School of Public Health and Management, Wenzhou Medical University, China
| | - Yeke Huang
- The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, China
| | - Jingwen Yang
- Department of Geriatric Medicine, The First Affiliated Hospital of Wenzhou Medical University, China
| | - Chan Chen
- Department of Geriatric Medicine, The First Affiliated Hospital of Wenzhou Medical University, China
| | - Zhiyi Wang
- Department of General Practice, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, China
| | - Shumei Ma
- South ZheJiang Institute of Radiation Medicine and Nuclear Technology, Wenzhou Medical University, China
- School of Public Health and Management, Wenzhou Medical University, China
| | - Xiaodong Liu
- South ZheJiang Institute of Radiation Medicine and Nuclear Technology, Wenzhou Medical University, China
- School of Public Health and Management, Wenzhou Medical University, China
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15
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Arora A, Bhuria V, Singh S, Pathak U, Mathur S, Hazari PP, Roy BG, Sandhir R, Soni R, Dwarakanath BS, Bhatt AN. Amifostine analog, DRDE-30, alleviates radiation induced lung damage by attenuating inflammation and fibrosis. Life Sci 2022; 298:120518. [PMID: 35367468 DOI: 10.1016/j.lfs.2022.120518] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 03/18/2022] [Accepted: 03/26/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND Radiotherapy of thoracic neoplasms and accidental radiation exposure often results in pneumonitis and fibrosis of lungs. Here, we investigated the potential of amifostine analogs: DRDE-07, DRDE-30, and DRDE-35, in alleviating radiation-induced lung damage. METHODS C57BL/6 mice were exposed to 13.5 Gy thoracic irradiation, 30 min after intraperitoneal administration of the analogs, and assessed for modulation of the pathological response at 12 and 24 weeks. KEY FINDINGS DRDE-07, DRDE-30 and DRDE-35 increased the survival of irradiated mice from 20% to 30%, 80% and 70% respectively. Reduced parenchymal opacity (X-ray CT) in the lungs of DRDE-30 pre-treated mice corroborated well with the significant decrease in Ashcroft score (p < 0.01). Two-fold increase in SOD and catalase activities (p < 0.05), coupled with a 50% increase in GSH content and a 60% decrease in MDA content (p < 0.05) suggested restoration of the antioxidant defence system. A 20% to 40% decrease in radiation-induced apoptotic and mitotic death in the lung tissue (micronuclei: p < 0.01), resulted in attenuated lung and vascular permeability (FITC-Dextran leakage) by 50% (p < 0.01), and a commensurate reduction (~50%) in leukocyte infiltration in the injured tissue (p < 0.05). DRDE-30 abrogated the activation of pro-inflammatory NF-κB and p38/MAPK signaling cascades, suppressing the release of pro-inflammatory cytokines (IL-1β: p < 0.05; TNF-α: p < 0.05; IL-6: p < 0.05) and up-regulation of CAMs on the endothelial cell surface. Reduction in hydroxyproline content (p < 0.01) and collagen suggested inhibition of lung fibrosis which was associated with attenuation of TGF-β/Smad pathway-mediated-EMT. CONCLUSION DRDE-30 could be a potential prophylactic agent against radiation-induced lung injury.
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Affiliation(s)
- Aastha Arora
- Institute of Nuclear Medicine & Allied Sciences, Delhi, India; Department of Biochemistry, Panjab University, Chandigarh, India
| | - Vikas Bhuria
- Institute of Nuclear Medicine & Allied Sciences, Delhi, India
| | - Saurabh Singh
- Institute of Nuclear Medicine & Allied Sciences, Delhi, India
| | - Uma Pathak
- Defence Research and Development Establishment, Gwalior, India
| | - Sweta Mathur
- Defence Research and Development Establishment, Gwalior, India
| | - Puja P Hazari
- Institute of Nuclear Medicine & Allied Sciences, Delhi, India
| | - Bal G Roy
- Institute of Nuclear Medicine & Allied Sciences, Delhi, India
| | - Rajat Sandhir
- Department of Biochemistry, Panjab University, Chandigarh, India
| | - Ravi Soni
- Institute of Nuclear Medicine & Allied Sciences, Delhi, India
| | - Bilikere S Dwarakanath
- Institute of Nuclear Medicine & Allied Sciences, Delhi, India; Central Research Facility, Sri Ramachandra Institute of Higher Education and Research, Chennai, India
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16
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Alshawa A, Cadena AP, Stephen B, Reddy A, Mendoza TR, McQuinn L, Lawhorn K, Zarifa A, Bernhardt AM, Fessaheye S, Warneke CL, Chang JY, Naing A. Effects of glutamine for prevention of radiation-induced esophagitis: a double-blind placebo-controlled trial. Invest New Drugs 2021; 39:1113-1122. [PMID: 33580845 PMCID: PMC11948488 DOI: 10.1007/s10637-021-01074-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 01/25/2021] [Indexed: 11/12/2022]
Abstract
Purpose Acute radiation-induced esophagitis (ARIE) leads to treatment delays, decreased quality of life (QOL), and secondary adverse events such as weight loss. Grade 3 ARIE occurs in 15%-30% of patients undergoing radiotherapy to the esophagus, leading to disruption or discontinuation of treatment. The purpose of this study was to assess the effects of glutamine, a common nutritional supplement, on ARIE in patients with thoracic malignancies. Patients and methods This double-blind, placebo-controlled trial enrolled patients with advanced thoracic malignancies receiving concurrent chemotherapy/radiotherapy or radiotherapy alone, with radiation doses to the esophagus ≥45 Gy. Patients were randomized (1:1) to receive 4 g of glutamine or glycine placebo twice daily. The primary objective was to determine whether glutamine decreases the severity of ARIE in these patients. Secondary objectives included assessment of the effects of glutamine on other measures of ARIE, weight, symptom burden measure assessed by the MD Anderson Symptom Inventory (MDASI-HN) questionnaire and the toxicity profile of glutamine. Results At the time of interim analysis, 53 patients were enrolled: 27 in the glutamine arm and 26 in the placebo arm. There was no difference in the incidence of esophagitis in the first 6 weeks of radiotherapy between the glutamine and placebo arms (74% versus 68%; P = 1.00). There were no significant differences between the two arms for time to onset of esophagitis. The duration of ARIE was shorter (6.3 versus 7.1 weeks; P = 0.54) and median weight loss was lower (0.9 kg versus 2.8 kg; p = 0.83) in the glutamine arm versus the placebo arm. The groups differ significantly in core symptom severity (2.1 vs 1.5, p < .03) but not in head and neck specific symptom severity (1.2 vs 1.1, p < .60) nor in symptom interference (2.1 vs 1.7, p < .22). There was no grade 3 or higher adverse event at least possibly related to glutamine. The study was terminated for futility following interim analysis. Conclusion Oral glutamine was not associated with significant improvement in severity of ARIE, weight loss, head and neck specific symptoms or symptom interference compared with placebo in patients with advanced thoracic malignancies receiving radiotherapy to the esophagus.Clinical trial information. NCT01952847, and date of registration is September 30, 2013.
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Affiliation(s)
- Anas Alshawa
- Department of Investigational Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Alexandra Perez Cadena
- Departments of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 1515 Holcombe Blvd, Unit 853, Houston, TX, 77030, USA
| | - Bettzy Stephen
- Department of Investigational Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Akhila Reddy
- Department of Palliative Care and Rehabilitation Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Tito R Mendoza
- Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Lacey McQuinn
- Department of Investigational Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kristie Lawhorn
- Department of Investigational Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Abdulrazzak Zarifa
- Department of Investigational Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Senait Fessaheye
- Department of Investigational Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Carla L Warneke
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Joe Y Chang
- Departments of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 1515 Holcombe Blvd, Unit 853, Houston, TX, 77030, USA.
| | - Aung Naing
- Department of Investigational Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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17
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Rahi MS, Parekh J, Pednekar P, Parmar G, Abraham S, Nasir S, Subramaniyam R, Jeyashanmugaraja GP, Gunasekaran K. Radiation-Induced Lung Injury-Current Perspectives and Management. Clin Pract 2021; 11:410-429. [PMID: 34287252 PMCID: PMC8293129 DOI: 10.3390/clinpract11030056] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 06/11/2021] [Accepted: 06/17/2021] [Indexed: 12/25/2022] Open
Abstract
Radiotherapy plays an important role in the treatment of localized primary malignancies involving the chest wall or intrathoracic malignancies. Secondary effects of radiotherapy on the lung result in radiation-induced lung disease. The phases of lung injury from radiation range from acute pneumonitis to chronic pulmonary fibrosis. Radiation pneumonitis is a clinical diagnosis based on the history of radiation, imaging findings, and the presence of classic symptoms after exclusion of infection, pulmonary embolism, heart failure, drug-induced pneumonitis, and progression of the primary tumor. Computed tomography (CT) is the preferred imaging modality as it provides a better picture of parenchymal changes. Lung biopsy is rarely required for the diagnosis. Treatment is necessary only for symptomatic patients. Mild symptoms can be treated with inhaled steroids while subacute to moderate symptoms with impaired lung function require oral corticosteroids. Patients who do not tolerate or are refractory to steroids can be considered for treatment with immunosuppressive agents such as azathioprine and cyclosporine. Improvements in radiation technique, as well as early diagnosis and appropriate treatment with high-dose steroids, will lead to lower rates of pneumonitis and an overall good prognosis.
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Affiliation(s)
- Mandeep Singh Rahi
- Division of Pulmonary Diseases and Critical Care, Yale-New Haven Health Bridgeport Hospital, 267 Grant Street, Bridgeport, CT 06610, USA;
| | - Jay Parekh
- Department of Internal Medicine, Yale-New Haven Health Bridgeport Hospital, 267 Grant Street, Bridgeport, CT 06610, USA; (J.P.); (P.P.); (S.A.); (G.P.J.)
| | - Prachi Pednekar
- Department of Internal Medicine, Yale-New Haven Health Bridgeport Hospital, 267 Grant Street, Bridgeport, CT 06610, USA; (J.P.); (P.P.); (S.A.); (G.P.J.)
| | - Gaurav Parmar
- Department of Radiology, Yale-New Haven Health Bridgeport Hospital, 267 Grant Street, Bridgeport, CT 06610, USA;
| | - Soniya Abraham
- Department of Internal Medicine, Yale-New Haven Health Bridgeport Hospital, 267 Grant Street, Bridgeport, CT 06610, USA; (J.P.); (P.P.); (S.A.); (G.P.J.)
| | - Samar Nasir
- Department of Internal Medicine, University at Buffalo, 462 Grider Street, Buffalo, NY 14215, USA;
| | - Rajamurugan Subramaniyam
- Department of Pulmonary Critical Care Medicine, St. Louis University, 3635 Vista Ave, St. Louis, MO 63110, USA;
| | - Gini Priyadharshini Jeyashanmugaraja
- Department of Internal Medicine, Yale-New Haven Health Bridgeport Hospital, 267 Grant Street, Bridgeport, CT 06610, USA; (J.P.); (P.P.); (S.A.); (G.P.J.)
| | - Kulothungan Gunasekaran
- Division of Pulmonary Diseases and Critical Care, Yale-New Haven Health Bridgeport Hospital, 267 Grant Street, Bridgeport, CT 06610, USA;
- Correspondence: ; Tel.: +1-203-384-5009
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18
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Tang W, Li X, Yu H, Yin X, Zou B, Zhang T, Chen J, Sun X, Liu N, Yu J, Xie P. A novel nomogram containing acute radiation esophagitis predicting radiation pneumonitis in thoracic cancer receiving radiotherapy. BMC Cancer 2021; 21:585. [PMID: 34022830 PMCID: PMC8140476 DOI: 10.1186/s12885-021-08264-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 04/28/2021] [Indexed: 12/25/2022] Open
Abstract
Background Radiation-induced pneumonitis (RP) is a non-negligible and sometimes life-threatening complication among patients with thoracic radiation. We initially aimed to ascertain the predictive value of acute radiation-induced esophagitis (SARE, grade ≥ 2) to symptomatic RP (SRP, grade ≥ 2) among thoracic cancer patients receiving radiotherapy. Based on that, we established a novel nomogram model to provide individualized risk assessment for SRP. Methods Thoracic cancer patients who were treated with thoracic radiation from Jan 2018 to Jan 2019 in Shandong Cancer Hospital and Institute were enrolled prospectively. All patients were followed up during and after radiotherapy (RT) to observe the development of esophagitis as well as pneumonitis. Variables were analyzed by univariate and multivariate analysis using the logistic regression model, and a nomogram model was established to predict SRP by “R” version 3.6.0. Results A total of 123 patients were enrolled (64 esophageal cancer, 57 lung cancer and 2 mediastinal cancer) in this study prospectively. RP grades of 0, 1, 2, 3, 4 and 5 occurred in 29, 57, 31, 0, 3 and 3 patients, respectively. SRP appeared in 37 patients (30.1%). In univariate analysis, SARE was shown to be a significant predictive factor for SRP (P < 0.001), with the sensitivity 91.9% and the negative predictive value 93.5%. The incidence of SRP in different grades of ARE were as follows: Grade 0–1: 6.5%; Grade 2: 36.9%; Grade 3: 80.0%; Grade 4: 100%. Besides that, the dosimetric factors considering total lung mean dose, total lung V5, V20, ipsilateral lung mean dose, ipsilateral lung V5, and mean esophagus dose were correlated with SRP (all P < 0.05) by univariate analysis. The incidence of SRP was significantly higher in patients whose symptoms of RP appeared early. SARE, mean esophagus dose and ipsilateral mean lung dose were still significant in multivariate analysis, and they were included to build a predictive nomogram model for SRP. Conclusions As an early index that can reflect the tissue’s radiosensitivity visually, SARE can be used as a predictor for SRP in patients receiving thoracic radiation. And the nomogram containing SARE may be fully applied in future’s clinical work.
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Affiliation(s)
- Wenjie Tang
- Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China.,Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jiyan Road 440, Jinan, 250117, Shandong, China
| | - Xiaolin Li
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jiyan Road 440, Jinan, 250117, Shandong, China
| | - Haining Yu
- Department of Human Resource, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China
| | - Xiaoyang Yin
- Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China.,Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jiyan Road 440, Jinan, 250117, Shandong, China
| | - Bing Zou
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jiyan Road 440, Jinan, 250117, Shandong, China
| | - Tingting Zhang
- Department of Surgical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China
| | - Jinlong Chen
- Department of Surgical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China
| | - Xindong Sun
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jiyan Road 440, Jinan, 250117, Shandong, China
| | - Naifu Liu
- Department of Surgical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China
| | - Jinming Yu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jiyan Road 440, Jinan, 250117, Shandong, China
| | - Peng Xie
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jiyan Road 440, Jinan, 250117, Shandong, China.
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19
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Kong M, Lee SH, Kim J, Lee BJ, Kim KI. The Efficacy and Safety of Acupuncture for Preventing Radiation Pneumonitis in Patients With Lung Cancer: A Prospective, Single-Blinded, Randomized Pilot Proof-of-Principle Study. Integr Cancer Ther 2021; 19:1534735420908327. [PMID: 32100576 PMCID: PMC7045295 DOI: 10.1177/1534735420908327] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Purpose: We evaluated the efficacy and safety of acupuncture for prevention of radiation pneumonitis in patients with lung cancer. Methods: Twenty-five patients were prospectively enrolled in this study and randomized to either intervention group or control group. The patients assigned to the intervention group received 15 minutes of acupuncture treatment twice a week. The patients assigned to the control group received RT alone without acupuncture treatment. The primary endpoint was incidence of radiation pneumonitis. The secondary endpoints were FEV1 (forced expiratory volume in 1 second), DLCO (diffusing capacity for carbon monoxide), 6-minute walk distance, and modified Borg scale. Results: The intervention group showed lower incidences of grade 3 and grade ≥2 radiation pneumonitis than the control group (10% vs 30% for grade 3 and 50% vs 60% for grade ≥2). In the control group, mean DLCO value was decreased from 62.1% at baseline to 49.1% after RT (P = .004). The DLCO was also decreased after RT in the intervention group, but the decrement was not statistically significant (56.7% at baseline and 50.9% after RT, P = .204). The FEV1 and 6-minute walk distance were decreased after RT in the control group. However, FEV1 and 6-minute walk distance were increased after RT in the intervention group. Conclusions: This study found that patients who received acupuncture treatment showed a lower incidence of radiation pneumonitis and a protective effect against aggravation of pulmonary function after RT in patients with lung cancer. To confirm the results of this study, well-designed randomized studies with large sample sizes will be required.
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Affiliation(s)
- Moonkyoo Kong
- College of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Seung Hyeun Lee
- College of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Jaehyo Kim
- College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.,College of Medicine, Yonsei University, Seoul, Republic of Korea
| | - Beom-Joon Lee
- College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Kwan-Il Kim
- College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
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20
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Afifi ANAM, Powerski M, Jechorek D, Brunner TB, Weigt J, Venerito M. Radiation-induced damage in the upper gastrointestinal tract: clinical presentation, diagnostic tests and treatment options. Best Pract Res Clin Gastroenterol 2020; 48-49:101711. [PMID: 33317797 DOI: 10.1016/j.bpg.2020.101711] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 11/05/2020] [Accepted: 11/09/2020] [Indexed: 01/31/2023]
Abstract
Radiation-induced damage of the upper gastrointestinal (GI) tract results from radiation of GI tumors or structures adjacent to the GI tract. Radiation-induced damages of the upper GI tract may be acute or delayed, and ranges from lack of appetite, mucosal inflammation (i.e. esophagitis, gastritis, duodenitis) to ulcers, which may be complicated by perforation, penetration, bleeding and stenosis. Radiation-related factors as well as individual patient predisposing factors may increase susceptibility to post-radiation damage. High quality evidence for the treatment of radiation-induced GI damage is scarce and the management is often extrapolated from studies on GI lesions of different etiology. Treatment depends on severity and localization of the radiation-induced damage, and ranges from supportive and dietary measures to endoscopic interventions or surgery. Modern radiation techniques may decrease the incidence and severity of the radiation-induced upper gastrointestinal disease.
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Affiliation(s)
- Ahmed N A M Afifi
- Universitätsklinik für Gastroenterologie, Hepatologie und Infektiologie, Germany
| | - Maciej Powerski
- Universitätsklinik für Radiologie und Nuklearmedizin, Germany
| | | | - Thomas B Brunner
- Universitätsklinik für Strahlentherapie, Otto-von-Guericke Universitätsklinikum Magdeburg, Germany
| | - Jochen Weigt
- Universitätsklinik für Gastroenterologie, Hepatologie und Infektiologie, Germany
| | - Marino Venerito
- Universitätsklinik für Gastroenterologie, Hepatologie und Infektiologie, Germany.
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21
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Käsmann L, Dietrich A, Staab-Weijnitz CA, Manapov F, Behr J, Rimner A, Jeremic B, Senan S, De Ruysscher D, Lauber K, Belka C. Radiation-induced lung toxicity - cellular and molecular mechanisms of pathogenesis, management, and literature review. Radiat Oncol 2020; 15:214. [PMID: 32912295 PMCID: PMC7488099 DOI: 10.1186/s13014-020-01654-9] [Citation(s) in RCA: 142] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 08/20/2020] [Indexed: 12/17/2022] Open
Abstract
Lung, breast, and esophageal cancer represent three common malignancies with high incidence and mortality worldwide. The management of these tumors critically relies on radiotherapy as a major part of multi-modality care, and treatment-related toxicities, such as radiation-induced pneumonitis and/or lung fibrosis, are important dose limiting factors with direct impact on patient outcomes and quality of life. In this review, we summarize the current understanding of radiation-induced pneumonitis and pulmonary fibrosis, present predictive factors as well as recent diagnostic and therapeutic advances. Novel candidates for molecularly targeted approaches to prevent and/or treat radiation-induced pneumonitis and pulmonary fibrosis are discussed.
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Affiliation(s)
- Lukas Käsmann
- Department of Radiation Oncology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377 Munich, Germany
- German Center for Lung Research (DZL), partner site Munich, Munich, Germany
- German Cancer Consortium (DKTK), partner site Munich, Munich, Germany
| | - Alexander Dietrich
- Walther Straub Institute of Pharmacology and Toxicology, Member of the German Center for Lung Research (DZL), Medical Faculty, LMU-Munich, Munich, Germany
| | - Claudia A. Staab-Weijnitz
- German Center for Lung Research (DZL), partner site Munich, Munich, Germany
- Institute of Lung Biology and Disease, Helmholtz Zentrum München, Munich, Germany
| | - Farkhad Manapov
- Department of Radiation Oncology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377 Munich, Germany
- German Center for Lung Research (DZL), partner site Munich, Munich, Germany
- German Cancer Consortium (DKTK), partner site Munich, Munich, Germany
| | - Jürgen Behr
- German Center for Lung Research (DZL), partner site Munich, Munich, Germany
- Department of Internal Medicine V, LMU Munich, Munich, Germany
| | - Andreas Rimner
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, USA
| | | | - Suresh Senan
- Department of Radiation Oncology, Amsterdam University Medical Centers, Amsterdam, Netherlands
| | - Dirk De Ruysscher
- Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Kirsten Lauber
- Department of Radiation Oncology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377 Munich, Germany
- German Cancer Consortium (DKTK), partner site Munich, Munich, Germany
| | - Claus Belka
- Department of Radiation Oncology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377 Munich, Germany
- German Center for Lung Research (DZL), partner site Munich, Munich, Germany
- German Cancer Consortium (DKTK), partner site Munich, Munich, Germany
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23
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Bansal N, Blanco JG, Sharma UC, Pokharel S, Shisler S, Lipshultz SE. Cardiovascular diseases in survivors of childhood cancer. Cancer Metastasis Rev 2020; 39:55-68. [PMID: 32026204 PMCID: PMC7123498 DOI: 10.1007/s10555-020-09859-w] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Over the past few decades, the diagnosis and management of children with various malignancies have improved tremendously. As a result, there are an increasing number of children who are long-term cancer survivors. With improved survival, however, has come an increased risk of treatment-related cardiovascular complications that can appear decades after treatment. These problems are serious enough that all caregivers of childhood cancer survivors, including oncologists, cardiologists, and other health care personnel, must pay close attention to the short- and long-term effects of chemotherapy and radiotherapy on these children. This review discusses the effects of treatment-related cardiovascular complications from anthracyclines and radiotherapy and the methods for preventing, screening, and treating these complications.
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Affiliation(s)
- Neha Bansal
- Division of Pediatric Cardiology, Children's Hospital at Montefiore, Bronx, NY, USA
| | - Javier G Blanco
- School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY, USA
| | - Umesh C Sharma
- Department of Medicine, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York at Buffalo, Buffalo, NY, USA
| | - Saraswati Pokharel
- Department of Pathology and Laboratory Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Shannon Shisler
- Department of Pediatrics, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York at Buffalo, Buffalo, NY, USA
| | - Steven E Lipshultz
- Department of Pediatrics, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York at Buffalo, Buffalo, NY, USA.
- John R. Oshei Children's Hospital, Buffalo, NY, USA.
- Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
- Kaleida Health, Buffalo, NY, USA.
- UBMD Pediatrics, 1001 Main Street, 5th Floor, Buffalo, NY, 14203, USA.
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24
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De Ruysscher D, Faivre-Finn C, Nackaerts K, Jordan K, Arends J, Douillard J, Ricardi U, Peters S. Recommendation for supportive care in patients receiving concurrent chemotherapy and radiotherapy for lung cancer. Ann Oncol 2020; 31:41-49. [DOI: 10.1016/j.annonc.2019.10.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/06/2019] [Accepted: 10/08/2019] [Indexed: 12/13/2022] Open
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Abstract
Radiation therapy is one of the most commonly used treatments for cancer. Radiation modifiers are agents that alter tumor or normal tissue response to radiation, such as radiation sensitizers and radiation protectors. Radiation sensitizers target aspects of tumor molecular biology or physiology to enhance tumor cell killing after irradiation. Radioprotectors prevent damage of normal tissues selectively. Radiation modifiers remain largely investigational at present, with the promise that molecular characterization of tumors may enhance the capacity for successful clinical development moving forward. A variety of radiation modifiers are described.
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Affiliation(s)
- Deborah E Citrin
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, Building 10 CRC, Room B2-3500, 10 Center Drive, Bethesda, MD 20892, USA.
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26
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Giuranno L, Ient J, De Ruysscher D, Vooijs MA. Radiation-Induced Lung Injury (RILI). Front Oncol 2019; 9:877. [PMID: 31555602 PMCID: PMC6743286 DOI: 10.3389/fonc.2019.00877] [Citation(s) in RCA: 240] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Accepted: 08/23/2019] [Indexed: 12/12/2022] Open
Abstract
Radiation pneumonitis (RP) and radiation fibrosis (RF) are two dose-limiting toxicities of radiotherapy (RT), especially for lung, and esophageal cancer. It occurs in 5-20% of patients and limits the maximum dose that can be delivered, reducing tumor control probability (TCP) and may lead to dyspnea, lung fibrosis, and impaired quality of life. Both physical and biological factors determine the normal tissue complication probability (NTCP) by Radiotherapy. A better understanding of the pathophysiological sequence of radiation-induced lung injury (RILI) and the intrinsic, environmental and treatment-related factors may aid in the prevention, and better management of radiation-induced lung damage. In this review, we summarize our current understanding of the pathological and molecular consequences of lung exposure to ionizing radiation, and pharmaceutical interventions that may be beneficial in the prevention or curtailment of RILI, and therefore enable a more durable therapeutic tumor response.
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Affiliation(s)
- Lorena Giuranno
- Department of Radiotherapy, GROW School for Oncology Maastricht University Medical Centre, Maastricht, Netherlands
| | - Jonathan Ient
- Department of Radiotherapy, GROW School for Oncology Maastricht University Medical Centre, Maastricht, Netherlands
| | - Dirk De Ruysscher
- Department of Radiotherapy, GROW School for Oncology Maastricht University Medical Centre, Maastricht, Netherlands
| | - Marc A Vooijs
- Department of Radiotherapy, GROW School for Oncology Maastricht University Medical Centre, Maastricht, Netherlands
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27
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Hanania AN, Mainwaring W, Ghebre YT, Hanania NA, Ludwig M. Radiation-Induced Lung Injury: Assessment and Management. Chest 2019; 156:150-162. [PMID: 30998908 PMCID: PMC8097634 DOI: 10.1016/j.chest.2019.03.033] [Citation(s) in RCA: 378] [Impact Index Per Article: 63.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 03/18/2019] [Accepted: 03/22/2019] [Indexed: 12/22/2022] Open
Abstract
Radiation-induced lung injury (RILI) encompasses any lung toxicity induced by radiation therapy (RT) and manifests acutely as radiation pneumonitis and chronically as radiation pulmonary fibrosis. Because most patients with thoracic and breast malignancies are expected to undergo RT in their lifetime, many with curative intent, the population at risk is significant. Furthermore, indications for thoracic RT are expanding given the advent of stereotactic body radiation therapy (SBRT) or stereotactic ablative radiotherapy (SABR) for early-stage lung cancer in nonsurgical candidates as well as oligometastatic pulmonary disease from any solid tumor. Fortunately, the incidence of serious pulmonary complications from RT has decreased secondary to advances in radiation delivery techniques. Understanding the temporal relationship between RT and injury as well as the patient, disease, and radiation factors that help distinguish RILI from other etiologies is necessary to prevent misdiagnosis. Although treatment of acute pneumonitis is dependent on clinical severity and typically responds completely to corticosteroids, accurately diagnosing and identifying patients who may progress to fibrosis is challenging. Current research advances include high-precision radiation techniques, an improved understanding of the molecular basis of RILI, the development of small and large animal models, and the identification of candidate drugs for prevention and treatment.
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Affiliation(s)
- Alexander N Hanania
- Department of Radiation Oncology, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX
| | - Walker Mainwaring
- Department of Radiation Oncology, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX
| | - Yohannes T Ghebre
- Department of Radiation Oncology, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX; Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX
| | - Nicola A Hanania
- Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX.
| | - Michelle Ludwig
- Department of Radiation Oncology, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX
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Long W, Wang J, Yang J, Wu H, Wang J, Mu X, He H, Liu Q, Sun YM, Wang H, Zhang XD. Naturally-Derived PHA-L Protein Nanoparticle as a Radioprotector Through Activation of Toll-Like Receptor 5. J Biomed Nanotechnol 2019; 15:62-76. [PMID: 30480515 PMCID: PMC6300143 DOI: 10.1166/jbn.2019.2665] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
High energy ray in medical diagnosis and therapy can benefit to patients, but can also cause the significant damages to biomolecules such as DNA, as well as free radical generation, inevitably leading to numerous side effects. Small molecular radioprotectors provide an effective route to preserve the healthy tissue and whole body from ionizing radiation, but always have a short circulation time in body. Inorganic nanoparticles show major protection effect but their heavy metal components considerably jeopardize translational promise due to suboptimal biocompatibility. Herein, we report a novel protein nanoparticle that can overcome limitations of both small molecular and inorganic nanoparticle radioprotectors and can be used as a radioprotector with spontaneous biocompatibility, outstanding pharmacokinetics and improvement on survival rate under exposure to γ-ray irradiation. PHA-L protein nanoparticle serves to clear excessive reactive oxygen species in vivo, prevents radiation-induced hematopoietic and gastrointestinal damages and boosts the survival rate of irradiated mice to ∼70%. A detailed study of the mechanism shows PHA-L protein nanoparticle can target and activate the toll-like receptor 5 in vitro and in vivo, and thus protect irradiated cells by immune response. Importantly, the PHA-L protein nanoparticle can perform highly efficient clearance while eliciting negligible toxicological response.
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Affiliation(s)
- Wei Long
- Tianjin Key Laboratory of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 238, Baidi Road, Tianjin 300192, China
| | - Junying Wang
- Department of Physics and Tianjin Key Laboratory of Low Dimensional Materials Physics and Preparing Technology, School of Sciences, Tianjin University, Tianjin 300350, China
| | - Jiang Yang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Hongying Wu
- Tianjin Key Laboratory of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 238, Baidi Road, Tianjin 300192, China
| | - Jingya Wang
- Tianjin Key Laboratory of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 238, Baidi Road, Tianjin 300192, China
| | - Xiaoyu Mu
- Department of Physics and Tianjin Key Laboratory of Low Dimensional Materials Physics and Preparing Technology, School of Sciences, Tianjin University, Tianjin 300350, China
| | - Hua He
- State Key Laboratory of Heavy Oil Processing and Center for Bioengineering and Biotechnology, China University of Petroleum (East China), Qingdao 266580, China
| | - Qiang Liu
- Tianjin Key Laboratory of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 238, Baidi Road, Tianjin 300192, China
| | - Yuan-Ming Sun
- Tianjin Key Laboratory of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 238, Baidi Road, Tianjin 300192, China
| | - Haichao Wang
- Laboratory of Emergency Medicine, North Shore University Hospital and The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA
| | - Xiao-Dong Zhang
- Department of Physics and Tianjin Key Laboratory of Low Dimensional Materials Physics and Preparing Technology, School of Sciences, Tianjin University, Tianjin 300350, China
- Tianjin Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, China
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29
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Han DW, Ji W, Lee JC, Song SY, Choi CM. Efficacy of nebulized acetylcysteine for relieving symptoms and reducing usage of expectorants in patients with radiation pneumonitis. Thorac Cancer 2018; 10:243-248. [PMID: 30585684 PMCID: PMC6360265 DOI: 10.1111/1759-7714.12938] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 11/19/2018] [Accepted: 11/20/2018] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Radiation pneumonitis is one of the most harmful and clinically significant complications of radiotherapy. This study investigated the benefits of nebulized acetylcysteine for lung cancer patients diagnosed with radiation pneumonitis after radiotherapy. METHODS We prospectively enrolled and followed 25 patients with radiation pneumonitis who used nebulized acetylcysteine three times a day for 12 weeks. We also reviewed the medical records of 106 control patients who had undergone radiotherapy for lung cancer but had not used acetylcysteine. We evaluated the effects of nebulized acetylcysteine by comparing visits 1 and 4 among nebulizer users and by comparing the acetylcysteine group with the control group. RESULTS Twenty-five acetylcysteine group patients and 101 control group patients were included in the analyses. The mean patient-rated severity score associated with sputum production decreased in the acetylcysteine group between visits 1 and 4 (from 1.10 to 0.95; P = 0.08). None of the patients used additional expectorant agents after using nebulized acetylcysteine and critical adverse events were not reported. The acetylcysteine group had a shorter mean duration of expectorant use among patients whose radiation pneumonitis required steroid therapy and covered > 10% of a single lung field on computed tomography (37.2 vs. 78.1 days, respectively; P = 0.07). CONCLUSIONS The beneficial effects of nebulized acetylcysteine for patients with radiation pneumonitis included relieving sputum severity and minimizing expectorant use, especially in severe cases. Further investigation is required to clarify and expand on the benefits of nebulized acetylcysteine for patients with radiation pneumonitis.
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Affiliation(s)
- Dong-Woo Han
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Wonjun Ji
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Jae Cheol Lee
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.,Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Si Yeol Song
- Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Chang-Min Choi
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.,Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.,Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
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30
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Pollock AE, Shinn L, Anderson R, Butler S, Pollock J. Amifostine- and chemoradiotherapy-related esophagitis in small cell lung cancer: a single institutional series and literature update. LUNG CANCER-TARGETS AND THERAPY 2018; 9:79-84. [PMID: 30237747 PMCID: PMC6136401 DOI: 10.2147/lctt.s155315] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Objectives Concurrent chemoradiotherapy is considered a standard option for patients with stage 3 small cell lung carcinoma. A 25% risk of acute esophagitis is experienced by patients as a result of the volume of esophagus encompassed within a conformal radiotherapy technique. We reviewed our institutional experience administering the radioprotectant amifostine prior to daily radiotherapy to determine its effects on the onset of esophagitis. Materials and methods From 2005 to 2016, 49 patients diagnosed with stage 3 small cell lung carcinoma received concurrent chemoradiotherapy. Chemotherapy (CT) consisted of cisplatin and etoposide with radiotherapy (RT) encompassing CT-identified gross tumor volume. In 32 patients (group 1), amifostine was delivered (500 mg subcutaneously divided in two injections) prior to the second daily RT fraction. The remaining 17 patients (group 2) did not receive amifostine due to choice or drug intolerance. Results Metrics of esophagitis included weight loss and opiate requirement during treatment. About 31% of group 1 required opiates at a median RT dose of 3300 cGy, and 41% of group 2 required opiates at a median dose of 2250 cGy. The dose of radiotherapy delivered to 50% of the esophageal volume for group 1 was significantly greater than that in group 2 (3000 cGy vs 576 cGy). Conclusion In this modern retrospective series of thoracic chemoradiotherapy in the treatment of stage 3 small cell lung cancer, amifostine that was delivered subcutaneously postponed the onset of esophagitis.
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Affiliation(s)
- Ariel E Pollock
- Department of Graduate Medical Education, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
| | - Lowell Shinn
- Division of Medical Oncology, Schiffler Cancer Center, Wheeling Hospital
| | - Richard Anderson
- Division of Radiation Oncology, Schiffler Cancer Center, Wheeling Hospital, Wheeling, WV, USA,
| | - Sarah Butler
- Division of Radiation Oncology, Schiffler Cancer Center, Wheeling Hospital, Wheeling, WV, USA,
| | - Jondavid Pollock
- Division of Radiation Oncology, Schiffler Cancer Center, Wheeling Hospital, Wheeling, WV, USA,
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Abstract
PURPOSE OF REVIEW The aim of this article is to examine significant advances in our understanding of the late respiratory effects of cancer treatment, including surgery, radiotherapy, chemotherapy, biological therapies and haematopoietic stem cell transplant, and to provide a framework for assessing such patients. RECENT FINDINGS Oncology therapies have advanced considerably over recent years but pulmonary toxicity remains a concern. Advances have been made in our understanding of the risk factors, including genetic ones that lead to toxicity from radiotherapy and chemotherapy and risk stratification models are being developed to aid treatment planning. Targeted biological treatments are continuously being developed and consequently the Pneumotox database of pulmonary toxicity continues to be an essential resource. Early detection of bronchiolitis obliterans in haematopoietic stem cell transplant patients has been found to be critical, with some positive results from intervention trials. SUMMARY Pulmonary toxicity is a common unwanted consequence of life enhancing or saving cancer treatments which remain difficult to treat. Developments in these fields are mainly in the areas of prevention, early detection and monitoring of unwanted side effects. We discuss some of these developments within this review.
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Ippolito E, Floreno B, Rinaldi CG, Trodella L, Meroni FL, Iurato A, D'Angelillo RM, Ramella S, Fiore M. Efficacy of a Propolis-Based Syrup (FARINGEL) in Preventing Radiation-Induced Esophagitis in Locally Advanced Lung Cancer. Chemotherapy 2018; 63:76-82. [PMID: 29554652 DOI: 10.1159/000487897] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 02/21/2018] [Indexed: 12/19/2022]
Abstract
AIM To evaluate the efficacy of a propolis-based syrup, FARINGEL®, in preventing radiation-induced esophagitis in locally advanced lung cancer patients. METHODS Patients were treated with concurrent chemoradiotherapy (CRT) using involved-field radiotherapy (RT). Every patient received FARINGEL at the beginning of CRT until the first follow-up. The data of the study group were compared with the data of a control group treated without the administration of the syrup. RESULTS Forty-five patients were enrolled. Forty-one (91.1%) completed the protocol and were evaluable for esophagitis. Grade ≥2 toxicity occurred in 9/41 patients (22%). No differences in overall toxicity were detected between the study group and the control group (n = 55, 60.9 vs. 54.5%; p = ns). Grade 2-3 esophagitis was lower in the study group in comparison with the control group (22 and 38%, respectively), but statistical significance was not reached (p = 0.09). However, the onset of grade ≥2 esophagitis was delayed in the study group compared to the control group, occurring at higher doses of RT (41.8 vs. 25.4 Gy; p < 0.001). Furthermore, the mean number of interruption days for esophagitis was lower in the study group than in the control group (0.6 ± 2.0 vs. 2.1 ± 3.6; p = 0.025). CONCLUSION FARINGEL was well-tolerated and delayed esophagitis that was induced by CRT for locally advanced lung cancer.
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Scotti V, Meattini I, Saieva C, Rampini A, De Luca Cardillo C, Bastiani P, Mangoni M, Agresti B, Santomaggio C, Di Cataldo V, Franzese C, Livi L, Magrini SM, Biti G. Limited-Stage Small-Cell Lung Cancer Treated with Early Chemo-Radiotherapy: The Impact of Effective Chemotherapy. TUMORI JOURNAL 2018; 98:53-9. [DOI: 10.1177/030089161209800107] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Aims and Background Small cell lung cancer is characterized by an aggressive clinical course and a high sensitivity to both chemotherapy and radiotherapy. We present the Florence University experience in concurrent early radio-chemotherapy in patients affected by limited-stage small cell lung cancer, with particular emphasis on treatment safety, disease outcome and prognostic factors. Methods and Study Design Fifty-seven patients were treated between June 2000 and February 2005. All patients underwent platinum-based chemotherapy, administered intravenously following two different regimens, for at least three cycles. Eighteen patients (31.6%) received epirubicin and ifosfamide in 3-week cycles alternating with etoposide and cisplatin, administered on day 1 to 3; 39 patients (68.4%) received etoposide and cisplatin. A total of 6 cycles were planned. Radiotherapy was administered concurrently to the first cycle of etoposide and cisplatin. Results Clinical stage (P = 0.036) and number of chemotherapy courses (P = 0.009) emerged as the only significant death predictors at univariate analysis. Number of chemotherapy courses persisted as a significant death predictor also at multivariate regression analysis, with a reduced death risk for 5–6 chemotherapy cycles in comparison to 3–4 cycles (hazard ratio, 0.44). At a mean follow up of 38.5 months (standard deviation, 3.24 years; range, 6–164 months), considering the best overall tumor response achieved at any time during the whole treatment period, we obtained 32 complete responses (56.1%), 23 partial responses (40.3%) and 2 stable diseases. Conclusions Our analysis showed that concurrent early radio-chemotherapy in limited-stage small cell lung cancer treatment represents a safe and effective approach in patients. We confirmed the relevant impact on overall survival of effective chemotherapy delivery.
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Affiliation(s)
- Vieri Scotti
- Department of Radiation-Oncology, University of Florence, Florence
| | - Icro Meattini
- Department of Radiation-Oncology, University of Florence, Florence
| | - Calogero Saieva
- Molecular and Nutritional Epidemiology Unit, ISPO, Cancer Prevention and Research Institute, Florence
| | | | | | - Paolo Bastiani
- Radiotherapy Unit, S. Maria Annunziata Hospital, Florence
| | - Monica Mangoni
- Department of Radiation-Oncology, University of Florence, Florence
| | | | | | | | - Ciro Franzese
- Department of Radiation-Oncology, University of Florence, Florence
| | - Lorenzo Livi
- Department of Radiation-Oncology, University of Florence, Florence
| | | | - Giampaolo Biti
- Department of Radiation-Oncology, University of Florence, Florence
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Hawkins PG, Boonstra PS, Hobson ST, Hayman JA, Ten Haken RK, Matuszak MM, Stanton P, Kalemkerian GP, Lawrence TS, Schipper MJ, Kong FMS, Jolly S. Prediction of Radiation Esophagitis in Non-Small Cell Lung Cancer Using Clinical Factors, Dosimetric Parameters, and Pretreatment Cytokine Levels. Transl Oncol 2017; 11:102-108. [PMID: 29220828 PMCID: PMC6002355 DOI: 10.1016/j.tranon.2017.11.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Accepted: 11/15/2017] [Indexed: 12/12/2022] Open
Abstract
Radiation esophagitis (RE) is a common adverse event associated with radiotherapy for non-small cell lung cancer (NSCLC). While plasma cytokine levels have been correlated with other forms of radiation-induced toxicity, their association with RE has been less well studied. We analyzed data from 126 patients treated on 4 prospective clinical trials. Logistic regression models based on combinations of dosimetric factors [maximum dose to 2 cubic cm (D2cc) and generalized equivalent uniform dose (gEUD)], clinical variables, and pretreatment plasma levels of 30 cytokines were developed. Cross-validated estimates of area under the receiver operating characteristic curve (AUC) and log likelihood were used to assess prediction accuracy. Dose-only models predicted grade 3 RE with AUC values of 0.750 (D2cc) and 0.727 (gEUD). Combining clinical factors with D2cc increased the AUC to 0.779. Incorporating pretreatment cytokine measurements, modeled as direct associations with RE and as potential interactions with the dose-esophagitis association, produced AUC values of 0.758 and 0.773, respectively. D2cc and gEUD correlated with grade 3 RE with odds ratios (ORs) of 1.094/Gy and 1.096/Gy, respectively. Female gender was associated with a higher risk of RE, with ORs of 1.09 and 1.112 in the D2cc and gEUD models, respectively. Older age was associated with decreased risk of RE, with ORs of 0.992/year and 0.991/year in the D2cc and gEUD models, respectively. Combining clinical with dosimetric factors but not pretreatment cytokine levels yielded improved prediction of grade 3 RE compared to prediction by dose alone. Such multifactorial modeling may prove useful in directing radiation treatment planning.
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Affiliation(s)
- Peter G Hawkins
- Department of Radiation Oncology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, United States of America
| | - Philip S Boonstra
- Department of Biostatistics, University of Michigan, 1415 Washington Heights, Ann Arbor, MI 48109, United States of America
| | - Stephen T Hobson
- Department of Radiation Oncology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, United States of America
| | - James A Hayman
- Department of Radiation Oncology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, United States of America
| | - Randall K Ten Haken
- Department of Radiation Oncology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, United States of America
| | - Martha M Matuszak
- Department of Radiation Oncology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, United States of America
| | - Paul Stanton
- Department of Radiation Oncology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, United States of America
| | - Gregory P Kalemkerian
- Department of Internal Medicine, Division of Medical Oncology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, United States of America
| | - Theodore S Lawrence
- Department of Radiation Oncology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, United States of America
| | - Matthew J Schipper
- Department of Radiation Oncology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, United States of America; Department of Biostatistics, University of Michigan, 1415 Washington Heights, Ann Arbor, MI 48109, United States of America
| | - Feng-Ming Spring Kong
- Department of Radiation Oncology, Indiana University, 535 Barnhill Drive, Indianapolis, IN 46202, United States of America
| | - Shruti Jolly
- Department of Radiation Oncology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, United States of America.
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Verma V, Simone CB, Werner-Wasik M. Acute and Late Toxicities of Concurrent Chemoradiotherapy for Locally-Advanced Non-Small Cell Lung Cancer. Cancers (Basel) 2017; 9:cancers9090120. [PMID: 28885561 PMCID: PMC5615335 DOI: 10.3390/cancers9090120] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 09/04/2017] [Accepted: 09/05/2017] [Indexed: 12/25/2022] Open
Abstract
For patients with unresectable locally-advanced non-small cell lung cancer (LA-NSCLC), concurrent chemoradiotherapy improves overall survival as compared to sequential chemotherapy and radiation therapy, but is associated with higher rates of toxicities. Acute, clinically significant esophagitis or pneumonitis can occur in one in five patients. The risks of esophagitis and pneumonitis can impact the decision to deliver concurrent therapy and limit the total dose of radiation therapy that is delivered. Hematologic toxicities and emesis are common toxicities from systemic therapies for LA-NSCLC and can result in delaying chemotherapy dosing or chemotherapy dose reductions. Late treatment morbidities, including pulmonary fibrosis and cardiac toxicities, can also significantly impact quality of life and potentially even survival. Recent advances in radiation therapy treatment delivery, better knowledge of normal tissue radiotherapy tolerances and more widespread and improved uses of supportive care and medical management of systemic therapy toxicities have improved the therapeutic ratio and reduced the rates of chemoradiotherapy-induced toxicities. This review details the acute and late toxicities associated with definitive chemoradiotherapy for LA-NSCLC and discusses toxicity management and strategies to mitigate the risks of treatment-related toxicities.
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Affiliation(s)
- Vivek Verma
- Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE 68106, USA.
| | - Charles B Simone
- Department of Radiation Oncology, University of Maryland Medical Center, Baltimore, MD 21201, USA.
| | - Maria Werner-Wasik
- Department of Radiation Oncology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA.
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Prévention médicale et traitement des complications pulmonaires secondaires à la radiothérapie. Cancer Radiother 2017; 21:411-423. [DOI: 10.1016/j.canrad.2017.03.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 03/13/2017] [Accepted: 03/24/2017] [Indexed: 12/12/2022]
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Deng G, Liang N, Xie J, Luo H, Qiao L, Zhang J, Wang D, Zhang J. Pulmonary toxicity generated from radiotherapeutic treatment of thoracic malignancies. Oncol Lett 2017; 14:501-511. [PMID: 28693198 PMCID: PMC5494764 DOI: 10.3892/ol.2017.6268] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 03/14/2017] [Indexed: 02/06/2023] Open
Abstract
Radiation-induced lung injury (RILI) remains a major obstacle for thoracic radiotherapy for the treatment of lung cancer, esophageal cancer and lymphoma. It is the principal dose-limiting complication, and can markedly impair the therapeutic ratio as well as a patient's quality of life. The current review presents the relevant concepts associated with RILI, including the pathogenic mechanisms and the potential treatment strategies, so as to achieve a general understanding of this issue. RILI comprises an acute radiation pneumonitis phase and subsequent late lung fibrosis. The established assessment criteria are clinical manifestations, imaging changes and the necessity for medical assistance. Risk factors are also considered in order to optimize treatment planning. Due to the underlying molecular mechanisms of RILI, the present review also discusses several targeted pharmacological approaches for its treatment, as well as corticosteroid therapy.
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Affiliation(s)
- Guodong Deng
- Department of Radiation Oncology, Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Ning Liang
- Department of Radiation Oncology, Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Jian Xie
- Department of Radiation Oncology, Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Hui Luo
- Department of Radiation Oncology, Henan Cancer Hospital, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Lili Qiao
- Department of Oncology, The Fifth People's Hospital of Jinan, Jinan, Shandong 250022, P.R. China
| | - Jingxin Zhang
- Division of Oncology, Graduate School, Weifang Medical College, Weifang, Shandong 261053, P.R. China
| | - Dawei Wang
- Department of Radiology, Qianfoshan Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China
| | - Jiandong Zhang
- Department of Radiation Oncology, Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
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Hrycushko BA, Chopra R, Sayre JW, Richardson JA, Folkert MR, Timmerman RD, Medin PM. Local Hypothermia as a Radioprotector of the Rectal Wall During Prostate Stereotactic Body Radiation Therapy. Int J Radiat Oncol Biol Phys 2017; 98:75-82. [DOI: 10.1016/j.ijrobp.2017.01.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Revised: 12/09/2016] [Accepted: 01/02/2017] [Indexed: 11/16/2022]
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Kim KI, Lee BJ, Kim DH, Han JW, Baek H, Jung HJ. Oral administration of herbal medicines for radiation pneumonitis in lung cancer patients: Protocol for a systematic review. Eur J Integr Med 2017. [DOI: 10.1016/j.eujim.2017.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Rajan Radha R, Chandrasekharan G. Pulmonary injury associated with radiation therapy - Assessment, complications and therapeutic targets. Biomed Pharmacother 2017; 89:1092-1104. [PMID: 28298070 DOI: 10.1016/j.biopha.2017.02.106] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 02/27/2017] [Accepted: 02/28/2017] [Indexed: 12/20/2022] Open
Abstract
Pulmonary injury is more common in patients undergoing radiation therapy for lungs and other thoracic malignancies. Recently with the use of most-advanced technologies powerful doses of radiation can be delivered directly to tumor site with exquisite precision. The awareness of technical and clinical parameters that influence the chance of radiation induced lung injury is important to guide patient selection and toxicity minimization strategies. At the cellular level, radiation activates free radical production, leading to DNA damage, apoptosis, cell cycle changes, and reduced cell survival. Preclinical research shows the potential for therapies targeting transforming growth factor-β (TGF-B), Toll like receptor (TLRs), Tumour necrosis factor-alpha (TNF-alpha), Interferon gamma (IFN-γ) and so on that may restore lung function. At present Amifostine (WR-2721) is the only approved broad spectrum radioprotector in use for patients undergoing radiation therapy. Newer techniques also offer the opportunity to identify new biomarkers and new targets for interventions to prevent or ameliorate these late effects of lung damage.
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Affiliation(s)
- Rasmi Rajan Radha
- Laboratory of Immunopharmacology and Experimental Therapeutics, Division of Cancer Research, Regional Cancer Centre, Trivandrum 695 011, Kerala, India
| | - Guruvayoorappan Chandrasekharan
- Laboratory of Immunopharmacology and Experimental Therapeutics, Division of Cancer Research, Regional Cancer Centre, Trivandrum 695 011, Kerala, India.
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Current Status of Targeted Radioprotection and Radiation Injury Mitigation and Treatment Agents: A Critical Review of the Literature. Int J Radiat Oncol Biol Phys 2017; 98:662-682. [PMID: 28581409 DOI: 10.1016/j.ijrobp.2017.02.211] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 02/22/2017] [Accepted: 02/23/2017] [Indexed: 01/17/2023]
Abstract
As more cancer patients survive their disease, concerns about radiation therapy-induced side effects have increased. The concept of radioprotection and radiation injury mitigation and treatment offers the possibility to enhance the therapeutic ratio of radiation therapy by limiting radiation therapy-induced normal tissue injury without compromising its antitumor effect. Advances in the understanding of the underlying mechanisms of radiation toxicity have stimulated radiation oncologists to target these pathways across different organ systems. These generalized radiation injury mechanisms include production of free radicals such as superoxides, activation of inflammatory pathways, and vascular endothelial dysfunction leading to tissue hypoxia. There is a significant body of literature evaluating the effectiveness of various treatments in preventing, mitigating, or treating radiation-induced normal tissue injury. Whereas some reviews have focused on a specific disease site or agent, this critical review focuses on a mechanistic classification of activity and assesses multiple agents across different disease sites. The classification of agents used herein further offers a useful framework to organize the multitude of treatments that have been studied. Many commonly available treatments have demonstrated benefit in prevention, mitigation, and/or treatment of radiation toxicity and warrant further investigation. These drug-based approaches to radioprotection and radiation injury mitigation and treatment represent an important method of making radiation therapy safer.
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Abstract
Radiation-induced lung injury is a well-known complication of thoracic radiation for patients with breast, lung, thymic, and esophageal malignancies, and mediastinal lymphomas. Improvements in radiation technique, as well as the understanding of the pathophysiology of radiation injury, have led to lower rates of pneumonitis and improved symptom control. Here, the authors provide an overview of the pathophysiology, diagnosis, and management of patients with radiation pneumonitis as a complication of treatment of chest malignancies.
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Affiliation(s)
- Trevor J Bledsoe
- Department of Therapeutic Radiology, Smilow Cancer Hospital at Yale-New Haven, 35 Park Street, Ste LL 513, New Haven, CT 06511, USA
| | - Sameer K Nath
- Department of Therapeutic Radiology, Smilow Cancer Hospital at Yale-New Haven, 35 Park Street, Ste LL 513, New Haven, CT 06511, USA.
| | - Roy H Decker
- Department of Therapeutic Radiology, Smilow Cancer Hospital at Yale-New Haven, 35 Park Street, Ste LL 513, New Haven, CT 06511, USA
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Coskun H, Andic F, Daglıoglu YK, Doran F, Sahin K, Tunalı C, Kucuk O. Lycopene in the Prevention of Radiation-Induced Esophagitis. Nutr Cancer 2017; 69:319-329. [PMID: 28094572 DOI: 10.1080/01635581.2017.1265133] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
We aimed to research whether lycopene (L) could prevent radiation-induced acute esophageal toxicity in Wistar albino rats. 60 rats were placed in five groups as follows: control, L, radiotherapy (RT), L before RT (L + RT), and L before and after RT (L + RT + L). 6 mg/kg bw/day L was administered 7 days in the L group, 7 days before RT in the L + RT group, and 7 days before and after in the L + RT + L group. 35 Gy thoracic RT was performed. Serum L levels were measured, and the esophagi were evaluated histopathologically for intraepithelial degenerative changes-necrosis, vacuole formation, inflammation, regeneration-mitosis, and subepithelial bulla formation. L levels were significantly higher in the L receiving groups. All histopathologic results were significantly worse in the RT group than in the none-RT groups. The L + RT and the L + RT + L groups had better results than the RT group. Grade 2-3 degenerative changes-necrosis and vacuole formation were significantly lesser in the L + RT and the L + RT + L groups than those in the RT group. There was a trend toward decreased subepithelial bulla formation and inflammation in the L + RT and the L + RT + L groups compared to the RT group. Regeneration-mitosis was insignificantly lesser in the L + RT and significantly fewer in the L + RT + L groups than that in the RT group.
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Affiliation(s)
- Hatice Coskun
- a Faculty of Medicine, Department of Radiation Oncology , Cukurova University , Adana , Turkey
| | - Fundagul Andic
- a Faculty of Medicine, Department of Radiation Oncology , Cukurova University , Adana , Turkey
| | | | - Figen Doran
- c Faculty of Medicine, Department of Pathology , Cukurova University , Adana , Turkey
| | - Kazım Sahin
- d Faculty of Veterinary Science, Department of Animal Nutrition , Firat University , Elazig , Turkey
| | - Candas Tunalı
- a Faculty of Medicine, Department of Radiation Oncology , Cukurova University , Adana , Turkey
| | - Omer Kucuk
- e Department of Medicine , Winship Cancer Institute of Emory University , Atlanta , Georgia , USA
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Radioprotection as a Method to Enhance the Therapeutic Ratio of Radiotherapy. CANCER DRUG DISCOVERY AND DEVELOPMENT 2017. [DOI: 10.1007/978-3-319-40854-5_4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Fogh SE, Deshmukh S, Berk LB, Dueck AC, Roof K, Yacoub S, Gergel T, Stephans K, Rimner A, DeNittis A, Pablo J, Rineer J, Williams TM, Bruner D. A Randomized Phase 2 Trial of Prophylactic Manuka Honey for the Reduction of Chemoradiation Therapy-Induced Esophagitis During the Treatment of Lung Cancer: Results of NRG Oncology RTOG 1012. Int J Radiat Oncol Biol Phys 2016; 97:786-796. [PMID: 28244415 DOI: 10.1016/j.ijrobp.2016.11.022] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 11/10/2016] [Accepted: 11/16/2016] [Indexed: 12/25/2022]
Abstract
PURPOSE Randomized trials have shown that honey is effective for the prevention of radiation-induced mucositis in head and neck cancer patients. Because there is no efficacious preventative for radiation esophagitis in lung cancer patients, this trial compared liquid honey, honey lozenges, and standard supportive care for radiation esophagitis. METHODS The patients were stratified by percentage of esophagus receiving specific radiation dose (V60 Gy esophagus <30% or ≥30%) and were then randomized between supportive care, 10 mL of liquid manuka honey 4 times a day, and 2 lozenges (10 mL of dehydrated manuka honey) 4 times a day during concurrent chemotherapy and radiation therapy. The primary endpoint was patient-reported pain on swallowing, with the use of an 11-point (0-10) scale at 4 weeks (Numerical Rating Pain Scale, NRPS). The study was designed to detect a 15% relative reduction of change in NRPS score. The secondary endpoints were trend of pain over time, opioid use, clinically graded and patient-reported adverse events, weight loss, dysphagia, nutritional status, and quality of life. RESULTS 53 patients were randomized to supportive care, 54 were randomized to liquid honey, and 56 were randomized to lozenge honey. There was no significant difference in the primary endpoint of change in the NRPS at 4 weeks between arms. There were no differences in any of the secondary endpoints except for opioid use at 4 weeks during treatment between the supportive care and liquid honey arms, which was found to be significant (P=.03), with more patients on the supportive care arm taking opioids. CONCLUSION Honey as prescribed within this protocol was not superior to best supportive care in preventing radiation esophagitis. Further testing of other types of honey and research into the mechanisms of action are needed.
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Affiliation(s)
- Shannon E Fogh
- University of California San Francisco, San Francisco, California.
| | - Snehal Deshmukh
- NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania
| | | | | | - Kevin Roof
- Southeast Cancer Control Consortium, Inc, CCOP, Winston-Salem, North Carolina
| | | | - Thomas Gergel
- Geisinger Medical Center CCOP, Danville, Pennsylvania
| | | | - Andreas Rimner
- Memorial Sloan Kettering Cancer Center, New York, New York
| | | | - John Pablo
- Lewis Cancer & Research Pavilion at St. Joseph's/Candler, Savannah, Georgia
| | - Justin Rineer
- UF Health Cancer Center - Orlando Health, Orlando, Florida
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Kwon OS, Kim KT, Lee E, Kim M, Choi SH, Li H, Fornace AJ, Cho JH, Lee YS, Lee JS, Lee YJ, Cha HJ. Induction of MiR-21 by Stereotactic Body Radiotherapy Contributes to the Pulmonary Fibrotic Response. PLoS One 2016; 11:e0154942. [PMID: 27171163 PMCID: PMC4865046 DOI: 10.1371/journal.pone.0154942] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 04/21/2016] [Indexed: 02/06/2023] Open
Abstract
Radiation-induced lung fibrosis, the most serious effect of lung cancer radiotherapy on normal tissue, remains a major technical obstacle to the broader application of radiotherapy to patients with lung cancer. This study describes the use of an image-guided irradiation system in mice mimicking stereotactic body radiotherapy (SBRT) to examine the molecular features of chronic fibrotic response after radiation injury. MicroRNA (miR) array analysis of injured pulmonary tissue identified a set of miRs whose expression was significantly increased in damaged lung tissue. In particular, miR-21 expression was increased at the radiation injury site, concurrent with collagen deposition. Although the inhibition of miR-21 by its specific inhibitor anti-miR-21 only marginally affected endothelial-mesenchymal transition (EndMT) in lung endothelial cells, this inhibition significantly reduced collagen synthesis in lung fibroblasts. Furthermore, ectopic expression of miR-21 was sufficient to promote a fibrotic response in lung fibroblasts, enhancing Smad2 phosphorylation concurrent with Smad7 downregulation. These findings indicate that the induction of miR-21 expression is responsible for fibrotic responses observed in mesenchymal cells at the injury site through the potentiation of TGF-β signaling. Local targeting of miR-21 at the injured area could have potential therapeutic utility in mitigating radiation-induced lung fibrosis.
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Affiliation(s)
- Ok-Seon Kwon
- Department of Life Sciences, Sogang University, Seoul, Korea
| | - Keun-Tae Kim
- Department of Life Sciences, Sogang University, Seoul, Korea
| | - Eunioo Lee
- College of Pharmacy and Wonkwang Oriental Medicines Research Institute, Wonkwang University, Jeonbuk, Korea
| | - Myoungjae Kim
- College of Pharmacy and Wonkwang Oriental Medicines Research Institute, Wonkwang University, Jeonbuk, Korea
| | - Seo-Hyun Choi
- Laboratory of Radiation Effect, Division of Radiation effect, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Henghong Li
- Department of Biochemistry and Molecular and Cellular Biology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D.C., United States of America
| | - Albert J. Fornace
- Department of Biochemistry and Molecular and Cellular Biology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D.C., United States of America
| | - Jae-Ho Cho
- Department of Radiation Oncology, Severance Hospital, Yonsei University, Seoul, Korea
| | - Yun-Sil Lee
- School of Pharmacy, Ewha University Seoul, Korea
| | - Ji-Seon Lee
- Burn Institute, Hangang Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, Korea
- * E-mail: (HJC); (YJL); (JSL)
| | - Yoon-Jin Lee
- Laboratory of Radiation Effect, Division of Radiation effect, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
- * E-mail: (HJC); (YJL); (JSL)
| | - Hyuk-Jin Cha
- Department of Life Sciences, Sogang University, Seoul, Korea
- * E-mail: (HJC); (YJL); (JSL)
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Benveniste MF, Gomez D, Carter BW, Betancourt Cuellar SL, De Groot PM, Marom EM. Radiation Effects in the Mediastinum and Surroundings: Imaging Findings and Complications. Semin Ultrasound CT MR 2015; 37:268-80. [PMID: 27261350 DOI: 10.1053/j.sult.2015.11.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Radiotherapy is one of the cornerstones for treatment of patients with cancer. Although advances in radiotherapy technology have considerably improved radiation delivery, potential adverse effects are still common. Postradiation changes to the mediastinum can include different structures such as the heart, great vessels, and esophagus. The purpose of the article was to illustrate the expected variety of changes to the mediastinum and adjacent lung resulting from external beam radiotherapy and radiotherapy-induced complications to the mediastinum and to discuss different radiotherapy delivery techniques.
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Affiliation(s)
- Marcelo F Benveniste
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX.
| | - Daniel Gomez
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Brett W Carter
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | - Patricia M De Groot
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Edith M Marom
- Department of Diagnostic Radiology, The Chaim Sheba Medical Center, Tel Hashomer, Israel
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Prevention and Management of Radiation-induced Late Gastrointestinal Toxicity. Clin Oncol (R Coll Radiol) 2015; 27:656-67. [DOI: 10.1016/j.clon.2015.06.010] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2015] [Revised: 05/26/2015] [Accepted: 06/09/2015] [Indexed: 12/18/2022]
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50
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Lee SJ, Yi CO, Heo RW, Song DH, Cho YJ, Jeong YY, Kang KM, Roh GS, Lee JD. Clarithromycin Attenuates Radiation-Induced Lung Injury in Mice. PLoS One 2015; 10:e0131671. [PMID: 26114656 PMCID: PMC4482753 DOI: 10.1371/journal.pone.0131671] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Accepted: 06/04/2015] [Indexed: 02/06/2023] Open
Abstract
Radiation-induced lung injury (RILI) is a common and unavoidable complication of thoracic radiotherapy. The current study was conducted to evaluate the ability of clarithromycin (CLA) to prevent radiation-induced pneumonitis, oxidative stress, and lung fibrosis in an animal model. C57BL/6J mice were assigned to control, irradiation only, irradiation plus CLA, and CLA only groups. Test mice received single thoracic exposures to radiation and/or oral CLA (100 mg/kg/day). Histopathologic findings and markers of inflammation, fibrosis, and oxidative stress were compared by group. On a microscopic level, CLA inhibited macrophage influx, alveolar fibrosis, parenchymal collapse, consolidation, and epithelial cell changes. The concentration of collagen in lung tissue was lower in irradiation plus CLA mice. Radiation-induced expression of tumor necrosis factor (TNF)-α, TNF receptor 1, acetylated nuclear factor kappa B, cyclooxygenase 2, vascular cell adhesion molecule 1, and matrix metallopeptidase 9 were also attenuated by CLA. Expression levels of nuclear factor erythroid 2-related factor 2 and heme oxygenase 1, transforming growth factor-β1, connective tissue growth factor, and type I collagen in radiation-treated lungs were also attenuated by CLA. These findings indicate that CLA ameliorates the deleterious effects of thoracic irradiation in mice by reducing pulmonary inflammation, oxidative damage, and fibrosis.
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Affiliation(s)
- Seung Jun Lee
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Republic of Korea
| | - Chin-ok Yi
- Department of Anatomy & Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Republic of Korea
| | - Rok Won Heo
- Department of Anatomy & Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Republic of Korea
| | - Dae Hyun Song
- Department of Pathology, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Republic of Korea
| | - Yu Ji Cho
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Republic of Korea
| | - Yi Yeong Jeong
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Republic of Korea
| | - Ki Mun Kang
- Department of Radiation Oncology, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Republic of Korea
| | - Gu Seob Roh
- Department of Anatomy & Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Republic of Korea
| | - Jong Deog Lee
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Republic of Korea
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