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Zhang Z, Li L, Ge Y, Chen A, Diao S, Yang Y, Chen Q, Zhou Y, Shao J, Meng F, Yu L, Tian M, Qian X, Lin Z, Xie C, Liu B, Li R. Verteporfin-Mediated In Situ Nanovaccine Based on Local Conventional-Dose Hypofractionated Radiotherapy Enhances Antitumor and Immunomodulatory Effect. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2413387. [PMID: 40231790 DOI: 10.1002/advs.202413387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 03/06/2025] [Indexed: 04/16/2025]
Abstract
In situ radiotherapy is the most successful cytotoxic therapy available for the treatment of solid tumors, while high-dose radiotherapy per fraction is not yet widely and reliably used. To some extent, the major considerations of the disappointing results are on the risk of high-dose irradiation-induced damage to the surrounding normal tissues and the difficulty in distant metastasis control. To break these restraints, a gelatinase-responsive amphiphilic methoxypolyethyleneglycol-PVGLIG-polycaprolactone (mPEG-PVGLIG-PCL) nanoparticles' loading verteporfin (N@VP), a special photosensitizer that can also be excited by X-rays to produce cytotoxic singlet oxygen and greatly enhance radiotherapy efficacy, is prepared in this study. Herein, it is shown that the formed N@VP combined with conventional-dose radiation therapy (RT, 2 Gy (gray, a radiation dose unit)) can realize an antitumor effect no less than high-dose RT (8 Gy) and minimize radiation dose necessary to achieve local tumor control. Moreover, this radiosensitive nanosystem can exert excellent systemic antitumor immunity and abscopal effect, providing a preferable "in situ vaccine" strategy based on conventional-dose RT to achieve efficient systemic management of distant tumor metastasis. When combined with immunotherapy, this novel strategy for radiosensitization results in better immunotherapy sensitivity by stimulating significant immunogenic tumor cell death and synergistic antitumor immune responses.
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Affiliation(s)
- Zhifan Zhang
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Lin Li
- Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Department of Oncology, Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210008, China
| | - Yuchen Ge
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Anni Chen
- Nanjing International Hospital, Medical School of Nanjing University, Nanjing, 210019, China
| | - Shanchao Diao
- State Key Laboratory for Organic Electronics and Information Displays & Institute of Advanced Materials (IAM), Jiangsu Key Laboratory for Biosensors, Nanjing University of Posts & Telecommunications, Nanjing, 210023, China
| | - Yueling Yang
- Department of Oncology, Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210008, China
| | - Qianyue Chen
- State Key Laboratory of Pharmaceutical Biotechnology, Ministry of Education Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, 210061, China
| | - Yingling Zhou
- Department of Oncology, Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210008, China
| | - Jie Shao
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Fanyan Meng
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Lixia Yu
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Manman Tian
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Xiaoping Qian
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Zhaoyu Lin
- State Key Laboratory of Pharmaceutical Biotechnology, Ministry of Education Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, 210061, China
| | - Chen Xie
- State Key Laboratory for Organic Electronics and Information Displays & Institute of Advanced Materials (IAM), Jiangsu Key Laboratory for Biosensors, Nanjing University of Posts & Telecommunications, Nanjing, 210023, China
| | - Baorui Liu
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Rutian Li
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
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Guo H, Yu R, Zhang H, Wang W. Cytokine, chemokine alterations and immune cell infiltration in Radiation-induced lung injury: Implications for prevention and management. Int Immunopharmacol 2024; 126:111263. [PMID: 38000232 DOI: 10.1016/j.intimp.2023.111263] [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: 10/22/2023] [Revised: 11/11/2023] [Accepted: 11/16/2023] [Indexed: 11/26/2023]
Abstract
Radiation therapy is one of the primary treatments for thoracic malignancies, with radiation-induced lung injury (RILI) emerging as its most prevalent complication. RILI encompasses early-stage radiation pneumonitis (RP) and the subsequent development of radiation pulmonary fibrosis (RPF). During radiation treatment, not only are tumor cells targeted, but normal tissue cells, including alveolar epithelial cells and vascular endothelial cells, also sustain damage. Within the lungs, ionizing radiation boosts the intracellular levels of reactive oxygen species across various cell types. This elevation precipitates the release of cytokines and chemokines, coupled with the infiltration of inflammatory cells, culminating in the onset of RP. This pulmonary inflammatory response can persist, spanning a duration from several months to years, ultimately progressing to RPF. This review aims to explore the alterations in cytokine and chemokine release and the influx of immune cells post-ionizing radiation exposure in the lungs, offering insights for the prevention and management of RILI.
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Affiliation(s)
- Haochun Guo
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China
| | - Ran Yu
- Department of Radiotherapy, Lianshui People's Hospital, Kangda College of Nanjing Medical University, Huai'an 223400, China; Jiangsu Nursing Vocational and Technical College, Huai'an 223400, China; School of Clinical Medicine, Medical College of Yangzhou University, Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou 225009, China
| | - Haijun Zhang
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China.
| | - Wanpeng Wang
- Department of Radiotherapy, Lianshui People's Hospital, Kangda College of Nanjing Medical University, Huai'an 223400, China; Jiangsu Nursing Vocational and Technical College, Huai'an 223400, China; School of Clinical Medicine, Medical College of Yangzhou University, Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou 225009, China.
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Liu X, Shao C, Fu J. Promising Biomarkers of Radiation-Induced Lung Injury: A Review. Biomedicines 2021; 9:1181. [PMID: 34572367 PMCID: PMC8470495 DOI: 10.3390/biomedicines9091181] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 09/05/2021] [Accepted: 09/06/2021] [Indexed: 12/15/2022] Open
Abstract
Radiation-induced lung injury (RILI) is one of the main dose-limiting side effects in patients with thoracic cancer during radiotherapy. No reliable predictors or accurate risk models are currently available in clinical practice. Severe radiation pneumonitis (RP) or pulmonary fibrosis (PF) will reduce the quality of life, even when the anti-tumor treatment is effective for patients. Thus, precise prediction and early diagnosis of lung toxicity are critical to overcome this longstanding problem. This review summarizes the primary mechanisms and preclinical animal models of RILI reported in recent decades, and analyzes the most promising biomarkers for the early detection of lung complications. In general, ideal integrated models considering individual genetic susceptibility, clinical background parameters, and biological variations are encouraged to be built up, and more prospective investigations are still required to disclose the molecular mechanisms of RILI as well as to discover valuable intervention strategies.
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Affiliation(s)
- Xinglong Liu
- Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China;
| | - Chunlin Shao
- Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China;
| | - Jiamei Fu
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
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Dreyfuss AD, Jahangiri P, Simone CB, Alavi A. Evolving Role of Novel Quantitative PET Techniques to Detect Radiation-Induced Complications. PET Clin 2019; 15:89-100. [PMID: 31735305 DOI: 10.1016/j.cpet.2019.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Radiation-induced normal tissue toxicities vary in terms of pathophysiologic determinants and timing of disease development, and they are influenced by the dose and radiation volume the critical organs receive, and the radiosensitivity of normal tissues and their baseline rate of cell turnover. Radiation-induced lung injury is dose limiting for the treatment of lung and thoracic cancers and can lead to fibrosis and potentially fatal pneumonitis. This article focuses on pulmonary and cardiovascular complications of radiation therapy and discusses how PET-based novel quantitative techniques can be used to detect these events earlier than current imaging modalities or clinical presentation allow.
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Affiliation(s)
- Alexandra D Dreyfuss
- Department of Radiology, Hospital of the University of Pennsylvania, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA
| | - Pegah Jahangiri
- Department of Radiology, Hospital of the University of Pennsylvania, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA
| | - Charles B Simone
- Department of Radiation Oncology, New York Proton Center, 225 East 126th Street, New York, NY 10035, USA.
| | - Abass Alavi
- Department of Radiology, Hospital of the University of Pennsylvania, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA
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Yin Z, Yang G, Deng S, Wang Q. Oxidative stress levels and dynamic changes in mitochondrial gene expression in a radiation-induced lung injury model. JOURNAL OF RADIATION RESEARCH 2019; 60:204-214. [PMID: 30590649 PMCID: PMC6430248 DOI: 10.1093/jrr/rry105] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Revised: 10/21/2018] [Indexed: 05/09/2023]
Abstract
The purpose of this study was to set up a beagle dog model, for radiation-induced lung injury, that would be able to supply fresh lung tissues in the different injury phases for research into oxidative stress levels and mitochondrial gene expression. Blood serum and tissues were collected via CT-guided core needle biopsies from dogs in the various phases of the radiation response over a 40-week period. Levels of reactive oxygen species (ROS) and manganese superoxide dismutase 2 (MnSOD) protein expression in radiation-induced lung injury were determined by in situ immunocytochemistry; malondialdehyde (MDA) content and reductase activity in the peripheral blood were also tested; in addition, the copy number of the mitochondrial DNA and the level of function of the respiratory chain in the lung tissues were assessed. ROS showed dynamic changes and peaked at 4 weeks; MnSOD was mainly expressed in the Type II alveolar epithelium at 8 weeks; the MDA content and reductase activity in the peripheral blood presented no changes; the copy numbers of most mitochondrial genes peaked at 8 weeks, similarly to the level of function of the corresponding respiratory chain complexes; the level of function of the respiratory chain complex III did not peak until 24 weeks, similarly to the level of function of the corresponding gene Cytb. Radiation-induced lung injury was found to be a dynamically changing process, mainly related to interactions between local ROS, and it was not associated with the levels of oxidative stress in the peripheral blood. Mitochondrial genes and their corresponding respiratory chain complexes were found to be involved in the overall process.
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Affiliation(s)
- Zhongyuan Yin
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guanghai Yang
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sisi Deng
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiong Wang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Corresponding author: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Tel: +86-159-2739-5672; Fax: +86-27-6565-0733;
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Tomasik B, Chałubińska-Fendler J, Chowdhury D, Fendler W. Potential of serum microRNAs as biomarkers of radiation injury and tools for individualization of radiotherapy. Transl Res 2018; 201:71-83. [PMID: 30021695 DOI: 10.1016/j.trsl.2018.06.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Revised: 05/31/2018] [Accepted: 06/04/2018] [Indexed: 12/30/2022]
Abstract
Due to tremendous technological advances, radiation oncologists are now capable of personalized treatment plans and deliver the dose in a highly precise manner. However, a crucial challenge is how to escalate radiation doses to cancer cells while reducing damage to surrounding healthy tissues. This determines the probability of achieving therapeutic success whilst safeguarding patients from complications. The current dose constraints rely on observational data. Therefore, incidental toxicity observed in a minority of patients limits the admissible dose thresholds for the whole population, theoretically narrowing down the curative potential of radiotherapy. Future tools for measurements of individual's radiosensitivity before and during treatment would allow proper treatment personalization. Variation in tissue tolerance is at least partially genetically-determined and recent progress in the field of molecular biology raises the possibility that novel assays will allow to predict the response to ionizing radiation. Recently, microRNAs have garnered interest as stable biomarkers of tumor radiation response and normal-tissue toxicity. Preclinical studies in mice and nonhuman primates have shown that serum circulating microRNAs can be used to accurately distinguish pre- and postirradiation states and predict the biological impact of high-dose irradiation. First reports from human studies are also encouraging, however biology-driven precision radiation oncology, which tailors treatment to individual patient's needs, still remains to be translated into clinical studies. In this review, we summarize current knowledge about the potential of serum microRNAs as biodosimeters and biomarkers for radiation injury to lung and hematopoietic cells.
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Affiliation(s)
- Bartłomiej Tomasik
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland; Postgraduate School of Molecular Medicine, Warsaw Medical University, Warsaw, Poland
| | | | - Dipanjan Chowdhury
- Department of Radiation Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
| | - Wojciech Fendler
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland; Department of Radiation Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
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Lierova A, Jelicova M, Nemcova M, Proksova M, Pejchal J, Zarybnicka L, Sinkorova Z. Cytokines and radiation-induced pulmonary injuries. JOURNAL OF RADIATION RESEARCH 2018; 59:709-753. [PMID: 30169853 PMCID: PMC6251431 DOI: 10.1093/jrr/rry067] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 07/11/2018] [Indexed: 05/20/2023]
Abstract
Radiation therapy is one of the most common treatment strategies for thorax malignancies. One of the considerable limitations of this therapy is its toxicity to normal tissue. The lung is the major dose-limiting organ for radiotherapy. That is because ionizing radiation produces reactive oxygen species that induce lesions, and not only is tumor tissue damaged, but overwhelming inflammatory lung damage can occur in the alveolar epithelium and capillary endothelium. This damage may result in radiation-induced pneumonitis and/or fibrosis. While describing the lung response to irradiation generally, the main focus of this review is on cytokines and their roles and functions within the individual stages. We discuss the relationship between radiation and cytokines and their direct and indirect effects on the formation and development of radiation injuries. Although this topic has been intensively studied and discussed for years, we still do not completely understand the roles of cytokines. Experimental data on cytokine involvement are fragmented across a large number of experimental studies; hence, the need for this review of the current knowledge. Cytokines are considered not only as molecular factors involved in the signaling network in pathological processes, but also for their diagnostic potential. A concentrated effort has been made to identify the significant immune system proteins showing positive correlation between serum levels and tissue damages. Elucidating the correlations between the extent and nature of radiation-induced pulmonary injuries and the levels of one or more key cytokines that initiate and control those damages may improve the efficacy of radiotherapy in cancer treatment and ultimately the well-being of patients.
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Affiliation(s)
- Anna Lierova
- Department of Radiobiology, Faculty of Military Health Sciences, University of Defence in Brno, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
| | - Marcela Jelicova
- Department of Radiobiology, Faculty of Military Health Sciences, University of Defence in Brno, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
| | - Marketa Nemcova
- Department of Radiobiology, Faculty of Military Health Sciences, University of Defence in Brno, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
| | - Magdalena Proksova
- Department of Molecular Pathology and Biology, Faculty of Military Health Sciences, University of Defence in Brno, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
| | - Jaroslav Pejchal
- Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence in Brno, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
| | - Lenka Zarybnicka
- Department of Radiobiology, Faculty of Military Health Sciences, University of Defence in Brno, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
| | - Zuzana Sinkorova
- Department of Radiobiology, Faculty of Military Health Sciences, University of Defence in Brno, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
- Corresponding author. Department of Radiobiology, Faculty of Military Health Sciences, University of Defence in Brno, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. Tel.: +420 973 253 219.
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Kim JH, Jenrow KA, Brown SL. Novel biological strategies to enhance the radiation therapeutic ratio. Radiat Oncol J 2018; 36:172-181. [PMID: 30309208 PMCID: PMC6226138 DOI: 10.3857/roj.2018.00332] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 08/29/2018] [Indexed: 02/06/2023] Open
Abstract
Successful anticancer strategies require a differential response between tumor and normal tissue (i.e., a therapeutic ratio). In fact, improving the effectiveness of a cancer therapeutic is of no clinical value in the absence of a significant increase in the differential response between tumor and normal tissue. Although radiation dose escalation with the use of intensity modulated radiation therapy has permitted the maximum tolerable dose for most locally advanced cancers, improvements in tumor control without damaging normal adjacent tissues are needed. As a means of increasing the therapeutic ratio, several new approaches are under development. Drugs targeting signal transduction pathways in cancer progression and more recently, immunotherapeutics targeting specific immune cell subsets have entered the clinic with promising early results. Radiobiological research is underway to address pressing questions as to the dose per fraction, irradiated tumor volume and time sequence of the drug administration. To exploit these exciting novel strategies, a better understanding is needed of the cellular and molecular pathways responsible for both cancer and normal tissue and organ response, including the role of radiation-induced accelerated senescence. This review will highlight the current understanding of promising biologically targeted therapies to enhance the radiation therapeutic ratio.
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Affiliation(s)
- Jae Ho Kim
- Department of Radiation Oncology, Henry Ford Hospital, Detroit, MI, USA
| | - Kenneth A Jenrow
- Department of Psychology/Neuroscience Program, Central Michigan University, Mount Pleasant, MI, USA
| | - Stephen L Brown
- Department of Radiation Oncology, Henry Ford Hospital, Detroit, MI, USA
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Abstract
Normal tissue injury from irradiation is an unfortunate consequence of radiotherapy. Technologic improvements have reduced the risk of normal tissue injury; however, toxicity causing treatment breaks or long-term side effects continues to occur in a subset of patients. The molecular events that lead to normal tissue injury are complex and span a variety of biologic processes, including oxidative stress, inflammation, depletion of injured cells, senescence, and elaboration of proinflammatory and profibrogenic cytokines. This article describes selected recent advances in normal tissue radiobiology.
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Affiliation(s)
- Deborah E Citrin
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
| | - James B Mitchell
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
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Lu Z, Tang Y, Luo J, Zhang S, Zhou X, Fu L. Advances in targeting the transforming growth factor β1 signaling pathway in lung cancer radiotherapy. Oncol Lett 2017; 14:5681-5687. [PMID: 29113195 DOI: 10.3892/ol.2017.6991] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Accepted: 07/21/2017] [Indexed: 02/06/2023] Open
Abstract
Lung cancer was demonstrated to be the most lethal type of malignant tumor amongst humans in the global cancer statistics of 2012. As one of the primary treatments, radiotherapy has been reported to induce remission in, and even cure, patients with lung cancer. However, the side effects of radiotherapy may prove lethal in certain patients. In past decades, the transforming growth factor β1 (TGFB1) signaling pathway has been revealed to serve multiple functions in the control of lung cancer progression and the radiotherapy response. In mammals, this signaling pathway is initiated through activation of the TGFB1 receptor complex, which signals via cytoplasmic SMAD proteins or other downstream signaling pathways. Multiple studies have demonstrated that TGFB1 serves important functions in lung cancer radiotherapy. The present study summarized and reviewed recent progress in elucidating the function of the TGFB1 signaling pathway in predicting radiation pneumonitis, as well as current strategies for targeting the TGFB1 signaling pathway in lung cancer radiotherapy, which may provide potential targets for lung cancer therapy.
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Affiliation(s)
- Zhonghua Lu
- Department of Radiation Oncology, Changzhou Cancer Hospital, Soochow University, Changzhou, Jiangsu 213001, P.R. China
| | - Yiting Tang
- Department of Radiation Oncology, Changzhou Cancer Hospital, Soochow University, Changzhou, Jiangsu 213001, P.R. China
| | - Judong Luo
- Department of Radiation Oncology, Changzhou Cancer Hospital, Soochow University, Changzhou, Jiangsu 213001, P.R. China
| | - Shuyu Zhang
- Department of Radiation Biology, School of Radiation Medicine and Protection and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Xifa Zhou
- Department of Radiation Oncology, Changzhou Cancer Hospital, Soochow University, Changzhou, Jiangsu 213001, P.R. China
| | - Lei Fu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China
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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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Citrin DE, Prasanna PGS, Walker AJ, Freeman ML, Eke I, Barcellos-Hoff MH, Arankalayil MJ, Cohen EP, Wilkins RC, Ahmed MM, Anscher MS, Movsas B, Buchsbaum JC, Mendonca MS, Wynn TA, Coleman CN. Radiation-Induced Fibrosis: Mechanisms and Opportunities to Mitigate. Report of an NCI Workshop, September 19, 2016. Radiat Res 2017; 188:1-20. [PMID: 28489488 PMCID: PMC5558616 DOI: 10.1667/rr14784.1] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
A workshop entitled "Radiation-Induced Fibrosis: Mechanisms and Opportunities to Mitigate" (held in Rockville, MD, September 19, 2016) was organized by the Radiation Research Program and Radiation Oncology Branch of the Center for Cancer Research (CCR) of the National Cancer Institute (NCI), to identify critical research areas and directions that will advance the understanding of radiation-induced fibrosis (RIF) and accelerate the development of strategies to mitigate or treat it. Experts in radiation biology, radiation oncology and related fields met to identify and prioritize the key areas for future research and clinical translation. The consensus was that several known and newly identified targets can prevent or mitigate RIF in pre-clinical models. Further, basic and translational research and focused clinical trials are needed to identify optimal agents and strategies for therapeutic use. It was felt that optimally designed preclinical models are needed to better study biomarkers that predict for development of RIF, as well as to understand when effective therapies need to be initiated in relationship to manifestation of injury. Integrating appropriate endpoints and defining efficacy in clinical trials testing treatment of RIF were felt to be critical to demonstrating efficacy. The objective of this meeting report is to (a) highlight the significance of RIF in a global context, (b) summarize recent advances in our understanding of mechanisms of RIF,
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Affiliation(s)
- Deborah E. Citrin
- Radiation Oncology Branch, Center for Cancer Research, Bethesda, Maryland
| | - Pataje G. S. Prasanna
- Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland
| | - Amanda J. Walker
- Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
| | - Michael L. Freeman
- Department of Radiation Oncology, Vanderbilt School of Medicine, Nashville, Tennessee
| | - Iris Eke
- Radiation Oncology Branch, Center for Cancer Research, Bethesda, Maryland
| | - Mary Helen Barcellos-Hoff
- Department of Radiation Oncology, University of California, San Francisco, San Francisco, California
| | | | - Eric P. Cohen
- Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Ruth C. Wilkins
- Radiobiology Division, Consumer and Clinical Radiation Protection Bureau, Health Canada, Ottawa, Ontario
| | - Mansoor M. Ahmed
- Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland
| | - Mitchell S. Anscher
- Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia
| | - Benjamin Movsas
- Department of Radiation Oncology, Henry Ford Hospital, Detroit, Michigan
| | - Jeffrey C. Buchsbaum
- Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland
| | - Marc S. Mendonca
- Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia
| | - Thomas A. Wynn
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | - C. Norman Coleman
- Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland
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Osborn VW, Leaf A, Lee A, Garay E, Safdieh J, Schwartz D, Schreiber D. Bilateral diffuse grade 5 radiation pneumonitis after intensity modulated radiation therapy for localized lung cancer. World J Clin Oncol 2017; 8:285-288. [PMID: 28638799 PMCID: PMC5465019 DOI: 10.5306/wjco.v8.i3.285] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 04/07/2017] [Accepted: 05/15/2017] [Indexed: 02/06/2023] Open
Abstract
We are reporting a case of fatal radiation pneumonitis that developed six months following chemoradiation for limited stage small cell lung cancer. The patient was a 67-year-old man with a past medical history of Hashimoto’s thyroiditis and remote suspicion for CREST, neither of which were active in the years leading up to treatment. He received 6600 cGy delivered in 200 cGy daily fractions via intensity modulated radiation therapy with concurrent cisplatin/etoposide followed by additional chemotherapy with dose-reduced cisplatin/etoposide and carboplatin/etoposide and then received prophylactic cranial irradiation. The subsequent months were notable for progressively worsening episodes of respiratory compromise despite administration of prolonged steroids and he ultimately expired. Imaging demonstrated bilateral interstitial and airspace opacities. Autopsy findings were consistent with pneumonitis secondary to chemoradiation as well as lymphangitic spread of small cell carcinoma. The process was diffuse bilaterally although his radiation was delivered focally to the right lung and mediastinum.
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Dinh TKT, Fendler W, Chałubińska-Fendler J, Acharya SS, O’Leary C, Deraska PV, D’Andrea AD, Chowdhury D, Kozono D. Circulating miR-29a and miR-150 correlate with delivered dose during thoracic radiation therapy for non-small cell lung cancer. Radiat Oncol 2016; 11:61. [PMID: 27117590 PMCID: PMC4847218 DOI: 10.1186/s13014-016-0636-4] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 04/14/2016] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Risk of normal tissue toxicity limits the amount of thoracic radiation therapy (RT) that can be routinely prescribed to treat non-small cell lung cancer (NSCLC). An early biomarker of response to thoracic RT may provide a way to predict eventual toxicities-such as radiation pneumonitis-during treatment, thereby enabling dose adjustment before the symptomatic onset of late effects. MicroRNAs (miRNAs) were studied as potential serological biomarkers for thoracic RT. As a first step, we sought to identify miRNAs that correlate with delivered dose and standard dosimetric factors. METHODS We performed miRNA profiling of plasma samples obtained from five patients with Stage IIIA NSCLC at five dose-points each during radical thoracic RT. Candidate miRNAs were then assessed in samples from a separate cohort of 21 NSCLC patients receiving radical thoracic RT. To identify a cellular source of circulating miRNAs, we quantified in vitro miRNA expression intracellularly and within secreted exosomes in five NSCLC and stromal cell lines. RESULTS miRNA profiling of the discovery cohort identified ten circulating miRNAs that correlated with delivered RT dose as well as other dosimetric parameters such as lung V20. In the validation cohort, miR-29a-3p and miR-150-5p were reproducibly shown to decrease with increasing radiation dose. Expression of miR-29a-3p and miR-150-5p in secreted exosomes decreased with radiation. This was concomitant with an increase in intracellular levels, suggesting that exosomal export of these miRNAs may be downregulated in both NSCLC and stromal cells in response to radiation. CONCLUSIONS miR-29a-3p and miR-150-5p were identified as circulating biomarkers that correlated with delivered RT dose. miR-150 has been reported to decrease in the circulation of mammals exposed to radiation while miR-29a has been associated with fibrosis in the human heart, lungs, and kidneys. One may therefore hypothesize that outlier levels of circulating miR-29a-3p and miR-150-5p may eventually help predict unexpected responses to radiation therapy, such as toxicity.
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Affiliation(s)
- Tru-Khang T. Dinh
- />Harvard Medical School, 25 Shattuck St, Boston, MA 02115 USA
- />Department of Radiation Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215 USA
| | - Wojciech Fendler
- />Department of Biostatistics and Translational Medicine, Medical University of Łódź, Al. Kościuszki 4, 90-419 Łódź, Poland
| | | | - Sanket S. Acharya
- />Department of Radiation Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215 USA
| | - Colin O’Leary
- />Department of Radiation Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215 USA
| | - Peter V. Deraska
- />Department of Radiation Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215 USA
| | - Alan D. D’Andrea
- />Harvard Medical School, 25 Shattuck St, Boston, MA 02115 USA
- />Department of Radiation Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215 USA
- />Center for DNA Damage and Repair, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215 USA
| | - Dipanjan Chowdhury
- />Harvard Medical School, 25 Shattuck St, Boston, MA 02115 USA
- />Department of Radiation Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215 USA
| | - David Kozono
- />Harvard Medical School, 25 Shattuck St, Boston, MA 02115 USA
- />Department of Radiation Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215 USA
- />Department of Radiation Oncology, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115 USA
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Stereotactic body radiation therapy and intensity modulated radiation therapy induce different plasmatic cytokine changes in non-small cell lung cancer patients: a pilot study. Clin Transl Oncol 2015; 18:1003-10. [PMID: 26687367 DOI: 10.1007/s12094-015-1473-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 12/08/2015] [Indexed: 12/22/2022]
Abstract
PURPOSE To assess kinetics of plasmatic cytokines during radiation therapy (RT) for locally advanced and early-stage non-small cell lung cancer (NSCLC). METHODS This prospective study was conducted on 15 early-stage NSCLC underwent to extreme hypofractionated regimen (52 Gy in 8 fractions) with stereotactic body RT (SBRT), and 13 locally advanced NSCLC underwent to radical moderated hypofractionated regimen (60 Gy in 25 fractions) with intensity modulated RT (IMRT). For patients undergoing SBRT, peripheral blood samples were collected on the first day of SBRT (TFd), the last day (TLd) and 45 days (T45d) after the end of SBRT. For patients undergoing IMRT, blood samples were collected at: TFd, 2 weeks (T2w), 4 weeks (T4w), TLd, and T45d. The following cytokines were measured: IL-1, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17A, EGF, FGF-2, INF-γ, MIP-1α, MIP-1β, TGF-α, TNF-α, and VEGF. Cytokine levels measured in different RT time and compared. RESULTS No difference in baseline levels of cytokines was documented between patient radiation approaches (except for MIP-1α). For SBRT patients, a mean reduction of IL-10 and IL-17 plasma level was documented between TLd and TFd, respectively (p < 0.05). For IMRT patients, a statistically significant (p < 0.05) mean plasma level reduction was documented between T4w and TFd for all the following cytokines: IL-1, IL-1ra, IL-2, IL-12, FGF-2, MIP-1α, MIP-1β, TGF-α, TNF-α, VEGF. CONCLUSIONS SBRT and IMRT induce different plasmatic cytokine changes in NSCLC patients, supporting hypothesis that RT regimes of dose schedules and techniques have different impacts on the host immune response.
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Abstract
In the past decade, several different radiotherapy treatment plan evaluation and optimization schemes have been proposed as viable approaches, aiming for dose escalation or an increase of healthy tissue sparing. In particular, it has been argued that dose-mass plan evaluation and treatment plan optimization might be viable alternatives to the standard of care, which is realized through dose-volume evaluation and optimization. The purpose of this investigation is to apply dose-mass optimization to a cohort of lung cancer patients and compare the achievable healthy tissue sparing to that one achievable through dose-volume optimization. Fourteen non-small cell lung cancer (NSCLC) patient plans were studied retrospectively. The range of tumor motion was less than 0.5 cm and motion management in the treatment planning process was not considered. For each case, dose-volume (DV)-based and dose-mass (DM)-based optimization was performed. Nine-field step-and-shoot IMRT was used, with all of the optimization parameters kept the same between DV and DM optimizations. Commonly used dosimetric indices (DIs) such as dose to 1% the spinal cord volume, dose to 50% of the esophageal volume, and doses to 20 and 30% of healthy lung volumes were used for cross-comparison. Similarly, mass-based indices (MIs), such as doses to 20 and 30% of healthy lung masses, 1% of spinal cord mass, and 33% of heart mass, were also tallied. Statistical equivalence tests were performed to quantify the findings for the entire patient cohort. Both DV and DM plans for each case were normalized such that 95% of the planning target volume received the prescribed dose. DM optimization resulted in more organs at risk (OAR) sparing than DV optimization. The average sparing of cord, heart, and esophagus was 23, 4, and 6%, respectively. For the majority of the DIs, DM optimization resulted in lower lung doses. On average, the doses to 20 and 30% of healthy lung were lower by approximately 3 and 4%, whereas lung volumes receiving 2000 and 3000 cGy were lower by 3 and 2%, respectively. The behavior of MIs was very similar. The statistical analyses of the results again indicated better healthy anatomical structure sparing with DM optimization. The presented findings indicate that dose-mass-based optimization results in statistically significant OAR sparing as compared to dose-volume-based optimization for NSCLC. However, the sparing is case-dependent and it is not observed for all tallied dosimetric endpoints.
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Affiliation(s)
- Ivaylo B. Mihaylov
- Department of Radiation Oncology, University of Miami, 1475 NW 12th Ave, Suite 1500, Miami, FL 33136
| | - Eduardo G. Moros
- Radiation Oncology and Cancer Imaging, H. Lee Moffitt Cancer Center, 12902 Magnolia Dr., Tampa, FL 33612
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Lu Z, Ma Y, Zhang S, Liu F, Wan M, Luo J. Transforming growth factor-β1 small interfering RNA inhibits growth of human embryonic lung fibroblast HFL-I cells in vitro and defends against radiation-induced lung injury in vivo. Mol Med Rep 2014; 11:2055-61. [PMID: 25385392 DOI: 10.3892/mmr.2014.2923] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Accepted: 09/24/2014] [Indexed: 11/05/2022] Open
Abstract
In the present study, a human transforming growth factor‑β1 (TGF‑β1) small interfering RNA (siRNA) plasmid vector (TGF‑β1‑siRNA) was constructed to investigate its effects on the proliferation and differentiation of human lung fibroblasts in vitro and its interference effects on radiation‑induced lung injury in vivo. Reverse transcription quantitative polymerase chain reaction and enzyme linked immunosorbent assay revealed that the mRNA and protein expression of TGF‑β1 in the HFL‑I cells were inhibited by TGF‑β1‑siRNA and flow cytometry demonstrated a significant increase in apoptosis of the HFL‑I cells. Adult, female, specific‑pathogen‑free C57BL/6 mice were used in the in vivo animal investigations and were randomly divided into the four following groups: control without any treatment, radiation alone, radiation followed by empty vector transfection and radiation followed by TGF‑β1‑siRNA vector transfection. Hematoxylin and eosin and Van‑Gieson staining revealed that certain radiation‑induced histopathological changes of the lung, including inflammation, edema, the density of surface pulmonary interstitial collagen fibers in the alveolar septum, TGF‑β1‑positive reactions in alveolar epithelial cells and pulmonary interstitial macrophages were less marked in the mice transfected with TGF‑β1‑siRNA compared with the mice without transfection or those transfected with empty vectors. The serum levels of TGF‑β1 levels in the irradiated mice increased significantly at four weeks and peaked at eight weeks after radiation, compared with the control. Serum levels of TGF‑β1 in the irradiated mice transfected with TGF‑β1‑siRNA also increased gradually and a significant difference was observed compared with those irradiated without transfection. The mRNA expression levels of TGF‑β1 in the mice transfected with TGF‑β1‑siRNA were markedly lower compared with those of the other radiation groups. The present study suggested that the TGF‑β1‑siRNA vector reduced the activity of TGF‑β1 by downregulating the mRNA expression of TGF‑β1 and thereby effectively suppressing inflammatory reactions and defending against radiation‑induced lung injury.
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Affiliation(s)
- Zhonghua Lu
- Department of Radiotherapy, Changzhou Tumor Hospital, Soochow University, Changzhou, Jiangsu 213001, P.R. China
| | - Yan Ma
- Department of Radiotherapy, Changzhou Tumor Hospital, Soochow University, Changzhou, Jiangsu 213001, P.R. China
| | - Shuyu Zhang
- Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Fenju Liu
- Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Meizhen Wan
- Department of Radiotherapy, Changzhou Tumor Hospital, Soochow University, Changzhou, Jiangsu 213001, P.R. China
| | - Judong Luo
- Department of Radiotherapy, Changzhou Tumor Hospital, Soochow University, Changzhou, Jiangsu 213001, P.R. China
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Suarez EM, Knackstedt RJ, Jenrette JM. Significant fibrosis after radiation therapy in a patient with Marfan syndrome. Radiat Oncol J 2014; 32:208-12. [PMID: 25324993 PMCID: PMC4194304 DOI: 10.3857/roj.2014.32.3.208] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Revised: 07/18/2014] [Accepted: 08/29/2014] [Indexed: 11/04/2022] Open
Abstract
Marfan syndrome is one of the collagen vascular diseases that theoretically predisposes patients to excessive radiation-induced fibrosis yet there is minimal published literature regarding this clinical scenario. We present a patient with a history of Marfan syndrome requiring radiation for a diagnosis of a right brachial plexus malignant nerve sheath tumor. It has been suggested that plasma transforming growth factor beta 1 (TGF-β1) can be monitored as a predictor of subsequent fibrosis in this population of high risk patients. We therefore monitored the patient's TGF-β1 level during and after treatment. Despite maintaining stable levels of plasma TGF-β1, our patient still developed extensive fibrosis resulting in impaired range of motion. Our case reports presents a review of the literature of patients with Marfan syndrome requiring radiation therapy and the limitations of serum markers on predicting long-term toxicity.
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Affiliation(s)
- Eva M Suarez
- Department of Radiation Oncology, Medical University of South Carolina, Charleston, SC, USA
| | - Rebecca J Knackstedt
- Department of Radiation Oncology, Medical University of South Carolina, Charleston, SC, USA
| | - Joseph M Jenrette
- Department of Radiation Oncology, Medical University of South Carolina, Charleston, SC, USA
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19
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Kim JH, Jenrow KA, Brown SL. Mechanisms of radiation-induced normal tissue toxicity and implications for future clinical trials. Radiat Oncol J 2014; 32:103-15. [PMID: 25324981 PMCID: PMC4194292 DOI: 10.3857/roj.2014.32.3.103] [Citation(s) in RCA: 210] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 08/18/2014] [Indexed: 01/10/2023] Open
Abstract
To summarize current knowledge regarding mechanisms of radiation-induced normal tissue injury and medical countermeasures available to reduce its severity. Advances in radiation delivery using megavoltage and intensity-modulated radiation therapy have permitted delivery of higher doses of radiation to well-defined tumor target tissues. Injury to critical normal tissues and organs, however, poses substantial risks in the curative treatment of cancers, especially when radiation is administered in combination with chemotherapy. The principal pathogenesis is initiated by depletion of tissue stem cells and progenitor cells and damage to vascular endothelial microvessels. Emerging concepts of radiation-induced normal tissue toxicity suggest that the recovery and repopulation of stromal stem cells remain chronically impaired by long-lived free radicals, reactive oxygen species, and pro-inflammatory cytokines/chemokines resulting in progressive damage after radiation exposure. Better understanding the mechanisms mediating interactions among excessive generation of reactive oxygen species, production of pro-inflammatory cytokines and activated macrophages, and role of bone marrow-derived progenitor and stem cells may provide novel insight on the pathogenesis of radiation-induced injury of tissues. Further understanding the molecular signaling pathways of cytokines and chemokines would reveal novel targets for protecting or mitigating radiation injury of tissues and organs.
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Affiliation(s)
- Jae Ho Kim
- Department of Radiation Oncology, Henry Ford Health System, Detroit, MI, USA
| | - Kenneth A. Jenrow
- Department of Radiation Oncology, Henry Ford Health System, Detroit, MI, USA
| | - Stephen L. Brown
- Department of Radiation Oncology, Henry Ford Health System, Detroit, MI, USA
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20
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Omarini C, Thanopoulou E, Johnston SRD. Pneumonitis and pulmonary fibrosis associated with breast cancer treatments. Breast Cancer Res Treat 2014; 146:245-58. [PMID: 24929676 DOI: 10.1007/s10549-014-3016-5] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2014] [Accepted: 05/28/2014] [Indexed: 01/07/2023]
Abstract
To review the available published data regarding the incidence, mechanisms of pathogenesis, clinical presentations and management of pneumonitis caused by anti-cancer treatments (radiotherapy (RT) and systemic agents) that are included in the guidelines of the treatment of breast cancer (BC) and address the issues on the current grading classification of pneumonitis. A literature search was performed between July and October 2013 using PubMed for papers published from January 1989 to October 2013. Any clinical trial, case report, case series, meta-analysis or systematic review that reported on pulmonary toxicity of any BC therapeutic modality was included (only papers published in English). Most of anticancer treatments currently used in the management of BC may induce some degree of pneumonitis that is estimated to have an incidence of 1-3 %. There is an obvious distinction between chemotherapy- and targeted treatment-related lung toxicity. Moreover, the current classification of pneumonitis needs to be modified as there is a clear diversity in grade 2. As pneumonitis is relatively common and reported as side effect of new anticancer agents, physicians need to be aware of the clinical and radiological manifestations of drug- and RT-induced toxicities in patients with BC. A key recommendation is the subdivision of grade 2 cases to two subgroups. We provide an algorithm, along with real life cases as managed in the breast Unit of Royal Marsden Hospital, with the aim to guide physicians in managing all possible eventualities that may come across in clinical practise.
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Affiliation(s)
- Claudia Omarini
- Department of Medicine, Royal Marsden NHS Foundation Trust, Fulham Road, Chelsea, London, SW3 6JJ, UK,
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21
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Kim JH, Kolozsvary AJJ, Jenrow KA, Brown SL. Mechanisms of radiation-induced skin injury and implications for future clinical trials. Int J Radiat Biol 2013; 89:311-8. [DOI: 10.3109/09553002.2013.765055] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Cao S, Wu R. Expression of Angiotensin II and Aldosterone in Radiation-induced Lung Injury. Cancer Biol Med 2012; 9:254-60. [PMID: 23691486 PMCID: PMC3643675 DOI: 10.7497/j.issn.2095-3941.2012.04.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Accepted: 12/04/2012] [Indexed: 01/21/2023] Open
Abstract
OBJECTIVE Radiation-induced lung injury (RILI) is the most common, dose-limiting complication in thoracic malignancy radiotherapy. Considering its negative impact on patients and restrictions to efficacy, the mechanism of RILI was studied. METHODS Wistar rats were locally irradiated with a single dose of 0, 16, and 20 Gy to the right half of the lung to establish a lung injury model. Two and six months after irradiation, the right half of the rat lung tissue was removed, and the concentrations of TGF-β1, angiotensin II, and aldosterone were determined via enzyme-linked immunosorbent assay. RESULTS Statistical differences were observed in the expression levels of angiotensin II and aldosterone between the non-irradiation and irradiation groups. Moreover, the expression level of the angiotensin II-aldosterone system increased with increasing doses, and the difference was still observed as time progressed. CONCLUSIONS Angiotensin II-aldosterone system has an important pathophysiological function in the progression of RILI.
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Affiliation(s)
- Shuo Cao
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, China
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23
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Long-term Changes in Pulmonary Function After Incidental Lung Irradiation for Breast Cancer: A Prospective Study With 7-Year Follow-up. Int J Radiat Oncol Biol Phys 2012; 84:e565-70. [DOI: 10.1016/j.ijrobp.2012.07.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2012] [Revised: 06/29/2012] [Accepted: 07/04/2012] [Indexed: 11/17/2022]
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Giroux Leprieur É, Fernandez D, Chatellier G, Klotz S, Giraud P, Durdux C. Cancers bronchiques non à petites cellules : facteurs prédictifs de survenue de pneumopathie radique. Cancer Radiother 2012; 16:257-62. [DOI: 10.1016/j.canrad.2012.03.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2011] [Revised: 03/05/2012] [Accepted: 03/07/2012] [Indexed: 10/28/2022]
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25
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Marsh JC, Wendt JA, Walker A, Turian JV, Kie K. Clinical predictive factors for radiation pneumonitis and pulmonary fibrosis during split course concurrent chemoirradiation for locally advanced non-small cell lung cancer. ACTA ACUST UNITED AC 2012. [DOI: 10.7243/2049-7962-1-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Volume-Dependent Expression of In-Field and Out-of-Field Effects in the Proton-Irradiated Rat Lung. Int J Radiat Oncol Biol Phys 2011; 81:262-9. [DOI: 10.1016/j.ijrobp.2011.03.021] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2010] [Revised: 03/15/2011] [Accepted: 03/18/2011] [Indexed: 12/25/2022]
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Abstract
With >10,000,000 cancer survivors in the U.S. alone, the late effects of cancer treatment are a significant public health issue. Over the past 15 years, much work has been done that has led to an improvement in our understanding of the molecular mechanisms underlying the development of normal tissue injury after cancer therapy. In many cases, these injuries are characterized at the histologic level by loss of parenchymal cells, excessive fibrosis, and tissue atrophy. Among the many cytokines involved in this process, transforming growth factor (TGF)-beta1 is thought to play a pivotal role. TGF-beta1 has a multitude of functions, including both promoting the formation and inhibiting the breakdown of connective tissue. It also inhibits epithelial cell proliferation. TGF-beta1 is overexpressed at sites of injury after radiation and chemotherapy. Thus, TGF-beta1 represents a logical target for molecular therapies designed to prevent or reduce normal tissue injury after cancer therapy. Herein, the evidence supporting the critical role of TGF-beta1 in the development of normal tissue injury after cancer therapy is reviewed and the results of recent research aimed at preventing normal tissue injury by targeting the TGF-beta1 pathway are presented.
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Affiliation(s)
- Mitchell S Anscher
- Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia, USA.
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Chopra RR, Bogart JA. Radiation Therapy–Related Toxicity (Including Pneumonitis and Fibrosis). Hematol Oncol Clin North Am 2010; 24:625-42. [DOI: 10.1016/j.hoc.2010.03.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Kim DR, Laurence B, Jan VM, Wilfried DN, Hubert T. Association of TGFβ1 polymorphisms involved in radiation toxicity with TGFβ1 secretion in vitro. Cytokine 2010; 50:37-41. [DOI: 10.1016/j.cyto.2009.12.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2009] [Revised: 11/25/2009] [Accepted: 12/24/2009] [Indexed: 11/29/2022]
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Bentzen SM, Parliament M, Deasy JO, Dicker A, Curran WJ, Williams JP, Rosenstein BS. Biomarkers and surrogate endpoints for normal-tissue effects of radiation therapy: the importance of dose-volume effects. Int J Radiat Oncol Biol Phys 2010; 76:S145-50. [PMID: 20171510 DOI: 10.1016/j.ijrobp.2009.08.076] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2009] [Revised: 08/21/2009] [Accepted: 08/29/2009] [Indexed: 12/21/2022]
Abstract
Biomarkers are of interest for predicting or monitoring normal tissue toxicity of radiation therapy. Advances in molecular radiobiology provide novel leads in the search for normal tissue biomarkers with sufficient sensitivity and specificity to become clinically useful. This article reviews examples of studies of biomarkers as predictive markers, as response markers, or as surrogate endpoints for radiation side effects. Single nucleotide polymorphisms are briefly discussed in the context of candidate gene and genomewide association studies. The importance of adjusting for radiation dose distribution in normal tissue biomarker studies is underlined. Finally, research priorities in this field are identified and discussed.
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Affiliation(s)
- Søren M Bentzen
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA.
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Christensen E, Pintilie M, Evans KR, Lenarduzzi M, Ménard C, Catton CN, Diamandis EP, Bristow RG. Longitudinal Cytokine Expression during IMRT for Prostate Cancer and Acute Treatment Toxicity. Clin Cancer Res 2009; 15:5576-83. [DOI: 10.1158/1078-0432.ccr-09-0245] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Coker R, Kiani-Alikhan S, Stewart A, Pusey C, Dale RG, Jones B. Plasma TGFbeta1 during pelvic radiotherapy for gynaecological malignancy. Acta Oncol 2009; 45:753-4. [PMID: 16938820 DOI: 10.1080/02841860600658195] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Chopra RR, Bogart JA. Radiation Therapy–Related Toxicity (Including Pneumonitis and Fibrosis). Emerg Med Clin North Am 2009; 27:293-310. [DOI: 10.1016/j.emc.2009.01.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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35
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Studies on Pentoxifylline and Tocopherol Combination for Radiation-Induced Heart Disease in Rats. Int J Radiat Oncol Biol Phys 2009; 73:1552-9. [DOI: 10.1016/j.ijrobp.2008.12.005] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2008] [Revised: 11/05/2008] [Accepted: 11/13/2008] [Indexed: 11/22/2022]
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Kumar S, Kolozsvary A, Kohl R, Lu M, Brown S, Kim JH. Radiation-induced skin injury in the animal model of scleroderma: implications for post-radiotherapy fibrosis. Radiat Oncol 2008; 3:40. [PMID: 19025617 PMCID: PMC2599892 DOI: 10.1186/1748-717x-3-40] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2008] [Accepted: 11/24/2008] [Indexed: 11/15/2022] Open
Abstract
Background Radiation therapy is generally contraindicated for cancer patients with collagen vascular diseases (CVD) such as scleroderma due to an increased risk of fibrosis. The tight skin (TSK) mouse has skin which, in some respects, mimics that of patients with scleroderma. The skin radiation response of TSK mice has not been previously reported. If TSK mice are shown to have radiation sensitive skin, they may prove to be a useful model to examine the mechanisms underlying skin radiation injury, protection, mitigation and treatment. Methods The hind limbs of TSK and parental control C57BL/6 mice received a radiation exposure sufficient to cause approximately the same level of acute injury. Endpoints included skin damage scored using a non-linear, semi-quantitative scale and tissue fibrosis assessed by measuring passive leg extension. In addition, TGF-β1 cytokine levels were measured monthly in skin tissue. Results Contrary to our expectations, TSK mice were more resistant (i.e. 20%) to radiation than parental control mice. Although acute skin reactions were similar in both mouse strains, radiation injury in TSK mice continued to decrease with time such that several months after radiation there was significantly less skin damage and leg contraction compared to C57BL/6 mice (p < 0.05). Consistent with the expected association of transforming growth factor beta-1 (TGF-β1) with late tissue injury, levels of the cytokine were significantly higher in the skin of the C57BL/6 mouse compared to TSK mouse at all time points (p < 0.05). Conclusion TSK mice are not recommended as a model of scleroderma involving radiation injury. The genetic and molecular basis for reduced radiation injury observed in TSK mice warrants further investigation particularly to identify mechanisms capable of reducing tissue fibrosis after radiation injury.
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Affiliation(s)
- Sanath Kumar
- Department of Radiation Oncology, Henry Ford Health System, Detroit, MI, USA.
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Liu Y, Yu H, Zhang C, Cheng Y, Hu L, Meng X, Zhao Y. Protective effects of berberine on radiation-induced lung injury via intercellular adhesion molecular-1 and transforming growth factor-beta-1 in patients with lung cancer. Eur J Cancer 2008; 44:2425-32. [PMID: 18789680 DOI: 10.1016/j.ejca.2008.07.040] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2008] [Revised: 07/19/2008] [Accepted: 07/24/2008] [Indexed: 01/06/2023]
Abstract
PURPOSE To investigate the protective effects of berberine on radiation-induced lung injury (RILI) in non-small cell lung cancer (NSCLC) patients treated with radiotherapy. PATIENTS AND METHODS In this randomised, double-blind study, 90 patients with NSCLC were divided into two groups. The trial group received radiation therapy plus berberine, and the control group received radiation therapy plus a placebo for 6 weeks. Soluble intercellular adhesion molecular-1 (sICAM-1) and transforming growth factor-beta-1 (TGF-beta1) were measured. RILI and pulmonary function were evaluated at 6 weeks and 6 months after treatment, respectively. RESULTS Of the 90 patients enroled, 43 in the control group and 42 in the trial group completed the study. The incidence of RILI was significantly lower in the trial group at 6 weeks and 6 months than that in the control group (45.2% versus 72.1% and 35.7% versus 65.1%, respectively, both P<0.05). sICAM-1 levels in the trial group were significantly lower at weeks 6 and 12 (373.64+/-89.33 versus 459.53+/-123.59 and 447.83+/-111.21 versus 513.91+/-150.46, both P<0.01), and plasma TGF-beta1 levels were lower at week 3 and 6 (5.43+/-1.47 versus 6.22+/-1.78 and 5.93+/-2.39 versus 7.67+/-2.74, P<0.05 and 0.01, respectively) in comparison with the control group. Significant differences were observed in FEV1 (P=0.033) and DLCO (P=0.003) between patients receiving berberine and those receiving placebo. Independent-samples T-test showed reductions from baseline FVC at week 6 (P<0.05), and FEV1 and DLCO at month 6 (P<0.05 and 0.01, respectively) in the trial group were significantly smaller than that in the control group. CONCLUSION Berberine significantly reduced the incidence of RILI, improved PF and decreased the levels of sICAM-1 and TGF-beta1. The exact mechanisms remain to be further explored.
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Affiliation(s)
- Yunfang Liu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Shandong University, Qilu Hospital, Jinan, Shandong Province, China.
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Rübe CE, Palm J, Erren M, Fleckenstein J, König J, Remberger K, Rübe C. Cytokine plasma levels: reliable predictors for radiation pneumonitis? PLoS One 2008; 3:e2898. [PMID: 18682839 PMCID: PMC2483418 DOI: 10.1371/journal.pone.0002898] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2008] [Accepted: 07/14/2008] [Indexed: 12/22/2022] Open
Abstract
Background Radiotherapy (RT) is the primary treatment modality for inoperable, locally advanced non-small-cell lung cancer (NSCLC), but even with highly conformal treatment planning, radiation pneumonitis (RP) remains the most serious, dose-limiting complication. Previous clinical reports proposed that cytokine plasma levels measured during RT allow to estimate the individual risk of patients to develop RP. The identification of such cytokine risk profiles would facilitate tailoring radiotherapy to maximize treatment efficacy and to minimize radiation toxicity. However, cytokines are produced not only in normal lung tissue after irradiation, but are also over-expressed in tumour cells of NSCLC specimens. This tumour-derived cytokine production may influence circulating plasma levels in NSCLC patients. The aim of the present study was to investigate the prognostic value of TNF-α, IL-1β, IL-6 and TGF-β1 plasma levels to predict radiation pneumonitis and to evaluate the impact of tumour-derived cytokine production on circulating plasma levels in patients irradiated for NSCLC. Methodology/Principal Findings In 52 NSCLC patients (stage I–III) cytokine plasma levels were investigated by ELISA before and weekly during RT, during follow-up (1/3/6/9 months after RT), and at the onset of RP. Tumour biopsies were immunohistochemically stained for IL-6 and TGF-β1, and immunoreactivity was quantified (grade 1–4). RP was evaluated according to LENT-SOMA scale. Tumour response was assessed according to RECIST criteria by chest-CT during follow-up. In our clinical study 21 out of 52 patients developed RP (grade I/II/III/IV: 11/3/6/1 patients). Unexpectedly, cytokine plasma levels measured before and during RT did not correlate with RP incidence. In most patients IL-6 and TGF-β1 plasma levels were already elevated before RT and correlated significantly with the IL-6 and TGF-β1 production in corresponding tumour biopsies. Moreover, IL-6 and TGF-β1 plasma levels measured during follow-up were significantly associated with the individual tumour responses of these patients. Conclusions/Significance The results of this study did not confirm that cytokine plasma levels, neither their absolute nor any relative values, may identify patients at risk for RP. In contrast, the clear correlations of IL-6 and TGF-β1 plasma levels with the cytokine production in corresponding tumour biopsies and with the individual tumour responses suggest that the tumour is the major source of circulating cytokines in patients receiving RT for advanced NSCLC.
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Affiliation(s)
- Claudia E Rübe
- Department of Radiotherapy and Radiooncology, Saarland University, Homburg, Saar, Germany.
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Kong FM(S, Ao X, Wang L, Lawrence TS. The Use of Blood Biomarkers to Predict Radiation Lung Toxicity: A Potential Strategy to Individualize Thoracic Radiation Therapy. Cancer Control 2008; 15:140-50. [DOI: 10.1177/107327480801500206] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Affiliation(s)
| | - Xiaoping Ao
- Department of Radiation Oncology at the University of Michigan, Ann Arbor, Michigan
| | - Li Wang
- Department of Radiation Oncology at the University of Michigan, Ann Arbor, Michigan
| | - Theodore S. Lawrence
- Department of Radiation Oncology at the University of Michigan, Ann Arbor, Michigan
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Sun SP, Jin YN, Yang HP, Wei Y, Dong Z. Serum transforming growth factor-β1 level reflects disease status in patients with esophageal carcinoma after radiotherapy. World J Gastroenterol 2007; 13:5267-72. [PMID: 17876899 PMCID: PMC4171310 DOI: 10.3748/wjg.v13.i39.5267] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the relationship between changes in serum transforming growth factor β1 (TGFβ1) level and curative effect of radiotherapy (RT) in patients with esophageal carcinoma.
METHODS: Ninety patients with histologically confirmed esophageal carcinoma were enrolled. Serum samples for TGFβ1 analysis were obtained before and at the end of RT. An enzyme-linked immunosorbent assay was used to measure serum TGFβ1 level. Multivariate analysis was performed to investigate the relationship between disease status and changes in serum TGFβ1 level.
RESULTS: Serum TGFβ1 level in patients with esophageal carcinoma before RT was significantly higher than that in healthy controls (P < 0.001). At the end of RT, serum TGFβ1 level was decreased in 67.82% (59/87) of the patients. The overall survival rate at 1, 3 and 5 years was 48.28% (42/87), 19.54% (17/87) and 12.64% (11/87), respectively. Main causes of death were local failure and regional lymph node metastasis. In patients whose serum TGFβ1 level decreased after RT, the survival rate at 1, 3 and 5 years was 61.02% (36/59), 28.81% (17/59) and 18.64% (11/59), respectively. The survival rate at 1 year was 17.86% (5/28) in patients whose serum TGFβ1 level increased after RT, and all died within 18 mo (P < 0.01).
CONCLUSION: Serum TGFβ1 level may be a useful marker for monitoring disease status after RT in patients with esophageal carcinoma.
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Affiliation(s)
- Su-Ping Sun
- Department of Radiation Oncology, Changzhou Second Hospital-Affiliated Hospital of Nanjing Medical University, Changzhou, 213003, Jiangsu Province, China.
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Yu HM, Liu YF, Cheng YF, Hu LK, Hou M. Effects of rhubarb extract on radiation induced lung toxicity via decreasing transforming growth factor-beta-1 and interleukin-6 in lung cancer patients treated with radiotherapy. Lung Cancer 2007; 59:219-26. [PMID: 17870203 DOI: 10.1016/j.lungcan.2007.08.007] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2007] [Revised: 07/23/2007] [Accepted: 08/06/2007] [Indexed: 11/26/2022]
Abstract
BACKGROUND Radiation induced lung toxicity (RILT) is the main adverse effect in the radiation therapy of lung cancer. However, the optimal management of RILT has not been defined. In this paper, we investigated the effects of rhubarb extract on RILT, pulmonary function (PF), transforming growth factor-beta-1 (TGF-beta1), and interleukin-6 (IL-6) in lung cancer patients treated with radiotherapy. PATIENTS AND METHODS We conducted a randomized, double-blind, placebo-controlled trial. Eighty consecutive patients were randomly enrolled into two groups: trial group and control group. The trial group received three-dimensional conformal radiation therapy (3D-CRT) plus rhubarb (at a dose of 20 mg kg(-1) once a day) for 6 weeks. The control group received 3D-CRT plus a placebo containing starch for 6 weeks. Plasma TGF-beta1 and serum IL-6 were measured in all patients before, every 2 weeks during, and at 6 weeks after the completion of the treatment. RILT and PF were evaluated at 6 weeks and 6 months after the end of the treatment, respectively. The differences of TGF-beta1, IL-6, RILT, and PF between the two groups were analysed. RESULTS The incidence of RILT in the trial group was significantly lower than that in the control group at 6 weeks and 6 months after treatment (32.4% versus 56.7% at week 6, and 27.0% versus 52.8% at month 6, both P<0.05). The plasma TGF-beta1 levels in the trial group were significantly lower than that in the control group during and after the treatment (P<0.05 or 0.01, respectively). The serum IL-6 levels in the trial group were significantly lower than that in the control group during the treatment (all P<0.01). The forced vital capacity (FVC), forced expiratory volume at 1s (FEV1) at 6 weeks and the diffusion capacity for carbon monoxide (DLCO) at 6 months in the trial group were significantly improved compared to the control group (P<0.05 or 0.01, respectively). CONCLUSIONS The rhubarb extract significantly attenuated RILT and improved PF, probably by decreasing the level of TGF-beta1 and IL-6. These results may be of value for the prophylaxis of RILT, but the exact mechanisms underlying these prophylactic effects remain to be further explored.
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Affiliation(s)
- Hui Ming Yu
- Department of Radiation Oncology, Qilu Hospital, Medical school, Shandong University, Jinan, Shandong Province 250012, China
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Madani I, De Ruyck K, Goeminne H, De Neve W, Thierens H, Van Meerbeeck J. Predicting Risk of Radiation-Induced Lung Injury. J Thorac Oncol 2007; 2:864-74. [PMID: 17805067 DOI: 10.1097/jto.0b013e318145b2c6] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Radiation-induced lung injury (RILI) is the most common, dose-limiting complication of thoracic radio- and radiochemotherapy. Unfortunately, predicting which patients will suffer from this complication is extremely difficult. Ideally, individual phenotype- and genotype-based risk profiles should be able to identify patients who are resistant to RILI and who could benefit from dose escalation in chemoradiotherapy. This could result in better local control and overall survival. We review the risk predictors that are currently in clinical use--dosimetric parameters of radiotherapy such as normal tissue complication probability, mean lung dose, V20 and V30--as well as biomarkers that might individualize risk profiles. These biomarkers comprise a variety of proinflammatory and profibrotic cytokines and molecules including transforming growth factor beta1 that are implicated in development and persistence of RILI. Dosimetric parameters of radiotherapy show a low negative predictive value of 60% to 80%. Depending on the studied molecule, negative predictive value of biomarkers is approximately 50%. The predictive power of biomarkers might be increased if they are coupled with radiogenomics, e.g., genotyping analysis of single nucleotide polymorphisms in transforming growth factor beta1, transforming growth factor beta1 pathway genes, and other cytokines. Genetic variability and the complexity of RILI and its underlying molecular mechanisms make identification of biological risk predictors challenging. Further investigations are needed to develop more effective risk predictors of RILI.
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Affiliation(s)
- Indira Madani
- Department of Radiotherapy, Ghent University Hospital, Ghent, Belgium.
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Hartsell WF, Scott CB, Dundas GS, Mohiuddin M, Meredith RF, Rubin P, Weigensberg IJ. Can Serum Markers Be Used to Predict Acute and Late Toxicity in Patients With Lung Cancer? Am J Clin Oncol 2007; 30:368-76. [PMID: 17762437 DOI: 10.1097/01.coc.0000260950.44761.74] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE To identify factors that are predictive of satisfactory acute and long-term pulmonary tolerance of definitive irradiation and, conversely, factors that are predictive of excessive impairment of pulmonary functions. To determine if there is any correlation between early elevation of biochemical markers obtained in blood of irradiated patients and subsequent pulmonary abnormalities as detected by clinical findings, pulmonary function tests, and/or radiographic findings of pneumonitis/fibrosis. MATERIALS AND METHODS This was a multi-institutional prospective trial sponsored by the Radiation Therapy Oncology Group. Eligible patients had surgically unresectable or medically inoperable stage II or III non-small cell lung cancer. Pretreatment evaluation included baseline dyspnea index (BDI) and pulmonary function tests (PFT). Radiation therapy consisted of once-daily treatment with 2 Gy to a total of 60 to 66 Gy. A quantitative nuclear medicine perfusion study was correlated to the radiation therapy portals to assess the proportion of lung irradiated. Blood for serum markers (surfactant apoprotein, procollagen type III, interleukin [IL]-1, interleukin-6, and tumor necrosis factor-alpha) was drawn prior to the beginning of radiation therapy and then weekly during treatment (at 10, 20, 30, 40, 50, and 60 Gy). Post-treatment follow-up included PFT every 3 months for 1 year and then annually. The BDI was reevaluated at the same intervals. RESULTS There were 127 analyzable patients. Squamous cell carcinoma was the predominant histology and 93% of the patients had AJCC stage III disease. The median survival time is 10.9 months with 43% of patients living 1 year and 10% living 3 years. Grade >or=2 acute lung toxicity was seen in 18% of patients; patients least likely to develop lung toxicity are those with undetectable levels of IL-6 at 10 Gy and diffusing capacity of the lung for carbon monoxide percent (DLCO%) >54. Patients most likely to develop acute toxicity are those with elevated IL-6 and age >60 years. Grade >or=2 late lung toxicity was seen in 30% of patients. Karnofsky performance status was the only pretreatment factor predictive of late lung toxicity. The proportion of lung within the irradiated field, BDI indices, physician-assessed baseline dyspnea, and baseline PFT were not predictive of pulmonary toxicity. Using grade >or=2 toxicity as an event, age >60 years, gender, and a surfactant level <797 at 20 Gy were predictive of late lung toxicity. CONCLUSIONS Elevated levels of serum IL-6 after 10 Gy of lung irradiation appear to predict grade >or=2 acute lung toxicity, and high serum levels of surfactant apoproteins at 20 Gy correlated with grade >or=2 late pulmonary toxicity. These findings need to be confirmed but could be useful in a model to predict risk of pulmonary injury with high doses of radiation. For future studies, it is necessary to evaluate serum markers at multiple time-points during treatment, and quality control is critical during the collection, storage, and analysis of these serum markers.
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Podar K, Raje N, Anderson KC. Inhibition of the TGF-beta signaling pathway in tumor cells. RECENT RESULTS IN CANCER RESEARCH. FORTSCHRITTE DER KREBSFORSCHUNG. PROGRES DANS LES RECHERCHES SUR LE CANCER 2007; 172:77-97. [PMID: 17607937 DOI: 10.1007/978-3-540-31209-3_6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Affiliation(s)
- Klaus Podar
- Department of Medical Oncology, Dana-Farber Cancer Institute, Jerome Lipper Multiple Myeloma Center, Boston, MA 02115, USA
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Abstract
Clinical trials showing longer survival when chemotherapy is combined with antiangiogenic agents (AAs) have led to growing interest in designing combined modality protocols that exploit abnormalities in tumor vasculature. Approved agents include bevacizumab, a recombinant monoclonal antibody that binds to vascular endothelial growth factor, and two small molecule multitargeted tyrosine kinase inhibitors of angiogenesis (SU11248 and BAY-43-9006) that have been approved for therapy of renal cancer. Targeting tumor vasculature has a strong biological rationale in radiation therapy, and preclinical studies consistently show an increase in radiosensitization with combined treatment. Preclinical studies indicate that excessive damage to tumor vasculature can result in radioresistance in some situations, and early clinical data suggest that treatment sequencing may be important when combining AAs with radiation. Radiation itself appears to antagonize any hypoxia that can be induced by long-term administration of AAs. The optimal biological doses of AAs with radiotherapy are unknown, and surrogate markers of efficacy remain to be validated. Early clinical trials should therefore include studies designed to identify mechanisms of interaction and increases in tumor hypoxia. This review highlights preclinical and early clinical data that are relevant for clinical trial design. Optimal radiation planning and delivery is required to minimize the volume of irradiated normal organs and to establish safe dose-volume parameters for phase II-III clinical trials.
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Affiliation(s)
- Suresh Senan
- Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands.
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Chou CH, Chen PJ, Lee PH, Cheng AL, Hsu HC, Cheng JCH. Radiation-induced hepatitis B virus reactivation in liver mediated by the bystander effect from irradiated endothelial cells. Clin Cancer Res 2007; 13:851-7. [PMID: 17289877 DOI: 10.1158/1078-0432.ccr-06-2459] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE Hepatitis B virus (HBV) reactivation is one unique pathogenesis in Asian carriers with liver toxicity after radiotherapy for hepatobiliary malignancies. This study attempts to delineate the biological mechanism of radiation-induced HBV reactivation. EXPERIMENTAL DESIGN Primary cultures of hepatocytes (PCC) were prepared from the noncancerous liver tissue removed perioperatively from 12 HBV carriers with hepatocellular carcinoma (HCC). The conditioned medium of irradiated PCCs, HCC, and endothelial cells from patients was transferred to PCCs or HepG2.2.15 cells (a human hepatoblastoma cell line transfected with HBV DNA) before subsequent irradiation. Forty-eight hours after irradiation, HBV DNA was measured by real-time quantitative PCR. Specific cytokines were determined by cytokine array and ELISA analysis. Preradiotherapy and postradiotherapy sera from 10 HBV carriers and 16 non-HBV carriers were analyzed for viral loads and cytokine activities. RESULTS Radiation induced HBV DNA replication in (a) irradiated PCCs cultured with the conditioned medium from irradiated PCCs (2.74-fold; P=0.004) and endothelial cells (9.50-fold; P=3.1x10(-10)), but not from HCCs (1.07-fold), and in (b) irradiated HepG2.2.15 cells (17.7-fold) cocultured with human umbilical vascular endothelial cells. Cytokine assay revealed increased expression of interleukin-6 (IL-6) in conditioned medium from irradiated human umbilical vascular endothelial cells. All 16 patients with liver irradiated had the increased serum IL-6 compared with 3 of 10 patients with irradiation excluding liver (P<0.001). All nine HBV carriers with liver irradiated had postradiotherapy increases in both HBV DNA and IL-6. CONCLUSIONS Radiation-induced liver toxicity with HBV reactivation is from a bystander effect on irradiated endothelial cells releasing cytokines, including IL-6.
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Affiliation(s)
- Chia Hung Chou
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
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Milano MT, Constine LS, Okunieff P. Normal Tissue Tolerance Dose Metrics for Radiation Therapy of Major Organs. Semin Radiat Oncol 2007; 17:131-40. [PMID: 17395043 DOI: 10.1016/j.semradonc.2006.11.009] [Citation(s) in RCA: 111] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Late organ toxicity from therapeutic radiation is a function of many confounding variables. The total dose delivered to the organ and the volumes of organ exposed to a given dose of radiation are 2 important variables that can be used to predict the risk of late toxicity. Three-dimensional radiation planning enables accurate calculation of the volume of tissue exposed to a given dose of radiation, graphically depicted as a dose-volume histogram. Dose metrics obtained from this 3-dimensional dataset can be used as a quantitative measure to predict late toxicity. This review summarizes the published clinical data on the risk of late toxicity as a function of quantitative dose metrics and attempts to offer suggested dose constraints for radiation treatment planning.
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Affiliation(s)
- Michael T Milano
- Department of Radiation Oncology and James P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
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Evans ES, Hahn CA, Kocak Z, Zhou SM, Marks LB. The Role of Functional Imaging in the Diagnosis and Management of Late Normal Tissue Injury. Semin Radiat Oncol 2007; 17:72-80. [PMID: 17395037 DOI: 10.1016/j.semradonc.2006.11.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Normal tissue injury after radiation therapy (RT) can be defined based on either clinical symptoms or laboratory/radiologic tests. In the research setting, functional imaging (eg, single-photon emission computed tomography [SPECT], positron-emission tomography [PET], and magnetic resonance imaging [MRI]) is useful because it provides objective quantitative data such as metabolic activity, perfusion, and soft-tissue contrast within tissues and organs. For RT-induced lung, heart, and parotid gland injury, pre- and post-RT SPECT images can be compared with the dose- and volume-dependent nature of regional injury. In the brain, SPECT can detect changes in perfusion and blood flow post-RT, and PET can detect metabolic changes, particularly to regions of the brain that have received doses above 40 to 50 Gy. On MRI, changes in contrast-enhanced images, T(1) and T(2) relaxation times, and pulmonary vascular resistance at different intervals pre- and post-RT show its ability to detect and distinguish different phases of radiation pneumonitis. Similarly, conventional and diffusion-weighted MRI can be used to differentiate between normal tissue edema, necrosis, and tumor in the irradiated brain, and magnetic resonance spectroscopy can measure changes in compounds, indicative of membrane and neuron disruption. The use of functional imaging is a powerful tool for early detection of RT-induced normal tissue injury, which may be related to long-term clinically significant injury.
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Affiliation(s)
- Elizabeth S Evans
- Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA
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Fleckenstein K, Gauter-Fleckenstein B, Jackson IL, Rabbani Z, Anscher M, Vujaskovic Z. Using Biological Markers to Predict Risk of Radiation Injury. Semin Radiat Oncol 2007; 17:89-98. [PMID: 17395039 DOI: 10.1016/j.semradonc.2006.11.004] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Recent advances in our understanding of the molecular events leading to the development of normal tissue complications after radiotherapy has led to an effort to identify biological markers that could identify patients at increased or decreased risk for treatment related injury. The goal of this effort is to improve the therapeutic ratio and enable physicians to optimize therapy for individual patients. In radiotherapy of the thoracic region, the lung is one of the most critical dose-limiting organs. This review briefly introduces the mechanisms of radiation-induced lung injury and gives a summary of clinical research focused on evaluating changes in biological markers before, during, and after radiation therapy of the thorax.
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Koh ES, Sun A, Tran TH, Tsang R, Pintilie M, Hodgson DC, Wells W, Heaton R, Gospodarowicz MK. Clinical dose-volume histogram analysis in predicting radiation pneumonitis in Hodgkin's lymphoma. Int J Radiat Oncol Biol Phys 2006; 66:223-8. [PMID: 16904523 DOI: 10.1016/j.ijrobp.2006.03.063] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2006] [Revised: 03/22/2006] [Accepted: 03/23/2006] [Indexed: 10/24/2022]
Abstract
PURPOSE To quantify the incidence of radiation pneumonitis (RP) in a modern Hodgkin's lymphoma (HL) cohort, and to identify any clinically relevant parameters that may influence the risk of RP. METHODS AND MATERIALS Between January 2003 and February 2005, 64 consecutive HL patients aged 18 years or older receiving radical mediastinal radiation therapy (RT) were retrospectively reviewed. Symptomatic cases of radiation pneumonitis were identified. Dose-volume histogram parameters, including V(13), V(20), V(30), and mean lung dose (MLD), were quantified. RESULTS At a median follow-up of 2.1 years, the actuarial survival for all patients was 91% at 3 years. There were 2 (2/64) cases of Radiation Therapy Oncology Group (RTOG) Grade 2 RP (incidence 3.1%). Both index cases with corresponding V(20) values of 47.0% and 40.7% were located in the upper quartile (2/16 cases), defined by a V(20) value of > or =36%, an incidence of 12.5% (p = 0.03). Similarly for total MLD, both index cases with values of 17.6 Gy and 16.4 Gy, respectively, were located in the upper quartile defined by MLD > or =14.2 Gy, an incidence of 11.8% (2/17 cases, p = 0.02). CONCLUSIONS Despite relatively high V(20) values in this study of HL patients, the incidence of RP was only 3%, lower compared with the lung cancer literature. We suggest the following clinically relevant parameters be considered in treatment plan assessment: a V(20) greater than 36% and an MLD greater than 14 Gy, over and above which the risk of RTOG Grade 2 or greater RP would be considered clinically significant.
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Affiliation(s)
- Eng-Siew Koh
- Department of Radiation Oncology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada
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